Encyclopedia of Cardiovascular Research and Medicine [1 ed.] 9780128096574, 9780128051542, 012805154X, 9781786846617, 1786846616, 0128096578

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ENCYCLOPEDIA OF CARDIOVASCULAR RESEARCH AND MEDICINE

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ENCYCLOPEDIA OF CARDIOVASCULAR RESEARCH AND MEDICINE EDITORS-IN-CHIEF

RAMACHANDRAN S. VASAN

DOUGLAS B. SAWYER

Boston University School of Medicine, Boston, MA, USA

Maine Medical Center Research Institute, Scarborough, ME, USA

SECTION EDITORS

RAGAVENDRA R. BALIGA

LUCY LIAW

The Ohio State University, Columbus, OH, USA

Maine Medical Center Research Institute, Scarborough, ME, USA

THOMAS DI SALVO Medical University of South Carolina, Charleston, SC, USA

CHRIS P. GALE

AMY MAJOR Vanderbilt University Medical Centre, Nashville, TN, USA

University of Leeds, Leeds, UK

SATISH R. RAJ

THORSTEN KESSLER

Libin Cardiovascular Institute of Alberta, University of Calgary, Calgary, AB, Canada

German Heart Centre, Munich, Germany

YOSHIHIRO KOKUBO National Cerebral and Cardiovascular Center, Osaka, Japan

DANIEL LENIHAN Washington University Medical Centre, St. Louis, MO, USA

HERIBERT SCHUNKERT German Heart Centre, Munich, Germany

Elsevier Radarweg 29, PO Box 211, 1000 AE Amsterdam, Netherlands The Boulevard, Langford Lane, Kidlington, Oxford OX5 1GB, UK 50 Hampshire Street, 5th Floor, Cambridge, MA 02139, USA Copyright © 2018 Elsevier Inc. All rights reserved No part of this publication may be reproduced or transmitted in any form or by any means, electronic or mechanical, including photocopying, recording, or any information storage and retrieval system, without permission in writing from the publisher. Details on how to seek permission, further information about the Publisher’s permissions policies and our arrangements with organizations such as the Copyright Clearance Center and the Copyright Licensing Agency, can be found at our website: www.elsevier.com/permissions. This book and the individual contributions contained in it are protected under copyright by the Publisher (other than as may be noted herein). Notices Knowledge and best practice in this field are constantly changing. As new research and experience broaden our understanding, changes in research methods, professional practices, or medical treatment may become necessary. Practitioners and researchers may always rely on their own experience and knowledge in evaluating and using any information, methods, compounds, or experiments described herein. In using such information or methods they should be mindful of their own safety and the safety of others, including parties for whom they have a professional responsibility. To the fullest extent of the law, neither the Publisher nor the authors, contributors, or editors, assume any liability for any injury and/or damage to persons or property as a matter of products liability, negligence or otherwise, or from any use or operation of any methods, products, instructions, or ideas contained in the material herein. Library of Congress Cataloging-in-Publication Data A catalog record for this book is available from the Library of Congress British Library Cataloguing-in-Publication Data A catalogue record for this book is available from the British Library ISBN 978-0-12-809657-4 For information on all publications visit our website at http://store.elsevier.com Printed and bound: YTC

Publisher: Oliver Walter Acquisition Editor: Will Smaldon Senior Content Project Manager: Richard Berryman Designer: Christian Bilbow

Cover: Photomicrographs were provided by Laura Pentassuglia, Sean Lenihan, Cristi Galindo, and Christian Zuppinger

CONTENTS OF ALL VOLUMES List of Contributors Preface

xvii xxxv

VOLUME 1 Adult Congenital Heart Disease

1

D Briston and E Bradley

Adverse Impact of Delayed Electrical Activation of the Heart and Benefits of Cardiac Resynchronization

10

A Guha and EG Daoud

AL Cardiac Amyloidosis: Classification, Diagnosis, and Treatment

34

OK Siddiqi and FL Ruberg

Alcohol

49

C Matsumoto

Alcoholic Cardiomyopathy

58

A Voiosu, S Wiese, JD Hove, T Voiosu, F Bendtsen, and S Møller

Amyloid Cardiomyopathy

66

T Sher and MA Gertz

Anemia in Heart Failure

80

A Patel and NL Altman

Angiogenesis

85

N Warmke, AMN Walker, and RM Cubbon

Animal Models of Ischemic Heart Disease: From Atherosclerosis and Thrombosis to Myocardial Infarction

97

R Covarrubias, AS Major, and RJ Gumina

Ankle-Brachial Pressure Index and Pulse Wave Velocity in Cardiovascular Risk Assessment

111

H Tomiyama and A Yamashina

Aortic Aneurysm

123

M Singh, BA Ziganshin, and JA Elefteriades

Aortic Valve Replacement in Patients With Congestive Heart Failure

143

VJ Nardy, JA Crestanello, and NP Jaik

Arrhythmias in Cancer and Cancer Treatment: A Review

162

D Haddad, A Guha, F Awan, EG Daoud, and R Baliga

Arrhythmogenic Right Ventricular Cardiomyopathy

182

MR Afzal, C Evanson, A Cardona, K Rusk, and R Weiss

Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy

192

GM Orgeron and H Calkins

v

vi

Contents of All Volumes

Athlete's Heart

205

LM Safi and MJ Wood

Atrial Tachycardia—Mechanisms and Management

212

J Ahmed and P LeLorier

Atrioventricular Node Reentrant Tachycardia

224

AG Carrizo, B Ballantyne, and A Baranchuk

ATTR Cardiac Amyloidosis: Classification, Diagnosis, and Management

242

JA Cowgill and JN Wight Jr.

Behavior Modification and Cardiovascular Disease

257

V Ramirez, B Starobin, and J Monti

Bicuspid Aortic Valve and Sports Activity

263

L Stefani, G Galanti, and N Maffulli

Bioinformatics Principles for Deciphering Cardiovascular Diseases

273

L Shu, D Arneson, and X Yang

Biomarkers in Heart Failure, Use of

293

PU Gandhi

Biomarkers in Ischemic Heart Disease

303

JT Neumann and RB Schnabel

Biomarkers: Heart Failure

315

SS Gogia and JE Ho

Biomarkers: Population Screening and Risk-Stratification

323

I Ratjen, RS Vasan, and W Lieb

Biophysics of Ablation—Radiofrequency and Cryoablation

334

JG Andrade, MW Deyell, and L Macle

Blood Pressure Variability Versus Blood Pressure Level in Risk Stratification

350

F-F Wei, K Asayama, A Hara, TW Hansen, Y Li, and JA Staessen

Brugada Syndrome

356

C Antzelevitch

Cardiac Anatomy, Physiology, and Pathophysiology

373

KN Hor and AJ Trask

Cardiac and Induced Pluripotent Stem Cells

384

A Salerno, W Balkan, K Hatzistergos, and JM Hare

Cardiac Arrhythmia in Heart Failure

394

T Okabe and SJ Kalbfleisch

Cardiac Biomechanics in Normal Physiology and Disease

411

KM Broughton

Cardiac Fibroblast

420

J Park and MD Tallquist

Cardiac Hypertrophy: Signaling and Cellular Crosstalk

434

D Tirziu

Cardiac Magnetic Resonance Imaging in Heart Failure

451

A Reynolds and KM Zareba

Cardiac Pacing and Monitoring: Past, Present, and Future

463

F Chalhoub and T Mela

Cardiac Regeneration and Stem Cells as Therapy for Heart Disease AJ Favreau-Lessard and DB Sawyer

468

Contents of All Volumes

Cardiac Resynchronization Therapy

vii 475

G Voros

Cardiac Transplantation

489

A Hasan

Cardiohepatic Interactions

514

J Shah and E Shao

Cardiopulmonary Exercise Testing

523

V Franco

Cardiovascular Complications and Management in Sarcoidosis: A Review

527

DJ Roberts, S Francis, JA Rosenblatt, and ST Coffin

Cardiovascular Disease and Obesity

535

Y Matsushita

Catecholaminergic Polymorphic Ventricular Tachycardia

542

PJ Kannankeril

Catheter Ablation for Atrial Fibrillation (Methods)

553

JG Andrade, MW Deyell, and L Macle

Catheter Ablation for Ventricular Tachycardia

566

RM John and WG Stevenson

Cellular Sinoatrial Node and Atrioventricular Node Activity in the Heart

576

HJ Jansen, TA Quinn, and RA Rose

Chronic Infections of the Heart

593

M Edwards, C Withers, and K Thakarar

Chronic Kidney Disease as a Risk Factor for Cardiovascular Disease

600

T Ninomiya

Clinical Assessment of the Cardiac Arrhythmia Patient

609

B Olshansky

Clinical Management of Inherited Arrhythmias

620

RL Jones and MV Perez

Clinical Trials for Atrial Fibrillation—What Do We Know?

630

DS Chew and SB Wilton

Complications of Pregnancy and Future Cardiovascular Risk

643

PH Andraweera, GA Dekker, M Arstall, T Bianco-Miotto, and CT Roberts

Comprehensive Lifestyle Modification for Hypertension and Lifestyle-Related Disease Under the New Guidelines

651

Y Kokubo and C Matsumoto

Computational Systems Biology for the VEGF Family in Angiogenesis

659

JC Weddell and PI Imoukhuede

Congenital Heart Valve Disease in the Adult

677

A Luk, J Alvarez, and J Butany

Coronary Anatomy

691

M Sivananthan

Coronary Artery Bypass Grafting

700

RS Kramer, JR Morton, RC Groom, and DL Robaczewski

Cyanotic Congenital Heart Disease MS Renno and JA Johns

730

viii

Contents of All Volumes

VOLUME 2 Dairy Products and Cardiovascular Diseases

1

M Yanagi, N Amano, and T Nakamura

Diabetes Mellitus

9

H Sone

Diagnosis and Imaging of Congenital Heart Disease

17

SR Fuchs and JH Soslow

Diagnosis of Non-ST-Elevation Myocardial Infarction (NSTEMI)

47

M Vafaie and E Giannitsis

Diet in Heart Failure

54

M Rozmahel, E Colin-Ramirez, and JA Ezekowitz

Dietary Fat and Risk of Cardiovascular Disease

60

ES Eshak, K Yamagishi, and H Iso

Digital Data (mHealth and Social Media)

90

R Bhattacharjee and T Hussein

Diseases of the Mitral Valve

98

L Mc Carthy and P Collier

Diuretic Therapy

107

A Vazir, V Sundaram, and AR Harper

Driving and Syncope

117

D Sorajja and W-K Shen

Echocardiography in Heart Failure

126

T Chen and JN Kirkpatrick

Echocardiography: Assessment of Valve Structure and Function

142

S Vallurupalli, A Siraj, and S Kenchaiah

Economics of Heart Failure

187

S Stewart, C Mainland, and A David

Electrocardiographic Monitoring Strategies (Holter, Implantable Loop Recorder, in Between)

197

H Nazzari, L Halperin, and AD Krahn

Electrophysiology Approaches for Ventricular Tachycardia

211

RM John and W Stevenson

Emergency Medicine Approach and Management of Traumatic Injuries: An Overview

221

E Lavine and E Legome

Environmental Air Pollution: An Emerging Risk Factor for Stroke

231

B Delpont, AS Mariet, C Blanc, Y Bejot, M Giroud, and J Reis

Environmental Risk Factors for Stroke and Cardiovascular Disease

238

J Reis, M Giroud, and Y Kokubo

Epidemiology of Atherosclerotic Cardiovascular Disease

248

N Townsend

Epigenomics

258

TA Turunen, M-A Väänänen, and S Ylä-Herttuala

Exercise and Cardiac Rehabilitation in Heart Failure

266

SR Schubert

Exercise, Physical Activity, and Cardiovascular Disease

274

A Bauman, M Alharbi, N Lowres, R Gallagher, and E Stamatakis

Extracorporeal Membrane Oxygenation A Kilic

281

Contents of All Volumes

Familial Hypercholesterolemia

ix 285

A Pirillo and AL Catapano

Frailty in Heart Failure Patients

298

S Pedraza, TA Barrett, and CM Hritz

Genetic Atrial Fibrillation

303

R Chia, A Mehta, H Huang, and D Darbar

Genetic Disorders Involving Valve Function

313

M Afshar and G Thanassoulis

Genetic Disorders of the Vasculature

327

AJ Brownstein, BA Ziganshin, and JA Elefteriades

Genetics of Heart Failure

368

A Briasoulis, R Asleh, and N Pereira

Heart Development

380

E Dees and S Baldwin

Heart Failure in African Americans

399

M Jame, S Jame, and M Colvin

Heart Failure in Cancer Patients

406

A Vallakati, B Konda, and R Baliga

Heart Failure in Low- to Middle-Income Countries

417

S Stewart, F Taylor, and AK Keates

Heart Failure in Minorities

429

ER Fox, ME Hall, JD Pollard, SK Musani, CJ Rodriguez, and RS Vasan

Heart Failure in the Elderly

437

S Katsanos and J Parissis

Heart Failure Monitoring

453

ES Shao

Heart Failure With Preserved Ejection Fraction

464

S Day

Heart Regeneration with Stem Cell Therapies

469

M Natsumeda, BA Tompkins, V Florea, AC Rieger, M Banerjee, W Balkan, and JM Hare

Heart–Lung Transplantation

484

B LeNoir, M Malik, and BA Whitson

Hemodynamic Changes of Pregnancy

489

P Divanji and NI Parikh

Hemodynamics of the Right Heart in Health and Disease

497

DM Gopal and A Alsamarah

Hormonal Therapy in the Treatment of Chronic Heart Failure

508

R Napoli, A Salzano, E Bossone, and A Cittadini

Hypertensive Heart Disease

517

MU Moreno, A González, B López, S Ravassa, J Beaumont, G San José, R Querejeta, and J Díez

Hypertrophic Cardiomyopathy

527

LK Williams

VOLUME 3 Imaging of Mitral Regurgitation

1

JB Strom, KF Faridi, and CW Tsao

Imaging: CT Scanning of the Heart and Great Vessels M Eid, MH Albrecht, CN De Cecco, D De Santis, A Varga-Szemes, D Caruso, VW Lesslie, and UJ Schoepf

12

x

Contents of All Volumes

Imaging: Echocardiology—Assessment of Cardiac Structure and Function

35

D Bamira and MH Picard

Immune Mechanisms in Cardiac Physiology

55

SM Peterson, DJ Roberts, and S Ryzhov

Immune-Mediated Mechanisms of Atherosclerosis

68

M Bäck, DFJ Ketelhuth, S Malin, PS Olofsson, G Paulsson-Berne, Z-Q Yan, and GK Hansson

Implanted Pacemakers—Indications and Novel Programming

77

R Willems

Induced Pluripotent Stem Cell–Derived Cardiomyocytes in Advancing Cardiovascular Medicine

87

C Zhang, AG Cadar, and CC Hong

Infective Endocarditis in 21st Century

94

VV Kandasamy, S Pant, and JL Mehta

Inflammatory and Infectious Disorders of the Aorta

102

V Noori, B Nolan, and C Healey

Inotropes in Heart Failure

108

M Ginwalla and C Bianco

Interventions: Endomyocardial Biopsy

119

B Kherad, U Kühl, and C Tschöpe

Intra-aortic Balloon Pumps (IABP) and Percutaneous Ventricular Assist Devices (VADs)

126

NK Kapur and ML Esposito

Ion Channelopathy Genetics

132

A Adler and MH Gollob

Ischemic Cardiomyopathy

145

S Airhart and S Murali

Kidney in Heart Failure

155

DN Pratt and A Diez

Lead-Related Complications

166

B Mondesert and R Parkash

Left and Right Ventricular Remodeling

171

D Pinkhas and X Gao

Left Ventricular Assist Device (LVAD) and Circulatory Devices in Heart Failure

186

P Lee

Left-Sided Obstructive Congenital Heart Lesions: Including Hypoplastic Left Heart

200

CJ Prendergast and GT Nicholson

Lipid-Mediated Mechanisms in Atherosclerosis

214

Q Liu, J Martinez, J Hodge, and D Fan

Lipids and Cardiovascular Diseases: Epidemiologic Perspectives

221

T Okamura, D Sugiyama, T Hirata, K Kuwabara, and A Hirata

Long QT Syndrome and Torsade de Pointes

230

N El-Sherif, G Turitto, and M Boutjdir

Management and Care of Older Cardiac Patients

245

AA Damluji, A Ramireddy, and DE Forman

Management of Cardiac Sarcoidosis

266

L Alghothani and ED Crouser

Management of Patients With Implantable Cardiac Devices Referred for Magnetic Resonance Imaging: A Rapidly Changing Landscape I Roifman and JA White

274

Contents of All Volumes

Management of Pregnancy With Underlying Congenital and Acquired Cardiac Disease

xi 282

AM Moran

Management of Ventricular Tachycardia in Ischemic and Nonischemic Cardiomyopathy

292

A AbdelWahab, VP Kuriachan, GL Sumner, LB Mitchell, and J Sapp

Managing Cardiovascular Disease in Sport and Athletes

302

AB Shah and AL Baggish

Mechanisms of Cardiac Arrhythmias: Molecular and Cellular Perspective

316

P Zhabyeyev and GY Oudit

Medical Management of Left Ventricular Assist Devices

328

S Emani

Metabolomics in Cardiovascular Research

331

V Salomaa and M Inouye

MicroRNAs in Cardiac Development and Function

340

Y Tian

Microvasculature in Health and Disease

349

JE Beare, L Curtis-Whitchurch, AJ LeBlanc, and JB Hoying

Mitochondrial Bioenergetics in the Heart

365

EJ Lesnefsky, Q Chen, B Tandler, and CL Hoppel

Modern Considerations in ICD Therapy

381

TD Richardson and CR Ellis

MR Imaging of the Heart and the Great Vessels

388

U Neisius and C Tsao

Myocardial Perfusion Imaging

404

RB Morgan

Myocardial Repair

425

K Breckwoldt and T Eschenhagen

Myocarditis

440

ALP Caforio, G Malipiero, R Marcolongo, and S Iliceto

Myocarditis in Heart Failure

452

G Sinagra, J Artico, P Gentile, E Fabris, R Bussani, A Cannatà, and M Merlo

Neurohormonal Blockade

459

L Cunningham, W Kayani, and A Deswal

Neurological Regulation of the Circulation

477

DN Jackson, NM Novielli, and J Twynstra

Noninfective Inflammatory Disorders of the Pericardium

492

B Ravaee and BD Hoit

Non-ST-Elevation Acute Coronary Syndrome Prognosis

502

H Haghbayan, CP Gale, and AT Yan

Non-ST-Elevation Myocardial Infarction: Management

522

M Cimci, B Gencer, and M Roffi

Nutrition—Macronutrients

531

T Nakamura and S Kuranuki

Nutrition: Soy and Fish

538

Y Yamori, M Sagara, H Mori, and M Mori

Obesity and the Obesity Paradox in Heart Failure AA Oktay, CJ Lavie, and HO Ventura

546

xii

Contents of All Volumes

Oral Health and Cardiovascular Disease: Recent Findings and Future View With a Novel Aspect

565

T Ono, M Kida, T Kosaka, and M Kikui

Orthostatic Hypotension and Vasovagal Syncope

573

BH Shaw, Jessica Ng, and SR Raj

VOLUME 4 Palliative Care in Advanced Heart Failure

1

M Ginwalla and BP Dhakal

Pediatric Catheter Ablation

8

AE Radbill, FA Fish, and TP Graham Jr.

Perioperative Management in Heart Failure

37

C Mayeur and A Mebazaa

Peripartum Cardiomyopathy

42

LJ Hassen and S Roble

Peripheral Arterial Disease

49

K Matsushita, A Barleben, and M Allison

Pharmacogenomics of Antiarrhythmic Drug Therapy for Atrial Fibrillation

60

D Darbar

Pharmacology of Medications Used in the Treatment of Atherosclerotic Cardiovascular Disease

68

R Khatib and F Wilson

Physical Examination: Heritable Cardiovascular Syndromes

89

K Puri and JP Zachariah

Physical Examination: Normal Examination in Adult Acquired and Congenital Heart Disease

106

TR Schlingmann and JP Zachariah

Physiological Adaptations of the Heart in Elite Athletes

116

A D’Andrea, J Radmilovich, L Riegler, R Scarafile, B Liccardo, T Formisano, A Carbone, R America, F Martone, M Scherillo, M Galderisi, and R Calabrò

Practical Guide to Evidence-Based Management of Heart Failure in the Outpatient Setting

125

AM Maw, RL Page II, and RS Boxer

Preclinical Cardiovascular Imaging

143

I Pinz

Preeclampsia and Hypertension in Pregnancy

154

N Jafar, N Hippalgaonkar, and NI Parikh

Pregnancy and Cardiovascular Disease

160

R Neki

Proteomics

166

G Suna and M Mayr

Pulmonary Arterial Hypertension

181

R El Yafawi, ME Knauft, K Stokem, JM Palminteri, and JA Wirth

Pulmonary Embolism

195

SC Berngard and J Mandel

Pulmonary Hypertension

204

DR Fraidenburg and JX-J Yuan

Pulmonary Hypertension Associated With Left-Sided Heart Disease

223

DN Tukaye and V Franco

Quality Indicators for the Management of Acute Myocardial Infarction O Bebb, M Hall, and C Gale

230

Contents of All Volumes

Recreational Drugs: Effects on the Heart and Cardiovascular System

xiii 240

B Starobin, S Jablonski, AM Andrle, and JB Powers

Relationship Between Vegetables and Fruits (Antioxidant Vitamins, Minerals, and Fiber) Intake and Risk of Cardiovascular Disease

249

J Ishihara, M Umesawa, C Okada, Y Kokubo, and H Iso

Remission and Recovery in Heart Failure

284

JS Guseh and JE Ho

Remote Monitoring of Cardiovascular Implantable Electronic Devices

292

B Plourde and R Parkash

Right Heart Catheterization

298

BC Lampert

Risk Factors for Cardiovascular Disease

307

EJ Teufel

Risk Prediction

315

H Yatsuya

Role of Coronary Artery Revascularization in Heart Failure

319

B Shukrallah, A Kilic, and T Lescouflair

Role of Digoxin in Heart Failure

323

A Bucca

Role of Echocardiography in Selection, Implantation, and Management of Left Ventricular Assist Device Therapy

327

M Dandel and R Hetzer

Salt and Blood Pressure

345

Y Yano

Sex and Gender Differences in Cardiovascular Disease

351

L Mathews, P Chandrashekar, M Prasad, VM Miller, K Sharma, T Sedlak, CN Bairey Merz, and P Ouyang

Sex Differences in the Physiology and Pathology of the Aging Heart

368

A Ghimire, AE Kane, and SE Howlett

Signaling in Cardiac Physiology and Disease

377

S Mukherjee, S Srikanthan, and SV Naga Prasad

Sinus Tachycardias: Inappropriate Sinus Tachycardia and Postural Tachycardia Syndrome

388

BH Shaw, J Ng, and SR Raj

Skeletal Muscle in Heart Failure

404

S Scheetz and R Baliga

Sleep and Circadian Cardiovascular Medicine

424

K Kario

Sleep-Disordered Breathing and Heart Failure Interactions and Controversies

438

WJ Healy and R Khayat

Socioeconomic Factors and CVD

442

M Kabayama and K Kamide

Stage A Heart Failure: Identification and Management of Heart Failure Risk Factors

446

KM Alexander and M Nayor

Stage B Heart Failure

456

J Aljabban, R Baliga, and I Aljabban

STEMI: Diagnosis PE Puddu, E Cenko, B Ricci, and R Bugiardini

465

xiv

Contents of All Volumes

STEMI: Management

474

R Beatrice, M Olivia, E Cenko, and R Bugiardini

STEMI: Prognosis

489

E Cenko, B Ricci, and R Bugiardini

Structure and Function of the Adult Vertebrate Cardiovascular System

499

JD Schultz and DM Bader

Sudden Cardiac Death

511

GL Sumner, VP Kuriachan, and LB Mitchell

Surgical Management of Atrial Fibrillation

521

G Shanmugam, D Exner, and R Damiano

Takotsubo Syndrome

533

MH Tranter and AR Lyon

Tobacco and Cardiovascular Diseases

537

H Kanda and T Hisamatsu

Total Artificial Heart

545

T Lee and G Torregrossa

Transcriptomics in Cardiovascular Medicine

558

D Börnigen and T Zeller

Transcriptome and Epigenome Applications for Coronary Heart Disease Research

572

R Joehanes

Transplant Arteriosclerosis

582

JC Choy

Trends in the Incidence and Mortality of Cardiovascular Disease

593

J Hata

Ultrafiltration for the Treatment of Acute Decompensated Heart Failure

600

S Emani

Unstable Angina: Presentation, Diagnosis, and Management

606

P Manning and EH Awtry

Vascular Guidance Cues

616

D Valdembri, G Serini, and N Gioelli

Vascular Repair at the Interface of the Endothelium: The Roles of Protease-Activated Receptors and Neuregulin-1

627

CL Galindo, O Odiete, and JH Cleator

Vasculogenesis in Development

640

SC Chetty, K Choi, and S Sumanas

Ventricular Arrhythmias and Sudden Cardiac Death in Hypertrophic Cardiomyopathy

654

MA Cain and MS Link

Ventricular Assist Devices and Heart Transplantation

664

A Kinsella, Y Moayedi, V Rao, HJ Ross, and J Butany

Ventricular Fibrillation and Defibrillation

674

H Kawata and U Birgersdotter-Green

Ventricular Remodeling in Heart Failure

683

I Aquila and AM Shah

Ventricular Tachycardia in Ischemic and Dilated Cardiomyopathy: Mechanisms and Diagnosis

690

VP Kuriachan, GL Sumner, AA Wahab, J Sapp, and LB Mitchell

Ventricular Tachycardia in Structurally Normal Hearts AG Bhatt and S Mittal

700

Contents of All Volumes

Wide QRS Complex Tachycardia: What is the Diagnosis?

xv 725

S Wang and FR Quinn

Wolff–Parkinson–White and Preexcitation Syndromes

747

B Brembilla-Perrot

Zebrafish

759

X-XI Zeng and TP Zhong

Zebrafish as a Tool to Study Congenital Heart Diseases

771

AM Shafik and D Cifuentes

Index

779

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LIST OF CONTRIBUTORS A AbdelWahab QEII Health Sciences Centre, Halifax, NS, Canada A Adler University of Toronto, Toronto, ON, Canada M Afshar University of Toronto, Toronto, ON, Canada MR Afzal Ohio State University Medical Center, Columbus, OH, United States J Ahmed LSU Health Sciences New Orleans, New Orleans, LA, United States S Airhart Cardiovascular Institute, Allegheny Health Network, Pittsburgh, PA, United States MH Albrecht Medical University of South Carolina, Charleston, SC, United States; University Hospital Frankfurt, Frankfurt, Germany KM Alexander Brigham and Women's Hospital, Boston, MA, United States L Alghothani The Ohio State University Wexner Medical Center, Columbus, OH, United States M Alharbi Sydney University, Sydney, NSW, Australia I Aljabban The Pennsylvania State University College of Medicine, Hershey, PA, United States J Aljabban The Ohio State University College of Medicine, Columbus, OH, United States M Allison University of California, San Diego, CA, United States

A Alsamarah Boston University School of Medicine, Boston, MA, United States NL Altman University of Colorado, Denver, United States J Alvarez Peter Munk Cardiac Center, Toronto, ON, Canada N Amano Konan Women's University, Kobe, Japan R America Luigi Vanvitelli University, Naples, Italy JG Andrade Université de Montréal, Montreal, QC, Canada; The University of British Columbia, Vancouver, BC, Canada PH Andraweera The University of Adelaide, Adelaide, SA, Australia AM Andrle Maine Medical Center, Portland, ME, United States C Antzelevitch Lankenau Heart Institute, Wynnewood, PA, United States I Aquila Brigham and Women's Hospital, Boston, MA, United States; Magna Graecia University, Catanzaro, Italy D Arneson University of California, Los Angeles, CA, United States M Arstall Lyell McEwin Hospital, Elizabeth Vale, SA, Australia; The University of Adelaide, Adelaide, Australia J Artico Azienda Sanitaria Universitaria Integrata and University of Trieste, Trieste, Italy K Asayama Tohoku University Graduate School of Pharmaceutical Sciences, Sendai, Japan; Teikyo University School of Medicine, Tokyo, Japan

xvii

xviii

List of Contributors

R Asleh Mayo Clinic, Rochester, MN, United States F Awan Ohio State University, Columbus, OH, United States EH Awtry Boston Medical Center, Boston, MA, United States M Bäck Karolinska Institutet, Stockholm, Sweden DM Bader Vanderbilt University School of Medicine, Nashville, TN, United States AL Baggish Massachusetts General Hospital, Boston, MA, United States CN Bairey Merz Cedars Sinai Medicine Center, Los Angeles, CA, United States S Baldwin Pediatric Heart Institute, Monroe Carell Jr. Children's Hospital at Vanderbilt, Vanderbilt University Medical Center, Nashville, TN, USA R Baliga The Ohio State University College of Medicine, Columbus, OH, United States; The Ohio State University Wexner Medical Center, Columbus, OH, United States; Davis Heart and Lung Research Institute (HLRI), Columbus, OH, United States

JE Beare University of Louisville, Louisville, KY, United States R Beatrice University of Bologna, Bologna, Italy J Beaumont University of Navarra, Pamplona, Spain; CIMA, Pamplona, Spain; Navarra Institute for Health Research, Pamplona, Spain; CIBERCV, Spain O Bebb University of Leeds, Leeds, United Kingdom; York Teaching Hospital NHS Foundation Trust, York, United Kingdom Y Bejot University Hospital François Mitterrand, Dijon, France; University of Burgundy, Dijon, France F Bendtsen University of Copenhagen, Copenhagen, Denmark SC Berngard University of California, San Diego, La Jolla, CA, United States AG Bhatt Valley Health System, Paramus, NJ, United States R Bhattacharjee National Institute for Stroke and Applied Neurosciences, Auckland, New Zealand

W Balkan University of Miami Miller School of Medicine, Miami, FL, United States

C Bianco Case Western Reserve University, Cleveland, OH, United States

B Ballantyne Western University, London, ON, Canada

T Bianco-Miotto The University of Adelaide, Adelaide, SA, Australia

D Bamira Massachusetts General Hospital, Boston, MA, United States

U Birgersdotter-Green UCSD Medical Center, Sulpizio Cardiovascular Center, La Jolla, CA, United States

M Banerjee University of Miami Miller School of MedicineMiami, FL, United States

C Blanc University Hospital François Mitterrand, Dijon, France; University of Burgundy, Dijon, France

A Baranchuk Queen's University, Kingston, ON, Canada

D Börnigen Clinic for General and Interventional Cardiology, University Heart Center Hamburg, Hamburg, Germany; German Center for Cardiovascular Research (DZHK e.V.), Partner Site Hamburg/Lübeck/Kiel, Hamburg, Germany

A Barleben University of California, San Diego, CA, United States TA Barrett The Ohio State University, Columbus, OH, United States A Bauman Sydney University, Sydney, NSW, Australia

E Bossone University Hospital “Scuola Medica Salernitana”, Salerno, Italy

List of Contributors

M Boutjdir State University of New York, Brooklyn, NY, United States; VA NY Harbor Healthcare System, New York, NY, United States; NYU School of Medicine, New York, NY, United States RS Boxer University of Colorado, Aurora CO, United States E Bradley The Ohio State University Wexner Medical Center, Columbus, OH, United States; Nationwide Children's Hospital, Columbus, OH, United States K Breckwoldt University Medical Center Hamburg-Eppendorf, Hamburg, Germany; DZHK (German Centre for Cardiovascular Research), Berlin, Germany B Brembilla-Perrot Department of Cardiology, Nancy University Hospital, Vandoeuvre-les-Nancy, France A Briasoulis Mayo Clinic, Rochester, MN, United States D Briston The Ohio State University Wexner Medical Center, Columbus, OH, United States; Nationwide Children’s Hospital, Columbus, OH, United States KM Broughton San Diego State University Heart Institute and the Integrated Regenerative Research Institute, San Diego, CA, United States AJ Brownstein Yale University School of Medicine, New Haven, CT, United States A Bucca Ohio State University College of Medicine, Columbus, OH, USA R Bugiardini University of Bologna, Bologna, Italy R Bussani Azienda Sanitaria Universitaria Integrata and University of Trieste, Trieste, Italy J Butany Peter Munk Cardiac Center, Toronto, ON, Canada; University of Toronto, Toronto, ON, Canada; Toronto General Hospital, Toronto, ON, Canada AG Cadar Vanderbilt University School of Medicine, Nashville, TN, United States

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ALP Caforio University of Padua, Padua, Italy MA Cain University of Texas Southwestern, Dallas, TX, United States R Calabrò Second University of Naples, Caserta, Italy H Calkins Johns Hopkins University, Baltimore, MD, United States A Cannatà Azienda Sanitaria Universitaria Integrata and University of Trieste, Trieste, Italy A Carbone Luigi Vanvitelli University, Naples, Italy A Cardona Ohio State University Medical Center, Columbus, OH, United States AG Carrizo McMaster University, Hamilton, ON, Canada D Caruso Medical University of South Carolina, Charleston, SC, United States; University of Rome “Sapienza", Latina, Italy AL Catapano IRCCS Multimedica, Milan, Italy; University of Milan, Milan, Italy E Cenko University of Bologna, Bologna, Italy F Chalhoub Harvard Medical School, Boston, MA, United States P Chandrashekar Mayo Clinic, Rochester, MN, United States Q Chen Virginia Commonwealth University, Richmond, VA, United States T Chen University of Washington School of Medicine, Seattle, WA, United States SC Chetty Cincinnati Children's Hospital Medical Center, Cincinnati, OH, United States DS Chew University of Calgary, Calgary, AB, Canada

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List of Contributors

R Chia University of Illinois at Chicago, Chicago, IL, United States K Choi Washington University School of Medicine, St. Louis, MO, United States JC Choy Simon Fraser University, Burnaby, BC, Canada D Cifuentes Boston University School of Medicine, Boston, MA, United States M Cimci Geneva University Hospitals, Geneva, Switzerland A Cittadini Federico II University School of Medicine, Naples, Italy JH Cleator Vanderbilt University Medical Center, Nashville, TN, United States ST Coffin Maine Medical Center, Portland, ME, United States E Colin-Ramirez National Institute of Cardiology ‘Ignacio Chavez’, Mexico City, Mexico P Collier Cleveland Clinic Lerner College of Medicine, Case Western Reserve University, Cleveland, OH, United States; Sydell and Arnold Miller Family Heart and Vascular Institute, The Cleveland Clinic Foundation, Cleveland, OH, United States M Colvin University of Michigan, Ann Arbor, MI, United States R Covarrubias Vanderbilt University Medical Center, Nashville, TN, United States JA Cowgill Maine Medical Center, Portland, ME, United States JA Crestanello The Ohio State University Wexner Medical Center, Columbus, OH, United States ED Crouser The Ohio State University Wexner Medical Center, Columbus, OH, United States

L Curtis-Whitchurch University of Louisville, Louisville, KY, United States R Damiano Washington University, Saint Louis, MO, United States AA Damluji LifeBridge Health Cardiovascular Institute, Baltimore, MD, United States; Johns Hopkins University, Baltimore, MD, United States M Dandel German Centre for Heart and Circulatory Research (DZHK), Berlin, Germany; Deutsches Herzzentrum Berlin, Berlin, Germany EG Daoud The Ohio State University, Columbus, OH, United States D Darbar University of Illinois at Chicago, Chicago, IL, United States A David Australian Catholic University, Melbourne, VIC, Australia S Day The Ohio State University Wexner Medical Center, Columbus, OH, United States CN De Cecco Medical University of South Carolina, Charleston, SC, United States D De Santis Medical University of South Carolina, Charleston, SC, United States; University of Rome “Sapienza", Latina, Italy E Dees Pediatric Heart Institute, Monroe Carell Jr. Children's Hospital at Vanderbilt, Vanderbilt University Medical Center, Nashville, TN, USA GA Dekker The University of Adelaide, Adelaide, SA, Australia; Lyell McEwin Hospital, Elizabeth Vale, SA, Australia B Delpont University Hospital François Mitterrand, Dijon, France; University of Burgundy, Dijon, France

RM Cubbon The University of Leeds, Leeds, United Kingdom

A Deswal Michael E. DeBakey Veterans Affairs Medical Center, Houston, TX, United States; Baylor College of Medicine, Houston, TX, United States

L Cunningham Baylor College of Medicine, Houston, TX, United States

MW Deyell The University of British Columbia, Vancouver, BC, Canada

List of Contributors

BP Dhakal University Hospitals Cleveland Medical Center, Cleveland, OH, United States A Diez The Ohio State University, Columbus, OH, United States J Díez University of Navarra, Pamplona, Spain; CIMA, Pamplona, Spain; Navarra Institute for Health Research, Pamplona, Spain; University of Navarra Clinic, Pamplona, Spain; CIBERCV, Spain P Divanji University of California San Francisco, San Francisco, CA, United States A D’Andrea Luigi Vanvitelli University, Naples, Italy M Edwards Maine Medical Center, Portland, ME, United States M Eid Medical University of South Carolina, Charleston, SC, United States R El Yafawi Maine Medical Center, Portland, ME, United States JA Elefteriades Yale University School of Medicine, New Haven, CT, United States ME Knauft Tufts University School of Medicine, Boston, MA, United States; Maine Medical Center, Portland, ME, United States CR Ellis Vanderbilt Heart and Vascular Institute, Nashville, TN, United States N El-Sherif State University of New York, Brooklyn, NY, United States; VA NY Harbor Healthcare System, New York, NY, United States S Emani The Ohio State University Wexner Medical Center, Columbus, OH, United States T Eschenhagen University Medical Center Hamburg-Eppendorf, Hamburg, Germany; DZHK (German Centre for Cardiovascular Research), Berlin, Germany ES Eshak Osaka University Graduate School of Medicine, Suita-shi, Japan; Minia University, Minia, Egypt

xxi

ML Esposito Tufts Medical Center, Boston, MA, United States C Evanson Ohio State University Medical Center, Columbus, OH, United States D Exner University of Calgary, Calgary, AB, Canada; Cumming School of Medicine, Calgary, AB, Canada JA Ezekowitz University of Alberta, Edmonton, AB, Canada E Fabris Azienda Sanitaria Universitaria Integrata and University of Trieste, Trieste, Italy D Fan University of South Carolina School of Medicine, Columbia, SC, United States KF Faridi Harvard Medical School, Boston, MA, United States AJ Favreau-Lessard Maine Medical Center Research Institute, Scarborough, ME, United States FA Fish Vanderbilt University, Nashville, TN, United States V Florea University of Miami Miller School of MedicineMiami, FL, United States DE Forman University of Pittsburgh, Pittsburgh, PA, United States; VA Pittsburgh Healthcare System, Pittsburgh, PA, United States T Formisano Luigi Vanvitelli University, Naples, Italy ER Fox University of Mississippi Medical Center, Jackson, MS, United States; University of Mississippi School of Medicine, Jackson, MS, United States DR Fraidenburg University of Illinois at Chicago, Chicago, IL, United States S Francis Maine Medical Center, Portland, ME, United States V Franco The Ohio State University, Columbus, OH, United States SR Fuchs Vanderbilt University Medical Center, Nashville, TN, United States

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List of Contributors

G Galanti University of Florence, Florence, Italy

MH Gollob University of Toronto, Toronto, ON, Canada

M Galderisi Federico II University of Naples, Napoli, Italy

A González University of Navarra, Pamplona, Spain; CIMA, Pamplona, Spain; Navarra Institute for Health Research, Pamplona, Spain; CIBERCV, Spain

CP Gale Professor of Cardiovascular Medicine, School of Medicine, University of Leeds, Leeds, UK CL Galindo Vanderbilt University Medical Center, Nashville, TN, United States R Gallagher Sydney University, Sydney, NSW, Australia PU Gandhi Yale University School of Medicine, New Haven, CT, United States X Gao The Ohio State University Wexner Medical Center, Columbus, OH, United States B Gencer Geneva University Hospitals, Geneva, Switzerland P Gentile Azienda Sanitaria Universitaria Integrata and University of Trieste, Trieste, Italy MA Gertz Mayo Clinic, Rochester, MN, United States

DM Gopal Boston University School of Medicine, Boston, MA, United States TP Graham Jr. Vanderbilt University, Nashville, TN, United States RC Groom Maine Medical Center, Portland, ME, United States A Guha The Ohio State University, Columbus, OH, United States RJ Gumina Vanderbilt University Medical Center, Nashville, TN, United States; Veterans Administration, Nashville, TN, United States JS Guseh Division of Cardiology, Department of Medicine, Massachusetts General Hospital, Boston, MA, United States

A Ghimire Dalhousie University, Halifax, NS, Canada

D Haddad Ohio State University, Columbus, OH, United States

E Giannitsis University Hospital of Heidelberg, Heidelberg, Germany

H Haghbayan Department of Medicine, University of Toronto, Toronto, Ontario, Canada

M Ginwalla Case Western Reserve University, Cleveland, OH, United States; University Hospitals Cleveland Medical Center, Cleveland, OH, United States

M Hall University of Leeds, Leeds, United Kingdom

N Gioelli Candiolo Cancer Institute – Fondazione del Piemonte per l’Oncologia (FPO) Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Candiolo, Torino, Italy M Giroud University Hospital François Mitterrand, Dijon, France; University of Burgundy, Dijon, France SS Gogia Cardiology Division, Department of Medicine, Massachusetts General Hospital, Boston, MA, United States

ME Hall University of Mississippi School of Medicine, Jackson, MS, United States L Halperin University of British Columbia, Vancouver, BC, Canada TW Hansen Gentofte and Research Center for Prevention and Health, Copenhagen, Denmark GK Hansson Karolinska Institutet, Stockholm, Sweden A Hara Showa Pharmaceutical University, Tokyo, Japan

List of Contributors

JM Hare University of Miami Miller School of Medicine, Miami, FL, United States AR Harper Royal Brompton and Harefield NHS Foundation Trust, London, United Kingdom; University of Oxford, Oxford, United Kingdom

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CC Hong Vanderbilt University School of Medicine, Nashville, TN, United States; Veterans Affairs Tennessee Valley Healthcare System, Nashville, TN, United States CL Hoppel Case Western Reserve University School of Medicine, Cleveland, OH, United States

A Hasan Advanced Heart Failure and Cardiac Transplantation Fellowship Program, Columbus, OH, United States

KN Hor Nationwide Children's Hospital, Columbus, OH, United States; The Ohio State University College of Medicine, Columbus, OH, United States

LJ Hassen The Ohio State University & Nationwide Children's Hospital, Columbus, OH, United States

JD Hove University of Copenhagen, Copenhagen, Denmark

J Hata Kyushu University, Fukuoka, Japan K Hatzistergos University of Miami Miller School of Medicine, Miami, FL, United States C Healey Maine Medical Center, Portland, ME, United States WJ Healy The Ohio State University Sleep Heart Program, Columbus, OH, United States R Hetzer Deutsches Herzzentrum Berlin, Berlin, Germany; Cardio Centrum Berlin, Berlin, Germany N Hippalgaonkar Florida Atlantic University, Boca Raton, FL, United States A Hirata Keio University School of Medicine, Tokyo, Japan T Hirata Keio University School of Medicine, Tokyo, Japan T Hisamatsu Shimane University, Izumo, Japan JE Ho Massachusetts General Hospital, Boston, MA, United States J Hodge University of South Carolina School of Medicine, Columbia, SC, United States BD Hoit University Hospitals Cleveland Medical Center, Cleveland, OH, United States; Case Western Reserve University, Cleveland, OH, United States

SE Howlett Dalhousie University, Halifax, NS, Canada JB Hoying University of Louisville, Louisville, KY, United States CM Hritz The Ohio State University, Columbus, OH, United States H Huang University of Illinois at Chicago, Chicago, IL, United States T Hussein AUT ICT Development, Auckland, New Zealand S Iliceto University of Padua, Padua, Italy PI Imoukhuede University of Illinois at Urbana-Champaign, Urbana, IL, United States M Inouye University of Melbourne, Parkville, VIC, Australia; Systems Genomics Lab, Baker Heart and Diabetes Institute, Melbourne, Victoria, Australia Junko Ishihara Sagami Women's University, Sagamihara, Japan H Iso Osaka University Graduate School of Medicine, Suita-shi, Japan S Jablonski Maine Medical Center, Portland, ME, United States DN Jackson The University of Western Ontario, London, ON, Canada N Jafar University of California San Francisco, San Francisco, CA, United States

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List of Contributors

NP Jaik Pinnacle Health Cardiovascular Institute, Harrisburg, PA, United States

K Kario Jichi Medical University School of Medicine, Shimotsuke, Tochigi, Japan

M Jame University of Michigan, Ann Arbor, MI, United States

S Katsanos Attikon University Hospital, Athens, Greece

S Jame University of Michigan, Ann Arbor, MI, United States

H Kawata UC Irvine School of Medicine, Orange, CA, United States

HJ Jansen Dalhousie University, Halifax, NS, Canada

W Kayani Baylor College of Medicine, Houston, TX, United States

R Joehanes Hebrew SeniorLife, Boston, MA, United States; Beth Israel Deaconess Medical Center, Boston, MA, United States; Harvard Medical School, Boston, MA, United States

AK Keates Mary MacKillop Institute for Health Research, Australian Catholic University, Melbourne, VIC, Australia

RM John Harvard Medical School, Boston, MA, United States; Vanderbilt University Medical Center, Nashville, TN, United States JA Johns Vanderbilt University Medical Center, Nashville, TN, United States RL Jones The Stanford University Medical Center, Stanford, CA, United States UJ Schoepf Medical University of South Carolina, Charleston, SC, United States M Kabayama Osaka University Graduate School of Medicine, Osaka, Japan SJ Kalbfleisch The Ohio State University Wexner Medical Center, Columbus, OH, United States K Kamide Osaka University Graduate School of Medicine, Osaka, Japan H Kanda Shimane University, Izumo, Japan VV Kandasamy University of Louisville School of Medicine, Louisville, KY, United States

S Kenchaiah University of Arkansas for Medical Sciences, Little Rock, AR, United States; Central Arkansas Veterans Healthcare System, Little Rock, AR, United States DFJ Ketelhuth Karolinska Institutet, Stockholm, Sweden R Khatib Leeds Teaching Hospitals NHS Trust, Leeds, United Kingdom; University of Leeds, Leeds, United Kingdom; University of Bradford, Bradford, United Kingdom R Khayat The Ohio State University Sleep Heart Program, Columbus, OH, United States B Kherad Department of Cardiology, Charité–University Medicine Berlin - Campus Virchow, Berlin, Germany M Kida Osaka University Graduate School of Dentistry, Osaka, Japan M Kikui Osaka University Graduate School of Dentistry, Osaka, Japan A Kilic The Ohio State University Wexner Medical Center, Columbus, OH, United States A Kinsella Peter Munk Cardiac Center, Toronto, ON, Canada

AE Kane Dalhousie University, Halifax, NS, Canada

JN Kirkpatrick University of Washington School of Medicine, Seattle, WA, United States

PJ Kannankeril Vanderbilt University Medical Center, Nashville, TN, United States

Y Kokubo National Cerebral and Cardiovascular Center, Suita, Japan

NK Kapur Tufts Medical Center, Boston, MA, United States

B Konda The Ohio State University, Columbus, OH, United States

List of Contributors

T Kosaka Osaka University Graduate School of Dentistry, Osaka, Japan AD Krahn University of British Columbia, Vancouver, BC, Canada RS Kramer Maine Medical Center, Portland, ME, United States U Kühl Department of Cardiology, Charité–University Medicine Berlin - Campus Virchow, Berlin, Germany S Kuranuki Kanagawa University of Human Services, Yokosuka, Japan VP Kuriachan Libin Cardiovascular Institute of Alberta, Calgary, AB, Canada; Foothills Hospital, Calgary, AB, Canada K Kuwabara Keio University School of Medicine, Tokyo, Japan BC Lampert The Ohio State University Wexner Medical Center, Columbus, OH, United States CJ Lavie John Ochsner Heart and Vascular Institute, Ochsner Clinical School, The University of Queensland School of Medicine, New Orleans, LA, United States E Lavine Icahn School of Medicine at Mount Sinai, New York, NY, United States AJ LeBlanc University of Louisville, Louisville, KY, United States P Lee The Ohio State University, Columbus, OH, United States T Lee Mount Sinai St. Luke's Hospital, Amsterdam, NY, United States E Legome Icahn School of Medicine at Mount Sinai, New York, NY, United States

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EJ Lesnefsky Virginia Commonwealth University, Richmond, VA, United States; McGuire Veterans Affairs Medical Center, Richmond, VA, United States VW Lesslie Medical University of South Carolina, Charleston, SC, United States Y Li Shanghai Jiao Tong University School of Medicine, Shanghai, China B Liccardo Luigi Vanvitelli University, Naples, Italy W Lieb Christian-Albrechts-University Kiel, Kiel, Germany MS Link University of Texas Southwestern, Dallas, TX, United States Q Liu University of South Carolina School of Medicine, Columbia, SC, United States B López University of Navarra, Pamplona, Spain; CIMA, Pamplona, Spain; Navarra Institute for Health Research, Pamplona, Spain; CIBERCV, Spain N Lowres Sydney University, Sydney, NSW, Australia A Luk Peter Munk Cardiac Center, Toronto, ON, Canada AR Lyon Imperial Centre for Translational and Biomedical Medicine, Hammersmith Hospital, London, United Kingdom; NIHR Cardiovascular Biomedical Research Unit, Royal Brompton Hospital, London, United Kingdom L Macle Université de Montréal, Montreal, QC, Canada N Maffulli University of Salerno, Salerno, Italy; Queen Mary University of London, London, United Kingdom

P LeLorier LSU Health Sciences New Orleans, New Orleans, LA, United States

C Mainland Australian Catholic University, Melbourne, VIC, Australia

B LeNoir Medical University of South Carolina, Charleston, SC, United States

AS Major Veterans Administration, Nashville, TN, United States; Vanderbilt University Medical Center, Nashville, TN, United States

T Lescouflair The Ohio State University Wexner Medical Center, Columbus, OH, United States

M Malik University of Washington, Seattle, WA, United States

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List of Contributors

S Malin Karolinska Institutet, Stockholm, Sweden

T Mela Harvard Medical School, Boston, MA, United States

G Malipiero University of Padua, Padua, Italy

M Merlo Azienda Sanitaria Universitaria Integrata and University of Trieste, Trieste, Italy

J Mandel UC San Diego School of Medicine, La Jolla, CA, United States P Manning Boston Medical Center, Boston, MA, United States R Marcolongo University of Padua, Padua, Italy AS Mariet University Hospital François Mitterrand, Dijon, France J Martinez University of South Carolina School of Medicine, Columbia, SC, United States F Martone Luigi Vanvitelli University, Naples, Italy L Mathews Johns Hopkins Medicine, Baltimore, MD, United States C Matsumoto Hyogo College of Medicine, Nishinomiya, Japan

VM Miller Mayo Clinic, Rochester, MN, United States LB Mitchell Libin Cardiovascular Institute of Alberta, Calgary, AB, Canada; Foothills Hospital, Calgary, AB, Canada S Mittal Valley Health System, Paramus, NJ, United States Y Moayedi Peter Munk Cardiac Center, Toronto, ON, Canada S Møller University of Copenhagen, Copenhagen, Denmark B Mondesert Montreal Heart Institute, Montreal, QC, Canada J Monti Maine Medical Center, Portland Maine, ME, United States; Tufts University School of Medicine, Boston, MA, United States

K Matsushita John Hopkins University, Baltimore, MD, United States

AM Moran Congenital Heart, Scarborough, ME, United States

Y Matsushita National Center for Global Health and Medicine, Toyama, Japan

MU Moreno University of Navarra, Pamplona, Spain; CIMA, Pamplona, Spain; Navarra Institute for Health Research, Pamplona, Spain; CIBERCV, Spain

AM Maw University of Colorado, Aurora CO, United States C Mayeur Lariboisière University Hospital, Paris, France M Mayr King's British Heart Foundation Centre, King's College London, London, United Kingdom L Mc Carthy University College Cork, Cork, Ireland A Mebazaa Lariboisière University Hospital, Paris, France A Mehta University of Illinois at Chicago, Chicago, IL, United States JL Mehta University of Arkansas for Medical Sciences, Little Rock, AR, United States

RB Morgan MMP MaineHealth Augusta Cardiology, Augusta, ME, United States H Mori Mukogawa Women's University, Nishinomiya, Hyogo, Japan M Mori Mukogawa Women's University, Nishinomiya, Hyogo, Japan JR Morton Maine Medical Center, Portland, ME, United States S Mukherjee Cleveland Clinic, Cleveland, OH, United States S Murali Cardiovascular Institute, Allegheny Health Network, Pittsburgh, PA, United States

List of Contributors

xxvii

SK Musani University of Mississippi School of Medicine, Jackson, MS, United States

T Okabe The Ohio State University Wexner Medical Center, Columbus, OH, United States

SV Naga Prasad Cleveland Clinic, Cleveland, OH, United States

C Okada Osaka University Graduate School of Medicine, Osaka, Japan

T Nakamura Kanagawa University of Human Services, Yokosuka, Japan; Ryukoku University, Otsu, Japan R Napoli Federico II University School of Medicine, Naples, Italy VJ Nardy The Ohio State University Wexner Medical Center, Columbus, OH, United States M Natsumeda University of Miami Miller School of MedicineMiami, FL, United States M Nayor Brigham and Women's Hospital, Boston, MA, United States H Nazzari University of British Columbia, Vancouver, BC, Canada U Neisius Harvard Medical School, Boston, MA, United States R Neki National Cerebral and Cardiovascular Center, Suita, Osaka, Japan JT Neumann University Heart Center, Hamburg, Germany J Ng University of Calgary, Calgary, AB, Canada GT Nicholson Vanderbilt University School of Medicine, Nashville, TN, United States T Ninomiya Kyushu University, Fukuoka, Japan B Nolan Maine Medical Center, Portland, ME, United States V Noori Maine Medical Center, Portland, ME, United States NM Novielli The University of Western Ontario, London, ON, Canada O Odiete Vanderbilt University Medical Center, Nashville, TN, United States

T Okamura Keio University School of Medicine, Tokyo, Japan AA Oktay John Ochsner Heart and Vascular Institute, Ochsner Clinical School, The University of Queensland School of Medicine, New Orleans, LA, United States M Olivia University of Bologna, Bologna, Italy PS Olofsson Karolinska Institutet, Stockholm, Sweden B Olshansky University of Iowa, Iowa City, IA, United States; Mercy Hospital – North Iowa, Mason City, IA, United States T Ono Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan; Osaka University Graduate School of Dentistry, Osaka, Japan GM Orgeron Johns Hopkins University, Baltimore, MD, United States GY Oudit University of Alberta, Edmonton, AB, Canada P Ouyang Johns Hopkins University School of Medicine, Baltimore, MD, United States RL Page II University of Colorado, Aurora CO, United States JM Palminteri Tufts University School of Medicine, Boston, MA, United States; Maine Medical Center, Portland, ME, United States S Pant University of Louisville School of Medicine, Louisville, KY, United States NI Parikh University of California San Francisco, San Francisco, CA, United States J Parissis Attikon University Hospital, Athens, Greece

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List of Contributors

J Park University of Hawaii, Honolulu, HI, United States R Parkash QEII Health Sciences Centre, Halifax, NS, Canada A Patel St. Vincent Hospital, Indianapolis, IN, United States G Paulsson-Berne Karolinska Institutet, Stockholm, Sweden S Pedraza The Ohio State University, Columbus, OH, United States N Pereira Mayo Clinic, Rochester, MN, United States MV Perez The Stanford University Medical Center, Stanford, CA, United States SM Peterson Maine Medical Center Research Institute, Scarborough, ME, USA MH Picard Massachusetts General Hospital, Boston, MA, United States D Pinkhas The Ohio State University Wexner Medical Center, Columbus, OH, United States I Pinz Maine Medical Center Research Institute, Scarborough, ME, United States; Tufts University, Sackler School of Graduate Biomedical Sciences, Boston, MA, United States A Pirillo Center for the Study of Atherosclerosis, Bassini Hospital, Cinisello Balsamo, Italy; IRCCS Multimedica, Milan, Italy

CJ Prendergast Vanderbilt University School of Medicine, Nashville, TN, United States PE Puddu Sapienza University of Rome, Rome, Italy K Puri Baylor College of Medicine, Houston, TX, United States R Querejeta University of the Basque Country, San Sebastian, Spain; Biodonostia Research Institute, San Sebastian, Spain; Donostia University Hospital, San Sebastian, Spain FR Quinn Libin Cardiovascular Institute of Alberta, Calgary, AB, Canada TA Quinn Dalhousie University, Halifax, NS, Canada AE Radbill Vanderbilt University, Nashville, TN, United States J Radmilovich Luigi Vanvitelli University, Naples, Italy SR Raj University of Calgary, Calgary, AB, Canada; Vanderbilt University, Nashville, TN, United States A Ramireddy University of Miami Miller School of Medicine, Miami, FL, United States V Ramirez Maine Medical Center, Portland Maine, ME, United States; Tufts University School of Medicine, Boston, MA, United States V Rao Peter Munk Cardiac Center, Toronto, ON, Canada; University of Toronto, Toronto, ON, Canada

B Plourde IUCPQ affiliated to University Laval, Quebec, Canada

I Ratjen Christian-Albrechts-University Kiel, Kiel, Germany

JD Pollard University of Mississippi School of Medicine, Jackson, MS, United States

B Ravaee University Hospitals Cleveland Medical Center, Cleveland, OH, United States; Case Western Reserve University, Cleveland, OH, United States

JB Powers Maine Medical Center, Portland, ME, United States M Prasad Mayo Clinic, Rochester, MN, United States DN Pratt The Ohio State University, Columbus, OH, United States

S Ravassa University of Navarra, Pamplona, Spain; CIMA, Pamplona, Spain; Navarra Institute for Health Research, Pamplona, Spain; CIBERCV, Spain J Reis University Hospital of Strasbourg, Strasbourg, France

List of Contributors

xxix

MS Renno Vanderbilt University Medical Center, Nashville, TN, United States

K Rusk Ohio State University Medical Center, Columbus, OH, United States

A Reynolds The Ohio State University, Columbus, OH, United States

S Ryzhov Maine Medical Center Research Institute, Scarborough, ME, USA

B Ricci University of Bologna, Bologna, Italy

LM Safi Harvard Medical School, Boston, MA, United States

TD Richardson Vanderbilt Heart and Vascular Institute, Nashville, TN, United States

M Sagara Disease Model Cooperative Research Association, Kyoto, Japan

AC Rieger University of Miami Miller School of MedicineMiami, FL, United States

A Salerno University of Miami Miller School of Medicine, Miami, FL, United States

L Riegler Luigi Vanvitelli University, Naples, Italy

V Salomaa National Institute for Health and Welfare, Helsinki, Finland

DL Robaczewski Maine Medical Center, Portland, ME, United States CT Roberts The University of Adelaide, Adelaide, SA, Australia DJ Roberts Maine Medical Center, Portland, ME, United States S Roble The Ohio State University & Nationwide Children's Hospital, Columbus, OH, United States CJ Rodriguez Wake Forest University School of Medicine, Winston-Salem, NC, United States M Roffi Geneva University Hospitals, Geneva, Switzerland I Roifman University of Toronto, Toronto, ON, Canada RA Rose Dalhousie University, Halifax, NS, Canada; University of Calgary, Calgary, AB, Canada JA Rosenblatt Maine Medical Center, Portland, ME, United States

A Salzano Federico II University School of Medicine, Naples, Italy G San José University of Navarra, Pamplona, Spain; CIMA, Pamplona, Spain; Navarra Institute for Health Research, Pamplona, Spain; CIBERCV, Spain J Sapp QEII Health Sciences Centre, Halifax, NS, Canada DB Sawyer Maine Medical Center Research Institute, Scarborough, ME, United States R Scarafile Luigi Vanvitelli University, Naples, Italy S Scheetz The Ohio State University College of Medicine, Columbus, OH, United States M Scherillo Rummo Hospital, Benevento, Italy TR Schlingmann Baylor College of Medicine – Texas Children's Hospital, Houston, TX, United States

HJ Ross Peter Munk Cardiac Center, Toronto, ON, Canada; University of Toronto, Toronto, ON, Canada

RB Schnabel University Heart Center, Hamburg, Germany

M Rozmahel University of Alberta, Edmonton, AB, Canada

SR Schubert The Ohio State University Wexner Medical Center, Columbus, OH, United States

FL Ruberg Boston University School of Medicine, Boston, MA, United States

JD Schultz Vanderbilt University School of Medicine, Nashville, TN, United States

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List of Contributors

T Sedlak University of British Columbia, Vancouver, BC, United States

G Sinagra Azienda Sanitaria Universitaria Integrata and University of Trieste, Trieste, Italy

G Serini University of Torino School of Medicine, Candiolo, Torino, Italy; Candiolo Cancer Institute – Fondazione del Piemonte per l’Oncologia (FPO) Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Candiolo, Torino, Italy

M Singh Yale University School of Medicine, New Haven, CT, United States

AM Shafik Boston University School of Medicine, Boston, MA, United States AB Shah Massachusetts General Hospital, Boston, MA, United States AM Shah Brigham and Women's Hospital, Boston, MA, United States; Magna Graecia University, Catanzaro, Italy J Shah Maine Medical Center, Portland, ME, United States G Shanmugam Libin Cardiovascular Institute, Calgary, AB, Canada; Foothills Medical Centre, Calgary, AB, Canada ES Shao Maine Medical Center, Scarborough, ME, United States; Maine Medical Center, Portland, ME, United States

A Siraj University of Arkansas for Medical Sciences, Little Rock, AR, United States; Central Arkansas Veterans Healthcare System, Little Rock, AR, United States M Sivananthan Leeds Teaching Hospitals NHS Trust, Leeds, United Kingdom H Sone Niigata University, Niigata, Japan D Sorajja Mayo Clinic Arizona, Phoenix, AZ, United States JH Soslow Vanderbilt University Medical Center, Nashville, TN, United States S Srikanthan Cleveland Clinic, Cleveland, OH, United States JA Staessen University of Leuven, Leuven, Belgium; Maastricht University, Maastricht, The Netherlands E Stamatakis Sydney University, Sydney, NSW, Australia

K Sharma Johns Hopkins Medicine, Baltimore, MD, United States

B Starobin Maine Medical Center, Portland, ME, United States; Tufts University School of Medicine, Boston, MA, United States

BH Shaw University of Calgary, Calgary, AB, Canada

L Stefani University of Florence, Florence, Italy

W-K Shen Mayo Clinic Arizona, Phoenix, AZ, United States

WG Stevenson Harvard Medical School, Boston, MA, United States

T Sher Mayo Clinic, Jacksonville, FL, United States

S Stewart Australian Catholic University, Melbourne, VIC, Australia

L Shu University of California, Los Angeles, CA, United States B Shukrallah The Ohio State University Wexner Medical Center, Columbus, OH, United States OK Siddiqi Boston University School of Medicine, Boston, MA, United States

K Stokem Maine Medical Center, Portland, ME, United States JB Strom Harvard Medical School, Boston, MA, United States D Sugiyama Keio University School of Medicine, Tokyo, Japan

List of Contributors

S Sumanas Cincinnati Children's Hospital Medical Center, Cincinnati, OH, United States GL Sumner Libin Cardiovascular Institute of Alberta, Calgary, AB, Canada; Foothills Hospital, Calgary, AB, Canada G Suna King's British Heart Foundation Centre, King's College London, London, United Kingdom V Sundaram Imperial College London, London, United Kingdom; Case Western Reserve University, Cleveland, OH, United States MD Tallquist University of Hawaii, Honolulu, HI, United States B Tandler CWRU School of Dental Medicine, Cleveland, OH, United States F Taylor Mary MacKillop Institute for Health Research, Australian Catholic University, Melbourne, VIC, Australia EJ Teufel MaineHealth Cardiology, Scarborough, ME, United States K Thakarar Maine Medical Center, Portland, ME, United States G Thanassoulis McGill University, Montreal, QC, Canada Y Tian Temple University School of Medicine, Philadelphia, PA, United States D Tirziu Yale University School of Medicine, New Haven, CT, United States H Tomiyama Tokyo Medical University, Tokyo, Japan BA Tompkins University of Miami Miller School of MedicineMiami, FL, United States G Torregrossa Mount Sinai St. Luke's Hospital, Amsterdam, NY, United States N Townsend University of Oxford, Oxford, United Kingdom MH Tranter Imperial Centre for Translational and Biomedical Medicine, Hammersmith Hospital, London, United Kingdom

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AJ Trask Nationwide Children's Hospital, Columbus, OH, United States; The Ohio State University College of Medicine, Columbus, OH, United States C Tsao Harvard Medical School, Boston, MA, United States CW Tsao Harvard Medical School, Boston, MA, United States C Tschöpe Department of Cardiology, Charité–University Medicine Berlin - Campus Virchow, Berlin, Germany; BerlinBrandenburg Center for Regenerative Therapies (BCRT), Berlin, Germany; German Centre for Cardiovascular Research (DZHK), Berlin, Germany DN Tukaye Emory University, Atlanta, GA, United States G Turitto New York Presbyterian-Brooklyn Methodist Hospital, Brooklyn, NY, United States TA Turunen A.I. Virtanen Institute, University of Eastern Finland, Kuopio, Finland J Twynstra The University of Western Ontario, London, ON, Canada M Umesawa Dokkyo Medical University, Mibu, Japan M-A Väänänen A.I. Virtanen Institute, University of Eastern Finland, Kuopio, Finland M Vafaie University Hospital of Heidelberg, Heidelberg, Germany D Valdembri University of Torino School of Medicine, Candiolo, Torino, Italy; Candiolo Cancer Institute – Fondazione del Piemonte per l’Oncologia (FPO) Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Candiolo, Torino, Italy A Vallakati The Ohio State University, Columbus, OH, United States S Vallurupalli University of Arkansas for Medical Sciences, Little Rock, AR, United States; Central Arkansas Veterans Healthcare System, Little Rock, AR, United States A Varga-Szemes Medical University of South Carolina, Charleston, SC, United States

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List of Contributors

RS Vasan The Framingham Heart Study, Framingham, MA, United States; Boston University School of Medicine, Boston, MA, United States; Boston University School of Public Health, Boston, MA, United States A Vazir Royal Brompton and Harefield NHS Foundation Trust, Imperial College London, London, United Kingdom HO Ventura John Ochsner Heart and Vascular Institute, Ochsner Clinical School, The University of Queensland School of Medicine, New Orleans, LA, United States A Voiosu University of Copenhagen, Copenhagen, Denmark; “Carol Davila” University of Medicine and Pharmacy, Bucures¸ ti, Romania T Voiosu “Carol Davila” University of Medicine and Pharmacy, Bucures¸ ti, Romania G Voros University Hospitals Leuven, Leuven, Belgium AMN Walker The University of Leeds, Leeds, United Kingdom S Wang Libin Cardiovascular Institute of Alberta, Calgary, AB, Canada N Warmke The University of Leeds, Leeds, United Kingdom JC Weddell University of Illinois at Urbana-Champaign, Urbana, IL, United States F-F Wei University of Leuven, Leuven, Belgium R Weiss Ohio State University Medical Center, Columbus, OH, United States JA White University of Calgary, Calgary, AB, Canada BA Whitson The Ohio State University Wexner Medical Center, Columbus, OH, United States S Wiese University of Copenhagen, Copenhagen, Denmark

JN Wight Jr. Tufts University School of Medicine, Maine Medical Center, Portland, ME, United States R Willems University Leuven, Leuven, Belgium LK Williams Papworth Hospital NHS Foundation Trust, Cambridge, United Kingdom F Wilson Leeds General Infirmary, Leeds, United Kingdom SB Wilton University of Calgary, Calgary, AB, Canada JA Wirth Tufts University School of Medicine, Boston, MA, United States; Maine Medical Center, Portland, ME, United States C Withers Maine Medical Center, Portland, ME, United States MJ Wood Harvard Medical School, Boston, MA, United States K Yamagishi University of Tsukuba, Tsukuba, Japan A Yamashina Tokyo Medical University, Tokyo, Japan Y Yamori Mukogawa Women's University, Nishinomiya, Hyogo, Japan; Disease Model Cooperative Research Association, Kyoto, Japan; Hyogo Prefecture Health Promotion Association, Hyogo, Japan AT Yan Division of Cardiology, St. Michael's Hospital, University of Toronto, Toronto, Ontario, Canada Z-Q Yan Karolinska Institutet, Stockholm, Sweden M Yanagi Tezukayama University, Nara, Japan X Yang University of California, Los Angeles, CA, United States Y Yano Northwestern University Feinberg School of Medicine, Chicago, IL, United States H Yatsuya Fujita Health University School of Medicine, Aichi, Japan

List of Contributors

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S Ylä-Herttuala A.I. Virtanen Institute, University of Eastern Finland, Kuopio, Finland; Heart Center, Kuopio University Hospital, Kuopio, Finland

X-XI Zeng East China Normal University, School of Life Sciences, Shanghai, China; Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA, United States

JX-J Yuan University of Arizona, Tucson, AZ, United States

Pavel Zhabyeyev University of Alberta, Edmonton, AB, Canada

JP Zachariah Baylor College of Medicine, Houston, TX, United States; Texas Children's Hospital, Houston, TX, United States

C Zhang Vanderbilt University School of Medicine, Nashville, TN, United States

KM Zareba The Ohio State University, Columbus, OH, United States

TP Zhong East China Normal University, School of Life Sciences, Shanghai, China; Fudan University School of Life Sciences, Shanghai, China

T Zeller Clinic for General and Interventional Cardiology, University Heart Center Hamburg, Hamburg, Germany; German Center for Cardiovascular Research (DZHK e.V.), Partner Site Hamburg/Lübeck/Kiel, Hamburg, Germany

BA Ziganshin Yale University School of Medicine, New Haven, CT, United States

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PREFACE The burden of cardiovascular disease is growing across the globe as the leading noncommunicable cause of morbidity and mortality. This is despite outstanding research that has improved our understanding of cardiovascular biology, the determinants of disease, and development of new therapies. We are optimistic that the next generation of scientists and clinicians will further these efforts and ultimately bring about changes that will reduce risk and improve outcomes for patients worldwide. We have assembled this encyclopedia with the explicit intent to provide this generation with easy access to past and current wisdom, with the hope that this helps to accelerate innovation in cardiovascular medicine. This encyclopedia represents both a dream and a labor of love. The dream is to create a scientific compendium that recognizes that the methods and tools used to access and study the scientific literature have changed, with a burgeoning impact of digital technology—the so-called pocket book encyclopedia that is accessible on a smart phone fitting into medical overalls, and that can also be read as a textbook at a desk! These changes in the access of publications have been accompanied by the evolving need for studying different aspects of biology and disease as stand-alone chapters not necessarily read sequentially. Furthermore, as editors we recognize the fundamental importance of conveying knowledge through brilliantly illustrated texts that are profusely embedded with links to key references. The critical importance to use multimedia tools and to provide downloadable slides for educational purposes is reflected in this encyclopedia. Additionally, we want to ensure the feasibility of updating text, figures, and other reading material iteratively even after a publication date, recognizing the rapid advent of information and huge strides made in cardiovascular medicine every day. Thus, this work represents the end of the beginning of a live text that will metamorphose over time, being guided by the rapid strides and advances in both cardiovascular medicine and publication science. Overall, we conceptualized this work as providing broad coverage of science and also serving the expansive needs of a readership that is quite diverse, that is, encompassing medical students, residents, fellows, and postdoctoral scientists interested in cardiovascular medicine. We hope the labor of love of an outstanding team of editors and a stellar group of authors is readily evident to the broad readership we have targeted. Assembling this compendium had many challenges. Early on we made the choice to cover the broad range of cardiovascular biology, pathophysiology, epidemiology, and treatment of disease. We sought to assure equal coverage to foundational cardiovascular cellular and molecular biology as well as state-of-the-art treatments. Covering the breadth inevitably led to some overlap between some chapters, and yet we certainly have some residual gaps. We hope to have the opportunity to fill these gaps in future editions. There is also inevitable variation in the style and scope of articles in this multiauthor publication. We and the section editors felt it was more important to allow our expert authors freedom in how they chose to present their topic. We invite feedback on how this encyclopedia can be improved as a resource for trainees worldwide. Undoubtedly, as noted above, there are gaps in content areas that need to be bridged in future iterations of this encyclopedia. We look forward to hearing from and listening to our readership about how the text can be better organized or better compiled to serve their scholarship better in future years. This project was made possible through the hard work of many people from across the globe. We were pleased to have section editors and authors from around the world. Drs. Kessler and Schunkert, renowned cardiologists with an outstanding record of accomplishment in genetic research, have compiled a series of chapters on genetics and genomics. Dr. Baliga, a distinguished cardiologist and educator, has conceptualized a tour de force of chapters that capture all aspects of the heart failure syndrome, whereas Dr. DiSalvo, a master clinician and educator, has synthesized a fine tapestry of chapters focusing on diagnostic testing with key sections on cardiac imaging, interventions, and device therapy. Dr. Raj, an outstanding clinical investigator and

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electrophysiologist, brought together an exemplary collection of chapters that offer coverage of a broad spectrum of topics in cardiac electrophysiology. Drs. Major and Liaw, both highly accomplished basic scientists and educators, were instrumental in identifying topics of fundamental importance to the field of cardiovascular biology and medicine. Dr. Lenihan, a pioneering clinical scientist and outstanding cardiologist, brought together a special set of articles that represent interactions between cardiovascular and other fields of medicine. Dr. Gale, a celebrated cardiologist with expertise in comparative effectiveness research and clinical cardiology, offers a series of stellar chapters underscoring various aspects of the pathogenesis and management of atherosclerotic cardiovascular disease. Dr. Kokubo, a leading preventive cardiologist with specialization in cardiovascular epidemiology, has orchestrated state-of-the-art chapters on cardiovascular epidemiology. We would like to thank our colleagues at Elsevier who provided steadfast support of an exemplary nature throughout this long journey. Last but not the least, the editors would like to thank their families, their mentors, and their respective institutions for the constant encouragement, advice, and support over the years. Ramachandran S. Vasan, MBBS, MD, DM Douglas B. Sawyer, MD PhD

A Adult Congenital Heart Disease D Briston and E Bradley, The Ohio State University Wexner Medical Center, Columbus, OH, United States; Nationwide Children's Hospital, Columbus, OH, United States © 2018 Elsevier Inc. All rights reserved.

Introduction Etiology Embryology Nomenclature Acyanotic Lesions Obstructive lesions Left-to-right shunts Cyanotic Lesions Treatment Cardiac Manifestations in ACHD Extracardiac Manifestations of ACHD Conclusions References

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Glossary

ACHD Adult congenital heart disease: Field of medicine dealing with adult survivors of cardiovascular birth defects relating to their prior pathology as well as consequences of prior interventions. ASD Atrial septal defect: A communication between the atria resulting from incomplete formation of the interatrial septum. CHD Congenital heart disease: Field of medicine dealing with cardiology resulting from embryologic errors and structural problems present since birth. CoA Coarctation of the aorta: A narrowing of the aorta, which may be defined or focal, commonly near to the juxtaductal region. ES Eisenmenger syndrome: Disease state in which a previously left-to-right shunting lesions reverses and becomes right-to-left. FALD Fontan-associated liver disease: Unique state of liver dysfunction found in the majority of patients who undergo singleventricle palliation. PAH Pulmonary arterial hypertension: Elevated blood pressure in the pulmonary vasculature. PDA Patent ductus arteriosus: A fetal blood vessel connecting the pulmonary artery to the descending aorta. VSD Ventricular septal defect: A communication between the atria resulting from incomplete formation of the interventricular septum.

Introduction Congenital heart disease (CHD) is a term used to describe structural malformations of the heart and/or great vessels present since birth. CHD is the most common major birth defect present in approximately 8/1000 live births (Bernier et al., 2010; Marelli et al., 2014; Shuler et al., 2013). The term CHD has been used for decades and is generally accepted in reference to children, as prior to the past few decades, few palliative/surgical options were available that permitted survival into adulthood. In the past 50 years significant advances in medical, surgical, and interventional treatments have changed the face of CHD. There are now more adults living with CHD than children, making the field of adult congenital heart disease (ACHD) a relatively new subspecialty that focuses on the unique care needs of the adult patient who has survived with CHD. Adults with CHD vary in their presentation to the healthcare system, with many asymptomatic to those with significant cardiovascular disease including late sequelae from the original CHD anatomy and/or repair. Commonly, these patients may experience heart failure, arrhythmia including malignant variants, and extracardiac involvement. Each ACHD patient has unique needs reflective of underlying anatomy, prior surgical

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procedures, catheter interventions, and other comorbid disease. Heterogeneity in any of these factors contributes to the complex care that this special population requires.

Etiology There is no readily identifiable precise cause of CHD. However, there are some important associations with CHD. For instance, maternal infections such as rubella are associated with increased risk of CHD in the fetus. Pregnant women with diabetes mellitus, whether gestational or pregestational, are known to have fetuses with higher rates of CHD (Simeone et al., 2015). Some medications are associated with increased risk of CHD: isotretinoin, lithium, anticonvulsant medications, folic acid antagonists, and thalidomide among others (Ruedy, 1984). Genetics, and more specifically cardiogenetics, is an evolving field. While there are no universal known genetic associations with CHD, research has shown that CHD can result from: single-nucleotide polymorphisms, microdeletions, duplications, single-gene mutations, and aneuploidy (Fahed et al., 2015; Emer et al., 2015; Su et al., 2016). Trisomy syndromes are relatively common; for instance, Trisomy 21 (Down's syndrome) is associated with midline defects involving the endocardial cushions such as partial and complete atrioventricular septal defects. Meanwhile, specific genetic mutations in TBX5, NKX2-5, TLL1, and others have been associated with other CHD lesions. Regardless of the cause, once the alteration in normal embryologic development is sustained, CHD can result.

Embryology To understand CHD, one must have a brief understanding of the embryologic basis of cardiac development. Errors at any of the steps in normal cardiovascular development may lead to CHD or even fetal demise. Cardiogenesis is dependent on multiple transcription factors and proteins interacting at specific times and locations throughout gestation and still is not completely understood. Cells destined to become cardiac structures are identified as early as 15 days and form a cardiac tube at approximately 21 days gestation. It develops into a sinus venosus structure, which ultimately forms atria, which receive venous structures as well as multiple primitive structures (Fig. 1). Over the following week, the bulboventricular region separates from the primitive atrium and ventricle, and the endocardial cushion forms and fuses dividing the atrioventricular canal into two segments. Around the same time, a septum forms in the primitive atrium both from the endocardial cushions and also from the ventral wall of the ostium primum. Also, the primitive ventricle undergoes septation via a distinct series of events, which lead to left and right ventricles forming side-byside. The interventricular septum has contributions from neural crest cells of the endocardial cushion, the bulboventricular flange, and the inferior edge of the spiral septum of the conotruncus, which is the outflow chamber for the primitive ventricles. The conotruncus undergoes spiral septation allowing the aortic valve to move posteriorly to the left ventricle and the pulmonary valve to align with the anterior right ventricle. This series of developmental folds and morphologic relationships form the structurally recognizable normal anatomic heart and great vessels.

Fig. 1 Schematic of cardiac morphogenesis. Illustrations depict cardiac development with color coding of morphologically related regions, seen from a ventral view. Cardiogenic precursors form a crescent (left-most panel) that is specified to form specific segments of the linear heart tube, which is patterned along the anterior–posterior axis to form the various regions and chambers of the looped and mature heart. Each cardiac chamber balloons out from the outer curvature of the looped heart tube in a segmental fashion. Neural crest cells populate the bilaterally symmetrical aortic arch arteries (III, IV, and VI) and aortic sac (AS) that together contribute to specific segments of the mature aortic arch, also color coded. Mesenchymal cells form the cardiac valves from the conotruncal (CT) and atrioventricular valve (AW) segments. Corresponding days of human embryonic development are indicated. A, atrium; Ao, aorta; DA, ductus arteriosus; LA, left atrium; LCC, left common carotid; LSCA, left subclavian artery; LV, left ventricle; PA, pulmonary artery; RA, right atrium; RCC, right common carotid; RSCA, right subclavian artery; RV, right ventricle; V, ventricle.

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Nomenclature There are multiple systems of nomenclature to describe CHD, and none of them is universally accepted. Herein we will use the presence of cyanosis at birth (saturation 85%) as the initial delineation (cyanotic vs acyanotic lesions). An acyanotic lesion is typically the result of an obstructive lesion or a left-to-right shunt. Among cyanotic lesions, a right-to-left shunt must be present. For the interested reader, complex nomenclature practices can be reviewed (Anderson et al., 1984; Van Praagh, 1972).

Acyanotic Lesions Obstructive lesions Obstructive lesions include those affecting the right ventricular outflow tract such as pulmonary stenosis, and those affecting the left ventricular outflow tract, such as aortic stenosis (subvalvular, valvular, and supravalvular) and coarctation of the aorta (CoA). By definition, obstructive lesions restrict forward flow of blood. Symptoms are largely dependent on the location and severity of obstruction. Pulmonary stenosis is among one of the most common types of CHD, and it is variable in its pathology, occurring below, at, or above the valve level. Pathology varies and can include valvular dysplasia and/or doming of the pulmonary valve leaflet due to abnormal coaptation and valve function. Depending on the extent of obstruction, atrial level shunting may occur if an interatrial communication persists. If this is the case, oxygen saturation may be affected until the obstruction is palliated. Commonly, even after palliation, poststenotic dilation of the main pulmonary artery is seen. In left ventricular outflow tract obstruction pathology is similar and can occur below, at, or above the valve level. Valvular pathology can include unicupsid, bicuspid, tricuspid, and quadricuspid aortic cusp variants with or without valvar dysplasia. Like pulmonary stenosis, poststenotic dilation commonly is seen (here of the aorta). Discrete and long-segment CoA subtypes may influence the type of intervention timing as well as age of presentation (including whether or not there is a well-developed spinal arterial system and dependent upon the presence of collateral blood vessels) (Fig. 2). Blood flow inferior to the diaphragm is

Fig. 2 Coarctation of the aorta is demonstrated here and represents an obstructive lesion of the aorta, which affects distal blood flow.

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compromised by this lesion when the patent ductus arteriosus (PDA) closes, and collateralization occurs to supply blood distal to the level of obstruction. The proximal segment is sometimes dilated and is exposed to increased blood pressure while the distal segment is often diminutive because of decreased flow and with subsystemic pressure. It is not uncommon for adults to present with CoA undiagnosed. They typically have few if any symptoms, and the only finding may be hypertension.

Left-to-right shunts Atrial septal defects (ASDs) constitute the most common ACHD lesion and occur when there is a defect in the septum between the atria. There are four major types, and all of them lead to varying degrees of the same shunting physiology (Fig. 3). ASDs typically lead to volume overload of the right atrium and ventricle. Over decades this volume-loading lesion may lead to elevated right-sided pressure and resistance, and in a minority of patients pulmonary arterial hypertension (PAH) may occur. Ventricular septal defects (VSDs) are another common type of intracardiac shunt. Given the embryologic origin of the ventricular septum, a VSD can form in several locations. Commonly VSDs are seen in the membranous septum, which lies beneath the aortic valve. Other defect locations include: conal septum, adjacent to the tricuspid valve and within the muscular septum, and muscular septum (Fig. 4). Defects vary in size, number, and shape, making their physiology and anatomy strikingly disparate. Lesions can coalesce and atrioventricular canal defects occur when the endocardial cushions fail to fuse properly. This leads to failure of the mitral valve to form correctly, and a cleft in the left-sided atrioventricular valve is always present. PDA is the persistence of a fetal vessel called the ductus arteriosus, which normally involutes in the first few days after birth. It is an artery connecting the aorta to the pulmonary artery (Fig. 5). Its persistence is more commonly seen in premature infants but may be seen in full term infants as well. The muscular artery's persistence leads to variable outcomes. If tortuous and narrow, then it acts as a resistor and protects the pulmonary vascular bed; however, it may be broad and straight, which may lead to pulmonary overcirculation and/or PAH early in life.

Fig. 3 Atrial septal defect is demonstrated here and represents a deficiency in the atrial septum that permits shunting of blood at this level.

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Fig. 4 Ventricular septal defect (VSD) is demonstrated here and represents a deficiency in any area of the ventricular septum that permits shunting of blood at this level. Levels of shunting include subarterial VSD (1), membranous VSD (2), inlet VSD (3), and muscular VSD (4).

Fig. 5 Patent ductus arteriosus is demonstrated here and represents the continued existence of a fetal structure, which connects the aorta to the pulmonary artery.

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Cyanotic Lesions Cyanotic CHD requires the presence of right-to-left or deoxygenated-oxygenated blood shunting. This scenario may exist in the form of parallel circulations when two usually interdependent circulations do not distribute and receive blood from one another appropriately. Instead, they work in isolation and recirculate their own blood that each pumps out redundantly. Cyanotic CHD occurs in the presence of such parallel circulations, obstruction leading to decreased pulmonary blood flow, or mixture of arterial or venous blood. In the unrepaired state (typically infants), Tetralogy of Fallot is the most common scenario where right-to-left shunting of blood occurs. This pathology occurs because of anterior–superior deviation of the conal septum leading to the presence of a VSD, pulmonary stenosis, right ventricular hypertrophy, and overriding aorta (Fig. 6). Coronary artery anomalies are sometimes seen, which may complicate surgical repair. ASDs are often present, which may lead to further shunting depending on the degree of right ventricular diastolic dysfunction. Lesions associated with pulmonary valve atresia also lead to right-to-left shunting whether at the atrial or ventricular level. Another cause of cyanotic CHD is complete transposition of the great arteries, where the aorta and pulmonary artery insert into the right and left ventricles, respectively. This ventriculoarterial discordance leads to a complicated physiologic state in which oxygenated blood is recirculated to the lungs and deoxygenated blood recirculates within the body. ASDs and VSDs as well as the PDA serve as shunts to allow for oxygenation of deoxygenated blood and circulation of oxygenated blood. This serious condition is incompatible with prolonged survival without surgical intervention. Any adult seen with this condition in the unrepaired state has survived strictly from mixing of oxygenated and deoxygenated blood at any the level of remaining shunt. Finally, mixture of arterial and venous blood may lead to net deoxygenated blood. Some examples of this are: atrioventricular valve atresia concurrent with an unrepaired shunt, total anomalous pulmonary venous return, in some cases partial anomalous pulmonary venous return, arteriovenous malformations, and truncus arteriosus. In truncus arteriosus for instance, cardiac output from the left and right ventricles join in a common outflow artery, termed the truncus. The lung gets blood via pulmonary arteries that emanate from the truncus arteriosus and sometimes also by PDA. The lungs are exposed to high pressure and volume overload, making early surgical repair important for normal cardiopulmonary development and competence.

Fig. 6 Tetralogy of Fallot (TOF) is demonstrated here and is characterized by a series of findings, which occurs secondary to anterior deviation of the conal septum. It is exemplified by ventricular septal defect (1), pulmonary stenosis (2), aortic override (3) and right ventricular hypertrophy (4).

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Single-ventricle patients represent a unique subpopulation of those with ACHD. These patients can have a diverse array of underlying CHD but ultimately have a similar palliative plan. Whether the systemic or pulmonary output is compromised, the first stage of surgical palliation ensures adequate cardiac output for both systems, adequate venous blood admixture at the atrial level and the integrity of the aortic arch (Fig. 7A). The second stage, commonly called a Bidirectional Glenn procedure or Bidirectional cavopulmonary anastomosis, redirects some of the systemic venous blood directly to the pulmonary arteries while permitting deoxygenated infradiaphragmatic blood flow to return to the heart (Fig. 7B). Finally, in the third stage which is commonly referred to as the Fontan completion, the deoxygenated venous blood that had been returning to the heart is redirected to the pulmonary artery leading to a circuit with only one pump and passive pulmonary blood flow as is required without a subpulmonary ventricle (Fig. 7C). Late findings in the Fontan-palliated patient are similar despite underlying native anatomy. The current standard modification performed is the extracardiac Fontan procedure (Fig. 8). We are just beginning to learn of both the late-cardiac and

Fig. 7 The traditional three step palliation is demonstrated here. In A, the modified Blalock-Taussig-Thomas shunt is shown connecting the right subclavian artery to the right pulmonary artery along with an aortic arch reconstruction. In B, the superior vena cava is redirected to the pulmonary arteries and the BlalockTaussig-Thomas shunt is taken down. In C, the sub-diaphragmatic blood is redirected to passively drain into the pulmonary artery.

Fig. 8 Iterations of the third palliative surgery step are demonstrated here. The Classic Fontan was initially utilized with sub-diaphragmatic blood flowing only to the left lung and using the right atrium as a conduit. In the Atriopulmonary Fontan, the right atrial appendage is anastomosed directly to the main pulmonary artery. In the Lateral Tunnel Fontan, sub-diaphragmatic blood utilizes native right atrial tissue within the baffle as it ascends to the pulmonary artery. In the Extracardiac Fontan, a conduit is placed outside of the heart, which connects sub-diaphragmatic blood to the pulmonary artery.

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extracardiac manifestations that result from this surgical procedure, as the first patients surviving this operation typically had the procedure in the early 1970s (Van Praagh, 1972).

Treatment Prior to the 1950s, surgical interventions were not possible, and CHD was a harbinger of early death. However, with the advent of cardiopulmonary bypass, surgical interventions have become increasingly more complex and common. Since the 1960s, however, catheter interventions have been utilized and changed diagnosis and treatment of CHD (Rashkind and Miller, 1966). Since the 1970s, such procedures have eliminated the need for some open surgical procedures (King and Mills, 1974). Transcatheter interventions are multiple and the details of them are beyond the scope of this article. They may be used to relieve valvar obstruction, dilate blood vessels, place stents, insert devices to occlude septal defects, coil anomalous vessels, and insert new valves, among other procedures. The benefits of transcatheter interventions are several: avoidance of thoracotomy/sternotomy including effects on respiratory mechanics, no requirement for cardiopulmonary bypass and therefore offer neurologic protection and potentially avert late neurocognitive abnormalities and shorter hospitalization, among others. The ability to place valve homografts in the pulmonary and aortic positions has revolutionized the treatment of CHD specifically as it relates to transcatheter pulmonary valve utilization particularly in Tetralogy of Fallot. It would be expected that these types of interventions will continue to develop and improve, offering more patients procedural success for treatment of CHD. Surgical interventions for CHD are widespread and specific to the underlying type of CHD. Similar to transcatheter interventions, valvular interventions and septal defects may be intervened upon but in this case with direct visualization. Although percutaneous options are increasing, there are times where surgical intervention is preferred for precise repair, for example, when defect repair is in a location that intimately interfaces with the conduction system. Creation of shunts and placement of conduits largely remain procedures that require surgical intervention; however, newer percutaneous options are in study and may be on the horizon in the near future. Interventions on arteries and veins to ensure patency or redirect flow are also routinely preferentially performed surgically. Staged repairs over weeks to years are commonly utilized alone or in concert with transcatheter interventions, particularly in complex CHD such as the single-ventricle population. In the setting of dire circumstances, heart transplantation may be performed by congenital heart surgeons when other options are deemed too risky.

Cardiac Manifestations in ACHD ACHD patients face several cardiovascular problems as they age. This may be the result of residual congenital lesions, or a result of the surgical palliation performed in childhood. Congestive heart failure is not uncommon, and although tolerable in youth, over time the same pressure–volume relationships may not be as well tolerated (Engelings et al., 2016). There remains a paucity of data about use of traditional heart failure medications in the CHD population, and it remains an important area of research (Book and Shaddy, 2014; Gurvitz et al., 2016). Medications may slow down this progression but reversal may not be possible (Stout et al., 2016). CHD patients with valvular heart disease typically progress independent of CHD and can compound existing hemodynamic derangements. Arrhythmia is another late common cardiac problem for many CHD patients (Moore, 2014). These issues can arise from scar tissue secondary to the original repair, for instance, the ventriculotomy scar in Tetralogy of Fallot, or from the abnormal hemodynamic milieu. PAH is a dreaded complication of CHD and is known to affect overall survival (Manes et al., 2014; Dimopoulos et al., 2014). This occurs when the mean pulmonary artery pressure is  25 mmHg, pulmonary capillary wedge pressure is 15 mmHg, and pulmonary vascular resistance is >3 Wood units. One common way that PAH develops is from an unrepaired nonrestrictive shunt. In this condition, such as is the case with an unrepaired VSD, a shunt that once went left-to-right reverses to right-to-left secondary to the increased pulmonary vascular resistance. This condition is known as Eisenmenger's syndrome (ES) and is associated with increased mortality and several extracardiac manifestations of CHD (Dimopoulos et al., 2014).

Extracardiac Manifestations of ACHD ACHD patients have pathology extending beyond the cardiopulmonary system. For those who have single-ventricle physiology, the ingenious palliative Fontan operation has permitted survival into adulthood for those who otherwise might have died young; however, late problems in adulthood are commonplace (Hsu, 2015; Cohen et al., 2013). These patients typically remain at least mildly cyanotic and secondary erythrocytosis is common, as is coagulopathy. Peripheral skin and soft tissue changes, particularly in the legs, are frequent due to passive and often congestive systemic venous return via the Fontan circuit. Liver involvement is common, and in fact has its own unique term: Fontan-associated liver disease (FALD), because it is unlike other liver disease due to common mechanisms such as hepatitis or alcohol abuse. Nearly all adults with a prior Fontan will have histopathology consistent with liver fibrosis, if not cirrhosis (Pundi et al., 2016). Hyperenhancing liver nodules are not uncommon in the Fontan population, and there is an increased incidence of hepatocellular carcinoma compared to other types of CHD (Wells et al., 2016). Protein losing enteropathy may also occur in adulthood and is characterized by fluid retention, low albumin, and is generally poorly tolerated with no good treatment strategies available (Hsu, 2015).

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In patients who have ES or cyanosis from unrepaired CHD, there is hematologic dysfunction characterized by coagulopathy and increased bleeding risk (Tay et al., 2011). Secondary erythrocytosis is responsible for microthorombi formation and the increased cell turnover of this state can also lead to gout and cholelithiasis (Shiina et al., 2011). Despite having increased hemoglobin and hematocrit, iron deficiency is common and contributes to bleeding diatheses and reduced oxygen delivery (Tay et al., 2011). Renal dysfunction manifests as reduced glomerular filtration rate and proteinuria. Severe infections are also more common with ES, in particular, cerebral abscesses and infective endocarditis. ES is truly a multisystem disease, even though the initial insult is cardiac in nature. Other systemic problems that are frequently seen in ACHD patients include: orthopedic problems such as scoliosis, respiratory insufficiency/dysfunction typically in the form of restrictive lung disease commonly related to prior surgery, and renal dysfunction (Cohen et al., 2013; Fredriksen et al., 2001; Buelow et al., 2013). Many of these comorbid disease states are only beginning to be discovered, and we continue to evaluate their significance in this special population.

Conclusions In summary, CHD is a heterogeneous disease state, where variable presentation is affected not only by the initial lesion, but also by surgical repair, and the normal aging process. Adults with CHD are a unique group of patients that require specialized cardiac and extracardiac medical care. It is crucial that these patients are cared for by physicians with expertise in their type of cardiovascular disease.

References Anderson RH, Becker AE, Freedom RM, Macartney FJ, Quero-Jimenez M, Shinebourne EA, Wilkinson JL, and Tynan M (1984) Sequental segmental analysis of congenital heart disease. Pediatric Cardiology 5: 281–288. Bernier P, Stefanescu A, Samoukovic G, and Techervenkov CI (2010) The challenge of congenital heart disease worldwide: Epidemiologic and demographic facts. Seminars in Thoracic and Cardiovascular Surgery. Pediatric Cardiac Surgery Annual 13(1): 25–34. Book WM and Shaddy RE (2014) Medical therapy in adults with congenital heart disease. Heart Failure Clinics 10(1): 167–178. Buelow MW, Dall A, Bartz PJ, Tweddell JS, Sowinski J, Rudd N, Katzmark L, and Earing MG (2013) Renal dysfunction is common among adults after palliation for previous tetralogy of Fallot. Pediatric Cardiology 34(1): 165–169. Cohen SB, Ginde S, Bartz PJ, and Earing MG (2013) Extracardiac complications in adults with congenital heart disease. Congenital Heart Disease 8: 370–380. Dimopoulos K, Wort SJ, and Gatzoulis MA (2014) Pulmonary hypertension related to congenital heart disease: A call for action. European Heart Journal 35(11): 691–700. Emer CS, Duque JA, Muller AL, Gus R, Sanseverino MT, da Silva AA, and Magalhaes JA (2015) Prevalence of congenital abnormalities identified in fetuses with 13, 18 and 21 chromosomal trisomy. Revista Brasileira de Ginecologia e Obstetrícia 37(7): 333–338. Engelings CC, Helm PC, Abdul-Khaliq H, Asfour B, Bauer UMM, Baumgartner H, Kececioglu D, Diller GP, and Tutarel O (2016) Cause of death in adults with congenital heart disease— An analysis of the German National Register for Congenital Heart Defects. International Journal of Cardiology 211: 31–36. Fahed AC, Gelb BD, Seidman JG, and Seidman CE (2015) Genetics of congenital heart disease: The glass half empty. Circulation Research 112(4): 707–720. Fredriksen PM, Veldtman G, Hechter S, Therrien J, Chen A, Warsi MA, Freeman M, Liu P, Siu S, Thaulow E, and Webb G (2001) Aerobic capacity in adults with various congenital heart diseases. American Journal of Cardiology 87(3): 310–314. Gurvitz M, et al. (2016) Emerging research directions in adult congenital heart disease: A report from an NHLBI/ACHA Working Group. Journal of the American College of Cardiology 67(16): 1956–1964. Hsu DT (2015) The Fontan operation: The long-term outlook. Current Opinion in Pediatrics 27(5): 569–575. King TD and Mills NL (1974) Nonoperative closure of atrial septal detects. Surgery 75: 383–388. Manes AA, Palazzini M, Leci E, Bacchi Reggiani ML, Branzi A, and Galie N (2014) Current era survival of patients with pulmonary arterial hypertension associated with congenital heart disease: A comparison between clinical subgroups. European Heart Journal 35(11): 716–724. Marelli AJ, Ionescu-Ittu R, Mackie AS, Guo L, Dendukuri N, and Kaouache M (2014) Lifetime prevalence of congenital heart disease in the general population from 2000 to 2010. Circulation 130: 749–756. Moore JP (2014) Arrhythmia management of the adult patient with congenital heart disease: an update and analytical review. Minerva Pediatrica 66: 415–439. Pundi K, Pundi KN, Kamath PS, Cetta F, Li Z, Poterucha JT, Driscoll D, and Johnson JN (2016) Liver disease in patients after the Fontan operation. American Journal of Cardiology 117(3): 456–460. Rashkind WJ and Miller W (1966) Creation of an atrial septal defect without thoracotomy: A palliative approach to complete transposition of the great arteries. JAMA 196: 991–992. Ruedy J (1984) Teratogenic risk of drugs used in early pregnancy. Canadian Family Physician 30: 2133–2136. Shiina Y, Toyoda T, Kawasoe Y, Tateno S, Shirai T, Matsuo K, Mizuno Y, Ai T, and Niwa K (2011) The prevalence and risk factors for cholelithiasis and asymptomatic gallstones in adults with congenital heart disease. International Journal of Cardiology 152: 171–176. Shuler CO, Black GB, and Jerrell JM (2013) Population-based treated prevalence of congenital heart disease in a pediatric cohort. Pediatric Cardiology 34: 606–611. Simeone RM, Devine OJ, Marcinkevage JA, Gilboa SM, Razzaghi H, Bardenheier BH, Sharma AJ, and Honein MA (2015) Diabetes and congenital heart defects: A systematic review, meta-analysis, and modeling project. American Journal of Preventive Medicine 48(2): 195–204. Stout KK, et al. (2016) Chronic heart failure in congenital heart disease: A scientific statement from the American Heart Association. Circulation 133: 770–801. Su W, Zhu P, Wang R, Wu Q, Wang M, Zhang X, Mel L, Tang J, Kumar M, Wang X, Su L, and Dong N (2016) Congenital heart diseases and their association with the variant distribution features on susceptibility genes. Clinical Genetics 9: 349–354. Tay ELW, Peset A, Papaphylactou M, Inuzuka R, Alonso-Gonzalez R, Giannakoulas G, Tzifa A, Goletto S, Broberg C, Dimopoulos K, and Gatzloulis MA (2011) Replacement therapy for iron deficiency improves exercise capacity and quality of life in patients with cyanotic congenital heart disease and/or the Eisenmenger syndrome. International Journal of Cardiology 151: 307–312. Van Praagh R (1972) The segmental approach to diagnosis in congenital heart disease. In: Bergsma D (ed.) Birth defects original article series, 8(5), National Foundation—March of Dimes, pp. 4–23, Baltimore, MD: Williams & Wilkins. Wells ML, Fenstad ER, Poterucha JT, Hough DM, Young PM, Araoz PA, Ehman RL, and Venkatesh SK (2016) Imaging findings of congestive hepatopathy. 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Adverse Impact of Delayed Electrical Activation of the Heart and Benefits of Cardiac Resynchronization A Guha and EG Daoud, The Ohio State University, Columbus, OH, United States © 2018 Elsevier Inc. All rights reserved.

Introduction Adverse Hemodynamics of Broad QRS Left Bundle Branch Block Conduction Pattern Native left bundle branch block conduction Right ventricular pacing-induced LBBB Nonleft Bundle Branch Block Conduction Delay Right bundle branch block Non-specific interventricular conduction delay Benefit of CRT Alteration in Hemodynamics Alterations in Cellular Physiology Implantation of Biventicular Pacing System Left Ventricular Lead Placement Complications of CRT Clinical Trials of CRT Trials Enrolling NYHA Class III and Ambulatory Class IV With LV EF 120 bpm. Monomorphic VT is termed “nonsustained” if the rhythm lasts less than 30 s and “sustained” if it lasts
30 s A rapid heart rhythm (heart rate >100 bpm) originating from the ventricles with continuously varying QRS interval and morphology seen on electrocardiography. Polymorphic VT carries a risk of degeneration to VF. In patients with congenital long QT syndrome, this arrhythmia is referred to as torsades de pointes Disorganized electric activity throughout the ventricles that prevents coordinated ventricular contraction. The arrhythmia causes cardiac arrest and can be fatal if not rapidly reversed

SA, sinoatrial; AV, atrioventricular; bpm, beats per minute.

– When delivered into intrapericardial or intrapleural space, nonsustained monomorphic VT occurs in 8% of patients. – SVT has been documented when used alongside etoposide, and atrial fibrillation has been documented when used alongside a cyclin-dependent kinase inhibitor, but these were single occurrences. – Bradycardia has been reported in a single case report. Mechanism of action Alkylating agents prevent cell division by cross-linking DNA strands, generating abnormal base pairing, and inducing DNA strand breaks. They are known to cause acute perimyocarditis and heart failure syndromes, but arrhythmias can also result (Guglin et al., 2009). Arrhythmias are thought to arise from direct cardiotoxicity to myocytes and ischemic damage from coronary vasospasms and intracapillary microthrombi (Tamargo et al., 2015; Kupari et al., 1990).

Anthracyclines Arrhythmias • QT prolongation occurs in 11.5%–14.2% of patients with an average prolongation of 14–25 ms. • Eleven cases of polymorphic VT have been reported, and sudden cardiac death has resulted. • In one study, 15.2% of patients receiving doxorubicin developed SVT. • In one study, 12.1% of patients receiving doxorubicin developed nonsustained monomorphic VT. • In one study, 10.3% of patients receiving doxorubicin developed paroxysmal atrial fibrillation. • In one study, 3.4% of patients receiving doxorubicin developed bradycardia. • There is a case report of complete heart block requiring a pacemaker following doxorubicin therapy. Mechanism of action Anthracyclines inhibit DNA and RNA synthesis by intercalating between base pairs on nucleic acid chains and via topoisomerase binding, thereby preventing cell growth and division (Geisberg et al., 2012). In vitro doxorubicin administration causes arrhythmias in neonatal rat cardiomyocyte cultures (Lampidis et al., 1980), a phenomenon that is blocked by esmolol pretreatment, suggesting that anthracyclines impact beta-adrenoceptor-mediated changes in cardiomyocyte calcium gradients (Gorelik et al., 2003). Further, doxorubicin increases peak current through L-type calcium channels in rat cardiomyocytes (Keung et al., 1991) and inhibits sarcoplasmic reticulum function in rabbit cardiomyocytes (Earm et al., 1994). Action potential prolongation following doxorubicin administration has been demonstrated in vitro (Binah et al., 1983) and may be mediated by sarcoplasmic reticulum calcium leak and inhibition of rectifier potassium currents causing a delayed rise but increased peak intracellular calcium concentrations (Wang and Korth, 1995). Sarcoplasmic calcium-ATPase function is potently inhibited by doxorubicinol, a doxorubicin metabolite, in canine cardiac cells (Boucek et al., 1987).

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Antimetabolites Arrhythmias • 5-Fluorouracil – QT prolongation can occur, but malignant ventricular arrhythmias are rare and often occur in the setting of coronary ischemia or coronary vasospasm rather than directly mediated through the chemotherapeutic agent. – SVT occurred in 8.8% of patients in one study. – Sinus bradycardia occurs in 2.9%–12%. – Nonsustained monomorphic VT occurs in 3.7%–7.4% of patients. – Sustained monomorphic VT has been documented in a case report. – Atrial fibrillation has been documented in case reports, and incidence may approximate 2.9%. – AV block is limited to rare case reports. • Capecitabine and gemcitabine – There was a case of QTc prolongation from 413 to 492 ms followed by polymorphic VT. – There was a case of VF felt to be secondary to coronary vasospasm. – Atrial fibrillation/flutter was documented in 1.1% of patients treated with capecitabine and in occasional case reports following gemcitabine. Fludarabine • – Atrial fibrillation occurred in 6.1%, and atrial flutter occurred in 2.2% of patients who received fludarabine in preparation for hematopoietic stem cell transplantation. • Methotrexate – There have been isolated case reports of atrial fibrillation, bradycardia, and nonsustained monomorphic VT. Mechanism of action Antimetabolites are associated with coronary vasospasm mediated through either endothelial nitric oxide synthase-associated direct toxic effects on vascular endothelium or endothelium-independent protein kinase C-mediated vasoconstrictive pathway (Alter et al., 2006; Porta et al., 1998). Other proposed mechanisms include direct endothelial damage causing microvascular thrombus formation and interruption of myocardial cellular metabolism (Becker et al., 1999). The myocardial supply–demand mismatch theory is consistent with ECG findings of ST segment deviation or inversion, pathological Q waves, and decrease in QRS amplitude (de Forni et al., 1992; Tamargo et al., 2015).

Antimicrotubule agents Arrhythmias • Taxanes are associated with asymptomatic bradycardia in 2.9%–30%. • Nonsustained monomorphic VT has been reported with rates as high as 9.1%. • Sustained monomorphic VT, SVT, AV block, and atrial fibrillation are limited to rare case reports. • QT prolongation of 2–9 ms is associated with eribulin. Mechanism of action Antimicrotubule agents prevent cell division by directly interacting with tubulin to stabilize microtubules. They produce cardiotoxicity by reducing coronary flow via vasoconstriction, likely causing the observed conduction abnormalities (Alloatti et al., 1998). They also induce histamine release, which causes bradycardia and AV conduction delays (Rowinsky et al., 1993; Tamargo et al., 2015).

Arsenic trioxide Arrhythmias • QT prolongation occurs in 38%–100% and often exceeds a 60 ms increase. • Nonsustained monomorphic VT occurs in 17%–50% of patients. • There are at least five reported cases of polymorphic VT. Mechanism of action Arsenic trioxide increases cardiac calcium currents and reduces trafficking of the human ether-a-go-gorelated gene (hERG)-mediated rapid (Ikr) and slow (Iks) delayed rectifier potassium channels from the endoplasmic reticulum to the cell membrane (Ficker et al., 2004; Chiang et al., 2002; Drolet et al., 2004; Cubeddu, 2009).

Cytokines Arrhythmias • Interferons – Eight percent of patients receiving interferon alpha developed SVT, and 12% developed atrial fibrillation. – Nonsustained monomorphic VT occurred in 35% of patients receiving interferon gamma. – Sustained monomorphic VT and polymorphic VT are limited to case reports. • Interleukins – 9.9%–21.5% of patients receiving IL-2 developed arrhythmia, almost exclusively SVT. – Atrial fibrillation and ventricular arrhythmias are limited to rare case reports.

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Histone deacetylase inhibitors Arrhythmias • QTc prolongation of an average of 14.4 ms is reported. • Ventricular arrhythmias, atrial fibrillation, and SVT are limited to rare case reports. Mechanism of action Histone deacetylases modulate histone acetylation, which regulates DNA compaction and ultimately gene expression. Histone deacetylase inhibitors interfere with this process, thereby inducing cell cycle arrest, redifferentiation, and apoptosis (Cuni et al., 2017). The mechanism by which they cause arrhythmias is unclear.

Monoclonal antibodies Arrhythmias • Rituximab – 2.3% of patients developed bradycardia, and 1.5% developed atrial fibrillation. – Nonsustained monomorphic VT is limited to rare case reports. – Polymorphic VT occurred in one patient. • Trastuzumab – Sinus bradycardia is reported in 15% of patients, and syncope has resulted. • Alemtuzumab and nivolumab – Atrial fibrillation, sustained monomorphic VT, and AV block are limited to rare case reports.

mTOR inhibitors Arrhythmias • There is a case report of bradycardia in a liver transplant patient. • In adults, SVT is limited to one patient receiving tacrolimus. In the pediatric population, 22.7% of patients receiving tacrolimus had SVT, but these patients also received either azathioprine or mycophenolate mofetil. • QT prolongation has been demonstrated in multiple animal models, and there are case reports from transplant patients using mTOR inhibitors for immunosuppression. • Sustained monomorphic VT and polymorphic VT are limited to rare case reports. Mechanism of action Tacrolimus is a calcineurin inhibition, while sirolimus blocks IL-2 receptor-dependent signal transduction. Both bind FK-binding protein 12 (FKBP12). FKBP12 binds ryanodine receptors in the sarcoplasmic membrane, and this interaction stabilizes calcium currents in cardiomyocytes. Gene knockout or mutation of FKBP12.6 or the ryanodine receptor in mouse models exhibits diastolic sarcoplasmic calcium leaking, atrial fibrillation, and catecholamine polymorphic VT (Li et al., 2012; Sood et al., 2008; Jiang et al., 2010). Overexpression or stabilization of FKP12.6 protects against catecholamine polymorphic VT in mice (Vinet et al., 2012; Gellen et al., 2008; Lehnart et al., 2006). Impaired calcium trafficking may cause action potential prolongation and early after depolarizations (Fauconnier et al., 2005). The arrhythmogenic effects may also be caused by dysregulation of cardiomyocyte sodium currents (Maruyama et al., 2011).

Nonreceptor tyrosine kinase inhibitors Arrhythmias • Ibrutinib – Atrial fibrillation ranges in incidence from 5.1% to 10.7%. Often, the atrial fibrillation persists despite medical treatment. – Ibrutinib also causes platelet dysfunction, which complicates thromboembolic prophylaxis of atrial fibrillation (Yun et al., 2017; Vrontikis et al., 2016). • Ribociclib – QTc prolongation occurred in 9% of patients at 600 mg/day dosing and 33% of patients at >600 mg/day dosing. Mechanism of action The increased risk of atrial fibrillation in ibrutinib use is thought to be due to decreased phosphoinositide 3-kinase (PI3K)-Akt activity as a result of Bruton tyrosine kinase and tec protein tyrosine kinase inhibition (McMullen et al., 2014). Ribociclib is a cyclin-dependent kinase 4/6 inhibitor (Infante et al., 2016).

Proteasome inhibitors Arrhythmias • Bradycardia was reported in 2.9% of patients. • Atrial fibrillation was reported in 2.9% of patients. • AV block, atrial fibrillation, and SVT are limited to rare case reports. Mechanism of action Bortezomib is a 26S proteasome inhibitor used to treat multiple myeloma. By upregulating the adrenergic GRK2, bortezomib may be protective against malignant ventricular tachyarrhythmias in the setting of myocardial ischemia (Yu

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et al., 2005; Huang et al., 2008). However, in the absence of myocardial ischemia, this same mechanism may predispose to bradyarrhythmias and AV conduction abnormalities (Enrico et al., 2007).

Thalidomide and analogs Arrhythmias • Bradycardia occurs in 12%–53% of patients with several requiring pacemaker implantation. • QT prolongation and AV block are limited to rare case reports. Mechanism of action Sinus bradycardia is likely mediated by inhibition of dorsal motor neurons by reduced TNF-a levels (Palumbo et al., 2008; Hinterseer et al., 2006). Coronary artery spasm is a less frequently proposed mechanism (Ali et al., 2013).

Topoisomerase inhibitors Arrhythmias • Topoisomerase I inhibitors – Atrial fibrillation was reported in 9.5% of patients receiving irinotecan, but they also received carboplatin and paclitaxel. – Sustained monomorphic VT and bradycardia are limited to rare case reports. • Topoisomerase II inhibitors – QT prolongation of an average of 64 ms has been reported but resolved within 24 h of infusion. – There are 31 cases of ventricular arrhythmia-associated cardiopulmonary arrest occurring within four hours of amsacrine (AMSA) infusion, 14 of which being fatal. – The majority of cases of VF occurred in the setting of profound hypokalemia. Mechanism of action Irinotecan may cause bradycardia by transient noncompetitive inhibition of acetylcholinesterase (Dodds and Rivory, 1999; Miya et al., 1998). Though amsacrine may not directly reduce potassium levels, it does cause acute hypomagnesemia (Seymour, 1993) and blocks cardiac hERG-mediated rectifier potassium currents (Thomas et al., 2004).

Tyrosine kinase inhibitors Arrhythmias • QT prolongation has been associated with cabozantinib, ceritinib, crizotinib, dasatinib, erlotinib, gefitinib, imatinib, lapatinib, nilotinib, osimertinib, sorafenib, sunitinib, vandetanib, and vemurafenib. • The most pronounced QT prolongation has been associated with vandetanib (36.4 ms), nilotinib (25.8 ms), lapatinib (23.4 ms), and sunitinib (22.4 ms). • VF has been associated in a case report with vandetanib. • Bradycardia is common following crizotinib with incidence reaching 42%–69%. The average decrease in heart rate is approximately 25 bpm, and patients can have severe bradycardia with heart rates less than 45 bpm. Mechanism of action Tyrosine kinase inhibitors reduce hERG phosphorylation and in turn inhibit rectifier potassium currents (Zhang et al., 2003, 2008, 2012; Barros et al., 1998; Davis et al., 2001). However, downregulation of PI3K also cause decreased L-type calcium current, decreased peak sodium ion current, and increased persistent sodium current (Lu et al., 2012).

QT Monitoring The QT interval is used as a surrogate for risk of polymorphic VT, and drugs that prolong the QT interval are felt to increase risk. There is not a consensus definition of QTc prolongation, but the most common definition is QTc >450 ms in men, >470 ms in women, or an increase of 60 ms from baseline (Yusuf et al., 2008). Polymorphic VT almost always occur in patients with a QTc of
500 ms, but the true association between QTc duration and risk of malignant arrhythmia is unknown (Piekarz et al., 2006; Bednar et al., 2002) as there are no trials assessing the correlation between QTc interval and patient outcomes (Strevel et al., 2007). Further, there are medications associated with polymorphic VT that do not significantly lengthen the QT interval (Morganroth, 1993). Drug-induced QT prolongation is almost always caused by blockade of hERG association rectifier potassium outflow channels, but not all medications that block hERG potassium channels cause significant QT prolongation (Sanguinetti and Mitcheson, 2005). Prior to testing for QTc prolongation in clinical trials, several preclinical experiments are performed using animal models and in vitro assays using nonhuman cells transfected with hERG (Sharma et al., 2017). The latest innovations in development involve human-induced pluripotent stem cells. Patient-specific hiPSCs can be induced to differentiate into cardiomyocytes, endothelial cells, and cardiac fibroblasts (Fig. 1). These cells can be used for in vitro studies on chemotherapy-associated cardiomyopathy and high-throughput cell contractility assessments. The results from these analyses can then be used to develop cardiac safety indexes for chemotherapeutic agents (Sharma et al., 2017). The 2005 International Conference on Harmonization E14 guideline advised clinical QT prolongation evaluation of all nonantiarrhythmic drugs seeking approval at up to maximally tolerated dosing (Food and Drug Administration HHS, 2005; Shah, 2005). The participants for these trials were intended to be healthy volunteers with normal baseline ECG, but given the

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Fig. 1 Using hiPSC-CMs made from somatic tissue samples. hiPSCs were differentiated into hiPSC-CMs, hiPSC-ECs, and hiPSC-CFs. Purified cardiomyocytes were treated with TKIs and examined for alterations in cell viability, contractility, cellular signaling, and gene expression. Reproduced from Sharma, A., Burridge, P. W., Mckeithan, W. L., Serrano, R., Shukla, P., Sayed, N., Churko, J. M., Kitani, T., Wu, H., Holmstrom, A., Matsa, E., Zhang, Y., Kumar, A., Fan, A. C., Del Alamo, J. C., Wu, S. M., Moslehi, J. J., Mercola, M. and Wu, J. C. (2017). High-throughput screening of tyrosine kinase inhibitor cardiotoxicity with human induced pluripotent stem cells. Science Translational Medicine 9, 377.

adverse effects of chemotherapy, it would not be ethical to carry out such studies on cancer medications in healthy patients. Instead, clinical trials are used to evaluate for drug-induced QTc prolongation in chemotherapies (Shah et al., 2013; Rock et al., 2009; Morganroth et al., 2010; Shah and Morganroth, 2012). Individuals with cancer have higher incidence of baseline QT prolongation (Varterasian et al., 2003, 2004; Cuni et al., 2017; Naing et al., 2012), receive additional QT-prolonging medications (Yusuf et al., 2008; Piekarz et al., 2006), and frequently have electrolyte abnormalities. Treatment regimens often include multiple chemotherapeutic agents at a time, making it difficult to determine which agent is responsible for a given outcome or effect (Tamargo et al., 2015). Thus, evaluating the propensity for chemotherapeutic agents to prolong the QTc interval is less straightforward than evaluating in other clinical settings. The clinical trials used to assess QT prolongation in chemotherapies likely underestimate rare adverse events due to limited sample size and short follow-up times. Postmarketing safety reporting can improve awareness of rare adverse events, but there is no ICD-10 code for QT interval prolongation (Schwartz and Woosley, 2016). Further, only symptomatic cases are reported, and such reports do not include total number of patients receiving medications, so frequency estimations are impossible (Cuni et al., 2017; Tuccori et al., 2015).

Prevention and Management of QT Prolongation There are multiple mechanisms in place to counteract repolarization abnormalities; thus, QT prolongation is only thought to occur when compensatory mechanisms are impaired. Prevention of QT prolongation centers around minimization of factors that deplete this repolarization reserve (Cuni et al., 2017). Careful family history can suggest congenital long QT syndromes and cardiac risk factors. Laboratory evaluation identifies electrolyte abnormalities that should be corrected, especially hypokalemia and hypomagnesemia. Renal and hepatic insufficiencies are important considerations when considering the pharmacokinetics of a given chemotherapy. Medication reconciliation must be performed to identify concomitate medications that predispose to electrolyte disturbances (such as diuretics) or cause QT prolongation (antiarrhythmics, antibiotics, antifungals, antidepressants, antipsychotics, antiemetics, and antihistamines) (Cuni et al., 2017). The QT interval should be monitored while administering medications with QT prolonging potential, and these medications should be infused slowly. Uvelin et al. and Tisdale have developed algorithm for management of patients with prolonged QT, which is adapted and presented in Table 3 (Uvelin et al., 2017; Tisdale, 2016). When polymorphic VT does occur, the algorithm in Table 4 should be implemented promptly to terminate the arrhythmias and prevent degeneration into VF.

170 Table 3

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1. Assess the risk for arrhythmia occurrence on admission – Measure the QT interval on ECG using Bazett's formula or QT nomogram – Corrected QTc >500 ms carries significant risk of polymorphic VT – If there is a prolonged QTc, what is the likely cause of this? Look at ○ Patient characteristics ○ Usage of medication prolonging the QT interval 2. Assess the risk for arrhythmia occurrence daily in patients with known risk factors – Compare QTc on admission to subsequent days – Compare QTc before and after administration of drugs that potentially prolong QT interval 3. Avoid coadministration of two or more medications that prolong QTc 4. Avoid the use of QTc interval-prolonging drugs in patients with QTc >450 ms 5. Avoid the use of QTc-prolonging drugs in patients with heart failure and left ventricular ejection fraction 4.0 mmol/L 12. Patients with known congenital long QT syndrome—same guidelines. These patients should be on a regular b1 adrenergic receptor antagonist Source: Uvelin A, Pekakovic J, Mijatovic V. J Anesth. 2017 Feb 22; Tisdale J. Can Pharm J (Ott). 2016 May; 149(3): 139–52.

Table 4

Therapeutic options for polymorphic VT

1. 2. 3. 4.

Identify and stop the offending agent immediately Call for help If hemodynamically unstable, defibrillate patient If hemodynamically stable, administer magnesium sulfate – 1–2 g intravenously administered over 15 min with continuous ECG monitoring – Can repeat dosing twice – Maintain magnesium levels >1 mmol/L 5. Consider lidocaine administration – Bolus 1–1.5 mg/kg body weight – Follow with 2 mg/h continuous intravenous infusion 6. Increase heart rate if bradycardia is present – Isoproterenol 2–10 mcg/min continuous intravenous infusion or temporary overdrive electric pacing – In congenital long QT interval syndrome, use temporary overdrive electric pacing 7. If no bradycardia and persistent polymorphic VT following magnesium, defibrillate patient Source: in A, Pekakovic J, Mijatovic V. J Anesth. 2017 Feb 22; Tisdale J. Can Pharm J (Ott). 2016 May; 149(3): 139-52.

Radiation-Induced Arrhythmia Risk of Arrhythmia Radiation therapy has become more precise over time allowing for lower doses and reduced risk for long-term adverse effects (Specht et al., 2014). Despite this, arrhythmias are still a known late adverse effect of mediastinal radiation therapy. In 703 patients with Hodgkin’s lymphoma and a mean follow-up of 9 years, 16% had an arrhythmia. Most of these patients, however, also received anthracyclines, vinca alkaloids, or both (Maraldo et al., 2015). In cancers with worse prognosis, higher radiation dose can be used as risk of late adverse effects is less of a concern. In 112 patients receiving radiation therapy for stage III non-small-cell lung cancer, atrial fibrillation/flutter occurred in 8.9% patients. This population received a high heart dose (mean 20 Gy) deemed acceptable due

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to expected prognosis of less than 2 years (Wang et al., 2017). There are multiple studies evaluating the association between heart radiation dose and cardiovascular adverse effects, but these center more on common sequelae such as myocardial infarction, heart failure, pericarditis, or valvular heart disease than on arrhythmias (Hancock et al., 1993; Hooning et al., 2007; van Nimwegen et al., 2015).

Radiation and CIEDs Radiation can cause CIED malfunction via direct irradiation to the device (Hurkmans et al., 2005a,b; Mouton et al., 2002; Rodriguez et al., 1991; Brambatti et al., 2015), indirectly due to scattered radiation of neutrons produced by the linear accelerator (Zecchin et al., 2016), or electromagnetic interference from the linear accelerator and betatrons (Brambatti et al., 2015; Makkar et al., 2012; Solan et al., 2004; Marbach et al., 1978; Yerra and Reddy, 2007). The degree of device malfunction varies from temporary changing to interference or safety mode during the radiation therapy session, persistent change to interference or safety mode requiring device reprogramming, to total device failure with cessation of pulse generation (Souliman and Christie, 1994). Radiation therapy causes device malfunction both in vitro (Zaremba et al., 2014) and in porcine model (Zaremba et al., 2013). In a study of 560 patients with CIED undergoing radiation, Zaremba et al. reported the annual rate of radiation treatment in this population increasing by 199% between 2003 and 2012. In device evaluations after radiation, pacemaker malfunction was 2.5%, while ICD malfunction was 6.8% with the majority of malfunctions being electric resets. There were no life-threatening events or device removals (Zaremba et al., 2015). Brambatti et al. evaluated 261 patients with CIEDs receiving radiation and reported 14.6% requiring device reprogramming and 3.4% undergoing device repositioning to the contralateral side. Three patients experienced inappropriate ventricular pacing, and one patient had a power-on reset of the device (Brambatti et al., 2015). In 69 patients with CIEDs receiving radiation, Makkar et al. reported two patients with resets of ICD with loss of historic diagnostic data, but there were no cases of device malfunction or premature battery depletion over the 6-month follow-up (Makkar et al., 2012). Predictors of CIED malfunction include high beam energy (
15 MV), neutron-producing radiation, and abdominal/pelvic radiation, while CIED radiation dose does not predict device malfunction (Grant et al., 2015; Zaremba et al., 2015). Device malfunction risks during radiotherapy are summarized in Table 5 (Viganego et al., 2016). Due to perceived association of CIED radiation dose and increased risk for device malfunction, there are institution-based standard guidelines currently used to determine when a device should be relocated (Brambatti et al., 2015; Makkar et al., 2012). International guidelines express similar concern about this potential link (in particular when receiving 10 Gy radiation to the CIED or when there is high pacing dependence) and advocate for consideration of device relocation (Hurkmans et al., 2012; Salerno et al., 2016). However, there are trials reporting no association between incident CIED radiation dose and device malfunction and advocate against device relocation (Grant et al., 2015). Further, various guidelines recommended safe radiation dose limits that differ significantly and thus are unreliable (Hudson et al., 2010). With limited available data and the lack of consensus between different guidelines, the decision on whether to relocate a CIED should be multidisciplinary – including cardiologists and oncologists combined input – and on a patient-specific basis (Carrillo, 2012; Zaremba et al., 2016). Manufacturer-based recommendations on RT in patients with a CIED are summarized in Table 6 (Viganego et al., 2016), and a patient-specific recommendation based on risk stratification is summarized in Table 7 (Viganego et al., 2016).

Table 5

Cardiac implantable electronic device complications due to RT

Type of CIED failure

Frequency

Permanent damage Early battery depletion Temporary loss of sensing Transient oversensing or EMI Temporary pacing inhibition Temporary loss of capture Temporary increase in pacing thresholds Very rapid pacing Temporary increased sensor rate or change in pacing rate Power-on reset or revision to safety mode Increase battery charge time, decreased shock energy Complete CIED failure (the loss of output/sensing)

Rare Rare Uncommon Uncommon Uncommon Rare Uncommon Very rare Common Common, especially if neutron-producinga Rare, described at radiation dose above recommended tolerance Rare, described at radiation dose above recommended tolerance

RT, radiotherapy; EMI, electromagnetic interference; CIED, cardiac implantable electronic device. a High-energy beam (>10 MV photons). Source: Viganego F, Singh R, Fradley MG. Curr Cardiol Rep. 2016 Jun; 18(6): 52.

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Table 6

Primary CIED manufacturer recommendations on device management during RT

Manufacturer Recommendation for RT Estimate radiation dose Cumulative radiation dose limit Shielding

Boston Scientific (Scientific, 2012)

Medtronic (Medtronic, 2013)

St. Jude Medical (Medical, 2013)

Yes

Yes

Yes

PPM ICD

None None

Nonea Nonea

CRT-D

None Yes

All models, 5 Gy 1 Gy; recent models, 3–5 Gy All CRT-D models, 5 Gy No protection against neutrons Yes

Position CIED outside RT beam Level of monitoring Programming considerations

Yes Patient-specific PPM ICD/CRT-D

Assessment of CIED after RT is completed Remote monitoring

Use device-based telemetry. Consider asynchronous pacing if PPMdependent Deactivate tachy therapy or place magnet on CIED Yes, detailed CIED evaluation Yes, LATITUDEW when available

Evaluate marker channel during initial RT session Consider asynchronous pacing if PPMdependent Deactivate tachy therapy or place magnet on CIED Yes, check for device resetb Not mentioned

Nonea Not mentioned Yes ECG monitoring advised Consider asynchronous pacing if PPMdependent. Turn sensor to OFF or PASSIVE for rate adaptive PPMs Deactivate tachy therapy or place magnet on CIED Yes, detailed CIED evaluation Not mentioned

CIED, cardiac implantable electronic device; RT, radiotherapy; PPM, permanent pacemaker; ICD, implantable cardiac defibrillator; CRT-D, cardiac resynchronization therapy defibrillator; Gy, gray; ECG, electrocardiography. a Manufacturer reports that current devices have been tested up to 30 Gy without adverse effects, but testing was not performed with high-dose sources such as linear accelerators. b For ICD or CRT-D patients, if alert tone is heard after placing a magnet over CIED, electric reset has occurred, and device should be checked. For PPM patients, if pacing rate is 65 bpm after placing a magnet over CIED, electric reset has occurred. Source: Viganego F, Singh R, Fradley MG. Curr Cardiol Rep. 2016 Jun; 18(6): 52.

Table 7

Recommendations on CIED management in patients undergoing RT

Recommendations based on risk level of patient General recommendations General

Definition

Before RT initiation

During RT

– – – – – – –

Low-risk patient

Avoid CIED in direct RT beam RT dose to PPM 2 Gy RT dose to ICD 0.5 Gy Inform pt of risks Review manufacturer records Avoid high-energy (>10 MV) beam Avoid neutron-producing beam CIED dose 90%) and the circuit uses the SP anterogradely and the FP retrogradely. In this type of AVNRT, induction is dependent on achieving a critical AH interval. It means that the antegrade conduction down the SP should be slow enough that allows for recovery of the FP to conduct retrogradely (Fig. 3). In the EP lab, this can be achieved with atrial extrastimuli testing or atrial burst pacing near the Wenckebach CL (Fig. 6). If this cannot be achieved, stimulation under infusion with isoproterenol may be required. During tachycardia, the EARA (via FP) is usually localized in the anterior septum which is recorded by the electrodes at the HB. However, posterior or even left sided EARA may occur in up to 8% of the patients (Fig. 7) (Chen et al., 2004; Nam et al., 2006). The EARA appears slightly before, at the onset, or just after the QRS complex thus maintaining AH/HA ratio >1. Most important, the HA interval is typically 70 ms with a most common EARA at proximal CS. JT is ruled out since the HA is 45%, NT-proBNP was found to be one of the strongest independent variables for all-cause mortality (Komajda et al., 2011). Use of NPs to guide management in patients with HFpEF remains uncertain, as only a small percentage of patients with HFpEF were included in clinical trials (Troughton et al., 2014b) and guideline-based therapies for HFpEF are yet to be established.

Troponin Biology The troponins are proteins that help regulate contraction of both cardiac and skeletal muscle. The cardiac troponin unit is composed of troponin I, troponin T, and troponin C. Troponin I and troponin T are found in two locations in the cardiomyocyte: a small percentage can be found in the cytoplasmic pool, but the majority is located in the contractile apparatus. Troponin is most commonly used to detect cardiomyocte injury in the setting of suspected acute coronary syndrome, for which it is highly sensitive and specific (Thygesen et al., 2012). The sensitivity of troponin assays continues to increase and the most current generation of

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high-sensitivity assays are employed in multiple parts of the world, and have recently been approved in the United States. In addition to their application for acute coronary syndrome, elevated troponin concentrations can also be found in HF for which multiple proposed etiologies exist, including cardiomyocyte necrosis due to increased wall stress, epicardial coronary artery disease, or even direct injury from neurohormones and inflammatory markers (Januzzi et al., 2012; Kociol et al., 2010).

Diagnosis Troponin is not used to diagnose HF, but acutely decompensated HF can be present in the setting of an acute coronary syndrome. If an elevated troponin concentration is found, it is imperative to determine the etiology as it may drastically change management, particularly if the elevated concentration is due to a type I myocardial infarction involving plaque rupture (Januzzi et al., 2012).

Prognosis Although troponin does not possess a significant role for diagnosis of HF, troponin measurement has established utility for prognosis. The ACC/AHA guidelines have assigned a class I recommendation in acutely decompensated HF and class IIb for chronic HF for the purpose of prognostication (Yancy et al., 2017). In patients hospitalized with acutely decompensated HF from the Acute Decompensated HF National Registry (ADHERE) database, 6.2% were found to have a troponin concentration that was deemed positive by a conventional assay. Those with an elevated concentration had a significantly higher rate of in-hospital mortality compared to those without an elevated concentration (8.0% versus 2.7%, P < 0.001) (Peacock et al., 2008). With high-sensitivity assays, nearly all patients with acute HF have measurable concentrations (Pascual-Figal et al., 2012), and higher concentrations are independently associated with worse prognosis, including cardiovascular mortality or death from HF (Felker et al., 2015). In patients with chronic HF from the Valsartan HF Trial (Val-HeFT), troponin was detected in 10.4% and 92% of the patients using both a conventional and highly sensitive assay, respectively. Elevated concentrations were found to be predictive of mortality and HF hospitalization; moreover, addition of highly sensitive troponin improved prognostication in risk prediction models (Latini et al., 2007). Finally, serial measurements of high-sensitivity troponin were also examined for prognostic value, and increasing concentrations over time were associated with an increase in all-cause mortality (Masson et al., 2012).

Management To date, no studies have specifically investigated the use of troponin to manage HF. However, troponin concentrations have been measured in various therapy trials and have found increased concentrations with use of omecamtiv mecarbil (Teerlink et al., 2016) and decreased concentrations with serelaxin (Metra et al., 2013) and valsartan/sacubitril (LCZ696) (Packer et al., 2015), but the significance of these changes remains unclear until further investigations are undertaken.

Preserved EF Similar to the NPs, concentrations of troponin tend to be lower in those with preserved EF compared to those with reduced EF (Santhanakrishnan et al., 2012), and troponin concentrations appear to have similar prognostic value in both types of HF (Sandersvan Wijk et al., 2015). Furthermore, in patients admitted with acutely decompensated HFpEF, troponin elevation was recently found to be independently associated with worse in-hospital and postdischarge outcomes (Pandey et al., 2016). With regard to treatment, valsartan/sacubitril (LCZ696) was also shown to reduce high-sensitivity troponin concentration in patients with HFpEF (Jhund et al., 2014).

ST2 and Galectin-3 Biology Suppression of tumorigenicity 2 (ST2) and galectin-3 are emerging HF biomarkers. ST2 is a member of the IL-1 receptor family, and it has multiple forms including a transmembrane ligand (ST2L) and a soluble form (sST2) (Weinberg et al., 2002). It is a marker of myocardial strain (Weinberg et al., 2003), fibrosis, and remodeling (Sanada et al., 2007), and expression of the ST2 gene is triggered in response to myocyte and fibroblast strain (Weinberg et al., 2002). Galectin-3 is a member of the b-galactoside-binding lectin family that is found in macrophages and fibroblasts. It is associated with fibrosis of many organs, including the heart (Sharma et al., 2004).

Diagnosis ST2 and galectin-3 are not useful to assist with diagnosis of HF.

Prognosis Both sST2 and galetcin-3 have been investigated for risk stratification in acute and chronic HF. In patients presenting with shortness of breath in the PRIDE study, sST2 was significantly elevated in those with acutely decompensated HF compared to those with

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shortness of breath from other causes. Additionally, elevated sST2 was associated with an increased risk of mortality in adjusted analyses. Combination of sST2 with NT-proBNP identified subjects with the highest mortality risk (Januzzi et al., 2007). Another study examined multiple biomarkers in over 5000 patients with acutely decompensated HF, and sST2 was found to be among the strongest predictors of mortality when combined with clinical factors of risk prediction (Lassus et al., 2013). Galectin-3 has also been investigated for prognosis in acutely decompensated HF. In data from a recent pooled analysis of three studies examining patients with acutely decompensated HF, elevated galectin-3 concentrations were associated with increased rehospitalization and mortality at 30, 60, 90, and 120 days after discharge. After adjustment for relevant clinical factors and NP concentrations, galectin-3 remained a useful predictor of HF rehospitalization (Meijers et al., 2014). The prognostic utility of both sST2 and galectin-3 has also been investigated in patients presenting with chronic HF. Soluble ST2 was investigated in 1,114 patients with ambulatory HF, and patients with sST2 concentrations in the highest tertile had an increased risk of adverse events (adjusted HR 1.9, P ¼ 0.002) compared to those in the lowest tertile. When combined with NT-proBNP and added to a conventional risk model (Seattle Heart Failure Model), 15% of patients were reclassified into different risk categories (Ky et al., 2011). Serial sST2 concentrations were found to possess even stronger prognostic merit when compared to other markers, including NT-proBNP and high-sensitivity troponin T (Gaggin et al., 2014). Multiple studies have investigated the utility of galectin-3 for risk stratification in chronic HF. In a substudy of the HF: A Controlled Trial Investigating Outcomes of Exercise TraiNing (HF-ACTION) trial, elevated galectin-3 concentrations were associated with reduced HF hospitalization-free survival, but its prognostic value was not retained when adjusted for other clinical factors, particularly with inclusion of NP concentrations (Felker et al., 2012). Similar results have been found with other studies, and subsequently a head-to-head trial was conducted comparing sST2 with galectin-3 which demonstrated its modest prognostic value when compared to sST2 (Bayes-Genis et al., 2014). However, a recent meta-analysis that investigated patients with both acute and chronic HF revealed that a 1% increase in circulating galectin-3 concentrations was associated with a 28% increase in all-cause mortality and a 59% increase in cardiovascular mortality in models including both renal function and NT-proBNP (Chen et al., 2015). The ACC/AHA guidelines have assigned a class IIb recommendation for measurement in acutely decompensated HF and symptomatic chronic HF to assist with prognosis for both sST2 and galectin-3 (Yancy et al., 2017).

Management Although there have been no prospective studies examining sST2 or galectin-3 to guide management, there have been a number of important retrospective observations. There appears to be a reduction in sST2 concentrations with use of beta-blocker therapy (Gaggin et al., 2013) as well as with the angiotensin receptor blocker valsartan (Anand et al., 2014). Additionally, another study found an interaction between elevated sST2 concentrations and mineralocorticoid receptor antagonist therapy (Maisel et al., 2014). Similar observations have been found for galectin-3, but interestingly those with lower (rather than elevated) galectin-3 concentrations seem to benefit from treatment with rosuvastatin (Gullestad et al., 2012) or valsartan (Anand et al., 2013). Although experimental models have suggested a potential relationship between galectin-3-mediated fibrosis and aldosterone (Calvier et al., 2013), clinical studies have not found a significant therapeutic interaction (Gandhi et al., 2015a). Finally, targeted anti-galectin therapies are also being investigated in experimental models and have demonstrated attenuation of fibrosis (Yu et al., 2013). At this time, more evidence is needed before sST2 or galectin-3 can be applied to guide HF management.

Preserved EF Data regarding sST2 in HFpEF appear to be conflicting. One study investigating patients with acutely decompensated HF and preserved EF did not show predictive value with regard to outcomes at 6 months (Frioes et al., 2015), whereas another study showed sST2 was an independent predictor of mortality in patients with acutely decompensated HF regardless of EF (Manzano-Fernandez et al., 2011). Galectin-3 has also been examined in patients with HFpEF, and it was found to be independently prognostic in this patient population for mortality and HF hospitalization (de Boer et al., 2011). Furthermore, the aforementioned pooled analysis included subjects with HFpEF and also showed elevated galectin-3 concentrations were associated with risk of short-term hospitalization in these subjects as well (Meijers et al., 2014).

Future Directions The number of biomarkers that are being investigated continues to rapidly expand (Januzzi and Felker, 2013) raising questions regarding the optimal method to investigate and apply biomarkers to patient care. To date, the NPs remain the gold standard and have truly exemplified how a biomarker can aid in diagnosis, prognosis, management, and development of novel therapies. Given that each biomarker provides a different window into the pathophysiology of HF, it is possible that a multimarker strategy may be the most optimal approach (Allen and Felker, 2010). One study examined a multimarker panel (BNP, high-sensitivity C-reactive protein, myeloperoxidase, soluble fms-like tyrosine kinase receptor-1, troponin I, soluble toll-like receptor 2, creatinine, and uric acid) incorporating a variety of biological pathways in 1513 patients with HFrEF for risk stratification and found that addition of this panel to the Seattle HF model resulted in a significant improvement in prognostication (Ky et al., 2012). Prior to clinical adaptation of a multimarker strategy, demonstration of incremental benefit beyond existing clinical information and risk prediction models, therapeutic implication, and cost-effectiveness is imperative (Allen and Felker, 2010).

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Conclusion The use of biomarkers in HF is a rapidly expanding area of interest. The NPs remain at the forefront of this field with troponin, sST2, and galectin-3 rapidly approaching. Future studies will assist in clarifying the appropriate use of both established and emerging markers for assisting in diagnosis, risk stratification, and management of this complex condition.

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Biomarkers in Ischemic Heart Disease JT Neumann and RB Schnabel, University Heart Center, Hamburg, Germany © 2018 Elsevier Inc. All rights reserved.

Introduction General Considerations Metabolic and Renal Biomarkers Biomarkers of Myocardial Injury Creatine Kinase and Myoglobin Cardiac Troponin Diagnosis of AMI High-sensitivity assays Baseline troponin concentration Current clinical practice Risk prediction Copeptin Heart-Type-Fatty-Acid-Binding-Protein MicroRNAs Biomarkers for Cardiac Stress and Remodeling B-Type Natriuretic Peptide Atrial-Natriuretic Peptide and Adrenomedullin Growth-Differentiation Factor 15 Biomarkers for Oxidative Stress and Inflammation C-Reactive Protein Other Markers Multibiomarker Approach Omics and Genetics Summary and Outlook References Further Reading

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Introduction Ischemic heart disease (IHD) is one of the most important cardiac diseases and defined by an inadequate oxygen supply of the myocardial cells (Task Force Members et al., 2013). The mismatch of demand and supply can be caused by various conditions including plaque-related obstruction of coronary arteries, microvascular dysfunction or vasospasm. Coronary artery disease (CAD) is one of the most important factors leading to IHD. It is an ongoing chronic process, which is based on accumulation of foam cells in the intima, followed by plaque formation and possible plaque-rupture. Stable IHD is defined by either stable symptoms (angina or dyspnea), which are thought to be related to CAD, or asymptomatic patients with prior-diagnosed CAD. An acute worsening or new onset of symptoms is defined as acute coronary syndrome (ACS). It includes acute myocardial infarction (AMI), which is caused by myocardial ischemia, or unstable angina (Roffi et al., 2016). Cardiovascular disease and especially IHD remains one of the most important causes of death accounting for up to 30% of all deaths worldwide in 2012 (World Health Organization, 2017). Within the past decades medical treatment with statins, antiplateletdrugs, and ACE-inhibitors, as well as revascularization have substantially improved the outcome of patients with IHD. The assessment of CAD in the population is difficult, as clinical information and imaging results are required. The prevalence of angina has been reported in the general population and is highly variable, as it ranges from 5% in younger women up to 14% in older men (Task Force Members et al., 2013). Therefore, the individual risk assessment in patients with suspected or diagnosed IHD remains an ongoing challenge. In clinical routine two important goals for patients with IHD include (1) the identification of individuals at high risk for future cardiovascular events and (2) the early diagnosis or rule-out of AMI in the acute setting. For risk prediction, several scores (e.g., Framingham Risk Score or ESC Score) have been established. They can identify high-risk individuals based on classical cardiovascular risk factors (Task Force Members et al., 2016a; D'Agostino et al., 2008). In patients with suspected AMI the use of biomarkers is well established and cardiac troponin is the gold-standard in clinical routine. In the past years, numerous novel biomarkers were discovered and evaluated with regard to their predictive and diagnostic ability in IHD. This article will provide an overview on established and novel biomarker applications in patients with IHD.

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General Considerations Many biomarkers have been evaluated with regard to their diagnostic and predictive ability in patients with cardiovascular diseases and especially IHD. The most promising biomarkers are summarized in the following (Fig. 1). However, so far only few biomarkers are routinely used in the clinical setting. When investigating new biomarkers several aspects should be kept in mind by researchers and physicians: (1) At first, a robust test is required to allow reproducible results with a low variation. This is particularly important, when comparing results from different groups or laboratories. (2) The new biomarker should be compared to other clinical risk markers or biomarkers and improve risk stratification. As an example, a biomarker might be compared to the Framingham risk score, which is an established and validated model for risk prediction. The improvement could be investigated by comparing the c-statistics or the net reclassification. This approach investigates, whether individuals are more likely to be assigned into the correct risk category when adding the biomarker. (3) The results should be tested and validated in independent samples. (4) Finally, the biomarker should ideally be cost-effective and improve patient management and outcome.

Metabolic and Renal Biomarkers Metabolic processes play a central role in the pathogenesis of atherosclerosis. In particular, dyslipidemia was identified as one of the most important risk factors more than half a century ago. The determination of total cholesterol, low-density-lipoprotein (LDL) cholesterol, and high-density-lipoprotein (HDL) cholesterol has been clinical standard for decades (Task Force Members et al., 2013; Piepoli et al., 2016). These biomarkers are also included in established risk score (e.g., Framingham or ESC Score) and are therefore included as the gold-standard, when comparing novel biomarkers for their ability of risk prediction in statistical analyses. For LDL cholesterol, numerous studies provided strong evidence of a causal role in the pathogenesis of atherosclerotic disease. This is different for HDL cholesterol, which is inversely correlated with IHD, but so far could not be related to disease in a direct causal pathway (Voight et al., 2012). Statin-treatment is one of the most effective strategies in secondary prevention and can reduce the LDL cholesterol substantially. This effect is associated with a strong reduction of the relative risk. Furthermore statins are even able to decrease the diameter of coronary plaques (Baigent et al., 2005; Ballantyne et al., 2008). The use of statin therapy is widely established in patients with relevant IHD nowadays. As a consequence, in well-treated IHD patients LDL concentrations lose their predictive ability for mortality (Ndrepepa et al., 2014). Current ESC guidelines recommend annual measurements of LDL cholesterol and aim for a concentration below 70 mg/dL (or a 50% reduction of the baseline concentration) for patients with prior history of CAD (Task Force Members et al., 2013). Lipoprotein A (Lp(a)) is a protein, which consists of the apolipoproteins B-100 and A (Malaguarnera et al., 2013). It is similar to LDL cholesterol and involved in the development of atherosclerotic disease. The plasma concentrations of Lp(a) are determined by

Fig. 1 Overview on selected biomarkers in patients with IHD.

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genetic factors and appear to be stable over the lifespan (Nordestgaard et al., 2010). Treatment with niacin or fibrates was able to reduce Lp(a) concentrations, but so far, no clinical benefit was shown for a reduction of Lp(a). Therefore current ESC guidelines do not recommend general testing, while Lp(a) should be measured in patients with high cardiovascular risk or with a strong family history of IHD (Task Force Members et al., 2016b). Impaired renal function is closely associated with IHD and poor outcome (Go et al., 2004). This is explained by accumulation of risk factors, but also by pathophysiological pathways including increased inflammation and aldosterone activity among others (Mule et al., 2015). In clinical routine the measurement of creatinine and the calculation of the estimated glomerular filtration rate (eGFR) are well established and validated. In a huge population of more than one billion individuals, decreased eGFR was associated with mortality and cardiovascular events (Go et al., 2004). Cystatin C has been investigated as an alternative biomarker for patients with renal impairment. It is thought to be less affected by confounding factors (e.g., age and muscle mass) and might be superior for detection of minor changes in renal function at early stages of renal impairment (Shlipak et al., 2013). In patients with IHD, cystatin C was associated with mortality. The cystatin C-based eGFR appears to be superior compared to the creatinine-based formula (Keller et al., 2009; Waldeyer et al., 2016). However, cystatin C-based IHD risk estimation has not been introduced widely in clinical routine and annual determination of creatinine and eGFR is recommended (Task Force Members et al., 2013).

Biomarkers of Myocardial Injury Patients with suspected AMI are one of the most important populations, who profit from rapid decision-making based on biomarkers. While patients with ST-elevation AMI can be identified using the electrocardiogram, the diagnosis of non-ST-elevation AMI (NSTEMI) relies on biomarkers and their dynamic changes (Thygesen et al., 2012a). In AMI patients timing is crucial and early diagnostic approaches are needed in the emergency department. On the one hand, high-risk patients with NSTEMI due to obstructive CAD, who receive an early invasive treatment, have an improved outcome, compared to delayed treatment (Mehta et al., 2009; Milosevic et al., 2016). On the other hand, emergency departments are usually crowded and an early discharge of lowrisk patients is required. In the past decades, several diagnostic biomarkers and approaches have been evaluated for patients with suspected AMI and are presented in the following. Improved diagnostic accuracy rendered them ideal, also for risk prediction.

Creatine Kinase and Myoglobin Among the first biomarkers applied in clinical routine for the detection of myocardial necrosis were creatine kinase myocardial band (CK-MB) and myoglobin (Duma and Siegel, 1965; Rosano et al., 1977). Due to a rather slow dynamic change, CK-MB is of secondary importance for acute decision-making. However, an increase of CK-MB remains an important biomarker for patients with diagnosed AMI. Here, the increase of CK-MB is associated with the infarct size (Costa et al., 2008). Furthermore, current ESC guidelines recommend CK-MB as the preferred biomarker for patients who present early after prior AMI, as CK-MB shows a fast decrease after AMI (Roffi et al., 2016). Myoglobin shows an early increase after myocardial necrosis, but is less cardiac-specific and expressed in myocardial as well as skeletal muscle cells. Therefore, myoglobin is not recommended for clinical use anymore (Thygesen et al., 2012b).

Cardiac Troponin Cardiac troponin is a protein complex, which has a central role in myocyte contraction. The three subcomplexes troponin C, I, and T are bound to tropomyosin and interact with the actin filament (Takeda et al., 2003). Troponin T and I are expressed exclusively in the myocyte and are released after myocardial necrosis (Parmacek and Solaro, 2004). The detection of troponin was first developed in 1987 using a radioimmunoassay (Cummins et al., 1987) and the first clinical application was presented in 1992, as troponin T positive patients with unstable angina had a poor outcome (Hamm et al., 1992). After introduction of troponin in clinical routine, elevated troponin concentrations were used as a diagnostic marker for patients with AMI (Alpert et al., 2000; Task Force Members et al., 2007). Ever since assays detecting troponin T and I underwent a rapid improvement in terms of sensitivity and accuracy. In the past years, numerous newer troponin assays were developed and used in clinical routine. These assays have a much higher sensitivity and can detect troponin concentrations not only in patients with AMI, but even in the general population. Furthermore, the accuracy, measured by the coefficient of variation at the 99th percentile, was improved impressively. Recently, the term of “highsensitivity” troponin (hs-Tn) assay was introduced for assays with a 10% coefficient of variation, which is below the 99th percentile and that are detectable in at least 50% of the general population. In Fig. 2 currently available troponin assays together with the specific limit of detection and the percentage detectable in the general population is displayed.

Diagnosis of AMI Troponin is the best established and most widely used biomarker in patients with suspected AMI. International guidelines for patients with NSTEMI recommended a troponin cutoff concentration at the 99th percentile (determined in the general population) to rule-out AMI (Task Force Members et al., 2007; Amsterdam et al., 2014). Using less sensitive assays at that time, serial sampling was recommended after six or twelve hours in order to assess dynamic changes. After introduction of more sensitive or even highsensitivity troponin assays a shorter time period of only three hours was suggested and recommended in the 2011 ESC guidelines

306 Biomarkers in Ischemic Heart Disease Fig. 2 Overview on selected currently available troponin assays, their limit of detection and rate detectable in the general population. Adapted from Westermann, D., Neumann, J. T., Soerensen, N. and Blankenberg, S. (2017). High-sensitivity assays for troponin in patients with cardiac disease. Nature Reviews Cardiology. https://doi.org/10.1038/nrcardio.2017.4.

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(Ridker et al., 2008; Reichlin et al., 2009; Keller et al., 2011; Hamm et al., 2011). The ESC working group on Acute Cardiac Care recommended a baseline cutoff concentration at the 99th percentile and a >50% increase after three hours, when the baseline concentration was below the 99th percentile, or a >20% increase of the initial value, when the baseline concentration was above the 99th percentile in order to rule-out or to diagnose AMI. An optional measurement after six hours was recommended.

High-sensitivity assays Using newer high-sensitivity troponin T and I assays the application of much lower cutoff concentrations became feasible and was investigated in several large cohorts of patients with suspected AMI (e.g., ADAPT, APACE, BACC, High-STEACS, and TRAPIDAMI cohorts). The ADAPT cohort was the first one to reduce the duration of serial sampling to two hours and measured hs-TnI (Than et al., 2012). A combined diagnostic approach based on the 99th hs-TnI percentile, the TIMI risk score, the ECG and history or symptoms, revealed a high diagnostic accuracy to rule-out AMI. A shorter timeframe of only one hour was evaluated in the APACE, BACC, and TRAPID-AMI cohorts (Mueller et al., 2016; Neumann et al., 2016a; Rubini Gimenez et al., 2015). In summary, all cohorts reported a high negative predictive value (NPV) to rule-out AMI based on very low hs-Tn concentrations at baseline (around 3 ng/L for hs-TnT and 2–6 ng/L for hs-TnI) and a low change after one hour (around 12 ng/L for hs-TnT and 5–6 ng/L for hs-TnI). On the other hand, the positive predictive value (PPV) was high, when the baseline concentration was high (52 ng/L for hs-TnT and hs-TnI) or delta change after one hour was high (around 5–6 ng/L for hs-TnT and hs-TnI). Importantly, these concentrations were significantly lower compared to the 99th percentile, which has been described at 27 ng/L (Zeller et al., 2014a).

Baseline troponin concentration One step further, a single hs-TnI concentration directly at admission was tested to rule-out AMI. The High-STEACS cohort suggested a low cutoff of 5 ng/L and rule-out AMI in 61% of all patients with a NPV of 99.6% (Shah et al., 2015a). The BACC cohort aimed for a NPV of 100%, which was reached at a hs-TnI concentration of 3 ng/L in combination with a low-risk ECG without ischemic signs (Neumann et al., 2016b). This performance was validated independently in the ADAPT and Stenocardia cohorts. Finally, the first US cohort UTROPIA suggested a cutoff concentration at the limit of detection at 1.9 ng/L and described a NPV of 99.6% (Sandoval et al., 2017).

Current clinical practice The improvements of troponin assay sensitivity enabled earlier decision-making in patients with suspected AMI. The 0/1 h approach has been incorporated in the 2015 ESC guidelines as an alternative to the three hours algorithm (Roffi et al., 2016). The suggested 0/1 h concept is based on assay-specific cutoff concentrations, which are provided in the guidelines. The general concept of early rule-out and rule-in is displayed in Fig. 3. Importantly, troponin concentrations are only one part of the decisionmaking process. Accurate evaluation of symptoms, patient history, physical examination, imaging results, and differential diagnoses is mandatory. Several aspects of the new biomarker algorithms have been discussed controversially (Crea et al., 2016). As an example, it has been argued, if sex-specific cutoff concentrations should be used (Cullen and Mills, 2016; Giannitsis, 2016; Rubini Gimenez et al., 2016; Shah et al., 2015b). Women tend to have lower troponin concentrations in general, which is reflected by a lower 99th percentile. However, currently available data on sex-specific cutoffs is limited and no general recommendation possible. Furthermore, data on patients who present early after symptom onset (e.g., less than three hours) is limited. In these patients, a troponin change might not yet be visible, even using hs-Tn assays. Therefore, the guidelines recommended the baseline rule-out of AMI only for those patients with symptom duration of more than three hours.

Fig. 3 Summary of the general concept of the ESC guideline 0/1 h approach. The exact cutoff concentrations are assay-specific. The baseline rule-out of AMI is only recommended for patients with symptom duration of more than 3 h.

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In the past years hs-Tn assays were used worldwide, excluding the US. Therefore, the current AHA/ACC guidelines still recommend three to six hours troponin serial sampling (Amsterdam et al., 2014). This might change in the future, as the first hs-TnT assay was approved by the FDA in the beginning of 2017 (FDA, 2017). This approval will have major impact on the clinical routine within the US, as application of faster diagnostic protocols will become available.

Risk prediction The improvement in assay sensitivity opened the venue for a much broader use of the biomarker troponin. Besides acute diagnostic application, the troponin-based risk prediction was investigated in study samples with cardiac disease. In 3679 patients from the PEACE study, which included patients with stable CAD, higher troponin T and I concentrations were associated with mortality and heart failure (Omland et al., 2009, 2013). In the BARI 2D study patients with stable CAD and prior-diagnosed diabetes were included and here hs-TnT concentrations above the 99th percentile were observed in 39% of the study population. Again, troponin concentrations were associated with mortality and future cardiovascular events (Everett et al., 2015a). Serial troponin sampling was performed in the LIPID study, which included patients with a history of AMI or unstable angina in combination with elevated LDL cholesterol (White et al., 2014). Patients were randomized to receive either placebo or pravastatin and followed for at least 1 year. Interestingly, a decrease of troponin was associated with risk reduction for future cardiovascular events and vice versa. Due to higher sensitivity, hs-Tn concentrations were evaluated for their ability of risk prediction in the community (de Lemos et al., 2010; Saunders et al., 2010). In the FINRISK population, three troponin assays with different sensitivity were compared with regard to their prediction of future cardiovascular events. Interestingly, the most sensitive assay showed the best predictive performance (Neumann et al., 2014). In the large BiomarCaRE consortium hs-TnI was determined in 70,000 individuals from several European cohorts (Blankenberg et al., 2016). Here, hs-TnI concentrations above 5.9 ng/L were strongly associated with incidence of cardiovascular disease within the long-term follow-up period of 20 years. Finally, the use of hs-Tn for risk prediction in primary prevention was evaluated. The JUPITER trial randomized patients with elevated hs-CRP, but without cardiovascular disease, to receive either placebo or rosuvastatin (Everett et al., 2015b). Again hs-TnI was impressively associated with cardiovascular events within the follow-up time of 2.5 years. The WOSCOPS trial included patients with elevated LDL cholesterol, but without cardiovascular disease and randomized them to receive either placebo or statin-treatment (Ford et al., 2016). Patients receiving statins had a high relative risk reduction, especially when their hs-TnI was high. These findings are interesting and promising, but do not qualify for guideline recommendations yet. Further studies are needed to provide more insight to a more personalized medicine. In future troponin will be an important tool for risk assessment of patients with IHD.

Copeptin Copeptin is a peptide, which is cleaved from the neurohypophysial hormone prepro-vasopressin and secreted in the blood during procession to vasopressin (Keller et al., 2010). It is released during stress and shows a rapid increasing kinetic. Therefore, several studies investigated the use of copeptin as a biomarker in patients with suspected AMI. Due to a low specificity, elevated copeptin concentrations can be observed in various conditions including sepsis, trauma, and shock. On the other hand, a negative copeptin results showed a high NPV for the diagnosis of AMI. When compared to sensitive troponin assays the additional use of a negative copeptin result increased the area under the curve (AUC) (Maisel et al., 2013). However, when using hs-Tn assays this effect does not appear relevant anymore (Mockel et al., 2015).

Heart-Type-Fatty-Acid-Binding-Protein The heart-type-Fatty-Acid-Binding-Protein (hFABP) is a protein, which is involved in intracellular myocardial transport (Bruins Slot et al., 2010; Reiter et al., 2013). After myocardial necrosis hFABP is rapidly released into the blood stream and was therefore investigated as a biomarker for AMI. However, due to low sensitivity and specificity hFABP has not been proven useful, compared to the diagnostic performance of hs-Tn assays (Bruins Slot et al., 2010; Reiter et al., 2013).

MicroRNAs In the past years microRNAs have been investigated as potential biomarkers in various diseases (Schulte and Zeller, 2015). MicroRNAs are small, circulating noncoding RNA molecules, which modulate the gene regulation. Up to date more than 2500 microRNAs have been described. MicroRNAs seem to be involved in the development of atherosclerosis and different microRNAs have been found in different stages of coronary plaque stages (Jovanovic et al., 2014). In patients with chest pain a combination set of eight microRNAs (miR-19a, miR-19b, miR-132, miR-140-3p, miR-142-5p, miR-150, miR-186, and miR-210) was able to discriminate patients with unstable angina from other patients (Zeller et al., 2014b). These eight microRNAs were further investigated in a large cohort of patients with CAD (stable and instable) (Karakas et al., 2016). Here, especially miR-132, miR140-3p, and miR-210 were associated with cardiovascular death within the follow-up of 4 years. In summary, current data on the use of microRNAs is limited and comparison with established biomarkers is needed. In the future, sets of microRNAs might be helpful to improve individual risk stratification.

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Biomarkers for Cardiac Stress and Remodeling B-Type Natriuretic Peptide Among cardiac biomarkers, the b-type natriuretic peptide (BNP) and the n-terminal fragment (NT-proBNP) are extremely well established. BNP is released from the ventricle during myocardial stress and can be detected in the blood using immunoassays. In the current guidelines for the diagnosis of heart failure, BNP is one of the most important cornerstones to diagnoses or to rule-out heart failure (Ponikowski et al., 2016). There is some substantial overlap of patients with heart failure and IHD, which makes BNP an important biomarker in this population as well. Already in 2001 BNP was shown to be a strong predictor for mortality in patients with acute coronary syndrome (de Lemos et al., 2001). Furthermore, in patients with suspected CAD undergoing angiography NT-proBNP was a strong predictor for mortality (Kragelund et al., 2005). In stable CAD patients from the PEACE study BNP and NT-proBNP were measured and significantly associated with cardiovascular mortality, heart failure, and stroke (Omland et al., 2007). Importantly, both biomarkers provided incremental value to established risk stratification tools. The HOPE study, which included high-risk individuals, identified NT-proBNP as the most important predictor for cardiovascular events, besides classical risk factors (Blankenberg et al., 2006). Finally, in a multibiomarker approach from the MORGAM project in the general population, NT-proBNP, troponin I, and CRP were the strongest predictors for cardiovascular events and improved the reclassification (Blankenberg et al., 2010). BNP-guided therapy in patients with heart failure has been intensively discussed and might improve patient care. It is currently recommended by the US, but not the ESC guidelines (Ponikowski et al., 2016; Troughton et al., 2014).

Atrial-Natriuretic Peptide and Adrenomedullin Similar to BNP, the atrial-natriuretic peptide (ANP) or its stable flanking protein MR-proANP, is released from the atrial myocytes during increased myocardial stress or pressure overload (Levin et al., 1998). Adrenomedullin (ADM) is a vasodilatory peptide, which is released in various acute and nonacute conditions. The mid-regional prohormone (MR-proADM) is more stable and can be measured using an immunoassay. It has been studied in patients with heart failure, hypertension, infections, and IHD (Peacock, 2014). Both biomarkers have been investigated in several studies and showed to further improve the risk stratification. In a population of patients with suspected AMI, MR-proANP, and MR-proADM were able to predict mortality or AMI and improved the reclassification, when compared to the GRACE score (Tzikas et al., 2013). Similar results were reported in the PEACE cohort, as both biomarkers were associated with mortality and incident heart failure. In the general population, MR-proADM was associated with subclinical and clinical cardiovascular disease (Neumann et al., 2013). However, the clinical use of these biomarkers is still limited.

Growth-Differentiation Factor 15 The growth-differentiation factor 15 (GDF-15) is a biomarker from the transforming growth factor-beta cytokine family (Wollert et al., 2017). It is increased after tissue damage, apoptosis, inflammation, and oxidative stress. GDF-15 has been evaluated in various cardiovascular disease cohorts where it predicted adverse outcome. In a large sample of patients with IHD, GDF-15 concentrations were associated with mortality, stroke, and AMI (Hagstrom et al., 2017). The AtheroGene study included patients with stabile angina undergoing angiography. In this cohort GDF-15 predicted coronary mortality (Kempf et al., 2009). GDF-15 concentrations were also investigated in the setting of patients with acute coronary syndrome, myocardial infarction, or cardiogenic shock. Here, GDF-15 was also a strong predictor for adverse events (Hagstrom et al., 2016; Fuernau et al., 2014; Eitel et al., 2011). In addition, GDF-15 was a predictor for major bleeding after ACS in the PLATO study (Hagstrom et al., 2016). Finally, the highest GDF-15 concentrations have been observed in patients with acute heart failure (Anand et al., 2010). In the community GDF-15 was a predictor for all-cause mortality (Rohatgi et al., 2012; Wang et al., 2012). These findings render GDF-15 a promising biomarker for risk prediction. However, current data indicates GDF-15 to be less specific for IHD, but rather a more general biomarker.

Biomarkers for Oxidative Stress and Inflammation Inflammatory processes and oxidative stress are directly involved in development and progress of atherosclerotic disease. Local inflammation is one of the important factors leading to plaque formation, while oxidative stress is a potent inductor of endothelial dysfunction and especially present in the acute setting of plaque disruption (Hansson et al., 2015). Therefore, biomarkers of these pathophysiological pathways have gained attention within the past years.

C-Reactive Protein The c-reactive protein (CRP) is one of the mostly used biomarkers worldwide to diagnose acute infections. CRP is released from the liver after stimulation by cytokines (e.g., interleukin-6 (IL-6) or tumor-necrosis-factor-alpha) and can be easily measured in blood. CRP concentrations are highly elevated in response to bacterial infections, but are also related to chronic inflammatory processes. Using newer high-sensitivity CRP (hs-CRP) assays lower concentrations can be detected, which makes this a promising biomarker to

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identify individuals at risk. In the PEACE study, patients with IHD and elevated hs-CRP above 1 mg/L were at higher risk for future events (mortality, stroke, AMI), even after multiple adjustment (Sabatine et al., 2007). In the ATHEROREMO study the relation of CAD plaque burden and hs-CRP was recently investigated. Interestingly, hs-CRP was associated with plaque burden and incident MACE within the follow-up, but not with thin-cap fibroatheroma (Cheng et al., 2014). These results indicate, that CRP is a more general marker of atherosclerosis and not specific for heart diseases. In contrast to that a large study, which investigated genetic variations resulting in increased CRP concentrations, did not find an association of these polymorphisms with cardiovascular events (Zacho et al., 2008). The JUITER trial was the first study to base treatment decisions on hs-CRP concentrations (Ridker et al., 2008). Patients with hs-CRP above 2 mg/L and LDL cholesterol below 130 mg/dL were randomized to receive placebo or rosuvastatin. The study reported an impressive risk reduction by statin therapy within the complete study population. Interestingly, this effect was most prominent in those individuals with a hs-CRP reduction below 1 mg/L in the follow-up period. In summary, the use of CRP in risk prediction remains an interesting topic, but the clinical implications are not clear yet.

Other Markers While CRP is the most prominent one, also other biomarkers have been investigated that represent inflammation and oxidative stress. The concentration of IL-6, a cytokine centrally involved in inflammation, is correlated with CRP which is explained by the inflammatory cascade since IL-6 stimulated CRP production and release. It has been shown to be associated with incident AMI or mortality (Fisman et al., 2006). Myeloperoxidase (MPO) is a product of neutrophil granulocytes and related to oxidative stress. With regard to IHD, higher MPO concentrations have been associated with cardiovascular events in patients after ACS (Baldus et al., 2003). In stable patients with CAD, MPO was also a prognostic marker (Tang et al., 2011). Furthermore, the lipoprotein-associated phospholipase A2, the pregnancy-associated plasma protein, and the phospholipase A2 have been discussed (Omland and White, 2017).

Multibiomarker Approach More recently, a multibiomarker approach has been suggested to improve risk prediction and diagnosis of CAD. The concept of a biomarker-score, which combines the pathological results of different markers, reflects the multifactorial background of atherosclerotic disease. In the Framingham Heart Study, a general population setting, the biomarkers BNP, CRP, urinary albumin-to-creatinine ratio, homocysteine, and renin were associated with a first cardiovascular event (Wang et al., 2006). The combination of 30 cardiovascular biomarkers improved risk assessment for long-term cardiovascular disease incidence (Blankenberg et al., 2010). In another multiplex approach, more than 100 biomarkers were investigated in a cohort of patients undergoing angiography (Ibrahim et al., 2017). The four biomarkers adiponectin, apo C-I, KIM-1, and midkine were selected and combined in a predicting model. These new biomarkers combine the different pathophysiological backgrounds including inflammation (midkine), metabolic status (adiponectin and apo C-1), and renal dysfunction (KIM-1) and resulted in an AUC of 0.87 for the diagnosis of CAD. To date, multimarker approaches have shown that natriuretic peptides and inflammatory biomarkers range among the strongest predictors of CAD. However, the efficiency of multimarker testing in clinical practice has not been proven to be efficient.

Omics and Genetics Most of the established biomarkers have been identified by classical, hypothesis-driven research. However, over the past years a novel tool for identification of potential biomarkers came up. By the term “omics” the comprehensive measurement evaluation of different biological steps from genome to transcriptome, proteome, and metabolome are summarized. Using mass array measurements huge amounts of data can be generated to detect potential target pathways. This approach requires large and wellcharacterized samples and novel statistical methods to identify potential biomarkers that may be clinically relevant. Most advanced are genomics with the identification of numerous genetic loci that are associated with disease risk by genome-wide association studies of common genetic polymorphisms and increasingly sequencing information (Abraham et al., 2016; Myocardial Infarction et al., 2016; Nikpay et al., 2015). Within the past 15 years the rapidly evolving field of genome-wide association studies (GWAS) and increasing sequencing data has provided fundamental insights into the genetics of IHD (Pjanic et al., 2016). These large studies aim to discover hitherto unknown pathophysiological pathways of the disease. They are wellsuited for this purpose because the approach is largely hypothesis-free and associates specific genetic loci with IHD. With regard to IHD, several large-scale studies have been performed (Samani et al., 2007). In a recently published metaanalysis including 185,000 individuals, 58 loci were identified to be associated with CAD (Nikpay et al., 2015). In the future, these studies will have major impact on our understanding of disease pathophysiology and potential treatment approaches. Genetics remain stable over a lifetime and genetic risk scores improve risk prediction beyond classical risk factors (Abraham et al., 2016). However, clinical use is still limited.

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Summary and Outlook Biomarkers in patients with IHD are well established and used in clinical routine. Cholesterol subfractions are true risk factors as their treatment results in modification of IHD risk. Cardiac troponin is one cornerstone for the diagnosis of AMI that is well established in clinical routine. Development of newer, high-sensitivity troponin assays enabled the detection of much lower concentrations, which are far below the routinely used 99th percentile. This improvement resulted in lower cutoff concentrations and rule-in or rule-out of AMI after only one hour after admission for many patients. Furthermore, high-sensitivity troponin assays are also used for risk prediction in diseased cohorts, e.g., with stable CAD or even the general population. Several other biomarkers are on the horizon and are evaluated in clinical studies. The most promising ones include microRNAs that have been proven to be modifiable and genetics that will help to gain deeper insights into the pathophysiology of IHD development and manifestation.

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Shlipak MG, Mattes MD, and Peralta CA (2013) Update on cystatin C: Incorporation into clinical practice. American Journal of Kidney Disease 62: 595–603. https://doi.org/10.1053/j. ajkd.2013.03.027. Takeda S, Yamashita A, Maeda K, and Maeda Y (2003) Structure of the core domain of human cardiac troponin in the Ca(2þ)-saturated form. Nature 424: 35–41. https://doi.org/ 10.1038/nature01780. Tang WH, Wu Y, Nicholls SJ, and Hazen SL (2011) Plasma myeloperoxidase predicts incident cardiovascular risks in stable patients undergoing medical management for coronary artery disease. Clinical Chemistry 57: 33–39. https://doi.org/10.1373/clinchem.2010.152827. Task Force Members, et al. (2007) Guidelines for the diagnosis and treatment of non-ST-segment elevation acute coronary syndromes. European Heart Journal 28: 1598–1660. https://doi.org/10.1093/eurheartj/ehm161. Task Force Members, et al. (2013) ESC guidelines on the management of stable coronary artery disease: The Task Force on the management of stable coronary artery disease of the European Society of Cardiology. European Heart Journal 34: 2949–3003. https://doi.org/10.1093/eurheartj/eht296. Task Force Members, et al. (2016a) European guidelines on cardiovascular disease prevention in clinical practice: The Sixth Joint Task Force of the European Society of Cardiology and other Societies on Cardiovascular Disease Prevention in Clinical Practice (constituted by representatives of 10 societies and by invited experts): Developed with the special contribution of the European Association for Cardiovascular Prevention and Rehabilitation (EACPR). European Journal of Preventive Cardiology 23: NP1–NP96. https://doi.org/ 10.1177/2047487316653709. Task Force Members, et al. (2016b) ESC/EAS guidelines for the management of dyslipidaemias: The Task Force for the management of dyslipidaemias of the European Society of Cardiology (ESC) and European Atherosclerosis Society (EAS) developed with the special contribution of the European Association for Cardiovascular Prevention and Rehabilitation (EACPR). Atherosclerosis 253: 281–344. https://doi.org/10.1016/j.atherosclerosis.2016.08.018. Than M, et al. (2012) 2-Hour accelerated diagnostic protocol to assess patients with chest pain symptoms using contemporary troponins as the only biomarker: The ADAPT trial. Journal of the American College of Cardiology 59: 2091–2098. https://doi.org/10.1016/j.jacc.2012.02.035. Thygesen K, et al. (2012a) Third universal definition of myocardial infarction. European Heart Journal 33: 2551–2567. https://doi.org/10.1093/eurheartj/ehs184. Thygesen K, et al. (2012b) How to use high-sensitivity cardiac troponins in acute cardiac care. European Heart Journal 33: 2252–2257. https://doi.org/10.1093/eurheartj/ehs154. Troughton R, Michael Felker G, and Januzzi JL Jr, (2014) Natriuretic peptide-guided heart failure management. European Heart Journal 35: 16–24. https://doi.org/10.1093/eurheartj/ eht463. Tzikas S, et al. (2013) MR-proANP and MR-proADM for risk stratification of patients with acute chest pain. Heart 99: 388–395. https://doi.org/10.1136/heartjnl-2012-302956. Voight BF, et al. (2012) Plasma HDL cholesterol and risk of myocardial infarction: A mendelian randomisation study. Lancet 380: 572–580. https://doi.org/10.1016/S0140-6736(12) 60312-2. Waldeyer C, et al. (2016) The predictive value of different equations for estimation of glomerular filtration rate in patients with coronary artery disease—Results from the AtheroGene study. International Journal of Cardiology 221: 908–913. https://doi.org/10.1016/j.ijcard.2016.07.067. Wang TJ, et al. (2006) Multiple biomarkers for the prediction of first major cardiovascular events and death. New England Journal of Medicine 355: 2631–2639. https://doi.org/ 10.1056/NEJMoa055373. Wang TJ, et al. (2012) Prognostic utility of novel biomarkers of cardiovascular stress: The Framingham Heart Study. Circulation 126: 1596–1604. https://doi.org/10.1161/ CIRCULATIONAHA.112.129437. White HD, et al. (2014) Association of contemporary sensitive troponin I levels at baseline and change at 1 year with long-term coronary events following myocardial infarction or unstable angina: Results from the LIPID Study (Long-Term Intervention With Pravastatin in Ischaemic Disease). Journal of the American College of Cardiology 63: 345–354. https:// doi.org/10.1016/j.jacc.2013.08.1643. Wollert KC, Kempf T, and Wallentin L (2017) Growth differentiation factor 15 as a biomarker in cardiovascular disease. 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Zeller T, et al. (2014a) High-sensitivity cardiac troponin I in the general population—Defining reference populations for the determination of the 99th percentile in the Gutenberg Health Study. Clinical Chemistry and Laboratory Medicine. https://doi.org/10.1515/cclm-2014-0619. Zeller T, et al. (2014b) Assessment of microRNAs in patients with unstable angina pectoris. European Heart Journal 35: 2106–2114. https://doi.org/10.1093/eurheartj/ehu151.

Further Reading Westermann D, Neumann JT, Soerensen N, and Blankenberg S (2017) High-sensitivity assays for troponin in patients with cardiac disease. Nature Reviews. Cardiology https://doi.org/ 10.1038/nrcardio.2017.4.

Biomarkers: Heart Failure SS Gogia and JE Ho, Cardiology Division, Department of Medicine, Massachusetts General Hospital, Boston, MA, United States © 2018 Elsevier Inc. All rights reserved.

Introduction Current Guidelines for Biomarkers in Heart Failure What Defines Potential Clinical Utility of Biomarkers in HF? Selected Biomarkers: What Do We Know? B-Type Natriuretic Peptide & N-Terminal Pro-B Type Natriuretic Peptide Highly Sensitive Troponin-I (hsTnI) & Highly Sensitive Troponin-T (hsTnT) Soluble ST2 Galectin-3 Growth Differentiation Factor-15 (GDF-15) Future Directions Biomarker-Guided HF Management Improving Risk Prediction Biomarkers in Prevention of Heart Failure Conclusion References

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Introduction Despite significant advances in the field of cardiology and an overall reduction in age-standardized rates of death attributable to cardiovascular disease (Wang et al., 2016), heart failure (HF) is becoming an increasingly prevalent chronic condition. In fact, HF is the most common admitting diagnosis in hospitals located in high-income countries for patients aged 65 years and older, accounting for approximately one million hospital admissions in the United States alone (Braunwald, 2015). While both medical and device-based therapies for HF have made significant inroads, survival after HF diagnosis still remains poor. The OPTIMIZE-HF (Organized Program to Initiate Lifesaving Treatment in Hospitalized Patients with Heart Failure) study demonstrated greater than 8% mortality within 90 days of discharge following a hospitalization for HF exacerbation; the combined endpoint of death or repeat hospitalization was 36% (Fonarow et al., 2008). Some studies estimate survival at 50% at 5 years, and as low as 10% at 10 years following diagnosis of HF (Roger, 2013). These studies illustrate the importance of continued improvements in our understanding of disease progression, management, and disease prevention. This review will examine the clinical utility of circulating biomarkers in disease management, and potential prevention strategies. Since the introduction of B-type natriuretic peptide (BNP) to guide HF diagnosis, management, and prognosis in 2001 (Maisel, 2009), there has been intense interest in novel biomarker discovery in heart failure, as evidenced by an exponential increase in publications on the topic (van Kimmenade and Januzzi, 2011). However, beyond natriuretic peptides, the clinical utility of biomarkers in HF remains unclear (Wilson Tang et al., 2007). In this review, we will (1) summarize current guidelines for the use of biomarkers in HF; (2) highlight general principles to evaluate clinical utility of novel biomarkers; (3) review existing studies to support the role of select biomarkers to guide prognosis, management, and risk prediction of HF; and (4) identify current knowledge gaps and future directions whereby biomarkers may inform clinical decision-making.

Current Guidelines for Biomarkers in Heart Failure Many recommendations outlining the use of biomarkers to guide diagnosis and management of HF are available, including practice guidelines from groups such as the American College of Cardiology Foundation (ACCF), American Heart Association (AHA), Heart Failure Society of America (HFSA), and the European Society of Cardiology (ESC). Though these guidelines were developed independently, one commonality has emerged: confirmation of the utility of measuring natriuretic peptides in patients with HF, as summarized in Table 1. All three society guidelines support the use of natriuretic peptides to aid diagnosis of HF in patients suspected of having HF (Ponikowski et al., 2016; America, 2010; Yancy et al., 2013). The ESC guidelines specifically point out the high negative predictive value of natriuretic peptides at specified thresholds and comment on their use to rule out HF but not necessarily to establish the diagnosis (Ponikowski et al., 2016). While useful in symptomatic individuals, the use of natriuretic peptides as a screening test in the absence of symptoms is not recommended by the HFSA guidelines. Once HF diagnosis has been established, ACC/AHA guidelines support a class I recommendation for the use of natriuretic peptides to aid in prognostication, whereas ESC supports a class IIa recommendation for initial assessment in newly diagnosed HF. Beyond aiding in HF diagnosis and prognosis, the ACCF/ AHA guidelines also support Class IIa and Class IIb recommendations for the use of natriuretic peptides in guiding medical therapy

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Biomarkers: Heart Failure Summary of major society recommendations for the use of biomarkers in heart failure

Biomarker

Society*

Class

Setting

Natriuretic peptides

ACC/AHA

I I IIa IIb

Diagnosis: ambulatory, acute Prognosis: ambulatory, acute Ambulatory HF: achieve guideline-directed medical therapy Acute HF: guide medical therapy Diagnosis: rule out HF Initial assessment in newly diagnosed HF Diagnosis: when HF is suspected Routine screening in asymptomatic individuals Prognosis: ambulatory, acute Additive risk stratification: ambulatory, acute

ESC HFSA Myocardial injury Myocardial fibrosis 

ACC/AHA ACC/AHA

IIa Recommended Not recommended I IIb

Guideline recommendations pertaining to heart failure from ACC/AHA 2013, ESC 2016, and HFSA 2010 documents.

in chronic HF and in acutely decompensated HF, respectively. By contrast, neither the ESC nor the HFSA guidelines remark on the utility of natriuretic peptides in the management of previously diagnosed HF. Beyond natriuretic peptides, however, the clinical applicability of other biomarkers in routine medical practice is less clear. The ACCF/AHA guidelines also support the use of cardiac troponins in establishing disease severity and prognosis in acute decompensated HF (Class I), and the use of biomarkers of myocardial fibrosis for additive risk stratification, with specific mention of soluble ST2 and galectin-3 (Class IIb). By contrast, the ESC guidelines state that there is no definite evidence supporting the use of other biomarkers in routine clinical practice. Lastly, the HFSA guidelines do not mention additional biomarkers beyond natriuretic peptides. Motivated by these differences, we will examine general principles used to evaluate biomarker studies and summarize key studies supporting current guidelines below.

What Defines Potential Clinical Utility of Biomarkers in HF? A number of objective criteria have been put forth in order to appraise the potential relevance of biomarkers to clinical practice. The AHA suggests six phases of evaluation for any new biomarker: proof of concept, prospective validation, incremental value, clinical utility, clinical outcomes, and cost-effectiveness (Hlatky et al., 2009). Others have specified three criteria to evaluate the utility of biomarkers: the biomarker must be measurable, informative, and actionable (Morrow and de Lemos, 2007). Specific to the field of HF, the National Academy of Clinical Biochemistry has elucidated similar goals for biomarkers specifically in the setting of HF; in this definition, biomarkers should be able to identify underlying causes of HF, confirm presence of HF syndrome, estimate severity of disease, and predict the risk of disease progression (Wilson Tang et al., 2007). Beyond assay-specific qualities such as reproducibility, accuracy, and cost, a given biomarker must first associate strongly with the disease in question. The additive value of a biomarker with respect to risk prediction can then be evaluated using metrics of discrimination, reclassification, and calibration. Discrimination indicates the ability of a biomarker to differentiate between an event and a nonevent (Ahmad et al., 2014). Often, the incremental discriminatory value of a biomarker when added to a clinical model is assessed by the change (or improvement) in the C-statistic. Given inherent limitations in the C-statistic, reclassification metrics have also been used (Pencina et al., 2008). The net reclassification improvement (NRI) metric evaluates whether a biomarker is able to assign higher risk to individuals who eventually develop the outcome of interest, while assigning lower risk to those who do not develop events (Pencina et al., 2011). Lastly, calibration is a measure of how frequently a predictive model matches the outcome in reality (Ahmad et al., 2014). While assessment of discrimination and reclassification help refine our understanding of biomarkers in risk prediction, it is important to note existing limitations. Despite strong associations with HF, the majority of biomarker studies have demonstrated only modest increments in C-statistics and NRI with respect to HF risk prediction (Wang, 2011). It may be that clinical predictors already result in a “high” C-statistic, above which an added improvement with any biomarker is much more difficult to demonstrate (Pencina et al., 2008). It is important to acknowledge that no accepted risk categories exist for HF, making the NRI somewhat more difficult to interpret. Lastly, studies of HF risk prediction have largely combined the categories of HF with preserved ejection fraction and HF with reduced ejection fraction, despite distinct underlying pathophysiology and therapies among the two HF subtypes (Echouffo-Tcheugui et al., 2015; Yancy et al., 2013). This amalgam reduces the specificity of existing risk prediction models.

Selected Biomarkers: What Do We Know? There has been intense interest in elucidating the role of biomarkers in HF, with studies focused on risk prediction of future HF, as well as prognostication among patients with acute and chronic HF as summarized in Table 2. Below we summarize key studies for selected biomarkers.

Biomarkers: Heart Failure Table 2

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Existing studies examining biomarkers relevant to the ACC/AHA clinical stages of heart failure

Biomarker Characteristic Natriuretic peptides High-sensitivity troponin Soluble ST2 Galectin-3 Growth differentiation factor-15 C-reactive protein Mid-regional proadrenomedullin Urinary albumin to creatinine ratio Neutrophil gelatinase-associated lipocalin

Stage A Risk factors

Stage B LV remodeling

Prediction of incident HF ✔✔ ✔✔ ✔ ✔ ✔ ✔ ✔ ✔

Stage C/D Symptomatic HF Diagnosis

Prognosis

Guide therapy

✔✔

✔✔ ✔✔ ✔✔ ✔ ✔ ✔ ✔ ✔ ✔

✔

✔ denotes one supporting study or multiple studies with some mixed results. ✔✔ denotes multiple supporting studies.

B-Type Natriuretic Peptide & N-Terminal Pro-B Type Natriuretic Peptide In the early 1990s, BNP was found to be secreted from the ventricular myocardium in response to pressure overload, in many cases itself a byproduct of volume expansion (Daniels and Maisel, 2007). Downstream effects of the binding of BNP to its receptor include natriuresis, vasodilation, inhibition of the renin–angiotensin–aldosterone system (RAAS), and increased myocardial relaxation (Kim and Januzzi, 2010). Studies focused on tailoring HF management to serum levels of natriuretic peptides began just a few years later, in the late 1990s (Murdoch et al., 1999; Troughton et al., 2000). These studies provided initial evidence that BNP-tailored management may improve clinical outcomes. Other studies from that time demonstrated that measurement of BNP could rapidly confirm the diagnosis of HF (Dao et al., 2001; Maisel et al., 2002). In a 2002 study known as the Breathing Not Properly Multinational Study, BNP levels alone were found to be more accurate than any other component of the history, physical exam, or additional laboratory values in determining the cause of a patient's dyspnea (Maisel et al., 2002). The PRIDE (Pro-Brain Natriuretic Peptide Investigation of Dyspnea in the Emergency Department) study, a similar study measuring NT-proBNP levels in the Emergency Department, provided further evidence that natriuretic peptide measurements could facilitate diagnosis of HF (Januzzi et al., 2005). A 2003 follow-up study to the Breathing Not Properly Multinational Study with 6 months of monitoring revealed that BNP levels were also highly predictive of cardiac events (Harrison et al., 2002). In an analysis of the Framingham Offspring Study, BNP levels were found to be independently predictive of the risk of death, heart failure, stroke, and atrial fibrillation, even after statistical adjustment for traditional risk factors (Wang et al., 2004). Larger, more recent studies have corroborated these early studies; BNP and NT-proBNP have been proven to be strongly associated with cardiovascular events and mortality in both symptomatic and asymptomatic patients (Doust et al., 2005; Di Angelantonio et al., 2009). However, more data are needed from low- and intermediate-risk populations before testing in the general population can be recommended without reservation (Di Angelantonio et al., 2009). There is some evidence that measurement of NT-proBNP levels in a healthy population may not offer reliable predictions regarding cardiovascular outcomes, though prognostic value was added with its measurement in patients with Stage A/B HF, a finding consistent with prior studies (McKie et al., 2010). Current research in this field is focused on the role of monitoring natriuretic peptide levels both in the inpatient and outpatient settings. During acute HF exacerbations requiring hospitalization, general consensus argues for measurement of BNP levels at time of admission and prior to discharge (Pang et al., 2012). Many studies have shown that a substantial decrease in BNP levels during hospitalization portends good outcomes, while patients with relatively stable or increased BNP levels were more likely to experience hospital readmissions or increased mortality rates (Van Cheng et al., 2001; Bettencourt, 2004; Michtalik et al., 2011). A number of studies have further examined the potential utility of natriuretic peptides in guiding medical therapy in the acute and chronic setting and are summarized under “Future Directions” later in this article. Outpatient monitoring of BNP levels remains controversial (Januzzi and Troughton, 2013; Desai, 2013), in no small part due to the fact that the intraindividual biological variability of BNP and NT-proBNP levels is quite high (O'Hanlon et al., 2007). For this reason, some support the establishment of a baseline or “steady-state” BNP level; recognizing a patient's normal BNP level allows for clinical decision-making based on variation from that mean (Daniels and Maisel, 2007). Lastly, the utility of BNP in screening approaches for the prevention of HF has also been recently examined and is summarized under “Future Directions.” Though there is no single perfect biomarker in HF, the utility of measuring BNP and NT-proBNP has been proven in many different studies, and its current use in establishing diagnosis and risk stratification of patients with HF is widespread. Future studies may further define BNP-guided management strategies and a potential role in screening and HF prevention. Significant value may also be gained from a multimarker approach in the context of several other biomarkers, as described later.

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Highly Sensitive Troponin-I (hsTnI) & Highly Sensitive Troponin-T (hsTnT) The measurement of cardiac proteins troponin-I and troponin-T is a mainstay for diagnosis and evaluation of patients with acute coronary syndrome. However, cardiac troponins have also been found to be elevated in patients with HF (Gaggin and Januzzi, 2013). As biomarker assays become more refined, highly sensitive troponin (hsTn) assays will be increasingly utilized. One benefit of the hsTn assays is that troponin values are measurable in the majority of patients, and therefore elevated levels may represent better discrimination when compared to traditional, low-sensitivity troponin assays. The measurement of hsTnI in patients with acute decompensated HF has been shown to have prognostic value. This is particularly notable because troponin proteins are often measured in patients with acute decompensated HF on presentation in order to rule out myocardial infarction as a cause of their acute symptoms. In a study of patients hospitalized with decompensated heart failure, Xue et al. (2014) showed that even small changes in troponin values during a HF exacerbation are associated with increased 90-day mortality and hospital readmission; moreover, increasing levels of hsTnI in admitted patients suggest higher mortality than patients in whom hsTnI levels are stable or decreasing. Increased levels of hsTn have also been seen in patients with chronic and symptomatic HF in proportion to the severity of disease (Latini et al., 2007). Notably, the prognostic value of hsTn may improve when evaluated in combination with other markers, such as NT-proBNP and soluble ST2 (Pascual-Figal et al., 2014). Lastly, hsTn concentrations predict incident HF among population-based studies (Wang et al., 2012; deFilippi et al., 2010). As more clinical centers adopt hsTn assays as part of routine medical care, the utility of hsTn measurements in HF will become clearer.

Soluble ST2 ST2, a member of the IL-1 receptor family, is a protein with transmembrane (ST2L) and soluble (sST2) isoforms (Sanada et al., 2007). Soluble ST2 acts as a decoy receptor for the ligand IL-33, which has been shown to be antifibrotic and antihypertrophic (Sanada et al., 2007). Therefore, the cardioprotective effects of the IL-33/ST2L interaction, shown in experimental models to reduce apoptosis and to improve myocardial function, are inhibited by sST2 (Pascual-Figal and Januzzi, 2015). Similar to BNP and NT-proBNP, ST2 is a protein induced by mechanical strain in cardiac myocytes; it has been found to be significantly higher in patients with severe HF when compared to patients without HF (Weinberg, 2003). Elevations in ST2 indicate a worse prognosis in patients with chronic HF and increases in ST2 levels over a 2-week period have proven to be an independent predictor of mortality or transplantation; notably, dynamic changes in BNP in this study were not shown to predict adverse outcome, suggesting that ST2 may be even more sensitive than natriuretic peptide levels (Weinberg, 2003). A subanalysis of PRIDE, a prospective study of more than 500 patients who presented to the Emergency Department with acute shortness of breath, demonstrated that ST2 levels were as predictive of mortality at 1 year as NT-proBNP (Januzzi et al., 2007). Importantly, elevations of both NT-proBNP and ST2 were associated with the highest 1-year mortality in the cohort, arguing there may be a role for clinical prediction using multiple HF biomarkers simultaneously (Januzzi et al., 2007). This finding has been confirmed in multiple additional studies (Bayes-Genis et al., 2014; Pascual-Figal et al., 2014). Some studies suggest that ST2 may be reliable even in elderly patients with ischemic disease, a population in which natriuretic peptide levels have been shown to be less useful (Broch et al., 2014). Outpatient monitoring of ST2 is not yet standard of care in clinical practice; however, some studies have demonstrated the utility of its measurement. An analysis of over 3000 patients in the Framingham Heart Study revealed the prognostic value of elevated ST2 levels in a community-based cohort. Patients in the Framingham Heart Study with elevated ST2 levels, only a small percentage of whom had prevalent cardiovascular disease, were more likely to experience adverse outcomes, including incident HF (Wang et al., 2012). At this point, there does not seem to be utility to serial measurements of ST2 obtained in an effort to guide therapy. However, a single measurement of ST2 might be useful in helping clinicians to make management decisions. One study, though limited by a small sample size, suggests that eplerenone may attenuate left ventricular remodeling in patients with high levels of ST2 following acute myocardial infarction (Weir et al., 2010). The ability of ST2 to reflect ventricular remodeling provides information beyond what can be determined by measuring natriuretic peptides alone. Further, unlike other biomarkers, ST2 levels do not appear to be affected by weight or kidney function, which allows for more standardized measurements across populations (Karayannis et al., 2013).

Galectin-3 Galectin-3 is a b-galactoside-binding lectin that is overexpressed in cardiac macrophages of failure-prone hearts even before overt clinical HF can be diagnosed (Sharma, 2004). Further supporting the idea that galectin-3 is related to cardiac dysfunction is evidence that intrapericardial delivery of exogenous galectin-3 leads to collagen deposition and fibrosis (Sharma, 2004). In fact, murine models showed that the level of galectin-3 associated strongly with the severity of future cardiac fibrosis (Sharma, 2004). It also plays a significant role in fibrosis of other organs, including the liver and kidney (Henderson et al., 2006, 2008). The aforementioned PRIDE study also identified galectin-3 as a possible biomarker for patients with acute decompensated heart failure. In that study, galectin-3 was found to be a better prognostic marker for 60-day mortality compared to NT-proBNP (Januzzi et al., 2005). Perhaps more importantly, the combination of biomarkers improved prognostic capability (van Kimmenade et al., 2006). A subset of these patients had a longer follow-up period; galectin-3 levels were associated with both 1- and 4-year mortality

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(Shah et al., 2014). Further, galectin-3 levels showed an association with echocardiographic markers of LV filling, diastolic function, valvular regurgitation, and RV function (Shah et al., 2014), suggesting that galectin-3 may associate strongly with HF with preserved ejection fraction. Other studies have also shown that the predictive value of galectin-3 may be greater in patients with preserved systolic function (de Boer et al., 2010). Additional research has demonstrated the value of galectin-3 as a biomarker in patients with chronic heart failure. The DEAL-HF study confirmed galectin-3 as an independent predictor of mortality in patients with moderate-to-advanced chronic HF (Lok et al., 2010). A study of patients with severe HF requiring mechanical circulatory support showed that galectin-3 levels were significantly higher in patients with HF than controls and that HF patients who did not survive ventricular assist device support had higher galectin-3 levels than those that were able to successfully undergo heart transplantation (Milting et al., 2008). Prospective studies to see whether galectin-3 might be used to guide therapy do not exist. However, multiple studies have shown that increasing galectin-3 levels increase the risk of repeat hospitalization for HF and the risk of death (van der Velde et al., 2013). Other studies have shown that therapies for HF may be more effective in patients with low galectin-3 levels at baseline. Val-HeFT, a study of the effect of valsartan in patients with heart failure demonstrated a reduction in repeat HF hospitalizations for patients with low galectin-3 levels; this finding was not seen in patients with high galectin-3 levels (Anand et al., 2014). Similarly, a post hoc analysis of the CORONA (Controlled Rosuvastatin Multinational Trial in Heart Failure) study appeared to show benefit with rosuvastatin therapy in patients with systolic HF and low levels of galectin-3 (Gullestad et al., 2012), despite a lack of evidence for statin therapy for all patients with heart failure. Lastly, galectin-3 was shown to predict incident HF among community-dwelling adults (Ho et al., 2012). While not yet shown to be a valuable diagnostic marker in heart failure, galectin-3 has been shown to contribute to cardiac fibrosis and ventricular remodeling; its role in the development and progression of HF may lead to significant advancements in disease treatment in the future. At the present time, however, it remains a useful biomarker with prognostic value in both acute and chronic heart failure.

Growth Differentiation Factor-15 (GDF-15) Growth differentiation factor-15 (GDF-15), a member of the transforming growth factor b (TGF- b) family of cytokines, has been shown to have antiapoptotic, antihypertrophic, and antiinflammatory in cardiovascular disease models (Wollert and Kempf, 2012). Wang et al. (2012) have shown that GDF-15 concentrations were strongly associated with risk of HF and with mortality. A 2007 study showed that GDF-15 levels were significantly increased in patients with HF and that there was a graded relationship between the level of GDF-15 at time of study entry and the risk of death during study follow-up (Kempf et al., 2007). The Val-HeFT study demonstrated similar findings; GDF-15 was again found to be an independent predictor of death. In this study, repeat measurement of GDF-15 12 months after first measurement provided additional information. Changes in GDF-15 levels over time were independent associated with risk of mortality. Further, it was found that the intraindividual variation between GDF-15 levels in patients with stable chronic HF were lower than with other common biomarkers (Anand et al., 2010), suggesting that repeat measurements of GDF-15 may be useful in biomarker-guided therapy.

Future Directions Biomarker-Guided HF Management Prior studies examining the use of natriuretic peptides in biomarker-guided care have demonstrated mixed results (Lainchbury et al., 2009; Pfisterer et al., 2009; Januzzi et al., 2011). This heterogeneity in results appears to be related to whether or not the active arm achieved lower natriuretic peptide levels through the trial, in addition to the population being studied, with younger patients and those with heart failure with reduced ejection fraction deriving the most benefit (Yancy et al., 2013). In the Pro-BNP Outpatient Tailored Chronic Heart Failure (PROTECT) study, targeting an NT-proBNP level of 1000 pg/mL or lower resulted in a reduction in cardiovascular events in the active vs standard of care groups (Januzzi et al., 2011). A substudy provided echocardiographic evidence that left ventricular volumes and function improved with lower NT-proBNP levels, irrespective of treatment allocation within the study (Weiner et al., 2014). Multiple other studies have supported improvements in clinical HF outcomes with NT-proBNP-guided therapy (Felker et al., 2009; Porapakkham et al., 2010; Pfisterer et al., 2009). However, the largest prospective, randomized trial to date, the Guiding Evidence-Based Therapy Using Biomarker Intensified Treatment (GUIDE-IT) trial, was recently halted by the Data Safety Monitoring Board 18 months prior to planned study completion in light of an interval analysis demonstrating no difference in the primary outcome between NT-proBNP-guided management and usual care. While the formal publication of GUIDE-IT results is still pending at this time, the future of biomarker-guided therapy remains very much unclear.

Improving Risk Prediction While single biomarker studies may demonstrate relatively modest effects with respect to discrimination and reclassification metrics, several biomarkers representing distinct physiologic pathways, when combined in a multimarker approach may improve upon current risk prediction models. In the MOCA (Multinational Observational Cohort on Acute heart failure) study, multiple biomarkers showed incremental value above and beyond clinical risk factors in patients with acute decompensated heart failure. The combination of CRP and MR-proADM predicted 30-day mortality, with an NRI of 36.8%, and CRP and soluble ST2 predicted

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1-year mortality with an NRI of 20.3% (Mebazaa et al., 2015). Multimarker models have also improved upon risk prediction of future HF in community-based populations. Among Framingham Heart Study participants, the combination of natriuretic peptides, soluble ST2, GDF-15, hsTnI, and hsCRP improved clinical prediction of incident HF with an NRI of 39% (Wang et al., 2012). With the emergence of large-scale mass spectrometry and newer aptamer-based technology (Ganz et al., 2016), the ability to rapidly ascertain a large number of known and novel biomarkers will continue to refine current HF risk prediction models in the future. Lastly, it is important to acknowledge that current HF risk prediction models are focused on overall HF and group together HF with preserved and reduced ejection fraction, despite distinct pathophysiologic drivers and therapies. To this end, future studies examining biomarkers in relation to specific HF subtypes are needed.

Biomarkers in Prevention of Heart Failure Two recent studies have examined the utility of natriuretic peptides in guiding preventive efforts in HF. The St Vincent's Screening to Prevent Heart Failure (STOP-HF) trial randomized 1374 participants with cardiovascular risk factors free of HF to BNP screening versus usual care. Participants in the BNP screening arm who had elevated BNP levels of 50 pg/mL or higher underwent echocardiography and collaborative subspecialty care. Investigators found that BNP-based screenng reduced incident left ventricular dysfunction and HF and appeared cost-effective (Ledwidge et al., 2013). Similarly, in the PONTIAC (NT-proBNP Selected PreventiOn of cardiac eveNts in a populaTion of dIabetic patients without A history of Cardiac disease) study, 300 patients with elevated NT-proBNP >125 pg/mL were randomized to “intensified” treatment in a cardiac clinic focused on uptitration of medical therapy versus usual care. PONTIAC demonstrated accelerated uptitration of renin angiotensin system antagonists and betablockers in the “intensified” group, with a significant reduction in cardiac events after 2 years compared to the usual care group (Huelsmann et al., 2013). These studies suggest that biomarkers may help identify at-risk individuals and have the potential to guide preventive strategies in the future.

Conclusion Despite the widespread use of natriuretic peptides and hsTn in the diagnosis and management of HF, the clinical utility of the myriad of other cardiovascular biomarkers that have been associated with HF alone or in combination remains unclear. The field of biomarkers in HF is at an exciting inflection point with the emergence of large-scale metabolomic and proteomic platforms now allowing for rapid assessment of existing and novel circulating biomarkers. Future studies will be necessary to refine current risk prediction models using multimarker approaches and HF subtypes, with the ultimate goal of assisting clinicians in risk stratifying and treating their patients with HF.

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Biomarkers: Population Screening and Risk-Stratification I Ratjen, Christian-Albrechts-University Kiel, Kiel, Germany RS Vasan, The Framingham Heart Study, Framingham, MA, United States; Boston University School of Medicine, Boston, MA, United States; Boston University School of Public Health, Boston, MA, United States W Lieb, Christian-Albrechts-University Kiel, Kiel, Germany © 2018 Elsevier Inc. All rights reserved.

What is a Biomarker? Key Requirements and Features of a Good Biomarker Assessment of Absolute Disease Risk and Principles of Risk Prediction Biomarkers in Population Screening Risk Stratification Different Types of Biomarkers Circulating Biomarkers C-reactive protein B-type natriuretic peptide Lipoprotein-associated phospholipase A2 Troponin Genetic, Metabolomic, and Proteomic Biomarkers Genetics Metabolomics and proteomics Imaging Biomarkers Coronary artery calcium Carotid intima-media thickness Flow-mediated dilation Ankle–Brachial index Left ventricular structure and function Combination of Multiple Biomarkers (Risk Scores) Summary and Perspectives References

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What is a Biomarker? A biomarker is a reflection of a biological, physiological, or pathological process or a pharmacologic response to a therapeutic intervention that can be measured objectively, accurately, and reproducibly (adopted from Strimbu and Tavel (2010) and Biomarkers Definitions Working Group (2001)). Thus, a broad spectrum of measures can be considered as biomarkers, including markers measured in various biosamples (e.g., blood, urine, stool, or tissue), imaging tests (e.g., echocardiography, magnetic resonance imaging, or computed tomography), and (electro-)physiological measures (e.g., blood pressure, electrocardiography) (Vasan, 2006). In recent years, also complex molecular markers and marker profiles are being increasingly evaluated as potential cardiovascular biomarkers, including genetic, metabolomic, and proteomic markers (Vasan, 2006; Ussher et al., 2016). In terms of their temporal relation to disease processes and their clinical application, biomarkers can be classified, for example, as markers that identify individuals at high risk of disease, before the disease has developed (antecedent biomarkers), as biomarkers that detect subclinical changes, for example, of the heart or the vascular system (screening biomarkers), or markers that detect clinically overt disease (diagnostic biomarkers) (Biomarkers Definitions Working Group, 2001; Vasan, 2006). Among patients with established disease, biomarkers can inform treatment strategies (e.g., by predicting the response to and efficacy of a given therapy; predictive biomarkers) and help in assessing disease severity (staging biomarkers) and prognosis of patients (e.g., by predicting the future course of disease; prognostic biomarkers) (Biomarkers Definitions Working Group, 2001; Vasan, 2006).

Key Requirements and Features of a Good Biomarker In order to be applicable in clinical practice, risk stratification, or population screening, biomarkers should meet several requirements, as outlined, for example, by the American Heart Association (AHA) (Hlatky et al., 2009). First, biomarkers need to be accurately and reproducibly measurable (Manolio, 2003). Additionally, one of the most basic requirements for a novel risk marker is a strong statistically significant association with the outcome of interest, independently of other risk factors (Hlatky et al., 2009). Furthermore, the biomarker should explain a reasonable proportion of the interindividual variation of the disease outcome of interest, and improve risk prediction models beyond established risk factors (please see below for

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details) (Hlatky et al., 2009; Manolio, 2003). Some characteristics of biomarkers vary with their intended use (e.g., screening, diagnosis, prognosis) (LaBaer, 2005). For example, in clinical settings, biomarker measurements need to be acceptable to the patient, be easy to interpret by clinicians, and should be linked to patient management (Manolio, 2003), in the sense that measuring the biomarker should impact clinical decision making, and ultimately improve patient outcomes. The present article aims to focus on biomarkers in the context of risk stratification and population screening. Important basic concepts for risk stratification and population screening are the estimation of absolute disease risks and the performance of risk prediction models, both of which are detailed in the next paragraph.

Assessment of Absolute Disease Risk and Principles of Risk Prediction The cardiovascular disease (CVD) risk of a given individual is determined by a complex interplay of multiple risk factors over the life course. To reflect the multifactorial nature of CVD, risk scores have been developed that incorporate information from multiple risk factors to generate estimates of absolute disease risk. Commonly used scores include, for example, the American College of Cardiology (ACC)/AHA 2013 risk score (Goff et al., 2014), the Framingham Risk Score (FRS) (Wilson et al., 1998), the Reynolds Risk Score (Ridker et al., 2007), or the SCORE of the European Society of Cardiology (ESC) (Conroy et al., 2003). To evaluate the performance of risk scores and prediction models and to assess the incremental value of biomarkers when added to these models, different metrices have been developed, including discrimination, calibration, and reclassification. Discrimination refers to the ability of a risk prediction model to distinguish individuals who do not develop the outcome of interest over a given follow-up period from those who develop the disease of interest (Greenland et al., 2010). A common measure of discrimination is the C statistic which is equivalent to the area under the receiver operating characteristic (ROC) curve (Hanley and McNeil, 1982). The C statistic incorporates the sensitivity and specificity of a screening or diagnostic test and predicts the probability that in two randomly paired individuals, one with and one without the disease, a given model correctly identifies the one who is diseased from the one who is not. Values for the ROC or C statistic range from 0.5 (uninformative model) to 1.0 (perfect discrimination) (Wang, 2011). As an example, the FRS, which is based on traditional cardiovascular risk factors, yields a C statistic of
0.75 (Wang et al., 2006). Calibration quantifies the agreement between predicted and observed risks, that is, the disease risk as predicted by the score on the one hand, and the risk that is actually observed in a given prospective cohort on the other hand (Wang, 2011). It is usually assessed in quantiles of baseline risk and tested using the Hosmer–Lemeshow test. The observed number of events within a given time horizon is compared to the expected number of events, as predicted by the score. Importantly, when transferred to other populations, risk prediction models may have to be recalibrated, in order to account for different mean risk factor levels and differences in the incidence rates of the outcome of interest between populations (Vasan, 2006; Wilson et al., 1998). A third performance measure, reclassification, refers to the ability of a (modified) score to reclassify individuals between defined risk categories. Individuals can be assigned, for example, to low risk, intermediate risk, and high risk, based on their absolute disease risk estimates. When a given score is modified (e.g., by adding a new biomarker to the model), some individuals will shift between risk categories because the predicted risk in the baseline model belonged to a different risk category than their risk based on the modified score. Reclassification refers to the proportion of individuals that is correctly assigned to a new risk category, once additional information is added to the risk prediction model, for example, by including information from a new biomarker (Hlatky et al., 2009). Reclassification of intermediate-risk individuals to the low- or high-risk category might be particularly helpful because for intermediate-risk individuals, treatment decisions are usually less clear as compared to low- and high-risk individuals (Helfand et al., 2009). However, simply quantifying the proportion of individuals that are being reclassified might be misleading, because down-classifying individuals who actually develop an event is inappropriate as is upward-classification of individuals who remain free of CVD. The net reclassification improvement (NRI) (Pencina et al., 2008) subtracts incorrectly reclassified individuals from the number of individuals who are correctly reclassified (in the right direction (upward-classification of individuals with an event during follow-up; downward-classification of individuals free of an event during follow-up). As an orientation, changes in the C statistic of >0.01 and an NRI >10% indicate meaningful improvement in risk prediction when adding a new biomarker to a traditional model (Folsom, 2013). More recently, Pencina et al. (2011) presented a modified version of the NRI, the continuous or category-free NRI, that counts the direction of change in an extended risk prediction model for every person rather than the crossing of a threshold (Pickering and Endre, 2012). In scenarios where no established categories of risk exist (or risk categories have no clinical/practical consequences), it might be more appropriate to use the continuous NRI (Pencina et al., 2011). As outlined by the AHA, novel biomarkers should improve the performance of risk prediction models beyond established risk factors (Greenland et al., 2010), including the reclassification of individuals in more appropriate risk strata, and the identification of particularly vulnerable people.

Biomarkers in Population Screening One of the main purposes of screening biomarkers in the general population is to identify individuals who are at high risk of future CVD but who are currently free of clinical CVD and who might benefit from some sort of intervention (lifestyle modification or pharmacological treatment) to prevent clinically overt disease. In order to serve this purpose, it is important that such biomarkers capture the disease process at an early stage and, for example, detect subclinical changes of the vascular or cardiac system that might

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predispose to overt CVD (Vasan, 2006; Naghavi et al., 2003) but that are potentially reversible or whose progression could be slowed down upon appropriate intervention. As an important hallmark, screening markers should have good discriminative abilities. Thus, they should be able to distinguish between individuals with future CVD and individuals who will remain free of CVD. One fundamental basis for such discrimination abilities is a very strong association between the biomarker level and future disease risk (Wald et al., 1999). In this context, it is worth noting that most causal risk factors (including high blood pressure and LDL-cholesterol) do not represent good screening tools because the distribution of risk factor levels in individuals with versus without the disease may substantially overlap leading to a low discrimination of these markers (Wald et al., 1999). In primary prevention settings, high specificity of a biomarker is particularly important because mislabeling a healthy individual (predicting disease when it is likely to be absent) can cause unnecessary anxiety, medical follow-up examinations (with associated costs), and treatment and may outweigh the consequences of missing a rare condition (Piepoli et al., 2016). However, extensive community screening in people at relatively low risk of CVD is uncertain to be effective in reducing the risk of cardiovascular events. The costs of such screening are high, and it is conceivable that these resources may be more efficiently used in people with higher baseline CVD risk (Piepoli et al., 2016). Official recommendations: Thus, the ESC does not recommend general systematic CVD risk assessment in men 50 years of age or in postmenopausal women without known risk factors. Additionally, the ESC recommends a regular repetition of risk assessment, for example, every 5 years (Piepoli et al., 2016). Similarly, the ACC/AHA guidelines recommend the estimation of absolute 10-year CVD risk beginning at the age of 40 years. The estimation of long-term or lifetime risk is recommended for individuals between 20 and 39 years of age and for those between 40 and 59 years of age who are determined to be at low 10-year risk (70 years of age (Mehra et al., 2006, 2016). Long-term follow-up of patients >65 years after cardiac transplant revealed similar 10-year survival and causes of death when compared with younger patients (groups included recipients 65 years); there was no difference in freedom from severe infection, cancer, or severe graft vasculopathy (Zuckermann et al., 2003). Moreover, older patients displayed immunosenescence, or a gradual decline in the immune system with age, leading to fewer rejection episodes and a larger percentage of patients who were not on maintenance steroid therapy. Review of the UNOS database (n ¼ 50,432) for transplanted patients from 1987 to 2014 confirmed similar outcomes for recipients in their 70s compared with recipients in their 60s despite being more likely to receive organs from donors with a history of tobacco, alcohol, or cocaine use or donors considered high risk for transmission of disease (Cooper et al., 2016). Contrary evidence has endorsed reduced survival in older recipients (Tjang et al., 2008; Marielli et al., 2008), therefore leading to current guideline recommendations to carefully select older patients based on comorbidities, such as renal function, with specific donor and recipient criteria in place at the transplanting center (Mehra et al., 2016). Upper age limit remains center-specific criteria with each individual center determining if they will have an absolute cutoff for candidacy based upon chronologic age.

Obesity Obesity in cardiac surgery is associated with complications of infections, poor wound healing, pulmonary status, and thromboembolic events. Risk associated with transplantation involves higher risk of rejection, vasculopathy, and mortality (Lietz et al., 2001). Weight gain is a likelihood posttransplant due to cardiac cachexia with end-stage heart failure, and is often related to age and gender (Williams et al., 2006); progression of preexisting comorbidities is a reality for this reason in addition to immunosuppression regimens that can affect weight gain and blood sugar. Therefore, recipient weight is an essential parameter for candidacy, measured as body mass index (BMI, weight in kilograms per height in meters squared) or percent ideal body weight (PIBW) for a given height and gender. Both measurements take into account height as opposed to considering weight only. The International Society for Heart and Lung Transplantation (ISHLT) guidelines recommend a pretransplant BMI 6, or a transpulmonary gradient >15 mmHg (difference of the mean PA and wedge pressure), transplant candidacy is usually not considered unless provocative testing with a vasodilator reduces the pressures and PVR to an acceptable level while maintaining a systemic blood pressure >85 mmHg

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Contraindications in cardiac transplantation (Mehra et al., 2016)

Advanced age (select patients >70 years) Obesity • BMI >35 kg/m2 or PIBW >140% Fixed pulmonary hypertensiont

• • • •

PVR >5 Woods units TPG >15 mmHg PA systolic pressure >50–60 mmHg or >50% systemic pressure in conjunction with the above parameters Inability to reduce PVR 85 mmHg

Diabetes mellitus complications • Persistent poorly controlled (Hgb A1c > 7.5 mg/dL) • End-organ complications other than nonproliferative retinopathy Irreversible renal, hepatic, or pulmonary disease unless undergoing dual organ transplantation Irreversible renal dysfunction with eGFR 10  99th percentile URL in patients with normal baseline cTn values (99th percentile URL). In addition, either (i) new pathological Q waves or new LBBB, or (ii) angiographic documented new graft or new native coronary artery occlusion, or (iii) imaging evidence of new loss of viable myocardium or new regional wall-motion abnormality.

Type 1 Versus Type 2 Myocardial Infarction Although some cases may be easily explained retrospectively, the prospective classification of a type 1 MI versus a type 2 MI is challenging without information on coronary anatomy such as the presence of plaque rupture, erosion, fissure, or dissection. Although there may be some differences regarding troponin peak concentrations, kinetic changes, and baseline clinical characteristics, a prospective classification is virtually impossible. Reports on the prevalence of type 2 MI are very heterogeneous. Since the diagnostic criteria include a wide range of clinical conditions, these often vary between studies due to variable interpretations of the universal definition (Collinson and Lindahl, 2015; Chapman et al., 2017). A higher prevalence of type 2 MI has been reported for women (Cediel et al., 2017). There are no data showing that a type 2 MI has to be treated the same way like a type 1 MI, that is, no data on the role of dual platelet inhibition, usefulness of ticagrelor or prasugrel, duration of treatment, or adjunctive therapies including anticoagulation and glycoprotein IIb/IIIa inhibitors. Importantly, mortality rates of patients with type 2 MI seem to be higher than mortality rates in patients with type 1 MI (Cediel et al., 2017; Saaby et al., 2013). Since type 2 MI is the only type of MI unrelated to coronary occlusion, some authors have suggested that future MI definitions should be more restrictive and group current type 2 MI with myocardial injury due to nonischemic causes (Nagele, 2016).

Type 4a MI (MI Associated With PCI) One important update in the current universal definition of MI takes into account the commonly observed troponin elevations after PCI. In the previous definition of MI, 15% of all patients treated with PCI were classified as having type 4a MI, since any elevation above 3 of the URL was considered as a periprocedural MI even when patients had no symptoms (Testa et al., 2009). The updated and current criteria had the goal of increasing the prognostic relevance of type 4a MI diagnoses, now demanding both clinical signs for myocardial ischemia and elevation above 5 of the URL when troponin levels are normal before PCI. In patients with elevated troponin levels before PCI, an increase of 20% is diagnostic if troponin levels were stable or falling beforehand. It now appears that rates of type 4 a MI have declined after introduction of the revised criteria. Myocardial injury, however, is still detectable in a substantial proportion of patients following elective PCI with or without stenting. Causes for periprocedural cTn elevations are multifactorial with a predominance of side branch occlusion (Park et al., 2013). Monitoring of periprocedural myocardial injury is feasible with cTn. However, it should be remembered that considerably higher increases from ULN are

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required using cTn or hsTn instead of CKMB in order to predict the same prognostically equivalent amount of injury due to the substantial higher sensitivity of cTn and particularly hsTn (Katus et al., 1991a; Apple, 2009). The thresholds for cTn defining a type 4a MI were set arbitrarily by convention in light of sparse study findings. In order to detect postprocedural myocardial injury or type 4a MI, serial measurements immediately before and up to 48 h post PCI are recommended (Thygesen et al., 2012). The consequences of relevant myocardial injury or a type 4a MI include extended monitoring for arrhythmias and reevaluation of procedural success.

The Electrocardiogram (ECG): First and Crucial Diagnostic Tool An electrocardiogram (ECG) should be obtained and interpreted by a physician within 10 min after admission (Roffi et al., 2016; Amsterdam et al., 2014). When patients present with significant ST elevations in at least two contiguous leads, presumed new left bundle branch block, anterior ST depressions indicative of true posterior MI, or ST elevation in aVR in combination with ST depression in eight or more surface leads suggestive of multivessel or left main coronary artery disease, immediate coronary angiography should be performed. Depending on the localization of infarction, ST segment elevations may be observed in anterior leads (V1–V6), inferior leads (II, III, and aVF), lateral/apical leads (I and aVL), and in leads representing the free wall of the right ventricle (V3R and V4R) or the inferobasal wall (V7–V9). In the third definition of MI, minor important modifications have been made to the ECG criteria, acknowledging age- and gender-specific differences in leads V2–V3. In these two leads, ST segment elevations are considered significant when the J point is elevated  0.15 mV in women,  0.2 mV in men  40 years, and  0.25 mV in men under 40 years. In all other leads, an elevation  0.1 mV is considered diagnostic (Table 1). True posterior MI may present with ST elevation in posterior chest leads V7–V9 and ST depression in V1–V3, which is why additional obtainment of ECG leads V7–V9 in patients with initial nondiagnostic ECG at intermediate/high risk for ACS is recommended. In the opinion of the authors, routine obtainment of V7–V9 should be considered in all patients with suspected MI. In patients with inferior MI and suspected right ventricular infarction, right precordial leads (V3R and V4R) should be obtained. In these leads, an ST elevation  0.05 mV ( 0.1 mV in men 0.1 mV in eight or more surface leads, multivessel or left main coronary artery disease should be suspected (Yan et al., 2007) (Figs. 1 and 2). ECG interpretation can be difficult in patients with left or right bundle branch block, early repolarization, and persisting ST elevations due to a residual aneurysm or due to incorrectly positioned leads. In patients with preexisting left bundle branch block (LBBB), comparison with a previous ECG and concordant ST elevations may help detect acute MI (Lopes et al., 2011).

Prior MI Regardless of symptoms, Q waves and QS complexes in the absence of left ventricular hypertrophy and LBBB suggest prior MI (Savage et al., 1977). The current universal definition specifies any Q wave in V2–V3 >0.02 s or QS complex in V2 and V3 as significant. Furthermore, Q waves  0.03 s and  0.1 mV deep or QS complex in two contiguous leads I, II, aVL, aVF or V4–V6 (or V7–V9) are considered significant. Prior MI may also be diagnosed in the presence of an R wave  0.04 s in V1–V2 and R/S  1 with a concordant positive T wave. New pathological Q waves in asymptomatic patients may be indicative of previous silent MI. It is important to remember that ST-T abnormalities are frequent in patients with Brugada syndrome, stress cardiomyopathy and early repolarization syndrome, making diagnosis of acute myocardial ischemia solely with ECG sometimes impossible. However, new ST segment elevations for a prolonged period of time in combination with reciprocal ST segment depressions are usually due to acute coronary occlusion (Wang et al., 2003). Other conditions associated with ST-T abnormalities are peri-/myocarditis, pulmonary embolism, hypothermia, intracranial processes, and electrolyte abnormalities.

Table 1

ECG manifestations of acute myocardial ischemia

ST elevation New ST elevation at the J point in two contiguous leads with the cut points: 0.1 mV in all leads other than leads V2–V3 where the following cut points apply:  0.2 mV in men 40 years, 0.25 mV in men 1 Thygesen, K. et al. (2012). Third universal definition of myocardial infarction. Journal of the American College of Cardiology 60, 1581–1598, modified by permission of Elsevier.

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Fig. 1 ECG of a patient with mild ST elevation in lead aVR and accompanying ST segment depressions in eight leads. Immediate coronary angiography revealed occlusion of left anterior descending artery and critical left main stenosis in this patient.

Fig. 2 Coronary angiogram of a patient with left main stem stenosis.

Cardiac Troponin: Preferred and Gold Standard Biomarker Cardiac troponin is a regulatory protein of the myocardial contractile apparatus. Of its three subtypes (troponin T, I, and C), only cardiac troponin T (cTnT) and troponin I (cTnI) are solely expressed in cardiomyocytes. Elevations of cTnT or cTnI therefore indicate myocardial injury (Katus et al., 1991a). Cardiac troponin is released during the first 24 h from the cytoplasmic pool. A plateau is reached after 48–72 h due to proteolytic degradation of the contraction apparatus (Katus et al., 1991b; Remppis et al., 1994). Rising

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and/or falling troponin levels and markedly elevated troponin levels at admission increase likelihood of acute myocardial injury. Stable serial troponin values are indicative of chronic myocardial injury. Laboratories should ensure certain quality standards, including an assay precision 10% coefficient of variation (CV) at the 99th percentile URL. Several manufacturers improved analytic sensitivities and precision of their assays at the 99th percentile value considerably. By convention, assays are graded by sensitivity and precision. Distinctions are made between guide acceptable, clinically useable, and not acceptable assays. Highsensitivity assays are further classified by their ability to measure cTn in healthy persons. Accordingly, a troponin assay can only be labeled hs if the assay can quantify concentrations in at least 50% of healthy subjects (Apple, 2009).

Cardiac Imaging in Patients with Suspected MI Diagnosis of MI can be made in the presence of evidence of new regional wall-motion abnormalities in echocardiography, myocardial scars in MRI or in nuclear tests, or an intracoronary thrombus during coronary angiography in combination with a significant rise and/or fall of cardiac troponin even in the absence of clinical symptoms. Transthoracic echocardiography (TTE) should always be available in chest pain units and emergency rooms. TTE allows detection of regional wall abnormalities and helps detect signs of other nonischemic causes of chest pain such as myocarditis, valvular disease, cardiomyopathy, pulmonary embolism, or aortic dissection. Another advantage of echocardiography is the detection of complications of MI such as ventricular wall rupture, secondary mitral valve regurgitation after papillary muscle rupture, or ischemia (Flachskampf et al., 2011). Myocardial disease can best be assessed with cardiac MRI. Multidetector computed tomography for anatomical evaluation of coronary arteries may be helpful in patients with low to intermediate pretest probability for ACS. In such patients, a normal CT scan can exclude coronary artery disease (Samad et al., 2012).

Diagnostic Protocols Introduction of hsTn assays has reduced the time to collect the second sample from 6–9 h after the first sampling to 3 h (Roffi et al., 2016). In countries and hospitals without access to hsTn, retesting of cTn should be performed 3–6 h after presentation with the use of a contemporary sensitive cTn or after 6–9 h with almost all POCT assays due to the lower analytic sensitivity. More recently, faster diagnostic protocols have been recommended by ESC guidelines as an alternative to the standard 0–3 h protocol. The 0–1 h accelerated diagnostic protocols for rule-out and rule-in are explicitly recommended provided that one of three validated hsTn assays is used (Roche Elecsys hsTnT, Abbott hsTnI Architect STAT or Siemens Dimension Vista hsTnI) (Roffi et al., 2016). MI can also be ruled out immediately in low-risk patients with undetectable admission levels below limit of detection (LoD) or limit of blank (LoB) without the need for a second sample. As an evolving or small MI may be missed during the short hs troponin blank period, an instant rule-out protocol should not be applied to very early presenters, who are presenting within 1 h after onset of symptoms. Conversely, in patients with very high troponin elevations at time of presentation, the diagnosis of MI is very likely with a positive predictive value of >85%, sometimes obviating the need for a second cTn sample (Mueller-Hennessen et al., 2017). This management cutoff may prompt immediate coronary angiography for suspected large MI in a typical clinical context. However, it is important to always consider other acute myocardial or valvular pathologies or acute endocarditis, which may also present with high initial troponin values and require different management. In order to increase practicability and permit a safer rule-out and discharge, some algorithms, particularly a 2 h accelerated diagnostic protocol with cTn measurements at 0 and 2 h, recommend implementation of a clinical risk score and ECG criteria (Than et al., 2012). Faster diagnostic algorithms generate an intermediate (or observational) diagnostic zone for patients who neither fulfill criteria for rule-out nor for rule-in. The final adjudicated diagnoses of patients in such an observational zone include NSTEMI but more often myocardial injury due to other reasons than ACS. Such patients often are male, have more comorbidities, are of higher age, have renal impairment, and have underlying cardiovascular disease. Long-term outcomes may be comparable with those of patients with confirmed MI (Nestelberger et al., 2016). Patients in the observational zone require monitoring, serial cTn testing, and extended diagnostics in order to provide an accurate diagnosis and specific treatment. Cardiac imaging with echocardiography and multislice CT are increasingly important for the diagnostic workup of patients in this subgroup. When sensitive or high-sensitivity cardiac troponin assays are unavailable, additional measurement of copeptin at admission is recommended. Normal copeptin levels without elevated cardiac troponin levels at presentation allow safe rule-out of MI. All algorithms should only be used in the context of the overall presentation of the patient. When patients arrive less than 1 h after onset of chest pain, testing after 3 h should be performed. Whenever there is high clinical suspicion or when symptoms persist, additional measurements should be performed.

Age- and Gender-Specific Cutoffs The introduction of more sensitive cTn assays allows detection of lower concentrations in women than in men, reflecting anatomical and functional differences of the heart between genders. The universal definition of MI recommends the use of

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sex-specific cutoffs, but validation in prospective trials is not available, and existing evidence is controversial regarding the relevance of sex-specific cutoffs for diagnostic or prognostic classification. So far, diagnostic protocols recommend a single sex-independent cutoff for the standard 0–3 h algorithm and for the faster alternatives using hsTnT or hsTnI (Roffi et al., 2016). It should be noted that implementation of sex-specific cutoffs may improve diagnosis of MI to a small extent but only at the cost of practicability complicating diagnosis extraordinarily, particularly if other comorbidities such as renal failure, heart failure, or age that can confound the troponin result are considered as well (Mueller-Hennessen et al., 2016).

Conclusion The current version of the universal definition of MI allows for a precise and consistent diagnosis of MI. Clinicians and researchers are strongly encouraged to study the detailed criteria to correctly diagnose or rule out acute MI.

Conflicts of Interest MV has received financial support for clinical trials from Bayer Healthcare Germany and has been reimbursed for travel expenses and fees associated with attending seminars and conferences by Bayer Vital, Daiichi Sankyo, Octapharma, Lilly Germany, GlaxoSmithKline, Roche Diagnostics, TEVA, Brahms, Leo Pharma, and Abbott. Dr. Giannitsis has received financial support for clinical trials from Roche Diagnostics Ltd., Switzerland; Mitsubishi Chemicals, Germany; Siemens Healthcare; BRAHMS Biomarkers; Clinical Diagnostics Division; and Thermo Fisher Scientific, Germany. He is consultant to Roche Diagnostics and BRAHMS Biomarkers and has received speaker’s honoraria from Roche Diagnostics, Siemens Healthcare, BRAHMS Biomarkers, and Mitsubishi Chemicals.

References Alpert JS, Thygesen K, Antman E, and Bassand JP (2000) Myocardial infarction redefined—A consensus document of The Joint European Society of Cardiology/American College of Cardiology Committee for the redefinition of myocardial infarction. Journal of the American College of Cardiology 36: 959–969. Amsterdam EA, Wenger NK, Brindis RG, Casey DE Jr., Ganiats TG, Holmes DR Jr., Jaffe AS, Jneid H, Kelly RF, Kontos MC, Levine GN, Liebson PR, Mukherjee D, Peterson ED, Sabatine MS, Smalling RW, and Zieman SJ (2014) 2014 AHA/ACC guideline for the management of patients with Non-ST-elevation acute coronary syndromes: A report of the American college of cardiology/American heart association task force on practice guidelines. Journal of the American College of Cardiology 64: e139–e228. Apple FS (2009) A new season for cardiac troponin assays: It’s time to keep a scorecard. Clinical Chemistry 55: 1303–1306. Cediel G, Gonzalez-Del-Hoyo M, Carrasquer A, Sanchez R, Boque C, and Bardaji A (2017) Outcomes with type 2 myocardial infarction compared with non-ischaemic myocardial injury. Heart 103: 616–622. Chapman AR, Adamson PD, and Mills NL (2017) Assessment and classification of patients with myocardial injury and infarction in clinical practice. Heart 103: 10–18. Collinson P and Lindahl B (2015) Type 2 myocardial infarction: The chimaera of cardiology? Heart 101: 1697–1703. Flachskampf FA, Schmid M, Rost C, Achenbach S, Demaria AN, and Daniel WG (2011) Cardiac imaging after myocardial infarction. European Heart Journal 32: 272–283. Katus HA, Remppis A, Neumann FJ, Scheffold T, Diederich KW, Vinar G, Noe A, Matern G, and Kuebler W (1991a) Diagnostic efficiency of troponin T measurements in acute myocardial infarction. Circulation 83: 902–912. Katus HA, Remppis A, Scheffold T, Diederich KW, and Kuebler W (1991b) Intracellular compartmentation of cardiac troponin T and its release kinetics in patients with reperfused and nonreperfused myocardial infarction. American Journal of Cardiology 67: 1360–1367. Lopes RD, Siha H, Fu Y, Mehta RH, Patel MR, Armstrong PW, and Granger CB (2011) Diagnosing acute myocardial infarction in patients with left bundle branch block. American Journal of Cardiology 108: 782–788. Lopez-Sendon J, Coma-Canella I, Alcasena S, Seoane J, and Gamallo C (1985) Electrocardiographic findings in acute right ventricular infarction: Sensitivity and specificity of electrocardiographic alterations in right precordial leads V4R, V3R, V1, V2, and V3. Journal of the American College of Cardiology 6: 1273–1279. Mendis S, Thygesen K, Kuulasmaa K, Giampaoli S, Mahonen M, Blackett K, and Lisheng L (2011) World Health Organization definition of myocardial infarction: 2008–09 revision. International Journal of Epidemiology 40: 139–146. Mueller-Hennessen M, Lindahl B, Giannitsis E, Biener M, Vafaie M, Defilippi CR, Christ M, Santalo-Bel M, Panteghini M, Plebani M, Verschuren F, Jernberg T, French JK, Christenson RH, Body R, McCord J, Dilba P, Katus HA, and Mueller C (2016) Diagnostic and prognostic implications using age- and gender-specific cut-offs for high-sensitivity cardiac troponin T—Sub-analysis from the TRAPID-AMI study. International Journal of Cardiology 209: 26–33. Mueller-Hennessen M, Mueller C, Giannitsis E, Biener M, Vafaie M, Defilippi CR, Christ M, Ordonez-Llanos J, Panteghini M, Plebani M, Verschuren F, Melki D, French JK, Christenson RH, Body R, McCord J, Dinkel C, Katus HA, and Lindahl B (2017) Serial sampling of high-sensitivity cardiac troponin T May Not Be required for prediction of acute myocardial infarction diagnosis in chest pain patients with highly abnormal concentrations at presentation. Clinical Chemistry 63: 542–551. Nagele P (2016) The case for a revised definition of myocardial infarction-resolving the ambiguity of type 2 myocardial infarction. JAMA Cardiology 1: 247–248. Nestelberger T, Wildi K, Boeddinghaus J, Twerenbold R, Reichlin T, Gimenez MR, Puelacher C, Jaeger C, Grimm K, Sabti Z, Hillinger P, Kozhuharov N, Du Fay De Lavallaz J, Pinck F, Lopez B, Salgado E, Miro O, Bingisser R, Lohrmann J, Osswald S, and Mueller C (2016) Characterization of the observe zone of the ESC 2015 high-sensitivity cardiac troponin 0 h/1 h-algorithm for the early diagnosis of acute myocardial infarction. International Journal of Cardiology 207: 238–245. Park DW, Kim YH, Yun SC, Ahn JM, Lee JY, Kim WJ, Kang SJ, Lee SW, Lee CW, Park SW, and Park SJ (2013) Frequency, causes, predictors, and clinical significance of periprocedural myocardial infarction following percutaneous coronary intervention. European Heart Journal 34: 1662–1669. Remppis A, Scheffold T, Karrer O, Zehelein J, Hamm C, Grunig E, Bode C, Kubler W, and Katus HA (1994) Assessment of reperfusion of the infarct zone after acute myocardial infarction by serial cardiac troponin T measurements in serum. British Heart Journal 71: 242–248. Roffi M, Patrono C, Collet JP, Mueller C, Valgimigli M, Andreotti F, Bax JJ, Borger MA, Brotons C, Chew DP, Gencer B, Hasenfuss G, Kjeldsen K, Lancellotti P, Landmesser U, Mehilli J, Mukherjee D, Storey RF, Windecker S, Baumgartner H, Gaemperli O, Achenbach S, Agewall S, Badimon L, Baigent C, Bueno H, Bugiardini R, Carerj S, Casselman F, Cuisset T, Erol C, Fitzsimons D, Halle M, Hamm C, Hildick-Smith D, Huber K, Iliodromitis E, James S, Lewis BS, Lip GY, Piepoli MF, Richter D, Rosemann T, Sechtem U, Steg PG, Vrints C, and Luis Zamorano J (2016) 2015 ESC Guidelines for the management of acute coronary syndromes in patients presenting without persistent ST-segment elevation: Task Force for the Management of Acute Coronary Syndromes in Patients Presenting without Persistent ST-Segment Elevation of the European Society of Cardiology (ESC). European Heart Journal 37: 267–315.

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Saaby L, Poulsen TS, Hosbond S, Diederichsen ACP, Larsen TB, Gerke O, Hallas J, Thygesen K, and Mickley H (2013) Mortality in type 1 vs. type 2 myocardial infarction. European Heart Journal 34: P1331. Samad Z, Hakeem A, Mahmood SS, Pieper K, Patel MR, Simel DL, and Douglas PS (2012) A meta-analysis and systematic review of computed tomography angiography as a diagnostic triage tool for patients with chest pain presenting to the emergency department. Journal of Nuclear Cardiology 19: 364–376. Savage RM, Wagner GS, Ideker RE, Podolsky SA, and Hackel DB (1977) Correlation of postmortem anatomic findings with electrocardiographic changes in patients with myocardial infarction: Retrospective study of patients with typical anterior and posterior infarcts. Circulation 55: 279–285. Testa L, Van Gaal WJ, Biondi Zoccai GG, Agostoni P, Latini RA, Bedogni F, Porto I, and Banning AP (2009) Myocardial infarction after percutaneous coronary intervention: A metaanalysis of troponin elevation applying the new universal definition. QJM 102: 369–378. Than M, Cullen L, Aldous S, Parsonage WA, Reid CM, Greenslade J, Flaws D, Hammett CJ, Beam DM, Ardagh MW, Troughton R, Brown AF, George P, Florkowski CM, Kline JA, Peacock WF, Maisel AS, Lim SH, Lamanna A, and Richards AM (2012) 2-hour accelerated diagnostic protocol to assess patients with chest pain symptoms using contemporary troponins as the only biomarker: The ADAPT trial. Journal of the American College of Cardiology 59: 2091–2098. Thygesen K, Alpert JS, and White HD (2007) Universal definition of myocardial infarction. European Heart Journal 28: 2525–2538. Thygesen K, Alpert JS, Jaffe AS, Simoons ML, Chaitman BR, White HD, Katus HA, Apple FS, Lindahl B, Morrow DA, Clemmensen PM, Johanson P, Hod H, Underwood R, Bax JJ, Bonow JJ, Pinto F, Gibbons RJ, Fox KA, Atar D, Newby LK, Galvani M, Hamm CW, Uretsky BF, Steg PG, Wijns W, Bassand JP, Menasche P, Ravkilde J, Ohman EM, Antman EM, Wallentin LC, Armstrong PW, Januzzi JL, Nieminen MS, Gheorghiade M, Filippatos G, Luepker RV, Fortmann SP, Rosamond WD, Levy D, Wood D, Smith SC, Hu D, LopezSendon JL, Robertson RM, Weaver D, Tendera M, Bove AA, Parkhomenko AN, Vasilieva EJ, Mendis S, Baumgartner H, Ceconi C, Dean V, Deaton C, Fagard R, Funck-Brentano C, Hasdai D, Hoes A, Kirchhof P, Knuuti J, Kolh P, McDonagh T, Moulin C, Popescu BA, Reiner Z, Sechtem U, Sirnes PA, Torbicki A, Vahanian A, Windecker S, Morais J, Aguiar C, Almahmeed W, Arnar DO, Barili F, Bloch KD, Bolger AF, Botker HE, Bozkurt B, Bugiardini R, Cannon C, De Lemos J, Eberli FR, Escobar E, Hlatky M, James S, Kern KB, Moliterno DJ, Mueller C, Neskovic AN, Pieske BM, Schulman SP, Storey RF, Taubert KA, Vranckx P, and Wagner DR (2012) Third universal definition of myocardial infarction. Journal of the American College of Cardiology 60: 1581–1598. Wang K, Asinger RW, and Marriott HJ (2003) ST-segment elevation in conditions other than acute myocardial infarction. New England Journal of Medicine 349: 2128–2135. Wong CK, Gao W, Stewart RA, Benatar J, French JK, Aylward PE, and White HD (2010) aVR ST elevation: An important but neglected sign in ST elevation acute myocardial infarction. European Heart Journal 31: 1845–1853. Yan AT, Yan RT, Kennelly BM, Anderson FA Jr., Budaj A, Lopez-Sendon J, Brieger D, Allegrone J, Steg G, and Goodman SG (2007) Relationship of ST elevation in lead aVR with angiographic findings and outcome in non-ST elevation acute coronary syndromes. American Heart Journal 154: 71–78.

Further Reading Nomenclature and Criteria (1979) Nomenclature and criteria for diagnosis of ischemic heart disease. Report of the Joint International Society and Federation of Cardiology/World Health Organization task force on standardization of clinical nomenclature. Circulation 59: 607–609.

Diet in Heart Failure M Rozmahel, University of Alberta, Edmonton, AB, Canada E Colin-Ramirez, National Institute of Cardiology ‘Ignacio Chavez’, Mexico City, Mexico JA Ezekowitz, University of Alberta, Edmonton, AB, Canada © 2018 Elsevier Inc. All rights reserved.

Heart Failure Diet in Heart Failure Dietary Sodium Intake Recommendations Clinical Studies on Dietary Sodium Intake in HF Fluid Intake Macronutrients Energy and Protein Macronutrient Composition of the Diet Omega-3 Supplementation Micronutrients Factors Related to Micronutrient Deficiency in HF Micronutrient Recommendations Cardiac Cachexia Diagnosis of Cardiac Cachexia Treatment of Cardiac Cachexia Dietary Patterns The Dietary Approaches to Stop Hypertension (DASH) Diet The Mediterranean Diet Conclusion References Further Reading

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Heart Failure Chronic heart failure (HF) is a growing public health problem associated with significant mortality, morbidity, and health care expenditures (Roger, 2013). It affects approximately 5.7 million Americans and carries a 5-year mortality rate of
50%. The prevalence of HF is expected to rise 46% from 2012 to 2030, due to improvements in medical and nonpharmacological care, allowing more patients to survive acute myocardial infarction and live to an older age (Mozaffarian et al., 2015). At present, approximately 1.5%–2% of Canadians are affected with HF (Ezekowitz et al., 2011). Heart failure occurs when the heart is unable to maintain an adequate cardiac output to meet metabolic requirements of the rest of the body (Kemp and Conte, 2012). HF induces a systemic response, leading to the activation of neurohormonal systems characterized by an overexpression of the sympathetic and renin–angiotensin aldosterone system. While this is initially beneficial in maintaining renal and organ perfusion, it becomes maladaptive over time and causes the exacerbation of hemodynamic abnormalities found in HF. This results in further remodeling and neurohormonal release and progressive cardiac impairment, leading to excessive sodium and fluid retention (Colin-Ramirez and Ezekowitz, 2016). This disruption contributes to the signs and symptoms seen in patients with HF, greatly affecting health-related quality of life and physical functioning (Yancy et al., 2013). Common symptoms include dyspnea from pulmonary congestion, peripheral edema from impaired venous return, nausea, lack of appetite, and fatigue (Kemp and Conte, 2012).

Diet in Heart Failure Dietary Sodium Intake Recommendations The disruption of various complex compensatory mechanisms in patients with HF alters the patient's ability to effectively balance salt intake and excretion, resulting in a significant amount of sodium and fluid retention. An excessive sodium intake can further increase this retention, causing the exacerbation of HF symptoms. Thus, dietary sodium restriction has been considered a major selfcare behavior recommended to these patients. However, due to a lack of conclusive evidence regarding the association between reduced sodium consumption and clinical events in the HF population, there is an inconsistency that exists among current recommendations for sodium intake in HF (Colin-Ramirez and Ezekowitz, 2016). The American College of Cardiology (ACC) and the American Heart Association (AHA) recommend decreasing sodium intake in patients with symptomatic HF, based on the association between sodium intake and hypertension, LV hypertrophy, and cardiovascular disease. It is recommended that stage

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A and B HF patients restrict their sodium intake to 1500 mg/day, while stage C and D patients consume 2800 mg/day) are at greater risk of an acute decompensated HF (ADHF) event (Arcand et al., 2011), while a recent longitudinal cohort study showed that a sodium intake 95% chance of successful repair and 50 mm Hg) mitral valve repair is also reasonable (Class IIa) (Nishimura et al., 2017). In general, mitral valve repair is preferable to replacement, the latter surgery used either after failed valve repair or if the anatomy is unsuitable for repair (Nishimura et al., 2017). Concomitant mitral valve surgery is indicated in patients undergoing other cardiac procedures with chronic severe (Class I) or chronic moderate (Class IIb) MR (Nishimura et al., 2017).

Secondary Mitral valve surgery is reasonable in chronic severe Stage C or D patients who are undergoing Coronary Artery Bypass Grafting (CABG) or Aortic Valve Replacement (AVR) (Class IIa) (Nishimura et al., 2017). Mitral valve surgery may be considered in Stage B patients who are undergoing cardiac surgery for other indications (Class IIb) (Nishimura et al., 2017). In the severely symptomatic NYHA III or IV Stage D patient with persistent symptoms despite optimal GDMT, mitral valve surgery should be considered (Class IIb) (Nishimura et al., 2017).

Pregnancy and MR Patients with MR generally tolerate pregnancy well in the absence of significant left ventricular dysfunction. While plasma volume rises by 50%, the systemic vascular resistance is reduced in pregnancy, therefore reducing the regurgitant volume across the mitral valve. However, patients with preexisting left ventricular dysfunction, pulmonary hypertension, or heart failure may experience exacerbation of MR symptoms. AHA/ACC guidelines recommend that all patients with suspected MR should undergo TTE before pregnancy (Class I) (Nishimura et al., 2017). All patients with severe MR (Stage C or D) should have prepregnancy counseling with a cardiologist with expertise in managing such patients (Class I) (Nishimura et al., 2017). These Stage C or D patients should be followed in a tertiary care center by a Heart Valve Team consisting of cardiologists, surgeons, anesthesiologists, and obstetricians (Class I) (Nishimura et al., 2017). As in patients with MS, angiotensin-converting enzyme inhibitors and angiotensin receptor blockers should be avoided during gestation (Class III harm) (Nishimura et al., 2017). In terms of surgical intervention, valve repair or replacement is recommended before pregnancy in Stage D patients (Class I) (Nishimura et al., 2017). Valve repair before pregnancy in the asymptomatic severe MR patient (Stage C) may be considered in patients with suitable valve morphology with whom detailed discussions regarding the operation and associated risks have taken place (Class IIb) (Nishimura et al., 2017). During pregnancy, valve operation is reasonable in the Stage D patient with intractable NYHA IV heart failure symptoms (Class IIa) (Nishimura et al., 2017). There is a Class III harm indication for such patients in the absence of heart failure symptoms (Nishimura et al., 2017).

Mitral Valve Prolapse Background Mitral valve prolapse (MVP) is the abnormal excessive motion of part or all of one or both mitral valve leaflets behind the mitral annulus into the left atrium during systole as seen in outflow tract views. It is the most commonly diagnosed valvular disorder and the most prevalent MR etiology requiring surgical intervention (Guy et al., 1980). MVP occurs in around 5% of the general population, with women exhibiting a higher incidence than their male counterparts (Devereux et al., 1986). However, this incidence was seen to be variable with age amongst females in the Framingham Study. MVP rates were found to be as high as 17% in females aged 20–29 years but only 1% in females aged in their 80s. (Savage et al., 1983).

Pathophysiology MVP is caused by myxomatous degeneration with subsequent expansion and prolapse of the cusp. (Hanson et al., 1996) The chordae tendineae also experience elongation and may rupture with resultant loss of leaflet tethering (Jeresaty et al., 1985). The commonest flail type involves the middle posterior scallop (P2) (Fig. 3). These patients can deteriorate from an initially benevolent asymptomatic systolic click to a mid–late systolic murmur, and later to a pansystolic murmur with or without left heart dilation. While often sporadic, there appears to be a genetic component to MVP with an autosomal dominant mode of inheritance seen in documented familial cases (Hayek et al., 2005). MVP is also seen among inherited connective tissue disorders such as Marfan’s and Ehlers–Danlos syndrome.

Signs and Symptoms Many patients with MVP may remain asymptomatic even in the presence of significant MR. However, a subset of patients may develop a constellation of symptoms including atypical chest pain, panic attacks, palpitations, dyspnea, exercise intolerance, and syncope. On auscultation, a midsystolic click with a late-systolic murmur can be best heard over the cardiac apex.

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Fig. 3 Three-dimensional echocardiographic view of a flail the middle posterior segment (P2) of the posterior mitral valve leaflet as seen from the left atrium (the surgeon’s view).

Diagnosis TTE is used to investigate MVP (Class I) (Nishimura et al., 2017). Owing to the mitral valve’s saddle shape, normal mitral valves may be detected as false positives. To minimize this, diagnosis is most reliable when assessed on parasternal long-axis or apical threechamber view. Electrocardiography and chest radiographs are likely to be normal with the exception of severe MR.

Medical Therapy In the asymptomatic patient, no specific treatment is necessary. Nor do they require antibiotic prophylaxis for endocarditis (Nishimura et al., 2017). Beta-blockers may relieve symptoms in certain patients but would not influence disease course (Shah, 2010). Patients with MVP but no MR should be reviewed every 3–5 years. Echocardiography should be performed in the patients with new onset symptoms or suspicious clinical examination. Those with severe MR should have yearly echocardiography performed (Nishimura et al., 2017).

Surgical Treatment Surgery is indicated in the presence of any severe MR presuming low operative risk and a high likelihood of repair (Nishimura et al., 2017). In general, surgery for MVP is generally associated with low mortality and low reoperation rates (at 10 years, survival was 88.1% and freedom from reoperation was 91.1% in one study) (Glauber et al., 2015).

References Arora R, Nair M, Kalra GS, Nigam M, and Khalilullah M (1993) Immediate and long-term results of balloon and surgical closed mitral valvotomy: A randomized comparative study. American Heart Journal 125: 1091–1094. Baumgartner H, Hung J, Bermejo J, Chambers JB, Evangelista A, Griffin BP, Iung B, Otto CM, Pellikka PA, and Quinones M (2009) Echocardiographic assessment of valve stenosis: EAE/ASE recommendations for clinical practice. Journal of the American Society of Echocardiography 22: 1–23. quiz 101-2. Carapetis JR, Steer AC, Mulholland EK, and Weber M (2005) The global burden of group A streptococcal diseases. Lancet Infectious Diseases 5: 685–694. Chiang CW, Lo SK, Ko YS, Cheng NJ, Lin PJ, and Chang CH (1998) Predictors of systemic embolism in patients with mitral stenosis. A prospective study. Annals of Internal Medicine 128: 885–889. Cilliers AM (2006) Rheumatic fever and its management. BMJ 333: 1153–1156. Dean LS (1994) Percutaneous transvenous mitral commissurotomy: A comparison to the closed and open surgical techniques. Catheterization and Cardiovascular Diagnosis (Suppl. 2): 76–81. Devereux RB, Kramer-Fox R, Brown WT, Shear MK, Hartman N, Kligfield P, Lutas EM, Spitzer MC, and Litwin SD (1986) Relation between clinical features of the mitral prolapse syndrome and echocardiographically documented mitral valve prolapse. Journal of the American College of Cardiology 8: 763–772. Fawzy ME, Hassan W, Shoukri M, Al Sanei A, Hamadanchi A, El Dali A, and Al Amri M (2005) Immediate and long-term results of mitral balloon valvotomy for restenosis following previous surgical or balloon mitral commissurotomy. American Journal of Cardiology 96: 971–975. Glauber M, Miceli A, Canarutto D, Lio A, Murzi M, Gilmanov D, Ferrarini M, Farneti PA, Quaini EL, and Solinas M (2015) Early and long-term outcomes of minimally invasive mitral valve surgery through right minithoracotomy: A 10-year experience in 1604 patients. Journal of Cardiothoracic Surgery 10: 181. Guy FC, Macdonald RP, Fraser DB, and Smith ER (1980) Mitral valve prolapse as a cause of hemodynamically important mitral regurgitation. Canadian Journal of Surgery 23: 166–170.

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Hameed A, Karaalp IS, Tummala PP, Wani OR, Canetti M, Akhter MW, Goodwin I, Zapadinsky N, and Elkayam U (2001) The effect of valvular heart disease on maternal and fetal outcome of pregnancy. Journal of the American College of Cardiology 37: 893–899. Hameed AB, Mehra A, and Rahimtoola SH (2009) The role of catheter balloon commissurotomy for severe mitral stenosis in pregnancy. Obstetrics and Gynecology 114: 1336–1340. Hanson EW, Neerhut RK, and Lynch C 3rd (1996) Mitral valve prolapse. Anesthesiology 85: 178–195. Harken DE, Dexter L, Ellis LB, Farrand RE, and Dickson JF 3rd (1951) The surgery of mitral stenosis. III. Finger-fracture valvuloplasty. Annals of Surgery 134: 722–742. Hayek E, Gring CN, and Griffin BP (2005) Mitral valve prolapse. Lancet 365: 507–518. Hung L and Rahimtoola SH (2003) Prosthetic heart valves and pregnancy. Circulation 107: 1240–1246. Inoue K, Owaki T, Nakamura T, Kitamura F, and Miyamoto N (1984) Clinical application of transvenous mitral commissurotomy by a new balloon catheter. Journal of Thoracic and Cardiovascular Surgery 87: 394–402. Jeresaty RM, Edwards JE, and Chawla SK (1985) Mitral valve prolapse and ruptured chordae tendineae. American Journal of Cardiology 55: 138–142. Lee JM, Shim J, Uhm JS, Kim YJ, Lee HJ, Pak HN, Lee MH, and Joung B (2014) Impact of increased orifice size and decreased flow velocity of left atrial appendage on stroke in nonvalvular atrial fibrillation. American Journal of Cardiology 113: 963–969. Nishimura RA, Otto CM, Bonow RO, Carabello BA, Erwin JP, 3rd, Fleisher LA, Jneid H, Mack MJ, Mcleod CJ, O’gara PT, Rigolin VH, Sundt TM, 3rd, and Thompson A (2017). 2017 AHA/ACC Focused Update of the 2014 AHA/ACC Guideline for the Management of Patients With Valvular Heart Disease: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. Journal of the American College of Cardiology. PMID: 28315732. Norrad RS and Salehian O (2011) Management of severe mitral stenosis during pregnancy. Circulation 124: 2756–2760. Reyes VP, Raju BS, Wynne J, Stephenson LW, Raju R, Fromm BS, Rajagopal P, Mehta P, Singh S, Rao DP, et al. (1994) Percutaneous balloon valvuloplasty compared with open surgical commissurotomy for mitral stenosis. New England Journal of Medicine 331: 961–967. Savage DD, Levy D, Garrison RJ, Castelli WP, Kligfield P, Devereux RB, Anderson SJ, Kannel WB, and Feinleib M (1983) Mitral valve prolapse in the general population. 3. Dysrhythmias: The Framingham Study. American Heart Journal 106: 582–586. Shah PM (2010) Current concepts in mitral valve prolapse—Diagnosis and management. Journal of Cardiology 56: 125–133. Silversides CK, Colman JM, Sermer M, and Siu SC (2003) Cardiac risk in pregnant women with rheumatic mitral stenosis. American Journal of Cardiology 91: 1382–1385. Turi ZG, Reyes VP, Raju BS, Raju AR, Kumar DN, Rajagopal P, Sathyanarayana PV, Rao DP, Srinath K, Peters P, et al. (1991) Percutaneous balloon versus surgical closed commissurotomy for mitral stenosis. A prospective, randomized trial. Circulation 83: 1179–1185. Vahanian A, Alfieri O, Andreotti F, Antunes MJ, Baron-Esquivias G, Baumgartner H, Borger MA, Carrel TP, De Bonis M, Evangelista A, Falk V, Iung B, Lancellotti P, Pierard L, Price S, Schafers HJ, Schuler G, Stepinska J, Swedberg K, Takkenberg J, Von Oppell UO, Windecker S, Zamorano JL, and Zembala M (2012) Guidelines on the management of valvular heart disease (version 2012). European Heart Journal 33: 2451–2496. Wilson W, Taubert KA, Gewitz M, Lockhart PB, Baddour LM, Levison M, Bolger A, Cabell CH, Takahashi M, Baltimore RS, Newburger JW, Strom BL, Tani LY, Gerber M, Bonow RO, Pallasch T, Shulman ST, Rowley AH, Burns JC, Ferrieri P, Gardner T, Goff D, and Durack DT (2007) Prevention of infective endocarditis: Guidelines from the American Heart Association: a guideline from the American Heart Association Rheumatic Fever, Endocarditis, and Kawasaki Disease Committee, Council on Cardiovascular Disease in the Young, and the Council on Clinical Cardiology, Council on Cardiovascular Surgery and Anesthesia, and the Quality of Care and Outcomes Research Interdisciplinary Working Group. Circulation 116: 1736–1754.

Further Reading Levine RA, Stathogiannis E, Newell JB, Harrigan P, and Weyman AE (1988) Reconsideration of echocardiographic standards for mitral valve prolapse: lack of association between leaflet displacement isolated to the apical four chamber view and independent echocardiographic evidence of abnormality. Journal of the American College of Cardiology 11: 1010–1019.

Recommended Reading Nishimura RA, Otto CM, Bonow RO, et al. (2014) AHA/ACC guideline for the management of patients with valvular heart disease: A report of the American College of Cardiology/ American Heart Association Task Force on Practice Guidelines. Journal of the American College of Cardiology 63(22): e57–e185.

List of Relevant Websites http://www.clevelandclinicmeded.com/medicalpubs/diseasemanagement/cardiology/mitral-valve-disease/—Mitral Valve Disease: Stenosis and Regurgitation.

Diuretic Therapy A Vazir, Royal Brompton and Harefield NHS Foundation Trust, Imperial College London, London, United Kingdom V Sundaram, Imperial College London, London, United Kingdom; Case Western Reserve University, Cleveland, OH, United States AR Harper, Royal Brompton and Harefield NHS Foundation Trust, London, United Kingdom; University of Oxford, Oxford, United Kingdom © 2018 Elsevier Inc. All rights reserved.

Introduction Types of Diuretic Loop Diuretics Thiazide and Thiazide-Like Diuretics Potassium Sparing Diuretics Evidence Base for the Use of Diuretics in AHF Placebo-Controlled Trials of Diuretics Thiazide Versus Loop Diuretics Comparison Between Loop Diuretics Dose of Loop Diuretic and Bolus Versus Continuous Infusion of Loop Diuretic Door to Diuretic Time and Prognosis Diuretic Resistance Strategies for Decongestion in AHF Patients with Impaired Diuretic Responsiveness Diuretic Strategies for Decongestion Nondiuretic Strategies for Decongestion (Summarized in Table 3) Conclusions References Further Reading

107 108 108 109 109 109 111 111 111 111 111 111 112 112 113 115 115 116

Abbreviations ADHF AHF GFR HF

Acute decompensated heart failure Acute heart failure Glomerular filtration rate Heart failure

Introduction Despite limited evidence, diuretic therapy has become a first-line therapy for the management of patients with acute heart failure (AHF). AHF is a life-threatening clinical syndrome that is characterized by an abrupt onset of symptoms, usually necessitating hospitalization. While this syndrome can occur de novo, it most frequently occurs in patients with a known diagnosis of HF in whom fluid has accumulated over days to weeks. In extreme cases, AHF can lead to cardiogenic shock, due to a low cardiac output state and a low systemic blood pressure, collectively preventing adequate end-organ perfusion. However, a consistent feature across the spectrum of AHF is fluid retention, which can manifest as ankle swelling, ascites, and/or pulmonary edema. Therapeutic strategies to relieve congestion can relieve symptoms and improve a patient’s quality of life. Before modern diuretics therapy was available, fluid retention was managed using rotating tourniquets to reduce cardiac preload, the insertion of Southey tubes subcutaneously to facilitate the drainage of fluid (Southey, 1877), recurrent venesection (Krishnakumar et al., 2007), and use of digoxin (Withering, 1785). In the 1920s, mercury-based therapies were noted for their diuretic effect. First noted by a medical student when these mercury-based agents were used for the treatment of syphilis, Merbaphen (novasurol) became a popular diuretic that could be administered as an intramuscular injection for the management of HF. It was not until the 1950s that more recognizable diuretics were introduced, first with the discovery of thiazide diuretics (Novello and Sprague, 1957) and later, in the 1960s, with loop diuretics (Robson et al., 1964). Such discoveries were considered revolutionary for the treatment of HF. In the present era, the evidence supporting diuretic usage is lacking. While there is evidence to support their role in effectively relieving congestion and thereby attenuating brain natriuretic peptide levels (Palazzuoli et al., 2015), their effect on cardiovascular and all-cause mortality is largely derived from small under-powered randomized studies (Felker et al., 2009). Nevertheless, diuretic therapy within HF is considered a “class I” recommendation from international guidelines, meaning usage is generally considered beneficial (Yancy et al., 2016; Ponikowski et al., 2016). International guidelines suggest diuretics should be used for the relief of dyspnea and edema in patients with signs and symptoms of congestion, irrespective of left ventricular ejection fraction, with the

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specified aim of achieving and maintaining a euvolemic state. They also recommend the use of the lowest possible dose of diuretic to achieve euvolemia to prevent hypotension, worsening renal function and neurohormonal activation. A lower dose of diuretic may enable up-titration of a disease modifying agents such as angiotensin converting enzyme inhibitors or sacubitril/valsartan, beta-blockers, and mineralocorticoid receptor antagonists (Ponikowski et al., 2016; Yancy et al., 2016). In this review, we discuss the evidence base for the use of these modern diuretics in the management of AHF.

Types of Diuretic There are four pharmacological classes of diuretics used in HF (Fig. 1): (a) (b) (c) (d)

Loop diuretics (furosemide, bumetanide, torsemide, ethacrynic acid) Thiazide diuretics (hydrochlorothiazide, bendroflumethiazide, Indapamide, or the “thiazide-like” metolazone) Directly acting potassium-sparing diuretics (amiloride and triamterene) Mineralocorticoid receptor antagonists (spironolactone, canrenoate, and eplerenone).

Loop Diuretics Loop diuretics act on the ascending limb of the loop of Henle, blocking the reabsorption of up to 20%–30% of filtered sodium by inhibiting the sodium, potassium, and chloride co-transporter. This results in an intense, and usually short-lived, diuresis. Loop diuretics must be delivered to the lumen of the nephron and its actions are dependent on glomerular filtration being sufficiently preserved. Loop diuretics can be administered orally, intravenously as a slow injection, or as an infusion. They have a rapid onset of action, working within minutes when given intravenously or within 30 min when given orally (Maxwell et al., 2002). They have a short duration of action, and consequently they may have to be given several times in a day to maintain the diuretic effect and to minimize rebound sodium reabsorption. However, gut edema may alter the rate of absorption of loop diuretics, but this effect is variable across the drug class. For instance, oral bumetanide achieves higher rates of absorption when compared with oral furosemide when administered to patients with gut edema (Sica, 2003). Thus, switching from oral furosemide to oral bumetanide can often lead to a diuresis that would not have been achieved with oral furosemide. Bumetanide is also more potent than furosemide, with 1 mg of oral bumetanide equivalent to approximately 40 mg of furosemide, and demonstrates higher bioavailability (approximately 70%) compared with oral furosemide (varying from 10% to 110%) in patients with marked fluid retention or gut edema. Furthermore, as furosemide is renally excreted, it can accumulate if administered to patients with renal dysfunction. Bumetanide and torasemide undergo hepatic elimination. However, torasemide has a longer half-life (3–4 h), meaning it should be administered less frequently than furosemide and bumetanide.

Fig. 1 Highlights mechanisms of actions of the different diuretics on the different areas of the nephron.

Diuretic Therapy Table 1

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Summary of common side effects of diuretics in acute decompensated heart failure

Hypokalaemia with loop and thiazides Hyperkalemia with potassium sparing diuretics Hyponatremia more frequent with thiazides than loop Impaired glucose metabolism with loop and thiazides Ototoxicity with high-dose loop Acute gout with loop and thiazide Activation of RAAS and sympathetic nervous system leading to progression of LV dysfunction RAAS, renin-angiotensin-aldosterone system.

All loop diuretics may cause changes in systemic hemodynamics that are initially unrelated to the degree and extent of natriuresis that they induce. For instance, short-term administration of furosemide can lead to a rapid increase in venous capacitance and a decline in cardiac filling pressure, coincident with a rise in plasma renin activity. This effect predominates over any rise in systemic vascular resistance in patients with pulmonary edema or decompensated AHF (Brater et al., 1984a). The side-effects of loop diuretics are summarized in Table 1, this includes: risk of ototoxicity (highest with ethacrynic acid); transient hearing loss, which may occur in patients receiving rapid intravenous bolus injection—so injection at a rate above 4 mg/min is not recommended; and permanent sensorineural hearing loss, which may occur at doses equivalent to furosemide 1000 mg per day (Rybak, 1985).

Thiazide and Thiazide-Like Diuretics Thiazide diuretics such as bendroflumethiazide, hydrochlorothiazide, and indapamide act on the distal tubule by inhibiting sodium and chloride reabsorption. This results in a
10%–15% reduction in sodium reabsorption. Compared with loop diuretics, while associated with a slower onset (1–2 h), they offer a more prolonged (12–24 h) and milder diuretic effect. The combination of a mild diuretic effect and long duration of action produces sodium excretion comparable to loop diuretics throughout 24 h (Vermeulen and Chadha, 1982). However, this also results in side effects such as nocturia, in addition to hypokalemia. Administered as a solo agent, thiazides are ineffective in individuals with a glomerular filtration rate below 30 mL/min. However, when thiazides, or indeed thiazide-like diuretics such as metolazone, are used in combination with loop diuretics, they facilitate sequential nephron blockade and are useful when managing refractory edema. Unlike thiazide diuretics, thiazide-like diuretics also act on the proximal tubule, where 60%–70% of sodium is reabsorbed and therefore can produce a profound diuresis.

Potassium Sparing Diuretics Potassium sparing diuretics (such as amiloride) produce a mild diuretic effect by blocking the sodium/potassium exchange pump in the distal tubule. This exchanger is highly active in patients with HF who receive both a loop and thiazide diuretic. As potassium sparing diuretics tend to have a weak diuretic effect, they are mainly used in combination with thiazide or loop diuretics to prevent hypokalemia, as they are more effective than potassium replacement (Townsend et al., 1984; Ghosh et al., 1987; Kohvakka, 1988). However, usage is associated with a risk of hyperkalemia, particularly in patients with known renal dysfunction (Krishna et al., 1988). Low-dose aldosterone (mineralocorticoid) receptor antagonists tend not to be used principally for diuresis in HF, but instead are administered for their potent antifibrotic properties to patients with chronic HF (RALES, 1996). However, in patients with fluid retention associated with right-sided HF, liver impairment, and ascites, very high circulating levels of aldosterone are detectable and high doses of aldosterone receptor antagonists (200–400 mg/day) can be useful in this setting for a diuretic effect. There is increasing evidence, from multiple small studies, that high doses of spironolactone (>100 mg /day) can induce a potent natriuresis, sufficient to provide a negative sodium balance in patients resistant to loop diuretics (Chamsi-Pasha et al., 2014). The ATHENA-HF (Aldosterone Targeted Neurohormonal Combined With Natriuresis Therapy in HF) trial is a randomized, doubleblind, placebo-controlled trial that aims to further evaluate the role of high-dose spironolactone (>100 mg/day) compared with placebo (or continued low-dose spironolactone use) on N-Terminal pro-Brain Natriuretic Peptide (NT-proBNP natriuretic peptide) levels for hospitalized AHF patients (Butler et al., 2016). The investigators of this study hypothesize that in patients with AHF, the early use of higher doses of spironolactone will produce a significant reduction in NT-proBNP, from randomization to 96 h, compared with standard care. This study should provide more insight into the safety and efficacy of higher doses of spironolactone in AHF and substantiate current clinical concerns relating to acute kidney injury and hyperkalemia.

Evidence Base for the Use of Diuretics in AHF The evidence base supporting diuretic use in AHF is limited. A summary of contemporary trials evaluating diuretic use within acute decompensated HF (e.g., trials containing patients hospitalized with worsening symptoms or those with New York Heart Association II–III characterized by fluid retention) is detailed in Table 2.

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Table 2

Summary of contemporary trials evaluating diuretic use within acute decompensated heart failure patients

Trials of diuretics for ADHF

Sample size

Population studied

Trial design

Diuretic drug

Outcomes

Bumetanide vs. furosemide vs. placebo Piretanide vs. placebo

Effective water excretion with both loop diuretics Improvement in all clinical and hemodynamic parameters in the absence significant side effects Greater reduction in body weight with diuretics Greater reduction with Torasemide

Placebo-controlled trials Kouroukli, 30 1976 Haerer, 1990 60

ADHF

Cross-over

NYHA II-III

Unblinded, controlled, nonrandomized

Kleber, 1990

247

Mild CHF

Patterson, 1994 Sherman, 1986

66

NYHA II-III

38

Mildmoderate CHF

Multicentre, double-blind, double-dummy, randomized Randomized, parallel, doubleblind, multicenter Double blind, randomized, parallel

Oral HCT vs. ibopamine vs. HCT þ ibopamine vs. placebo Oral torasemide 5 mg vs. torasemide 10 mg vs. placebo Piretanide vs. placebo

ADHF, Resistant edema

Cross-over trial

Furosemide vs. bendrofluazide vs. Ethacrynic acid

Thiazide vs. loop diuretic Stewart, 11 1965 Crawford, 1988

47

CCF, primary care based

Unblinded

Frusemide-amiloride vs. cyclopenthiazide-potassium

Gonska, 1985

30

NYHA II-III

Open, controlled, randomized study

Piretanide vs. hydrochlorothiazidetriamterene

Gabriel, 1981

18

At 28 days, improved symptoms with piretanide Furosemide at doses of 200 mg leads to effective diuresis, similar to ethacrynic acid, and better than bendrofluazide Furosemide lead to better response, more free from PND and orthopnoea Significant Weight loss in both groups. Piretanide group were more recompensated (10 vs. 4) Bumetanide least change in plasma potassium compare to bendrofluazide

Elderly with cardiac edema Comparison between loop diuretics Noe, 1999 240 NYHA II-III

Cross-over trial design

Bendrofluazide, frusemide and bumetanide

Prospective study, randomized

Torasemide vs. furosemide

Stroupe, 2000

193

ADHF

Prospective, randomized, nonblind study

Torasemide vs furosemide

Murray, 2001

234

ADHF

Open-label trial

Oral torasemide vs. furosemide

Muller, 2003

237

Primary care NYHA II-IV

Open randomized trial

Oral torasemide vs. furosemide

Prospective, 2  2 factorial design, double-blind, randomized trial

IV furosemide bolus low vs. high dose vs. continuous low vs. high dose

Over 72 h. No difference for symptoms or renal function between IV bolus vs. continuous infusion. Higher dose (2.5  oral dose at admission) had better secondary outcomes such as relief of dyspnea, change in weight, fluid loss, with worsening renal function, but there was no worse 60-day outcome

Randomized cross-over trial, single dose Randomized

Bumetanide and bendrofluazide

More diuresis with combined treatment Bendrofluazide and metolazone were equally effective in establishing a diuresis

Low dose vs. high dose loop Felker, 2011 308 ADHF

Combined thiazide and loop diuretic Sigurd, 1975 18 ADHF Channer, 1994

33

ADHF

Iv furosemide and bendrofluazide or metolazone

At 6 months, Torasemide group were heavier but had better quality of life at 1 month only At 1 year Torasemide leads to lower readmission to hospitalization 18 vs. 34%; P ¼ 0.013. Torasemide was more costeffective Less readmission with torasemide 32% vs. 19%; p < 0.01 at 1 year and more improved dyspnea and fatigue scores At 9 months, more clinical improvement and better quality of life in patients with Torasemide

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Placebo-Controlled Trials of Diuretics Placebo-controlled, randomized trials that have evaluated diuretic therapy in HF have been limited to a relatively small number of patients, ranging from 3 to 247 patients. These studies reported that diuretics significantly improve symptoms in HF (Kourouklis et al., 1976; Haerer et al., 1990; Kleber and Thyroff-Friesinger, 1990; Patterson et al., 1994; Sherman et al., 1986; Stewart and Edwards, 1965). However, none were powered to estimate the effect on mortality, but a meta-analysis of three short-term studies reporting mortality up to 12 months suggested a 75% mortality reduction [95% CI 16%–93% P ¼ 0.03], but the main issue with this analysis was that the number of deaths was low—12 in the placebo group and 3 in the diuretic group—and the majority of the patients were unlikely to have met the contemporary definition of acute decompensated HF (Faris et al., 2002).

Thiazide Versus Loop Diuretics Several small studies suggest that loop diuretics appear to be more effective at decongestion than thiazides alone in the management of HF (Crawford et al., 1988; Gonska and Kreuzer, 1985; Stewart and Edwards, 1965). Thiazide diuretics have a less harsh onset and longer duration of action, and for this reason they may be more acceptable to patients over loop diuretics (Funke Kupper et al., 1986). However, they are also more likely to result in hypokalemia and hyponatremia (Stewart and Edwards, 1965; Gabriel and Baylor, 1981; Vermeulen and Chadha, 1982).

Comparison Between Loop Diuretics Comparisons between loop diuretics have principally evaluated torasemide and furosemide, with findings of these studies summarized in Table 2. Assessed using a randomized and unblinded study design, oral torasemide appears to offer a lower HF-related readmission rate compared to oral furosemide (Noe et al., 1999; Stroupe et al., 2000; Murray et al., 2001; Muller et al., 2003). It has been suggested that torasemide is also better tolerated by patients, compared with furosemide, with less urinary urgency (Muller et al., 2003). However, international guidelines provide no recommendations between specific loop diuretics.

Dose of Loop Diuretic and Bolus Versus Continuous Infusion of Loop Diuretic The Diuretic Optimization Strategies Evaluation (DOSE) trial, assessed the initial diuretic strategies in patients with acute decompensated HF (Felker et al., 2011). DOSE used a 2  2 factorial design and randomized 308 acutely decompensated HF patients to receive intravenous furosemide, either as a twice-daily bolus or a continuous infusion, using either a low-dose (intravenous dose numerically equivalent to the patient’s oral dose) or a high-dose (an intravenous dose 2.5 times higher than the patient’s oral dose) regime. Dose adjustments were permitted following 48 h of intravenous therapy. At 72 h, there were no significant differences in either: (1) global assessment of symptoms or (2) change in serum creatinine; the studies predefined coprimary endpoints. Patients randomized to receive a high-dose intravenous furosemide regime reported an improvement in dyspnea (area under the curve for dyspnea 4478  1550 in low dose vs. 4669  1496 in high dose, P ¼ 0.04), reduction in weight (6.1  9.5 lbs in low dose vs. 8.7  8.5 lbs in high dose, P ¼ 0.01), and greater net fluid loss (3575  2635 mL in low dose vs. 4899  3479, P ¼ 0.001). However, the high-dose intravenous furosemide regime was also associated with a greater risk of serum creatinine measurements rising by >0.3 mg/dL within 72 h (23% vs. 14%, P ¼ 0.04). There was no difference in length of initial hospital stay or in days alive and out of hospital at day 60. In addition, there were no statistically significant differences between continuous infusion or twice-daily bolus injection of furosemide in terms of the patients’ global assessment of symptoms, mean change in serum creatinine, net fluid loss, change in weight, or length of hospital stay. This supported findings from a previous study (Allen et al., 2010). While the DOSE trial did not achieve either coprimary endpoint, secondary outcome measures suggest that high-dose intravenous furosemide can enable rapid decongestion, with concomitant symptomatic relief, at the expense of an increased risk of renal dysfunction, with no medium-term clinically significant consequences.

Door to Diuretic Time and Prognosis In a prospective registry based study assessing the time taken to give diuretics to patients presenting with acute decompensated heart failure, Matsue et al found that among 1291 patients, door to diuretic time of less than 60 minutes was associated with lower in-patient mortality (2.3 versus 6, P¼0.002) and in a multivariate analysis, patients receving diuretics within 60 minutes had lower inpatient mortality (odds ratio of 0.39 95% confidence interval (0.20 to 0.76); p¼0.006) (Matsue et al., 2017).

Diuretic Resistance A frequent problem experienced when treating patients with advanced HF is diuretic resistance. Diuretic resistance is a term used when the diuretic response is either diminished or lost before the therapeutic goal can be reached. Diuretic resistance is common, which occurs in up to one-third of hospitalized patients (Ravnan et al., 2002), and is associated with a poor prognosis (Neuberg et al., 2002). There are several mechanisms that contribute toward diuretic resistance (see Fig. 2), including:

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Diuretic Therapy

Fig. 2 Highlights the different mechanisms of diuretic resistance. Some are not related to the nephron and some involving different parts of the nephron.

• • •

• •

Decreased bioavailability of diuretics: In congested states, bowel wall edema may lead to reduced diuretic absorption. This effect is particularly noticeable with oral furosemide (Brater et al., 1984b; Vasko et al., 1985). Reduced glomerular filtration rate (GFR): A reduction in the GFR can occur due to poor renal perfusion, secondary to either low cardiac output or venous congestion. Additionally, chronic kidney disease or acute kidney injury can also prevent diuretics from entering the nephron’s proximal tubule lumen. Both mechanisms reduce the delivery of diuretics and therefore any potentially beneficial diuretic effects cannot be harnessed (de Silva et al., 2006). Excessive sodium uptake within the proximal tubule, loop of Henle, and the distal tubules may occur secondary to the following mechanisms: – Excessive neuro-hormonal activation (renin-angiotensin system and vasopressin) leading to excessive sodium and water retention throughout the proximal and distal tubules – The presence of the Braking phenomenon. This is a rebound of excessive sodium reabsorption that occurs when there is no diuretic detectable within lumen of either the proximal tubule or the loop of Henle. This typically occurs in the period between boluses of loop diuretics. Renal adaptation: The chronic use of diuretics may lead to hypertrophy of distal convoluted tubule, which may lead to more sodium and water resorption (Stanton and Kaissling, 1988; Kaissling and Stanton, 1988). Drug interaction: NSAIDS, aspirin (Bartoli et al., 1980), pioglitazone

Importantly, compliance with diuretic therapy needs to be addressed with the patient, their family, or their careers, prior to establishing a diagnosis of diuretic resistance.

Strategies for Decongestion in AHF Patients with Impaired Diuretic Responsiveness Several strategies can be employed to aid the decongestion of patients with acute HF who manifest impaired diuretic responsiveness. These include diuretic and nondiuretic strategies.

Diuretic Strategies for Decongestion 1. Changing the route of administration from oral to intravenous (thus overcoming bioavailability issues); 2. Continuous infusion of loop diuretic rather than intermittent bolus injections (although this may only offer a minor improvement); 3. Using higher doses of intravenous loop diuretics to increase the diuretic dose reaching the tubules, particularly in the context of a low GFR; 4. Sequential nephron blockade by using a combination of diuretics (Kiyingi et al., 1990; Sigurd et al., 1975) such as metolazone or bendroflumethiazide in addition to a loop diuretic. This approach requires close monitoring, with attendant risks of marked electrolyte disturbance, hypotension, dehydration, and worsening renal function.

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5. Restricting excessive dietary sodium and fluid intake may improve diuretic resistance, as less sodium and water are processed by the nephron. This strategy can be unpleasant for patients and should be limited to not less than 1.5 L of fluid intake daily.

Nondiuretic Strategies for Decongestion (Summarized in Table 3) 1. Renal dose dopamine. The exact mechanism through which renal dose dopamine (2–3 mcg/kg/min) increases renal blood flow remains debated, but is likely to involve a combination of increased cardiac output (via beta-1 receptors, traditionally associated with doses of 5–10 mcg/kg/min) and reduced renal and peripheral vasodilation (via peripheral dopaminergic receptors). (Bock and Gottlieb, 2010; Elkayam et al., 2008). The addition of dopamine to standard therapy for patients with AHF and a preserved systolic blood pressure have been evaluated in two reasonably sized randomized trials. • In the DAD-HF II trial (Triposkiadis et al., 2014), 161 patients with AHF with mean systolic blood pressures of 157  28 mmHg were randomized to dopamine 5 mcg/kg/min with furosemide vs. furosemide alone. The trial was prematurely discontinued due to a high incidence of tachycardia and the lack of benefit within the low-dose dopamine arm, with respect to 60-day or 1-year mortality, hospitalization for HF, or overall change in dyspnea score. • In the ROSE-AHF trial (Chen et al., 2013b), patients with AHF and a median systolic blood pressure of 114 (104–127) mmHg received low-dose dopamine at 2 mcg/kg/min, but did not significantly increase their cumulative urine output or improve renal function, as measured by cystatin C levels at 72 h. In addition, there were no significant differences between secondary endpoints such as HF rehospitalization rate, death, or adverse events for 60 days. The incidence of tachycardia was higher in the dopamine group. Therefore, current data do not support the use of dopamine in nonhypotensive patients presenting with AHF. However, the role for low-dose dopamine in AHF with hypotension, in the absence of cardiogenic shock, merits further study. In our own clinical practice, we do use renal dose dopamine in congested patients with impaired diuretic responsiveness, who demonstrates a systolic blood pressure of 80–100 mmHg to aid decongestion. 2. Vasopressin receptor antagonists (aquaretics) Aquaretics promote the loss of electrolyte-free water by inhibiting vasopressin 2 receptors, which subsequently prevents recruitment of aquaporin 2 channels to the luminal cell membrane within the nephron’s collecting duct. Furthermore, aquaretics use is not associated with many of the side effects seen with traditional diuretics, with no alteration in renal blood flow, glomerular filtration rate, changes in serum potassium, creatinine or osmolality, and no activation of either noradrenaline or plasma renin (Narayan and Mandal, 2012). Aquaretics are particularly useful in the context of euvolaemic or hypervolaemic hyponatraemia (sodium 1.65

55 62 49 38 65 39 52 48 49 52 51 52

21.9 40.6 49.4 69.1 35.7 31.4 33.2 71.1 49.6 25.5 41.6 55.9

8.8–33.2 25.2–52.8 30.3–63.3 44.8–82.7 21.1–47.6 47.2–10.9 18.3–45.4 51.6–82.8 30.6–63.5 11.8–37.1 23.8–55.2 36.6–69.3

33.4 (3) P < .0001

Life time number of spells

Frequency of spells prior to the previous year

26.2 (3) P < .0001 12.1 (3) P ¼ .0071

Estimated 12-month survival rates with 95% CI and the log rank statistic.

treatment (Task Force for the Diagnosis and Management of Syncope et al., 2009). For patients with a cardiac cause or neurocardiogenic cause of their syncope, the risk of recurrence is increased compared to other etiologies (Soteriades et al., 2002; Sorajja et al., 2009). For vasovagal syncope, one predictor is the number of syncope events in the prior year. In patients with abnormal tilt table test with less than 2 syncopal episodes in the prior year, a 22% recurrence rate over 1 year was observed. In comparison, those patients with 2 or 3 syncopal episodes in the prior year had a 41% recurrence rate (Table 2) (Sumner et al., 2010). However, in a metaanalysis of vasovagal syncope, even among highly symptomatic patients, the spontaneous remission rate is high (Pournazari et al., in press). For patients presenting to an emergency department for evaluation of syncope, one meta-analysis showed recurrence to be almost linear over time increasing from 0.3% at 1 month to 22% at 24 months (Solbiati et al., 2015). For those patients with syncope while driving, the actuarial recurrence of syncope while driving is actually quite low, being 0.7% at 6 months (Sorajja et al., 2009). This recurrence rate overall is similar to those patients who have an index syncopal event not while driving (Sorajja et al., 2009). However, those patients with syncope not while driving tend to have more recurrences in follow-up (Fig. 1). In analysis of prospective data from the Prevention of Syncope Trial 1 and 2, the occurrence of syncope while driving was 0.48% and the estimated probability of syncope while driving was 0.62% per year; however it is unknown how much patients actually drove in this study (Tan et al., 2016). In terms of prediction of morbidity within 7–30 days and mortality within 1 year of initial evaluation, a number of clinical tools are available to try and determine if patients require expedited work-up or not. Many of these risk scoring systems, such as OESIL, SFSR, Boston Syncope Rule, STEPS, and the Syncope risk score, most commonly include age and presence of an abnormal ECG (Colivicchi et al., 2003; Quinn et al., 2004; Grossman et al., 2007; Costantino et al., 2008; Sun et al., 2009). However, these studies are limited by sample size, inclusion of all syncope patients regardless of cause, and inconsistent definitions of syncope and its associated risk across these studies (Colivicchi et al., 2003; Quinn et al., 2004; Grossman et al., 2007; Costantino et al., 2008; Sun et al., 2009). As a general rule, these scoring systems should not replace clinical judgment, but can be considered as an adjunct in decision-making.

Rationale for Driving Privileges and Restrictions In the United States and many developed countries, motor vehicle travel remains an important means of transportation. On a societal level, driving is a privilege, but for many persons, driving is a necessity due to demands such as from family and work. For a

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Fig. 1 Recurrence of syncope in syncope while driving and not while driving (Sorajja et al., 2009).

patient to be fit to drive, many factors come into consideration, which include knowledge of road laws, vision acuity, and alertness among others (Sorajja and Shen, 2010). For the public interest, the main concern is whether a person can drive a vehicle safely enough to avoid causing harm to others. Restrictions on driving and driving guidelines have been developed to prevent or reduce motor vehicle accidents with the outcome being improved personal and public safety. However, accidents still occur and sudden driver incapacitation contributes to 1%–3% of all motor vehicle accidents, and 8%–10% are believed to be due to a heart condition (Petch, 1998; Epstein et al., 1996). Despite the incapacitation, only 2% or less of reported cases result in injury or death to other road users or bystanders (Ostrom and Eriksson, 1987; Parsons, 1986).

Determining Risk of Harm from Syncope While Driving The determinant principal factors can be summarized in the risk of harm (RH) formula. This formula quantifies the amount of risk that can occur with sudden incapacitation, and then the level of risk can then be judged as acceptable or not. Society recognizes that certain driving groups, such as younger and elderly drivers, are allowed to drive despite their higher risk of potentially harming others (Simpson et al., 2004; Curtis and Epstein, 2009; Larsen et al., 1994). As such, policy should be fair to other higher risk groups, while considering the welfare of others where these higher risk individuals will drive. The threshold of acceptable risk may depend on the eye of the beholder. While a society may accept a limited number of higher risk drivers, the goal should not necessarily be to allow as many high-risk drivers as possible. Conversely, driving restrictions should not be prohibitive to certain higher risk drivers who number far fewer than the cohort of younger and elderly drivers. The RH formula is derived from 4 components: (1) time spent driving or distance driven in a given time period (TD); (2) size of the vehicle driven (V); (3) risk of sudden cardiac incapacitation (SCI); and (4) the probability that incapacitation will cause a fatal or injury-producing accident (Ac). The formula can be expressed as: RH ¼ TD  V  SCI  Ac The time spent driving (TD) for noncommercial drivers is usually 4% daily (approximately 1 h) and less than 36,000 km per year or less than 720 h per year. For commercial drivers, the time spent driving is usually 25% daily (approximately 6 h) with longer distances and hours logged than the private driver definition (Simpson et al., 2004). Longer and shorter durations of driving can be accounted for with adjustment in this portion of the formula. For the size of the vehicle (V), those with a weight over 3500 kg are attributed a value of 1, and this amount includes vehicles such as ambulances, semitrucks, and buses. Vehicles less than 3500 kg are assigned a value of 0.28. A list of representative vehicles and their weights are given in Table 3. Of note, motorcycles do not have a “V” assigned, but theoretically would be much lower than 0.28. Conversely, the weight of a bus can increase to 16,000 kg with a load of people and belongings, and the weight of a semi-trailer truck with a trailer can be up to 50,000 kg in the United States. With such a significant amount of mass, the “V” assigned should be theoretically different than a car weighing just over 3500 kg, but this difference is not accounted for in the formula. The risk of sudden cardiac incapacitation varies among persons depending on their underlying conditions. Common conditions associated with syncope or sudden incapacitation are listed in Table 4. For commercial drivers, the risk of sudden cardiac incapacitation (SCI) is acceptable if their annual risk is 1% or less. This threshold is based on prior data from patients who are at least 3 months post-myocardial infarction and are able to complete seven METS on stress testing (Simpson et al., 2004).

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Types of Motor Vehicles and Weight (Sumner et al., 2010)

Moped/motorcycle Compact car Midsize car Large car Compact truck/SUV Midsize truck/SUV Large truck/SUV Ambulance Semi-trailer truck Bus

Table 4

225–500 kg 1350 kg 1600 kg 2000 kg 1600 kg 1900 kg 2500 kg 5500 kg 10,500 kg 12,500 kg

Causes of syncope and risk of loss of consciousness

Bradycardia: 4%–5% annually (Ng Kam Chuen et al., 2014; Aste et al., 2016) Brugada syndrome: 28%–40% prevalence (Sacher et al., 2006, 2012) Carotid sinus syndrome: 7%–40% annually (Gaggioli et al., 1995; Claesson et al., 2007) Hypertrophic cardiomyopathy: 2%–19% prevalence (Kofflard et al., 2003; Kim et al., 2016) Long QT syndrome: 17%–34% prevalence, 5% annually (Moss et al., 1991; Goldenberg et al., 2008) Orthostatic intolerance: 12%–31% prevalence (Atkins et al., 1991; Sarasin et al., 2002; Beckett et al., 1999) Supraventricular tachycardia: 4%–14% prevalence (Page et al., 2016; Walfridsson and Walfridsson, 2005) Vasovagal syncope: 40% prevalence, 22%–69% (Sumner et al., 2010; Tan et al., 2016) Ventricular arrhythmias in primary prevention patient: 2% annually (Thijssen et al., 2011; Freedberg et al., 2001; Bardy et al., 2005) Ventricular arrhythmias in a secondary prevention patient: 8% annually (Thijssen et al., 2011; Freedberg et al., 2001; Bansch et al., 1998; Kim et al., 2015)

The probability of a fatal or injury-producing accident (Ac) to other road users or bystanders is approximately 2% for all drivers (Ostrom and Eriksson, 1987; Parsons, 1986). When these data are plugged into the RH formula for a commercial driver: RH ¼ TD  V  SCI  Ac RH ¼ 0:25  1  0:01  0:02 RH ¼ 0:00005 This RH equates to a 1 in 20,000 chance of harm from a commercial driver. As a result, for a noncommercial driver, the SCI resulting in the equivalent RH can be calculated after adjusting for time spent driving (TD) and the vehicle size (V): RH ¼ TD  V  SCI  Ac 0:00005 ¼ 0:04  0:28  SCI  0:02 SCI ¼ 0:22 While a 22% chance of SCI may be acceptable for most noncommercial drivers, if the time spent driving increases or the size of vehicle increases, this SCI also increases and may no longer be acceptable. Conversely, for commercial drivers, if the time spent driving decreases or the vehicle size decreases, the RH may become acceptable. Based on this RH formula, many untreated conditions, such as bradycardia or supraventricular tachycardia that result in syncope, would disqualify both commercial and noncommercial driver patients from driving. However, appropriate treatment, such as with a pacemaker or ablation, would reduce these patients’ risk of SCI to less than 1% and allow for driving to be resumed (Brunner et al., 2004). Some conditions have a higher rate of recurrence and SCI, which may not allow for patients to drive on a temporary or even permanent basis. While the annual risk of SCI may be less than the 22% threshold, this fact does not preclude the presence of higher risk periods of time where the risk of SCI is excessive. For instance, as the time from a ventricular tachyarrhythmia event increases, the risk of incapacitating ventricular arrhythmias decreases. At some point, the RH may be acceptable for noncommercial drivers to resume driving, but in commercial drivers the acceptable risk threshold may never be reached. Of note, ventricular arrhythmias should not be taken as an equivalent for syncope. For patients with an ICD who receive an appropriate shock for ventricular tachyarrhythmias, only 31% experience syncope or near syncope during their event (Thijssen et al., 2011; Freedberg et al., 2001). The degree and severity of symptoms including loss of consciousness depend on the rate and duration of the ventricular arrhythmia as well as a patient's underlying cardiac dysfunction (Zipes et al., 2006). For primary prevention patients, using SCD-HeFT data, ICD discharge occurred in 7.5% of patients annually including appropriate and inappropriate shocks. Patients with appropriate shocks comprised 5.1% of the overall cohort (Bardy et al., 2005). So for primary prevention patients, we would expect an annual rate of syncope of 1.6% (or 0.31  0.051). In addition, the presence of an ICD only addresses the risk of SCD, and appropriate ICD therapy is frequently too late to prevent loss of consciousness even when programmed to deliver an immediate defibrillation (Task Force for the Diagnosis and Management of Syncope et al., 2009; Olshansky et al., 2008;

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Bansch et al., 1998). For secondary prevention patients, the risk of recurrent ventricular is approximately 25% annually (Fig. 2) (Bansch et al., 1998; Kim et al., 2015). Thus for these patients, we would expect an annual rate of syncope of 7.8% (or 0.31  0.25). It should be emphasized that the RH formula is one method for determining RH from driving, but it should not replace clinical judgment. As clinicians, patients with the same condition may have very different prognoses depending on comorbidities, therapy, and compliance with therapy. For most conditions, there is incomplete data regarding recurrence of syncope or sudden cardiac incapacitation with and without optimal therapy. Intuitively, patients with syncope are more likely to have a motor vehicle crash, and the data bears that out (Nume et al., 2016). Certain patients are more likely to have a motor vehicle crash from syncope; these include an approximate twofold increased risk for men compared to women, and those patients aged 18–35 years (Nume et al., 2016). In addition, the RH formula does not supercede local driving regulations. The authors strongly recommend that physicians, who care for syncopal patients, know the pertinent driving laws and restrictions, particularly in regard to the duty of the patient or the physician to report a patient's inability to drive a motor vehicle. In our large retrospective cohort, the patients with syncope while driving had a more frequent occurrence of injury (28.6% vs. 23.7%) than those without episodes while driving, but there was no significant increase in injuries requiring hospital care (Sorajja et al., 2009). This finding may be related to neurocardiogenic syncope being the most frequent cause, and the presence of a prodrome being a protective factor. As a group, there is no increase in mortality for syncope while driving patients compared to age- and sex-matched controls (Fig. 3). Prior studies have suggested sudden natural death while driving poses no

Fig. 2 Risk of sudden cardiac incapacitation based on event rates of ICD shocks (Kim et al., 2015).

Fig. 3 Survival of patients with syncope while driving compared to the general population (Sorajja et al., 2009).

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Fig. 4 Time elapsed from syncope and risk of motor vehicle crashes (Nume et al., 2016).

threat to other road users (Christian, 1988), but the presence of underlying cardiac disease, including ventricular tachycardia and myocardial infarction, carries a decreased survival rate similar to what has been shown in other studies (Sorajja et al., 2009; Kapoor, 1990). While some studies show the risk of recurrence to decrease from the index evaluation, one study found the risk of motor vehicle crash to remain elevated through 5 years of follow-up (Fig. 4) (Sorajja et al., 2009; Nume et al., 2016; Thijssen et al., 2011).

Ethical Considerations of Driving Restrictions In the United States, private or noncommercial automobile driving is regulated by individual states which may or may not require reporting of a syncopal event. The laws for driving restrictions are a form of ethical judgments that attempt to balance the rights of the individual and the good of society. The two notions do not necessarily coincide, as an individual is allowed to act in whatever manner they choose as long as that action does not infringe upon the rights of others. Actual harm does not have to occur, as the potential for harm is the real threshold. For instance, drunk driving does not have to result in an accident, but the potential for harm is great enough that driving incapacitated due to alcohol is illegal. For medical providers caring for patients with syncope, the question distills to what is the risk of harm. As a society, we accept a certain level of risk by letting higher risk drivers continue to drive. For teenagers aged 16–19 years in the United States, 2270 teenagers were killed by motor vehicle crashes and another 221,313 teenagers were injured in 2014 (Prevention CfDCa,https://www.cdc.gov/motorvehiclesafety/older_adult_drivers/). Considering this cohort comprises approximately 7% (22.4 million people) of the US population which was 320 million in 2014 (Bureau USC,https://www.census.gov/ popclock/), the RH by teenage drivers is 0.01, which is significantly higher than what is established as acceptable (RH ¼ 0.00005) for commercial drivers. Similar for elderly drivers, those older than 65 years, in the United States, 50 older adults were killed and 214,000 were injured in motor vehicle accidents in 2012 (Prevention CfDCa,https://www.cdc.gov/motorvehiclesafety/older_adult_drivers/). Older adults make up 13% of the US population, which was 315 million in 2012, resulting in a cohort of 41 million (Bureau USC,https://www. census.gov/popclock/). With these numbers, the RH is 0.005, which is also quite a bit higher than the acceptable risk for commercial drivers. Put another way, the risk for older adults and teenagers driving is 100–200 times higher than what has been deemed acceptable for commercial drivers. There are also aggravating and mitigating factors too. For instance, younger drivers tend to be more frequently intoxicated, wear seat beats less often, and drive at excessive speed (Halinen and Jaussi, 1994; Simons-Morton et al., 2005; Voas et al., 2012), but with more driving experience, we as a society expect their driving to improve. Elderly drivers, on the other hand, are cognizant of their limitations and tend to drive shorter distances and less so at night (Prevention CfDCa,https:// www.cdc.gov/motorvehiclesafety/older_adult_drivers/). Of note, many patients will not stop driving after being recommended to do so, regardless of how short or long the driving restriction is. Due to occupational and social demands on the patient, the compliance with driving restrictions is simply poor. The driving restriction given by most physicians is at least 6 months (Curtis et al., 1995; Akiyama et al., 2001). In the Antiarrhythmics versus Implantable Defibrillators (AVID) trial, the most common driving proscription was 6 to 11 months. However, 57% of

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patients resumed driving within 3 months, and 78% within 6 months did so mainly because being unable to drive represented a “severe hardship” for 59% of the patients (Akiyama et al., 2001). In another study, 79% of patients remembered their physicianrecommended driving restriction of 3 to 6 months, but 100% had continued to drive (Maas et al., 2003). There are benefits to advising a driving restriction, however. Whether patients have or have not been shocked by their ICD, patients may continue to drive, but they impose self-restrictions such as driving shorter distances and only “if necessary”(Conti et al., 1997). In a large Canadian study of patients deemed unfit to drive, those patients who were warned by their physicians about driving had a 45% reduction in the annual rate of crashes (Redelmeier et al., 2012). The probable need of some sort of driving restriction and the lack of compliance with it poses a legal and ethical morass. One key aspect is the principle of patient–physician confidentiality. Under almost any circumstance, a physician has an obligation to maintain confidentiality for a patient's medical condition. However, if a patient's condition poses a significant risk to others, then this information should not be withheld from the appropriate recipients or authorities. In this situation, the ethical principles of beneficence (doing good for society) outweigh the principle of confidentiality.

Driving Restriction Recommendations By Different Societies The driving restrictions from American Heart Association, American College of Cardiology, and the Heart Rhythm Society are summarized in Table 5 (Shen et al., 2017). The European Society of Cardiology (Task Force for the Diagnosis and Management of Syncope et al., 2009) has a separate set of recommendations, summarized in Table 6. While these recommendations do not cover all scenarios, they cover the far majority of them, and they still require physician discretion in applying them to patients. There are several pertinent differences between the different societal recommendations. The main difference is the lack of recommendations for commercial driving in the AHA/ACC/HRS Guidelines. While commercial drivers’ licenses are issued by each state and Washington D.C., these drivers are federally regulated in the United States by the Department of Transportation and Federal Motor Carrier Safety Administration who develop and issue the standards that must be met for a person to be a commercial driver. Other differences in the AHA/ACC/HRS include the separation of treatment by pharmacologic means and invasive procedures for a number of conditions such as supraventricular tachycardia, depressed ejection fraction with and without structural heart disease, and ventricular tachycardias (Task Force for the Diagnosis and Management of Syncope et al., 2009; Shen et al., 2017). Of note, whether the episode of syncope occurs while driving or not should not necessarily result in different treatment or driving restrictions (Sorajja et al., 2009; Sorajja and Shen, 2010).

Table 5

Suggested driving restrictions after an episode of syncope per AHA/ACC/HRS (Shen et al., 2017)

Condition

Symptom-free waiting time

OH VVS, no faints prior year VVS 1–6 faints per year VVS >6 faints per year

1 month No restriction 1 month Not fit to drive until symptoms resolved 1 month Not fit to drive 1 month Not fit to drive 1 week Not fit to drive 1 week Not fit to drive 1 month 1 week Not fit to drive 3 month Not fit to drive 3 months Not fit to drive 3 months Not fit to drive 3 months

Situational syncope other than cough syncope Cough syncope, untreated Cough syncope, treated with cough suppression Carotid sinus syncope, untreated Carotid sinus syncope, treated with permanent pacemaker Syncope due to nonreflex bradycardia, untreated Syncope due to nonreflex bradycardia, treated with permanent pacemaker Syncope due to SVT, untreated Syncope due to SVT, pharmacologically suppressed Syncope due to SVT, treated with ablation Syncope with LVEF $550), ease, lack of contraindications, and critical details obtained, echocardiography (typically using the least expensive option of a transthoracic approach as opposed to the more expensive transesophageal approach (>$594)) is generally the preferred modality for diagnosing underlying cardiomyopathy and associated cardiac dysfunction, whether it be in the form of HF with reduced (HFrEF) or preserved ejection fraction (HFpEF). Accordingly, echocardiography represents the cornerstone for the diagnosis (and ongoing management) of HF (Ponikowski et al., 2016; Yancy et al., 2013). As per contemporary expert guidelines (Ponikowski et al., 2016; Yancy et al., 2013), initial HF investigations may involve determining the plasma concentration of NPs (>$89), especially in the cases where echocardiography is not immediately available. While relatively inexpensive, NP testing cannot be used to definitively establish a diagnosis of HF, and is only recommended to rule out HF. This is also the case for a 12-lead electrocardiogram (ECG) (>$41), which cannot be used to definitively diagnose HF due to the low specificity of the test. However, the 12-lead ECG is relatively inexpensive, often available in situations in which an echocardiogram is not, and can be used to determine which patients require echocardiography. Regardless of the combination of diagnostic tests applied, they require trained technicians to perform the test(s), and expert cardiology review to diagnose the presence of HF and, if confirmed, the extent, nature, and underlying cause of associated cardiac dysfunction, further adding to the costs involved. A range of common diagnostic tests (most notably a chest x-ray (>$68)) is also typically undertaken during the diagnostic phase of management. If, after echocardiography, the diagnosis or causality of HF requires further elucidation, additional imaging options of varied costs include cardiac magnetic resonance (>$1,154), positron emission tomography (>$2,809), coronary angiogram (>$8,911), and coronary computed tomographic angiography (>$918).

Pharmacological treatment Initial pharmacological treatment of the most common form of HF, HFrEF secondary to ischemic cardiomyopathy, generally entails a combination of angiotensin converting enzyme inhibitors (>$9 per 30 day supply) and beta-blockers (>$7 per 30 day supply), with mineralocorticoid receptor antagonists (>$9 per 30 day supply), ivabradine (>$209 per 30 day supply), digoxin (>$21 per 30 day supply), hydralazine and isosorbide dinitrate (>$97 per 30 day supply), and/or loop-diuretics (>$6 per 30 day supply) considered on an individual basis. The replacement of angiotensin converting enzyme inhibitors with angiotensin receptor neprilysin inhibitors (>$215 per 30 day supply) may also be indicated (Ponikowski et al., 2016). The total pharmacological treatment cost per patient per annum is estimated to be between $750 and $1626 (Voigt et al., 2014). While the evidence-based management of HFpEF (an increasingly more common form of HF within the aging populations of high-income countries) is less clear, the cost (per annum) of treating such patients is likely to be equivalent given the typical presentation with hypertension and/or AF. For example, in combination with typical signs and symptoms of congestion associated with the syndrome, active treatment is mandated (Ponikowski et al., 2016; Yancy et al., 2013).

Device-based therapies There are currently two nonsurgical device based therapies routinely recommended for the treatment of HFrEF: implantable cardioverter-defibrillators (ICDs) (>$64,560) and cardiac resynchronization therapy (CRT) (Ponikowski et al., 2016; Yancy et al., 2013). While US costing for CRT is not made widely available, a Belgian assessment has placed the price at >$23,000 for the device alone (Van Brabandt et al., 2010). Costs for these devices are extremely high, and both require ongoing monitoring and maintenance by cardiologists and highly trained technicians once implanted, with the prospect of replacement in younger individuals with prolonged survival. There is a broad variability in both device cost, and the cost of remotely monitoring devices within and between countries. Analysis of cardiac implantable device usage within the Asia-Pacific region revealed that the cost of remote monitoring can vary from as low as an additional 5% of the device cost (in Japan), to as high as an additional 20% in expenditure (in China, Hong Kong, and South East Asia) (Lau and Zhang, 2013).

Surgical procedures Many surgical procedures can be used to treat HF depending on the underlying causes and consequences of the syndrome. Current guidelines recommend the application of coronary artery bypass grafting (CABG) (>$51,072), percutaneous coronary intervention

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(PCI) (>$21,694), surgical aortic valve replacement (>$60,609), transcatheter aortic valve implantation (TAVI) (>$78,415), and mitral valve surgery (>$62,364) on a case-by-case basis (Ponikowski et al., 2016; Yancy et al., 2013). More rarely, heart transplantation may be considered (>$196,774). The insertion of an intraaortic balloon pump (IABP) (>$181,340) or a left ventricular assist device (LVAD) (>$187,535) is most commonly used as bridging strategies until patients can undergo a more permanent procedure. However, LVADs are increasingly being used as a permanent solution for patients not eligible for heart transplantation (Kilic, 2015). It is worthwhile to note that these costs represent only the surgical procedure, and not the cost of hospitalization pre and postprocedure monitoring, and specialist management and treatment in the longer-term. These costs are substantive.

HF-specific management: Hospital and community-based care As noted, hospitalization (particularly in the form of recurrent, unplanned admissions denoting ongoing clinical instability in a subset of high cost patients) represents a substantive component of the overall economic burden of HF, as demonstrated in Fig. 1 using data collected from a recently completed, large, multicenter trial of HF management in Australia where the primary outcome was health-care costs during 12 months follow-up (Scuffham et al., 2017). Typically, those admitted with acute HF require management (noting a substantive burden imposed by those who receive Emergency Department management without subsequent admission) in high-cost facilities. Moreover, the short- and longer-term rate of recurrent hospitalization is extremely high; in the United States, as in many parts of the world, all-cause readmission is as high as 20%–25% within 30-days of an HF admission (Jencks et al., 2009; Wiley et al., 2017). A recent estimate has placed the median hospital cost for HF hospitalization in the US at $23,051 (Bress et al., 2016) and hospitalization costs are projected to rise 154% between 2012 and 2030 (Heidenreich et al., 2013). While the majority of people admitted to hospital for HF for the first time are discharged home, 21% are discharged to a long-term care facility/residential care. Significantly, the proportion of those requiring such long-term care increases with age and each subsequent HF-related admission, denoting the progressive and debilitating nature of the syndrome in affected individuals (Chan et al., 2016). Community-based care (often specialist in nature) is critical to the ongoing management of HF, particularly for those recently admitted with acute HF and/or treated with specialist pharmacotherapy requiring routine monitoring (e.g., electrolyte levels and renal function) or devices (e.g., routine pacemaker and ICD checks to ensure optimal function). This component of health-care includes primary care physician visits (>$176 per 15 min visit), medical specialist (>$505 per visit), allied health outpatient appointments (>$195 per visit), and ongoing surveillance costs (Voigt et al., 2014). For high-risk hospitalized patients, postdischarge multidisciplinary management (typically HF nurse-led) is also recommended to reduce the risk of rehospitalization and to prolong survival. The cost of applying these multifaceted programs will vary according to the level of specialist outpatient, community/home visits, remote monitoring (from structured telephone support and remote monitoring techniques), and referrals to other services (from pharmacological reviews to exercise programs) applied. In the recently completed WHICH? II Trial undertaken in the subsidized health-care system of Australia, the median cost of applying an intensive form of HF management was $285 per month per patient (Scuffham et al., 2017).

Fig. 1 Breakdown of HF costs (per person, per month). Data obtained from Scuffham, P. A., Ball, J., Horowitz, J. D., et al. (2017). Standard vs. intensified management of heart failure to reduce healthcare costs: results of a multicentre, randomized controlled trial. European Heart Journal. https://doi.org/10.1093/ eurheartj/ehx259 [Epub ahead of print].

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Palliative care Within an aging HF patient population in whom survival rates have improved (Mamas et al., 2017), the need for palliative care is becoming increasingly more common. It is suggested that patients with advanced and intractable forms of HF now represent the second most common reason for hospice admission (after cancer patients) (Heidenreich et al., 2013). However, compared to patients with the common forms of malignancy, their end-of-life trajectory is quite unclear and unpredictable, broadly differing between patients. Perhaps due to the difficulty in predicting the life expectancy of patients with HF, they are more likely to be either discharged alive or to remain in hospice for more than 6 months (Heidenreich et al., 2013). Accordingly, costs accumulated by HF patients during the last 6 months of life are high, and continue to rise (Unroe et al., 2011), with recent estimates placing this figure at an average of $23,606 (Nicholson et al., 2016).

Indirect Costs The indirect costs associated with HF (particularly in the setting of multimorbidity) are often difficult to define. However, they can be broken down into two broad categories: microeconomic versus macroeconomic costs (as detailed below). As described by Stewart and colleagues (2002), it is critical to consider the indirect cost of HF through its contribution to hospital admissions where the syndrome is listed as a secondary diagnosis. Reflective of the complicated nature of HF (as a syndrome that complicates more clearly defined clinical conditions), the ratio of primary versus secondary HF admissions is often 1:1.5–2.0. Consequently, when considered in economic analyses, these admissions almost double estimated HF-related expenditure (Chan et al., 2016).

Microeconomic costs Microeconomic costs can be defined as out-of-pocket expenses associated with HF treatment and management. These costs typically infer negative, downstream economic consequences such as the loss of monetary savings or the sale of a house to cover health-care expenses (Braunwald and Bonow, 2012). Microeconomic costs may vary depending on the health-care system and are influenced by the age and broader socioeconomic profile of the affected individual, the cost and comprehensiveness of health insurance, transport to health-care appointments, pharmacological costs, and potential loss of employment/income due to illness.

Macroeconomic costs Macroeconomic costs relate to the loss of worker productivity and economic growth when individuals with HF and their carers reduce work hours or drop out of the workforce entirely as a result of illness (Braunwald and Bonow, 2012). Macroeconomic costs are difficult to quantify. However, whole population data from Sweden suggest that the wider societal impact of HF is larger than the most common forms of cancer for both men and women in respect to total life-years and quality-adjusted life-years lost (Stewart et al., 2010).

The Cost Dynamics of HF: A Case Study As outlined above, management and treatment of HF can be associated with significant direct and indirect costs. Fig. 2 details the sequence of events relating to a patient's diagnosis of HF and the associated costs. The key economic aspects of their case are outlined below.

Fig. 2 Sequence of events relating to the patient's diagnosis of heart failure.

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Primary and Secondary Care The patient had regular visits with his primary care personnel, who were essential for early detection of disease and management of symptoms to prevent (or at least delay) subsequent HF-related morbidity and mortality that would be costly for an individual to societal perspective. His primary care personnel were involved in both pharmacological and nonpharmacological management of his symptoms. Secondary care commenced when the patient's primary care physician referred him immediately for an acute hospital admission with specialist cardiology treatment and management.

Treatment and Management The patient's diagnosis of HFrEF (characterized by progressive cardiac dysfunction and multimorbidity—including type 2 diabetes and renal disease) required costly inpatient and outpatient management. Due to the typical natural history of the syndrome, this management was aimed at providing clinical stability, rather than a cure, in order to reduce costly hospitalizations and prolong his life (Ponikowski et al., 2016).

Palliative Care As the patient's HF symptoms worsened, his ability to perform daily self-care activities declined markedly and, despite the support of his wife, he was placed into a nursing home for long-term, high-level care. His subsequent advanced-stage HF was treated with palliative management until he died at the age of 77 years, 3 years following his de novo acute HF presentation.

The Impact of HF and Multimorbidity As shown in Fig. 2, those affected by HF have health issues that are both complicated and not confined to the syndrome. As is often the case in HF (Stewart et al., 2016), in the presented case study, HF contributed to subsequent hospitalizations for the management of chronic AF and an ischemic stroke, these conditions contributed to his clinical instability and decline. The 12 most common comorbidities in HF are hypertension, coronary artery disease, anemia, arrhythmias (predominantly AF), cognitive dysfunction, depression, diabetes, musculoskeletal disorders, renal dysfunction, respiratory disease, sleep disorders, and thyroid disease (Stewart et al., 2016). The close link between multimorbidity and incremental health-care costs in patients affected by HF is now well established (Glynn et al., 2011; Picco et al., 2016) with a recent study finding that multimorbid HF patients have an increased risk of 30-day all cause readmission upon discharge compared to those with lone HF (Wiley et al., 2017). This economic effect is well demonstrated in the recently reported WHICH? II Trial of HF management (Scuffham et al., 2017). Figs. 3 and 4 show a breakdown of length of stay and hospitalization costs accumulated over a 12-month follow-up of the WHICH? II Trial cohort. These data demonstrate that of $7,489,876 total health-care expenditure due to hospitalization during 12-month follow-up, only $1,944,461 (26%) was HF-related, meaning the residual portion of expenditure ($5,545,415 or 74% was attributable to HF-related multimorbidity).

Fig. 3 Breakdown of 12-month hospitalization length for 391 HF patients. Data obtained from Scuffham, P. A., Ball, J., Horowitz, J. D., et al. (2017). Standard vs. intensified management of heart failure to reduce healthcare costs: results of a multicentre, randomized controlled trial. European Heart Journal. https://doi.org/10. 1093/eurheartj/ehx259 [Epub ahead of print].

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Fig. 4 Breakdown of 12-month hospitalization costs for 391 HF patients. Data obtained from Scuffham, P. A., Ball, J., Horowitz, J. D., et al. (2017). Standard vs. intensified management of heart failure to reduce healthcare costs: results of a multicentre, randomized controlled trial. European Heart Journal. https://doi.org/10. 1093/eurheartj/ehx259 [Epub ahead of print].

Fig. 5 Global comparison of HF costs. Data obtained from Cook, C., Cole, G., Asaria, P., Jabbour, R. & Francis, D. P. (2014). The annual global economic burden of heart failure. International Journal of Cardiology 3, 368–376. The World Bank (2017). GNI per capita, Atlas method (current US$). http://data.worldbank.org/ indicator/NY.GNP.PCAP.CD (accessed 1 May 2017); Population Reference Bureau. (2012). 2012 world population data sheet. [online] Washington: PRB, pp. 6–9. http://www.prb.org/Publications/Datasheets/2012/world-population-data-sheet.aspx (accessed 0505.17).

Global Economic Burden of Heart Failure As noted previously, it is now estimated that HF affects more than 26 million people globally, with figures on the rise as many populations progressively age (Ambrosy et al., 2014; Bui et al., 2011). Increasing HF prevalence places a varied burden on the global economy (as shown in Fig. 5). However, the economics of HF is difficult to calculate and compare between countries due to the complexity of the syndrome, variability in definitions, and the differing characteristics of health-care and insurance systems

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Fig. 6 Direct and indirect HF costs per country. Data obtained from Cook, C., Cole, G., Asaria, P., Jabbour, R. & Francis, D. P. (2014). The annual global economic burden of heart failure. International Journal of Cardiology 3, 368–376.

(Voigt et al., 2014). Despite these caveats, Cook and colleagues (2014) estimated that in 2012, the annual economic cost of HF was $108 billion globally (comprising $65 direct and $43 billion indirect expenditure). The cost dynamics of HF-related expenditure varied greatly between high-income and low- and middle-income countries (LMICs), the former spending a larger proportion of direct costs, while the pattern was reversed in LMICs (Fig. 6).

A Low- and Middle-Income Country Perspective When compared to high-income countries, the cost of HF in LMICs differs for a variety of reasons. For example, the average age of HF patients in sub-Saharan Africa is markedly lower than many other regions of the world. This places a burden on the economy through loss of income and productivity, and through needing to care for those who may normally be caregivers themselves. For example, direct HF costs are substantially lower in Nigeria (approximately 50% of the total cost of HF) as compared to high-income countries (Ogah et al., 2014). The mean cost of care per HF patient per annum in Nigeria is approximately $2000: while this is far lower than the approximate cost of $20,000 in the US, this represents a far higher proportion of the gross national income (GNI) per capita, at 72% and 36%, respectively (Voigt et al., 2014; The World Bank, 2017). However, the approximate mean cost of care per annum (for patients with HFrEF) in Turkey was $608, representing only 6% of their per capita GNI (Aras et al., 2016). In China, the per annum HF cost was $4204, representing 53% of their per capita GNI (Huang et al., 2017), demonstrating a large variation in the relative economic burden of HF among LMICs.

Cost Pressures in Heart Failure As the prevalence of HF is predicted to increase in the foreseeable future, so too will the economic burden. An aging population will contribute to a greater proportion of men and women at higher risk of HF (Cook et al., 2014). The US-based data has indicated that HF prevalence will increase by 46% during the period 2012–2030 (Heidenreich et al., 2013). Concurrently, improved health-care and expanded treatment options are contributing to increased longevity following an initial diagnosis of HF, which in turn increases its economic impact. As highlighted previously, while this is occurring globally, there may be a greater and more adverse economic impact of HF in LMICs. Additionally, more people are being diagnosed with HF than ever before. This reflects both increased awareness and an expansion of the syndrome definition, recent European guidelines defining HFpEF and HF with midrange ejection fraction (HFmrEF) in addition to the more traditionally recognized HFrEF (Ponikowski et al., 2016). As surveillance efforts and definitions have broadened, so too have HF risk factors. Globally, there are currently historically high levels of obesity and

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physical inactivity. As noted, there is also an alarming trend in the growing burden of multimorbidity, contributing to increased rates of hospitalization, and more complicated treatment patterns (Stewart et al., 2016).

Cost Evaluation in Heart Failure It is worth noting that much of the early (and cheapest) treatment modalities in HF were (and still remain) untested from a robust scientific and subsequent health economic perspective, loop-diuretics being the most obvious example. However, with an evolving armory of more expensive pharmacological agents and devices, in particular, there is increasing need to evaluate the cost of different diagnostic and treatment modalities in HF, from an individual to societal perspective. Either in the form of cost-effectiveness estimates (e.g., quality adjusted life-years gains per health-care expense) or cost–benefit analyses (e.g., potential cost-savings relative to an old treatment), most new therapeutic modalities in HF are formally assessed before being subject to subsidized funding by governments or health insurance agencies. Rarely is one therapeutic option [one recent example being the superiority of homebased versus clinic-based management of HF in Australia (Maru et al., 2015)] proven to be “dominant” over another in terms of both health benefits and cost-savings. For example, in the UK, the National Institute for Health and Care Excellence established a cost-effective threshold (relative to optimal pharmacotherapy) of up to £30,000 per quality adjusted life-year gained to support a recommendation of implanting a device with cardiac resynchronization and internal defibrillator capacities in a subset of patients with HF (National Institute for Health and Excellence, 2014). Increasingly, in the setting of limited financial resources and an expanding patient population with HF, thresholds for subsidizing therapeutic strategies (when individuals cannot pay directly) will undoubtedly become more stringent.

Reducing the Economic Burden of Heart Failure Having provided an overview of the nature of the economic burden of HF, how then do we reduce its adverse impact? Around half of all US HF-related hospitalizations (the greatest component of HF expenditure) are potentially preventable (Braustein et al., 2003). Recent Australian data placed the median cost per month of hospital-based care for patients with HF at $734, compared to only $196 per patient per month for community-based care, and $89 per patient per month for HF-specific management (Scuffham et al., 2017). Any strategy that reduces hospital stay by even a modest amount, therefore, is likely to have a favorable economic profile. Accordingly, reducing readmission rates in those patients with clinical instability could lead to a substantial lowering of HF-related expenditure. While some factors leading to high readmission rates are largely beyond the scope of the direct healthcare system (such as severity of illness and socioeconomic factors) potentially modifiable factors include: ● Increased communication between health-care providers: As highlighted previously, multimorbidity and HF is common, being the primary cause of hospitalization for those with HFpEF (Stewart et al., 2016). As such, it is necessary for HF patients to see a variety of specialists in addition to their primary care physician. Increasing communication levels between these practitioners may lead to a clearer understanding of the patient's health-care plan to all involved (practitioners, patient, and other carers), which may, in turn, lead to greater adherence and reduced likelihood of rehospitalization. This is especially apparent in patients in long-term care facilities, who often have a large amount of personnel, with a broad range of skill- and knowledge-levels involved in their care (Heckman et al., 2016). ● Providing clear and high-quality discharge instructions to patients: Along the same lines, ensuring that this information is then provided to patients in a manner which is clear, easily understood, and remembered, is important. For all but the sickest HF patients, the majority of time is spent at home, and if the patient does not understand or cannot remember their health-care instructions, they are at increased risk of not following them. ● Implementing early outpatient appointments: Beginning HF-related outpatient appointments soon after discharge may lead to a reduction in hospital readmission rates (Soundarraj et al., 2017). A recent study revealed that follow-up appointments were only organized for 50% of patients discharged home post HF-related hospitalization, and that appointments were less likely to have been organized for patients aged over 65 years, and for patients with HFpEF (vs HFrEF) (Goyal et al., 2016). ● Reducing initial hospital stay: A fine balance needs to be found between ensuring a hospitalization stay is not unnecessarily long and ensuring that a patient is not discharged prematurely, increasing the likelihood of recurrent instability and readmission or death. ● Specialist management: Recent American research has suggested that intensive care unit (ICU) admission, while significantly more expensive than general medicine stays, was not significantly associated with differences in 30-day mortality for HF. As such, being more selective with those patients admitted to ICU may lead to a reduction in hospitalization costs without compromising the care of the patient (Valley et al., 2017). Specialist HF management programs, particularly in the form of outreach models of care have the potential to markedly reduce rehospitalization and prolong survival (Maru et al., 2015), although implementing more intensive management may not necessarily deliver cost-savings (Scuffham et al., 2017).

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The cost of new device-based therapies and pharmaceutical treatments for HF continue to exert an increasing economic burden. As previously discussed, while necessary, both of these treatment techniques can be quite expensive. There is a variety of potential cost saving mechanisms associated with HF-related devices. Improving the battery life of devices has been highlighted as of potential benefit—recent studies have shown that longer device battery life could save 60.4 million Swedish Krona (USD6.83 million) over a 6-year period in Sweden, and reduced device-related costs by 29%–34% over 15 years in Europe (Gadler et al., 2016; Boriani et al., 2013). Additionally, reducing the variability of cardiac device costs between and within countries may reduce costs. The price of cardiac devices is often established via confidential agreements between hospitals and/or insurance companies, and device companies—a method which may work to inflate prices. Similarly, there is broad variability in pharmaceutical pricing.

Summary The economic footprint of HF, from the individual to societal level in nearly all part of the globe is substantial. In the US alone it is estimated that costs directly associated with the management of HF will rise from a current level of >$21 billion per annum to >$53 billion per annum by 2030 (Heidenreich et al., 2013). Indirect costs attributable to HF are likely to double these figures. Hospital costs and an increasing armory of expensive pharmacological and device-based therapies in an increasing number of older patients with complex clinical needs will be instrumental in driving the future cost burden imposed by the syndrome. Beyond preventing progression to HF, key targets to limit its economic impact include reducing the number of preventable hospital admissions (often recurrent in the same individual) and reducing the inflationary costs of new therapeutic strategies.

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Journal of the American College of Cardiology 42: 1226–1233. Bress AP, King JB, Brixner D, et al. (2016) Pharmacotherapy treatment patterns, outcomes, and health resource utilization among patients with heart failure with reduced ejection fraction at a U.S. academic medical centre. Pharmacotherapy 36: 174–186. Bui AL, Horwich TB, and Fonarow GC (2011) Epidemiology and risk profile of heart failure. Nature Reviews Cardiology 8: 30–41. Chan YK, Tuttle C, Ball J, et al. (2016) Current and projected burden of heart failure in the Australian adult population: A substantive but still ill-defined major health issue. BMC Health Services Research 16: 501. Cook C, Cole G, Asaria P, Jabbour R, and Francis DP (2014) The annual global economic burden of heart failure. International Journal of Cardiology 3: 368–376. Gadler F, Ding Y, Verin N, et al. (2016) Economic impact of longer battery life of cardiac resynchronization therapy defibrillators in Sweden. ClinicoEconomics and Outcomes Research 8: 657–666. Glynn LG, Valderas JM, Healy P, et al. (2011) The prevalence of multimorbidity in primary care and its effect on health care utilization and cost. Family Practice 28(5): 516–523. Goyal P, Sterling MR, Beecy AN, et al. (2016) Patterns of scheduled follow-up appointments following hospitalization for heart failure: Insights from an urban medical centre in the United States. Clinical Interventions in Aging 11: 1325–1332. Healthcare Bluebook. (2017). Find your fair price. https://www.healthcarebluebook.com/page_ConsumerFront.aspx (accessed 05.05.17). Heckman GA, Boscart VM, D’Elia T, et al. (2016) Managing heart failure in long-term care: Recommendations from an interprofessional stakeholder consultation. Canadian Journal on Aging 35: 447–464. Heidenreich PA, Albert NM, Allen LA, et al. (2013) Forecasting the impact of heart failure in the United States: A policy statement from the American Heart Association. Circulation. Heart Failure 6: 606–619. Huang J, Yin H, Zhang M, Ni Q, and Xuan J (2017) Understanding the economic burden of heart failure in China: Impact on disease management and resource utilization. Journal of Medical Economics 20(5): 549–553. Jencks SF, Williams MV, and Coleman EA (2009) Re-hospitalizations among patients in the Medicare fee-for-service program. The New England Journal of Medicine 360: 1418–1428. Keates AK, Mocumbi AO, Ntsekhe M, Sliwa K, and Stewart S (2017) Cardiovascular disease in Africa: Epidemiological profile and challenges. Nature Reviews Cardiology 14(5): 273–293. Khatibzadeh S, Farzadfar F, Oliver J, Ezzati M, and Moran A (2013) Worldwide risk factors for heart failure: A systematic review and pooled analysis. International Journal of Cardiology 168: 1186–1194. Kilic A (2015) The future of left ventricular assist devices. Journal of Thoracic Disease 7: 2188–2193. Lau CP and Zhang S (2013) Remote monitoring of cardiac implantable devices in the Asia-Pacific. Europace 15: i65–i68. Mamas MA, Sperrin M, Watson MC, et al. (2017) Do patients have worse outcomes in heart failure than in cancer? A primary care-based cohort study with 10-year follow-up in Scotland. European Journal of Heart Failure. https://doi.org/10.1002/ejhf.822 (Epub ahead of print). Maru S, Byrnes J, and Carrington MJ WHICH? Trial Investigators. (2015) Cost-effectiveness of home versus clinic-based management of chronic heart failure: Extended follow-up of a pragmatic, multicentre randomized trial cohort—The WHICH? study (Which Heart Failure Intervention Is Most Cost-Effective & Consumer Friendly in Reducing Hospital Care). International Journal of Cardiology 201: 368–375. Mozaffarian D, Benjamin EJ, Go AS, et al. (2016) Heart disease and stroke statistics-2016 update: A report from the American Heart Association. Circulation 133: e38–e360. National Institute for Health and Care Excellence. (2014). 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Ogah OS, Stewart S, Onwujekwe OE, et al. (2014) Economic burden of heart failure: Investigating outpatient and inpatient costs in Abeokuta, Southwest Nigeria. PLoS One 9: e113032. Picco L, Achilla E, Abdin E, et al. (2016) Economic burden of multi-morbidity among older adults: Impact on healthcare and societal costs. BMC Health Services Research 16: 173. Ponikowski P, Voors AA, Anker SD, et al. (2016) 2016 ESC guidelines for the diagnosis and treatment of acute and chronic heart failure: The Task Force for the diagnosis and treatment of acute and chronic heart failure of the European Society of Cardiology (ESC). Developed with the special contribution of the Heart Failure Association (HFA) of the ESC. European Journal of Heart Failure 18: 891–975. Scuffham PA, Ball J, Horowitz JD, et al. (2017) Standard vs. intensified management of heart failure to reduce healthcare costs: Results of a multicentre, randomized controlled trial. European Heart Journal. https://doi.org/10.1093/eurheartj/ehx259 (Epub ahead of print). Shimokawa H, Miura M, Nochioka K, and Sakata Y (2015) Heart failure as a general pandemic in Asia. European Journal of Heart Failure 17: 884–892. Soundarraj D, Singh V, Satija V, and Thakur RK (2017) Containing the cost of heart failure management: A focus on reducing readmissions. Heart Failure Clinics 13: 21–28. Stewart S, Jenkins A, Buchan S, et al. (2002) The current cost of heart failure to the National Health Service in the UK. European Journal of Heart Failure 4: 361–371. Stewart S, Ekman I, Ekman T, Odén A, and Rosengren A (2010) Population impact of heart failure and the most common forms of cancer: A study of 1 162 309 hospital cases in Sweden (1988 to 2004). Circulation. Cardiovascular Quality and Outcomes 3: 573–580. Stewart S, Riegal B, Boyd C, et al. (2016) Establishing a pragmatic framework to optimise health outcomes in heart failure and multimorbidity (ARISE-HF): A multidisciplinary position statement. International Journal of Cardiology 212: 1–10. The World Bank. (2017). GNI per capita, Atlas method (current US$). http://data.worldbank.org/indicator/NY.GNP.PCAP.CD> (accessed 01.05.17). Unroe KT, Greiner MA, Hernandez AF, et al. (2011) Resource use in the last 6 months of life among medicare beneficiaries with heart failure, 2000–2007. Archives of Internal Medicine 171: 196–203. Valley TS, Sjoding MW, Ryan AM, Iwashyna TJ, and Cooke CR (2017) Intensive care unit admission and survival among older patients with chronic obstructive pulmonary disease, heart failure, or myocardial infarction. Annals of the American Thoracic Society. https://doi.org/10.1513/AnnalsATS.201611-847OC (Epub ahead of print). Van Brabandt H, Camberlin C, Neyt M, et al. (2010) Cardiac resynchronisation therapy: A health technology assessment. Brussels: Belgian Health Care Knowledge Centre (KCE). Voigt J, John MS, Taylor A, et al. (2014) A reevaluation of the costs of heart failure and its implications for allocation of health resources in the United States. Clinical Cardiology 37: 312–321. Wiley JF, Chan YK, Ahamed Y, et al. (2017) Multi-morbidity and the risk of all-cause 30-day readmission in the setting of multidisciplinary management of chronic heart failure: A retrospective analysis of 830 hospitalized patients in Australia. The Journal of Cardiovascular Nursing. https://doi.org/10.1097/JCN.0000000000000391 (Epub ahead of print). Yancy CW, Jessuf M, Bozkurt B, et al. (2013) 2013 ACCF/AHA guideline for the management of heart failure: A report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. Journal of the American College of Cardiology 62: e147–e239.

Relevant Websites Gapminder tools—www.gapminder.org. Healthcare Bluebook—www.healthcarebluebook.com. National Institute of Health Care Excellence—www.nice.org.uk.

Electrocardiographic Monitoring Strategies (Holter, Implantable Loop Recorder, in Between) H Nazzari, L Halperin, and AD Krahn, University of British Columbia, Vancouver, BC, Canada © 2018 Elsevier Inc. All rights reserved.

Introduction Clinical Scenarios Necessitating Cardiac Monitoring Palpitations Syncope Atrial Fibrillation Postmyocardial Infarction Arrhythmia Atrial Fibrillation and Embolic Stroke of Undetermined Source Electrocardiographic Monitoring Modalities Short-Term Recording Inpatient telemetry Holter monitoring Prolonged Recording External cardiac event recorders Loop-recorders Mobile cardiac outpatient telemetry Patch ECG monitors Future Directions Smartphone monitoring Conclusion References

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Introduction The understanding and application of the electrocardiogram (ECG) has evolved immensely since 1912, when Einthoven first described his equilateral triangle to the Chelsea Clinical Society in London, and coined the term “EKG” in his landmark paper published in the Lancet (Barold, 2003). Advancements in the ECG continued in the early 1900s when Emanuel Goldberger created the augmented leads, which led to the modern-day 12-lead ECG (Burch, 1978). The ability to monitor patients remotely is largely attributed to the work of Norman Holter, who developed the first “Holter Monitor” in the 1940s. It allowed for a single ECG to be recorded for several hours, giving physicians the ability to monitor their patients ECG outside of the hospital setting (Roberts and Silver, 1983; Holter, 1961; Holter and Generelli, 1949). The original Holter monitor was a 75-pound backpack that utilized analog electronics and large batteries (Holter, 1961). Although it lacked practicality in its design, the Holter monitor revolutionized our ability to record and analyze ambulatory ECG data of patients not in hospital (Roberts and Silver, 1983) (Fig. 1). Since the original Holter monitor, substantial technological advancements provide the ability to monitor patients continuously from days to years, and as a result, our diagnostic capabilities have dramatically improved. Clinical trials examining the role of implantable cardiac monitors (ICMs) have validated their role in patients with unexplained syncope. Furthermore, they have shown increased utility in patients with vasovagal syncope and postmyocardial infarction arrhythmia detection. The era of smartphones has brought with it the potential for cardiac-monitoring technology integrated into our daily activities. This can offer real-time feedback to patients and couple ECG monitoring to other physiological parameters (blood pressure, oxygen saturation, etc.). This article will focus on summarizing the different modalities of electrocardiographic monitoring used in the context of common cardiac scenarios.

Clinical Scenarios Necessitating Cardiac Monitoring Cardiac monitoring aids clinicians in obtaining a rhythm profile and helps to establish a symptom–rhythm correlation. Various monitoring modalities are utilized in patients with palpitations, syncope, postmyocardial infarction arrhythmia detection, atrial fibrillation management, and detection of atrial fibrillation in patients with cryptogenic stroke. With the continued advances in monitoring technology, the scope of clinical application continues to expand.

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Fig. 1 Holter monitor device. The patient wears the device using a shoulder strap or belt loop, attached to 3–5 skin electrodes for continuous monitoring. An event button (not shown) at the top of the housing of the device is pressed in the event of symptoms to mark the recording.

Palpitations Palpitations represent one of the most commonly encountered symptoms by general practitioners and emergency department (ED) physicians, and frequently prompt referral to a cardiologist (Zimetbaum and Goldman, 2010). Palpitations can be completely benign or abnormal depending on the clinical scenario; therefore, a careful history needs to be elicited (Zimetbaum and Goldman, 2010; Weber and Kapoor, 1996). In patients with palpitations that remain unexplained after initial evaluation with routine ECG, cardiac monitoring is often considered. Monitoring can help establish symptom–rhythm correlation and detect asymptomatic arrhythmias that are inferred to be relevant, which can help to establish a diagnosis. Typically, the interval between palpitations can be lengthy and therefore, the type of continuous monitoring strategy chosen needs to be carefully considered (Zimetbaum and Goldman, 2010). Multiple studies have compared the diagnostic yield of the different monitoring devices, an important consideration for choosing the appropriate device based on symptom frequency.

Syncope Syncope is a common presentation encountered by primary care and ED physicians. It accounts for 1%–3% of ED visits and 0.6%–1% of all hospitalizations (Olde Nordkamp et al., 2009). It is estimated that the lifetime cumulative incidence of syncope in the general population is between 35% and 39%, with the majority of patients having their first syncopal episode before the age of 30 (Sud et al., 2009). Despite its prevalence, the management of syncope remains a challenge for many physicians. Obstacles in the diagnosis of syncope include the high spontaneous remission rates as well as the episodic and unpredictable frequency of events. Syncope falls under the broad definition of “transient loss of consciousness” and therefore the differential diagnosis for patients presenting with syncope can be extensive in some cases (Olde Nordkamp et al., 2009; Anon, 2016). The differential can include a number of life-threatening causes, which often leads to physicians feeling compelled to complete an extensive diagnostic work-up. Monitoring is often considered when the syncope likely attributed to a cardiac etiology. However, despite a full diagnostic evaluation, the etiology of the syncope is not found in approximately one-third of patients. Therefore, monitoring strategies are utilized to help record or exclude an arrhythmia as a contributing cause of syncope (Zimetbaum and Goldman, 2010; Subbiah et al., 2013). Extended monitoring is typically necessary to record the ECG during a spontaneous episode of syncope, but asymptomatic arrhythmias may have compelling inferential use (Krahn et al., 2004).

Atrial Fibrillation With an increasingly aging population, the prevalence of atrial fibrillation (AF) continues to rise (Colilla et al., 2013). It is estimated that by 2030, 12.1 million individuals will be living with AF in the United States (Colilla et al., 2013). Many of the adverse events

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associated with AF can be correlated with episode duration, frequency, and overall arrhythmia burden. Therefore, there is a great deal of interest in AF monitoring to help guide anticoagulation therapy, rate control, rhythm control efficacy, and burden in patients with heart failure (Botto et al., 2009). Multiple studies have examined the role and utility of different monitoring strategies, and there is evidence that longer duration ECG monitoring enhances arrhythmia detection rates (Boriani et al., 2014; Andrade and Krahn, 2013; Brachmann et al., 2016; Korompoki et al., 2016; Sposato et al., 2015).

Postmyocardial Infarction Arrhythmia Individuals who survive an acute myocardial infarction (AMI) that are left with left ventricular dysfunction (ejection fraction 40%) are at high risk of sudden death due to cardiac arrhythmias (Solomon et al., 2005; Huikuri et al., 2001). There is evidence to support that prophylactic implantation of an implantable cardioverter-defibrillator (ICD) late after an AMI reduces all cause mortality (Hohnloser et al., 2004). This benefit is lessened when the ICD is implanted early after an AMI. In addition, use of left ventricular function alone selects high-risk individuals for ICD implantation, but has a modest effect on population sudden death risk, because the majority of sudden deaths occur in apparently low-risk patients (Adabag et al., 2010; Myerburg et al., 1992) Prolonged ECG monitoring is an area of interest to identify improved noninvasive risk stratifiers that may help identify which patients post AMI may find the most benefit from ICD implantation. The Cardiac Arrhythmias and Risk Stratification after AMI (CARISMA) trial was the first large-scale prospective trial that utilized a prolonged ECG monitoring strategy to help identify invasive and noninvasive risk markers that may predict the occurrence of arrhythmias in patients post AMI (Huikuri et al., 2009). Overall, evidence to support prolonged ECG monitoring in these patients is limited by low positive predictive value, and more studies will be necessary to make definitive recommendations.

Atrial Fibrillation and Embolic Stroke of Undetermined Source As many as 25% of patients presenting with an ischemic stroke have no probable cause identified after a thorough evaluation, which includes an ECG, echocardiogram, in-patient telemetry, magnetic resonance imaging (MRI), or computed tomographic (CT) imaging of the brain. These patients are ultimately diagnosed as having a cryptogenic stroke or more recently termed as an embolic stroke of undetermined source (ESUS) (Sanna et al., 2014; Saver, 2016; Seet et al., 2011). Some of these strokes are attributed to embolism of venous thrombi through a patent foramen ovale (PFO) (Meier et al., 2013; Calvert et al., 2011). Several randomized clinical trials have demonstrated that closure of PFO failed to yield significant benefit (Carroll et al., 2013), suggesting that ischemic strokes through paradoxical embolism of venous thrombi are very rare. More recently, studies have focused on better understanding the extent to which AF contributes to ESUS. AF increases risk of thromboembolic strike as much as fivefold (Boriani et al., 2014). In the evaluation of patients with ischemic strokes, the incidence of either persistent or paroxysmal AF predating the stroke is approximately 15% (Joundi et al., 2016; Liao et al., 2007). Following their stroke, an additional 8% and 5% of patients presenting with sinus rhythm are identified as having AF through inpatient cardiac telemetry or 24-h monitoring, respectively (Brachmann et al., 2016). Clinical trials using longer duration monitoring strategies have shown an even greater yield in the identification of AF in this patient population and will be discussed further.

Electrocardiographic Monitoring Modalities Short-Term Recording Inpatient telemetry Classically, hospital electrocardiographic monitoring allowed for basic heart rate and rhythm monitoring. Advancements in technology now allow for evaluation of more complex rhythm disturbances, including myocardial ischemia, extent and nature of bradycardia, ectopy, ventricular arrhythmia burden/morphology, and QT interval prolongation. The challenge lies in which patients warrant inpatient monitoring. Logistical and economic constraints limit the number of patients that can be monitored at any given time. In the case of syncope, inpatient ECG monitoring is recommended for patients deemed to be at high risk for an arrhythmic cause, such as those with known structural heart disease (Subbiah et al., 2008; Simpson et al., 1999). The European Society of Cardiology (ESC) and Canadian Cardiovascular Society (CCS) have outlined characteristics, which necessitate urgent hospitalization (Table 1). Despite these recommendations, the overall yield for 72-h inpatient monitoring is only 16%; nonetheless, in select patients, this modality of monitoring is appropriate and justified for risk stratification.

Holter monitoring Holter monitoring is the most commonly utilized diagnostic tool for ambulatory monitoring and consists of a portable recording device attached to cutaneous electrodes on the chest wall (Roberts and Silver, 1983; Galli et al., 2016). Holter monitors can provide 2, 3, or 12 electrodes and typically provide recordings for 24–48 h; however, newer monitors now have the capability of offering up to 2 weeks of monitoring (Galli et al., 2016). The data is stored in the device using digital media, analyzed with software by a technologist, and subsequently edited and reported by the physician.

200 Table 1

Electrocardiographic Monitoring Strategies (Holter, Implantable Loop Recorder, in Between) ESC and CCC guidelines for inpatient telemetry

Canadian cardiovascular society

European society of cardiology

•

• •

•

Major risk factors (should have urgent cardiac assessment) ○ Abnormal ECG (any bradyarrhythmia, tachyarrhythmia, or conduction disease; new ischemia or old infarct) ○ History of cardiac disease (ischemic, arrhythmic, obstructive, valvular) ○ Hypotension (systolic BP 60 ○ Dyspnea ○ Anemia (hematocrit 6 min in duration 1 month prior to the event (Healey et al., 2012). More importantly, most of the SCAF occurring before these embolic events were less than 48 h, which has previously been felt to be the minimum duration necessary for thrombus formation in the left atrial appendage (Healey et al., 2012; Weigner et al., 1997). Patients in the ASSERT trial had an absolute stroke risk of 1.7% per year, which is lower than previously published reports. The initial results of the ASSERT trial were followed up by a posthoc analysis, which focused on the duration of device-detected subclinical AF and the occurrence of stroke (Van Gelder et al., 2017). In this substudy, patients with SCAF 6 min were excluded from the study. The 2455 patients that were included in the post-hoc analysis were stratified based on the longest single episode of SCAF. They defined four categories of SCAF: (1) no SCAF, (2) SCAF with a duration of >6 min–6 h, (3) SCAF between >6 h–24 h, and (4) SCAF >24 h. The

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post-hoc analysis revealed that SCAF lasting >6–24 h occurred in 7% of patients and episodes lasting >24 h occurred in 11% of patients. Importantly, they reported a significantly higher absolute risk (3.1%) of ischemic stroke or systemic embolism compared to patients with no SCAF. This absolute risk is similar to patients with clinical AF and higher than that reported in the primary ASSERT study. In patients with SCAF 10,000 patients from the SOS AF project (Stroke prevention strategies based on atrial fibrillation information from implanted devices). European Heart Journal 35(8): 508–516. Botto GL, Padeletti L, Santini M, Capucci A, Gulizia M, Zolezzi F, et al. (2009) Presence and duration of atrial fibrillation detected by continuous monitoring: Crucial implications for the risk of thromboembolic events. Journal of Cardiovascular Electrophysiology 20(3): 241–248. Brachmann J, Morillo CA, Sanna T, Di Lazzaro V, Diener HC, Bernstein RA, et al. (2016) Uncovering atrial fibrillation beyond short-term monitoring in cryptogenic stroke patients: Threeyear results from the cryptogenic stroke and underlying atrial fibrillation trial. Circulation. Arrhythmia and Electrophysiology 9(1)e003333. Brignole M, Menozzi C, Moya A, Garcia-Civera R, Mont L, Alvarez M, et al. (2001) Mechanism of syncope in patients with bundle branch block and negative electrophysiological test. Circulation 104(17): 2045–2050. Brignole M, Sutton R, Menozzi C, Garcia-Civera R, Moya A, Wieling W, et al. (2006) Early application of an implantable loop recorder allows effective specific therapy in patients with recurrent suspected neurally mediated syncope. European Heart Journal 27(9): 1085–1092. Brignole M, Menozzi C, Moya A, Andresen D, Blanc JJ, Krahn AD, et al. (2012) Pacemaker therapy in patients with neurally mediated syncope and documented asystole: Third International Study on Syncope of Uncertain Etiology (ISSUE-3): A randomized trial. Circulation 125(21): 2566–2571. Burch GE (1978) History of precordial leads in electrocardiography. European Journal of Cardiology 8(2): 207–236. Calvert PA, Rana BS, Kydd AC, and Shapiro LM (2011) Patent foramen ovale: Anatomy, outcomes, and closure. Nature Reviews Cardiology 8(3): 148–160. Carroll JD, Saver JL, Thaler DE, Smalling RW, Berry S, MacDonald LA, et al. (2013) Closure of patent foramen ovale versus medical therapy after cryptogenic stroke. The New England Journal of Medicine 368(12): 1092–1100. Cheung CC, Kerr CR, and Krahn AD (2014) Comparing 14-day adhesive patch with 24-h Holter monitoring. Future Cardiology 10(3): 319–322. Colilla S, Crow A, Petkun W, Singer DE, Simon T, and Liu X (2013) Estimates of current and future incidence and prevalence of atrial fibrillation in the U.S. adult population. The American Journal of Cardiology 112(8): 1142–1147. Daoud EG, Glotzer TV, Wyse DG, Ezekowitz MD, Hilker C, Koehler J, et al. (2011) Temporal relationship of atrial tachyarrhythmias, cerebrovascular events, and systemic emboli based on stored device data: A subgroup analysis of TRENDS. Heart Rhythm 8(9): 1416–1423. Diemberger I, Gardini B, Martignani C, Ziacchi M, Corzani A, Biffi M, et al. (2015) Holter ECG for pacemaker/defibrillator carriers: What is its role in the era of remote monitoring? Heart 101(16): 1272–1278. Edvardsson N, Frykman V, van Mechelen R, Mitro P, Mohii-Oskarsson A, Pasquie JL, et al. (2011) Use of an implantable loop recorder to increase the diagnostic yield in unexplained syncope: Results from the PICTURE registry. Europace 13(2): 262–269. Farwell DJ, Freemantle N, and Sulke AN (2004) Use of implantable loop recorders in the diagnosis and management of syncope. European Heart Journal 25(14): 1257–1263. Farwell DJ, Freemantle N, and Sulke N (2006) The clinical impact of implantable loop recorders in patients with syncope. European Heart Journal 27(3): 351–356. Fogel RI, Evans JJ, and Prystowsky EN (1997) Utility and cost of event recorders in the diagnosis of palpitations, presyncope, and syncope. The American Journal of Cardiology 79(2): 207–208. Galli A, Ambrosini F, and Lombardi F (2016) Holter monitoring and loop recorders: From research to clinical practice. Arrhythmia & Electrophysiology Review 5(2): 136–143. Giada F, Bertaglia E, Reimers B, Noventa D, and Raviele A (2012) Current and emerging indications for implantable cardiac monitors. Pacing and Clinical Electrophysiology 35(9): 1169–1178. Gladstone DJ, Spring M, Dorian P, Panzov V, Thorpe KE, Hall J, et al. (2014) Atrial fibrillation in patients with cryptogenic stroke. The New England Journal of Medicine 370(26): 2467–2477. Glotzer TV, Daoud EG, Wyse DG, Singer DE, Ezekowitz MD, Hilker C, et al. (2009) The relationship between daily atrial tachyarrhythmia burden from implantable device diagnostics and stroke risk: The TRENDS study. Circulation. Arrhythmia and Electrophysiology 2(5): 474–480.

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Electrophysiology Approaches for Ventricular Tachycardia RM John, Harvard Medical School, Boston, MA, United States; Vanderbilt University Medical Center, Nashville, TN, United States W Stevenson, Harvard Medical School, Boston, MA, United States © 2018 Elsevier Inc. All rights reserved.

Introduction Types of VT Diagnosis Management of Ventricular Arrhythmias Premature Ventricular Contractions (PVCs) and Nonsustained VT Sustained Monomorphic VT Polymorphic VT and Resuscitated VF Structural Heart Disease Associated With VT Coronary Artery Disease Nonischemic Cardiomyopathy Inherited cardiomyopathies Genetic Arrhythmia Syndromes Abnormalities of Repolarization and the QT Interval Catecholaminergic Polymorphic VT Drug Therapy for Ventricular Arrhythmias Implantable Cardioverter Defibrillators Catheter Ablation for VT Management of VT Storm Summary References

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Introduction Ventricular tachycardia (VT) and fibrillation (VF) are the most common cause of cardiac arrest and sudden death. Hence, the presence of ventricular arrhythmia warrants careful assessment to determine risk for arrhythmic death and its prevention. In the absence of structural or genetic abnormalities, these arrhythmias are termed idiopathic. While idiopathic VF is a rare life-threatening condition, idiopathic monomorphic VT usually originates from a single focus or may be due to interfascicular reentry. Idiopathic VT is usually considered benign and infrequently associated with sudden death. Occasionally, ventricular arrhythmias such as frequent Premature ventricular contractions (PVCs), repetitive VT, or slow incessant VT can initiate systolic LV dysfunction or worsen preexisting heart failure.

Types of VT Nonsustained VT refers to episodes that last less than 30 s. Episodes of VT that persist for longer than 30 s cause syncope or cardiac arrest or require an intervention such as cardioversion or overdrive pacing for termination is commonly designated sustained VT. VT at a rate less than a 100 bpm is usually due to an accelerated idioventricular rhythm but occasionally it may be due to a slow reentrant tachycardia involving a scar. Monomorphic VT has the same QRS configuration from beat to beat, indicating a stable VT origin from a focus or structural substrate. The ECG morphology suggests the ventricular origin (Josephson and Callan, 2005). A left bundle branch block-like configuration, defined by a dominant S wave in lead V1, suggests that the arrhythmia originates in the right ventricle or interventricular septum. A right bundle branch block-like configuration defined by a dominant R wave in V1 typically originates from the left ventricle (Fig. 1). VT that originates from the base of the heart usually has an inferiorly directed frontal plane axis with positive QRS in the inferior limbs leads and prominent R waves in the apical precordial leads (V5 and V6). Inferior wall origin is suggested by superiorly directed frontal plane axis with predominantly negative QRS complexes in the inferior limb leads (Fig. 1). Polymorphic VT has a continually changing QRS axis indicating a varying ventricular activation sequence. A fixed anatomic substrate is not required. Acute myocardial ischemia, genetic arrhythmia syndromes, or electrolyte disturbances are the causes. Polymorphic VT associated with QT prolongation often has a characteristic waxing and waning QRS amplitude referred to as “torsade de pointes (TdP) (Roden, 2008).”

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Fig. 1 Morphology and frontal plane axis of a monomorphic suggests site of origin (see text for details). Reproduced from John, R.M. and Stevenson, W.G. (2014). Ventricular arrhythmias. In: Kasper, D.L., Fauci, A.S., Hauser, S.L., Longo, D.L., Jameson, J.L. and Loscalzo, J. (eds.) Harrison’s principles of internal medicine (19th edn.). New York: McGraw Hill. Chapter 277.

Diagnosis Because ventricular arrhythmias originate below the His bundle, the QRS duration is typically wider than 120 ms. However, VT that originates from the Purkinje fibers or the high septum can be relatively narrow and mimic supraventricular arrhythmias. The main differential diagnoses of wide complex tachycardia include VT, supraventricular tachycardia (SVT) with aberration, or preexcited tachycardias. SVTs with preexisting wide QRS, arrhythmias associated with drug toxicity, and pacemaker-mediated tachycardia may also present with wide complex tachycardia. Clinically, the most common cause of a wide complex tachycardia is VT, accounting for 80% of cases (Miller and Das, 2009). A history of structural heart disease increases the probability of VT with a positive predictive value of >95% (Alzand and Crijns, 2011). Patients with VT tend to be older. Age below 35 years and recurrent events over >3 years support SVT with aberration. Hemodynamic stability is not a good marker for VT diagnosis as VT can present with stable hemodynamics. Several ECG criteria have been published to distinguish monomorphic VT from SVT with aberration. In general, SVT with aberration tend to follow typical bundle branch block of fascicular block patterns, whereas VT that originates outside of the bundle branches or Purkinje system tend to have atypical patterns. Scar-related reentrant VT exit into ventricular myocytes. Hence, initial ventricular activation is usually slower compared with terminal activation. Lead aVR yields a negative QRS during SVT as the ventricular activation wavefront is conducted away from this lead. The presence of an initial R in aVR is thus supportive of VT (Alzand and Crijns, 2011; Vereckei et al., 2008). In addition, the direction of ventricular activation from supraventricular stimulation gives rise to an R wave in at least one or several precordial leads, therefore the absence of RS complex in the precordial leads indicates VT (Fig. 2) (Vereckei et al., 2008). None of these criteria are perfect. Because a definitive diagnosis is mandatory for assessing risk and guiding therapy, an electrophysiologic study maybe required if the diagnosis remains in doubt. ECG artifacts can mimic VT, particularly polymorphic VT, and can lead to inappropriate treatments if not recognized.

Management of Ventricular Arrhythmias VT frequently cause symptoms, but some are recognized on routine evaluation or present with progressive heart failure symptoms. The common presentation is with palpitations, syncope, or cardiac arrest. Initial management of an unstable arrhythmia should follow established advanced cardiac life support guidelines. History and physical examination should focus on identifying heart disease. Potential aggravating factors should be sought and addressed, including electrolyte imbalances, stimulants such as caffeine and amphetamine analogues, and other drugs. The electrocardiogram often provides the first indication of underlying heart disease or a genetic arrhythmia syndrome (see below). Coronary artery disease is the initial major consideration in adults. Ventricular

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Fig. 2 Algorithm to differentiate ventricular tachycardia (VT) from supraventricular tachycardia (SVT) with aberration. Reproduced from John, R.M. and Stevenson, W.G. (2014). Ventricular arrhythmias. In: Kasper, D.L., Fauci, A.S., Hauser, S.L., Longo, D.L., Jameson, J.L. and Loscalzo, J. (eds.) Harrison’s principles of internal medicine (19th edn.). New York: McGraw Hill. Chapter 277.

imaging, usually with echocardiography, is warranted to detect myopathies and assess ventricular function. Cardiac MR imaging and 18F-fluoro-deoxy-glucose PET imaging with CT can be helpful in assessing the presence of scar, infiltration, and inflammation (Blankstein and Waller, 2016; MEMBERS WRITING COMMITTEE and MEMBERS ACCF TASK FORCE, 2010). Long-term management strategies for VT management are determined primarily by the nature of the underlying heart disease and the risk for sudden arrhythmic death. The specifics of the arrhythmia can often direct one to specific evaluation and management.

Premature Ventricular Contractions (PVCs) and Nonsustained VT PVCs are common, and are observed in up to 27% of healthy individuals during exercise testing (Morshedi-Meibodi et al., 2004). Their prevalence increases with age and with the presence and severity of heart disease. Exercise-induced and recovery-phase PVCs or nonsustained VT (NSVT) are associated with increased mortality, likely because they are markers for underlying heart disease. In the absence of structural heart disease or an underlying genetic arrhythmia syndrome, prognosis is excellent. Specific therapy is rarely required; beta-blockers may be used for control of symptoms. Very frequent PVCs, typically in excess of 20% of total heartbeats per 24 h, or incessant repetitive monomorphic VT (Figs. 3 and 4) can depress LV ejection fraction in a manner similar to tachycardia-induced cardiomyopathy from incessant SVT or rapid atrial fibrillation (Cha et al., 2012). However, accurate measurement of ventricular function can prove difficult due to frequent arrhythmia. In addition, an underlying cardiomyopathy may be present causing the PVCs. Reassessment of ventricular function after suppression of the arrhythmia with drugs or ablation is often required to clarify the initiating event.

Sustained Monomorphic VT When structural heart disease is present, monomorphic VT is usually due to scar-related reentry and tends to be recurrent. Although myocardial ischemia can act as a trigger for such VT, revascularization therapies alone are unlikely to prevent recurrences. More than 40% of patients presenting with sustained monomorphic VT will have recurrent arrhythmia within 2 years and there is a risk of sudden death (Kuck et al., 2010). An implantable cardioverter defibrillator (ICD) should therefore be considered in such patients. ICDs terminate, but do not prevent VT episodes. Recurrent VT is common and is associated with increased mortality and hospitalizations and reduced quality of life if VT elicits ICD shocks (Aliot et al., 2009; Poole et al., 2008). Antiarrhythmic drugs or catheter ablation are used to reduce the frequency of recurrences and to control incessant VT. It is important to achieve adequate control of VT before implantation of an ICD to prevent recurrent ICD shocks. In experienced centers, ablation for VT should be considered early in such situations (see what follows) (Aliot et al., 2009).

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Fig. 3 Frequent MM PVC of LV outflow tract origin.

Fig. 4 A 50-year-old male with exercise-induced palpitation. During an ETT, single monomorphic PVCs were present. During recovery phase after 8 min of exercise, he developed repetitive monomorphic VT with morphology similar to PVCs at rest. The VT has a left bundle branch morphology with rightward inferior axis. Because of continued symptoms despite beta-blockers, he underwent ablation of a focus in the anterior septal aspect of the right ventricular outflow tract with suppression of the arrhythmia and no recurrence.

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Idiopathic VTs are those that occur in the absence of structural heart disease. Most commonly, these are monomorphic and originate from the right ventricular outflow tract, although several other sites including the left ventricular outflow tract, papillary muscles, and perivalvular areas can give rise to these VTs. The diagnosis requires exclusion of underlying heart disease, and diseases such as ARVC and sarcoidosis that can cause VTs with similar characteristics to idiopathic VTs. Distinguishing idiopathic VT from VT with structural heart disease is of critical importance as the latter often warrants an ICD. Detection of ventricular scar on cardiac imaging can be helpful (MEMBERS WRITING COMMITTEE and MEMBERS ACCF TASK FORCE, 2010). Idiopathic monomorphic VT may be present with frequent PVCs that occur in clusters or as repetitive monomorphic VT usually during exercise (Fig. 4). Fascicular reentrant VT can similarly cause monomorphic VT that may respond to verapamil. Although idiopathic VTs occasionally cause syncope, sudden death is rare (Shimizu, 2009). Beta-blockers, calcium channel blockers, or catheter ablation (see what follows) are often effective in controlling symptoms.

Polymorphic VT and Resuscitated VF Polymorphic VT generally indicates the presence of significant heart disease due to acute myocardial ischemia, cardiomyopathies, or a genetic arrhythmia syndrome (see what follows). Drugs causing QT prolongation and metabolic derangements are other causes (Fig. 5) (Roden, 2008). Unless a clear precipitant can be identified and corrected, an ICD is often warranted (Epstein et al., 2008). Polymorphic VT or VF complicating the first 48 h of acute myocardial infarction is associated with greater in-hospital mortality, but not greater long-term mortality for patients who survive to hospital discharge, and an ICD is not warranted (Mehta et al., 2009). Patients who are found in VF and resuscitated may have had sustained monomorphic VT or polymorphic VT as the initial arrhythmia, requiring a broader evaluation for specific diagnoses.

Fig. 5 A 40-year-old male developed recurrent VT following abdominal surgery. He was being treated with levofloxacin and haloperidol and had a resting ECG that showed QT prolongation at baseline. The 12-lead ECG trace in figure shows a closely coupled PVC (arrow) with a compensatory pause followed by a sinus beat with longer QT and PVC arising from the T wave that initiates polymorphic VT. This initiation with long short short coupling is typical of torsade de pointes VT associated with QT prolongation. In this particular case, the use of QT prolonging drugs (levafloxacin and haloperidol) on an underlying long-QT syndrome provoked the arrhythmia.

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Structural Heart Disease Associated With VT Coronary Artery Disease Ischemic cardiomyopathy with infarct scar is the most common substrate for VT. Infarct-related monomorphic VT typically arises from regions of poorly coupled surviving myofibers within scar tissue that characteristically demonstrates slowed electrical conduction. These arrhythmia substrates related to ischemic cardiomyopathy are commonly located subendocardially but can also occur intramurally and subepicardially. A single area of infarct scar can give rise to multiple morphologies of VT (Aliot et al., 2009). Progressive fibrosis and ventricular remodeling can give rise to onset of VT late after a myocardial infarction. A small proportion (approximately 10%) of monomorphic VT in ischemic cardiomyopathy is due to automaticity or reentry involving the Purkinje system (Lopera et al., 2004).

Nonischemic Cardiomyopathy Nonischemic cardiomyopathy (NICM) is a heterogeneous group of diseases including idiopathic cardiomyopathy, genetic LV cardiomyopathies, arrhythmogenic RV cardiomyopathy (ARVC), inflammatory disease (sarcoid heart disease, myocarditis, Chagas disease), and hypertrophic cardiomyopathy (HCM). Key differences in the VT substrate of NICM compared to ischemic cardiomyopathy include: (i) generally smaller scars with multiple reentrant VTs despite small scar; (ii) predilection for anatomical location around the valve annuli or septum; (iii) less frequent transmural scars; (iv) more frequent intramural scars; (v) extensive epicardial scarring that may occur in the presence of normal endocardium or extend beyond the region of endocardial scarring (Piers et al., 2013; Desjardins et al., 2013). Because the replacement scar of NICM is smaller and diffusely distributed especially during its early stages, patients may present with polymorphic VT or VF. As the disease progresses, scarring becomes more confluent. Sustained monomorphic VT is due to scar-mediated reentry in over 80% of patients with the remainder being focal in origin or due to bundle branch reentry.

Inherited cardiomyopathies Genetic, familial cardiomyopathies account for 30%–40% of cases originally diagnosed as idiopathic or nonischemic dilated cardiomyopathy (Jacoby and McKenna, 2012). Some are associated with skeletal muscular dystrophy. Autosomal dominant, recessive, X-linked, and mitochondrial inheritance patterns are recognized. Mutations in genes coding for structural proteins of the nuclear lamina (lamins A and C) and the SCN5A gene are particularly associated with conduction system disease and ventricular arrhythmias in association with a cardiomyopathy (Van Tintelen et al., 2007). One study suggested that defects in the giant molecule titin maybe one of the most common causes of inherited dilated cardiomyopathy (Herman et al., 2012). HCM is the most common genetic cardiovascular disorder occurring in 1 in 500 individuals and is a prominent cause of sudden death before the age of 35 years (Gersh et al., 2011). Most cases are due to mutations in sarcomeric proteins, but once the diagnosis is made, genotyping has a limited role in assessing sudden death risk. Sudden death can be due to polymorphic VT/VF. Risk factors include young age, nonsustained VT, failure of blood pressure to increase during exercise, recent (within 6 months) syncope, ventricular wall thickness >3 cm, and possibly the severity of LV outflow obstruction (Christiaans et al., 2011). Cardiac MRI demonstrating scar has been suggested as a high-risk profile (Chan et al., 2014). An ICD is recommended for high-risk subjects, but the specific risk profile warranting an ICD continues to be debated. Surgical myectomy is effective for relief of symptoms from outflow obstruction and has been associated with a sudden death rate of less than 1% per year (Gersh et al., 2011). The reported annual rate of sustained VT or sudden death after transcoronary ethanol septal ablation has been reported to range between 1% and 5% (Gersh et al., 2011). Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a group of genetic disorders characterized by VT arising in regions of fibrosis and/or fatty replacement of ventricular myocardium (Corrado et al., 2017). Most are due to mutations in genes involved in cell to cell adhesion proteins in desmosomes, such as plakoglobin and plakophilin. Approximately 50% has a familial transmission with an autosomal dominant inheritance. Left ventricular involvement occurs in approximately a third of cases and can predominate. The sinus rhythm ECG displays inverted T-waves in the anterior precordial leads in over 75% of patients. Sudden death and ventricular arrhythmias are often the initial presentation and frequently provoked by exercise (Corrado et al., 2017). Right ventricular monomorphic VT may be the initial manifestation of ARVC and care must be taken to differentiate it from idiopathic RV outflow VT. If a diagnosis of ARVC is confirmed, an ICD is usually warranted. Autosomal recessive forms result in cardiocutaneous syndromes such as Naxos disease and Carvajal syndromes associated with plantar and palmar hyperkeratosis.

Genetic Arrhythmia Syndromes An increasing number of single gene mutations are being defined that cause arrhythmias and sudden death by disrupting cardiac ion channel function (channelopathies) or causing cardiomyopathy. Most are uncommon, or rare, but the first point of medical contact is often the primary care physician when an otherwise healthy individual develops arrhythmia symptoms or is seen after the sudden death of a relative. The electrocardiogram is an important screening tool, but abnormalities can be subtle and can vary from day to day in some disorders (Juntilla et al., 2012; Narayanan and Chugh, 2015). Family screening is further complicated by substantial

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variability in penetrance, such that the same mutation can cause frequent arrhythmias in one individual and be asymptomatic in another. Genotyping is playing an increasing role in confirming the type of disorder, identifying other affected family members, and in some, but not all disorders, helping to assess risk of sudden death.

Abnormalities of Repolarization and the QT Interval The congenital long-QT syndrome (LQTS) is due to mutations in genes encoding cardiac ion channels or their supporting proteins. The corrected QT (QTc) interval is typically prolonged to greater than 440 ms in men and 460 ms in women. Syncope or cardiac arrest due to TdP VT is the presenting symptom (Fig. 5). Depending on the mutation, other clinical features can include bradycardia, dysmorphic features, and deafness. Several different forms of congenital LQTS have been identified, but three groups of mutations that lead to LQT-1, LQT-2, or LQT-3 syndromes account for 90% of cases (Cerrone and Priori, 2011; Ackerman et al., 2011). The most common form, LQT-1, is due to a loss-of-function mutation in the gene encoding the alpha subunit for the slow inward rectifier potassium channel (KvLQT1). Symptoms typically occur during exertion, notably swimming. LQT2 is due to a loss-offunction mutation of the hERG gene that reduces rapid component of the delayed rectifier potassium current IKr. Arrhythmias are often triggered by surprise, such as a sudden loud noise. LQT3 is due to a mutation that increases the cardiac sodium current. Sudden death during sleep is a notable feature. Most patients with LQT-1 and LQT-2 respond to beta-blocker therapy especially of symptoms are provoked by adrenergic stimulation (Goldenberg et al., 2012). Markers of increased risk include longer QT intervals (particularly >0.5 s), female gender, and a history of syncope or cardiac arrest. Recurrent syncope despite beta-blocker therapy or high-risk profiles merit consideration of an ICD (Epstein et al., 2008). Left cardiac sympathetic denervation is effective when betablockers are not tolerated or when arrhythmias occur despite adequate beta blockade (Schwartz et al., 2004). Avoidance of QT prolonging drugs is critical for all patients with the LQTS including those who are genotype positive, but have normal QT intervals. Acquired LQTS is common due to electrolyte disturbances and drugs blocking the IKr currents mediated via the KCNH2 potassium channel, the primary mechanism of action of drugs such as sotalol and dofetilide. QT prolongation with associated risk factors of hypokalemia, hypomagnesemia, bradycardia, older age, and female sex increases the risk for TdP VT. Common nonantiarrhythmic drugs include haloperidol, macrolide, and quinolone antibiotics, but a number of drugs have been implicated. Mutations affecting LQTS genes may be present in 5% of patients with drug-induced TdP and gene polymorphisms that contribute to the risk is present in another 5%–10% (Yang et al., 2002). The short QT syndrome is very rare compared to the LQTS. The QTc is shorter than 0.36, and usually less than 0.3 s. The genetic abnormality causes a gain of function of the potassium channel (IKr) or reduced inward depolarizing currents. The abnormality is associated with atrial fibrillation, polymorphic VT, and sudden death (Patel et al., 2010). The Brugada syndrome is diagnosed by characteristic electrocardiographic appearance with ST segment elevation in at least two of leads V1–V3 with a typical coved morphology (referred to as Type I Brugada ECG) either spontaneously or induced by administration of a sodium channel blocking drug, combined with syncope, resuscitated cardiac arrest, or a family history of the disorder (Priori et al., 2013). Syncope and sudden death are due to polymorphic VT with a predilection during sleep or acute illnesses associated with fever. There is male predilection. Gene mutations are identified in fewer than 30% of patients, and most have involved the cardiac sodium channel gene SCN5A with an autosomal dominant inheritance pattern. Abnormal conduction and fibrosis in the RV outflow tract and overlap with ARVC have been described, suggesting that the syndrome may have multiple causes (Priori et al., 2013). An ICD is indicated for individuals who have had unexplained syncope or been resuscitated from cardiac arrest. Quinidine has been shown to be effective for the prevention of recurrent ventricular arrhythmias.

Catecholaminergic Polymorphic VT Catecholaminergic polymorphic VT (CPVT) is due to mutations in the ryanodine receptor or the sarcoplasmic calcium binding protein calsequestrin 2. These mutations result in abnormal calcium handling, and polymorphic ventricular arrhythmias that can resemble those of digitalis toxicity, for example, bi-directional VT. Patients typically present with syncope or cardiac arrest during exertion or emotional upset (Priori et al., 2013). ICD, restriction of physical activity, and beta-adrenergic blocker are the mainstays of therapy. The antiarrhythmic drugs flecainide and propafenone are effective for arrhythmia suppression (van der Werf et al., 2011). Left cardiac sympathectomy can be helpful in refractory cases (Wilde et al., 2008).

Drug Therapy for Ventricular Arrhythmias Drugs have an important role in reducing the frequency of recurrent symptomatic arrhythmias. Beta-adrenergic blockers are the most commonly used drugs because many arrhythmias are provoked by sympathetic stimulation, and they have a favorable safety profile. However, they have limited efficacy for suppressing reentrant arrhythmias associated with structural heart disease. Membrane active antiarrhythmic drugs that block cardiac ion channels have little role in preventing sudden death in patients with structural heart disease, but are useful for reducing symptomatic arrhythmias. The sodium channel blocking drugs such as flecainide and propafenone are occasionally considered for idiopathic VTs, but these agents should be avoided in patients with heart disease. They have negative inotropic effects, and flecainide increased mortality when given to survivors of myocardial infarction (Zipes et al., 2006). Quinidine is better tolerated hemodynamically due to its effect on action potential duration and its vasodilatory

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properties that tend to offset any negative inotropy from sodium channel blockade. However, all these drugs have significant proarrhythmic effects such that use of sodium channel blockers in patients with structural heart disease is largely limited to those with an ICD. Drugs that predominantly block potassium channels (sotalol, dofetilide) prolong repolarization and are better tolerated in heart failure. However, these drugs can cause TdP VT, and the risk is likely increased in heart failure due to electrophysiologic changes that accompany myocardial hypertrophy, impaired excretion of many drugs, and diuretic-induced hypokalemia. Careful monitoring for excessive QT prolongation during initiation is required. Both oral amiodarone and sotalol reduce ventricular and atrial arrhythmias that can lead to ICD shocks (Connolly et al., 2006). Amiodarone is most effective for control of ventricular arrhythmias but extra-cardiac toxicities (prominently thyroid, lung, liver, and neurologic) prevent long-term use in more than 20% of patients. In a recent trial in patients with LVEF < 35%, amiodarone had no effect on mortality in NYHA class II heart failure, but was associated with increased mortality in class III heart failure (Bardy et al., 2005). Nevertheless, amiodarone is a reasonable consideration for patients who have had spontaneous sustained VT or VF, but who have a contraindication to or refuse to have an ICD (Zipes et al., 2006). In patients who are refractory of combination of drugs, addition of ranolazine, a slow sodium channel blocker, has shown promise in case series and small studies (Bunch et al., 2011).

Implantable Cardioverter Defibrillators ICDs are highly effective for termination of VF or tachycardia and have been shown to improve mortality in cardiac arrest survivors and in patients at risk for sudden death due to structural heart diseases (Epstein et al., 2008). ICDs are recommended only if there is also expectation for survival of at least a year with acceptable functional capacity. The exception is in cases of patients with end-stage heart disease who are awaiting cardiac transplantation outside the hospital, or who have left bundle branch block QRS prolongation such that they are likely to have improvement in ventricular function with cardiac resynchronization therapy from a biventricular ICD. Despite their high efficacy for termination of ventricular arrhythmias, there is considerable morbidity associated with their use. ICD shocks are painful, associated with increased mortality, mostly from deteriorating heart failure and may result in post traumatic stress disorder. With improved programming parameters and early detection of lead malfunction, the annual rate of inappropriate or unnecessary shocks due to sinus tachycardia, atrial fibrillation, nonsustained VT, or lead malfunction has dropped to approximately 2.5% (Moss et al., 2012). Dual-chamber ICDs are better than single-chamber devices in reducing inappropriate shocks (Kolb et al., 2014). ICD implantation has a 3% risk of complications, including pneumothorax, perforation, bleeding, and heart failure decompensation, but the procedure-related mortality is less than 1% (Lee et al., 2010). ICD infections require device and lead removal, with a 0.25% procedural mortality in experienced centers. Patients receiving ICDs require careful follow-up to detect arrhythmias that are predictive of heart failure deterioration and monitoring for device malfunction, and assessment of battery life. Remote-monitoring systems that allow automated and patient-triggered transmissions of ICD recordings have simplified follow-up, and enhanced early detection of arrhythmias and device malfunction. A recent meta-analysis of three randomized trials suggests reduced mortality with remote monitoring of ICD patients (Hindricks et al., 2017).

Catheter Ablation for VT Catheter ablation is a reasonable first-line therapy for many symptomatic idiopathic VTs (Aliot et al., 2009). Most idiopathic VTs originate from a focus in the right ventricular outflow tract and ablation in this location has 80%–90% success rate for prevention of recurrence. Success rates are less well defined, but likely lower for those arising in less common locations such as the left ventricular outflow tract, aortic root, along the AV valve annuli, and from the papillary muscles. Failure of ablation is often due to inability to induce the arrhythmia for precise localization, or VT origin in a location that is inaccessible or in close proximity to a coronary artery that precludes safe ablation. In patients with structural heart disease, catheter ablation of VT is used to reduce the frequency of symptomatic VT that triggers ICD therapies, or to control VT storms that are life-threatening (see what follows) (Aliot et al., 2009). For arrhythmias that hemodynamically stable, mapping and ablation is performed during induced VT in an attempt to terminate VT. For hemodynamically unstable VTs, the likely arrhythmia substrate is sought by identifying areas of scar and abnormal conduction. These regions are indicated by low voltage and abnormal electrograms during stable sinus or paced rhythm. In this “substrate mapping” approach, regions within the scar likely to contain the reentry circuits can then be targeted for ablation without inducing VT. Substrate mapping can also be combined with limited mapping during VT for more focal targeting of the reentry circuit. Hemodynamic support with intraaortic counterpulsation or temporary ventricular assist devices has also been used to improve the ability to map during VT. Catheter ablation reports are largely limited to experienced centers. Procedural complications occur in approximately 3% of patients with idiopathic VT, and 6% of patients with structural heart disease, including tamponade, stroke, heart block, and, most frequently, vascular access complications (Aliot et al., 2009). Procedural mortality is rare in idiopathic VT, but ranges from 1% to 3% for patients with structural heart disease, usually due to uncontrollable ventricular arrhythmias when the procedure fails. Risks

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are greater with percutaneous epicardial access and ablation, which has a 5% risk of major complications, including coronary artery injury and pericardial bleeding, that is usually self-limited, but deaths have been reported. When antiarrhythmic drug therapy and catheter ablation fails, or is not an option, surgical cryoablation, often combined with aneurysmectomy, can be effective therapy for recurrent VT due to prior myocardial infarction and has also been used successfully in a few patients with nonischemic heart disease (Anter et al., 2011). Few centers now maintain the expertise for this therapy. Transcoronary ethanol ablation has also been used, in a small number of patients who have failed catheter ablation and drugs, with modest success (Tokuda et al., 2011).

Management of VT Storm An electrical or ventricular arrhythmia storm is increasingly being recognized as a distinct syndrome because of specific management issues and prognostic consequences that differ from a single episode of VT. An electrical storm refers to three or more episodes of VT or VF or ICD shocks within a period of 24 h and is associated with a high mortality (Sesselberg et al., 2007). In the long-term follow-up of AVID study participants who received a secondary prevention ICD, mortality was 5.6-fold higher compared to patients who had ventricular arrhythmia unrelated to a storm (Exner et al., 2001). Scar-related VT accounts for over 80% of VT storms (Nayyar et al., 2013). Acutely administration of beta-blockers, amiodarone, and sedation combined with general anesthesia is required to suppress sympathetic tone. Reversible causes such as ischemic and electrolyte disturbance should be sought and corrected. In the event of hemodynamic deterioration, ventricular support with assist devices, or extracorporeal membrane oxygenation might be required. Catheter ablation can be life saving and effective for suppression of a storm in 70% of patients (Nayyar et al., 2013). Failure of catheter ablation is associated with a high mortality. Left cardiac sympathetic denervation and thoracic epidural anesthesia have been reported with variable success for suppressing VT storms (Bourke et al., 2010). Patients with an electrical storm should be considered for transfer to a high volume, tertiary center for expert management.

Summary The significance of ventricular arrhythmias relate to symptoms, associated structural or genetic heart disease and the risk of sudden cardiac death. The primary focus in assessment is the determination of the risk of arrhythmic death and its prevention. In the absence of a risk of sudden death, management is primarily aimed at symptom relief. The less common role of ventricular arrhythmias as a primary initiator of ventricular dysfunction is increasingly being recognized, but prospective clinical trials are just getting under way to determine if suppression of arrhythmia will improve outcome. Although management strategies for ventricular arrhythmias have been defined for several forms of heart disease, prevention of VT-related sudden death in the rare genetic arrhythmia syndromes remain a challenge. Data from multicenter registries and rapidly accumulating genetic database will continue to provide important insights to guide managements of these uncommon but important causes of sudden arrhythmic death.

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(2008) Prognostic importance of defibrillator shocks in patients with heart failure. The New England Journal of Medicine 359(10): 1009–1017. Priori SG, Wilde AA, Horie M, et al. (2013) HRS/EHRA/APHRS Expert consensus statement on the diagnosis and management of patients with inherited primary arrhythmia syndromes. Heart Rhythm 10: 1933–1963. Roden DM (2008) Clinical practice. Long-QT syndrome. The New England Journal of Medicine 358: 169–176. Schwartz PJ, Priori SG, Cerrone M, et al. (2004) Left cardiac sympathetic denervation in the management of high-risk patients affected by the long-QT syndrome. Circulation 109: 1826–1833. Sesselberg HW, Moss AJ, McNitt S, Zareba W, Daubert JP, Andrews ML, Hall WJ, McClinitic B, and Huang DT (2007) Ventricular arrhythmia storms in post-infarction patients with implantable defibrillators for primary prevention indications: A MADIT-II substudy. Heart Rhythm 4: 1395–1402. Shimizu W (2009) Arrhythmias originating from the right ventricular outflow tract: How to distinguish “malignant” from “benign”? Heart Rhythm 6: 1507–1511. Tokuda M, Sobieszczyk P, Eisenhauer AC, et al. (2011) Transcoronary ethanol ablation for recurrent ventricular tachycardia after failed catheter ablation: An update. Circulation. Arrhythmia and Electrophysiology 6: 889–896. van der Werf C, Kannankeril PJ, Sacher F, et al. (2011) Flecainide therapy reduces exercise induced ventricular arrhythmia in patients with catecholaminergic polymorphic ventricular tachycardia. Journal of the American College of Cardiology 57: 2244–2254. Van Tintelen JP, Tio RA, Kerstjens-Frederickse WS, et al. (2007) Severe myocardial fibrosis caused by deletion of 50 end of the lamin A/C gene. Journal of the American College of Cardiology 49: 2430. Vereckei A, Duray G, Szenasi G, Altemose GT, and Miller JM (2008) New algorithm using only lead aVR for differential diagnosis of wide QRS complex tachycardia. Heart Rhythm 5: 89–98. Wilde AA, Bhuiyan ZA, Crotti L, et al. (2008) Left cardiac sympathetic denervation for catecholaminergic polymorphic ventricular tachycardia. The New England Journal of Medicine 358: 2024–2029. Yang P, Kanki H, Drolet B, et al. (2002) Allelic variants in long-QT genes in patients with drug-associated torsade de pointes VT. Circulation 105: 1943. Zipes DP, Camm AJ, Borggrefe M, et al. (2006) ACC/AHA/ESC 2006 Guidelines for Management of Patients With Ventricular Arrhythmias and the Prevention of Sudden Cardiac Death: A report of the American College of Cardiology/American Heart Association Task Force and the European Society of Cardiology Committee for Practice Guidelines (Writing Committee to develop Guidelines for Management of Patients With Ventricular Arrhythmias and the Prevention of Sudden Cardiac Death): Developed in collaboration with the European Heart Rhythm Association and the Heart Rhythm Society. Circulation 114: e385–e484.

Emergency Medicine Approach and Management of Traumatic Injuries: An Overview E Lavine and E Legome, Icahn School of Medicine at Mount Sinai, New York, NY, United States © 2018 Elsevier Inc. All rights reserved.

Introduction Preparation for the Patient Evaluation of the Patient in the Emergency Department Airway Management Breathing Circulation Disability Secondary Survey Traumatic Head Injuries Neck Injuries Musculoskeletal Disorders of the Spine Chest Trauma Abdominal Trauma Conclusion References

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Introduction A multidisciplinary team made up of emergency physicians, surgeons, nurses, and ancillary staff is optimal to promptly and efficiently manage severely traumatized patients throughout the continuum of care. However, as this level of resources may not be available, it is critical that a formal process of planning for all stages of care occur to best understand and utilize the resources available. This planning should lead to a structure where each member of the care team will understand their well-defined role in the management of the trauma patient.

Preparation for the Patient Prior to arrival at the hospital, emergency medical service (EMS) providers will typically inform the receiving emergency department (ED) regarding the arrival of a significant trauma patient. While there are expectations for ACS level one trauma centers regarding specific resource requirements on selected patients, trauma centers often use a combination of physiological and mechanistic criteria in deriving their formal activation process (Markovchick and Moore, 2007). Criteria based on mechanism alone, such as pedestrian struck, motor vehicle collision with intrusion, or prolonged extrication, have mixed results and relatively poor specificity, but when used in combination with anatomical or physiological criteria, the accuracy increases (Kohn et al., 2004). Generally it is felt that some reasonable level of over triage is preferred to under triage in assembling a bedside trauma response.

Evaluation of the Patient in the Emergency Department The ED care of the trauma patient begins with an assessment of potentially life-threatening injuries. Although every patient should have a complete and thorough evaluation, the rapidity, extent, and amount of testing are related to the mechanism, initial findings, chief complaints, age, and co-morbidities of the patient. In the primary survey, a rapid assessment of the airway, breathing, and circulation is completed. In principle, as major injuries are identified, they are treated before moving to the next part of the primary survey. In reality, however, there are often multiple concurrent interventions. The ability to perform simultaneous interventions, however, often depends on both the number and makeup of the team. What is critical is that there is a team leader who is prioritizing interventions through a systematic, clear, and consistent approach. Specific injuries that must be immediately addressed include the loss of airway integrity, inability to oxygenate or ventilate, tension pneumo- or hemo- thorax, massive external hemorrhage, and cardiac tamponade. Geriatric trauma patients present an additional challenge. Patients >60 years of age have higher mortality and complication rates in comparison with younger patients with similar injuries. Special awareness must be given to this patient population (Campbell-Furtick et al., 2016; Kuhne et al., 2005).

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Airway Management Inadequate oxygenation or ventilation can be life-threatening but is often easily reversible. The airway assessment should include patency and ability to protect the airway both at the time of evaluation and in the near future. General indications for intubation include inability to protect the airway, inability to successfully oxygenate or ventilate, airway obstruction, and Glasgow Coma score 60 Persistent amnesia Visible trauma above the clavicles seizure

Age 2.5 mm but 100 nm but 50–55, and >55 dB). In multiple adjustment models, the relative risk (RR) for stroke was 1.24 for daytime aircraft noise (>63 dB v 51 dB) and 1.29 for nighttime noise (>55 dB v 50 dB). The RR of mortality was similar to those for hospital admissions at the higher noise levels. Thus the RR is the highest with high daytime noise levels and nighttime aircraft noise (Hansell et al., 2013). An 2009 U.S. study, recruited 6 million seniors (>65 years) living near one of the 89 largest airports to evaluate the association between airport-related noise and the risk of hospital admission for CVD and heart failure. Despite the study's methodological limitations, a statistically significant association between exposure to aircraft noise and risk of hospitalization for CVDs was shown (Correia et al., 2013). One explanation of these contradictory results is related to the difficulty to deal with two major confounders, “indoor noise” produced by the neighborhood in a residential area (Tenaillon et al., 2015) and environmental (ambiant) air pollution, as this pollution shares many common sources with environmental noise (Tétreault et al., 2013). The pathological effects of noise involve many functions: sleep disruption, disautonomic perturbations (e.g., increases of blood pressure and heart rate), stress reactions (release of stress hormone), and increase of oxidative stress, which in turn may result in vascular endothelial dysfunction and arterial hypertension (Münzel et al., 2014).

Altitude, Air Planes, and Erythropoietin Altitude is a geophysiological condition which impacts all living organisms. Physical and climatological characteristics, decrease of available oxygen, lower atmospheric pressure and lower temperature, more frequent winds, and a larger exposure to solar radiation are determining Life. These conditions vary according to the altitude, low (5000 m) and also to the latitude. Adaptation to high-altitude challenges the brain. As hypoxemia can be deleterious for cellular adaptation and survival, the regulatory homeostasis favors all mechanisms related to convective oxygen transport (cardiovascular, respiratory, and hematopoietic functions) that will counteract a possible cellular hypoxia (Petousi and Robbins, 2014). The first adaptative mechanism is hyperventilation which has the quickest effect. An increase in cerebral blood flow up to 31% of values measured at sea level can occur in few days (3–7) of a subject's transition to high altitudes. The return to sea-level base values follows, depending on the degree of the hypoxic stimulus and on the cerebrovascular sensitivity to hypoxia and carbon dioxide (Bor-Seng-Shu et al., 2012). The heart function is modified typically with tachycardia and no change in stroke volume but a slight temporary blood pressure increase. After a few days of adaptation, cardiac output returns to normal (Naeije, 2010). Supply of oxygen is favored by an adaptative release at the tissue level and an increase of the red blood cells (RBC) production. The direct effect of production is an increase of the hematocrit and the blood viscosity. Other factors contribute also to increased coagulability: namely, increases in platelets (mean platelet volume), erythrocyte aggregability, and plasma viscosity (Bor-Seng-Shu et al., 2012; Alper et al., 2009). Protection of the cellular metabolism involves hypoxia-inducible factor(s) (HIFs) (capable of inducing protective metabolites and proteins) (Kumar and Choi, 2015) as well as chemical agents such as nitric oxide (NO), carbon monoxide (CO), eicosanoid products, oxygen-derived free radicals, endothelins, Kþ, Hþ, and adenosine (Bor-Seng-Shu et al., 2012), and an control of key enzymes (Na-, K-ATPase). Oxygen-derived free radicals and H2O2, NO, and oxidized glutathione are the signaling messengers that make Na-, K-ATPase systems “oxygen-sensitive” (Bogdanova et al., 2016). The number of exposed people varies; thus, more than 140 million people around the globe reside at high altitude (
3000 m) in Africa (Ethiopian Highlands; Kilimanjaro), Asia (Himalaya Mountains and Tibet), and the American continents (Rocky Mountains and Andes Mountain Range) (Ronen et al., 2014). Two types of population must be distinguished, the native

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mountain-born and the sea-level-born people who need to adapt. In fact, altitude stress and its neuro-cardiovascular consequences differ markedly depending on the cerebrovascular regulation and on the capability to adapt. Impairment of the cerebral autoregulation is the major risk for travelers who rapidly reach altitudes above 2500 m. They may manifest several syndromes: altitude headache (HAH), acute mountain sickness (AMS), high-altitude cerebral oedema (HACO/ HACE), and high-altitude pulmonary oedema (HAPO/HAPE) (Wilson et al., 2009; Yanamandra et al., 2014). Although rarely reported, acute stroke is possible during short-term visits to high-altitude regions (Chan et al., 2012). Thus, stroke or stroke-like episodes have been described in association with high altitude for the first time in 1895 (Szawarski et al., 2012). Differential diagnosis must consider cerebral venous thrombosis (Chan et al., 2012) and HACO, which can mimic stroke and provoke deficits; those resolve with the resolution of cerebral oedema (Yanamandra et al., 2014). In case of stroke, an asymptomatic patent foramen ovale should be excluded (Szawarski et al., 2012; Murdoch, 2015). High-altitude impact during long-term stays (e.g., several months) has been investigated notably among soldiers stationed in the Himalaya Mountains. The relative risk for stroke above altitudes of 3000 m is significantly increased (Jha et al., 2002) by a factor as high as 10-fold (Niaz and Nayyar, 2003); extreme altitudes (over 5000 m) are associated with a 30-fold risk of spontaneous vascular thrombosis (Anand et al., 2001). Polycythaemia is clearly a major risk factor. The effect of altitude on native populations is a different issue. Several publications (USA, Kashmir, South America, India) have shown that the incident stroke is lower in these populations compared to populations living at sea-level and lower altitudes (Mahajan et al., 2004), to the contrary of a Saudi Arabian study (al Tahan et al., 1998). A study in Cuzco (Peru), located at 3380 m above sea level, showed a crude prevalence ratio of 6.47 per 1000 (cohort of 3246 individuals). The prevalence risk was related to age, polycythemia, high alcohol consumption, residence's area (down-town versus suburban), blood pressure, and increased hematocrit. These two last parameters may vary following altitude (Jaillard et al., 1995). In the large Swiss National Cohort, a clear dose–response relationship between lifetime altitude exposure and mortality was demonstrated: mortality from coronary heart disease and stroke decreased with increases of altitude (22% per 1000 m and 12% per 1000 m, respectively). Switzerland has specific characteristics: altitude of residence between 200 and 2000 m and minimal changes in geographic latitude. However, this study has several limitations related to the methodology and the impossibility of collecting data on individual risk factors (e.g., atherosclerosis). The conclusion, that being born at higher altitude (although the range is not clear) has a protective effect, needs a clear confirmation. Possible physiological explanations could be found: solar radiation and Vit D, less air pollution, genetics, etc. (Faeh et al., 2009). In any case, these studies point to acclimatization, which differs from adaptation, as it is a long-term populationbased process, involving both genetic and gene-environmental mechanisms (Petousi and Robbins, 2014). All populations living at high altitude do not show the same acclimatization. For example, at similar high altitudes, Tibetans have significantly lower hemoglobin concentrations than their Andean or Han Chinese immigrants counterparts (Petousi and Robbins, 2014); they also suffer less from chronic mountain sickness (CMS). Stroke risks should likewise be different. The stroke's risk related to altitude during airplane travel (potentially associated with hypobaric and hypoxic conditions) is low even in patients with symptomatic carotid occlusion (Reynolds et al., 2014). Recently, the incidental risk has been reevaluated; it is now estimated to be 1 stroke in 35,000 flights (Álvarez-Velasco et al., 2016), or less than one in a million passengers (Humaidan et al., 2016). There is no difference between short-haul (2 h) for healthy individuals (Reynolds et al., 2014). The role of blood erythropoietin (Epo) in the adaptation to high-altitude hypoxic exposure in humans led to its use as medicine and doping in competitive sports (Robinson et al., 2006). Epo causes a rise in red cell mass accompanied by elevated hemoglobin concentrations and hematocrit. Its side effects have been documented (Pope et al., 2014).

Climatic and Meteorological Variables: Seasonality and Temperature In the context of an increasing interest in the health effects of climate change, climate and weather characteristics are now scrutinized as possible risk factors for stroke. When considering the admission to a hospital or the mortality, the incidence of ischemic stroke seems to be cyclic during the year. Seasonality has been observed worldwide (Chen et al., 2013a) although some studies have reported no seasonality; for instance, a study in Taiwan (Lee et al., 2008). Furthermore, the peak season differs for different countries. In Japan (Takashima stroke register), an excess of ischemic stroke fatality occurs in spring followed by winter (after adjusting for age, gender); the rates are more when compared to during summer (Turin et al., 2009). In the United States, an epidemiological study conducted in the VA hospitals showed that the peak occurrence for ischemic stroke was mid-May, with the lowest occurrence in early December. The authors emphasized that, “Neither the region (i.e., climate) nor the race of the patient substantially modified the seasonal trend” (Oberg et al., 2000). In Melbourne, Australia, ischemic stroke occurrence was significantly higher during spring than summer (incidence rate ratio (IRR) 1.14) (Mao et al., 2015). Peak season was in winter in Hong Kong (Goggins et al., 2012) and in August in Eastern Turkey, with the lowest occurrence in spring (Anlar et al., 2002). Diverse explanations for these patterns have been proposed, including lunar patterns (Mao et al., 2015), rainfalls related to the El Niño Southern Pacific Oscillation (ENSO) (Kintoki Mbala et al., 2016), and in the case of global mortality, relations to air pollution, and meteorological variables (Qian et al., 2010). The question addressed in a 2010 paper, “What is it with weather and stroke?” (McArthur et al., 2010), remains crucial. Most evidences suggest that cold and hot apparent temperatures (which consider both air temperature and humidity) are associated with stroke mortality, as shown by the eight Large Chinese Cities Study (Chen et al., 2013a). The results show a U-shaped relationship,

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with increased risk at extreme high or low temperatures. The potential effect of cold temperature might last more than 2 weeks in contrast to the more immediate effect of hot temperature. However, the burden of stroke mortality is different. In the six large Chinese cities (2007–2013) the stroke burden was caused by cold temperature and was higher in males and seniors (Yang et al., 2016). The same patterns are known for mortality by all causes (Gasparrini et al., 2015; Medina-Ramón et al., 2006). Several subpopulations are particularly susceptible to temperature extremes, for example, patients with atrial fibrillation (Medina-Ramón et al., 2006). The relationship between heat waves and stroke has been addressed by several articles. Heat waves have a strong adverse effect on stroke mortality with an excess mortality of 6%–52% (Chen et al., 2015). A multicity case-only analysis of 50 U.S. cities showed that extremely high-temperature days posed a higher relative stroke mortality risk compared to pneumonia and CVD (Medina-Ramón et al., 2006). Heat wave (with a 2-day lag) is significantly associated with the risk of hospitalization for stroke (odds ratio [OR] 1.173) with more significance for men and over 80 years, in a study conducted in Pennsylvania (Ha et al., 2014). A Chinese study pointed to a clear spatial pattern of stroke mortality during heat waves; the risk was higher in rural areas (Luhe district) compared to the urban area of Nanjing, probably because of a higher vulnerability of the populations; this vulnerability seems to be linked to the socioeconomic level, the air condition availability, the population's age, and the medical facilities’ access (Chen et al., 2015). Obviously, further works are needed to assess the real impact of weather (characterized by temperature, humidity, sunshine duration, etc.) on stroke subtypes and pathogenesis (hemorrhagic/stroke, lacunar/atherothrombotic/ cardioembolic). Biological explanations involve complex interactions between endothelium function, vasomotricity, blood pressure, brain demand for oxygen, and change of the quality of blood components (thrombogenic factors) and blood properties (viscosity). For example, cold induces vasoconstriction while heat promotes dilation (Chen et al., 2013a).

Geomagnetic Storms Can Trigger Stroke: A New Environmental Risk Factor The term “geomagnetic activity” concerns natural variations in the geomagnetic field (Feigin et al., 2014). A geomagnetic storm is a temporary disturbance of the Earth's magnetosphere caused by a solar wind shock wave and/or cloud of magnetic field which interacts with the Earth's magnetic field; these are prominent during the solar maximum phase of the solar cycle. The sun has a solar cycle which averages 11 years in length; at the end of each cycle, the polar magnetic field of the sun reverses. During these cycles, there is an increased solar activity, which generally has a peak in the middle of the solar cycle. During the solar maximun, the increase of sunspots and the solar storms produce the emission of large quantities of electromagnetic and particle radiation. Theses events are known to disrupt technology such as power grids, magnetic compasses, damage satellite microchips and disturb radio and radar transmissions. The solar minimum refers to a relatively low solar activity. This takes place 5–6 years after the solar maximum. Levels of geomagnetic activity are commonly measured by the Ap Index. Of all locales, Auckland (Feigin et al., 2014) had the most data collected during the solar maximum years, and even had high levels of geomagnetic activity including during 2003, a solar minimum year. Oxfordshire and Melbourne (Feigin et al., 2014) had data collected during solar minimum years only. However, the solar minimum that Oxfordshire data was collected for had high levels of geomagnetic activity. Melbourne (Feigin et al., 2014) data were collected during times of very low geomagnetic activity. The remaining Northern hemisphere cities had more data collected during solar minimum years: Dijon (8 out of the 11 years) and Northern Sweden (12 of the 20 years). Perth had data collected equally over solar maxima and solar minima. It is important to note that data collection for the four cities overlapped during very low levels of geomagnetic activity (1996–1997). Overall, geomagnetic storms (Ap Index 60 þ) were associated with a 19% increase in the risk of stroke occurrence (95% CI, 11%–27%). The triggering effect of geomagnetic storms was most evident across the combined group of all strokes in those aged < 65 years, increasing stroke risk by >50%: moderate geomagnetic storms (60–99 Ap Index) were associated with a 27% (95% CI, 8%–48%) increased risk of stroke occurrence, strong geomagnetic storms (100–149 Ap Index) with a 52% (95% CI, 19%–92%) increased risk, and severe/extreme geomagnetic storms (Ap Index 150þ) with a 52% (95% CI, 19%–94%) increased risk (test for trend, P65% suggesting an equal need for interventions that may reduce admissions and mortality. Given the lack of success of pharmaceutical trials in HFpEF, the potential for benefit from cardiac rehabilitation is intriguing and deserves greater study.

References Aragam KG, et al. (2015) Gaps in referral to cardiac rehabilitation of patients undergoing percutaneous coronary intervention in the United States’. Journal of the American College of Cardiology 65(19): 2079–2088. Belardinelli R, et al. (2012) 10-year exercise training in chronic heart failure. Journal of the American College of Cardiology 60(16): 1521–1528. Centers for Medicare and Medicaid Services (2009) 42 CFR 410.49: Cardiac rehabilitation program and intensive cardiac rehabilitation program: Conditions of coverage. Federal Register 74(226): 396–398. Centers for Medicare and Medicaid Services (2014) Decision memorandum for coverage of cardiac rehabilitation (CR) programs for chronic heart failure (HF) (CAG-00437 N). pp. 1–31. Downing J and Balady GJ (2011) The role of exercise training in heart failure. Journal of the American College of Cardiology 58(6): 561–569. Ellingsen Ø, et al. (2017) High-intensity interval training in patients with heart failure with reduced ejection fraction clinical perspective. Circulation 135(9): 839–849. Franciosa JA, Park M, and Levine TB (1981) Lack of correlation between exercise capacity and indexes of resting left ventricular performance in heart failure. The American Journal of Cardiology 47(1): 33–39. Golwala H, et al. (2015) Temporal trends and factors associated with cardiac rehabilitation referral among patients hospitalized with heart failure. Journal of the American College of Cardiology 66(8): 917–926. Herrick JB (1912) ‘Clinical features of sudden obstruction of the coronary ARr. Journal of the American Medical Association LIX(23): 2015. Hopker JG, Jobson SA, and Pandit JJ (2011) Controversies in the physiological basis of the “anaerobic threshold” and their implications for clinical cardiopulmonary exercise testing’. Anaesthesia 66(2): 111–123. Hunt SA, et al. (2005) ACC/AHA 2005 guideline update for the diagnosis and management of chronic heart failure in the adult. Circulation 112(12). Kato N, et al. (2012) Depressive symptoms are common and associated with adverse clinical outcomes in heart failure with reduced and preserved ejection fraction’. Journal of Cardiology 60(1): 23–30. Kelly JP, et al. (2016) The potential impact of expanding cardiac rehabilitation in heart failure. Journal of the American College of Cardiology 68(9): 977–978. Kerrigan DJ, et al. (2014) Cardiac rehabilitation improves functional capacity and patient-reported health status in patients with continuous-flow left ventricular assist devices: The Rehab-VAD randomized controlled trial. JACC: Heart Failure 2(6): 653–659. Keteyian SJ, et al. (2011) Relation between volume of exercise and clinical outcomes in patients with heart failure. Journal of the American College of Cardiology 60(19): 1899–1905. Labate V and Guazzi M (2015) Past, present, and future rehabilitation practice patterns for patients with heart failure. Heart Failure Clinics 11(1): 105–115. Levine SA and Lown B (1952) “Armchair”; treatment of acute coronary thrombosis. Journal of the American Medical Association 148(16): 1365–1369. Luo N, et al. (2017) Exercise training in patients with chronic heart failure and atrial fibrillation. Journal of the American College of Cardiology 69(13): 1683–1691. McDonald CD, Burch GE, and Walsh JJ (1972) Prolonged bed rest in the treatment of idiopathic cardiomyopathy. The American Journal of Medicine 52(1): 41–50. McNeely J, et al. (2016) Abstract 15035: Regional variation in the availability and utilization of cardiac rehabilitation services among eligible medicare fee-for-service beneficiaries: Where are the opportunities for improvement? Circulation 134(Suppl 1). Mueller E, et al. (2009) Effect of a computerized referral at hospital discharge on cardiac rehabilitation participation rates. Journal of Cardiopulmonary Rehabilitation and Prevention 29(6): 365–369. Myers J and Ashley E (1997) Dangerous curves. A perspective on exercise, lactate, and the anaerobic threshold. Chest 111(3): 787–795. Pack QR, et al. (2014) The current and potential capacity for cardiac rehabilitation utilization in the United States. Journal of Cardiopulmonary Rehabilitation and Prevention 34(5): 318–326. Reeves GR, et al. (2017) Rehabilitation therapy in older acute heart failure patients (REHAB-HF) trial: Design and rationale. American Heart Journal 185: 130–139. Taylor RS, et al. (2015) Home-based versus centre-based cardiac rehabilitation. In: Taylor RS (ed.) Cochrane database of systematic reviews, Chichester: Wiley. Vanhees L, et al. (2012) Importance of characteristics and modalities of physical activity and exercise in the management of cardiovascular health in individuals with cardiovascular disease (Part III). European Journal of Preventive Cardiology 19(6): 1333–1356. Wasserman K (1987) Determinants and detection of anaerobic threshold and consequences of exercise above it. Circulation 76(6 Pt 2): VI29–VI39. Wisloff U, et al. (2007) Superior cardiovascular effect of aerobic interval training versus moderate continuous training in heart failure patients: A randomized study. Circulation 115(24): 3086–3094.

Further Reading Balady GJ, et al. (2010) Clinician’s guide to cardiopulmonary exercise testing in adults: A scientific statement from the American Heart Association. Circulation 122(2): 191–225. O’Connor CM, et al. (2009) Efficacy and safety of exercise training in patients with chronic heart failure. JAMA 301(14): 1439. Taylor RS, et al. (2014) Exercise-based rehabilitation for heart failure. In: Taylor RS (ed.) Cochrane database of systematic reviews. Chichester: Wiley. CD003331.

Exercise, Physical Activity, and Cardiovascular Disease A Bauman, M Alharbi, N Lowres, R Gallagher, and E Stamatakis, Sydney University, Sydney, NSW, Australia © 2018 Elsevier Inc. All rights reserved.

Introduction: Physical Activity, Exercise, and Heart Disease The Cardiovascular Health Benefits of Physical Activity: A Primary Prevention Approach The Role of Exercise as a Secondary Prevention in Managing CVD Exercise and Heart Failure Exercise and Atrial Fibrillation Sedentary Behavior and CVD: Current Evidence Overview Conclusion References Further Reading

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Introduction: Physical Activity, Exercise, and Heart Disease For six decades, researchers have explored the cardiovascular benefits of exercise and physical activity, and documented consistent protective and therapeutic benefits for being physically active. This article reviews some of this evidence, with a focus on cardiovascular disease (CVD), defined here particularly as coronary heart disease (CHD). Exercise is defined as planned and structured large muscle activity with the aim of improving maintaining physical fitness, performance, and health (Boden et al., 2013). It is a subset of “physical activity” which is more broadly defined as any movement involving large skeletal muscles leading to energy expenditure (Caspersen et al., 1985; Boden, 2013). Physical activity includes all large muscle movement throughout the day, at work, in travel to or from places, at home and in recreation or leisure time. We review the primary prevention evidence for physical activity in reducing the risks of developing CVD among populations initially free of disease. We consider the new evidence on sedentary behavior (prolonged sitting time) and CVD. Then we consider the roles of physical activity and exercise for people with heart disease, and for common forms of heart disease: people with atrial fibrillation (AF) and patients with heart failure (HF), as exemplars of common cardiac conditions related to, or treated by physical activity and exercise. (Note that strictly this is tertiary prevention (as secondary prevention is screening for disease), but the term secondary prevention is widely used in cardiovascular health to mean patient-related prevention, so that this terminology is used here.) The evidence for primary prevention comes from population-based epidemiological studies; the evidence for exercise and physical activity and potential benefits for people with cardiac disease comes from epidemiological, clinical, and basic science research. Hence, the perspectives in this chapter are multidisciplinary, emanating from both population and clinical sciences.

The Cardiovascular Health Benefits of Physical Activity: A Primary Prevention Approach This section reviews the evidence for physical activity in the primary prevention of CVD, and is based on the epidemiological and population health research evidence accumulated over several decades. Primary prevention implies that in physical activity is beneficial in reducing the risk of developing CVD in populations of healthy individuals who are free of CVD. Much of this research emanates from epidemiological studies, starting in the 1950s with the observation that London bus drivers had higher CVD event rates than bus conductors, with the latter group being more active throughout the working day (Morris et al., 1953). Many studies followed, with consistent evidence provided for occupational and leisure time physical activity. Up until the 1990s, physical activity for health was usually defined as vigorous intensity “aerobic exercise,” at least three times per week for at least 20 min each time (Kravitz et al., 2011). By 1990, there was a meta-analysis (Berlin and Colditz, 1990) and a systematic review (Powell et al., 1987) that clearly identified the risks of physical inactivity; on average, those who were least active were 1.9 times as likely to develop heart disease compared to the most active in the population. A decade later, the US Surgeon General’s report on the health benefits of physical activity was released (USSG, 1996) that redefined the minimal quantum of physical activity required to realize most cardiovascular and health benefits. This was a minimum recommendation of 30 min of at least moderate-intensity physical activity on most days of the week, a guideline that emphasized a new and more achievable level of physical activity for population health (USSG, 1996). The rationale for this was that most mortality risk and cardiovascular risk occurs in those who were completely inactive, and that maximum population benefit occurs if these inactive individuals start doing some activity, ideally half an hour a day (Powell et al., 2011). Benefit continued to accrue up to an hour a day of moderate-vigorous physical activity (MVPA), but beyond an hour a day, little additional benefit was noted (Arem et al., 2015). These benefits focused on all causes of mortality, but included risks of cardiovascular deaths, and risks of incident CVD events. These cardiovascular benefits are now well established. Li and Siegrist (2012) conducted a meta-analysis of 21 epidemiological cohort studies, and compared to low active males, the men who met the recommended levels of activity had a 24% reduction in

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CVD events; the same analysis showed a 27% risk reduction for women. These recent studies mostly focused on leisure time physical activity, with the role of occupational activity less clear (Li et al., 2013). The dose-response relationship was further verified by a 2011 meta-analysis of 33 cohorts (Sattelmair et al., 2011) which showed greater risk reduction for 300 min/week (an hour a day) compared to the minimum recommended level of 150 min/week of MVPA. The cardioprotective relationship was greater for women than men. Earlier meta-analyses had reached similar conclusions (Nocon et al., 2008; Oguma and Shinoda-Tagawa, 2004; Gebel et al., 2015), with even regular walking providing clear cardioprotection (Oguma and Shinoda-Tagawa, 2004). A consistent observation was that there was a stronger relationship for objective measures of fitness or movement, compared to self-report physical activity, indicating that the many self-report studies may underestimate the association (LaMonte and Blair, 2006; Nocon et al., 2008). Although moderate activity does, by itself, confer much of the preventive benefit, adding some vigorous activity further increases the benefit (Gebel et al., 2015). One additional concept is the notion of the burden of disease, or the attributable fraction for disease; in other words, what proportion of diseases could be prevented if the risk factor was reduced or eliminated. According to the World Health Organization (2009), 57% of cardiovascular deaths can be traced back to one of the lifestyle risk factors and conditions (physical inactivity, smoking, unhealthy diet, hazardous alcohol use, and the resultant hypertension, obesity, and hypercholesterolemia). Physical inactivity is responsible for 3–5 million preventable deaths per year, and is the fourth ranked of these risk factors, ranking ahead of overweight and obesity (especially for CVD risk, WHO, 2009). These physical inactivity-related deaths and cardiovascular events occur in high and middle income countries, and especially in middle income countries may lead to premature mortality of people of middle age, which has national economic and productivity implications in many countries. Given the strong evidence base, many Government and non-Government organizations have developed and adopted physical activity guidelines for preventing heart disease. The recent guidelines by the American Heart Association point to the benefits of at least half an hour of moderate-vigorous intensity physical activity on most days of the week (Haskell et al., 2007); the World Health Organization has a similar recommendation, of 150–300 min MVPA per week. For most patients with heart disease, the same recommendation, 30–60 min of activity on most days of the week remains current. In addition, sedentary behavior guidelines, to reduce prolonged and uninterrupted sitting time, are being developed, although the exact cut-points and nature of sitting-related risk remains uncertain (Young et al., 2016).

The Role of Exercise as a Secondary Prevention in Managing CVD Exercise and physical activity are evidence-based approaches to the management of CVD, and in particular to cardiac rehabilitation following a cardiac event (Anderson et al., 2016). The physiological mechanisms underlying the beneficial effects of exercise in the secondary prevention for patients with CHD are well established. Exercise remains an important component of recovery from cardiac events, because it protects against cardiac ischemia/reperfusion injury (Boden et al., 2013). A number of reviews showed that regular moderate or vigorous-intensity exercise benefits people who have CHD by: (i) preventing the coronary arteries from further narrowing (antiatherosclerotic), (ii) inhibiting blood clotting (antithrombotic), (iii) promoting perfusion (antiischaemic), (iv) maintaining a normal heart rhythm (antiarrhythmic), (v) positively impacting on established cardiovascular risk factors (antiatherogenic), (vi) lowering inflammatory markers (antiinflammatory), and (vii) improving autonomic and vascular endothelial function (Boden et al., 2013; Fletcher et al., 2013; Leon et al., 2005). To exemplify this, exercise evokes antithrombotic effects by increasing fibrinolysis and decreasing platelet adhesiveness, fibrinogen, and blood viscosity (Fletcher et al., 2013). Moreover, the antiarrhythmic effect of exercise is stimulated through reduced adrenergic activity and increasing both vagal tone and heart rate variability (Fletcher et al., 2013). These changes help to decrease the load on the heart at rest and during exercise, which diminishes some of the symptoms of CHD (Fletcher et al., 2013). It is well documented that people diagnosed with CHD who engage in aerobic exercise generate cardiac and peripheral adaptations including improvements in peak oxygen uptake, cardiac output, myocardial oxygen demand, and autonomic function (Fletcher et al., 2013; Mezzani et al., 2013). Regular, long-term exercise generates a range of morphological and phenotypic alterations in the myocardium such as resting bradycardia, left ventricle hypertrophy, cellular growth/adaptations in cardiac myocytes, and modified coronary vascular function (Brown et al., 2003; Fletcher et al., 2013). Moreover, participants diagnosed with heart disease who engaged in aerobic exercise frequently demonstrate an increase in cardiorespiratory fitness (VO2 max levels, Mezzani et al., 2013). In addition, exercise may increase cardiac output which leads to improved vasomotor function (e.g., coronary dilatation) resulting in improved myocardial oxygen delivery to the myocardium leading to increased stroke volume (Leon et al., 2005). People with CHD who exercise at high-intensity levels show improvements in their cardiac function such as increased ejection fraction, stroke volume, diastolic function, and wall motion parameters (Fletcher et al., 2013). Exercise also promotes lowered myocardial oxygen demand after training for participants with CHD, leading to lower heart rate, systolic blood pressure, and circulating catecholamines (Fletcher et al., 2013; Leon et al., 2005). In summary, a plethora of evidence confirms a dose-response relationship between exercise and cardiovascular-related physiology and risk (Varghese et al., 2016). When CHD is established, exercise and physical activity play a beneficial and significant role in the disease management. This is primarily because increased physical activity levels and cardiorespiratory fitness appear to mitigate CHD progression (Boden et al., 2013; Leon et al., 2005). Exercise also favorably influences some CHD risk factors, including insulin resistance, glycaemic control, blood pressure, lipid profile, fibrinolysis, endothelial function, inflammatory defense systems, and hemostatic factors

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(Fletcher et al., 2013; Varghese et al., 2016). Exercise improves cardiorespiratory fitness, muscle strength, body composition, and flexibility—which ultimately lead to enhanced functional capacity and improvements in the functionality of the cardiovascular and endocrine systems (Varghese et al., 2016). Recent meta-analyses reported a 26% reduction in the risk of cardiac mortality (Anderson et al., 2016), a 13% reduction in all-cause mortality (Heran et al., 2011), and an 18% reduction in hospital admissions (Anderson et al., 2016), at 12 months in participants who undertook exercise-based cardiac rehabilitation compared to those who did not undertake cardiac rehabilitation. The meta-analyses demonstrated improvements in CHD risk factors, a greater increase in functional capacity, and enhanced health-related quality of life (Anderson et al., 2016; Taylor et al., 2015). Structured exercise for 12 months in patients with stable angina may even produce better outcomes than the standard therapy of percutaneous coronary intervention as measured by greater event-free survival, reduced hospitalization, and repeated vascularization procedures (Hambrecht et al., 2004). These findings reinforce the importance of exercise and physical activity as a therapeutic approach in the management of people diagnosed with CHD. Given the numerous benefits of exercise-based cardiac rehabilitation, it forms part of national health policy recommendations (Achttien et al., 2013; Anderson et al., 2016). Most programs include supervised exercise sessions with an exercise physiologist and education on physical activity recommendations (Achttien et al., 2013). Guidelines for cardiac rehabilitation recommend that during phase II of the program, exercise sessions should be offered twice weekly for a minimum of 6 weeks (Achttien et al., 2013). The guidelines suggest that cardiac rehabilitation should be individualized and include a review of progress at each contact, plus follow-up telephone contact to facilitate long-term exercise behavior change (Piepoli et al., 2016). Guidelines also recommend counseling interventions for patients that promote setting specific and short-term goals; offer feedback on progress; advocate behavioral self-monitoring; and use tailored and personalized interventions, built on readiness to change, motivational interviewing, and enhanced patient self-efficacy (Piepoli et al., 2016; Varghese et al., 2016). Physical activity should comprise at least 150 min of moderate-intensity per week (or for 30 min, 5 days/week, overall) or 75 min of vigorous-intensity per week or equivalent combinations of moderate and vigorous activity, along with 2–3 days per week of resistance and flexibility exercise (Piepoli et al., 2016). Health care professionals are encouraged to evaluate patients’ physical activity levels at every visit and prescribe exercise at suitable dosages along with the use of mobile wearable physical activity devices and use social media platforms to increase physical activity awareness and motivation, and to self-monitor exercise progress (Kaminsky et al., 2016). It is also important to note that when cardiac rehabilitation is completed, exercise should be promoted as a lifetime habit (Achttien et al., 2013).

Exercise and Heart Failure Exercise reduces the risk of HF, but the type and intensity of exercise have different effects on risk, and the effects persist into later life. For example, walking pace and leisure activity reduce the risk of developing HF, but the intensity of exercise does not. Reduced risk for HF occurs when walking at a moderate pace, versus a slow pace (>3 vs. 2 miles/hour, hazard ratio (HR): 0.74, 0.63–0.86). Higher total leisure time physical activity also reduces the risk of developing HF in comparison to lower physical activity levels (>845 vs. 65 years) exercise can have benefits for reducing the risk of HF. The mechanisms for the benefit of exercise in primarily through decreasing arterial stiffening and left ventricular changes commonly associated with aging, although there are no effects on cardiac stiffening (Fujimoto et al., 2010). When HF occurs, there are marked effects on exercise tolerance leading to reduced capacity to complete normal daily activities and reduced health-related quality of life, and in the longer-term HF results in admissions to hospital and mortality. Reduction in exercise capacity occurs regardless of whether ejection fraction is preserved or reduced. Exercise training improves exercise intolerance and is recommended globally for HF patients as an effective and safe component of HF management (McMurray et al., 2012; O’Gara et al., 2013; National Clinical Guideline, 2014). Exercise training is usually delivered as a component of comprehensive cardiac rehabilitation programs. While exercise-based cardiac rehabilitation does not reduce mortality in HF patients, there are significant benefits for patients in terms of risk of hospital admission for any cause (RR 0.75; 0.62–0.92) and HF-specific cause (RR 0.61, 0.46–0.80), as well as clinical improvements in HF-specific health-related quality of life (mean difference
5.8 points,
9.2 to
2.4) (Sagar et al., 2015). The specific quantum or type of exercise training required to achieve these effects was not identified, as the programs varied greatly. The effects noted were found to be independent of the type of exercise (aerobic or resistance) and the dose of exercise, as well as the length of follow-up. However, post hoc analyses of the HF-ACTION trial indicated that 3–7 metabolic-equivalent hours/week is needed to achieve a clinical benefit in HF (Keteyian et al., 2012). The mechanism of the effects of exercise training in HF patients is through improved oxygen extraction by skeletal muscle rather than by improving cardiac compliance or ventriculo-arterial coupling, both hallmarks of HF (Haykowsky et al., 2012). Further, the evidence for the effects of exercise in HF patients applies best to chronic, stable HF patients as patients with comorbid conditions and/frailty are excluded from trials. Given the greater prevalence and severity of comorbid conditions, such as diabetes, musculoskeletal disorders and cerebrovascular disease, in HF, this is an important limitation (Fleg et al., 2015).

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Exercise and Atrial Fibrillation The relationship between physical activity and risk of incident AF is complex: it appears a U-shaped risk-curve exists in men, and a dose-response association among women (Mohanty et al., 2016). Sedentary lifestyles are associated with an increased risk of incident AF, odds ratio (OR) 2.47 (Mohanty et al., 2016). Moderate physical activity lowers AF risk for both women (OR 0.91) and men (OR 0.81) (Mohanty et al., 2016); with a graded reduction in cardiac arrhythmias of 4.8% for every metabolic equivalent (MET)h/day run or walked (Williams and Franklin, 2013). Physical activity is thought to protect against AF through lowering systemic inflammation, lowering resting heart rate, blood pressure, and improving lipoprotein profiles (Aizer et al., 2009). Some associations are not necessarily protective. Previous meta-analyses associated high-intensity exercise with increased AF risk in endurance athletes (OR 5.29, Abdulla and Nielsen, 2009), but recent analyses suggest this increased risk is only for males (OR 3.30). Excess risk is highest in men aged 30–50 years performing >5 sessions/week, with risk reducing with increasing age (Aizer et al., 2009; Abdulla and Nielsen, 2009; Drca et al., 2014). Endurance exercise is thought to increase AF risk through left atrial enlargement, longer p-wave duration, increased vagal tone affecting the atrial refractory period, increased atrial ectopy, and chronic systemic inflammation (Wilhelm et al., 2011; Swanson, 2006). Improving cardiorespiratory fitness is likely to reduce AF risk. For each additional 1 MET achieved on baseline-exercise testing, AF risk reduces by 7% (Qureshi et al., 2015); and each 1 MET increase is associated with a decreased risk of AF recurrence (HR 0.87) (Pathak et al., 2015a,b). Recent evidence suggests possible reversal of AF, and significant improvement in AF recurrence, symptom burden, and arrhythmia-free survival, through both weight reduction (Abed et al., 2013; Pathak et al., 2015a) and increasing cardiorespiratory fitness >2 METs from baseline (Pathak et al., 2015a,b), in patients with paroxysmal and persistent AF. Structured exercise, ranging from aerobic exercise to walking and yoga, are demonstrated to be safe for people with AF, and can improve exercise capacity, resting heart rate, quality of life (Lowres et al., 2012; Wahlstrom et al., 2017), management and treatment of AF, and may even reduce the incidence of AF (Giacomantonio et al., 2013).

Sedentary Behavior and CVD: Current Evidence Overview Sedentary behavior SB is defined as a low-energy expenditure rate (35 MET-hours of physical activity per week (just over 1 h of moderate intensity physical activity per day) eliminated the association between sitting time and CVD mortality. Although these results are encouraging in highlighting that the risks of prolonged sitting can be offset by being more active, it is worth noting that this amount of physical activity is achieved only by a minority of adult populations in developed countries. Smaller previous prospective studies also found that average daily amounts of physical activity roughly equivalent to (Petersen et al., 2014) or greater than (Chomistek et al., 2013) meeting the public health recommendations attenuate the CVD risk associated with sitting. The introduction of frequent and regular interruptions of continuous bouts of sitting (termed as “sedentary breaks”) has been proposed as a promising intervention to counteract the cardiometabolic risks of prolonged sitting (Healy et al., 2008). Currently there are no prospective epidemiological studies examining the association between sedentary breaks and cardiovascular biomarkers (Chastin et al., 2015) and even cross-sectional studies showed inconsistent or no associations (Healy et al., 2011; van der Berg et al., 2016). Some laboratory trials in type 2 diabetic patients have showed beneficial effects of frequently interrupting sitting time with simple resistance activities (Dempsey et al., 2016) or light intensity walking on resting blood pressure and nonesterified fatty acids (Dempsey et al., 2016; Henson et al., 2015). In summary, sedentary behavior is associated with CVD risk in adults who report relatively large amounts of sitting per day (>10 h/day) and do not report relatively high amounts of physical activity (approx. 1 h/day). To date, all prospective studies in this area estimated sitting times using questionnaires that appear to be subject to underreporting; it is therefore important that future studies using objective measures of sitting and physical activity revisit these thresholds and associations, as self-report sitting time

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might underestimate the epidemiological risk. The concept of sedentary breaks for CVD risk reduction is promising but needs further evidence through large prospective studies with objective measures of sitting and physical activity.

Conclusion Physical activity, and its more structured form, exercise, are useful in the treatment of people with heart disease, through cardiac rehabilitation programs. New forms of telehealth and remote contact cardiac rehabilitation are required, such that more people can access physical activity programs after cardiac events (Huang et al., 2015). The role of exercise in HF is also well established, with increasing interest in the role of activity in AF. Other forms of CVD are outside the scope of this review, but may be strongly related to physical activity, such as the prevention of stroke (McDonnell et al., 2013; Diep et al., 2010), and the clinical treatment of stroke and maintenance of functional capacity (Billinger et al., 2014). There are a subset of cardiac diseases where excessive exercise may pose hazards, for example, extreme exercise in athletes (La Gerche, 2016; Merghani et al., 2016). Further, a small number of young people with inherited cardiac disease may be susceptible to sudden cardiac death, and need early identification and special provision made for participation in physical activity (Diller and Baumgartner, 2016; Hammond-Haley et al., 2016). In summary, physical activity and exercise remain substantial risk factors for the development of heart disease, and substantial elements of managing many people with CVDs. In terms of primary prevention, maintaining lifelong regular and active lifestyles has consistent and strong associations with reduced CHD morbidity and mortality. It is still somewhat neglected in clinical practice, as many professionals focus on clinical prevention, biomarker-improving pharmacotherapy, and the main areas of advice are around tobacco cessation. Physical activity is as important in global health as either tobacco control or obesity control (Lee et al., 2012), especially in the prevention and management of CVD.

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Petersen CB, Bauman A, Gronbaek M, Helge J, Thygesen L, and Tolstrup J (2014) Total sitting time and risk of myocardial infarction, coronary heart disease and all-cause mortality in a prospective cohort of Danish adults. International Journal of Behavioral Nutrition and Physical Activity 11(1): 13. Piepoli MF, Hoes AW, Agewall S, Albus C, Brotons C, Catapano AL, Cooney MT, Corrà U, Cosyns B, Deaton C, and Graham IAuthors/Task Force Members (2016) 2016 European guidelines on cardiovascular disease prevention in clinical practice. European Heart Journal 37: 2315–2381. Powell KE, Thompson PD, Caspersen CJ, and Kendrick JS (1987) Physical activity and the incidence of coronary heart disease. Annual Review of Public Health 8(1): 253–287. Powell KE, Paluch AE, and Blair SN (2011) Physical activity for health: what kind? How much? How intense? On top of what? Public Health 32(1): 349. Qureshi WT, et al. (2015) Cardiorespiratory fitness and risk of incident atrial fibrillation: results from the Henry Ford exercise testing (FIT) project. Circulation 131(21): 1827–1834. Sagar VA, Davies EJ, Briscoe S, et al. (2015) Exercise-based rehabilitation for heart failure: systematic review and meta-analysis. Open Heart 2(1): e000163. Sattelmair J, Pertman J, Ding EL, Kohl HW, Haskell W, and Lee IM (2011) Dose response between physical activity and risk of coronary heart disease: A meta-analysis. Circulation 124(7): 789–795. SBRN (Sedentary Behaviour Research Network) (2012) Standardized use of the terms “sedentary” and “sedentary behaviours”. Applied Physiology, Nutrition, and Metabolism 37: 540–542. Schuler G, Adams V, and Goto Y (2013) Role of exercise in the prevention of cardiovascular disease: results, mechanisms, and new perspectives. European Heart Journal 34(24): 1790–1799. Stamatakis E, Hamer M, Tilling K, and Lawlor DA (2012) Sedentary time in relation to cardio-metabolic risk factors: differential associations for self-report vs accelerometry in working age adults. International Journal of Epidemiology 41(5): 1328–1337. Stamatakis E, Coombs N, Tiling K, Mattocks C, Cooper A, Hardy LL, et al. (2015) Sedentary time in late childhood and cardiometabolic risk in adolescence. Pediatrics 135(6): e1432–e1441. Swanson DR (2006) Atrial fibrillation in athletes: implicit literature-based connections suggest that overtraining and subsequent inflammation may be a contributory mechanism. Medical Hypotheses 66(6): 1085–1092. Taylor RS, Dalal H, Jolly K, Zawada A, Dean SG, Cowie A, and Norton RJ (2015) Home-based versus centre-based cardiac rehabilitation. The Cochrane Library. USSG (1996) US Surgeon General’s report on physical activity and health. Washington, DC: US Department of Health and Human Services, Centers for Disease Control and Prevention. van der Berg JD, Stehouwer CD, Bosma H, van der Velde JH, Willems PJ, Savelberg HH, et al. (2016) Associations of total amount and patterns of sedentary behaviour with type 2 diabetes and the metabolic syndrome: the Maastricht study. Diabetologia 59(4): 709–718. Varghese T, Schultz WM, McCue AA, Lambert CT, Sandesara PB, Eapen DJ, and Sperling LS (2016) Physical activity in the prevention of coronary heart disease: implications for the clinician. Heart 102(12): 904–909 heartjnl-2015-308773. Wahlstrom M, Karlsson R, Medin J, and Frykman V (2017) Effects of yoga in patients with paroxysmal atrial fibrillation – a randomized controlled study. European Journal of Cardiovascular Nursing 16(1): 57–63. WHO (2009) Global health risks: mortality and burden of disease attributable to selected major risks. Geneva: World Health Organization ISBN 978 92 4 156387 1. Wilhelm M, et al. (2011) Atrial remodeling, autonomic tone, and lifetime training hours in nonelite athletes. American Journal of Cardiology 108(4): 580–585. Williams PT and Franklin BA (2013) Reduced incidence of cardiac arrhythmias in walkers and runners. PLoS One 8(6): e65302. Young DR, Hivert M-F, Alhassan S, Camhi SM, Ferguson JF, Katzmarzyk PT, et al. (2016) Sedentary behavior and cardiovascular morbidity and mortality. A science advisory from the American Heart Association. Circulation 134(13): e262–e279.

Further Reading Shiroma EJ and Lee IM (2010) Physical activity and cardiovascular health: lessons learned from epidemiological studies across age, gender, and race/ethnicity. Circulation 122: 743–752.

Extracorporeal Membrane Oxygenation A Kilic, The Ohio State University Wexner Medical Center, Columbus, OH, United States © 2018 Elsevier Inc. All rights reserved.

Introduction Indications Components of ECMO Outcomes Discussion References

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Introduction Extracorporeal membrane oxygenation (ECMO) has its roots with the development and idea of supporting the cardiopulmonary system by way of an artificial oxygenator and ventilator as well as a perfusion circuit to provide circulatory support. This became a reality in the 1950s through the work of Gibbon and his heart–lung machine and the development of a bubble oxygenator following early experience with cross circulation by Lillehei (Gibbon, 1954; Lillehei, 1982). These were designed to provide cardiopulmonary support for the performance of cardiac surgery and not as a temporary support. The ability to use ECMO as a standalone tool to provide cardiopulmonary support for recovery was first successfully performed in 1972 for an adult suffering from respiratory failure (Lewandowski, 2000). In the 1970s, a government-funded randomized trial to evaluate ECMO efficacy in adults with respiratory failure versus traditional mechanical ventilatory support failed to show a benefit of ECMO (Zapol et al., 1979). However, there was evidence of success with ECMO in neonates with the first successful therapy being instituted in 1975 (Bartlett et al., 1976). Building upon Bartlett and his colleagues’ early success, the Extracorporeal Life Support Organization (ELSO) was founded in 1989 as an international, multiinstitutional effort in pushing the field forward. More recently with improvements in technology, advancements in critical care medicine, and understanding of physiology combined with success with its use for the H1N1 epidemic in late 2000s, ECMO has been thrusted into the mainstream of therapeutic consideration for patients with cardiopulmonary collapse (Peek et al., 2009).

Indications ECMO is the tool by which to provide extracorporeal life support (ECLS) in those patients suffering from cardiopulmonary collapse. The three main indications for ECLS are for patients suffering from cardiac failure, respiratory failure, and a combination needing extracorporeal cardiopulmonary resuscitation (ECPR). Patients requiring ECMO for strictly respiratory failure by definition have an intact cardiovascular system and the mode for delivering ECMO is via veno-venous cannulation (VV-ECMO). This provides only the ability to oxygenate and ventilate a patient with hemodynamic support and circulation to the body remaining by way of the patients own cardiovascular system. The main indications for this therapy are worsening hypoxia and/or hypercarbia refractory to maximal medical and ventilator therapy secondary to a reversible etiology. The most common causes of this are patients with pneumonia, vasculitis, acute or chronic graft failure following lung transplantation, chemical pneuomonitis, pulmonary hemorrhage or contusion, pancreatitis, and massive pulmonary embolism. The advantage of VV-ECMO for these patients is the avoidance of instrumentation of a large cannula into a systemic artery, thereby preventing systemic thromboembolic phenomenon as well as ischemia to the peripheral arterial system where the cannula is placed. In this article, we will not discuss VV-ECMO further, but concentrate on the use of ECMO for patients with primary cardiogenic shock and/or failure requiring ECLS. Venoarterial ECMO (VA-ECMO) is required for patients suffering from either cardiopulmonary failure or primarily cardiac failure. Patients with cardiopulmonary failure are those patients with witnessed in-hospital cardiac arrest whose indication for ECMO is for ECPR. Although not universal, the generalized indications for institution of VA-ECMO in these patients are for adults who are in cardiac or respiratory arrest following a witnessed, in-hospital arrest where effective, uninterrupted, and ongoing CPR without evidence of hypoxia and/or anoxic brain injury have occurred. Additionally, patients should be immediately evaluated for initiation of ECPR as best results are obtained in patients for whom VA-ECMO is instituted within 10–15 min of cardiopulmonary arrest. Primary cardiovascular collapse can be an immediate phenomenon or may take several days to develop. Those patients with evidence of hypotension that is medically refractory and does not respond to inotropes, vasopressors, or mechanical circulatory support (intraaortic balloon pump, percutaneous ventricular offloading device, etc.) to maintain appropriate perfusion to end organs warrants screening for VA-ECMO. Decreased organ perfusion can be seen in patients with persisting lactic acidosis >3.2 mmol/L, decreasing urine output, cool and diaphoretic extremities, altered mental status, rise of creatinine of >1 mg/dL in 24 h, elevation in transaminases or development of pulmonary edema or hypoxia should raise concern, and profound cardiogenic

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shock should be diagnosed in patients requiring high dose of one or more inotropes, persistent cardiac index 75 years), life expectancy from end-stage/active malignancy with less than 1 year, severe peripheral vascular disease, end-stage renal disease on dialysis, advanced liver disease, current intracranial hemorrhage or other contraindication to systemic anticoagulation, unwitnessed cardiopulmonary arrest with ongoing cardiopulmonary resuscitation, and witnessed cardiopulmonary arrest with prolonged cardiopulmonary resuscitation (>30 min) without return of spontaneous circulation.

Components of ECMO The VA-ECMO circuit consists of a pump, a membrane oxygenator, a controller, cannulas for venous return from patient to circuit, and arterial outflow from pump to patient as well as tubing (Fig. 1) (Rodriguez-Cruz et al., n.d.). The pump is usually a centrifugal pump that can generate up to 4000 rotations per minute and flow up to 8 L per minute. The oxygenator functions not only to oxygenate blood but also to eliminate carbon dioxide. The controller for the oxygenator has the ability to alter the fraction of inspired oxygen into the system as well as the sweep in liters per minute for the purpose of carbon dioxide removal. The controller displays information to the clinician and allows for adjustments to pump speed in rotations per minute and ultimately flow through the entire system. In determining the best method for cannulation in the initiation of VA-ECMO, it is imperative to consider the indications, patient baseline characteristics, and anatomic pitfalls. In the most simplistic terms, there is a drainage cannula that takes blood from the patient to the circuit and a return cannula that takes blood from the circuit back to the patient. Dual lumen, single cannulas can be employed for veno-venous support, but is beyond the scope of this article. The drainage cannula is inserted into the venous system of the patient and is typically a large diameter (21–25 French) and longer (up to 60 cm) than its arterial counterpart.

Fig. 1 The extracorporeal membrane oxygenation circuit. Courtesy of EMedicine.com.

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The venous drainage cannula can be either single or multistage to facilitate drainage and hence inflow into the ECMO circuit. The return cannula is inserted into the arterial system, is typically 15–19 French in diameter, and is shorter with lengths of 20–25 cm when inserted peripherally. The initiation of VA-ECMO in patients suffering from postcardiotomy shock, inability to wean from cardiopulmonary bypass, or in cases of emergent reentry sternotomy in a recent cardiac surgery patient represents arguably the most straightforward cannulation decision. Central cannulation with a drainage (venous) cannula inserted directly into the right atrium and a return (arterial) cannula directly into the ascending aorta are the most efficient and least problematic cannulation strategy. This is how cardiopulmonary bypass during routine cardiac surgery is performed and should be second nature to the cardiothoracic surgeon. For most patients, the chest is left open with packing material and cannulas tunneled away from the midline wound. In certain instances where aortic insufficiency may be present and/or left ventricular distension is seen on echocardiography, a left ventricular vent can be directly inserted into the left atrium and “y-ed” into the drainage cannula to facilitate left ventricular offloading and stagnation. In the patient who is not status post recent cardiac surgery, peripheral VA-ECMO is the most common cannulation strategy. Peripheral cannulation requires vessels that can accommodate appropriate diameter cannulas for both drainage and perfusion. For these reasons and ease of access, the femoral artery and vein are the most frequently utilized vessels. Although there can be multiple configurations of VA-ECMO that can be employed, the most common indication and clinical scenario is one where emergent VA-ECMO is required during active cardiopulmonary resuscitation. As this is a hectic time and no adequate pulsatility and/or oxygenation exists, it is unreliable to use the usual measures to delineate venous versus arterial entry such as palpation of pulses, color of blood return, and presence of pulsatile flow. In this setting, the optimal configuration for cannulation is the ipsilateral femoral venous and femoral arterial access as the first cannula can act as the anatomic landmark for the second cannula. If an intraaortic balloon pump is already in place, one can utilize the ipsilateral femoral venous access based on relative anatomy and the contralateral side for femoral arterial access. Other, less expeditious methods for return (arterial) cannulation include placement of a 8 mm graft (woven double velour vascular graft, polyester, or polytetrafluorethylene) sewn to the axillary artery or femoral artery. The advantage is to prevent distal limb ischemia and prevent high line pressures, and the disadvantage is the time necessary to dissect out the appropriate vessel and make a hemostatic anastomosis. Important considerations are to ensure systemic anticoagulation immediately once access is obtained and commencement of VA-ECMO. This is often the time to pause and ensure appropriate circuit function. An activated clotting time (ACT) >220 s or an activated partial thromboplastin time (aPTT) >70 (depending on local laboratory normalization values) will ensure appropriate thinness of the blood for the circuit. The patient should be maintained on intravenous heparin infusion to prevent thrombus formation in the oxygenator and the need for an urgent circuit replacement. Cannula position should be immediately evaluated using an array of diagnostics. Arterial line pressures >200 mm Hg can signal vascular injury, dissection, malpositioning, as well as an impending retroperitoneal hematoma. To further reduce the chance of vascular ischemia to the lower extremity of the femoral artery used, a 7 French armored (wire wound) catheter in the superficial femoral artery placed in an antegrade manner after the patient has been initiated on VA-ECMO support. Lack of venous return can signal hemorrhage, inadequate volume resuscitation, vasoplegia, or malpositioned venous cannula. In peripherally inserted cases, the tip of the venous cannula should be in the distal inferior vena cava by the cavoatrial junction. This position can be confirmed by echocardiography or chest X-ray postprocedure. Other methods of providing venous drainage access have been via internal jugular vein in cases of inferior vena cava thrombosis or inferior vena cava filters. It is imperative to ensure that cannulas are secure as to prevent migration and dislodgement. This should be done by a pursestring suture at the entrance site, multiple heavy sutures along the skin exit site, as well as course of cannulas to prevent any tension in addition to securing all tubing connection sites. In some cases, where left ventricular distension is occurring either via intracardiac shunt, inappropriate venous drainage, or intracardiac shunt, adjunctive measures can be taken to decompress the left ventricle. These include left atrial or ventricular vents, intraaortic balloon pumps, and percutaneous ventricular offloading devices. The central idea is to allow reduction of myocardial wall stress and oxygen demand and ultimately improving the chance of ventricular recovery.

Outcomes Along with the increased use of ECMO in the last decade, there has been an increase in the scrutiny of outcomes, definition of success or futility, and the cost to benefit ratio of this technology (Shah, 2016). Secondary to the inherit differences for the indication for ECMO initiation, center-specific guidelines on utilization of the technology, and definition of success, there are quite varied reports of outcomes following ECMO. Outcomes, as defined by ELSO, can be reported as survival to decannulation or survival to discharge. According to the ELSO database for those patients supported with ECMO in the registry between 1990 and 2015, 66% and 58% survived to decannulation and survival for respiratory indication for support (n ¼ 9102), 56% and 41% for patients supported for cardiac reason (n ¼ 7850), respectively, and 40% and 30% for patients with ECPR (n ¼ 2374), respectively. When compared with conventional CPR rates of 17% survival, these outcomes are encouraging as are the outcomes for respiratory and cardiac reasons for initiation (Extracorporeal Life Support Organization Registry Report, n.d.). Even in patients supported for cardiac reasons alone, there are variances in outcomes reported. In patients where there exists a reversible insult such as acute fulminant myocarditis, a multicenter analysis demonstrated cardiac recovery and weaning from VA-ECMO in up to 76% of cases with survival to hospital discharge of 72% (Lorusso et al., 2016). In cases of ECMO institution following the postcardiac surgery

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phase, a single institution series of 233 patients demonstrated a much lower survival rate to hospital discharge of only 36% (Elsharkawy et al., 2010). An equally important consideration in addition to survival to decannulation and/or discharge from the hospital is the absence of complications. In particular, ELSO definitions of quality measures include mechanical complications of ECMO (cannula, oxygenator clots), hemorrhagic complications, neurologic complications, renal failure, metabolic complications, infectious complications, and cardiopulmonary complications. Aside from nonrecovery of cardiac function and multiorgan failure, vascular complications are the most frequent cause of death with utilization of VA-ECMO. The rate of hemorrhagic complications can be as high as 40%, malperfusion with critical lib ischemia can occur in 15%–20% (10% fasciotomy requirement, 5% amputation rate), acute kidney injury in 55% (45% with need for renal replacement therapy), neurologic complications in 10%–15%, and infection in 30% of patients supported with ECMO (Cheng et al., 2014).

Discussion In patients suffering from witnessed in-hospital cardiopulmonary arrest, respiratory failure refractory to mechanical ventilation with advanced maneuvers, and those in cardiogenic shock, ECMO can be a life-saving intervention. The moribund nature of these patients has to be remembered when trying to determine the success or futility of this therapy. In fact, ELSO recommendation for the consideration for ECMO is the presence of a 50% mortality with initiation of therapy when 80% mortality risk exists in appropriate patients. ECMO has become an increasingly prominent treatment modality in the armamentarium of clinicians who treat patients with acute, medically refractory circulatory failure. Although general guidelines and techniques exist for this therapy, there are no large randomized, controlled studies that can serve as unbiased studies in cardiogenic shock. Indeed, this form of therapy is a last resort in patients who are in desperate need of cardiopulmonary support. It is crucial to develop a multidisciplinary institutional team in the management and selection of patients that will benefit from this therapy. It is the hope in all cases that there exists a reversible cause for patient deterioration, but a realistic time frame (i.e., 14 days) for support of these patients needs to be made in conjunction with patient and their families. Any steps to aid in recovery or escalate therapy such as suitability for decannulation, more permanent mechanical support, an ablation procedure, a revascularization procedure, or transplantation should be considered on an ongoing and daily basis. Undoubtedly, there will always exist a significant risk of mortality and morbidity in these patients. Clear goals of care with constant communication with patient and their family in conjunction with help from palliative care medicine can stress the importance of not just treating a pathology but the patient. A healthy understanding of the indications and management will be essential in continuing to optimize survival while reducing the complication rates of this technology. Furthermore, suprainstitutional networks of early referral and transfer of patients to tertiary care centers for consideration for ECMO can improve outcomes in patients prior to the onset of multiorgan failure (Aubin et al., 2016). In cases of ECPR, the education of first line respondents such as emergency room, critical care, and interventional cardiology physicians are paramount to increase survival from patients in shock. Despite the ongoing challenges of ECMO, there is no doubt that it has already saved thousands of critically ill patients’ lives and will continue to do so in the foreseeable future.

References Aubin H, Petrov G, Dalyanoglu H, et al. (2016) A suprainstitutional network for remote extracorporeal life support: A retrospective cohort study. JACC: Heart Failure 4(9): 698–708. Bartlett RH, Gazzaniga AB, Jefferies MR, Huxtable RF, Haiduc NJ, and Fong SW (1976) Extracorporeal membrane oxygenation (ECMO) cardiopulmonary support in infancy. Transactions – American Society for Artificial Internal Organs 22: 80–93. Cheng R, Hachamovitch R, Kittleson M, et al. (2014) Complications of extracorporeal membrane oxygenation for treatment of cardiogenic shock and cardiac arrest: A meta-analysis of 1,866 adult patients. Annals of Thoracic Surgery 97: 610–616. Elsharkawy HA, Li L, Esa WA, Sessler DI, and Bashour CA (2010) Outcome in patients who require venoarterial extracorporeal membrane oxygenation support after cardiac surgery. Journal of Cardiothoracic and Vascular Anesthesia 24: 946–951. Extracorporeal Life Support Organization Registry Report. Available online at: https://www.elso.org/Registry/Statistics/InternationalSummary.aspx (accessed 30.08.16). Gaies MG, Jeffries HE, Niebler RA, et al. (2014) Vasoactive-Inotropic Score (VIS) is associated with outcome after infant cardiac surgery: An analysis from the pediatric cardiac critical care consortium (PC4) and virtual PICU system registries. Pediatric Critical Care Medicine 15(6): 529–537. Gibbon JH Jr., (1954) Application of a mechanical heart and lung apparatus to cardiac surgery. Minnesota Medicine 37(3): 171–185. Lewandowski K (2000) Extracorporeal membrane oxygenation for severe acute respiratory failure. Critical Care 4: 156–168. Lillehei CW (1982) A personalized history of extracorporeal circulation. Transactions – American Society for Artificial Internal Organs 28: 5–16. Lorusso R, Centofanti P, Gelsomino S, et al. (2016) Venoarterial extracorporeal membrane oxygenation for acute fulminant myocarditis in adult patients: A 5-year multi-institutional experience. Annals of Thoracic Surgery 101: 919–926. Peek GJ, Mugford M, Tiruvoipati R, et al. (2009) Efficacy and economic assessment of conventional ventilatory support versus extracorporeal membrane oxygenation for severe adult respiratory failure (CESAR): A multicentre randomised controlled trial. Lancet 374(9698): 1351–1363. Rodriguez-Cruz, E., Walters, III., Aggarwal, S. Extracorporeal membrane oxygenation. www.emedicine.medscape.com/article/1818617-overview (accessed 30.08.06). Shah AS (2016) Cheating death with ECMO: Coming soon to a theater near you. JACC: Heart Failure 4(9): 709–710. Zapol WM, Snider MT, Hill J, et al. (1979) Extracorporeal membrane oxygenation in severe acute respiratory failure: A randomized prospective study. Journal of the American Medical Association 242(20): 2193–2196.

F Familial Hypercholesterolemia A Pirillo, Center for the Study of Atherosclerosis, Bassini Hospital, Cinisello Balsamo, Italy; IRCCS Multimedica, Milan, Italy AL Catapano, IRCCS Multimedica, Milan, Italy; University of Milan, Milan, Italy © 2018 Elsevier Inc. All rights reserved.

Introduction Genetics of Familial Hypercholesterolemia Other Lipid Abnormalities in FH: Focus on Lipoprotein(a) Levels Diagnosis of Familial Hypercholesterolemia Cardiovascular Risk and Complications in Patients With FH FH in Childhood Guidelines for the Management of Familial Hypercholesterolemia Current Treatments of Familial Hypercholesterolemia Liver Transplantation LDL Apheresis Statins Ezetimibe Lomitapide Mipomersen PCSK9 Inhibitors PCSK9 Inhibition and Lp(a) Plasma Levels Conclusions References

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Introduction Autosomal dominant hypercholesterolemia (ADH) is a genetic disorder affecting low-density lipoprotein cholesterol (LDL-C) metabolism, characterized by very high levels of circulating LDL-C and premature cardiovascular disease, myocardial infarction or death early in the life, especially in untreated subjects (Nordestgaard et al., 2013; Cuchel et al., 2014; Wiegman et al., 2015; Krogh et al., 2016). Despite the current availability of several cholesterol-lowering drugs, which appear to be very effective also in the treatment of genetically determined hypercholesterolemia, a main gap in the management of this disease to prevent its cardiovascular complications is the detection of familial hypercholesterolemia (FH) subjects. In fact, while the most severe forms are generally characterized by the presence of unequivocal physical features, the less severe forms may remain undetected until the first cardiovascular event occurs. Due to the high burden of cholesterol exposure from the birth, the early detection of such subjects is essential so that they can be treated from childhood to reduce their cardiovascular risk and gain decades of life free of cardiovascular events. In this chapter, we will describe the features of FH disease and present the results of clinical trials of currently available drugs approved for the treatment of FH patients.

Genetics of Familial Hypercholesterolemia Several genetic defects cause ADH; FH (or ADH1) is the most common form of ADH and is due to mutations in the LDLR gene, encoding for the LDL receptor (LDLR), responsible for the binding and uptake of LDL particles in the liver (Fig. 1) (Sniderman et al., 2014). Mutations in the APOB gene, which block the association of the LDL particle to LDLR, are the cause of familial defective apolipoprotein B100 (FDB, or ADH2) (Fig. 1; Whitfield et al., 2004; Andersen et al., 2016); gain-of-function (GOF) mutations in PCSK9 gene reduce LDLR recycling and accelerate its lysosomal degradation, causing a condition referred to as ADH3 (Fig. 1; Sniderman et al., 2014). Finally, a rare recessive form of hypercholesterolemia (autosomal recessive hypercholesterolemia, ARH), caused by the loss-of-function (LOF) mutations in the LDLRAP1 gene (encoding for a protein promoting the hepatic internalization

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Fig. 1 Genetic causes of autosomal dominant hypercholesterolemia or autosomal recessive hypercholesterolemia.

Fig. 2 Inheritance of homozygous or heterozygous familial hypercholesterolemia in a pedigree and prevalence in the general population.

of LDLR/LDL complex), has also been described (Fig. 1; Garcia et al., 2001; Fellin et al., 2015). All these conditions are commonly referred to as FH. Being a genetic disorder, FH can present either in the less severe heterozygous form (HeFH) or in the rarer homozygous form (HoFH) (Fig. 2; Cuchel et al., 2014; Singh and Bittner, 2015). HeFH has a prevalence of
1/500–1/200 in the general population and is characterized by a reduced LDLR activity (
50%) which translates into a two- to threefold increase of LDL-C levels and the occurrence of coronary heart disease (CHD) before the age of 55 (60 for women) (Nordestgaard et al., 2013). HoFH includes the true homozygotes, carrying the same mutation in both gene alleles, compound heterozygotes, carrying two distinct mutations in the two alleles of the same gene, and the rare form of double heterozygosity, due to the presence of mutations in two different genes (Nordestgaard et al., 2013; Cuchel et al., 2014). HoFH, with a prevalence of
1/160,000–1/300,000, is characterized by a significantly reduced LDLR activity and includes either receptor-defective subjects (2%–30% residual LDLR activity) or receptornegative subjects (500 mg/dL) from birth, receptor-negative HoFH may present clinical signs of heart disease very early and may experience myocardial infarction before the age of 20 if untreated (Cuchel et al., 2014; Sniderman et al., 2014). Subjects with FDB present a less severe hypercholesterolemia, lower occurrences of tendon xanthoma, and a lower incidence of coronary artery disease compared with FH (Whitfield et al., 2004). Heterozygous and homozygous FH determined by PCSK9 mutations exhibit a milder phenotype compared with FH caused by LDLR mutations (Mabuchi et al., 2014).

Other Lipid Abnormalities in FH: Focus on Lipoprotein(a) Levels Lipoprotein(a) (Lp(a)) is an LDL-like particle to which apolipoprotein(a) is linked to apoB via a disulfide bond; several epidemiological studies have suggested that elevated plasma levels of Lp(a) represent a cardiovascular risk factor independently of LDL-C levels (Nordestgaard et al., 2010). It has been shown that FH patients, particularly those with cardiovascular disease, exhibit

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significantly higher plasma levels of Lp(a) compared with their nonaffected relatives (Alonso et al., 2014), although no difference was observed between FH patients carrying PCSK9 GOF mutations and FH patients carrying LDLR mutations (Tada et al., 2016). Furthermore, Lp(a) represents an independent predictor of CVD in these subjects (Alonso et al., 2014). Lp(a) levels are higher in FH subjects with early CHD events than in FH subjects with late or no CHD (Nenseter et al., 2011). Finally, although statin therapy has significantly improved the prognosis of FH patients, a considerable degree of CAD in asymptomatic FH under long-term statin treatment has been observed, suggesting that additional risk factors independent of LDL-C levels may contribute to the residual CVD risk in treated FH patients, and Lp(a) may play a role. Experimental and clinical evidence indicate a desirable Lp(a) levels below 50 mg/dL (Nordestgaard et al., 2010). An association between Lp(a) levels and c-IMT has been observed both in the general population and in hypercholesterolemic subjects (Baldassarre et al., 1996; Schreiner et al., 1993). Surprisingly, when analyzed in FH, patients with high or low Lp(a) levels (>30 mg/dL and 30 mg/dL, respectively) had the same plaque prevalence and similar c-IMT values (Bos et al., 2015). A possible explanation for this finding is that patients were relatively young (mean age 48 years) and treated with aggressive statin therapy. On the other hand, another study reported an association between Lp(a) plasma levels and aortic valve calcification (which is a significant risk factor for aortic valve stenosis and cardiovascular disease), but not with coronary artery calcification (Vongpromek et al., 2015). Although statin therapy attenuates the progression of CAC, as a result of LDL-C lowering, it does not appear sufficient to provide better clinical outcomes in patients with aortic valve calcification, possibly because it does not reduce Lp(a) levels (Vongpromek et al., 2015). In fact, while it is possible that LDLR is involved in Lp(a) uptake and degradation, the observations that non-FH subjects have lower levels of Lp(a) compared with FH patients, that carriers of null LDLR mutations have higher Lp(a) levels compared with those with defective mutations (Alonso et al., 2014), and that HoFH have higher Lp(a) levels compared with HeFH suggest a gene-dosage effect (Kraft et al., 2000). However the effect of statins (which upregulate LDLR) on Lp(a) levels is inconsistent (Tziomalos et al., 2009). On the contrary, PCSK9 inhibitors, which act also on LDLR expression, seem to reduce significantly also Lp(a) levels. Altogether these observations suggest that Lp(a) levels should be assessed in FH patients to identify those who could benefit from more aggressive lipid-lowering treatments.

Diagnosis of Familial Hypercholesterolemia The diagnosis of FH can be based on either clinical criteria or genetic tests. The last provide a definitive diagnosis of FH, although some patients presenting with clinical characteristics of FH may have a negative genetic test, suggesting the possible involvement of unknown genes. Several criteria exist for the diagnosis of FH, including the Simon Broome register (Scientific Steering Committee on behalf of the Simon Broome Register Group, 1991), the WHO criteria (World Health Organization, 1999), and the Dutch Lipid Clinic Network (DLCN), the latter being the most commonly used. DLCN criteria establish a score that gives the probability that a subject has FH (Table 1). The score is calculated based on family history of premature CHD or hypercholesterolemia, on patient history of premature CHD or presence of high levels of LDL-C, on the presence of physical signs such as tendon xanthomas or corneal arcus (Table 1). HoFH can be diagnosed based on the clinical conditions of the patient, including very high levels of untreated LDL-C (>13 mmol/L or >500 mg/dL) or treated LDL-C  8 mmol/L or  300 mg/dL, the presence of cutaneous or Table 1

Dutch Lipid Clinic Network (DLCN) criteria for the diagnosis of FH

Criteria Family history First degree relative with known premature (40%. Reproduced with permission from Ouzounian, J. G. (2012). Physiologic changes during normal pregnancy and delivery. Cardiology Clinics 30, 317–329.

38 """" "" "" """"" """"""" ##### "

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493

Fig. 3 Percent change in stroke volume, heart rate, blood volume, and CO during pregnancy. Reproduced with permission from Liu, L. X. and Arany, Z. (2014). Maternal cardiac metabolism in pregnancy. Cardiovascular Research 101, 545–553. Table 2

Changes in regional blood flow during normal pregnancy

Organ

Change

Comments

Uterus Kidneys Extremities Skin Liver Brain Breast

Increased Increased Increased Increased Unchanged Unchanged Increased

Increase from 50 mL/min at 10 wk to 1200 mL/min at term 30%–80% increase with 50% increase in GFR. Returns to nonpregnant state at term Flow to hands greater than flow to feet Results in warm skin, clammy hands, nasal congestion — — May cause flow murmurs

Reproduced with permission from Ouzounian, J. G. (2012). Physiologic changes during normal pregnancy and delivery. Cardiology Clinics 30, 317–329.

increase in the GFR by 50% (Thornburg et al., 2000). In fact, the positional variation in CO due to aortocaval compression makes it such that maternal resuscitation is more effective if the mother is in the left lateral position (Tan and Tan, 2013).

Anatomic Changes and Echocardiography The noted changes in plasma volume, vascular resistance, and CO result in distinctive cardiac remodeling during normal pregnancy. As volume expands during pregnancy, all the four cardiac chambers increase in size to accommodate this physiologic state (Liu and Arany, 2014). The relative impact of this volume is greater on the right, with an up to 20% increase in right atrial and ventricular sizes, compared to an approximate increase of 10% in the left-sided chambers (Ain et al., 2012). This chamber dilation also results in dilation of the valve annulus, causing clinically insignificant tricuspid or mitral valve regurgitation in up to a third of pregnant women. Ventricular remodeling may occur, along with other anatomic changes to the heart as a result of the loading conditions. As a result of increased wall stress, eccentric hypertrophy occurs, resulting in progressive increase in left ventricular mass of, peaking at 15%–25% above prepregnancy levels at term (Robson et al., 1989; Geva et al., 1997; Simmons et al., 2002). Left ventricular enddiastolic dimension also increases, without a significant change in ventricular filling pressure, pulmonary artery pressure, or pulmonary capillary wedge pressure, as noted by both echocardiography and cardiac catheterization (Clark et al., 1989; Bader et al., 1955; Estensen et al., 2013). Notably, cardiac remodeling during pregnancy appears similar to the changes seen in athletes (Simmons et al., 2002). These physiologic changes to the structure of the heart are typically well tolerated, without significant morbidity, mortality, or long-term negative effects on cardiac function (Li et al., 2012). Echocardiography reveals no significant change in ejection fraction during normal pregnancy (Katz et al., 1978), though the elevated CO can be noted via Doppler echocardiography (Vered et al., 1991). Additionally, as pregnancy progresses, functional multivalvular regurgitation may be noted in a majority of women due to the aforementioned annular dilatation. Reflecting relatively greater increase in right-sided chamber size, physiologic valvular regurgitation of the tricuspid and pulmonic valves is noted more frequently than mitral regurgitation (Campos et al., 1993). Aortic regurgitation is not a normal finding in pregnancy (Campos et al., 1993; Dennis, 2011). Finally, a trace to small pericardial effusion may be noted in up to 40% of pregnant women, typically resolving after delivery (Haiat and Halphen, 1984; Ristic et al., 2003). In twin pregnancies, these changes are more pronounced, with a particular increase in heart rate, CO, and atrial size (Robson et al., 1987a). New research with speckle-tracking will provide further insights regarding the noninvasive evaluation of maternal cardiac function during pregnancy (Cong et al., 2015).

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Electrocardiogram These anatomic changes, in combination with the expansion of the gravid uterus and elevation of the diaphragm, result in anterior and leftward displacement of the heart, which prompts changes on the electrocardiogram (Vårtun et al., 2015). The culmination of the various cardiovascular changes of pregnancy can yield an increased sinus rate, left axis deviation, nonspecific ST-T changes, T-wave inversion, and increased atrial/ventricular ectopy (Wenger et al., 1964; Schwartz and Schamroth, 1979; Carruth et al., 1981). Additionally, there is an increase in the prevalence of supraventricular tachyarrhythmias, potentially driven by physiologic atrial enlargement (Adamson and Nelson-Piercy, 2007).

Physical Exam The physical examination in pregnancy reflects the physiologic state of hypervolemia, with its associated changes in CO, chamber size, and blood pressure. Resulting from the increased circulating volume, we see increases in the level of jugular venous pulsation and a systolic flow murmur (often along the left sternal border). Pedal edema is often present, caused by elevated hydrostatic pressure in the venous system and a relative decrease in albumin concentration. Changes in the cardiac chambers can result in a loud first heart sound (S1), a split second heart sound (S2), and even a third heart sound (S3), in addition to a laterally displaced point of maximal impulse. Furthermore, with the aforementioned increase in annular diameter, systolic murmurs associated with valvular regurgitation are common. Coincident with this hyperdynamic state, tachycardia and bounding peripheral pulses can also be noted (Goodlin et al., 1983). With increased blood flow to peripheral tissues, nasal congestion may be noted and the extremities can be warm and erythematous. Consequently, mammary blood flow also increases, causing superficial vasodilation and a continuous murmur known as the mammary souffle (Tabatznik et al., 1960).

Delivery/Postpartum The hemodynamic changes of pregnancy serve to provide adequate supply of oxygen and nutrients for the mother and maturing fetus. At delivery, these changes are further augmented by the uterine contractions, driven by increased sympathetic tone, and mobilization of extravascular tissue. These events result in elevated heart rate, higher stroke volume, and thus increased CO, both at baseline and during contractions. In the first stage, CO can increase up to 15%, with an additional 50% increase in the second stage of labor. Consequently, blood pressure also rises transiently during this time (Robson et al., 1987b). CO peaks immediately postdelivery, due to autotransfusion from the placenta and relief of aortocaval compression, resulting in a significantly increased venous return. Within 1 h of delivery, however, CO returns to prelabor levels via reduction in heart rate, stroke volume, and blood pressure (Soma-Pillay et al., 2016). The return to prepregnancy hemodynamics, however, takes more time (Ruys et al., 2013). CO begins to drop further in the first 24 h, returning to baseline at 6–8 weeks postdelivery. Notably, ANP and brain natriuretic peptide (BNP), both elevated as a result of the elevated circulating volume of pregnancy, help mediate postpartum diuresis and a return to prepregnancy volume status by 6 weeks postpartum (Peck and Arias, 1979; Ouzounian, 2012). Vascular resistance and blood pressure require up to 12 weeks to return to normal, and cardiac chamber size by echo can be enlarged for up to 24 weeks. Notably, our recent research suggests that these changes in heart structure and function may not revert completely to prepregnancy homeostasis, may accumulate with each successive pregnancy, and be detectable in midlife on cardiac MRI (Parikh et al., 2012). However, these changes may persist beyond a year and are potentiated by subsequent pregnancies (Clapp and Capeless, 1997). Given the complex hemodynamic and anatomic effects of pregnancy on the cardiovascular system, clinical history, physical examination, and diagnostic testing must be considered with these changes in mind.

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Hemodynamics of the Right Heart in Health and Disease DM Gopal and A Alsamarah, Boston University School of Medicine, Boston, MA, United States © 2018 Elsevier Inc. All rights reserved.

Introduction RV Anatomy Normal Right Heart Hemodynamic Concepts RV Preload RV Afterload Relationship of RV to Load Pressure Proportionality in the Right Heart Resistance and Compliance: An Inverse Relationship in the Pulmonary Circuit Ventricular Interdependence Invasive Right Heart Hemodynamic Assessment Definitions of Pulmonary Hypertension Hemodynamic Approach for Assessment of RV Performance RA Pressure RV Stroke Work Index Pulmonary Compliance Pulmonary Vascular Resistance Pulmonary Artery and Ventricular Elastance (Right Heart Ventriculo-Arterial Coupling) Pulmonary Artery Pulsatility Index Structural/Functional Considerations by Noninvasive Evaluation Right Heart Hemodynamics in Disease States Pressure Overload Volume Overload Conclusion References

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Introduction Historically relegated the “underdog” ventricle, a status perhaps bolstered by seminal work in the 1940s and 1950s supporting cardiac output preservation even in the face of complete right ventricular cauterization (Kagan, 1952; Starr et al., 1943), the right ventricle (RV), and right heart, has leapt in repute and respect as it has humbled us with its importance in functional capacity and prognosis in congenital heart disease, pulmonary arterial hypertension, myocardial infarction, and heart failure (D’Alonzo et al., 1991; Di Salvo et al., 1995; Gavazzi et al., 1997; Ghio et al., 2001). In this article, we summarize salient features of RV anatomy and physiology, review important hemodynamic concepts of the right heart in health and apply these concepts in major disease states, and review right heart hemodynamic assessment by both invasive and noninvasive approaches.

RV Anatomy Located immediately behind the sternum and most anteriorly situated, the RV is demarcated by the tricuspid valve and pulmonary valves. The RV can be divided into tripartite components: (1) inlet (tricuspid valve, chordae tendineae, and papillary muscles); (2) apical trabeculated myocardium; and (3) smooth outlet region. This classification approach lends itself clinically relevant particularly in congenital heart disease where one or more of the components may be absent (Goor and Lillehei, 1975; Ho and Nihoyannopoulos, 2006). Hallmark differences between the left ventricle (LV) and RV are shown in Table 1. Importantly, the RV myocardial two-layer fiber orientation dictates its contraction pattern; the outer circumferential fibers contribute toward inward movement compared to the longitudinal fibers at the endocardial level promoting longitudinal motion. This longitudinal shortening of the RV myocytes at the endocardial level lends insight into why longitudinal measures of RV systolic function, particularly via echocardiography, are robust in RV function assessment.

Normal Right Heart Hemodynamic Concepts RV Preload The primary function of the right heart, specifically RV, is to receive all the blood returning from the periphery (venous return) and to pump into the pulmonary circulation with the rate of venous return dictated by peripheral resistance. Due to the low-pressure, highly

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Table 1

Key differentiating features of RV compared to LV

Embryologic Myocyte fiber orientation Morphologic differences

Shape Size Perfusion

Second heart field (RV, portions of atria, outflow tract, interatrial septum, cardiac conduction system) First heart field (LV, atrioventricular canal, portions of atria) RV—2 layers (outer – oblique/circumferential, inner – longitudinal) LV—3 layers (outer – oblique, middle – circumferential, inner – longitudinal) (1) Hinge point of septal leaflet is more apical in relation to anterior mitral valve leaflet (2) Greater than 2 papillary muscles (3) Coarse apical trabeculations (4) Presence of moderator band in RV (5) Trileaflet configuration of tricuspid valve with septal papillary attachments Triangular when viewed from side; crescent-shaped in cross-section RV mass is 1/6th of LV; slightly larger end-diastolic volume than LV; thinner than LV Infundibulum and anterior RV receive more constant arterial supply (conal artery) from right coronary artery; coronary artery dominance impacts vascularization of inferior/diaphragmatic wall and inferior septum; left coronary artery supplies the free wall of the RV adjacent to the anterior portion of septum and apical RV

compliant pulmonary circuit the RV pumps the same stroke volume of the LV but at one-fourth of the stroke work (Anastasiadis, 2015). Hemodynamic studies by Pinky and colleagues (Pinsky, 2014) evaluating the effect of positive end-expiratory pressure on RV function showed that RA transmural pressure (or RV filling pressure) has no relationship on RV end-diastolic volume, supporting the concept that the RV operates under its unstressed volume; thus RA pressure should not be equated to RV preload (Pinsky, 2014; Tyberg et al., 1986). A clinically important fact, RA pressure should be not used to predict volume responsiveness (Shippy et al., 1984) but can help predict impending RV failure when ongoing fluid resuscitation results in no cardiac output increase and an abrupt increase in RA pressure is seen (Jardin et al., 1985). A corollary finding is if RV volume does impact RA pressure it is in the setting of an abnormal RV (RV hypertrophy, RV diastolic dysfunction, or RV over-distension) (Pinsky, 2014).

RV Afterload While the right and left ventricles circulate the same blood volume, the pulmonary circulation is notably one of low-resistance, only one-sixth of the systemic circulation, and utilizes one-fifth of energy of the left ventricle (Lammers et al., 2012). This high-flow, lowpressure system of the right heart requires efficient ventricular-vascular coupling. In its purest sense, RV afterload is the RV wall stress that occurs during RV ejection. With its small ventricular radius and constant wall thickness during ejection, the largest contributor to RV wall stress is the RV pressure during ejection. However, the RV pressure during ejection is complex and composed of four main components: (1) resistance to blood flow during steady state; (2) compliance (the blood storage capacity of the pulmonary system); (3) arterial wave reflections that occur as a result of pulsatile blood flow; and (4) blood inertance during RV ejection (Tedford, 2014). The most comprehensive method for RV vascular load assessment, taking into account all four components, is pulmonary artery input impedance (with application of Fourier transformation which separated pressure and flow signals into their respective sums of harmonic oscillations) classically described in 1965 (Milnor et al., 1969). However, pulmonary impedance is both difficult to measure and interpret; simpler models, such as the 3-element Windkessel models, (extending original work in a two-element model by Frank (1899)) have been applied to the arterial circulation. The three-element model, resistance, capacitance, and impedance, is a lumped model of the entire systemic arterial tree to define the total load on the heart (Westerhof et al., 2010). In physiologic terms, resistance (due to dependence on vessel diameter) is quantified by small arteries, arterioles, and capillaries as the pulmonary vascular resistance (PVR)—a static, steady-state resistance. Compliance, representing the storage capacity of all arteries and arterioles with the largest contribution usually from the proximal elastic conduit arteries, takes into consideration the pulsatile load in the system. However, in the pulmonary tree, the total compliance is distributed throughout the arterial tree with the main, right, and left PA only contributing to 15%–20% of the pulmonary compliance (Saouti et al., 2009). Characteristic impedance (Zc) of the proximal pulmonary artery accounts for the fact that blood must be accelerated in early ejection and into a compliant artery; thus blood mass, pulmonary artery diameter, and wave speed components are utilized (Tedford, 2014; Westerhof et al., 2010; Saouti et al., 2010).

Relationship of RV to Load The heart pumps at near maximal efficiency and maximal power. Whether it maintains at this operational level depends on both its cardiac and arterial state, that is, ventriculo-arterial coupling. The RV adapts to increased vascular load by enhancing “coupling” to maintain flow (Vonk Noordegraaf et al., 2017). This coupling concept is best depicted by constructing RV pressure-volume (P-V) loops for a single cardiac cycle with the four sides of the loop denoting: (1) isovolumetric contraction; (2) ejection; (3) isovolumetric relaxation; (4) filling. The loop demarcates boundaries on the end-systolic pressure-volume relationship (ESPVR) and enddiastolic pressure–volume relationship (EDPVR). Relatively linear, ESPVR slope is RV end-systolic elastance (Ees) which represents RV contractility (muscular properties and muscle hypertrophy) with the intercept volume-axis Vo. The pulmonary arterial elastance (Ea), generated at the end-diastolic volume axis extending to the intersection of the ESPVR at the end-systolic pressure–volume point

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of the RV P-V loop, represents RV afterload (often simplistically, PVR). EDPVR, a nonlinear parameter, represents diastolic properties and can characterize two characteristics: (1) diastolic stiffness (represented by the change in pressure divided by the change in volume on any given point on the EDPVR curve); (2) ventricular capacitance (the ventricular volume at any given pressure) (Vonk Noordegraaf et al., 2017; Burkhoff et al., 2015). Ventriculo-arterial coupling can be defined as the ratio of RV elastance to pulmonary elastance (Ees/Ea). RV mechanical work and oxygen consumption is most optimal when this ratio is between 0.5 and 2.0 (Burkhoff and Sagawa, 1986; Sunagawa et al., 1985; Kuehne et al., 2004; Sagawa, 1988). Fig. 1 depicts a normal RV P-V loop with changes in Ea and Ees with changes in afterload, preload, and RV contractility.

Fig. 1 Overview of pressure-volume loops and RV-arterial coupling. (A) Normal pressure-volume loop depicting ESPVR, EDPVR, Ea, and Ees. Right ventriculararterial coupling relationship is Ees/Ea. (B) Ea slope is altered with changes in resistance and volume; ESPVR and EDPVR are static assuming no other changes are occurring with the heart. (C) Changes in contractility of RV are reflected with ESPVR shifts; leftward-upward with increase in contractility; downward-rightward with decrease in contractility. Modified from Burkhoff, D., Sayer, G., Doshi, D., Uriel, N. (2015). Hemodynamics of mechanical circulatory support. Journal of the American College of Cardiology 66, 2663–2674, with permission from Elsevier.

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Pressure Proportionality in the Right Heart Compared to the 50% increase in systemic vascular resistance in hypertension, PVR may increase by a factor of 4 or more in the pulmonary circuit (Handoko et al., 2016; London et al., 1987). Accordingly, the pulmonary arterial pressure will increase and interestingly (and likely underappreciated), the pulmonary arterial (PA) systolic and diastolic pressures are proportional to the mean pulmonary pressures (Chemla et al., 2004; Syyed et al., 2008) even across a wide range of increased PVRs with and without elevated pulmonary capillary wedge pressure (PCWP) (Handoko et al., 2016). Reliable calculations of mean and diastolic pressures estimated from invasive or echocardiography-derived PA systolic pressures (sPAP) are as follows: diastolic pulmonary pressure (dPAP) ¼ 0.36  sPAP; mean PAP (mPAP) ¼ 0.61  sPAP; pulmonary pulse pressure (PP) ¼ 0.6  sPAP (Handoko et al., 2016).

Resistance and Compliance: An Inverse Relationship in the Pulmonary Circuit The source of compliance is a major difference between the pulmonary and systemic arterial systems. Compliance in the pulmonary system is distributed over the entire arterial system (which is dependent on the number of peripheral vessels which is 8-10 times more compared to the systemic arterial system where 80% of compliance is located in the thoracic-abdominal aorta) (Kind et al., 2011). Due to this difference, pulmonary resistance and compliance pulmonary resistance and compliance are inextricably related in the pulmonary system. Originally described in 1971 (Reuben, 1971), the hyperbolic relationship between PVR and pulmonary compliance has been further studied in pulmonary hypertension (PAH) and chronic thromboembolic pulmonary hypertension (CTEPH) (Saouti et al., 2009; Lankhaar et al., 2008; Lankhaar et al., 2006). In addition, the impact of elevated PCWP shifts this hyperbolic relationship downward-leftward; thus, elevated filling pressures may augment pulmonary pulsatile load leading to lower compliance for any given PVR (Tedford et al., 2012). Fig. 2 depicts this hyperbolic relationship between PVR and pulmonary compliance.

Ventricular Interdependence The impact of size, shape, and compliance of one ventricle on the performance of the other ventricle via mechanical interactions is called interventricular dependence (Feneley et al., 1985), a critical concept in the pathophysiology of right heart dysfunction. Three main components contribute to ventricular interdependence: (1) the interventricular septum; (2) the pericardium; (3) the muscular fiber continuity between the RV and LV; the contribution of each of this components varies by phase in cardiac cycle. Unquestionably, diastolic ventricular interaction is paramount; seminal hemodynamic studies have shown that increasing RV volume shifts the LV EDPVR upward and leftward (i.e., less compliance) and reciprocally, as LV volume increases, a similar upward-leftward of the EDPVR curve is seen in the RV. This relationship was similarly shown with independent loading of a ventricle (with a fixed volume) resulting in similar upward-leftward shift of the EDPVR of the contralateral ventricle (Bemis et al., 1974; Elzinga et al., 1974;

Fig. 2 Hyperbolic relationship between pulmonary vascular resistance and pulmonary compliance (represented by stroke volume/pulse pressure) with interaction with left ventricular filling pressures (represented by PCWP). PCWP, pulmonary capillary wedge pressure. Adopted from Tedford, R. J. (2014). Determinants of right ventricular afterload (2013 Grover Conference series). Pulmonary Circulation 4, 211–219.

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Laks et al., 1967; Santamore et al., 1976; Taylor et al., 1967). These have significant clinical consequences: decreased distensibility (with the shift of the EDPVR upward-leftward), LV preload decline, increase in LV end-diastolic pressure, and lowering of cardiac output (Haddad et al., 2008a). Impaired LV filling can be related to: (1) parallel interaction—leftward bowing of the septum into the LV or (2) series interaction—decreased LV filling due to lower RV stroke volume (Gan et al., 2006). The septum and pericardium are both important in diastolic ventricular interdependence and the presence of the pericardium enhances the proportion of mechanical contribution of the septum to ventricular interdependence (Slinker and Glantz, 1986). However, the pericardium may be less vital in systolic interdependence (Feneley et al., 1985; Santamore and Dell’Italia, 1998). The interventricular septum mediates the major contribution to systolic interdependence; animal studies show LV contraction contributes to 20%–40% of the RV systolic pressure and volume outflow (Santamore and Dell’Italia, 1998; Damiano et al., 1991) and without RV dilation, the septum can maintain circulatory stability even in the setting of an inert RV patch or RV scarring (Hoffman et al., 1994).

Invasive Right Heart Hemodynamic Assessment Invasive measurements via Swan-Ganz catheterization continue to be the mainstay in assessment of right heart hemodynamics in clinical practice. Variables of interest with normal ranges are displayed in Table 2.

Definitions of Pulmonary Hypertension Pulmonary hypertension (PH) is defined as a mPAP  25 mmHg at rest (Hoeper et al., 2013). PH can be divided into two main subtypes: (1) precapillary PH (mPAP  25 mmHg and PCWP  15 mmHg); and (2) postcapillary PH (mPAP  25 mmHg and PCWP  15 mmHg (Hoeper et al., 2013; Galie et al., 2016). Precapillary PH includes the clinical groups pulmonary arterial hypertension (PAH) (precapillary PH criteria in addition to PVR > 3 WU in the absence of other etiologies), PH due to lung disease, chronic thromboembolic PH, and PH due to other/multifactorial mechanisms. Postcapillary PH includes PH secondary to left heart disease and PH due to other/multifactorial mechanisms (Galie et al., 2016). Pulmonary vascular resistance (PVR) is calculated taking mPAP-PCWP/cardiac output. PVR > 3 WU is part of the hemodynamic definition for PAH (McLaughlin et al., 2009). Importantly, patients with left heart disease can have additional classification by evaluating the trans-pulmonary gradient (TPG) or diastolic pressure gradient (DPG). TPG, the difference between mPAP-PCWP, has been used to define “passive” PH (TPG < 12 mmHg) vs. “reactive” PH (TPG  12 mmHg) (Galie et al., 2009). Some studies have proposed that TPG is influenced by mechanisms that impact mPAP including resistance, cardiac output, compliance, and left heart filling pressures (Naeije et al., 2013; Provencher et al., 2008; Vachiery et al., 2013) and advise the use of the DPG (end-diastolic pressure (dPAP)—PCWP) to determine pulmonary vascular disease (Naeije et al., 2013; Provencher et al., 2008). In most patients, the DPG lies between 1 and 3 mmHg, and even with patients with left heart disease (excluding shunts) the DPG  5 mmHg (Naeije et al., 2013; Vachiery et al., 2013). A DPG < 7 mmHg (and/or PVR  3 WU) can be classified as isolated postcapillary PH compared to combined post- and precapillary PH is defined with a DPG  7 mmHg (and/or PVR  3 WU) (Galie et al., 2016). Recently, Handoko and colleagues (Handoko et al., 2016) conducted an elegant hemodynamic study with 1054 patients comprised of patients without PH, patients with elevated mPAP and low PCWP, and patients with elevated mPAP and elevated PCWP. The conclusions of this study implied that dPAP and mPAP depend equally on PCWP (with PCWP between 1 and 31 mmHg) and both depend similarly on CO, and

Table 2

Normal right heart catheterization hemodynamics

Right atrium (RAP) Mean pressure Right ventricle (RV) Peak-systolic pressure End-diastolic pressure Pulmonary artery Mean pressure (mPAP) Peak-systolic pressure (sPAP) End-diastolic pressure (dPAP) Pulmonary capillary wedge pressure (PCWP) Mean pressure Resistance [(mPAP-PCWP)/cardiac output)] Pulmonary vascular resistance Cardiac index (cardiac output/BSA) Trans-pulmonary gradient (mPAP-PCWP) Diastolic pressure gradient (DPG) RV stroke work index (RVSWI) Pulmonary compliance (PAC) Pulmonary artery pulsatility index (PAPi)

0–6 mmHg 18–24 mmHg 0–6 mmHg 11–20 mmHg 18–28 mmHg 6–15 mmHg 8–12 mmHg 15 mmHg are predictive of RV failure in the mechanical circulatory support (MCS) literature (Atluri et al., 2013; Dang et al., 2006). An elevated RAP/PCWP ratio (greater than 0.63) has been shown to be predictive of RV failure in patients receiving LVAD (Kormos et al., 2010).

RV Stroke Work Index RV stroke work index (RVSWI) provides a quantitative measure of the ability of the RV to generate pressure and flow incorporating both hemodynamics and right ventricular function and serves as a measure of RV contractility. The calculation for the formula is as follows:

RVSWI mmHg  mL=m2 ¼ ½mPAP ðmmHgÞ  RAP ðmmHgÞ  SV ðmLÞ=BSA m2 To convert to g/m2/beat multiply by the density of mercury factor of 0.0136 to the equation. SV, stroke volume; BSA, body surface area. Several studies have shown that RVSWI can predict mortality and length of hospitalization following lung transplantation (Armstrong et al., 2013), predict right ventricular failure prompting RV assist device post-LVAD implantation (Fitzpatrick et al., 2008), and predict duration of inotropic therapy for RV failure post-MCS therapy (Schenk et al., 2006). RVSWI < 300–600 mmHg  mL/m2 (Starr et al., 1943) generally portends worse RV performance (Ochiai et al., 2002).

Pulmonary Compliance Pulmonary compliance (PAC) is an attribute in the pulmonary system that, in simple terms, can be defined as a change in lumen area for a given change in pressure. Compliance calculation allows the characterization of all the pulmonary vasculature to accommodate blood in systole and release in diastole and is a measure of arterial distensibility. Calculation of pulmonary compliance via hemodynamic measurements using stroke volume and pulmonary pulse pressure has been validated (Lankhaar et al., 2006; Stergiopulos et al., 1999; Stergiopulos et al., 1995) with prognosis in HF (Dupont et al., 2012). Calculation of pulmonary compliance allows calculation of the pulsatile load (in addition to resistive load) contribution to afterload in the pulmonary circulation (Ghio et al., 2015). Pulmonary compliance, thus, can be defined with the following formula: PAC ðmL=mmHgÞ ¼ SV ðmLÞ=pulmonary artery pulse pressure ðmmHgÞ Pulmonary artery pulse pressure ¼ sPAP (mmHg)  dPAP (mmHg)

Pulmonary Vascular Resistance PVR, a major component of RV afterload, contributes significantly to RV dysfunction and has been shown to be a powerful predictor of RV failure early postoperative following LVAD implantation with increasing weight with increasing quartile of PVR (Drakos et al., 2010). Calculation of PVR is as follows: PVR ðWood’s unitÞ ¼ ½mPAP ðmmHgÞ  PCWP ðmmHgÞ=CO ðL= min Þ 

5

To convert to dynes s/cm , multiple above equation by 80.

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Pulmonary Artery and Ventricular Elastance (Right Heart Ventriculo-Arterial Coupling) Ventriculo-arterial coupling quantification usually requires complex invasive measurements with specialized, conductance catheters and varying loading conditions which often precludes its application in clinical practice (Sunagawa et al., 1985; Chantler et al., 2008; Sanz et al., 2012). Single-beat methods have been described and validated by multiple studies with the following derived equations (Sunagawa et al., 1985; Chantler et al., 2008; Sanz et al., 2012). RV elastance ¼ Ees ðmmHg=mL=m2 Þ ¼ mPAP ðmmHgÞ=end  systolic volume ðmLÞ Pulmonary arterial elastance ðmmHg=mL=m2 Þ ¼ Ea ¼ ½mPAP ðmmHgÞ  PCWP ðmmHgÞ=stroke volume ðmLÞ Ventriculo  arterial coupling ¼ Ees =Ea With borderline pulmonary hypertension, end-systolic pressure (numerator in elastance equation) is best estimated using sPAP instead of mPAP (Vanderpool et al., 2015).

Pulmonary Artery Pulsatility Index Pulmonary artery pulsatility index (PAPi) is a novel hemodynamic index described by Kapur et al. (Korabathina et al., 2012) as a tool to predict RV dysfunction and need for RV support following acute myocardial infarction. PAPi also predicted RV failure and need for RV support after LVAD implantation (Kang et al., 2016; Morine et al., 2016). PAPi has not been studied in other populations of RV failure and requires additional study for generalizability. PAPi ¼ ½sPAP ðmmHgÞ  dPAP ðmmHgÞ=RAP ðmmHgÞ

Structural/Functional Considerations by Noninvasive Evaluation From an imaging perspective, a comprehensive RV assessment for structure and function should include the following parameters: (1) RV shape and architecture; (2) RV volume; (3) RV hypertrophy and mass; (4) RV contractility; (5) ventricular interdependence. Echocardiography remains the first-line imaging modality for RV assessment, particularly due to its versatility and accessibility. Cardiac magnetic resonance imaging (CMR) has been becoming more utilized as an informative and vital tool in RV evaluation. RV volume is most accurately characterized by CMR. Ideally, a contractility index would be a parameter independent of loading conditions, sensitive to inotropic conditions, independent of cardiac size and mass, and with clinical utility (Carabello, 2002). Several indices of RV contractility have been applied widely; however, many do not meet these ideal conditions and may be imperfect in reflecting contractility. Lastly, assessment of ventricular interdependence can be evaluated by the flattening of the interventricular septum (D-shaped left ventricle) during the cardiac cycle. RV volume overload is present if the septal flattening is evident only during diastole; flattening throughout the cardiac cycle with prominence in end systole heralds RV pressure overload. Selected parameters of RV structure, volume, contractility, and interventricular dependence with normal values are shown in Table 3.

Right Heart Hemodynamics in Disease States RV adaptation to disease and pathology is complex and is dependent on a multitude of factors. The most three most vital factors include: (1) the type and severity of right heart injury or stress; (2) time course (acute vs. chronic); (3) time of onset of the disease (newborn, pediatric, or adult years) (Haddad et al., 2008b). RV ventricular failure has been defined as a complex clinical syndrome (with cardinal symptoms including exercise limitations and fluid retention) as a consequence of the RV’s inability to maintain flow output to match metabolic needs and consequent increase in right heart filling pressures (Naeije and Manes, 2014; VonkNoordegraaf et al., 2013). Most pathophysiologic states that contribute to RV failure include pressure overload, volume overload, combination of pressure-volume overload, and intrinsic RV failure in the absence of pulmonary hypertension (e.g., myocardial infarction). Table 4 reviews mechanisms and specific causes of right heart failure.

Pressure Overload When the RV is faced with a sudden increase in afterload, cardiac output is preserved via two proposed mechanisms: (1) increase in RV end-diastolic volume via Starling’s law of the heart can be applied to beat-to-beat changes in preload and afterload; and (2) a homeometric contractile adaptation described by Anrep’s law of the heart (de Vroomen et al., 2000; von Anrep, 1912). In the setting of chronic pulmonary hypertension, the highest wall stress initially is believed to develop in the pulmonary infundibulum, the RV region that develops the earliest evidence of hypertrophy (Naeije and Manes, 2014). Over time, infundibular hypertrophy with normal RA pressures extends to generalized RV hypertrophy with sustained elevated RA pressures with eventual progression to RV dilation similar to end-stage LV failure (Pinsky, 2016). The transition point from adaptive compensatory remodeling (concentric hypertrophy with preservation of systolic and diastolic function, preserved Ees/Ea coupling) to maladaptive remodeling resulting in decrease in contractility, eccentric hypertrophy, with dilation is not completely understood but likely the result of mismatch in

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Table 3

Selected parameters of RV structure, volume, interventricular dependence, and contractility

Characteristic

Criteria

Significance 2

RV volume RV mass

Ventricular interdependenceD-shaped LV

>101 mL/m (CMR) >32 g/m2 in females (CMR) >36 g/m2 in males (Maceira et al., 2006) (CMR) RV wall thickness >5 mm (Lang et al., 2015) (TTE) Eccentricity index >1 (Ryan et al., 1985)

TAPSE

0.43 (via pulse-wave) (TTE)

RV myocardial performance index

Volume overloaded Pressure overloaded—concentric hypertrophy Volume overloaded—eccentric hypertrophy RV pressure or volume overload Diastolic D-shaped LV supports volume overload; systolic D-shaped LV supports pressure overload Decreased contractility/systolic function Prognostic value Decreased contractility Decreased RV global function Prognostic value

CMR, cardiac magnetic resonance; TTE, transthoracic echocardiography.

Table 4

Mechanisms and specific causes of right heart failure

Pressure overload Left-sided heart failure (most common cause) Pulmonary embolism (common) Other causes of PH RV outflow tract obstruction Peripheral pulmonary stenosis Double-chambered RV Systemic RV Volume overload Tricuspid regurgitation Pulmonary regurgitation Atrial septal defect Anomalous pulmonary venous return Sinus of Valsalva rupture into RA Coronary artery fistula to RA or RV Carcinoid syndrome Rheumatic valvulitis Ischemia and infarction RV myocardial infarction Ischemia contributing to RV dysfunction in congenital heart disease and RV overload states (particularly pressure overload) Intrinsic myocardial process Cardiomyopathy and heart failure Arrhythmogenic RV dysplasia Sepsis Inflow limitation Tricuspid stenosis Superior vena cava stenosis Complex congenital defect Ebstein’s anomaly Tetralogy of Fallot Transposition of the great arteries Double-outlet RV with mitral atresia Pericardial disease Constrictive pericarditis RA, right atrium; RV, right ventricle; PH, pulmonary hypertension. Reproduced from Haddad, F., Doyle, R., Murphy, D. J., Hunt, S. A. (2008). Right ventricular function in cardiovascular disease, part II: Pathophysiology, clinical importance, and management of right ventricular failure. Circulation 117, 1717–1731. With permission from Wolters Kluwer Health, Inc.

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myocardial oxygen demand and perfusion, oxidative stress, inflammation, apoptosis, mitochondrial dysfunction, and pathologic neurohormonal signaling (Naeije and Manes, 2014; Vonk-Noordegraaf et al., 2013). How the RV adapts is impacted by the type of original insult (e.g., Eisenmenger syndrome often exhibits adaptive remodeling with RVF only very late in disease course vs. PAH with connective tissue or idiopathic PAH with maladaptive remodeling often early and progressive) (Campo et al., 2010; Chung et al., 2010). Many studies have evaluated RV-arterial coupling in a variety of PH models and RV failure is evident once RV function and afterload lose equilibrium.

Volume Overload Congenital heart disease and valvular disease (congenital/acquired) often have substantial volume loads on the RV; the three most common lesions associated with RV volume overload are tricuspid regurgitation, atrial septal defects, and pulmonic regurgitation. The RV is known to have better adaptation mechanisms to volume overload than pressure overload. Eccentric hypertrophy is the initial adaptive response of the RV to chronic volume overload; cardiomyocytes lengthen by increasing sarcomeres in series and increasing myofibrils, capillary supply, and mitochondria (Apostolakis and Konstantinides, 2012). Initially, the hypertrophic response maintains coupling, but over time and with progressive insults, ventriculo-arterial uncoupling is seen. In addition, progressive RV hypertrophy outstrips the underlying capillary bed capacity, tricuspid annular dilation with secondary tricuspid regurgitation creates a vicious cycle of worsening volume overload, and RV dilation creates leftward septal shift leading to impairment in LV filling. Over many decades, cardiac dysfunction and heart failure can ensue (Apostolakis and Konstantinides, 2012).

Conclusion Right heart health, previously undervalued, has been recognized as an important predictor of survival and functional capacity. Deepening our foundation of the basic physiology and hemodynamics of this unique system aids us in our efforts to target and understand RV disease while developing effective therapeutics in right heart failure.

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Hormonal Therapy in the Treatment of Chronic Heart Failure R Napoli and A Salzano, Federico II University School of Medicine, Naples, Italy E Bossone, University Hospital “Scuola Medica Salernitana”, Salerno, Italy A Cittadini, Federico II University School of Medicine, Naples, Italy © 2018 Elsevier Inc. All rights reserved.

Introduction GH/IGF-1 Axis Androgens Insulin Action Thyroid Hormone Conclusions References Further Reading

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Introduction Chronic heart failure (CHF) is a clinical syndrome in which structural and functional cardiac abnormalities induce an impairment of cardiac output or an increase of intracardiac pressures at rest or during stress, resulting in typical symptoms (e.g., ankle swelling, fatigue, dyspnea) or signs (peripheral edema, pulmonary crackles, or elevated jugular venous pressure) (Ponikowski et al., 2016; Yancy et al., 2016). In the last few decades, cardiovascular disease (CVD) mortality rates have dropped dramatically by about twothird in high-income countries (Nabel and Braunwald, 2012). Nevertheless, among the CVDs, CHF represents an unfortunate exception to such encouraging trend, showing a 5-year mortality that is still approximately 50%, even worse than many cancers (Askoxylakis et al., 2010; Braunwald, 2013). In the last few years, the so-called model of neurohormonal activation has been used to provide mechanistic basis of the natural progression of CHF. According to such a model, the overactivity of neurohormone pathways, that is, the renin–angiotensin–aldosterone or the adrenergic system, in the first stages of the disease, plays a compensatory role, but soon becomes in itself responsible for the worsening and progression of CHF, triggering a vicious circle leading to further and following deleterious increase of neurohormonal action (Braunwald, 2013; Mann, 1999). Based on this model, to counteract the neurohormonal activation, a therapeutic approach aimed at blocking the activated pathways has been postulated and implemented through the current guidelines (beta-blockers, ACE-I/ARBs, aldosterone receptor blockers) (Cole et al., 2014). However, since apparently CHF progress at a certain point independent of neurohormonal status, some limitations on the full effectiveness of the proposed therapy have been postulated. In particular, the obstacle to fully antagonize the overactivated hormonal pathways with the available drugs and the presence of alternative escaping metabolic pathways, such as the action of myocardial chimases for the conversion of angiotensin I in angiotensin II, have partially nullified the neurohormonal model. Thus, the uncertainty regarding the comprehension of all the mechanisms behind the pathogenesis of CHF has lead the way to the search of alternative approaches, capable of improving patient survival and relieving his/her symptoms. Increasing evidences suggest that, rather than the increase of the pathways regulated by the neurohormonal overactivity in itself, might be the loss of balance between the activation of these catabolic pathways and the impairment of a set of anabolic hormonal stimuli to characterize the progression of the disease. Reduction in the activity of anabolic hormones can be due to either reduction of their circulating plasma levels (e.g., growth hormone (GH) and its tissue effector insulin-like growth factor-1 (IGF-1), thyroid hormone (TH), anabolic steroids) or inhibition of their intracellular signaling pathways (i.e., GH resistance, insulin signaling impairment, resulting in insulin resistance (IR)) (Broglio et al., 2000; Suskin et al., 2000; Kontoleon et al., 2003; Pingitore et al., 2005; Doehner et al., 2005; Jankowska et al., 2006). Such a novel approach, rooted in the downregulation of many hormonal pathways, can be defined the hormonal-metabolic model and considers the CHF as a multiple hormonal deficiency syndrome (MHDS) (Saccà, 2009; Arcopinto et al., 2015a,b; Salzano et al., 2016). The deficiency of the action of a given hormone can be associated with reduced functional capacity of the heart and is an independent risk factor for poor clinical outcome (Niebauer et al., 1998; Iervasi et al., 2003; Doehner et al., 2005; Marra et al., 2012, 2016; Arcopinto et al., 2015a, 2017). Strikingly, the deficiency in the anabolic pathway sustained by the impairment of multiple hormones has been associated with even worst impaired cardiovascular performance and poor prognosis in CHF (Jankowska et al., 2006).

GH/IGF-1 Axis GH and IGF-1 have an indispensable role in preserving cardiac performance and morphology in adulthood (Saccà and Fazio, 1996; Saccà, 1999). Activation of GH/IGF-1 pathway promotes a myocardial profile characterized by preserved capillary density, absence of fibrosis, and changes of calcium regulatory proteins, all factors playing a role in the protection against ischemia–reperfusion and mechanical stretching (Cittadini et al., 1996; Stromer et al., 2006; Bruel and Oxlund, 1999). In addition, GH/IGF-1 stimulation induces reduction of apoptosis and release of endothelial nitric oxide, resulting in vasodilation (Cittadini et al., 1997; Saetrum

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Opgaard and Wang, 2005; Boger, 1998; Merola et al., 1996; Napoli et al., 2002, 2003). In particular, IGF-1 but not GH, through calcium sensitization of the myofilaments, increases myocardial contractility, a downstream mechanism not associated with arrhythmias (Cittadini et al., 1998). Moreover, GH increases skeletal muscle protein content suggesting an additional role in improving CHF by contrasting the consequences of skeletal muscle cachexia (Napoli et al., 1995). IGF-1 administration in preclinical studies induces an increase in the size of cardiomyocytes and in the expression of mRNAs for actin, myosin light chain 2, and troponin associated with the reduction in apoptosis (Ito et al., 1993; Ren, 2002). GH deficiency (GHD) is present in more than one-third of patients with CHF (Cittadini et al., 2009; Broglio et al., 2000). Many mechanisms might be involved in the reduced activity of GH/IGF-1 axis in CHF: reduced GH secretion or peripheral resistance to its action, hypothalamic somatostatin hyperactivity, drug interference, poor nutritional status, or increased circulating and tissue levels of inflammatory cytokines (Broglio et al., 1999, 2000; Cicoira et al., 2003; Climent et al., 2007; Saccà et al., 2003; Mann, 1999; Colao, 2008). In the general population, GHD is associated with increased cardiovascular mortality and the coexistence of many factors might trigger this increase (Rosen and Bengtsson, 1990). GHD patients show impaired cardiac performance, increased peripheral vascular resistance, and reduced exercise capacity (Saccà, 1997) and the degree of severity of the deficiency appears to be a major determinant of cardiac impairment (Colao et al., 2004). Recently, we have shown that the presence of GHD in patients with CHF identifies a subgroup with worse clinical status and increased all-cause mortality, higher depression scores, impaired quality of life, presence of left ventricular (LV) remodeling, lower physical performance, and increased NT-proBNP levels (Arcopinto et al., 2017). Larger LV volumes with elevated wall stress, as well as higher filling pressures, and impairment of right ventricle function characterize patients with CHF and GHD. In addition, at similar values at anaerobic threshold, these patients demonstrated a worse cardiopulmonary performance with significantly lower peak VO2 and reduced ventilatory efficiency. The data regarding the effects of perturbations in circulating plasma levels of IGF-1 are less consistent. In the general population, a low level of IGF-1 is predictive of cardiovascular mortality, ischemic heart disease, and CHF (Juul et al., 2002; Vasan et al., 2003; Laughlin et al., 2004). In the population of patients with CHF, IGF-1 levels have been found decreased, normal, or even increased when compared with healthy controls (Anker et al., 2001; Al-Obaidi et al., 2001; Anwar et al., 2002; Andreassen et al., 2009). Several studies show that low levels of IGF-1 associate with poor outcome, greater neurohormonal activation and cytokine activation, reduced skeletal muscle performance, and endothelial dysfunction (Niebauer et al., 1998; Napoli et al., 2002; Petretta et al., 2007). Recently, our group demonstrated that IGF-1 circulating plasma levels are predictors of all-cause mortality in CHF patients (Arcopinto et al., 2015a,b). Given the inconsistency of the data about circulating levels of IGF-1 in the population with CHF, there is no agreement on which one can be the best marker of GH/IGF-1 axis activity. Rather than isolated IGF-1 levels, the IGF-1/GH ratio relates to survival in CHF patients (Petretta et al., 2007). Watanabe showed that the IGF-1/IGF-binding protein-3 ratio is associated with increased rate of all-cause mortality, cardiac death, and a composite outcome of cardiac death and rehospitalization in a population of CHF patients (Watanabe et al., 2010). Experimental studies in animal models of postischemic heart failure have reported beneficial effects of treatments with GH, or GH-releasing peptide, on cardiac function, peripheral vascular resistance, and survival (Yang et al., 1995; Duerr et al., 1996; Ryoke et al., 1999). Early treatment of large myocardial infarction with GH attenuates pathologic LV remodeling and improves LV function (Cittadini et al., 2009). Since the nineties, many studies have focused on the effect of GH treatment in patients with CHF: the results have not been always consistent (Fazio et al., 1996; Frustaci et al., 1996; Isgaard et al., 1998; Osterziel et al., 1998; Genth-Zotz et al., 1999; Jose et al., 1999; Spallarossa et al., 1999; Perrot et al., 2001; Smit et al., 2001; Napoli et al., 2002; Acevedo et al., 2003; Adamopoulos et al., 2003; Cittadini et al., 2003). Le Corvoisier and colleagues, in an elegant meta-analysis summarizing the findings, show that GH treatment improves several relevant cardiovascular parameters in patients with CHF; in particular, they reported an increase in LV ejection fraction (LVEF) and a reduction in systemic vascular resistance (Le Corvoisier et al., 2007). Moreover, a long-term modification in cardiac morphology (reduction of LV diastolic diameter and an increase in LV wall thickness) was demonstrated. Tritos et al., in another meta-analysis, illustrated that treatment with GH resulted in an increase of exercise duration, maximum oxygen uptake, LVEF, cardiac output, and improvement in systemic vascular resistance and NYHA class level (Tritos and Danias, 2008). The inconsistency of the results obtained from different trials on GH treatment of patients with CHF might be explained by differences in duration of treatment, target, or dosage. Recently, the concept has emerged that the GH/IGF-1 patient profile might prejudice the response to the treatment with GH. Therefore, patient selection is extremely relevant to obtain the hoped-for results. In particular, GHD appears to be the condition needed to get the best response in CHF patients. In a randomized, single-blind, controlled trial, we studied the relevance of GHD on the effects of GH replacement therapy in patients with CHF. After 6 months of treatment, GH replacement therapy increased LVEF, peak oxygen uptake, exercise duration and flow-mediated vasodilation, and improved the quality of life score. Furthermore, GH administration decreased circulating N-terminal pro-brain natriuretic peptide levels (Cittadini et al., 2009). On these premises, we extended the study with a 4-year follow up. After 4 years, the GH replacement therapy induced the significant reductions of both LV end-diastolic and end-systolic volume indexes, circumferential wall stress, and an increase in LVEF, suggesting the activation of the reverse remodeling of the LV. Although the result did not reach statistical significance, GH treatment improved remarkably the peak VO2. Finally, the combination of death from any cause and hospitalization due to CHF worsening was sensibly reduced by the treatment with GH in this group of patients with CHF, although hard clinical endpoints were not the purpose of the study (Cittadini et al., 2013). TNF-a, interleukin-6, and other proinflammatory cytokines increased levels have also been associated with poorer prognosis in patients with CHF. GH therapy has shown to normalize the circulating levels of TNF-a andinterleukin-6 (Adamopoulos

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et al., 2002). Consistently, the levels of soluble adhesion molecules, granulocyte-macrophage colony-stimulating factor, and macrophage chemoattractant protein-1 were also affected by GH administration (Acevedo et al., 2003), suggesting an immunomodulatory role for GH therapy in CHF.

Androgens The role of anabolic steroids on cardiovascular system and skeletal muscle is well recognized. Testosterone is the primary androgen in the adulthood and some evidences have linked its levels to the risk of CVDs (Khaw et al., 2007). Consistently, male gender is an independent risk factor of atherosclerosis (Criqui, 1986). Furthermore, several evidences, in vivo and in vitro, suggested that androgens exert adverse effects on the cardiovascular risk factor profile and induce the development of atherosclerosis (Muller et al., 2003; Dubey et al., 2002; Adams et al., 1995; McCrohon et al., 1999; Ng et al., 2003). Several clinical studies have shown that low levels of androgens associates with increased carotid intima-media thickness in middle-aged and elderly men (Mäkinen et al., 2005; Muller et al., 2003) and risk of CVDs and all-cause mortality (Haring et al., 2010; Laughlin et al., 2008; Malkin et al., 2010a). Dehydroepiandrosterone (DHEA) and its sulfate ester (DHEA-S), produced mainly by the adrenal glands, are the most abundant androgens in humans. Although DHEA-S derives mainly from the conversion to testosterone in peripheral tissues, direct actions on the cardiovascular system (Komesaroff, 2008) and association with cardiovascular variables have also been shown (Tivesten et al., 2014). Testosterone exerts its effects through genomic and nongenomic actions and testosterone receptors (TR) are present in cardiomyocytes, where their stimulation induces protein synthesis and cell hypertrophy (Marsh et al., 1998) and regulates myocardial contractility, through a mechanism involving L-type Ca2þ channel, the Na2þ/Ca2þ exchanger, b1-adrenoceptors, and myosin heavy chain subunits (Golden et al., 2003, 2004). TR are present also in endothelial and vascular smooth muscle cells, where testosterone decreases the intracellular Ca2þ flux through interaction with voltage-operated calcium and potassium channels (Liu et al., 2003). Moreover, the endogenous testosterone/TR system exerts a protective action on the angiotensin II-induced vascular remodeling by inhibiting the gene expression for the components of NADPH oxidase, resulting in control of superoxide production and reduction in the activation of JNK and TGF-beta-Smad signaling pathways (Ikeda et al., 2009). In healthy males, the decline in androgens levels with aging contributes to sarcopenia, visceral adiposity deposition, and osteopenia. The physiologic phenomenon of andropause is characterized by a decrease in serum testosterone level of about 3.5 ng/dL per year starting from the forth decade of life (Lapauw et al., 2008). Even circulating DHEA-S levels shows an agedependent decline starting at the age of about 25 years (Kaufman and Vermeulen, 2005). However, it must be said that the criterion for testosterone deficiency is not widely accepted, although is often considered when morning total testosterone level drops below 300 mg/dL in two or more occasions in presence of consistent symptoms and signs (Bhasin et al., 2010). However, signs and symptoms of testosterone deficiency blend with those of common comorbidities making uncertain the identification of reliable testosterone deficiency in elderly. Nowadays, the annual incidence of hypogonadal levels of testosterone in men is 20% in people 60 or older and 30% in 70 or older (Harman et al., 2001). Epidemiological studies demonstrated that testosterone deficiency in old men associates with increased risk of death (Haring et al., 2010; Laughlin et al., 2008) and low serum testosterone levels might be used as a marker of poor survival (Haring et al., 2010). In patients with CHF syndrome, 25% of patients have low plasma levels of testosterone (Anker et al., 1997; Moriyama et al., 2000; Kontoleon et al., 2003; Malkin et al., 2009) and such reduction might well be involved in the impairment of skeletal muscle function and exercise tolerance (Iellamo et al., 2010a) and contributes to the poor survival (Pugh et al., 2004; Malkin et al., 2010b; Volterrani et al., 2012). In addition, reduced serum levels of DHEA-S predict all-cause and cardiovascular mortality in elderly (Ohlsson et al., 2010). The concept that testosterone deficiency affects cardiac function encouraged studies on the effects of testosterone replacement in CHF. In an experimental model of CHF, testosterone treatment induced physiological cardiac growth without increase in markers of hypertrophy or accumulation of collagen (Nahrendorf et al., 2003). In animal model of ischemia–reperfusion injury, testosterone administration preserved cardiomyocytes by activating ATP-sensitive K channels and upregulating cardiac alpha(1)-adrenoceptors (Tsang et al., 2008). Compared with placebo, in 12 male patients with CHF, a single dose of testosterone (60 mg orally) induced a decrease in peripheral vascular resistance and after-load, associated with higher cardiac output (Pugh et al., 2002). In a following double-blind, placebo-controlled study, the same group showed that intramuscular testosterone therapy (100 mg every 2 weeks for 12 weeks) in 20 male patients with CHF increased the 6-min walking distance and improved the Minnesota Living with Heart Failure Questionnaire (Pugh et al., 2004). These promising results prompted a robust randomized, double-blind, placebo-controlled trial on the effects of testosterone replacement therapy in unselected CHF patients (Malkin et al., 2006). In such a study, 76 men with CHF were randomly assigned to receive either testosterone (5 mg/day administered by an adhesive skin patch) or placebo for 12 months. In the group treated with the hormone, an increase in serum testosterone level by 40% was observed. Despite testosterone did not modify LV morphology or function, a significant increase in shuttle walk distance and dominant handgrip strength was observed. Moreover, the clinical severity of CHF improved as demonstrated by the shift of at least one New York Heart Association class for 35% of patients treated with testosterone versus 8% of patients receiving placebo. Since the functional improvement recorded during testosterone treatment was not associated with any relevant change in heart function or morphology, an hypothetical positive effect of testosterone on skeletal muscle could be invoked to justify the improvement in

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patient performance. On the other hand, the involvement of peripheral mechanisms in the maintenance and progression of CHF is so relevant that the possibility that testosterone may act through such mechanisms does not undermine the potential importance of its use. A few years ago, in a double-blind, randomized, placebo-controlled study, 70 elderly patients with CHF were treated for 12 weeks with very long acting intramuscular testosterone. The data from this trial showed that peak VO2 and ventilatory efficiency, as assessed by the VE/VCO2 slope, improved significantly. In addition, the beneficial effects of testosterone therapy were confirmed by improvement in IR and the slowdown of skeletal muscle deterioration, in particular in large, weight-bearing muscles, as demonstrated by the increase in quadriceps maximal voluntary contraction. The deterioration of skeletal muscle strength in elderly patients with CHF is a relevant phenomenon capable of bringing about early fatigue and limiting exercise tolerance (Caminiti et al., 2009). More recently, 50 male CHF patients recruited in a RCT receiving intramuscular long-acting androgen injection once every 4 weeks for 12 weeks confirmed the previous finding (Mirdamadi et al., 2014). The effects of testosterone (intramuscular testosterone 6  100 mg in 12 weeks) have been studied also during a rehabilitation program in male patients with CHF and low testosterone status. After 24 supervised sessions of mixed exercise, an improvement in peak oxygen consumption, leg strength, and response to quality of life questionnaire was demonstrated in the patients treated with testosterone (Stout et al., 2012). The decline of androgen levels with aging is a phenomenon detectable also in women. Such consideration prompted a study involving 36 female patients with CHF, treated with either transdermal testosterone (300 mg patch, applied twice/week) or placebo for 6 months (Iellamo et al., 2010b). At the end of the study, treated patients displayed an improvement in 6-min walking distance and peak oxygen consumption and a reduction of IR. Taken together, the studies looking at the effects of testosterone administration did not show changes in the size or function of heart ventricles. However, they invariably exhibited an improvement in cardiovascular performance and muscular strength, supporting the hypothesis that the action of testosterone might be mediated through peripheral mechanisms involved in the pathogenesis of CHF, that is, improvement in skeletal muscle or vascular function, rather than on the heart function in itself.

Insulin Action The existence of an intimate link between diabetes and CHF has been apparent for many years. Since the first data from the Framingham heart study were published, the fact that among diabetic patients there is a large prevalence of patients with CHF and that CHF patients have an increased risk of being diabetic appeared clear. In addition to the increased risk of CVDs, diabetic patients show abnormalities in the metabolism of the heart able to induce a condition of cardiomyopathy independent of atherosclerosis, hypertension, and coronary artery disease: the so-called diabetic cardiomyopathy. In the last few years, the concept emerged that the mechanisms behind the development of diabetic cardiomyopathy are quite complex. In particular, among the defects critically present in diabetes and potentially responsible for heart damage, IR has emerged forcefully. On the other hand, IR can be present in patients with CHF independent from diabetes and recent data prove that, roughly, one-third of patients with CHF are insulin resistant and almost half have diabetes or IR (Suskin et al., 2000). Furthermore, IR does not appear to be a simple bystander, but plays an active role in the development and prognosis of the disease. In particular, in a population of elderly people, the presence of IR, as measured by hyperinsulinemic euglycemic clamp study, independently of obesity, showed to be a powerful predictor of CHF (Ingelsson et al., 2005). IR correlates with the severity of CHF when categorized by the 6-min walking distance or VO2max (Swan et al., 1997; Suskin et al., 2000). Finally, and more importantly, the presence of IR is strictly associated with poor prognosis in patients with CHF (Doehner et al., 2005). On the other hand, it has been experimentally demonstrated in animals that once CHF is established, IR can rapidly develop or worsen in the heart and skeletal muscle (Nikolaidis et al., 2004). Many different mechanism can potentially be evoked to explain the onset or worsening of IR in patients with CHF, such as endothelial dysfunction, skeletal muscle loss, cytokines surge, sympathetic nervous system overactivity, FFA elevation, physical inactivity, etc., likely induced by the impaired hemodynamic. With regard to the mechanisms dangerously triggered by IR and responsible of the worsening of CHF performance and prognosis, a few hypothesis can be proposed. Under normal circumstances, heart metabolism is very flexible and myocardiocytes are capable of switching from FFA to glucose utilization according to the metabolic and energetic needs and the different age (Witteless and Fowler, 2008; Iozzo et al., 2010). When CHF develops, heart metabolism switches from a preferential FFA oxidation to the more convenient glucose uptake (Huss and Kelly, 2005; Witteless and Fowler, 2008). Preferential glucose oxidation under the circumstances supports a favorable energetic profile, allowing the production of ATP and other high-energy substrates with lower oxygen consumption (Huss and Kelly, 2005). Unfortunately, when IR is present, heart metabolism becomes less agile and capable of utilizing glucose, and cardiomyocytes are compelled to an unfavorable inflexibility with the preferential use of FFA to produce energy (Witteless and Fowler, 2008). On the assumption that IR represents a relevant player in the maintenance and progression of CHF, the aim of the therapy of the disease should be to counteract IR. Life style interventions, a pharmacologic approach, or both can oppose IR. The life style interventions, pillars of the treatment of IR in the general population, are weight control and physical activity. Unfortunately, in patients with CHF both approaches have pitfalls. Weight control or reduction must be weighed against the risk of cachexia, a frequent and serious complication of CHF. On the other hand, physical activity is of limited use, given the difficulty that CHF patients have in this regard. Several different drugs, used for the treatment of diabetes, are capable of improving IR. First, the insulin sensitizers thiazolidinediones are drugs directly addressing IR. Although the treatment with glitazones has shown some interesting results (Masoudi et al., 2005), they are contraindicated in patients with CHF and diabetes for the increased paradoxical risk of inducing or worsening CHF (Gerstein et al., 2006). Metformin, first choice drug for the

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treatment of diabetes, has been for long time contraindicated in patients with CHF for the potential risk of lactic acidosis enhanced by the tissue ischemia present in CHF. However, in an experimental model of CHF, metformin, but not rosiglitazone, improves cardiac function and performance very powerfully (Cittadini et al., 2012). Recently, a critical analysis of the data available in the literature has clearly indicated that the use of metformin was not associated with an increased risk of lactic acidosis (Masoudi et al., 2005) and associated with the improvement of many functional parameters (Wong et al., 2012). Therefore, metformin has become the drug of choice in patients with diabetes and reduced EF (Ponikowski et al., 2016). Recently, the field of diabetes has been flooded with a series of new and promising drugs. A series of drugs act by increasing the plasma activity of glucagon-like peptide-1 (GLP-1). Native GLP-1 cannot be routinely used for treatment because of its short half-life (less than 2 min) and the need of parenteral administration. However, GLP-1 administration under experimental circumstances has provided promising results in the field of CHF. In dogs with CHF, GLP-1 administration improved LV function (Nikolaidis et al., 2004). In 12 patients with severe CHF, with or without diabetes, continuous subcutaneous administration of GLP-1 for 5 weeks improved LVEF, VO2max, 6-min walking distance, and the response to a QoL questionnaire (Sokos et al., 2006). The mechanisms responsible for the striking improvement in these patients are unclear. However, it has been hypothesized that improvement of IR might have played a role. Given the short half-life of native GLP-1, increase in the activity of GLP-1 can be achieved through two different approaches. Dipeptidyl-peptidase IV inhibitors (DPP-IVi) or GLP-1 agonists act by increasing the GLP-1 activity, by either inhibiting the enzyme DPP-IV, responsible of the degradation of endogenous GLP-1 and in so doing increasing the level of endogenous GLP-1, or providing a GLP-1 analog resistant to the action of the DPP-IV, respectively. Three recent randomized clinical trials of cardiovascular safety, involving more than 36,000 patients with diabetes, half of them treated with DPP-IVi, have been completed (Scirica et al., 2013; White et al., 2013; Green et al., 2015). Although CHF was not the focus of the three trials, surprising observations have been made. In the SAVOR-TIMI trial (Scirica et al., 2013), an unexpected statistically significant increase in the number of patients hospitalized for heart failure was reported for the group treated with saxagliptin. In the EXAMINE trial (White et al., 2013), the treatment with alogliptin showed a 19%, although nonsignificant, increase in the incidence of hospitalization for CHF in the 2700 patients treated with the drug. Finally, in the TECOS trial (Green et al., 2015), no signal of increase in CHF hospitalization was observed treating the patients with sitagliptin. However, the safety data collected in the real world practice suggest that this family of drug is generally safe to use, but certainly, the hopes of improving the burden of CHF have been neglected. With regard to the data relative to the GLP-1 agonists, three RCT have been published so far (Pfeffer et al., 2015; Marso et al., 2016a,b)). In these trials, the diabetic patients did not show any change in CHF hospitalization due to the treatment with lixisenatide, liraglutide, or semaglutide, respectively. However, the effects of liraglutide, a long-acting analog of GLP-1 administered once a day, on heart performance and patient safety in patients with CHF have been investigated (Jorsal et al., 2017). In this study, 241 CHF patients, with (74 patients) or without diabetes, were treated with either liraglutide (122 patients) or placebo in a randomized, double-blinded, placebocontrolled, multicentre trial. Primary end-point of the study was changed in LVEF. At the end of the 24 weeks of treatment, LVEF improved more in the placebo group than in the liraglutide arm, although the difference did not reach statistical significance (LVEF: 0%–8% active vs. placebo group). Unfortunately, serious cardiac adverse events were more frequent with liraglutide than placebo (P ¼ 0.04). In a similar, but smaller and open label, trial, albiglutide was tested versus placebo (Lepore et al., 2016). In this study also, GLP-1 analog failed to improve ventricular function in patients with CHF. Extremely interesting data have been recently provided by the diabetic patients treated with empagliflozin in the EMPA-REG OUTCOME trial were (Zinman et al., 2015). Empagliflozin is the first drug of the family of the inhibitors of sodium glucose cotransporter 2 (SGLT2i) to complete the cardiovascular safety trial required by the FDA to approve the drug in the United States. Other drugs with the same mechanism of action, dapagliflozin and canagliflozin, are currently being studied in similar CV safety trials. The administration of gliflozins induces the reduction of blood glucose concentration by increasing the loss of glucose with the urine. Such reduction removes the impact of glucose mass effect on the cells, improving IR and glucose transport (Rossetti et al., 1987; Napoli et al., 1995). During the EMPA-REG OUTCOME trial, diabetic patients treated with the empagliflozin, in addition to reduction in all-cause and CVD mortality, showed a significant reduction in hospitalization for CHF. Similarly, in a recent large real world study recruiting 300,000 diabetic patients, dapagliflozin, empagliflozin, and canagliflozin induced a reduction in death or hospitalization for HF (Kosibord et al., 2017). The relevant mechanisms behind such reduction are unclear and many of them have been invoked: changes in substrate (i.e., butyrate, glucose), hormones (i.e., glucagon), changes in the intracellular metabolism, or reduction in IR might be implicated. However, the diuretic effect of the gliflozins must be kept in mind when data on hospitalization are analyzed, since diuresis per se may improve the hemodynamic in patients with CHF.

Thyroid Hormone The importance of the TH role in the regulation of cardiovascular function has been clear for many years. TH perturbations, as in hypo- or hyperthyroidism, have a potent impact on the cardiovascular apparatus, involving both the regulation of heart rhythm and function. TH exerts its powerful intracellular effects through genomic and nongenomic mechanisms. The action of TH on heart function might be divided in a direct action on cardiac structure and an indirect action mediated by the very potent effects the TH have, both acutely (Napoli et al., 2007) and chronically (Napoli et al., 2001; Napoli et al., 2010) on the vessel wall. The effects on cardiac structure are mediated through the expression of proteins involved in many different ways in the contractile response of the ventricles (Iervasi et al., 2003). On the other hand, the effects observed on the peripheral circulation have a potent effects on hemodynamic and, consequently, on cardiac function. The implications of TH action on heart function can be easily evaluated by

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looking at the effects that hypo- or hyperthyroidism have on hemodynamic. In particular, thyroid diseases are associated with changes in cardiac output, contractility, and vascular resistance. On the other hand, the treatment of these diseases, if quickly started, before irreversible changes have taken place, is rapidly followed by the restoration of normal cardiovascular functions (Klein and Danzi, 2007; Napoli et al., 2010). The levels of circulating TH must be maintained in a pretty narrow normal range, as suggested by the fact that either elevation or decrease of TH is followed by increased cardiovascular mortality (Biondi et al., 1999; Iervasi et al., 2007). Treatment with low dose of oral (0.1 mg/day of T4) of CHF patients has led to an increase in LVEF and improvement in exercise tolerance (Moruzzi et al., 1996). T3 administration induces an increase in cardiac output in few hours (Malik et al., 1999; Hamilton et al., 1998; Pingitore et al., 2008). On the other hand, T3 has potent and rapid activity on the vessel wall and is capable of improving endothelial function when infused intra-arterially in healthy volunteers (Napoli et al., 2007). In addition to the obvious hemodynamic effect of heart function and structure, the improvement of endothelial function with T3 administration has important implication in CHF, since a better perfusion of peripheral tissue, including skeletal muscle, might potentially improve exercise tolerance.

Conclusions In the last few years, the hypothesis that CHF is a clinical syndrome characterized by an imbalance between catabolic and anabolic pathways has prepotently emerged. Such imbalance is sustained by the neurohormonal activation from one side and MHDS on the other side. Reduction in the activity of GH/IGF-1 axis, androgens, insulin, and TH is associated with the clinical worsening of CHF. More importantly, the correction of these defects is followed by significant clinical improvements. On the basis of these observations, new trials focusing on the identification and treatment of multiple hormonal deficiencies in CHF patients should be supported. Meanwhile the MHDS should be routinely searched in the patients with CHF and a consistent treatment evaluated.

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Further Reading Mann DL and Bristow MR (2005) Mechanisms and models in heart failure. The biomechanical model and beyond. Circulation 111: 2837–2849.

Hypertensive Heart Disease MU Moreno, A González, B López, S Ravassa, J Beaumont, and G San José, University of Navarra, Pamplona, Spain; CIMA, Pamplona, Spain; Navarra Institute for Health Research, Pamplona, Spain; CIBERCV, Spain R Querejeta, University of the Basque Country, San Sebastian, Spain; Biodonostia Research Institute, San Sebastian, Spain; Donostia University Hospital, San Sebastian, Spain J Díez, University of Navarra, Pamplona, Spain; CIMA, Pamplona, Spain; Navarra Institute for Health Research, Pamplona, Spain; University of Navarra Clinic, Pamplona, Spain; CIBERCV, Spain © 2018 Elsevier Inc. All rights reserved.

Introduction Pathophysiological Aspects Cardiomyocyte Lesions Hypertrophy Death Noncardiomyocyte Lesions Myocardial fibrosis Microvascular alterations Clinical Aspects Clinical Manifestations Diagnosis, Prevention, and Treatment Impact on Public Health Current Challenges Search for Patients Predisposed to LVH and LV Dysfunction Noninvasive Diagnosis of Myocardial Remodeling Antiremodeling Strategies Conclusion References

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Introduction Hypertensive heart disease (HHD) can be defined as the response of the heart to the afterload imposed on the left ventricle by the progressively increasing arterial pressure and total peripheral resistance that entails hypertension (Frohlich et al., 1992). HHD is characterized by increased left ventricular (LV) mass leading to left ventricular hypertrophy (LVH). In fact, hypertension-induced LVH consists of a constellation of genetic, structural and functional alterations of cardiac tissue that allow its differentiation as a separate entity (Lip et al., 2000). LVH is associated with alterations of cardiac contractility and relaxation, abnormalities of myocardial perfusion, and disturbances of cardiac rhythm in hypertensive patients. In addition, LVH is an independent risk factor related to cardiovascular complications in these patients. Diagnostic methods to detect LVH in the routine clinical setting include electrocardiography and echocardiography, although novel biochemical and imaging tools are being developed to help diagnose and treat patients in a personalized manner. A number of studies have established that reduction of LV mass is attained with effective antihypertensive treatment and that reversal of LVH and its underlying mechanisms decreases the occurrence of adverse cardiovascular events in hypertensive patients. However, there is still room for further improvement because it is now appreciated that treated hypertensive patients in which LVH regresses still have considerable cardiovascular risk (Struthers, 2013). On the other hand, due to the aging of the population and the increase in the prevalence of hypertension and related comorbidities, HHD remains a major socioeconomic problem. Therefore, there is an important need for physicians to recognize this entity, understand its pathophysiology, and be aware of the available treatment options.

Pathophysiological Aspects Physically, in conditions of pressure overload due to systemic hypertension, the left ventricle undergoes hypertrophic growth, which is characterized by the thickening of the LV wall and the augmentation of LV mass, thus resulting in concentric LVH. This is as predicted by the law of Laplace. Functionally, this early LVH is a compensatory process that helps the heart in sustaining cardiac output despite increased afterload imposed by systemic hypertension (Frohlich et al., 2011). However, this process is only an initial “adaptive” response to biomechanical stress associated with hemodynamic load; chronic exposure to the stress eventually leads to impaired inotropic (contraction)/lusitropic (relaxation) function which, in many cases, progresses to congestive heart failure (HF). This “maladaptive” evolution is intimately linked to the underlying histological changes of the cardiomyocyte and noncardiomyocyte components of the myocardium that result in its structural remodeling (Fig. 1) (Knöll et al., 2011).

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Fig. 1 Main microscopic lesions found in the hypertensive myocardium: (A) view of a transversely enlarged cardiomyocyte (Masson’s trichrome staining, magnification 100); (B) a cardiomyocyte exhibiting apoptotic appearance (TUNEL, magnification 100); (C) excessive interstitial collagen deposition (picro-sirius red staining, magnification 20); (D) perivascular fibrosis (picro-sirius red staining, magnification 20); (E) an intramyocardial artery presenting wall thickening and lumen narrowing (Masson’s trichrome staining, magnification 20); (F) capillary rarefaction (von Willebrand staining, magnification 20).

Cardiomyocyte Lesions As mentioned before, the response of the cardiomyocyte to pressure overload must not be considered simply as an adaptive compensation, as it has critical detrimental consequences (Frohlich et al., 2011).

Hypertrophy The primary mechanism by which the heart reduces the stress on the LV wall imposed by pressure overload is the hypertrophic growth of cardiomyocytes. This entails the stimulation of intracellular signaling cascades that activate gene expression and promotes protein synthesis, protein stability, or both, with consequent increases in protein content and in the size and organization of force-generating units (sarcomeres). This, in turn, leads to increased size of individual cardiomyocytes with resulting augmentation in LV mass and thus LVH (Sugden and Clerk, 1998). Although it is unclear how the mechanical stretch of cardiomyocytes is transduced across the cell membrane, it probably involves stretch-sensitive ion channels, a Naþ/Hþ exchanger, integrins and integrin-interacting molecules as well as other internal and membrane-bound stretch sensors, in a complex network that links the extracellular matrix, the cytoskeleton, the sarcomere, calcium (Ca2þ)-handling proteins, and the nucleus (Clerk et al., 2007). The changes in genetic expression characteristic of the cardiomyocyte hypertrophic response involve reexpression of a fetal gene program, as well as repression of postdevelopmental genes (Table 1) (Barry et al., 2008; Kuwahara et al., 2012). The long-held views are that, in response to pressure overload, these morphological and genetic changes are positive and serve to restore cardiac

Hypertensive Heart Disease Table 1

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Genes whose expression is altered during cardiomyocyte hypertrophy

Activated genes b-Myosin heavy chain Fetal isoforms of contractile proteins (skeletal a-actin and b-myosin heavy chain) Fetal type cardiac ion channels (hyperpolarization activated cyclic nucleotide-gated channel and T-type Ca2þ channel) IVS3A form of calcium channel a3-Subunit of Naþ, Kþ-ATPase B subunit of creatine kinase Atrial and brain natriuretic peptides Switch from fatty acid oxidation to glycolysis genes Lactate dehydrogenase M subunits Genes directing cardiomyocyte lengthening Smooth muscle genes (smooth muscle a-actin and SM22a) Inhibited genes a-Myosin heavy chain Calcium ATPase of sarcoplasmic reticulum (SERCA2) b1-Adrenergic receptors M2 muscarinic receptors Early transient Kþ current, Ito Myoglobin N2BA titin isoform

muscle economy and counteract myocardial dysfunction. However, blunting of cardiomyocyte hypertrophy and attenuation of the fetal gene reexpression do not necessarily result in immediate LV dysfunction or HF despite the pressure overload. Therefore, genetic reprogramming associated with cardiomyocyte hypertrophy may no longer be considered as an adaptive process (Meijs et al., 2007). Moreover, the detailed analysis of the genetic changes that accompany cardiomyocyte hypertrophy indicates that they translate into derangements in energy metabolism, contractile cycle and excitation–contraction coupling, cytoskeleton and membrane properties. These changes determine mechanical dysfunction which, in turn, provides the basis for cardiomyocyte malfunction, which is associated with LVH and predisposes the ventricle to diastolic and/or systolic dysfunction (Dhalla et al., 2009).

Death The death of cardiomyocytes by apoptosis is abnormally increased in patients with HHD with HF (González et al., 2006). Cardiomyocyte apoptosis has been proposed to occur as a result of an imbalance between the factors that induce or block apoptosis. In this sense, inducers of cardiomyocyte apoptosis (e.g., mechanical stretching and angiotensin II) predominate over suppressors (e.g., agonists of the gp130/LIFR survival pathway) in arterial hypertension (Fortuño et al., 2001). Apoptosis of cardiomyocytes may contribute to the development of LV dysfunction/failure through three different pathways. First, apoptosis may be one mechanism involved in the loss of contractile mass and function of the hypertensive myocardium, as association of increased cardiomyocyte apoptosis with diminished cardiomyocyte number has been found in hypertensive patients (González et al., 2006). Second, some mechanisms that are activated during the apoptotic process may also interfere with the function of viable cardiomyocytes before death (Narula et al., 2001). For instance, caspase-3 cleaves cardiac myofibrillar proteins, resulting in an impaired force/Ca2þ relationship and myofibrillar ATPase activity. Also, the release of cytochrome C from mitochondria during apoptosis may impair oxidative phosphorylation and ATP production, thus leading to energetic compromise and functional impairment. Third, in addition to contributing to histological remodeling of the myocardium, cardiomyocyte apoptosis may also contribute to geometric remodeling of the LV chamber. In fact, severe cardiomyocyte apoptosis may lead to sideto-side slippage of cells, mural thinning, and chamber dilatation. This wall restructuring secondary to severe cardiomyocyte apoptosis may create an irreversible state of the myocardium, facilitating progressive dilatation and the continuous deterioration of LV hemodynamics and performance with time (Chandrashekhar, 2005). It is important to point out that, although apoptosis is a hallmark of HHD, in the response to any given cardiac injury various modalities of cell death are stimulated, as they are interconnected by common cellular pathways at multiple points (Whelan et al., 2010). For instance, autophagy is activated during hypertensive LVH, serving to maintain cellular homeostasis. Excessive autophagy eliminates, however, essential cellular elements and possibly provokes cardiomyocyte death, which contributes to myocardial remodeling (Wang et al., 2010).

Noncardiomyocyte Lesions It has become evident in the last 25 years that in addition to lesions involving the cardiomyocytes, changes in the extracellular matrix and the microvasculature are also key components of the structural remodeling of the myocardium and have a profound detrimental impact on the overall cardiac function, thus contributing to the development of HHD.

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Myocardial fibrosis Myocardial fibrosis is the exaggerated accumulation of extracellular matrix, namely collagen type I fibers, within the interstitium and surrounding intramural coronary arteries and arterioles in the myocardium. This excess of myocardial collagen present in hypertensive LVH is the result of the combination of several alterations (Berk et al., 2007): (i) increased procollagen synthesis by fibroblasts and phenotypically transformed fibroblast-like cells or myofibroblasts; (ii) increased extracellular conversion of procollagen into microfibril-forming collagen by specific proteinases; (iii) increased spontaneous microfibril assembly to form fibrils; (iv) enhanced cross-linking of fibrils to form fibers by the action of lysyl oxidases (LOX); and (v) unchanged or even decreased fiber degradation by matrix metalloproteinases (MMPs). Fibrosis might contribute to the structural and clinical alterations of HHD through diverse mechanisms. First, there is a connection between fibrosis and LV dysfunction (Brower et al., 2006). The accumulation of collagen fibers compromises the rate of relaxation, diastolic suction, and passive stiffness, thereby contributing to impaired diastolic function. In addition, continued accumulation of collagen fibers, together with changes in their spatial orientation, further impairs diastolic filling. These changes further compromise cardiomyocyte contraction and myocardial force development thus impairing systolic performance. Second, the impaired coronary flow reserve associated with LVH might be related to, among others, perivascular fibrosis (Schwartzkopff et al., 1993). In fact, the amount of perivascular collagen has been correlated inversely with coronary flow reserve in patients with LVH (Dai et al., 2012). Third, the increased deposition of fibrotic tissue which occurs in association with hypertension and LVH, results in diffusion problems in a situation in which oxygen and nutritional demands are increased (Frohlich, 2001). Finally, interstitial fibrosis may also contribute to ventricular arrhythmias in hypertension (McLenachan and Dargie, 1990). Thus, hypertensive patients with dysrhythmias exhibit higher values of LV mass and myocardial collagen than patients without arrhythmias, despite the finding that the ejection fraction and the frequency of coronary vessels with significant stenosis may be similar in the two groups of patients. Fibrosis induces conduction abnormalities thereby promoting local reentry arrhythmias. Moreover, whereas the key role of ectopic foci in pulmonary veins, which may trigger atrial fibrillation, has been recognized, atrial fibrosis has been identified as the main mechanism for atrial fibrillation (Boldt et al., 2004). This suggests that atrial fibrosis in hypertensive patients (namely those with chronic HF) may promote more widespread changes in the myocardial collagen matrix. It is worth mentioning that the alterations in the quantity (namely amount of type I collagen) and quality (namely the degree of cross-linking of the fibers) of the myocardial collagen matrix also may influence adversely the clinical outcome in patients with HHD. For instance, it has been shown that whereas increased collagen type I cross-linking is associated per se with HF hospitalization in patients with HHD and HF (López et al., 2016), the coincidence of increased collagen type I cross-linking with severe collagen type I deposition is associated with HF hospitalization and mortality (cardiovascular and all-cause) (Ravassa et al., 2017).

Microvascular alterations The hypertensive myocardium is characterized by multiple structural alterations in the small intramyocardial vessels (Feihl et al., 2008). On the one hand, hyperplasia or hypertrophy, and altered vascular smooth muscle cellular alignment may promote encroachment of the tunica media into the lumen, thereby causing both increased medial thickness/lumen ratio and reduced maximal cross-sectional area of intramyocardial arteries. On the other hand, vascular density in LVH becomes relatively decreased. This seems to result from capillary rarefaction or inadequate vascular growth in response to increasing muscle mass. These microcirculatory alterations, together with perivascular fibrosis, contribute to decreased coronary flow reserve (CFR) of patients with HHD (Kelm and Strauer, 2004). In fact, there is an association between decreased CFR and LV systolic and diastolic dysfunction in HHD during stress maneuvers (Galderisi et al., 2002; Ikonomidis et al., 2012; Kozàkovà et al., 2003). Recently, the role of coronary microvascular endothelial inflammation in HF with preserved ejection fraction (HFpEF), in the context of systemic conditions such as hypertension, has been highlighted (Paulus and Tschöpe, 2013). Coronary microvascular endothelial inflammation would decrease the bioavailability of nitric oxide and cyclic guanosine monophosphate content, resulting in decreasing cardiomyocyte protein kinase G (PKG) activity. Thus low PKG activity may promote cardiomyocyte hypertrophy, hypophosphorylation of the cytoskeletal protein titin, stimulation of fibroblast differentiation into myofibroblasts with high fibrogenic activity, and increased myocardial stiffness. This sequence of events suggests that coronary microvascular endothelial inflammation may be responsible for myocardial remodeling in HFpEF of hypertensive etiology. This idea was recently supported by the demonstration that CFR was abnormally reduced in hypertensive patients with LVH and patients with HFpEF of hypertensive etiology (Kato et al., 2016). Of interest, reduced CFR was found to be associated with microvascular endothelial activation in HFpEF patients (Franssen et al., 2016).

Clinical Aspects HHD evolves progressively along two consecutive phases, one subclinical in which elements of myocardial remodeling may be present but do not result in altered clinical parameters, and one clinically overt in which remodeling causes signs, symptoms, and a clinical profile of HF (Drazner, 2011). HHD is a multifactorial disease: whereas several factors linked to genetics, gender and lifestyle will determine the initial hemodynamic and nonhemodynamic damage of the left ventricle in the hypertensive patient, other factors related to ageing and comorbidities (e.g., diabetes, obesity, and chronic kidney disease) will influence the subclinical evolution of HHD (Fig. 2).

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Fig. 2 Phases of the hypertensive heart disease continuum. BP, Blood pressure; CKD, chronic kidney disease; LVH, left ventricular hypertrophy; CV, cardiovascular.

Clinical Manifestations Most patients with HHD, although at risk, are asymptomatic. However, dyspnea, edema, angina, palpitations, syncope, and sudden death can be present when complications occur. In fact, epidemiological studies have suggested that hypertension is the most common etiological factor for chronic congestive HF, being present in 50% of cases. Besides alterations of LV myocardium characteristic of HHD, hypertension may itself result in HF as a consequence of underlying coronary artery disease and arrhythmias, such as atrial fibrillation. Unlike HF caused by coronary artery disease, in which HF progresses after a discrete event (myocardial ischemia or infarction) that damages the heart muscle, LV dysfunction/failure in the patient with HHD may progress gradually from the stage of compensated LVH with subclinical LV dysfunction to clinically overt HF (Drazner, 2011). It is worth mentioning that it has been estimated that among 30%–45% of hypertensive patients with HF present diastolic dysfunction, but normal systolic function (i.e., HFpEF). In addition, hypertensive patients with LVH may have symptoms and electrocardiographic signs of myocardial ischemia in the absence of atherosclerosis of epicardial vessels due to a combination of microvascular disease and diminished CFR (Preik et al., 2003). On the other hand, ventricular arrhythmias, atrial fibrillation, and sudden cardiac death are more prevalent in patients with hypertension and LVH than in those hypertensive patients without hypertrophy or in normotensive individuals (Yiu and Tse, 2008).

Diagnosis, Prevention, and Treatment The classical physical findings in patients with HHD are related to the presence of LVH and include a sustained, enlarged, and displaced outside the midclavicular line apical impulse and an S4 gallop best heard in the left lateral decubitus position. The two most common tools used to confirm the diagnosis of LVH are the electrocardiogram (Schillaci et al., 2012) and the echocardiogram (Marwick et al., 2015) (Table 2). Beyond the diagnosis of LVH, the electrocardiogram provides unique information on rhythm disturbances, PR and QT intervals, whereas the echocardiogram supplies precise information about LV wall thickness (and thus on the geometric pattern of LVH), LV function, wall motion abnormalities, and left atrial size. Each provides different performance for diagnosis of LVH, with the electrocardiogram being more specific (95% vs. 84%) but much less sensitive (50% vs. 88%) than the echocardiogram. The echocardiographic determination of the cardiac architecture with the use of LV mass and relative wall thickness data allows for the identification of three LV geometry patterns (concentric hypertrophy, eccentric hypertrophy, concentric remodeling) with clear implications regarding prognosis (Marwick et al., 2015). In fact, concentric LVH carries the highest risk and eccentric LVH an intermediate risk, whereas concentric remodeling is associated with a smaller, albeit important risk (Koren et al., 1991). The first step in HHD prevention is the control of blood pressure by the control of predisposing factors and, of course, the use of antihypertensive therapies (Pfeffer, 2017). Clinical studies have consistently shown that blood pressure reduction is a fundamental strategy to prevent LVH in patients with arterial hypertension (Georgiopoulou et al., 2010). However, there may be differences on risk-reduction effectiveness among the available antihypertensive therapies (Georgiopoulou et al., 2010; Sciarretta et al., 2011), which may be linked to the different ability of the drugs to interfere with myocardial remodeling. Antihypertensive drugs are, in fact, effective in reducing LV mass. One meta-analysis including 80 double-blind, randomized controlled trials with 146 active treatment arms and 17 placebo arms showed that after adjustment for treatment duration and change in diastolic pressure, there was a significant difference among medication classes in decreasing LV mass (Klingbeil et al., 2003). The decreased LV mass indexed by body surface area or LV mass index induced by the different classes was as follows: AT1

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Hypertensive Heart Disease Table 2

Electrocardiographic and echocardiographic diagnostic criteria for left ventricular hypertrophy

Electrocardiograma Sokolow-Lyon index SV1 þ (RV5 or RV6) >3.5 mV RaVL >1.1 mV Cornell voltage criteria SV3 þ RaVl  2.8 mV (for men) SV3 þ RaVl  2.0 mV (for women) Cornell voltage-duration product QRS duration  Cornell voltage >2436 mm  ms QRS duration  sum of voltages in all 12 leads >17,472 mm  ms Romhilt-Estes point score system (LVH is diagnosed if 5 points are computed) Any limb lead R wave or S wave 2.0 mV: 3 points SV1 or SV2 3.0 mV: 3 points RV5 to RV6 3.0 mV: 3 points ST-T wave abnormality (no digitalis therapy): 3 points ST-T wave abnormality (digitalis therapy): 1 point P terminal force in V1 >40 mV-ms: 3 points Left axis deviation: 2 points Intrinsicoid deflection in V5 or V6  50 ms: 1 point Echocardiogramb Indexed left ventricular mass (left ventricular mass:body surface area) Men >115 g/m2 Women >95 g/m2 Indexed left ventricular mass (left ventricular mass: [height])2.7 Men >48 g/m2.7 Women >44 g/m2.7 Relative wall thickness (2  posterior left ventricular wall thickness): left ventricular diameter in diastole) 0.42 a

Schillaci et al. (2012). Marwick et al. (2015).

b

receptor blockers > calcium antagonists>ACE inhibitors>diuretics>beta-blockers. In paired comparisons, AT1 receptor blockers, ACE inhibitors, and calcium antagonists were more effective at reducing LV mass index than diuretics and beta-blockers. Additional strategies, such as selective denervation of the renal sympathetic nerves to lower blood pressure, have also been shown to significantly reduce LV mass and improve diastolic function in patients with resistant hypertension (Brandt et al., 2012). It is worth to note that patients who did not respond hemodynamically to renal denervation did show LVH regression, supporting the notion of renal denervation effects on LVH independent of blood pressure.

Impact on Public Health The impact of HHD on public health is undeniable (Ambrosy et al., 2014; Pfeffer, 2017). First, LVH is highly prevalent in hypertensive patients, as assessed either by electrocardiogram (Cuspidi et al., 2012a) or by echocardiography (Cuspidi et al., 2012b), with an average of 40%–45%. Second, considered as a categorical variable, LVH significantly and independently increases the risk of HF and other cardiac (e.g., coronary artery disease, arrhythmias, sudden death) and noncardiac (e.g., stroke) complications, as shown by data from the Framingham study (Levy et al., 1990). Third, recent evidence challenge the notion that blood pressure control by antihypertensive treatment completely prevents HHD-associated risk. It is classically admitted that cardiovascular risk decreases significantly in hypertensive patients in whom LVH regresses with antihypertensive treatment compared to patients in whom LVH persists, in spite of similar hemodynamic effectiveness of the treatment (Devereux et al., 2004). However, a meta-regression analysis of 14 studies in 12,809 hypertensive patients failed to demonstrate a continuous relationship between treatment-induced LVH changes and the occurrence of cardiovascular events (namely, myocardial infarction and new onset HF) (Constanzo et al., 2013). Moreover, a study conducted in 763 hypertensive patients followed up for an average of 12 years showed that the progression of LV mass with respect to the baseline value had a predictive value for cardiovascular events independent of the initial measurement and course of the office blood pressure (Gosse et al., 2012).

Current Challenges Although current management of HHD is still focused on controlling blood pressure and reducing the increased LV mass (Schiattarella and Hill, 2015), it must be remarked that the impact of currently available antihypertensive agents on myocardial remodeling may not be optimal (Table 3). This may in part be due to the lack of personalized diagnosis and therapy in HHD.

Hypertensive Heart Disease Table 3

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Clinical evidence-based hemodynamic and cardiac effects of antihypertensive agents

Pharmacological class

Decrease of blood pressure

Reduction of LV mass

Repair of remodeling lesionsa

Alpha-blockers Beta-blockers Calcium antagonists Diuretics Aldosterone antagonists Direct renin inhibitors Angiotensin converting enzyme inhibitors Angiotensin receptor blockers Angiotensin receptor blocker and neprilysin inhibitor

Yes Yes Yes Yes Yes Yes Yes Yes Yes

Mild Mild–moderate Moderate Mild Mild–moderate Marked Marked Marked Unknown

Unknown Apparently not Apparently not Proven for torasemideb Proven for spironolactonec Unknown Proven for lisinoprild Proven for losartane Unknown

LV, left ventricular. a Refers to some of the lesions (namely, fibrosis). b López et al. (2004). c Izawa et al. (2005). d Brilla et al. (2000). e Díez et al. (2002).

Therefore, additional strategies aimed at specific diagnosis by noninvasive biochemical (González et al., 2009) or imaging (Hoey et al., 2014) techniques, as well as individually tailored therapeutic repair (González et al., 2011) of the microscopic changes responsible for hypertensive myocardial remodeling are needed.

Search for Patients Predisposed to LVH and LV Dysfunction Emerging evidence indicates that identification of subsets of patients with a common denominator may help select a therapeutic approach. For instance, 24 h monitoring of blood pressure may help identify those hypertensive patients highly predisposed to develop LVH (i.e., patients with early morning pressure rise or with a nondipping profile) and therefore more prone to benefit from the ability of some antihypertensive drugs to prevent it (Kawano et al., 2008). LV mass is a highly complex phenotype influenced by interacting effects of multiple hemodynamic and nonhemodynamic factors, including genetic factors. Identification of genes influencing LV mass may enhance the detection of those patients requiring early treatment. In this regard, a meta-analysis of case–control and association studies has shown that the D allele of the insertion/ deletion (I/D) polymorphism of the angiotensin converting enzyme (ACE) gene behaved as a marker of future LVH in untreated hypertensive patients (Kuznetsova et al., 2000). Finally, novel diagnostic tools, such as quantification of the myocardial strain by speckle-tracking echocardiography, may help shed light in the cardiac dysfunction of patients with HFpEF (Saito et al., 2016), providing clues for specific preventive and therapeutic approaches of this growing clinical entity.

Noninvasive Diagnosis of Myocardial Remodeling The noninvasive assessment of the histological alterations that underlie HHD is key to personalized diagnosis and treatment. On the one hand, novel imaging tools are key contributors of diagnosis of myocardial remodeling. Cardiac magnetic resonance imaging (CMR) not only can measure LV mass and dimensions more accurately than conventional echocardiographic techniques (Hoey et al., 2014; Janardhanan and Kramer, 2011), but it is also a promising technique for characterizing the myocardial composition, particularly with the analysis of T1 mapping and late gadolinium enhancement areas in the myocardium may represent fibrotic regions (Janardhanan and Kramer, 2011). In addition, CMR is rapidly evolving with the introduction of an increasing number of high-affinity molecular probes potentially useful to monitoring specific alterations in the myocardium such as apoptosis (i.e., using 99mTc-labeled annexin A5 that binds to apoptotic cardiomyocytes) and collagen synthesis (i.e., using 99mTclabeled peptides that bind to activated fibroblasts) (Chun et al., 2008). On the other hand, the identification of biochemical markers of potential usefulness for clinical management of cardiac diseases is emerging as a very active field (González et al., 2009). Regarding biochemical markers related to cardiomyocyte alterations, plasma concentration of CT-1 has been correlated with LV mass in untreated hypertensive patients (González et al., 2009), suggesting that plasma CT-1 may be a potential marker for assessment of cardiomyocyte hypertrophy and LVH in hypertensive patients. In addition, the decrease of plasma CT-1 induced by antihypertensive treatment is associated with the reduction of LV mass in patients with LVH (González et al., 2009), suggesting that this cytokine may be useful to assess ability of antihypertensive drugs to reduce cardiomyocyte growth and decrease LV mass. Moreover, CT-1 is associated with myocardial systolic dysfunction in asymptomatic hypertensive patients (Ravassa et al., 2013), indicating that CT-1 may also provide information regarding the clinical impact of myocardial remodeling. Regarding biochemical markers related to myocardial fibrosis, diverse studies indicate that they are promising tools to assess this aspect of myocardial remodeling in hypertensive patients (González et al., 2009; López et al., 2015). Clinical data indicate that the serum levels of the carboxy-terminal propeptide of procollagen type I (PICP), excised from the

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procollagen molecule in its maturation process, is a marker of the amount of collagen in the myocardium (González et al., 2009; López et al., 2015). In addition, a recent work indicates that the circulating levels of the carboxyl-terminal telopeptide of collagen type I, normalized by circulating MMP-1 levels, may be indicative of the degree of cross-linking of myocardial collagen (López et al., 2016; Ravassa et al., 2017). As mentioned before, not only do these biomarkers help diagnose by giving evidence of the remodeling that takes place in the myocardium, but they may also provide information about hospitalization or death risk (López et al., 2016; Ravassa et al., 2017) and may even influence therapeutic approaches (Díez et al., 2002; López et al., 2007, 2015). Another aspect of myocardial remodeling that may benefit from noninvasive diagnosis is the coronary microcirculation (Paulus and Tschöpe, 2013). Although research so far has focused mainly in coronary artery disease, novel imaging techniques may clarify the role of altered cardiac microcirculation in HHD (Camici et al., 2015).

Antiremodeling Strategies Available experimental and clinical data suggest that the goal of repairing myocardial remodeling is also achievable in HHD using available antihypertensive agents (Table 3). For instance, in patients with HHD, ACE inhibition reduced myocardial fibrosis, irrespective of blood pressure and LV mass reduction, and was accompanied by improved LV diastolic function (Brilla et al., 2000). In addition, despite similar antihypertensive and antihypertrophic efficacy, the AT1 receptor blocker losartan, but not the calcium channel blocker amlodipine, reduced cardiomyocyte apoptosis (González et al., 2002) and myocardial fibrosis (Díez et al., 2002) in patients with HHD. Reduction of myocardial fibrosis by the AT1 blocker was associated with decreased LV chamber stiffness and the improvement of diastolic filling in hypertensive patients (Díez et al., 2002). Since the action of most of the reviewed antihypertensive therapies on myocardial remodeling is limited, the attention has been recently turned to the potential of targeting specific intracellular events (González et al., 2011). Hypothetically, these novel therapeutic interventions could be directed to the following aspects: first, to block the detrimental intracellular mechanisms activated in mechanical stress-triggered cardiomyocyte hypertrophic response (e.g., kinases such as Rho-kinase, and phosphatases such as calcineurin). Second, to prevent inhibition of “negative” signaling modulators and interacting proteins that are repressed in such conditions (e.g., increasing the availability and actions of cyclic GMP). Third, to take advantage of beneficial mechanisms inherent in the mechanical stress-triggered cardiomyocyte hypertrophic response (e.g., via enhancement of important aspects of the IGF1/PI3K/Akt pathway like angiogenesis). Fourth, to block the deleterious modulation that pathological stresses impose on protein synthesis (e.g., through regulation of HDACs or sets of microRNAs). Fifth, to prevent mitochondrial oxidative stress (e.g., through mitochondrial targeted small molecules and peptides). Sixth, to preserve functioning cardiomyocytes (e.g., through the inhibition of the process of apoptosis and/or preservation of cell survival mechanisms). Seventh, to regenerate lost cardiomyocytes (e.g., using stem cell therapy). Eighth, to restore the normal turnover of collagen network (e.g., inhibiting exaggerated collagen synthesis and deposition at nonphysiological localizations). Two examples may illustrate the mentioned possibilities. First, experimental data in mice show that the systemic administration of the mitochondrial targeted antioxidant peptide SS-31 ameliorated angiotensin II-induced LVH, diastolic dysfunction, myocardial apoptosis, and fibrosis in these animals, despite the absence of blood pressure-lowering effect (Dai et al., 2011). SS-31 reduced also angiotensin II-induced mitochondrial reactive oxygen species and oxidative damage, as well as mitochondrial biogenesis in cardiac cells. Second, circulating miRNA-21 is increased in hypertensive patients, as well as in the experimental model of HHD of the spontaneously hypertensive rat (SHR). MiR-21 targeting in SHR normalized mitochondrial cytochrome-b expression and oxidative stress, which resulted in attenuated blood pressure, cardiomyocyte hypertrophy, and myocardial fibrosis (Li et al., 2016).

Conclusion HHD begins with the hypertrophic response of cardiomyocytes to increased hemodynamic load. The increase in LV wall thickness normalizes increased wall stress and, therefore, LVH is initially beneficial. However, sustained and progressive load, that is accompanied by the activation of humoral factors, is associated with additional responses of the cardiomyocyte and noncardiomyocyte compartments of the myocardium that result in its structural remodeling and the deleterious long-term consequences on myocardial function, electrical activity, and perfusion that significantly increase the morbidity and mortality in hypertensive patients with LVH. A detailed understanding of the complexities underlying these responses will aid in the development of novel diagnostic and therapeutic approaches aimed to prevent or minimize their deleterious impact on the heart of the hypertensive patient in a tailored, effective, and safe manner. This knowledge is also critical due to the increasing prevalence of HHD and its risk factors, and taking on account its social and economic burden (Ambrosy et al., 2014; Pfeffer, 2017).

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Hypertrophic Cardiomyopathy LK Williams, Papworth Hospital NHS Foundation Trust, Cambridge, United Kingdom © 2018 Elsevier Inc. All rights reserved.

Introduction Genetic Basis of the Disease Pathophysiology Diastolic and systolic function Obstruction Myocardial ischaemia Arrhythmias Autonomic dysfunction Clinical Presentation Investigations and Diagnosis Clinical examination Electrocardiography (ECG) Imaging Exercise testing Ischaemic testing Differential Diagnosis Disease Course and Progression Clinical Management Pharmacologic Intervention Risk stratification Family screening References

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Introduction Hypertrophic cardiomyopathy (HCM) is a common genetic cardiovascular disorder affecting 1 in 500 of the general population. While historically it was viewed as a rare condition associated with excess mortality, in the current era with contemporary management strategies the majority of patients will achieve normal or near-normal life expectancy (Maron et al., 2015). Despite this, HCM remains one of the most common causes of sudden cardiac death (SCD) in young people and athletes. An increase in left ventricular wall thickness or hypertrophy (LVH), in the absence of coexistent cardiac or systemic conditions which could result in LVH (such as hypertension and aortic valve stenosis), is central to the diagnosis. This increase in wall thickness can involve virtually any segment of the left or less frequently the right ventricular myocardium. On a microscopic level there is evidence of myocyte disarray, patchy myocardial fibrosis or scarring, and abnormalities of the small intramural blood vessels.

Genetic Basis of the Disease HCM is typically inherited in an autosomal dominant pattern, whereby each offspring of an affected individual has a 50% chance of inheriting a pathogenic mutation. Most cases are caused by a mutation in the genes coding for the sarcomere proteins, with over 80% of cases arising from a mutation in either the MYH7 (myosin heavy chain) or MYBPC3 (myosin binding protein C) genes. However, in some cases the disease can result from a sporadic mutation in one of these genes.

Pathophysiology Diastolic and systolic function The presence of LVH, myocardial disarray, and fibrosis results in an increase in left ventricular stiffness. This adversely affects myocardial relaxation and diastolic function, leading to an increase in intracavitary pressures in both the left ventricle (LV) and left atrium (LA). In a small subset of patients (10 mm) T-wave inversion is a distinctive pattern seen in patients with apical hypertrophy. Ambulatory ECG monitoring plays a vital role not only in the investigation of symptoms of palpitations but also for the identification of patients at risk for SCD (nonsustained ventricular tachycardia) and stroke (paroxysmal atrial fibrillation) (Fig. 2).

Imaging Transthoracic echocardiography (TTE) is the mainstay of diagnosis, allowing direct assessment not only of LV wall thickness but also assessment of LVOTO, concomitant mitral valve disease and dysfunction, and the assessment of diastolic and systolic function. The diagnosis hinges on the presence of a wall thickness of >15 mm in any myocardial segment, or in the paediatric population  2 standard deviations above the mean (Z-score) after correction for age and body surface area (Nagueh et al., 2011). While the classic description is of asymmetric hypertrophy involving the interventricular septum, hypertrophy can be concentric or involve the apical segments of the ventricle preferentially. LVOTO is present in over two-thirds of patients, occurring under resting conditions in 30% of cases, and provocable in a further 40% (Maron et al., 2006). Mitral regurgitation is seen frequently in patients with obstruction due to systolic anterior motion of the mitral valve, with a typically posteriorly directed jet into the LA (Fig. 3). However, intrinsic structural abnormalities of the mitral valve and subvalvular apparatus frequently coexist in patients with HCM, and further contribute to the degree of mitral regurgitation. Diastolic dysfunction, LVOTO, and mitral regurgitation all result in progressive LA dilation. Cardiac magnetic resonance imaging (CMR) adds valuable additional information to the diagnostic work-up of patients with presumed or confirmed HCM (Nagueh et al., 2011). It is particularly helpful in patients with suboptimal TTE image quality, and in patients in whom the ECG is strikingly abnormal and the diagnosis is suspected but TTE is equivocal. CMR provides superior

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Fig. 1 The classic findings on clinical examination in patients with hypertrophic cardiomyopathy. Most abnormalities on examination are related to the presence of left ventricular outflow tract obstruction and associated mitral regurgitation. Some of the “red flags” which may point to an alternative diagnosis or disease “phenocopy” are shown as well, and highlight the importance of a complete clinical examination.

Fig. 2 The classic imaging findings on ECG and imaging are shown in a patient with asymmetric septal hypertrophy (upper panel) and apical hypertrophy (lower panel). Upper panel—the marked septal hypertrophy is noted (red asterisk), along with LVH and repolarization abnormalities on the ECG (ST segment and T-wave changes). The CMR image demonstrates the presence of extensive myocardial fibrosis in the hypertrophied segments (blue asterisk). Lower panel—hypertrophy is confined to the apical segments of the left ventricle (red asterisk), with the classic giant negative T-waves seen on ECG. In this patient, myocardial fibrosis is again seen in the hypertrophied segments of the LV apex (blue asterisk).

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Fig. 3 On color flow imaging on transthoracic echocardiography there is marked turbulence of blood flow in the left ventricular outflow tract (red arrow), along with a posteriorly directed jet of mitral regurgitation (yellow arrow). A cursor is placed across the outflow tract and using continuous wave Doppler an outflow tract gradient of 100 mmHg can be recorded, indicating severe outflow tract obstruction under resting conditions.

delineation of apical hypertrophy and allows identification of apical infarction and aneurysm formation. Gadolinium contrast agents allow identification of underlying myocardial scar and fibrosis, the pattern and degree of which may often alert the clinician to the possible presence of a “mimic” or phenocopy of HCM such as cardiac amyloidosis or Anderson-Fabry disease. The degree of myocardial fibrosis may relate to risk of development of heart failure, arrhythmia, and SCD (Fig. 2).

Exercise testing Exercise testing allows objective assessment of exercise capacity, blood pressure response to exercise, and exercise-induced arrhythmia. When combined with TTE, it can identify patients with provocable LVOTO.

Ischaemic testing Exercise ECG and functional testing such as myocardial perfusion scanning and stress echocardiography are not sensitive markers of underlying epicardial coronary artery disease, given that inducible ischaemia and ECG changes may occur in the absence of significant stenosis of an epicardial coronary artery. CT coronary angiography is most useful in those cases in whom a low likelihood of coronary artery disease (CAD) exists, but in the presence of traditional risk factors for CAD and an intermediate to high likelihood of CAD coronary angiography is preferred.

Differential Diagnosis The presence of LVH does not always represent a pathological response, and can represent a physiological or compensatory response to high levels of athletic training. However, the presence of LVH represents a pathologic response to hemodynamic loading of the ventricle in cases such as systemic hypertension and aortic stenosis. Unexplained LVH can also occur in a range of systemic and genetic disorders, most notably lysosomal and glycogen storage disorders such as Anderson-Fabry disease and Danon disease. Infiltrative disorders such as cardiac amyloidosis, mitochondrial disorders, and genetic syndromes such as Noonan syndrome account for a small percentage of cases. Accurate identification of the underlying cause of unexplained LVH is important to guide appropriate therapy. In patients in whom a “mimic” or phenocopy of HCM is suspected, a routine panel of blood tests to assess renal and liver function, full blood count, plasma BNP, and troponin should be performed. Impaired renal function and proteinuria may be seen in systemic amyloidosis and Anderson-Fabry disease, whereas liver tests and serum creatine phosphokinase may be abnormal in mitochondrial and glycogen storage disorders. In cases of suspected amyloidosis, serum and urine protein electrophoresis are mandatory. Assessment of plasma/leucocyte alpha galactosidase A activity should be performed in all men aged >30 years, and in

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any case where Anderson-Fabry disease is clinically suspected. Enzyme levels are often within the normal range in affected females and genetic testing is necessary to confirm the diagnosis (Elliott et al., 2014).

Disease Course and Progression While the majority of patients have minimal or no symptoms, and follow a benign and stable clinical course, in some cases progressive congestive heart failure or sudden cardiac death may occur. Progressive symptoms, secondary to diastolic dysfunction, LVOT obstruction, mitral regurgitation, or development of left ventricular systolic dysfunction, may occur and significantly impact quality of life (Fig. 4). Three distinctive modes of death have been demonstrated in patients with HCM, with an overall annual mortality of 50% left main disease (and ischemia or FFR 0.80 for stenosis 50% (and ischemia or FFR 0.80 for stenosis 95%) (Barreras and Gurk-Turner, 2003). ARBs are excreted as unchanged drug and metabolites in the urine and via bile in the feces to varying degrees (Burnier, 2001). Adverse effects ARBs have a similar side effect profile to ACE inhibitors. Unlike ACE inhibitors, ARBs do not inhibit the degradation of bradykinin and are therefore much less likely to cause cough (Lacourcière et al., 1994). Angioedema, which may also be linked to elevated

Fig. 15 Summary of the pharmacological action, mechanism of action, and adverse effects of angiotensin II receptor blockers (ARBs).

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bradykinin, occurs less frequently with ARBs; however, some cases have been reported (van Rijnsoever et al., 1998). ARBs may be an option for patients with a pressing indication for therapy who are unable to take ACE inhibitors due to angioedema; however, extreme caution is necessary as cross-reactivity may occur (Beavers et al., 2011). Drug interactions Many interactions of ACE inhibitors and ARBs relate to additive risk of hypotension, hyperkalemia, or renal impairment when used alongside other medications that share these actions. Combining ACE inhibitors with ARBs increases risk of hypotension, hyperkalemia, renal impairment, and angioedema. Careful monitoring is required when ACE inhibitors or ARBs are combined with mineralocorticoid receptor antagonists, potassium sparing diuretics, antihypertensives and ciclosporin. Plasma concentration of lithium and digoxin can be increased in the presence of ACE inhibitors and ARBs; concurrent use warrants therapeutic close monitoring. NSAIDs may counter vasodilatory effects.

Practical points

• • •

Dose should be started low and uptitrated to a target or maximum tolerated dose. This will be dictated by blood pressure, renal function, and serum potassium. Administering ACE inhibitors and ARBs in two divided doses may increase tolerability. Symptomatic hypotension, particularly profound first-dose hypotension, may be overcome by administering ACE inhibitors or ARBs at night.

Mineralocorticoid receptor antagonists This class includes both spironolactone and eplerenone. However, currently it is only eplerenone which is licensed for use post MI in patients with reduced left ventricular ejection fraction and hence the focus on eplerenone. Fig. 16 summarizes the pharmacological action, mechanism of action, and adverse effects of eplerenone. Mechanism of action Eplerenone is a competitive antagonist of aldosterone, which selectively binds to the mineralocorticoid receptor over other steroid receptors (Brown, 2003). This prevents the binding of aldosterone and subsequent gene expression. It is used following acute MI only in those patients who experience heart failure symptoms with a left ventricular ejection fraction of less than 40% (Joint Formulary Committee, 2016). Its effects on plasma volume through reduction of sodium and water reabsorption may contribute to its therapeutic benefit; however, it is likely that other mechanisms are more important for its cardioprotective effects (Pitt et al., 2003). Aldosterone, both in the heart and plasma, is increased following acute MI and contributes to ventricular remodeling by stimulating the sympathetic nervous system, endothelial dysfunction, and overproduction cardiac interstitial collagen. Eplerenone reduces these effects, to attenuate ventricular remodeling and improve left ventricular systolic function (Fraccarollo et al., 2003). Pharmacokinetics Eplerenone peaks in the plasma 1.5 h after oral administration. It is converted to inactive metabolites, primarily by CYP3A4 and has a half-life of 4–6 h (Brown, 2003). Adverse effects Eplerenone may cause headache, drowsiness, GI disturbances, and diarrhea (Joint Formulary Committee, 2016). Hypercholesterolemia and raised liver transaminases have also been reported (Brown, 2003). Eplerenone decreases excretion of potassium, which can lead to hyperkalemia. The incidence and severity of hyperkalemia is increased in patients with renal impairment, diabetes, and those taking other medication which increase serum potassium. Eplerenone should be avoided in patients with severe renal impairment. Smaller starting doses should be used and potassium monitored closely for those with moderate renal impairment (Pfizer, 2016b). Due to its selectivity for mineralocorticoid receptors, eplerenone has a lower incidence of hormone-related side effects, such as gynecomastia and mastodynia in men and vaginal bleeding in women, compared to other aldosterone antagonists such as spironolactone (Brown, 2003).

Fig. 16 Summary of the pharmacological action, mechanism of action, and adverse effects of eplerenone.

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Drug interactions Administration of eplerenone alongside ACE inhibitors, ARBs, potassium sparing diuretics, and trimethoprim can increase the risk of hyperkalemia. Renal function and potassium should be monitored. Similarly, tacrolimus and ciclosporin can adversely affect renal function which, in the presence of eplerenone, further increases the risk of hyperkalemia. Concomitant use should be avoided. NSAIDs should be used with caution due to their potential to cause renal impairment (Joint Formulary Committee, 2016). Potent inhibitors of CYP3A4 can greatly increase the plasma concentration of eplerenone, thus increasing the risk of adverse effects. Concomitant administration of potent inhibitors such as clarithromycin, itraconazole, and ritonavir should be avoided. Careful monitoring and dose adjustment may be required with mild to moderate CYP3A4 inhibitors, such as erythromycin, amiodarone, diltiazem, and verapamil. Strong inducers of CYP3A4, including carbamazepine, rifampicin, phenytoin, and St John’s wort, may reduce the efficacy of eplerenone (Pfizer, 2016b).

Practical points

• • •

Indicated only post-acute MI with evidence of left ventricular failure Increased hypotensive effect when administered with other antihypertensives—monitor blood pressure ACE inhibitor, ARB, and eplerenone should not be given together as a triple combination

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Further Reading Swerdlow DI, Preiss D, Kuchenbaecker KB, et al. (2015) HMG-coenzyme A reductase inhibition, type 2 diabetes, and bodyweight: evidence from genetic analysis and randomised trials. Lancet 385: 351–361.

Physical Examination: Heritable Cardiovascular Syndromes K Puri and JP Zachariah, Baylor College of Medicine, Houston, TX, United States © 2018 Elsevier Inc. All rights reserved.

Physician Examination: Heritable Cardiovascular Syndromes Syndromes With Abnormal Chromosome Number Down Syndrome Turner Syndrome Trisomy 18 and 13 Deletion Syndromes 22q11 Deletion Syndrome Williams–Beuren Syndrome (Williams Syndrome) Jacobsen Syndrome Cat Eye Syndrome Single Gene Deletion Syndromes Noonan Syndrome CHARGE Syndrome Marfan Syndrome and Loeys–Dietz Syndrome Alagille’s Syndrome Holt–Oram Syndrome Long-QT Syndrome References

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Physician Examination: Heritable Cardiovascular Syndromes The savvy clinician is a detective in pursuit of keys to unlock the conundrum of a patient’s current concerns and future implications. A critical avenue of that pursuit is apprehension of physical exam findings. Physical exam findings are then leveraged by clinical training to induce information on diagnoses, needed treatments, and prognosis. Included in clinical training are education about genetic syndromes, congenital associations, and congenital sequences which exemplify this methodology, allowing one or a collection of particular exam findings to trigger identification of more exam findings, relevant diagnoses, and prognosticate the future. A genetic syndrome or a genetic disorder is defined as a pattern of congenital malformations that are commonly associated together, with a known causal or underlying genetic change. In comparison, a congenital association is a set of physical examination findings occurring together more frequently than would be expected by chance, without a known genetic mutation identified (e.g., VACTERL association). A congenital sequence, finally, is a combination of physical anomalies which occur due to an instigating underlying event or anomaly with other malformations occurring as a consequence (e.g., Pierre–Robin sequence, in which underdevelopment of the mandible leads to a small mouth, posterior displacement of the tongue, cleft palate, and airway difficulties). While congenital heart disease (CHD) is a common birth defect and is present in about 9 of every 1000 children, the majority of CHD is not associated with genetic syndromes (Blue et al., 2018). With the emergence of widespread, high-throughput gene sequencing and analysis technologies being performed in numbers allowing economics of scale, an increasing number of variations of single-gene mutations, deletions, or duplications with more subtle effect sizes are being associated with CHD, in addition to the more well-known and more penetrant Mendelian disorders. An increasing number of new mutations are being studied in relation to CHD, and broader ranges of presentation are being found for well-known genes. Furthermore, previously well-described, often dismal associations of chromosomal aneuploidy with CHD are also evolving due to clinical courage to treat these children robustly, leading to new, modified natural histories in terms of postoperative care complications, long-term survival, recurrence risk, and care needs (Postma et al., 2015). What follows is discussion on a selection of genetic syndromes associated with CHD sorted by type of genetic alteration, with specific exposition of dysmorphology, cardiac and noncardiac phenotype, and their genetic testing. In addition, at the end of the chapter, we briefly discuss the arrhythmia-prone long-QT syndromes.

Syndromes With Abnormal Chromosome Number Down Syndrome Down syndrome (DS) (Fig. 1) is the most common genetic syndrome associated with CHD, found in about 1 in 1200 live births, and roughly 50% of DS patients will have CHD (Presson et al., 2013; Kazemi et al., 2016). The variety of CHD in these patients is dominated by the atrioventricular septal defects (AVSD), comprising about 60% of CHD in DS patients. The remainder is constituted by secundum atrial septal defects (ASD), ventricular septal defects (VSD), and tetralogy of Fallot (ToF) (Goldmuntz et al., 2016). Encyclopedia of Cardiovascular Research and Medicine

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Fig. 1 Down syndrome. Young infant. Flat facies, straight hair, protrusion of tongue. Reproduced from Jones, K. L., Jones, M. C., Del Campo, M. (2014). Moderate short stature, facial and genital. In: Jones, K. L., Jones, M. C., Del Campo, M. (eds.) Smith’s recognizable patterns of human malformation (7th edn.), Philadelphia, PA: Elsevier. Permission from Elsevier.

Physical exam In the current era, a majority of DS is diagnosed in the newborn and infant stage, with generalized hypotonia (low muscle tone), protruding tongue, epicanthal fold (skin fold over the eye), transverse palmar crease, shortened and curved fingers due to abnormal development of interphalangeal joints (clinodactyly), and a gap between the first and second toes. As children, they may have difficulty feeding due to poor tone, in addition to possible congestive heart failure (CHF) symptoms. Children with DS with CHD have a 5 times higher risk of dying in the first year of life, but 20-year survival rate is 82% (Presson et al., 2013). Recent reports indicate that the median survival is age 49 years (Presson et al., 2013). Given the high awareness about the condition, the diagnosis of DS may be made at birth. As per the American Academy of Pediatrics’ recommendation for health supervision, all infants diagnosed with DS should undergo an echocardiogram to diagnose CHD (Bull, 2011). The typical CHD lesions (AVSD, VSD) in DS present with features of CHF and pulmonary overcirculation around 2–4 months of age (Goldmuntz et al., 2016). The pulmonary vascular resistance which is high at birth gradually drops which allows the shunting left to right across the lesion to increase, which returns back to the heart and cycle begins again. This progressive cycle overtime leads to much of the heart’s work and the baby’s energy intake going to the inefficient circular flow from the left heart, across the lesion to the right heart, to the lungs, and back to the left heart. If the CHD goes undiagnosed, these children may continue to overcirculate and then develop pulmonary hypertensive vascular changes. This is accompanied by a seeming improvement in the clinical picture, with lesser overcirculation and better weight gain. However this actually marks a closing window for opportunity for surgical intervention, as the lesions may become inoperable if the pulmonary vascular changes become irreversible (Goldmuntz et al., 2016). After CHD surgery, they have equivalent survival as compared to nontrisomy 21 patients (Goldmuntz et al., 2016; Fudge et al., 2010). While the overall surgical mortality for AVSDs in particular in the current surgical era is less than 3%, the need for reintervention due to atrioventricular valve regurgitation or stenosis remains about 10%–15% at the 5-year postoperative mark (Hoohenkerk et al., 2010; Pontailler et al., 2014). Children with DS also have a higher risk for development of pulmonary hypertension, with or without preceding pulmonary overcirculation. Autopsy studies and molecular pathology in mouse models has suggested that this may be attributed to the overexpression of antiangiogenic factors from chromosome 21 (Galambos et al., 2016; Bush et al., 2017). This leads to disruption of normal development of alveoli, alveolar simplification, persistence of double capillary networks, and development of intrapulmonary bronchopulmonary anastomoses, leading to pulmonary hypertensive vascular changes (Bush et al., 2017). Several mouse models of trisomy 21 have been developed and studied, with the Ts65Dn being the most popular. It has replicated analogous neurological features of DS, but not the cardiac anatomic lesions (Gupta et al., 2016). Genetic testing The most common underlying genetic change is a complete trisomy of the chromosome 21, which are most commonly de novo changes during meiosis during egg or sperm formation (Kazemi et al., 2016). About 90% of these are inherited through the egg, while the remainder are through the sperm. Overall, about 6% of the cases have a partial trisomy due to mosaicism. These may be de

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novo, or occur in the parents. The parents are typically unaffected, with a translocation of chromosome 21 material onto another chromosome (Kazemi et al., 2016). During meiosis, this may lead to triple copies of chromosome 21 material, which may also be inherited further. Karyotype can confirm the diagnosis of trisomy 21. While more high-definition testing like chromosomal microarray and sequencing will also make the diagnosis, they are unnecessary unless additional syndromes or defects are suspected.

Turner Syndrome Turner syndrome (TS) (Fig. 2) is present in 1 of 2500 live-born females. About half of the patients with TS have CHD, most commonly left-sided lesions including bicuspid aortic valve (BAV), aortic stenosis (AS), coarctation of the aorta (CoA), or hypoplastic left heart syndrome (HLHS) (Levitsky et al., 2015; Cramer et al., 2014). About 10% of TS patients have CoA. The classic phenotype of a vascular malformation leading to the webbing of the neck and lymphedema is also associated with the findings of left-sided obstructive lesions (Levitsky et al., 2015). This co-occurrence has spurred the hypothesis that the vascular malformations causing the lymphedema may also cause the cardiac lesions. Further, about half of the adults with TS have hypertension (HTN). The risk of aortic dissection in TS is six times that of the general population, and occurs at relatively lesser degrees of aortic dilation (Carlson et al., 2012). These have further prompted the suspicion for an underlying vasculopathic process underpinning these manifestations (Loscalzo et al., 2005). Physical exam Fetuses with TS may have lymphedema, hydrops, or lymphatic malformations in the neck. On birth, these newborns may demonstrate neck webbing, low hairline, and puffy extremities (Levitsky et al., 2015). As a child and young adult, they may present with hypertension (about 25% of adolescents), short stature, or infertility, or have a wide carrying angle (cubitus valgus at the elbow) and a broad chest with wide-set nipples on exam. The short stature is thought to be due to decreased sensitivity to growth

Fig. 2 Turner syndrome. Note prominent ears, loose folds of skin in posterior neck with low hairline, broad chest with widely spaced nipples. Reproduced from Jones, K. L., Jones, M. C., Del Campo, M. (2014). Moderate short stature, facial and genital. In: Jones, K. L., Jones, M. C., Del Campo, M. (eds.) Smith’s recognizable patterns of human malformation (7th edn.), Philadelphia, PA: Elsevier. Permission from Elsevier.

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hormone and is responsive to growth hormone administration (Hjerrild et al., 2008). Another common feature is premature ovarian failure, with an accelerated destruction of germ cells starting at 15–18 weeks of gestation. Follicle-stimulating hormone and luteinizing hormone concentrations approach menopausal levels by the end of adolescence. While about 30% of the girls with TS will have some signs of puberty, only about 2%–3% will have spontaneous sustained menstrual cycles (Hjerrild et al., 2008). The deficiency of sex hormones also has a deleterious impact on bone mass, with lower bone mineral density and greater fracture risk. Initiation of sex hormone replacement therapy allows pubertal development at appropriate time, as well as better maintenance of bone health (Hjerrild et al., 2008). TS patients also have neurodevelopmental abnormalities, with average to below-average intelligence and preserved verbal domain skills. However there is impairment of executive functioning and processing, including visual-motor and arithmetic skills (Hong and Reiss, 2014). Genetic testing The most common genotype for TS is monosomy of the X chromosome, followed by 46 XY/45 XO mosaicism which is phenotypically less severe (Levitsky et al., 2015; Hjerrild et al., 2008). These aneuploidies are detected by karyotype analysis. Girls with the typical physical exam findings, infertility, primary amenorrhea, or pathologically short stature should undergo karyotype testing for TS (Levitsky et al., 2015; Hjerrild et al., 2008).

Trisomy 18 and 13 Trisomy 18 (Edwards syndrome) (Figs. 3 and 4) and Trisomy 13 (Patau syndrome) (Figs. 5 and 6) are present in 1 in 6700 and 1 in 12,300 live births, respectively (Bruns, 2011; Macias and Riley, 2016). About 80% of children with trisomy 13% and 90% of the patients with trisomy 18 have associated CHD (Macias and Riley, 2016). The most common lesions in trisomy 13 include double outlet right ventricle (DORV), VSDs and ASDs. The most common lesions in trisomy 18 patients include polyvalvar dysplasia (stenosis or regurgitation), VSDs and ASDs (Bruns, 2011). There has been a recent shift in the approach to these patients, to enhance quality of life with palliative cardiac surgery in order to obtain stable enough physiology to facilitate the parents taking the baby home (Meyer et al., 2016; Maeda et al., 2011; Janvier et al., 2016). While the greatest mortality for these disorders is in the first week of life, population-based studies have shown an improvement in 1- and 5-year survival in these disorders. Reported 1-year survival from a population cohort from 1999 to 2007 is 11% for trisomy 13% and 13% for trisomy 18, with a 5-year survival of about 10% for trisomy 13 and about 12% for trisomy 18 (Meyer et al., 2016). These numbers are higher than the 1-year survival rate of about 5% reported from a cohort from 1968 to 1999 (Rasmussen et al., 2003). Only in cases of a major CHD like truncus arteriosus, transposition of the great arteries (TGA), ToF, CoA, aortic stenosis, AVSD, or HLHS has CHD been shown to be associated with mortality (Maeda et al., 2011; Janvier et al., 2016).

Fig. 3 Trisomy 18. Clenched hand with index finger overlying third and hypoplasia of fingernails. Reproduced from Jones, K. L., Jones, M. C., Del Campo, M. (2014). Moderate short stature, facial and genital. In: Jones, K. L., Jones, M. C., Del Campo, M. (eds.) Smith’s recognizable patterns of human malformation (7th edn.), Philadelphia, PA: Elsevier. Permission from Elsevier.

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Fig. 4 Older child with trisomy 18 syndrome. Reproduced from Jones, K. L., Jones, M. C., Del Campo, M. (2014). Moderate short stature, facial and genital. In: Jones, K. L., Jones, M. C., Del Campo, M. (eds.) Smith’s recognizable patterns of human malformation (7th edn.), Philadelphia, PA: Elsevier. Permission from Elsevier.

Fig. 5 Newborn child with trisomy 13 syndrome. Note sloping forehead with variable defect in facial development. Reproduced from Jones, K. L., Jones, M. C., Del Campo, M. (2014). Moderate short stature, facial and genital. In: Jones, K. L., Jones, M. C., Del Campo, M. (eds.) Smith’s recognizable patterns of human malformation (7th edn.), Philadelphia, PA: Elsevier. Permission from Elsevier.

Physical exam Trisomy 18 patients have increased extensor muscle tone, with scissoring of the legs and overlapping fingers of the hand, in addition to rocker-bottom feet, small mouth (micrognathia), microcephaly, and renal anomalies (Roberts et al., 2016). Patients with trisomy 13 demonstrate polydactyly, cleft lip/palate, cutis aplasia of the scalp, small eyes (microphthalmia), and holoprosencephaly (cerebral hemisphere division failure) (Rasmussen et al., 2003).

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Fig. 6 Aplasia cutis congenital over posterior occiput. Reproduced from Jones, K. L., Jones, M. C., Del Campo, M. (2014). Moderate short stature, facial and genital. In: Jones, K. L., Jones, M. C., Del Campo, M. (eds.) Smith’s recognizable patterns of human malformation (7th edn.), Philadelphia, PA: Elsevier. Permission from Elsevier.

Genetic testing Diagnosis of trisomy 13 or 18 can be made on karyotype testing. Any child with polyvalvar disease or multiple valves with dysplasia or thickening should be assessed for these underlying genetic trisomies (Maeda et al., 2011; Janvier et al., 2016).

Deletion Syndromes 22q11 Deletion Syndrome DiGeorge syndrome, velocardiofacial syndrome, conotruncal anomaly (Takao) syndrome, and isolated outflow tract defects of the heart are different names for what we now understand to be a family of syndromes associated with a microdeletion on the long arm of chromosome 22, the 22q11.2 deletion (Fig. 7). This occurs in 1 in about 4000–6000 live births and is associated with CHD in about 75%–80% of the patients (Perez and Sullivan, 2002; Hacıhamdioğlu et al., 2015). The CHD spectrum is quite distinct, including interrupted aortic arch, ToF, truncus arteriosus, and perimembranous VSD with aortic arch anomalies. Children diagnosed with these specific CHD lesions are screened for 22q11.2 deletion due to the strength of the association. The deleted region encapsulates >35 genes; however TBX-1 is the most studied gene in this region (Perez and Sullivan, 2002; Hacıhamdioğlu et al., 2015). It is expressed in the pharyngeal arches, is an important transcription factor for development of the second heart field during cardiac embryogenesis, and is needed for the migration of the cardiac neural crest cells in cardiac outflow tract development and other locations. Hence, a mutation in TBX-1 causes defective development in multiple locations, leading to the cardiac, thymic, and parathyroid deficiencies, as well as the facial anomalies and possibly the feeding difficulties found in these patients (Perez and Sullivan, 2002; Hacıhamdioğlu et al., 2015). As repairs for the associated CHD have improved, longer survival has uncovered myriad manifestations of the syndrome. Children with 22q11.2 deletion often have feeding difficulties, and developmental delay, along with behavioral problems like impulsivity and overactivity (Norkett et al., 2017). Nearly one-third are diagnosed with attention deficit hyperactivity disorders, and autism spectrum disorders or general social impairment in about 20%–30% of the cases. They may also go on to be diagnosed with anxiety and mood disorder and may have progressive decline in cognitive abilities (Roberts et al., 2016). About 20%–30% of the adults with 22q11.2 deletion are unfortunately diagnosed with frank schizophrenia or other psychotic illnesses (Norkett et al., 2017). Physical exam In the age of prenatal CHD diagnosis, 22q11.2 deletion syndromes are often detected in during infancy. Physical examination features suggestive of this syndrome are—small mouth (micrognathia), flat cheek bones (malar flattening), small nostrils

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Fig. 7 Photograph of 12-year-old boy. Facial features emphasizing the nasal configuration. Reproduced from Jones, K. L., Jones, M. C., Del Campo, M. (2014). Moderate short stature, facial and genital. In: Jones, K. L., Jones, M. C., Del Campo, M. (eds.) Smith’s recognizable patterns of human malformation (7th edn.), Philadelphia, PA: Elsevier. Permission from Elsevier.

(hypoplastic alae nasi), cleft lip/palate, hypocalcemia, immunodeficiency, airway anomalies due to vascular rings, renal anomalies, developmental delay, and behavioral disorders (Perez and Sullivan, 2002). A memory aid for these syndromes is CATCH-22— CHD, abnormal facies, hypoplasia of the thymus (immunodeficiency), cleft palate, and calcium (hypocalcemia—due to hypoparathyroidism). The presence of an aortic arch anomaly increases the chance of 22.q11 deletion, regardless of the underlying CHD. Genetic testing Diagnosis of 22q11.2 deletion can be made on fluorescent in situ hybridization (FISH) testing (Perez and Sullivan, 2002; Hacıhamdioğlu et al., 2015). It may also be made by multiplex ligation-dependent probe amplification (MLPA) or chromosomal microarray analysis, the latter of which will also be beneficial in detecting CHARGE (Coloboma, Heart defects, choanal Atresia, Growth retardation, and Genital anomalies and Ear abnormalities) syndrome, since many of the physical exam findings may overlap with 22q11 deletion syndromes.

Williams–Beuren Syndrome (Williams Syndrome) Williams syndrome (WBS) (Figs. 8 and 9) is a multisystem genetic cardiovascular disorder occurring in about 1 in 10,000–20,000 live births (Collins, 2013). It is characterized by typical facial features, hypercalcemia, CHD, and a diffuse arteriopathy with stenotic lesions and fibrosis. Most of these children have developmental delay and cognitive weakness, and a characteristic social personality (cocktail party personality). The elastin (ELN) gene has been mapped to the region which experiences a mutation in WBS. This may explain the vascular findings of the condition discussed below (Merla et al., 2012). Physical exam WBS facies are characterized as elfin, with a broad forehead, star-shaped irides, flattened nasal bridge with rounded tip of nose, wide mouth and full lips (Collins, 2013). About half the patients have hypercalcemia, which is noted in infancy and thereafter usually is asymptomatic. CHD is present in about 80% of the patients, with about 75% having supravalvar aortic stenosis, 40%–50% having pulmonary artery stenosis, and about 5% having coronary artery stenotic lesions (Merla et al., 2012; Zalzstein et al., 1991). The pulmonary artery lesions typically involve the branch pulmonary arteries or the more distal branches. While the aortic lesions may remain stable or worsen over time, the pulmonary lesions tend to either remain stable or improve as the child grows older (Zalzstein et al., 1991). However in cases where the pulmonic stenosis do not improve, the stenoses tend to be deep into the lung and diffuse, making them difficult to remediate by surgery or cath. A special concern exists with sedation since coronary artery stenoses can be silent until pharmacologically induced changes in arterial pressure may become insufficient to overcome these coronary stenoses and cause sudden death (Bird et al., 2004). A varied range of patients are also being reported to have stenosis of the thoracic aorta, and the elastin deficiency is the putative mechanism of these systemic vasculopathic features (Bird et al., 2004). Genetic testing Williams syndrome can be attributed to 7q11.23 deletion in about 90% of the patients (Morris, 1999). This can be detected on FISH or MLPA testing or chromosomal microarray analysis.

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Fig. 8 Williams syndrome. Reproduced from Jones, K. L., Jones, M. C., Del Campo, M. (2014). Moderate short stature, facial and genital. In: Jones, K. L., Jones, M. C., Del Campo, M. (eds.) Smith’s recognizable patterns of human malformation (7th edn.), Philadelphia, PA: Elsevier. Permission from Elsevier.

Fig. 9 Note the typical stellate pattern of the iris. Reproduced from Jones, K. L., Jones, M. C., Del Campo, M. (2014). Moderate short stature, facial and genital. In: Jones, K. L., Jones, M. C., Del Campo, M. (eds.) Smith’s recognizable patterns of human malformation (7th edn.), Philadelphia, PA: Elsevier. Permission from Elsevier.

Jacobsen Syndrome Jacobsen syndrome is a syndrome caused by a deletion on chromosome 11, found in about 1 in 100,000 live births. It is characterized by developmental and behavioral problems, distinctive facial features, coagulopathy, heart defects, and immunodeficiency (Tassano et al., 2016; Dalm et al., 2015). Physical exam The typical facies of Jacobsen syndrome include low-set ears, hypertelorism (wide-spaced eyes), ptosis (drooping eyelids), epicanthal folds, broad nasal bridge, downturned corners of the mouth, and a thin upper lip, in the setting of macrocephaly (Tassano et al., 2016; Dalm et al., 2015). Over 90% of the patients have a bleeding disorder called Paris–Trousseau syndrome which affects the alpha-granules in the platelets. This manifests as easy bruising and abnormal bleeding. CHD is present in just over 50% of the patients (Goldmuntz et al., 2016). The cardiac anomalies are predominantly VSDs, followed by left-sided obstructive lesions like mitral or aortic stenosis, Shone’s complex and variants, and hypoplastic left heart syndrome (Goldmuntz et al., 2016; Tassano et al., 2016). Genetic testing Jacobsen syndrome is caused by deletion of the terminal material of the long arm of chromosome 11 (Tassano et al., 2016; Dalm et al., 2015). This deletion is large enough to be assessed on karyotyping or readily by FISH testing. The mutation is de novo in about 85% of the cases.

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Fig. 10 Cat-eye syndrome. Infant showing coloboma of iris and ocular hypertelorism. Reproduced from Jones, K. L., Jones, M. C., Del Campo, M. (2014). Moderate short stature, facial and genital. In: Jones, K. L., Jones, M. C., Del Campo, M. (eds.) Smith’s recognizable patterns of human malformation (7th edn.), Philadelphia, PA: Elsevier. Permission from Elsevier.

The cat-eye syndrome (Fig. 10) is reported in about 1 in 150,000 live births and is named for its association with vertical colobomas, insensitively called “cat-eye.” (Rosias et al., 2001)

Cat Eye Syndrome Physical exam The classic triad of this syndrome includes iris colobomas, ear anomalies, and anal malformations (Rosias et al., 2001). Other eye anomalies include hypertelorism and down slanting palpebral fissures, and the facies may also demonstrate ear anomalies and a broad nasal bridge. Cardiac anomalies present in this syndrome include total anomalous pulmonary venous return, ToF, and VSD (Rosias et al., 2001; Timoney and MacNicholas, 2014). Anorectal malformations and genitourinary defects may also be present. Genetic testing This syndrome is caused by the partial tetrasomy of chromosome 22, which can be tested for by karyotyping. Confirmatory testing may also be performed by FISH or chromosomal analysis (Rosias et al., 2001; Timoney and MacNicholas, 2014).

Single Gene Deletion Syndromes Noonan Syndrome Noonan syndrome (NS) (Figs. 11 and 12) is an autosomal dominant condition with characteristics facies and habitus, cardiac disease, and developmental delay. NS occurs in 1 in about 1000–2500 live births (Tafazoli et al., 2017). About 50%–66% of patients with NS have an affected parent. NS is one of a family of disease classified as the RASopathies, conditions with mutations in the RAS-mitogen activated protein kinase (RAS-MAPK) pathway (Tafazoli et al., 2017; Tartaglia et al., 2011). This pathway helps in the communication of growth factor signals into cells, and influences cell division, differentiation and proliferation. These RASopathies include NS, neurofibromatosis type 1, NS with multiple lentigines (discussed below), Costello syndrome, and cardiofaciocutaneous syndrome, among other conditions (Tartaglia et al., 2011). This collection of disorders are seen to have physical craniofacial dysmorphisms, cardiovascular abnormalities, cutaneous findings, musculoskeletal findings, and cognitive impairment. Patients with NS who go on to later develop pigmented spots called lentigines during childhood may be diagnosed with the NS with multiple lentigines. This is a rare multisystem congenital disorder that has findings involving the skin, facial, and cardiac anomalies (Aoki et al., 2016). NS patients commonly suffer from developmental delay as well as growth retardation and short stature. There is also a greater prevalence of attention deficit hyperactivity disorder and learning delays (Tartaglia et al., 2011). Physical exam NS has characteristics facies with hypertelorism, micrognathia, low-set fleshy ears, and high-arched palate, a webbed neck, a broad chest with widely spaced nipples, decrease in growth velocity around puberty, and delayed development (Tafazoli et al., 2017; Tartaglia et al., 2011). Their cardiac anomalies include valvar pulmonic stenosis, hypertrophic cardiomyopathy, and electrocardiographic anomalies like right or left axis deviation. Patients with NS with lentigines can also carry the label LEOPARD syndrome: Lentigines, ECG abnormalities, Ocular hypertelorism, Pulmonic stenosis, Abnormal genitalia, Retardation of growth, and Deafness

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Fig. 11 Noonan syndrome. Reproduced from Jones, K. L., Jones, M. C., Del Campo, M. (2014). Moderate short stature, facial and genital. In: Jones, K. L., Jones, M. C., Del Campo, M. (eds.) Smith’s recognizable patterns of human malformation (7th edn.), Philadelphia, PA: Elsevier. Permission from Elsevier.

Fig. 12 Affected mother and daughter. Reproduced from Jones, K. L., Jones, M. C., Del Campo, M. (2014). Moderate short stature, facial and genital. In: Jones, K. L., Jones, M. C., Del Campo, M. (eds.) Smith’s recognizable patterns of human malformation (7th edn.), Philadelphia, PA: Elsevier. Permission from Elsevier.

Genetic testing About half of NS patients carry mutations in the PTPN11 gene (Tafazoli et al., 2017; Tartaglia et al., 2011; Aoki et al., 2016). The remainder are accounted for by six other genes—SOS1, RAF1, KRAS, NRAS, SHOC2, and CBL. PTPN11 may be tested by a targeted gene testing. Currently there is a panel that can be ordered which tests for multiple genes whose mutations can lead to a phenotype of or similar to Noonan syndrome (Tafazoli et al., 2017; Tartaglia et al., 2011; Aoki et al., 2016).

CHARGE Syndrome CHARGE syndrome (Fig. 13) abbreviating Coloboma, Heart defects, choanal Atresia, Growth retardation, and Genital anomalies and Ear abnormalities is a multisystem disorder found in 1 in 8500–10,000 live births. When this constellation of findings is suspected, early involvement of the respective specialist is recommended (Lalani et al., 2012; Bergman et al., 2011). Physical exam Patients have a typical facies with prominent forehead, flat midface and prominent nasal bridge. Ear anomalies present in over 90% of the patients include low set anteverted cup-shaped ears, and occasionally microtia or preauricular tags (Lalani et al., 2012;

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Fig. 13 CHARGE syndrome. Reproduced from Jones, K. L., Jones, M. C., Del Campo, M. (2014). Moderate short stature, facial and genital. In: Jones, K. L., Jones, M. C., Del Campo, M. (eds.) Smith’s recognizable patterns of human malformation (7th edn.), Philadelphia, PA: Elsevier. Permission from Elsevier.

Bergman et al., 2011). Absence of semicircular canals detected on head imaging is highly associated with CHARGE syndrome. Colobomas can be present in one or both eyes in about 80%–90% of the patients and are most commonly chorioretinal in location (Lalani et al., 2012). CHD is present in about 80% of the patients and are most commonly conotruncal defects (interrupted aortic arch, ToF, DORV) or AVSD, although almost any type of CHD can be found in these patients (Goldmuntz et al., 2016; Lalani et al., 2012). Choanal atresia is reported in about 65% of the patients, although over half of the patients may also have obstruction distal to the choanae and have multiple levels of obstruction. About 15%–20% of the patients may have cleft lip or palate and a similar frequency may have tracheoesophageal fistula (Lalani et al., 2012; Bergman et al., 2011). Genital anomalies include hypoplastic genitalia. Patients with CHARGE syndrome experience somatic growth restriction in late infancy, global developmental delays, and delayed puberty (Bergman et al., 2011). Genetic testing CHD7 mutations, most commonly deletions, account for 90%–95% of the patients with CHARGE syndrome (Lalani et al., 2012; Bergman et al., 2011). A vast majority of the mutations occur de novo and there is no family history, although the inheritance pattern thereafter is autosomal dominant (Lalani et al., 2012).

Marfan Syndrome and Loeys–Dietz Syndrome Marfan syndrome (MFS) (Figs. 14 and 15) is an autosomal dominant negative condition, with manifestations involving the connective tissue of the cardiovascular system, the eyes, and the musculoskeletal system. It occurs in 1 in about 10,000–15,000 people (Groth et al., 2015; Loeys et al., 2010). It is caused by the fibrillin gene (FBN1) mutation. It is also a part of the family of conditions impacting the thoracic aorta, known as the heritable thoracic aortic diseases, and FBN1 is one of the 13 genes known to be causative (Loeys et al., 2010; Romaniello et al., 2014). In MFS, the aorta may dilate over time leading to sudden catastrophic rupture. Loeys–Dietz syndrome (LDS) is another vasculopathy with potentially catastrophic outcomes, associated with mutations in the genes for TGF-b receptors, TGFBR1 and TGFBR2. It is characterized by aneurysmal involvement of the aorta, increased vascular tortuosity, and higher risk of aortic dissection (MacCarrick et al., 2014; Van Laer et al., 2014). Physical exam MFS is diagnosed by the revised Ghent criteria, which include aortic root dilation, ectopia lentis, and fibrillin gene mutation as cornerstone criteria, the presence of any two of which clinches the diagnosis (Table 1) (Romaniello et al., 2014). The presence of any one of these along with a confirmed family history of MFS based on the revised Ghent criteria is also adequate to confirm the MFS diagnosis. Further, a physical exam to evaluate for the “wrist sign” and the “thumb sign,” pectus carinatum, hindfoot deformity, decreased upper segment to lower segment ratio and increased arm to height ratio, reduced elbow extension, scoliosis or thoracolumbar kyphosis, skin striae, and facial features including a long face (dolichocephaly), posteriorly displaced eyeballs within socket (enophthalmos), downslanting palpebral fissures, malar hypoplasia and retrognathia, are a part of the systemic

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Fig. 14 Marfan syndrome. Note the long slim limbs, pectus excavatum, narrow face, and reduced elbow extension. Reproduced from Jones, K. L., Jones, M. C., Del Campo, M. (2014). Moderate short stature, facial and genital. In: Jones, K. L., Jones, M. C., Del Campo, M. (eds.) Smith’s recognizable patterns of human malformation (7th edn.), Philadelphia, PA: Elsevier. Permission from Elsevier.

Fig. 15 Joint laxity, Steinberg thumb sign, and ability to join thumb and fifth finger around the wrist (Walker–Murdoch sign). Reproduced from Jones, K. L., Jones, M. C., Del Campo, M. (2014). Moderate short stature, facial and genital. In: Jones, K. L., Jones, M. C., Del Campo, M. (eds.) Smith’s recognizable patterns of human malformation (7th edn.), Philadelphia, PA: Elsevier. Permission from Elsevier.

scoring system (Romaniello et al., 2014). A score equal to or greater than 7 along with any one of the 3 major criteria will also confirm the diagnosis of Marfan syndrome (Romaniello et al., 2014). LDS may be diagnosed in patients with wide-set eyes (hypertelorism), cleft palate, craniosynostosis, and aneurysmal dilation of the aortic root, or other segments of the aorta (MacCarrick et al., 2014; Van Laer et al., 2014). They may also have other skeletal features of kyphosis or joint laxity overlapping with MFS. About 98% of the patients of LDS have aortic root aneurysms, while about 10% have abdominal aortic aneurysms. Patients with LDS are also more likely to have an atrial septal defect or patent ductus arteriosus than the general population, with these lesions found in about 20%–30% of the patients. LDS patients are at greater risk

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Diagnostic criteria of MFS according to the Ghent-2 nosology

In the absence of family history 1. Aortic root diameter (Z-score 2) and ectopia lentis ¼ MFS 2. Aortic root diameter (Z-score 2) and causal FBN1 mutation ¼ MFS 3. Aortic root diameter (Z-score 2) and systemic score 7 points ¼ MFS 4. Ectopia lentis and causal FBN1 mutation with known aortic root dilatation ¼ MFS In the presence of family history 5. Ectopia lentis and family history of MFS (as defined above) ¼ MFS. 6. Systemic score 7 points and family history of MFS (as defined above) ¼ MFS 7. Aortic root diameter (Z-score 2 above 20 years old, 3 below 20 years) and family history of MFS (as defined above) ¼ MFS  Caveat: without discriminating features of Shprintzen–Goldberg syndrome, Loeys–Dietz syndrome or vascular form of Ehlers–Danlos syndrome AND after TGFBR1/ 2, collagen biochemistry, COL3A1 testing if indicated. Scoring of systemic features of MFS 1. Wrist and thumb sign—3 points (wrist or thumb sign—1 point) 2. Pectus carinatum deformity—2 points (pectus excavatum or chest asymmetry—point) 3. Hindfoot deformity—2 points (plain pes planus—1 point) 4. Protrusio acetabuli—2 points 5. Reduced upper segment/lower body segment ratio and increased arm/height and no severe scoliosis – 1 point 6. Scoliosis or thoracolumbar kyphosis—1 point 7. Reduced elbow extension—1 point 8. Facial features (3/5)—1 point (dolichocephaly, enophthalmos, downslanting palpebral fissures, malar hypoplasia, retrognathia) 9. Pneumothorax—2 points 10. Skin striae—1 point 11. Myopia .3 diopters—1 point 12. Mitral valve prolapse (all types)—1 point 13. Dural ectasia—2 points The systemic features number 1–13 are used for the systemic score in the Ghent-2 nosology, where a maximum total score points of 20 points can be obtained. We number the systemic features as 1–8 and address these as “skeletal score,” and the systemic features as 9–12 and address these as “nonskeletal score”. Copyright © 2010. BMJ Publishing Group Ltd. Reproduced from Loeys, B. L., Dietz, H. C., Braverman, A. C. et al. (2010). The revised Ghent nosology for the Marfan syndrome. Journal of Medical Genetics 47 (7), 476–485. MFS, Marfan syndrome.

for aortic dissection and aneurysm rupture, and hence typically undergo intervention at an earlier stage of dilation (aortic root diameter >4 cm or increasing at rate >0.5 cm per year) (Williams et al., 2007). Genetic testing When a complete diagnosis of MFS can be made by clinical signs, genetic testing is not essential to proceed with management. Testing for FBN1 mutation can help diagnose the mutation and allow for testing of future generations that may meet subdiagnostic clinical criteria (Loeys et al., 2010; Romaniello et al., 2014). The first test recommended is the FBN1 gene sequence analysis, followed by the targeted gene deletion/duplication testing if the sequencing is negative. In patients who have distinct physical examination features raising clinical suspicion for LDS, target gene testing can be performed to confirm diagnosis (MacCarrick et al., 2014; Van Laer et al., 2014). If specific gene testing is normal and the concerning clinical finding is thoracic aortic disease, another panel exists to test for the panel of genes associated with other heritable thoracic aortic diseases.

Alagille’s Syndrome Alagille’s syndrome (Fig. 16) is an autosomal dominant condition found in about 1 in 30,000 live births (Press, 2016). Alagille’s syndrome is diagnosed by the presence of classic phenotypic features in a patient with cholestasis. Alagille’s syndrome is a multisystem disorder of varying expression, with studies showing that about half of mutation-positive individuals would not meet clinical criteria (Press, 2016). Prognosis is also determined by the number, extent, and severity of organ involvement. Physical exam The following criteria help define Alagille’s syndrome: cholestasis, ophthalmologic abnormalities (most commonly embryotoxon), characteristic facial features, skeletal abnormalities, cardiac abnormalities, and renal and vascular problems (Press, 2016; Saleh et al., 2016). The facies are characterized by a prominent forehead, hypertelorism, deep set eyes, and a pointed chin. Posterior embryotoxon of the eye, a thickened and centrally displaced anterior border of the ring of Schwalbe visible on external examination without a slit lamp, occurs in about 80%–90% patients. Cardiac involvement occurs in about 90% of the patients including rightsided obstructive lesions (Press, 2016; Saleh et al., 2016). A majority have pulmonary stenosis (about 67%–70%), with ToF being the second most common (
17%). Pulmonic stenosis in these patients can also be distal in the vascular arborization and poorly responsive to intervention (Sugiyama et al., 2004). Skeletal abnormalities seen commonly are butterfly vertebrae and clefting of vertebral bodies. Renal and vascular anomalies seen in these patients include renal artery stenosis, renal cysts, and intracranial

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Fig. 16 Alagille syndrome. Reproduced from Jones, K. L., Jones, M. C., Del Campo, M. (2014). Moderate short stature, facial and genital. In: Jones, K. L., Jones, M. C., Del Campo, M. (eds.) Smith’s recognizable patterns of human malformation (7th edn.), Philadelphia, PA: Elsevier. Permission from Elsevier.

aneurysms, the latter accounting for up to a third of the mortality in one report. The widespread vascular findings, and the finding of hypertension suggest that there may be an underlying vasculopathy at play in this condition (Salem et al., 2012). Other exam findings associated with cholestasis will include pruritus and subsequent excoriations, scleral icterus, acholic stools, and xanthomas. Liver biopsy reveals a paucity of bile ducts although a biopsy is not essential for diagnosis per the current guidelines, and cholestasis with two other classic phenotypic features with suffice. If there is a first degree relative with Alagille’s syndrome, then only 2 of the clinical features suffice to make a diagnosis (Press, 2016; Saleh et al., 2016). Genetic testing About 95% of patients Alagille’s syndrome have a mutation in chromosome 20p12 in the JAG1 gene for the Notch ligand (Press, 2016; Saleh et al., 2016). The remainder of the patients have a NOTCH2 mutations in the chromosome 1p12-p11 region. Looking for the mutations on chromosomal microarray, MLPA as well as targeted gene sequencing testing for the specific deletions aids in diagnosis.

Holt–Oram Syndrome Holt–Oram syndrome (Fig. 17) is an association of birth defects within the family of so-called heart hand syndromes characterized by cardiac septal defects and limb anomalies. The estimated frequency is about 1 in 100,000 live births (McDermott et al., 2004). Physical exam The thumb may be triphalangeal, syndactylized to the index finger or resting in the plane of the fingers. The forearm may be involved, with possible deficient or absent radius (McDermott et al., 2004; Da-guang et al., 1986). The upper limb anomalies are often bilateral. Rarely the lower limbs may be involved. ASDs and VSDs are the most common CHD lesions seen in this condition, followed by conduction defects. Genetic testing TBX5 is a transcription factor located at 12q24.1 (McDermott et al., 2004). Mutations in this gene resulting in a deletion are associated with Holt–Oram syndrome, although only about a third of the diagnosed cases are associated with known mutations. The condition demonstrates an autosomal dominant transmission with full penetrance.

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Fig. 17 Holt–Oram syndrome. Reproduced from Jones, K. L., Jones, M. C., Del Campo, M. (2014). Moderate short stature, facial and genital. In: Jones, K. L., Jones, M. C., Del Campo, M. (eds.) Smith’s recognizable patterns of human malformation (7th edn.), Philadelphia, PA: Elsevier. Permission from Elsevier.

Long-QT Syndrome Long-QT syndrome (LQTS) occurs in about 1 in 2000 people, and is characterized by an increased risk of sudden cardiac death in an otherwise normal individual with a structurally normal heart (Nakano and Shimizu, 2016; Mizusawa et al., 2014). Some forms of LQTS may have also have associated extracardiac features: (a) Jervell and Lange–Nielsen syndrome (JLNS)—JLNS is a rare multisystem disorder with LQTS, in association with profound sensorineural hearing loss. It occurs in 1 in 2–6 million people, with an exceptionally higher prevalence in the Scandinavian nations of Denmark, Sweden, and Norway, at about 1 in 200,000 (Tranebjærg et al., 2002). Physical exam Diagnosis of JLNS is based on presence of QTc interval >480 ms and a history of congenital deafness, and difficult to control tachyarrhythmias inspite of beta blocker therapy (Tranebjærg et al., 2002). These patients are at high risk of sudden cardiac death. Genetic testing It is caused by an autosomal recessive mutation in the KCNQ1 (90% cases) or the KCNE1 (10% cases) gene, causing defective outflow of potassium ions across membranes in cardiac cells (Tranebjærg et al., 2002). This defect also leads to deficient production of endolymph leading to the congenital deafness seen in this disorder. Testing for this syndrome includes targeted gene analysis (especially if known gene mutation in family), gene sequence analysis (starting with the KCNQ1 mutation), or multigene testing during LQTS evaluation. (b) Anderson–Tawil Syndrome (ATS) (Statland et al., 2004)—This is a rare disorder that has been reported in about a 100 patients across the world. The chief cardiac finding is a prolonged QTc longer than 480 msec and an increased risk of ventricular tachyarrhythmias and sudden death. Bidirectional ventricular tachycardia is a classic finding, which is otherwise found in only two other situations, namely CPVT and digoxin toxicity. Physical exam This diagnosis is suspected in patients with two of the following three criteria: (i) dysmorphic facies, (ii) episodic paralysis, and (iii) history of ventricular tachyarhythmias or prolonged QTc. The dysmorphisms are characterized by micrognathia, hypertelorism, low-set ears, clinodactyly of the fifth digit, syndactyly of second and third toes, scoliosis, and short stature (Statland et al., 2004). The periodic paralysis may be in the setting of hypokalemia (absolute 5%) in adults can be found in the setting of a PDA and pulmonary hypertension, leading to right-to-left shunting across the PDA. A murmur may be absent in that case, and further testing is warranted.

Anthropometrics Anthropometric data like height and weight can provide helpful clues in patients with suspected heart disease. Failure to thrive: Failure to thrive is a common presenting symptom in infants and children with congenital heart disease. In adults, cachexia can be seen in patients with heart failure (cardiac cachexia) and is usually associated with a poor prognosis (von Haehling et al., 2017). In addition, cachexia can be an indicator of an underlying malignancy. This is important to note as

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chemotherapy-induced cardiomyopathy is a well-described entity. Furthermore, unintended weight loss can be an early symptom in patients with Takayasu’s arteritis (Direskeneli, 2017). Obesity: Excess body weight is a common component of metabolic syndrome with well-known cardiac sequelae described elsewhere. It can also be an indicator of a sedentary lifestyle that is due to underlying heart disease with poor exercise tolerance. Beyond that, obesity may suggest an underlying genetic syndrome having a cardiomyopathy component, such as Bardet–Biedl syndrome (Suspitsin and Imyanitov, 2016). Short stature: Unusually low height can be an important clue to an underlying genetic syndrome (Ko, 2015). For example, Turner syndrome is associated with short stature, primary gonadal failure, and in about one-third of cases, congenital heart disease, including excessive risk of aortic dissection. Noonan syndrome is also characterized by short stature and congenital heart disease including pulmonary valve dysplasia, pulmonary stenosis, and hypertrophic cardiomyopathy. Both conditions require lifelong cardiac care. Tall stature: Unusually large height may reflect a person’s unique nutritional and hereditary endowment or may signal more sinister processes. For example, tall stature is a hallmark of patients with Marfan syndrome or other connective tissue disorders, especially when associated with excessive chest wall growth like pectus deformities or excessive back curvature like scoliosis (Loeys et al., 2010). Connective tissue disorders are associated with excesses in valve structure, typically mitral or tricuspid valve prolapse and dysfunction, and aortic dilation (particularly of the aortic root) with its dreaded complication, aortic dissection.

Inspection Even before laying hands on the patient, vital clues can be gathered from careful, informed, visual inspection.

Distress Pain, often considered the fifth vital sign, should be assessed in every patient. Although more commonly noncardiac in nature, chest pain in particular can be the hallmark of myocardial ischemia, myo-/pericarditis, aortic dissection, or a pulmonary embolism. Respiratory distress, as outlined above under “tachypnea” and “hypoxemia,” is visually evident by vital signs but also by apperception of labored breathing, excessive muscle use with breathing, and visibly apparent fatigue as an indicator of prolonged accessory muscle use. Respiratory distress may be the result of underlying lung disease or various types of heart disease, both congenital and acquired. The presence of respiratory distress mandates rapid assessment and prompt management to prevent respiratory failure. More subtle may be distress that is limited to activity. Patients may appear comfortable at rest but display significant limitations with activities of daily living. Subconsciously, such individuals may self-limit activity and therefore never consciously appreciate the fairly profound limitation in activities of daily living. In addition to a thorough history, asking the patient to walk across the room, down the hall or up a flight of stairs may reveal otherwise missed signs of heart failure. Inappropriate diaphoresis at rest or with light activity should also catch the examiners attention. While this is a common presenting sign in infants with congestive heart failure and increased sympathetic tone, in the adult population this can be a consequence of diabetic autonomic neuropathy leading to autonomic dysregulation. If diaphoresis is caused by acute sense of doom, it may be an alarming sign associated with myocardial infarction, aortic dissection, or pulmonary embolism. Similarly subtle to detect on exam may be changes in mental health, affect, or mood. While these are more commonly noncardiac in nature, lethargy and fatigue may be signs of underlying heart failure and require specific attention. Less common, but no less severe, is a form of cardiomyopathy referred to as Takotsubo cardiomyopathy or “broken heart syndrome.” (Chen and Dilsizian, 2017) As a response to emotional stress, significant organic cardiac dysfunction has been described, similar to myocardial ischemia, but with normal coronary perfusion. Thankfully, Takotsubo cardiomyopathy is often characterized by spontaneous recovery. Finally, mental health disorders are now recognized as cardiometabolic risk factors worthy of attention for cardiovascular prevention (Goldstein et al., 2015).

Dysmorphism As described extensively in other chapters, several genetic syndromes can be associated with congenital (or acquired) heart disease (Ko, 2015). Many of these syndromes are characterized by classic dysmorphic features that should be assessed in every patient. From a cardiac perspective, the most notable of these syndromes are: Down syndrome, Turner syndrome, Noonan syndrome, Marfan syndrome, Ehlers–Danlos syndrome, Holt–Oram syndrome, 22q11.2 deletion syndromes, CHARGE syndrome, and VACTERL association.

Stigmata of Systemic Disease Many systemic diseases (or their treatments) can be associated with congenital or acquired heart disease. In the absence of a known diagnosis, small visual clues can be of great importance. - Osler nodes (painful, red, raised lesions on hands or feet), Janeway lesions (small nontender, erythematous macules on palms or soles), or splinter hemorrhages (tiny linear blood clots of the nailbeds) can be signs of infective endocarditis (Baddour et al., 2015).

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- A malar rash, a flat red or purplish eruption of the cheeks and nasal bridge, can be a sign of Systemic Lupus Erythematosus, which, in turn, can be associated with pericarditis, myocarditis, conduction defects, valvular disease, and coronary artery disease (Chen et al., 2016). Malar rash may also suggest dermatomyositis. Dermatomyositis has cardiac involvement with frequent subclinical manifestations including conduction abnormalities and arrhythmia and uncommon clinically overt manifestations of congestive heart failure, arrhythmia/conduction abnormalities, and coronary artery disease, possibly due to small vessel involvement (Lundberg, 2006; Schwartz et al., 2016). - Skin induration and tightening of the face or the fingers (sclerodactyly) is a classic finding in scleroderma, which, in its systemic form, may lead to myocardial disease, conduction system abnormalities, arrhythmias, or pericardial disease (Lambova, 2014). - The presence of lupus pernio (bluish-red or violaceous nodules and plaques over the nose, cheeks, and ears) or erythema nodosum (reddish, tender lumps most commonly located in the front of the legs below the knees) may be a sign of sarcoidosis which can involve the myocardium and has been associated with sudden cardiac death (Birnie et al., 2016). - Characteristic joint deformities can point to Rheumatoid Arthritis (RA). RA significantly increases the risk of atherosclerosis, myocardial infarction, and stroke. Recent data suggest disease modulating therapies also prevent CVD (Prasad et al., 2015). - The presence of an enlarged thyroid (goiter) should prompt evaluation for thyroid disorders. Thyroid disorders are commonly associated with heart rate changes and/or dyslipidemia. - Acanthosis nigricans (dark, velvety discoloration in body folds and creases) can point at underlying dysglycemia, whereas xanthomata (yellow to orange papules, commonly over joints and tendons) or xanthelasma (when present over the eye lids) can be associated with dyslipidemia. - Muscle weakness or atrophy as well as calf pseudohypertrophy are classic findings in patients with muscular dystrophy. Many forms of muscular dystrophy are associated with cardiomyopathy, which requires lifelong cardiac care (Palladino et al., 2016). - Jaundice, as a nonspecific sign of liver disease, can be important to notice since it may point at congestive hepatopathy or cirrhosis in the setting of heart failure. It may also be a complication of alcoholism which, in turn, can lead to cardiomyopathy. Less commonly, jaundice in an adult can lead to a late diagnosis of Alagille syndrome which is often associated with different types and degrees of pulmonary stenosis (Saleh et al., 2016). - Lastly, a rare but important clue can be the presence of a cochlear implant, since congenital deafness is part of Jervell and Lange–Nielson syndrome, a subtype of long QT syndrome, associated with ventricular tachycardia and sudden cardiac death (Lu and Kass, 2010).

Cyanosis Visible cyanosis of the skin is a key hallmark of many forms of congenital heart disease. Central, peripheral, and differential cyanosis are discussed above, under “Oxygen saturation.”

Clubbing Nail clubbing of the fingers and/or toes is a nonspecific finding in many chronic diseases. Among those, chronic lung disease and cyanotic heart disease are most prominent, along with gastrointestinal conditions and various malignancies. From a cardiac perspective, any heart disease associated with chronic hypoxemia can lead to the development of progressive clubbing over time. The ubiquity of clubbing is due to its nature as a nonspecific vascular proliferative response to low-oxygen tension. It is important to note both presence and distribution of nail clubbing. Occasionally, clubbing may occur in the lower limbs only, sparing the upper limbs. This is known as differential clubbing and may occur in patients with a PDA associated with pulmonary hypertension and right to left shunting across the PDA. In this setting, there is also differential hypoxia/cyanosis, as outlined above.

Jugular Venous Distention: Jugular venous distention is assessed with the patient sitting at a 45 degree angle with the head turned slightly sideways. The height of the oscillating top of the internal jugular venous pulse above the sternal angle is noted. Right atrial pressure is then approximated by adding 5 cm to the height of the venous pulse, since it is assumed that the right atrium is located about 5 cm below the sternal angle. When the venous pressure is high, the venous pulsations are best seen when the trunk is elevated to 90 degree. Elevated venous pressure can be a sign of superior vena cava obstruction (prior surgery, malignancy, etc.) or elevated right atrial pressure, such as with right ventricular dysfunction, pulmonary hypertension, or tricuspid regurgitation. In any case, an elevated venous pressure estimate based on jugular venous distention should prompt further evaluation.

Auscultation Cardiac auscultation should occur in an environment with minimal noise using the stethoscope on the patient’s bare chest. The order of conducting an auscultation exam is probably less important than a complete and thorough evaluation. The following order may serve as a suggestion:

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Rate The heart rate can be assessed and counted manually by auscultation to complement the heart rate measured during vital sign assessment with careful attention to any changes between the two time points. For a differential diagnosis of tachycardia and bradycardia, please refer to the section on “Heart rate” above.

Rhythm - Normal sinus rhythm should be regular with mild, physiologic variation throughout the respiratory cycle (slight rate increase during inspiration, followed by a decrease during expiration). - A rhythm that is regular but tachycardic and without obvious variability should raise the suspicion for an arrhythmia, such as atrial flutter, supraventricular tachycardia, or an unusually stable ventricular tachycardia. - If the rhythm is irregular, it can be helpful to determine whether the rhythm is regularly irregular or irregularly irregular. A regularly irregular rhythm follows a particular pattern, such as a dropped beat every few beats. This could be due to second degree heart block with Wenckebach (Mobitz 1) in which the PR interval progressively lengthens, until a beat is no longer conducted. An irregularly irregular rhythm appears erratic without a particular pattern. This can be due to pronounced sinus arrhythmia, atrial fibrillation, or premature atrial or ventricular contractions

Heart Sounds S1: The first heart sound is caused by closure of the atrioventricular (tricuspid and mitral) valves. It can be soft/muffled in the setting of pericardial effusion. Rarely, S1 can be split. An abnormally wide split can be found in the setting of right bundle branch block or Ebstein’s anomaly of the tricuspid valve. A wide split should be distinguished from an ejection click and S4 gallop described below. In patients following mechanical atrioventricular valve replacement, S1 often has a “metallic” quality. S2: The second heart sound is caused by closure of the semilunar (pulmonary and aortic) valves and consists of a pulmonary component (P2) and an aortic component (A2). It can be soft/muffled in the setting of pericardial effusion. It is often loud (i.e., louder than S1) in the setting of pulmonary hypertension. In a normal heart, A2 and P2 occur simultaneously during expiration, but split slightly (A2 occurring earlier than P2) during inspiration, secondary to increased right heart filling and flow across the pulmonary valve during inspiration. This behavior is considered physiologic splitting. Abnormally wide or fixed splitting of S2 is seen in the setting of right ventricular volume overload (ASD, partial anomalous pulmonary venous return), right bundle branch block, or severe pulmonary stenosis. Furthermore, the second heart sound can be single if there is only one semilunar valve (e.g., aortic atresia or pulmonary atresia), both semilunar valves are connected to the same vessel (following a Damus–Kaye–Stansel procedure), P2 is early (pulmonary hypertension), or A2 is delayed (severe aortic stenosis). In patients following mechanical aortic or pulmonary valve replacement, S2 often has a “metallic” quality. S3: A third heart sound is a low-frequency sound in early diastole (following S2), caused by rapid filling of the ventricles. It can be normal in children and young adults. In the setting of tachycardia, however, it constitutes an abnormal S3 gallop and could be a sign of congestive heart failure. A variant of S3 is the so-called pericardial knock. This is a somewhat higher pitch early diastolic sound that occurs distinctly earlier than the usual S3, due to rapid ventricular filling being abruptly halted by a restricting pericardium, such as with restrictive pericarditis. S4: A fourth heart sound is a low-frequency sound in late diastole (preceding S1). It is thought to be caused by turbulent blood flow during atrial contraction into a ventricle with reduced compliance. S4 is always pathologic and commonly associated with heart failure, often in the form of a tachycardic S4 gallop.

Murmurs A murmur is an audible sound caused by nonlaminar blood flow. As outlined in the following, nonlaminar flow need not always indicate pathology, and most murmurs are benign.

Timing Systolic Midsystolic (ejection type): This type of murmur begins shortly after S1 and ends before S2 with a crescendo–decrescendo contour. To define this pattern, S1 and S2 should be clearly audible and unobscured by the murmur. It is usually associated with turbulent flow across semilunar valves (aortic or pulmonary) due to mismatch between the size and shape of the orifice and the flow traversing the orifice. For example, a structural defect in the semilunar valve such as in aortic or pulmonary stenosis may cause this murmur by being an inaudible obstruction to flow until the ventricle generates enough pressure to overcome the obstruction. Once that pressure is achieved, the valve structure itself causes turbulent, nonlaminar flow audible as the murmur. Similarly, an atrial septal defect inducing markedly increased flow across a normal pulmonary valve may lead to nonlaminar flow patterns again causing this murmur. The location of the midsystolic murmur (see below) can help distinguish aortic from pulmonary stenosis. A midsystolic (ejection type) murmur also occurs as an innocent flow murmur (Still’s murmur) described below.

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Holosystolic (regurgitant): This type of murmur begins with S1 and continues through S2. There is no delay between S1 and the murmur, which is an important feature distinguishing it from a midsystolic murmur. The intensity of the murmur is usually constant throughout systole (band-like). Holosystolic murmurs are cause by mitral regurgitation, tricuspid regurgitation or VSDs, circumstances in which the pressure difference between the two chambers involved is different from very beginning to the end of systole. When the murmur is new onset and associated with clinical compromise an acute life-threatening process may be occurring such as either mitral papillary muscle rupture or necrotic VSD following myocardial infarction. Early systolic (regurgitant): This type of murmur begins with S1, decreases quickly in intensity (decrescendo), and ends well before S2. It is caused by the same conditions that cause holosystolic murmurs, however, with more rapid equalization of pressures and, hence, earlier cessation of flow. Late systolic: A late systolic murmur begins in late systole and lasts up to S2. It is most commonly caused by mitral regurgitation due to mitral valve prolapse. In that case it is preceded by a midsystolic click.

Diastolic Early diastolic: This murmur type begins with or even obscures S2 and quickly decreases in intensity (decrescendo). It is associated with semilunar valve (aortic or pulmonary) regurgitation. Although the location of the murmur is similar in both cases (left sternal border), the murmur of aortic regurgitation tends to be higher pitch due to the higher pressure difference between upstream and backflow chambers. Mid- or late-diastolic: These low-frequency murmurs begin well after S2 (mid diastolic) or just before S1 (late diastolic). They are caused by turbulent flow across the tricuspid or mitral valve. This can happen due to the mismatch between atrioventricular valve structure and flow. Structural mitral stenosis or less commonly tricuspid stenosis may cause such a murmur. Alternatively, increased flow across a normal valve such as a large VSD or PDA leading to excess flow across the mitral valve or a large ASD or partial anomalous pulmonary venous return leading to excessive flow across the tricuspid valve.

Continuous Hallmark of a continuous murmur is that it begins in systole and lasts without interruption into diastole. It need not last throughout the entire cardiac cycle since all that is required is a connection between two chambers that have a pressure difference and possible flow in systole and diastole. A continuous murmur can be caused by a PDA, aortopulmonary collaterals, coronary artery fistula, or arteriovenous fistula. Of note, in patients with a PDA and pulmonary hypertension, the diastolic component of the murmur may be abolished due to equalized pulmonary and systemic pressure during diastole. Continuous murmurs are distinct from combined midsystolic and early diastolic murmurs (“to-and-fro” murmurs) which occur with mixed semilunar valve disease (stenosis plus regurgitation).

Intensity Grade I: Barely audible. Audible to roughly half of examiners. Grade II: Soft, but easily audible Grade III: Moderately loud, but not accompanied by a thrill Grade IV: Loud and associated with a thrill Grade V: Audible with the stethoscope barely on the chest. Thrill present Grade VI: Audible with the stethoscope off the chest. Thrill present

Location See Fig. 1.

Fig. 1 Murmur locations. Aortic (right upper sternal border); pulmonary (left upper sternal border); tricuspid (left lower sternal border); mitral (apex). Modified from Parks (2014).

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Radiation The pattern of radiation can be useful in determining the etiology of a murmur. Murmurs of aortic origin are more likely to radiate to the right upper sternal border and neck along the course of the downstream chamber, the carotid arteries. Murmurs of pulmonary origin are more likely to radiate into the back and the axillae along the course of the proximal pulmonary arteries. A mitral regurgitation murmur is best heard over the LLSB with radiation into the lower back. A murmur prominently heard in the interscapular area may signal narrowing at classic site for coarctation of the aorta. A continuous murmur in the intraclavicular region with radiation to both left and right chest could indicate a PDA or other aortopulmonary collateral.

Innocent murmurs Still’s murmur: This is the most common innocent murmur. It is a midsystolic ejection type murmur, no more than III/VI in intensity (never with a thrill), and best heard along the left sternal border. The hallmark of this murmur is its vibratory “twangy” quality that is also often described as musical. The murmur is more prominent in the supine position. Outflow tract murmurs: These murmurs are caused by exaggeration of normal ejection vibrations along the right or left ventricular outflow tract. They are midsystolic ejection type murmurs, no more than III/VI in intensity, and best heard along the left upper sternal border (RVOT) or right upper sternal border (LVOT). Since they occur in the setting of normal anatomy, there are no associated clicks or thrills. Venous hum: This murmur is caused by turbulence in the jugular venous system. It is a soft, continuous murmur, best heard over the right or left infraclavicular area. It is only heard in the upright position and usually disappears in the supine position. It may be confused with a PDA murmur. However, the diastolic component of a venous hum is louder than the systolic component. The reverse is true for the PDA murmur. In addition, the PDA murmur does not disappear in the supine position. A venous hum can be obliterated in the upright position by turning the neck so as to occlude the jugular vein, or direct application of light pressure, taking care to avoid the carotid bulb.

Clicks Ejection click: An ejection click is a high-pitch sound that follows S1 closely. It is caused by sudden systolic doming of an abnormal semilunar valve. An aortic click (often in the setting of a bicuspid aortic valve) is best heard at the left lower sternal border. It does not vary with inspiration. A pulmonary click (often in the setting of a dysplastic or bicuspid pulmonary valve) is best heard over the left upper sternal border and becomes softer with inspiration. Midsystolic click: This sound occurs later is systole in the setting of mitral valve prolapse. If mitral regurgitation is present, it may be accompanied by a late systolic murmur (see above). Opening snap: This early diastolic sound is caused by the opening of a stenotic atrioventricular valve. It is best heard over the LLSB (tricuspid stenosis) or apex (mitral stenosis).

Other Adventitial Sounds Rubs: Pericardial friction rubs usually occur in the setting of pericarditis. They are caused by friction between the inflamed pericardial surfaces. It is a rocking to-and-fro sound that resembles walking in fresh snow. It is more pronounced with the patient leaning forward. Of note, once a large pericardial effusion develops, the rub may become softer or disappear. This should not be misinterpreted as a resolution of pericarditis. Bruits: A bruit is a continuous murmur caused by turbulent arterial flow. This can occur either in the setting of arterial obstruction or due to increased flow through an unobstructed artery. Carotid and femoral artery bruits should raise concern for peripheral artery disease and warrant further evaluation (Writing Committee M et al., 2017). In patients who have undergone a prior cardiac catheterization with femoral arterial access, a femoral bruit may be a sign of an iatrogenic AV fistula. Renal artery stenosis can cause a bruit over the renal arteries. This is best auscultated above the level of the umbilicus along the lateral edge of either rectus muscle. This is particularly important in the evaluation of a hypertensive patient. Bruits heard over the liver can be a sign of an underlying liver malignancy, alcoholic hepatitis/cirrhosis, or of an arteriovenous malformation. Cerebral bruits (auscultated best over the cranium, through a fontanelle, or over the orbit/eyeball) can occur in the setting of high cardiac output or decreased blood viscosity, such as with severe anemia. In the absence of those conditions, cerebral bruits may be a sign of intracranial hemangiomas or arteriovenous malformations. Less commonly, they can be appreciated in the setting of Paget’s disease due to increased blood flow through the abnormal bone structure.

Palpation Palpation, that is, manual investigation, of the cardiovascular system is an ancient practice which is falling out of favor in modern clinical practice. Since personal manual sensation of physical phenomena may not be uniform or easily standardizable among examiners, palpation is in danger of becoming a relic of bygone times. Focusing on aspects still relevant to modern practice,

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palpation is classifiable by frequency, duration, timing, and location. Some sources state that while fingertips are the prime tools for palpable investigation, fingertips are ill-suited for long duration events, especially at low frequencies (Hurst et al., 2011). Palms may be better suited to longer duration events. First palpation of pulses, typically with the examiners fingertips, is a requisite for every physical examination. While much information can be gleaned from pulse qualities since ancient times, in modern practice pulse exam is limited to presence versus absence and timing delay (O’Rourke et al., 2001). Pulses where arteries course over bony prominences like the wrist, dorsum of the foot, medial malleolus of the ankle, neck location of the carotid, and the temporal artery. The absence of pulses must first be investigated as being caused by low cardiac output such as shock. More stable situations where pulses are absent would include very rare Takayasu’s arteritis or much more common congenital absence of the dorsalis pedis pulse of the foot (Chavatzas, 1974). The abnormal presence of a brisk or bounding pulse at the palms of a premature infant can be a clue for the presence of an important patent ductus arteriosus, even when the baby might be intubated and covered in monitoring equipment precluding proper auscultative apprehension of a continuous murmur. The timing of pulses can be important such as when a perceptible delay exists between two sites. For example a delay between femoral pulse in the groin versus carotid pulse in the neck may signal collateral vessels supplying the femorals due to coarctation of the aorta. The quality of the palpation may also signal important concerns. For example, “diffusion” of a pulse from a sharp, smooth, brisk phenomenon to a longer sensation described as “worms crawling below the fingertips” signals the presence of a thrill. A thrill suggests the presence of nonlaminar flow, such as a thrill at the carotid site suggesting the occurrence of significant aortic valve stenosis. Second palpation of the chest and trunk can be informative. Many of the features of palpation in these locations can be enhanced by using the palm rather than the fingertips. The point of maximum impulse is the point usually on the fifth intercostal space at the midclavicular line. This point may show visible pulsation of the heart in small or young people and may have a palpable impulse in larger older persons. However the point of maximal impulse may not always be properly assigned to that location. One example would be the rare circumstance where the cardiac mass is not located in the left chest in so-called dextrocardia when in the right chest or mesocardia when the cardiac mass is more midline. Another example would be changes in LV dimensions such as dilated cardiomyopathy that can lead to the point of maximal impulse to be displaced leftwards. As yet another example, right ventricular pressure overload or right ventricular volume overload can cause a right ventricular heave or palpable pulsation through the chest wall just to the left of the sternum at the fourth or fifth intercostal space, termed an RV heave. Referenced to carotid pulse for timing, sensitive examiners may be able to distinguish an early-in-systole heave consistent with volume overload versus more prominent later-in-systole heave which is more consistent with pressure overload. The difference in timing may be due to the time needed for the ventricle to generate the pressure needed to overcome the pressure overload and initiate outflow. Another key aspect of precordial palpation is the presence of thrill accompanying a murmur defining a more “severe” murmur of at least four out of six on the Levine scale (Freeman and Levine, 1933). Severe chest pain accompanied by a palpable thrill or pulsation in the sternoclavicular area can suggest a prominence of the aortic contour rising to the cranial border of the sternum, possibly due to aneurysm or pseudoaneurysm with impending rupture. Finally, a timing delay between the apical impulse on the chest and the carotid pulse can be a useful signal of important aortic stenosis, especially when echocardiography-based gradient measures can be problematic (Schlingmann et al., 2015).

Conclusion Physical Examination is still the entry-point for diagnosis and treatment for clinical patients of all ages. Proper attention should be paid to vital signs and general appearance to glean enormous amounts of actionable information. Discovery and confirmation through auscultation and palpation still offer uniquely valuable data points on diagnosis, treatment, and prognosis even in this age of high-resource-intensity solutions to old problems. Retrenchment into time-tested physical exam diagnostic skills would serve modern medicine very well. A lack of focus on the physical exam would be a loss of practical value and an irreparable disruption in the tradition of medical care.

Acknowledgment Financial Support: NHLBI Career Development Award K23 HL111335 (JPZ)

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Physiological Adaptations of the Heart in Elite Athletes A D’Andrea, J Radmilovich, L Riegler, R Scarafile, B Liccardo, T Formisano, A Carbone, R America, and F Martone, Luigi Vanvitelli University, Naples, Italy M Scherillo, Rummo Hospital, Benevento, Italy M Galderisi, Federico II University of Naples, Napoli, Italy R Calabrò, Second University of Naples, Caserta, Italy © 2018 Elsevier Inc. All rights reserved.

Introduction Physiological Adaptation ECG Echocardiographic Analysis of Physiological Adaptations Left Ventricle Left Atrium Right Ventricle Athlete’s Heart and Exercise Exercise ECG Exercise Stress Echocardiography Cardiopulmonary Exercise Testing Conclusions References

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Introduction Competitive athletes and highly active individuals are a growing segment of the global population. This growth is driven by increasing recognition of the health benefits of routine physical exercise and greater access to competitive sporting opportunities and recreational exercise programs. The American College of Cardiology and European Society of Cardiology (ESC) (Mitten et al., 2015) identify a qualitative definition for a competitive athlete, as a person who participates in regular competition, in which emphasis is placed on excellence and achievement, with a usual intense systematic training and a tendency to physical limits during exertion. From a quantitative point of view, an athlete may be considered “elite” if competing regularly at the regional, national, or international level and exercising for
6 h/week (Sheikh et al., 2014). Long-term physical training in elite athletes is characterized by physiological adaptation of cardiovascular structures, with functional, structural, and electrical remodeling, defined as athlete’s heart. The identification of these changes is essential to distinguish athlete’s heart from other pathological conditions. Moreover some of the exercise-induced changes may be associated with acute and chronic cardiac damage, and in a small number of athletes this may predispose to atrial and ventricular arrhythmias (D’Andrea et al., 2015). Cardiac remodeling may be evaluated not only at rest but also during exercise with electrocardiography (ECG), standard echocardiography, advanced ultrasound techniques, and other noninvasive cardiac imaging modalities. The aim of this chapter is to provide a comprehensive assessment of physiological adaption of the heart in elite athletes.

Physiological Adaptation Morganroth identified two main models of training adaptation characterized by two distinct patterns of cardiac remodeling (myocardial hypertrophy) (Morganroth et al. 1975). Endurance training is typical of aerobic sports with dynamic–isotonic muscular involvement, such as long-distance swimming and running. These activities cause a gradual decrease in systemic arterial resistance and an increase in venous return, with a predominant volume overload, resulting in higher left ventricular (LV) enddiastolic volume (EDV) and stroke volume (eccentric hypertrophy). In contrast, strength training is typical of anaerobic sports with predominant static–isometric muscular exercise, such as bodybuilding, short-distance running, and swimming. These sport categories cause mainly an increase in myocardial wall thickness rather than cavity diameters (concentric remodeling and hypertrophy), in response to the predominant pressure overload. Morganroth’s original hypothesis has been criticized because cardiac remodeling is also influenced by other factors like ethnicity, age, sex, genetics, and body size. Moreover it has to be noted that most sports are actually characterized by a variable combination of both endurance and strength exercise, rather than only one of them (Fig. 1). Heart rate reduction and stroke volume increases, associated with systemic vascular resistance reduction are typical hemodynamic changes in athlete’s heart: it results in a slight elevation of cardiac output (¼SV  HR) during exercise. The long-run hemodynamic changes during exercise cause an increase in both left ventricular (LV) internal size (LV dilation) and LV hypertrophy

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Fig. 1 Models of cardiac remodeling in elite athletes.

(LVH), a response that normalizes LV wall stress. LV dilation and LVH may be pronounced enough to mimic a pathological state. However LV systolic and diastolic function are normal or even supranormal in athlete’s heart (Galderisi et al., 2015). Moreover ejection fraction (EF) calculated as (¼100  SV/LV end-diastolic volume) is normal or can be even marginally reduced at rest in athletes: EF increases markedly during effort when larger LV end-diastolic volume allows to best utilize the Frank–Starling mechanism (the higher preload, the more rapid diastolic filling, and the smaller LV end-systolic volume) and increase SV compared with nonathletes (Abergel et al., 2004). Concerning the molecular adaptations of the heart, exercise-induced cardiac remodeling is associated with cardiac myocyte hypertrophy and proliferation, sarcomeric and mitochondrial adaptations, electrical remodeling and increased endogenous cardiac stem cell, induced by signaling pathways activated by growth factors, hormones (thyroid and growth), and mechanical stretch. In contrast the adverse effects of endurance training are more similar to the disease-induced pathological remodeling, with beta1adrenoreceptor desensitization and prolonged tumor necrosis factor alpha-nuclear factor kappa B-p38 signaling (Bernardo and McMullen, 2016).

ECG The 12-lead ECG in elite athletes has typical characteristics, and it is influenced by the physiologic, electrical, structural, and functional adaptations related to intensive physical activity. Some ECG findings of athlete’s heart may overlap with those described in pathological conditions, thus creating a grey area in ECG interpretation and the need of further investigation (Corrado et al., 2010). Competitive athletes have increased vagal tone responsible of bradyarrhythmias, such as sinus bradycardia greater than 30 beats/ min (bpm), first-degree and second-degree Mobitz type 1 atrioventricular block, sinus arrhythmias, wandering atrial pacemaker, and ectopic atrial rhythm. Increased vagal tone influences ethnic-specific repolarization changes: white athletes typically show concave ST segment elevation, while Afro-Carribean/black athletes have convex ST segment elevation, often associated with biphasic or deep T-wave inversion in V1–V4 (Yeo and Sharma, 2016). Manifestation of increased cardiac chamber size and wall thickness includes incomplete right bundle branch block and isolated Sokolow–Lyon voltage criteria (combined amplitude of S wave in V1 þ largest R wave in V5 or V6 >3.5 mV, or R wave in aVL >1.1 mV), often regarded as physiologic adaptation in athlete’s heart (Yeo and Sharma, 2016). Standard ECG identifies right atrial abnormalities (RAA) as P-wave amplitude >2.5 mm in DII, DIII, or aVF leads and left atrial abnormalities (LAA) as prolonged P-wave duration greater than 120 ms in leads DI or DII with negative portion of the P-wave greater than or equal to 1 mm in depth and greater than or equal to 40 ms in duration in lead V1. Concerning the prevalence of atrial abnormalities in athletes it may be more common in younger athletes, but there is a low prevalence in adult athletes: Pelliccia et al. (2000) identified the prevalence of LAA to be 4% and RAA to be 0.8% in 1005 trained athletes. As a consequence, in adult athletes, atrial abnormalities should be regarded as abnormal and lead to deeper investigations (Fig. 2).

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Fig. 2 Common training-related features in an athlete’s ECG: isolated QRS voltage criteria for LVH, associated with early repolarization.

ESC 2010 recommendations for interpretation of 12-lead electrocardiogram in the athlete incorporated physiologic adaptations commonly found in athletes, by classifying ECG abnormalities into common and training-related findings versus uncommon and training-unrelated changes, useful to identify those pathological conditions as HCM and arrhythmogenic right ventricle cardiomyopathy (ARVC), with higher risk of sudden cardiac death in competitive athletes (Corrado et al., 2010). In 2013 the Seattle Criteria (Table 1) provided quantitative cut-off, not specified in previous ESC document: these criteria were structured to distinguish normal versus abnormal findings in athletes. The Seattle Criteria include revised contemporary limits for QTc intervals and T-wave inversion and are therefore superior to the ESC criteria in specificity, with further reduction of falsepositive findings (Drezner et al., 2013). The main determinants of ECG patterns in athlete’s heart include age, gender, ethnicity, type, and intensity of sport (Table 2) (Yeo and Sharma, 2016).

Echocardiographic Analysis of Physiological Adaptations Echocardiographic analysis is essential in revealing athlete’s heart characteristics and in differentiating physiological and pathological LV remodeling.

Left Ventricle Previous studies on elite athletes reported that 55% had increased LV end-diastolic diameter, and only 15% of them had values >60 mm, with preserved EF; moreover LVH involved all myocardial segments, with a maximal wall thickness 15 mm mainly in basal septum is typical of patients with Hypertrophic cardiomyopathy (HCM), with a grey zone between 13 and 15 mm. After a deconditioning period of at least three months a reduction in wall thickness can be observed in athletes, but not in HCM (D’Andrea et al., 2015). In elite athletes, LV diastolic function is often supranormal (E/A >2 with a low A velocity), in particular in endurance sports, due to a LV remodeling associated with normal or increased myocardial relaxation, as an expression of increased elastic recoil, different from HCM patients, in whom diastolic dysfunction is typically present (E/A < 1) (George et al., 2011). Pulsed tissue Doppler (TDI)-derived early diastolic myocardial velocity (e0 ) of basal septal and basal lateral wall is increased in athletes, without regional dysfunction (e0 /a0 < 1) and with low E/e0 ratio; after ultra long-duration exercise, as marathons, a reduction of e0 velocity of both septal and lateral annulus is common (Cardim et al., 2003). Finally pulsed TDI gives additional information regarding myocardial systolic performance at rest, showing normal or supranormal values in athlete’s heart, with normal EF, normal or supranormal stroke volume, and systolic peak velocity (s0 ) > 9 cm/s (Zoncu et al., 2002) (Fig. 3).

Physiological Adaptations of the Heart in Elite Athletes Table 1

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Modified 2013 Seattle criteria (Drezner et al., 2013)

Normal variants in athletes: do not require further diagnostic evaluation Sinus bradycardia
30 bpm Sinus pauses 200 ms Mobitz Type 1–II AV block Incomplete RBBB Isolated QRS voltage criteria for LVH Except: QRS voltage criteria for LVH occurring with any nonvoltage criteria for LVH (left atrial enlargement, left axis deviation, pathological Q waves, ST segment depression, T-wave inversion) Early repolarization J-point elevation, ST elevation, J-waves, or terminal QRS slurring Convex ST segment elevation associated with T-wave inversion in leads V1–V4 in black/African athletes Abnormal variants in athletes: require further diagnostic evaluation Left atrial enlargement Prolonged P-wave duration of >120 ms in leads I or II (negative portion of the P wave
1 mm in depth and
40 ms in duration in lead V1) Atrial tachyarrhythmias Supraventricular tachycardia, atrial-fibrillation, atrial-flutter Extreme sinus bradycardia 1 mm in depth in two or more leads V2–V6, II and aVF, or I and aVL (excludes III, aVR, and V1) Right ventricular hypertrophy pattern R  V1 þ S  V5 > 10.5 mm AND right axis deviation >120 Ventricular preexcitation PR interval 120 ms) Long QT interval QTc
470 ms (male) QTc
480 ms (female) Short QT interval QTc  320 ms Brugada-like ECG pattern High take-off and downsloping ST segment elevation followed by a negative T wave in
2 leads in V1–V3 ST segment depression
0.5 mm in depth in two or more leads Pathologic Q waves >3 mm in depth or >40 ms in duration in two or more leads (except for III and aVR) Premature ventricular contractions
2 PVCs per 10 s tracing Ventricular arrhythmias Couplets, triplets, and nonsustained ventricular tachycardia AV, atrioventricular; bpm, beats per minute; LVH, left ventricular hypertrophy; ms, milliseconds; RBBB, right bundle branch block; LBBB, left bundle branch block.

Table 2

Determinants of ECG patterns

Determinants of ECG patterns Age Gender Ethnicity Type and intensity of sport

Characteristics Adolescent athletes have more frequent juvenile ECG pattern with T-wave inversion in V1–V3 (Migliore et al., 2012) Abnormal ECG patterns are four times more frequent in male athletes compared with their female counterparts (Pelliccia et al., 1996) Black athletes have more frequent repolarization abnormalities including T-wave inversion, voltage criteria for left and right ventricular hypertrophy, and left and right atrial enlargement (Papadakis et al., 2011) Endurance athletes have more common right ventricle hypertrophy and T-wave inversion in V1–V3 Elite athletes show abnormal ECG changes more frequently than amateurs (Pelliccia et al., 1991)

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Fig. 3 Standard echocardiography and tissue Doppler in an endurace athlete. Apical 4-chamber view (A) and parasternal short axis view (B) showing eccentric left ventricular (LV) hypertrophy and right ventricular (RV) enlargement. Transmitral flow pattern (C) and Tissue Doppler (D) evidencing “supernormal” early diastolic function. LA: left atrium; RA: right atrium.

Concerning the application of strain variation in competitive athletes at different loading conditions, there is LV adaptation at rest and a load dependency of strain measurements; athletes have normal longitudinal deformation despite left ventricular hypertrophy and higher values for transverse, radial, and circumferential strains when compared with HCM (Richand et al., 2007). A speckle-tracking echocardiography (STE) analysis shows a different pattern of myocardial deformation between endurance and strength athletes’ heart: while global radial strain (GRS) is similar, GLS is lower in runners and global circumferential strain (GCS) is lower in bodybuilders (Szauder et al., 2015). Finally, STE shows reduction of longitudinal, circumferential, and radial strains and also reduction and delay of peak twisting in triathletes soon after ultra long-duration exercises (Douglas et al., 1990) (Fig. 4). Using three-dimensional (3D) echocardiography Caselli et al. showed LV end-diastolic volumes and mass increases in athletes compared to untrained controls, with preserved LV systolic function; male gender and endurance disciplines had the highest impacts on LV end-diastolic volume and mass (Caselli et al., 2011). Athlete’s heart is characterized by harmonic LV remodeling, differently from patients with hypertrophic or dilated cardiomyopathy. De Castro et al. measured LV remodeling index (LVRI) to describe the pattern of LV remodeling in athletes: athletes’ LVRI was similar to that of controls, suggesting that the LV remodeling associated with intensive athletic conditioning does not alter LV geometry (De Castro et al., 2006).

Left Atrium In a large population of elite athletes, mild left atrial enlargement is relatively common and may be identified as a physiologic adaptation to exercise conditioning. Pelliccia et al. (2005) stated that enlarged left atrial dimension greater than or equal to 40 mm was relatively common in athletes (20%), with the upper limit of 45 mm in women and 50 mm in men, distinguishing physiologic cardiac remodeling from pathologic cardiac conditions. Moreover a mild enlargement of left atrial volume index (LAVi) is relatively common in athlete’s heart: D’Andrea et al. (2010) analyzed 615 consecutive elite athletes 370 endurance versus 245 strengthtrained and identified a mild enlarged LAVi (29–33 mL/mq) in 150 athletes (24.3%) and a moderate enlarged LAVi (greater or equal to 34 mL/mq) only in 20 (3.2%), all male athletes. Lavi was significantly greater in endurance athletes. Left atrial myocardial deformation assessed by strain is normal in competitive athletes compared to sedentary controls and hypertensive patients, and it is closely associated with functional capacity. Especially in middle-aged male athletes with a history of intensive long-term endurance training, left atrial remodeling is associated with a higher risk of atrial fibrillation (D’Andrea et al., 2016).

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Fig. 4 Automated function imaging (AFI) of left ventricular 2-D strain of endurance athlete, showing normal longitudinal regional myocardial deformation despite left ventricular hypertrophy (arrows) (Douglas et al., 1990).

Right Ventricle Endurance exercise is associated with cardiac remodeling of the right ventricle (RV), while strength training has minimal impact on RV function. Structural and functional recovery of RV changes in elite athletes might be incomplete after a detraining period (D’Andrea et al., 2009). The right heart (RH) clearly participates in the process of enlargement of the athlete’s heart, with an increase in internal diameters and thickness of its free walls. D’Andrea et al. (2003) documented that RH measures were all significantly greater in highly trained endurance athletes, compared to age and sex-matched, strength-trained athletes. Resting RV global systolic function, measured by fractional area change (FAC) and Tricuspid Annular Plane Systolic Excursion (TAPSE), may be lower in endurance athletes compared with nonathletic controls. The reduction is more pronounced in the presence of higher RV dilation (D’Andrea et al., 2013). D’Andrea et al. (2012) identified comparable 2D and 3D RV systolic indexes between endurance athletes and controls. In this setting, a mild reduction in global RV function could be considered a physiological consequence of RV dilation, since an efficient stroke volume will be reached with higher end-diastolic volumes and therefore at lower ejection fraction. On the other hand, a severe reduction in RV global systolic function should be considered an abnormal finding even among athletes (Fig. 5). In athlete’s heart RV characteristics can resemble those found in ARVC: in ARVC the enlargement of the RV cavity involves both RV inflow and outflow and may be associated with RV wall segmental morphological and functional abnormalities; in athletes RV enlargement involves only the inflow tract and systolic function is typically normal (Sen-Chowdhry et al., 2004). The RV is more susceptible than the LV to prolonged exercises, with dysfunction after long-term endurance training (Neilan et al., 2006). D’Andrea et al. (2010) observed RV dilatation following an ultraendurance triathlon without changes of LV dimension, by using M-mode, 2D echo, and STE (reduction of longitudinal strain about 15% relative to baseline values). High altitude training induces increased hypoxic pulmonary vasoconstriction and raised hematocrits due to polycythaemia: both changes contribute to raised pulmonary arterial pressure and RV hypertrophy. These RV adaptations are usually reversible in high-altitude sports athletes. Concerning the pulmonary vascular hemodynamic, whose upper limit of normal was 40 mmHg, endurance-trained athletes show the highest values, compared with strength-trained athletes (D’Andrea et al., 2011). Finally the inferior vena cava appears to be dilated in a study involving 58 endurance athletes (Goldhammer et al., 1999).

Athlete’s Heart and Exercise Exercise ECG Dynamic exercise is associated with increased sympathetic drive and a reduction of vagal tone. Rhythm disturbances such as sinus bradycardia, sinus arrest, and wandering pacemaker, as well as the atrioventricular conduction defects, all disappear with exercise.

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Fig. 5 Right ventricular 2-D strain of endurance athlete, showing normal myocardial longitudinal deformation (arrow) (D’Andrea et al., 2012).

Repolarization abnormalities also normalize with exercise. These observations lead to the conclusion that the described alterations are functional characteristics of athlete’s heart and not structural abnormalities (Fagard, 2003).

Exercise Stress Echocardiography Exercise stress echocardiography (SE) is a feasible, low cost, widely available, and safe technique and is better accepted than pharmacological stress echocardiography by athletes. It gives information about cardiac function, reserve, exercise capacity, and arrhythmias. SE exercise in athletes may have three different clinically relevant targets besides assessment of ischemia: intraventricular gradients (detected by Continuous Wave (CW) Doppler examination of the Left Ventricular Outflow Tract (LVOT)), pulmonary hemodynamic (Systolic Pulmonary Arterial Pressure (SPAP), LV filling pressure), and evolution of mitral regurgitation (by color Doppler echocardiography), lung sonography for detection of pulmonary congestion (as B-lines). An exercise SE test in athletes can give valuable information about cardiac function, reserve, exercise capacity, and arrhythmias (Lancellotti et al., 2016). Exercise stress echo is of particular interest in endurance-trained athletes with EF 5%) during exercise; a considerable EF increase suggests low EF at rest to be related to low preload, and not to LV systolic dysfunction (Galderisi et al., 2015). SE performed in athletes with LV hypertrophy complaining of shortness of breath or tendency to syncope; a suggestive finding could be an LVOT gradient >50 mmHg during or immediately after exercise in the presence of symptoms. The development of a gradient during exercise in symptomatic athletes is, however, a frequent finding and might help link the reported symptoms (postexercise dizziness or syncope) to a potential cause (the development of an intraventricular gradient) (Cotrim et al., 2010). Finally stress lung ultrasound (B-lines detection during or immediately postexercise) is useful in two separate settings, HF and extreme physiology. In healthy elite apnoea, high-altitude trekkers, scuba divers, and extreme athletes involved in sports such as triathlon or marathon, B-lines can be detected in the absence of symptoms of pulmonary oedema (Fagenholz et al., 2007).

Cardiopulmonary Exercise Testing Cardiopulmonary exercise testing (CET) is a clinically useful technique to assess cardiorespiratory function and exercise capacity in elite athletes. Previous studies indicated that peak oxygen consumption (pVO2) values in elite athletes usually range between 55 and 70 mL/ kg/min and exceed predicted maximum values by as much as 50%; these athletes also have a high anaerobic threshold (AT) and oxygen pulse (O2P) (Sharma et al., 2000). Anastasakis et al. (2005) compared CET metabolic parameters of 9 strength athletes, 20 endurance athletes, and 27 patients with nonobstructive HCM: endurance athletes had higher pVO2, percentage of predicted Vo2, anaerobic threshold, percentage of

Physiological Adaptations of the Heart in Elite Athletes Table 3

123

Cardiopulmonary exercise testing parameters in elite athletes

pVO2 mL/kg/min pVO2 (% VO2 max) AT l/min AT (% VO2 max) O2P mL/beat DVO2/DWR mL/min/W VE/VCo2 slope

Sharma et al. (2000)

Anastasakis et al. (2005)

66.2  4.1 156.4  6.8 – 61.6  1.8 27.1  3.2 – –

58  4.5 136.40  11.51 2.5  0.4 74.55  10.99 25.3  2.6 9.2  0.8 22.3  1.8

AT, anaerobic threshold; AT%, percentage of predicted anaerobic threshold; O2P, oxygen pulse at peak exercise; pVo2, peak oxygen consumption; pVo2%, percentage of predicted peak oxygen consumption; VE, minute ventilation; VCo2, carbon dioxide production; Vo2, oxygen consumption; WR, work rate.

predicted anaerobic threshold, and oxygen pulse than strength athletes and patients with HCM (p < 0.05). None of the CET parameters differed significantly between strength athletes and patients with HCM. The minute ventilation/carbon dioxide production (VE/VCo2) slope was decreased (p < 0.001) in the endurance athletes, but similar in patients with HCM and strength athletes. The DVo2/Dwork rate (WR) slope was not significantly different between the three groups (Table 3). Sharma et al. (2000) demonstrated a separation in pVO2, AT and O2P between elite athletes with physiological LVH and patients with HCM and mild LVH: a pVO2 >50 mL/kg/min or >20% above the predicted VO2 max, an AT >55% of the predicted VO2 max, and an O2P >20 mL/beat would discriminate physiologic LVH from HCM. The pVO2 is determined by peak cardiac output and the systemic arterio-venous oxygen difference (A-V): athletes obtain high pVO2 values through large increases in cardiac output and greater widening of the A-V during exercise. The augmentation of stroke volume (SV) is mainly responsible for the increase in cardiac output, while the increase in the A-V is due to the enhanced oxidative capacity within the exercising muscle, resulting from a high cellular mitochondrial concentration (Holloszy, 1967). Analysis of the oxygen pulse profile (product of SV and A-V) provides evidence for the mechanisms responsible for the higher pVO2 in athletes: the O2P is higher throughout exercise in elite athletes with LVH compared with athletes with HCM, indicating a superior SV and A-V from the beginning to the end of exercise and confirming the physiological differences between the two entities outlined above. Scharhag et al. analyzed right and left ventricular mass and function in male endurance athletes, demonstrating the correlation of left ventricular mass (LVM) and right ventricular mass (RVM) to maximal oxygen uptake (Vo2max) (Scharhag et al., 2002).

Conclusions Elite athletes have a physiological remodeling of cardiovascular structures, with structural, functional, and electrical characteristics, caused by intensive and competitive training. Two main models of sport adaptation of athlete’s heart are eccentric hypertrophy, typical of endurance training, and concentric hypertrophy, usual of strength training. Many instruments, as ECG and echocardiography, are useful to study characteristics of elite athlete’s heart and to distinguish the physiological training adaptations of cardiac structures from pathological conditions. Future improvement in differentiating normal and abnormal cardiac features in athletes is essential to recognize at early-stage cardiac disorders and reduce sudden cardiac death risk.

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Practical Guide to Evidence-Based Management of Heart Failure in the Outpatient Setting AM Maw, RL Page II, and RS Boxer, University of Colorado, Aurora CO, United States © 2018 Elsevier Inc. All rights reserved.

Introduction Patient Assessment Essentials of the Clinic Visit Monitoring Clinical Indices Symptoms Signs Investigations Pharmacological Treatment of Heart Failure Drugs With Demonstrated Mortality Benefit in HFrEF Angiotensin-converting enzyme inhibitors, Angiotensin Receptor Blockers and Beta-Blockers Aldosterone receptor antagonists, Hydralazine/Isosorbide and Angiotensin Receptor-Neprilysin Inhibitors Other Recommended Agents Ivabridine Digoxin Pharmacological Treatment of HFpEF Management of Important Co-morbidities in Heart Failure Blood pressure management Anemia Sleep Disordered Breathing Implantable Cardiac Devices Implantable Cardiac Defibrillators Cardiac Resynchronization Therapy Implantable Sensors Nonpharmacologic, Nondevice Interventions Multidisciplinary programs Patient and caregiver education in self-care behaviors Behavior change Diet Exercise When to Refer to a HF and Advanced HF Program or Cardiologist When to Refer Patients to Palliative and Hospice Care Conclusion Appendix 1 Appendix 2 References

125 126 126 126 127 127 127 127 130 130 130 130 131 131 131 131 131 131 133 133 133 133 133 134 134 134 134 134 135 136 136 137 137 139 141

Introduction Heart failure remains a highly prevalent and morbid disease. Because of its large public health impact, it has been the focus of avid research for the last several decades. Management has evolved significantly in that time with high-quality evidence demonstrating mortality and quality of life benefits of many pharmacologic and nonpharmacologic interventions (Yancy et al., 2013). In spite of these advances, the three most important patient outcomes in heart failure, namely mortality, hospitalization, and quality of life remain poor. Upon diagnosis, the 5-year life expectancy is 50% (Bui et al., 2011). Heart failure continues to be among the leading causes of hospitalization for patients 65 and older (Hall et al., 2012). There are still many gaps in evidence requiring providers to make clinical decisions based on expert opinion and common sense. However, it is also known that providers are significantly under-prescribing guideline-directed therapies to patients (Mosalpuria et al., 2014). Given the high prevalence of disease, medical complexity, high hospitalization, and mortality rates of patients with heart failure, in addition to the limited time and resources of providers, outpatient management is challenging. It has been observed that patients cared for by internists are less likely to be on guideline-directed medical therapy (GDMT) than patients cared for by cardiologists (Mosalpuria et al., 2014). This may reflect less familiarity with recommended drugs and concerns about adverse effects. It also suggests that wider dissemination of easily accessible clinical practice guidelines with specific suggestions for safely implementing medication use may improve prescribing habits.

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With these considerations in mind, the aim of this review is twofold: (1) help providers improve adherence to guideline-directed care by providing detailed information and practical strategies for implementation and (2) offer practical guidance concerning common management decisions that reflects expert opinion when high-quality evidence is lacking.

Patient Assessment Heart failure is a clinical syndrome, defined by signs and symptoms that can be caused by dysfunction of virtually any aspect of the heart. However, the majority of heart failure cases are caused by impairment of the left ventricle’s ability to fill or eject blood (Yancy et al., 2013). The underlying etiology of heart failure must be identified at diagnosis so that the disease process can be treated and progression can be slowed. Because heart failure with reduced ejection fraction (HFrEF) and heart failure with preserved ejection fraction (HFpEF) are importantly different with regard to demographics, prognosis, and response to therapy, evaluation of ejection fraction is an important branch point in diagnosis and treatment (Yancy et al., 2013). Table 1 offers the diagnostic cutoffs for HFrEF and HFpEF offered by the AHA/ACC guidelines. NYHA functional class is another important categorization for standardized clinical assessment of patients with heart failure. It is a simple tool that allows clinicians to communicate the patient’s current condition based on the severity of symptoms. Although it relies on subjective information that is based on the patient’s report and physician’s interpretation of symptoms, it has been shown to correlate with objective measures including the 6 min walk test (Yap et al., 2015). More importantly, it is known from the randomized control trial (RCT) data investigating ACE-inhibitors that NYHA class is a powerful predictor of mortality in HFrEF (Swedberg and Kjekshus, 1988; Cohn et al., 1987) and there is retrospective evidence that it is predictive of mortality in the HFpEF population as well (Ahmed et al., 2006). The RCTs that underlie the clinical practice guideline recommendations regarding heart failure treatment generally base their inclusion criteria on these definitions. Therefore, selecting the appropriate therapy in patients with heart failure requires evaluation of both a patient’s ejection fraction and NYHA class upon diagnosis (Tables 1 and 2).

Essentials of the Clinic Visit Monitoring Clinical Indices Patient behaviors and understanding of prognosis, medications, and self-care behaviors should be evaluated at every visit. This serves to identify gaps in patient knowledge as well as help patients troubleshoot areas of difficulty with adherence. Given the prevalence of comorbidities among patients with heart failure, medication review is particularly important not only to ensure appropriate use of heart failure medications, but also address polypharmacy and screen for important medication interactions and contraindications. For example, it is not uncommon for a patient with heart failure to assume taking non-steroidal antiinflammatory drugs (NSAIDs) for arthritis is safe because it can be purchased without a prescription. Table 1 Ejection fraction (%)

Definitions of HFrEF and HFpEF Classification

Description Formally referred to as systolic HF

41–49

Heart failure with reduced ejection fraction (HFrEF) Heart failure with preserved ejection fraction (HFpEF) HFpEF, borderline

>40

HFpEF, improved


40 50

Formally referred to as diastolic heart failure Likely have elements of mild systolic dysfunction and diastolic dysfunction. More research needed to define prognosis and treatment in this group Include the subset of patients that had once had HFrEF with improvement in EF. Further study is necessary to delineate prognosis and effective treatment in this group

Adapted from AHA/ACC 2013 Guidelines.

Table 2 I II III IV

NYHA Functional Classification

No limitations of physical activity Slight limitation of physical activity. Comfortable at rest but symptomatic with activities of daily living Marked limitation of physical activity. Comfortable at rest but symptomatic with less exertion than required for activities of daily living Symptoms at rest

Adapted from AHA/ACC 2013 Guidelines.

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Symptoms Symptoms of decompensation (e.g., decreased exercise tolerance, orthopnea, worsening dyspnea, increased abdominal girth) and medication side effects and toxicity (e.g., dizziness with standing) should be evaluated at every clinic visit. Patient education regarding symptoms can be performed during this assessment. Patients should be taught to recognize their individual signs of decompensation. Not all patients will develop lower extremity edema or an increase in weight Symptom recognition must be patient-centered.

Signs Signs of decompensation, dehydration, and medication side effect should be evaluated at every visit. This includes checking heat rate and rhythm, blood pressure both supine and standing, JVP, pulmonary and cardiac auscultation, abdomen, lower extremities and weight.

Investigations Laboratory values including creatinine, potassium, magnesium, and sodium should be checked every 3–6 months once the patient is on a stable regime. A complete blood count to check for anemia can be performed routinely once annually. Chest radiograph, cardiac enzymes, and echocardiogram should be performed upon clinical change. The use of basic natriuretic peptide in the monitoring of chronic heart failure is controversial. It is not currently recommended by the AHA/ACC, however RCTs evaluating its utility in chronic heart failure patients are ongoing (Okwuosa et al., 2016) (Table 3).

Pharmacological Treatment of Heart Failure In patients with HFrEF, there are multiple guideline-directed pharmacologic therapies that have a demonstrated mortality benefit. All of these drugs work by addressing the neurohormonal derangements seen in HFrEF. In spite of their demonstrated benefits, it is known that only a fraction of eligible heart failure patients are prescribed these life-prolonging medications (Mosalpuria et al., 2014). Guidelines are much less specific regarding pharmacologic management of HFpEF which represents 50% of patients with heart failure. Although patients with HFpEF have slightly better prognosis than those with HFrEF, (Owan et al., 2006) it is known that their hospitalization rate and quality of life are equally poor (Hoekstra et al., 2011). Therefore, efforts to encourage better adherence to treatment recommendations by providers and patients alike should be undertaken for all patients with heart failure. With this in mind, we offer a review of the medications currently recommended by the AHA/ACC and ESC offering specifics regarding indications, contraindications, and strategies for monitoring in order to address potential concerns about appropriate use by providers who may have limited experience using these medications. Currently, there are five classes of medications that have demonstrated survival benefit through large high-quality RCTs in the HFrEF population and have therefore been given a Class I recommendation by the ESC and AHA/ACC: angiotensin-converting enzyme inhibitors (ACE-inhibitors), angiotensin receptor blockers (ARBs), aldosterone receptor antagonists (ARAs), beta-blockers (BBs), and angiotensin receptor-neprilysin inhibitors (ARNIs). Table 4 provides a list of these medications in addition to specific indications, contraindications, common adverse effects, target doses, and strategies for safe titration and monitoring (Yancy et al., 2013; Paul and Page, 2016; McMurray et al., 2014; McIlvennan and Page, 2016; Swedberg et al., 2010). Table 3

Checklist of outpatient clinic assessment

Symptoms

Frequency

Dyspnea, orthopnea, paroxysmal nocturnal dyspnea, decreased exercise tolerance, chest pain, lower extremity swelling, increasing abdominal girth Physical exam HR, BP, weight, JVP, cardiac auscultation, abdomen, lower extremities Investigations CBC Electrolytes/creatinine Echocardiogram

Every visit

Cardiac enzymes Chest X-ray EKG Medication review Patient education Symptom recognition Medication reconciliation/education Exercise Diet Advanced directive 

Aspects adapted from Nicholis et al., 2007.

Every visit Annually 2–3 months Clinical suspicion, worsening symptoms Clinical suspicion Clinical suspicion Clinical suspicion Every visit Every visit Every visit Every visit Every visit Progression of disease

Table 4

Drugs that decrease morbidity and mortality in HFrEF

Angiotensin receptor blocker

Aldosterone receptor

Close

Lisinopril Initial dose 2.5–5 mg daily Target dose 20–40 mg daily Enalapril Initial dose 2.5 bid Target dose 10–20 mg bid Losartan Initial dose: 25–50 mg daily Target dose 50–150 mg daily Valsartan Initial dose 20–40 mg bid Target dose 160 mg bid Candesartan Initial dose 4–8 mg daily Target dose 32 mg daily antagonists

monitoring of potassium and serum creatinine should be checked in 3 days of initiation and at 1 week and at least monthly for the first 3 months; the risk of

a

Contraindications

Recommended in all patients with HFrEF and current or prior HF symptoms to reduce morbidity and mortality

Angioedema’ Cr > 2.5 mg/dL, pregnancy, bilateral renal artery stenosis, hyperkalemia (K > 5.0 meq/L)

Recommended in patients with HFrEF who are ACE-inhibitor intolerant (e.g., cough, angioedema)

Spironolactone Initial dose 12.5–25 mg daily Target dose 25 mg daily or bid Eplerenone Initial dose: 25 mg daily Target dose 50 mg daily

Class Ia ACC/AHA recommendation

Common adverse effects

How to titrate

Monitoring

Cough, Hyperkalemia, neutropenia, renal dysfunction, angioedema, hypotension. Dysgeusia

Increase at intervals no less than 2 weeks to the target dose based on blood pressure and renal function

Serum, renal function, CBC, blood pressure

Angioedema Cr > 2.5 mg/dl, pregnancy, bilateral renal artery stenosis, hyperkalemia (K > 5.0 meq/L),

Hyperkalemia, neutropenia, renal dysfunction, hypotension

Same as ACE-inhibitors

Same as ACE-inhibitors

Recommended in patients with NYHA class II–IV and who have a LVEF 40 mmHg or asymptomatic patients with an RVSP > 50 mmHg should generally undergo further investigation into the etiology of their PH. All therapy for PH is based on the etiology as outlined in the PH classification system. It is therefore important to identify the cause(s) of PH in order to determine the appropriate therapy. The initial diagnostic work up for common etiologies of PH (i.e., groups 2 and 3) includes pulmonary function tests, assessments of oxygenation, EKG, and echocardiogram. Chest computed tomography and polysomnography may also be needed as contingent tests. To exclude group 4 PH (CTEPH), patients should undergo ventilation–perfusion scanning, which has superior diagnostic characteristics to CT pulmonary angiography. A normal or low-probability scan effectively excludes CTEPH. Formal pulmonary angiography by an experienced center is generally needed to confirm the diagnosis (Hoeper et al., 2006; Coulden, 2006). Group 1 PH patients should have further testing performed to exclude collagen vascular disease (ANA and RF) and liver disease (liver function tests and right-upper-quadrant Doppler ultrasound) and thyroid function studies (Hoeper et al., 2013b). Right heart catheterization (RHC) is essential in all patients with suspected PAH after completion of the noninvasive evaluation. The RHC is the gold standard used for hemodynamic evaluation to confirm the presence of PAH, determine initial prognosis and initial management. There are several essential components to a complete RHC evaluation; this includes oxygen saturations to exclude a left-to-right shunt, cardiac output by the Fick method, right atrial pressure, right ventricular pressure, pulmonary artery pressure (PAP; systolic, diastolic, and mean), PCWP to estimate left atrial pressure, cardiac output and index (traditionally performed by thermodilution method), PVR, systemic blood pressure, and heart rate. If the PCWP is uncertain or elevated, a direct measurement of LVEDP via left heart catheterization is often necessary to definitively exclude left heart disease. The hemodynamic definition of PAH is a mean PAP greater than 25 mmHg, a PCWP or LVEDP less than 15 mmHg, with a PVR greater than 3 Wood units in the absence of significant (i.e., hypoxemic) chronic lung disease or CTEPH (McLaughlin et al., 2009; Hoeper et al., 2013b; Authors/Task Force et al., 2015). Acute vasodilator/vasoreactivity testing (AVT) should be performed on all IPAH patients. IPAH patients who demonstrate a significant acute vasodilator response have a better prognosis and are more likely to benefit from oral calcium-channel blockers (CCB) (Sitbon et al., 2005; Morales-Blanhir et al., 2004). Once the diagnosis and classification of PAH have been established, exercise testing by 6 min walking distance testing (6MWD) or cardiopulmonary exercise testing should be performed to establish a baseline functional status (Deboeck et al., 2005, 2012; Wensel, 2002; Hansen et al., 2004; ATS/Committee, 2002).

Table 3

Diagnostic evaluation of pulmonary hypertension

PAH subgroup

1 (PAH)

2 (Left heart disease)

3 (Lung disease, hypoxemia)

4 (CTEPH)

5 (Unclear/multifactorial)

Core testing

•

ANA, RF, LFTs, TFTs, HIV RHC 6MWD testing or CPET

• •

• •

PFTs Oximetry • Overnight • Ambulatory Chest radiograph

•

• •

CBC (Complete Blood Count) CMP (Complete Metabolic Panel)

Acute vasodilator test (for IPAH) RUQ Doppler ultrasound (for POPH)

•

Polysomnogram (for SBD (Sleep Breathing Disorders)) High-resolution CT (for ILD (Interstitial Lung Disease)) High altitude simulation test (for flight)

•

•

Other testing as warranted by clinical picture (see Table 1)

• • Additional testing

• •

EKG Echocardiogram

•

•

RHC with exercise or volume challenge LHC (for left heart failure)

• • •

•

V/ Q(VentilationPerfusion Scan) Pulmonary angiogram CTPA (CT Pulmonary Angiogram)

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Clinical Management of PAH General Measures in the Management of the PAH Patient General medical care of the PAH patient includes vaccination (influenza and pneumococcal), psychosocial support, and avoidance of pregnancy (Table 4). Supervised exercise training (while avoiding overly strenuous physical activity) is strongly endorsed due to several small but concordant studies demonstrating that PAH patients undergoing supervised cardiopulmonary rehabilitation achieved enhanced physical activity, improved 6MWD testing and patient-reported quality of life, and decreased fatigue when compared with untrained controls (Weinstein et al., 2013; Chan et al., 2013). The optimal timing, methods, intensity, and duration for rehabilitation have yet to be determined. Supplemental long-term domiciliary oxygen should be provided to maintain the partial pressure of blood oxygen above 60 mmHg or oxyhemoglobin saturation above 90% during all conditions encountered (rest, exercise, sleep, and flight/altitude). General medication measures include the use of diuretics to reduce fluid retention (edema or ascites) when necessary. Loop diuretics are generally preferred, and aldosterone antagonists should be added when appropriate. Patients should be monitored for electrolyte derangements, and careful attention should be given to avoiding hypovolemia that can quickly negatively impact renal function. Warfarin anticoagulation should be considered for patients with PAH due to IPAH, heritable PAH, and PAH due to anorexigens. Patients with PAH on long-term IV prostaglandin therapy are generally anticoagulated (absent contraindications) to reduce risk of catheter-associated thrombosis. The targeted international normalized ratio range varies from 1.5–2.5 to 2.0–3.0 depending upon local experience and preferences. Anticoagulation of other group 1 patients is not generally considered beneficial but may be considered for certain individuals where the benefit is thought to outweigh the risks of bleeding. Digoxin may be considered for select PAH patients, however, as with most of the ancillary medications. There are limited data to support this recommendation (Galie et al., 2009).

Acute Vasodilator (Vasoreactivity) Testing and Therapy Acute vasoreactivity testing (AVT) is mandatory in patients with IPAH to identify patients who are likely to have an excellent longterm outcome to treatment with CCB. AVT should not be performed if the patient is hemodynamically unstable. In cases of associated PAH, AVT is generally not performed due to a very low rate of reactivity found. Inhaled nitric oxide is the preferred agent for acute vasoreactivity testing due to safety, efficacy, and expediency. Epoprostenol or adenosine may also be used; however, these agents carry the risk of systemic hypotension (Galie et al., 2009). Only about 13%–15% of patients with IPAH demonstrate a positive AVT response during the hemodynamic study. This response is defined as a decrease in mPAP by greater than 10 mmHg, a final mPAP under 40 mmHg, and stable or increase in cardiac output (Rich et al., 1992; Sitbon et al., 2005). CCB should only be prescribed to those patients with a positive AVT. Satisfactory results are reported using nifedipine (120–240 mg daily), diltiazem (240–720 mg daily), and amlodipine (up to 20 mg daily). The exact CCB is chosen based upon the baseline heart rate (bradycardia supporting nifedipine or amlodipine and tachycardia supporting diltiazem). The recommended method of beginning CCB is to start with a low dose and increase gradually to the maximum tolerated dose. Patients who meet the criteria for a positive AVT and are treated with CCB therapy must be monitored regularly for safety and efficacy. About half of these patients will continue to do well with CCB in the long run (Rich et al., 1992; Sitbon et al., 2005). If a patient does not show marked hemodynamic improvement to CCB and WHO-FC I or II status within 3–4 months or alternatively loses their responsiveness over time, PAH-specific therapy should be instituted (Galie et al., 2009).

Table 4

General management of the PAH patient

Intervention

Recommendation(class)

Level of evidencea

Supervised exercise training Psychosocial support Avoid strenuous physical activity Avoid pregnancy Influenza and pneumococcal immunization Oral anticoagulants: IPAH, heritable PAH, and PAH due to anorexigens APAH Diuretics Oxygen Digoxin

Recommended/indicated Recommended/indicated Recommended/indicated Recommended/indicated Recommended/indicated

A C C C C

Should be considered May be considered Recommended/indicated Recommended/indicated May be considered

C C C C C

A, Data derived from multiple randomized clinical trials or meta-analyses; B, data derived from a single randomized clinical trial or large nonrandomized studies; C, consensus of opinion of the experts and/or small studies, retrospective studies, registries. a Level of evidence definition. Source: Galie, N., Corris, P. A., Frost, A., Girgis, R. E., Granton, J., Jing, Z. C., Klepetko, W., McGoon, M. D., McLaughlin, V. V., Preston, I. R., Rubin, L. J., Sandoval, J., Seeger, W. and Keogh, A. (2013). Updated treatment algorithm of pulmonary arterial hypertension. Journal of the American College of Cardiology 62, D60–D72.

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PAH-Specific Medication Therapy Presently, in the United States, there are 12 PAH-specific medications in four different classes—endothelin receptor antagonists (ERA), phosphodiesterase-5 inhibitors, soluble guanylate cyclase stimulators, and prostacyclin analogs or agonists. These medications have a variety of administration routes (oral, inhaled, and continuous subcutaneous or intravenous) leading to significant administration complexity. Direct comparisons among different compounds are not available, and there are no evidence-based initial treatment recommendations favoring any specific agent except for the most ill patients. The choice of initial therapy is dependent on a variety of factors including the PAH disease severity (e.g., PAH functional classification), route of administration, side effect profile, and patient preferences. The current standard of care is to use combination therapy with drugs of different classes employed to optimize patient outcomes (Pulido et al., 2013; Galie et al., 2013, 2015; McLaughlin et al., 2010; Ghofrani et al., 2013). A treatment algorithm (Table 5) recommends a risk-based management strategy to optimally tailor initial and ongoing therapy based on each individual patient’s PAH severity and goals of care (Authors/Task Force et al., 2015; Galie et al., 2013; Taichman et al., 2014). Once initiated on PAH-specific therapy, patients should be regularly monitored with defined treatment goals (McLaughlin et al., 2009, 2013). Treating providers need to be vigilant regarding inadequate clinical responses to initial therapy or clinical disease progression, both of which occur commonly (Table 6). Although oral agents are simpler to administer and more commonly used, parenteral therapies remain the preferred treatment as an initial therapy or subsequent intervention for patients with advanced PAH in the appropriate clinical setting (Galie et al., 2013; Authors/Task Force et al., 2015). Continuous IV epoprostenol is recommended as initial therapy for WHO-FC IV PAH patients because of the proved survival benefit in this population. Oral agents are considered as second-line treatments in severely ill patients. Earlier, medical intervention is associated with reduced unwanted clinical outcomes such as hospitalization and urgent initiation of advanced therapies that generally precede death (Burger et al., 2014; Farber et al., 2015a,b; Galie et al., 2015). Combination PAH-specific medication therapy should be given to patients with a high-risk profile at presentation or who have a continued inadequate clinical response (WHO-FC III or IV, low 6MWD or exercise performance, and elevated biomarkers). The multicenter, prospective, blinded, placebo-controlled AMBITION trial (a randomized, multicenter study of first-line ambrisentan and tadalafil combination therapy in subjects with pulmonary arterial hypertension) compared first-line monotherapy with tadalafil or ambrisentan to combination therapy with tadalafil and ambrisentan as initial treatment strategies for WHO-FC II and III PAH patients. This study showed initial combination therapy resulted in a significantly lower risk of clinical failure events (principally hospitalization for worsening PAH, disease progression, or unsatisfactory long-term clinical response) than either drug as initial monotherapy (Galie et al., 2015). Strategies of “up front” versus sequential combination therapy should both be considered, as the optimal approach and medication combinations are still being determined. For patients with PAH who have a persistently inadequate clinical response and fail to meet treatment goals despite maximal medical therapy, atrial septostomy and/or lung transplantation may be indicated.

Table 5

Recommended initial PAH-specific therapy based on WHO status of most subjects in the pivotal medication clinical trials

Medication recommendation

Levela

WHO FC II

WHO FC III

WHO FC IV

A

Ambrisentan Bosentan Macitentan Sildenafil Tadalafil Riociguat Treprostinil PO Selexipag

Ambrisentan Bosentan Macitentan Sildenafil Tadalafil Riociguat Treprostinil SC, inhaled, or PO Selexipag Iloprost inhaled Epoprostenol IV Iloprost IV Treprostinil IV Beraprost Initial combination therapy

Epoprostenol IV

B

Ambrisentan Bosentan Macitentan Sildenafil Tadalafil Riociguat Iloprost inhaled, IV Treprostinil SC, IV, or Inhaled Initial combination therapy

PO, oral route; SC, subcutaneous route; IV, intravenous route. a Level of recommendation defined as the following: (A) is recommended or indicated and (B) should be considered. Source: Galie, N., Corris, P. A., Frost, A., Girgis, R. E., Granton, J., Jing, Z. C., Klepetko, W., McGoon, M. D., McLaughlin, V. V., Preston, I. R., Rubin, L. J., Sandoval, J., Seeger, W. and Keogh, A. (2013). Updated treatment algorithm of pulmonary arterial hypertension. Journal of the American College of Cardiology 62, D60–D72.

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Table 6

Variables with prognostic value at follow-up and goals of PAH therapy used in clinical practice

Measure type

Variable

Therapeutic goal

Symptoms Exercise tolerance

WHO Functional Class 6MWD CPET testing Right atrial pressure Cardiac index Sv02 RA and RV size and function TAPSE Exercise RVSP BNP/NT-proBNP

WHO FC I or II >380–440 m VO2 maximum >10.4mL/kg/min RAP 2.5 L/min-m2 Sv02 >62% Normal or near normal RA and RV size and function TAPSE >1.8 cm Ability to raise RVSP >30 mmHg during supine exercise BNP 5 servings of total fruit/vegetable compared to 5 servings with 5 servings to 5 servings to 30% of marketed drugs target GPCR function either activating/inhibiting their function in pathology (Stevens et al., 2013). Structurally, GPCRs are membrane proteins characterized by seven transmembrane spanning domains interconnected by three intracellular and three extracellular loops. Despite GPCRs binding to a plethora of agonists, they structurally have a classically conserved core where agonist binds, an extracellular amino terminal (Nterminal) that plays a role in agonist binding, and an intracellular carboxyl terminal (C-terminal) region key for regulating receptor signaling (Madamanchi, 2007). GPCRs are activated following extracellular stimuli such as hormones (epinephrine/norepinephrine), light, sound, and odor that transmit the stimuli into the cell (Rockman et al., 2002). In this context, bARs are the key sensors for epinephrine and norepinephrine and mediate cellular responses through three receptor subtypes: b1, b2, or b3ARs (Xiao, 2001). b2AR is the most ubiquitously expressed receptor subtype, while b1AR is the most abundant subtype in the heart accounting for 75%–80% of bARs. b3AR is expressed almost exclusively in adipose tissues (Madamanchi, 2007; Xiao, 2001). Activation of the bARs subtypes leads to a conformational change in the receptor, allowing interaction with heterotrimeric G-proteins.

Heterotrimeric G-proteins The heterotrimeric G-proteins are composed of three subunits, a, b, and g, which are localized to the inner leaflet of the plasma membrane. Conformational changes that occur following activation of the receptor lead to interaction with G-proteins, and dissociation of the heterotrimeric G-protein into Ga and bg subunits. The dissociation of the Ga from the bg subunits exchanges GDP with GTP, leading to activation of downstream signals primarily by coupling to effectors like adenylyl cyclase, phosphodiesterases, phospholipase C, and ion channels (Wettschureck and Offermanns, 2005b). Activated effectors in turn tightly regulate the intracellular concentration of downstream secondary messengers like cAMP, diacylglycerol, sodium or calcium cations that titrate the physiological response through posttranslational signaling mechanism for acute responses, and gene transcription/translation for long-term chronic remodeling responses (Wettschureck and Offermanns, 2005a; Wettschureck et al., 2005). Hydrolysis of the GTP-bound Ga subunit to GDP results in reassociation with Gbg subunits, completing a cycle and terminating the signal initiated by the activated receptors. The length of the G-protein signal is determined by the duration of the GTP-bound Ga-subunit, which could be regulated by regulator of G-protein signaling (RGS) proteins or by covalent modifications of the G-protein subunits (Sato et al., 2006; Sjogren and Neubig, 2010). There are four subtypes of Ga-subunits Gas, Gai, Gaq, and Ga12, enabling diversity in responses (Madamanchi, 2007). Gas is stimulatory while Gai is inhibitory in the context of adenylyl cyclase activation and cAMP generation following bAR interaction with epinephrine or norepinephrine (Lefkowitz, 1998; Communal et al., 1999). Classically, the Gbg subunits of the G-proteins were thought to be the brakes on G-protein signaling as their reassociation with Ga leads to termination of signaling. However, increasing evidence shows that the Gbg subunits themselves also mediate downstream signaling, independent of Ga-subunits, that has significant physiological and pathological implications. The Gbg subunits are always complexed together and tethered to the membrane by posttranslational prenylation of the g subunit (Kisselev et al., 1995). Although the role of different isoforms of Ga subunits in regulating downstream signaling is well understood, the role of multiple isoforms of the G b and g subunits in signaling is being appreciated only recently have studies have shown that the isoform combination of Gbg subunits can provide diversity in signaling and response to extracellular stimuli (Khan et al., 2013).

bAR Downstream Signaling Engagement of bAR with agonist classically leads to G-protein activation in the cardiac system, which couples to the stimulatory Gas G-protein subunit leading to activation of adenylyl cyclase. Consequently, adenylyl cyclase mediates generation of cAMP, activating PKA that in turn through a series of subsequent steps results in increased cardiac contractility (Movsesian, 1998; Zaccolo, 2009). Simultaneously, the dissociated Gbg subunit of the heterotrimeric G-protein recruits G-protein-coupled receptor kinase 2 (GRK2) that phosphorylates bAR, allowing for b-arrestin binding, which terminates the signals from GPCRs, resulting in desensitization (Wolfe and Trejo, 2007). b-Arrestin is a cytosolic scaffolding protein. However, recent studies have shown that while b-arrestin terminates signals from activated GPCRs, it also simultaneously initiates b-arrestin-dependent signaling (Dorn, 2009b; DeWire et al., 2007). These observations lead to the concept that GPCRs can initiate G-dependent signaling and G-protein independent, b-arrestin-dependent signaling (Dorn, 2009b) (Fig. 1). Increasing evidence suggests that b-blockers that traditionally block G-protein signaling may mediate unique beneficial effects via G-protein-independent mechanisms. In addition, stimulation of GPCR leads to unique signals that allow for cross-talk and subsequent activation of traditional receptor tyrosine kinases (epidermal

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Fig. 1 Illustration of beta-adrenergic receptor (bAR) downstream signaling: G-protein-dependent and G-protein-independent signaling pathways.

Fig. 2 Illustration showing mechanisms of cardiac remodeling.

growth factor receptor (EGFR), platelet-derived growth factor receptor), resulting in transactivation (Fig. 2). These signaling pathways provide multiple mechanisms by which GPCRs can regulate, titrate, and mediate responses to diverse sets of extracellular stimuli.

G-Protein-Dependent Signaling Stimulation of b1 and b2AR leads to coupling to stimulatory G-protein Gas that activates adenylyl cyclase, generating the cAMP that initiates signals mediating inotropic effects. However, persistent stimulation of b2ARs leads to switching of coupling from stimulatory Gas to inhibitory Gai resulting in inhibition of adenylyl cyclase activation, reducing cAMP and inotropic effects (Boknik et al., 2009). Interestingly, b3ARs mediate negative inotropic effects by activation of protein kinase G through cGMP pathways showing how a hormonal epinephrine or norepinephrine stimulation response can be diversified in a cell to provide an appropriate contractile response. A primary role of cAMP is to activate PKA, which mediates phosphorylation of a set of regulatory proteins in cardiomyocytes resulting in positive inotropy (increased contraction) and also concomitant increased relaxation (lusitropy) (Zaccolo, 2009; Movsesian, 1998). PKA mediates phosphorylation of proteins in the sarcoplasmic reticulum (SR) that regulate both inotropic and lusitropic effects. PKA phosphorylation of phospholamban releases its inhibitory effect on SR Ca2þ

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ATPase-2 (SERCA2a), accelerating Ca2þ uptake increasing the available pool of Ca2þ for the next contraction (Bers, 2002). Similarly, there is increased phosphorylation of the ryanodine receptor, contributing to a faster onset for contraction following bAR stimulation (Maltsev et al., 2006; Tilley and Rockman, 2006). In addition to regulation of SR proteins, PKA also plays a critical role in regulating positive inotropy by phosphorylating the L-type Ca2þ channel, increasing the influx of Ca2þ (Shaw et al., 2009). Finally, PKA also phosphorylates cardiac troponin I (cTnI), reducing Ca2 þ sensitivity to enhance cardiac relaxation (Wattanapermpool et al., 1995). These observations show how G-protein-dependent signaling is a key player underlying the process of cardiac contraction mediated via increased bAR stimulation due to elevated sympathetic drive in response to mechanical demands (Bers, 2002). Although PKA is primarily activated by Gas-G-protein due to bAR, the cardiac systems also respond to mechanical needs by activating the Gaq-G-protein via angiotensin or endothelin receptors (Rosano and Bagnato, 2009). Gaq initiates phospholipase C (PLC)-mediated hydrolysis of phosphatidylinositol 4,5-bis-phosphate (PIP2) to diacyl glycerol (DAG) and inositol trisphosphate (IP3) which acts as second messengers similar to cAMP. DAG activates protein kinase C (PKC), while IP3 regulates Ca2þ channels in the SR (Carrasco et al., 2004). PKC activation leads to phosphorylation of numerous substrates including activation of the MAPK signaling pathway that primarily drive cell growth responses resulting in cardiac hypertrophy (Kehat and Molkentin, 2010) (Dorn and Force, 2005). In addition, IP3-mediated Ca2þ release regulates calmodulin, which in turn mediates hypertrophic response through calcineurin and Ca2þ/calmodulin-dependent protein kinase II (CAMKII) (Kehat and Molkentin, 2010; Chen et al., 2011). These observations show the critical role G-protein-dependent signaling plays in dynamically regulating cardiac responses to the ever changing needs of the body.

G-Protein Independent Signaling The concept of G-protein independent signaling has evolved only recently, as small molecules have been developed that can generate unique GPCR confirmations to selectively activate specific downstream signaling pathways (Carrasco et al., 2004). This concept came from studies showing unconventional angiotensin receptor desensitization in response to modified peptide agonists (Feng et al., 2005). The findings from this study suggested that agonist binding of the receptor could lead to different confirmations with each of the confirmations potentially coupling to a diverse downstream components including activation of G-proteinindependent signaling. b-Arrestins are recruited to the receptor following phosphorylation, initiating signals that are independent of G-proteins, as its recruitment terminates G-protein signaling (Lefkowitz, 1998). The role of b-arrestin 1 and 2 in G-proteinindependent signaling is only being appreciated recently, in contrast to their classical role in desensitization and receptor internalization (Shenoy and Lefkowitz, 2011a; Kendall et al., 2011). b-Arrestin 2 forms a signalosome initiating activation of extracellular regulated kinase 1/2 that in turn mediates phosphorylation of ribosomal S6 kinase, mediating proliferation in neonatal cardiomyocytes (Cuello et al., 2011; Ahn et al., 2009). In addition, b-arrestin 1 interacts with Rho GTPase-activating protein that in turn activates Rho, mediating stress fiber formation (Barnes et al., 2005; Anthony et al., 2011). Given the role of b-arrestin as a scaffold that can mediate G-protein-independent signaling, proteomic studies have shown that b-arrestins interact with a large set of key molecules involved in signal transduction that have clear implications in manifestation of the phenotypes. For example, b-arrestins can scaffold exchange protein activated by cAMP (EPAC) and CAMKII to potentially modulate cardiac contractility (Mangmool et al., 2010). Similarly, interaction with actin, cofilin, and myosin could alter actin remodeling and stress fiber formation (Xiao et al., 2007, 2010; Christensen et al., 2010), while interaction with the myosin-binding subunit of myosin phosphatase could be an integral regulator of cardiac contractility (Kooij et al., 2010; Godin and Ferguson, 2010). These observations provide an understanding of the broader scale of b-arrestin activity in mediating cardiac contraction, cytoskeleton remodeling, and proliferation. b-Arrestin-dependent signaling pathways have attained prominence due to their persistent recruitment to GPCRs following GRK mediated phosphorylation, indicating that they play a key role in G-protein-independent signaling (Dorn, 2009b). GPCRs can be classified into Class A or Class B receptors based on their internalization and strength of interaction with b-arrestin. Class A receptors tend to have preferential binding to b-arrestin 2, which undergoes faster recycling as b-arrestin falls off the receptor complex during internalization of receptors such as b1AR, b2AR, or vasopressin receptors (Luttrell and Gesty-Palmer, 2010). In contrast, Class B receptors undergo internalization but have slower recycling rates because b-arrestin forms a more stable complex with the receptor in the endosome in the case of the angiotensin receptor 1 (AT1R) (Pierce and Lefkowitz, 2001). Interestingly, Class B GPCRs do not have a preference for b-arrrestin 1 or 2 (Zhang et al., 1999; Noor et al., 2011). The formation of the complex with the receptor allows for prolonged cytosolic endosomal signaling via ERK activation (DeWire et al., 2007), which can regulate cardiomyocyte survival and hypertrophy (Tohgo et al., 2002; Aplin et al., 2007). However, release of b-arrestin from Class A receptors including bARs allows for the b-arrestin signals to be more widespread, allowing for increased signals within the cell compared to Class B receptors. This is important given that b-blockers that bind bARs to block G-protein coupling mediate G-protein-independent signaling, which underlies some of the benefits associated with b-blocker treatment.

Transactivation In addition to the G-protein-dependent and -independent signaling mediated by GPCR ligands, GPCR can also mediate cell survival signal through transactivation of EGFR. It is important to note that b-arrestin plays a key role in the process of the cross-talk between GPCR and EGFR (Heitzler et al., 2009; Cattaneo et al., 2014; Maudsley et al., 2000; Noma et al., 2007; Tilley et al., 2009). Studies have shown that many GPCRs induce EGFR transactivation, wherein ERK1/2 is significantly activated, mediating a cardiac

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hypertrophy response (Noma et al., 2007). Importantly, it is known that b1AR-mediated EGFR transactivation is a key pathway in mediating cardiac hypertrophic response, resulting in dilated cardiomyopathy (Toker and Cantley, 1997; Esposito et al., 2011; Kim et al., 2009; Zhai et al., 2006). Although multiple studies have shown the role of b-arrestin in the transactivation pathway, there are also studies that have described the role of G-proteins in the process of transactivation (Cattaneo et al., 2014; Heitzler et al., 2009). This brings forth the idea that depending on the agonist and the GPCR, the GPCR could engage in G-protein-dependent as well as independent pathways to mediate the downstream effects. However, studies have shown that the cardio-protective effects of b-blocker are mediated by transactivation of EGFRs, which is primarily regulated through b-arrestin (Toker and Cantley, 1997; Kim et al., 2008).

Regulation of bAR Activation/Signaling It is important for GPCRs like bARs to be activated in response to hormones to initiate signals. On the other hand it is also critical to tightly control termination of signals to prevent overstimulation. This process is choreographed as the activated bARs are phosphorylated by GRKs (Lymperopoulos et al., 2012; Lefkowitz, 1998; Monto et al., 2012; Aguero et al., 2012; Zhu et al., 2012; Belmonte and Blaxall, 2011), resulting in b-arrestin binding and termination of G-protein coupling/signaling. b-Arrestin binding to the phosphorylated bAR leads to endocytosis into endosomes (Lefkowitz, 1998; Shenoy and Lefkowitz, 2011b; Shukla et al., 2011; Lymperopoulos, 2011; Patel et al., 2009; Rajagopal et al., 2010). Resensitization of bARs occurs by dephosphorylation of the receptors by protein phosphatase 2A (PP2A) in the endosomes before being recycled back to plasma membranes (Ferguson, 2001; Rockman et al., 2002; Krueger et al., 1997; Drake et al., 2006).

Desensitization Epinephrine or norepinephrine binding to bARs results in activation of G-protein and dissociation of Gas and Gbg subunits. Agonist bound receptor is then phosphorylated by PKA, protein kinase C, and GRKs to uncouple from the G-proteins, initiating classical desensitization (Walker et al., 2011). In this context, Gas through cAMP activates PKA, and Gbg through Ca2þ activates PKC, both of which phosphorylate GPCRs indiscriminately, desensitizing the receptors independent of the agonist (Lefkowitz, 1998). Such a phenomenon is termed heterologous desensitization or agonist-independent desensitization, wherein stimulated and unstimulated GPCRs are phosphorylated (Rockman et al., 2002; Penn et al., 1998). In contrast, GRK-mediated phosphorylation and desensitization is an agonist-specific response mediated by GRKs. There are seven GRKs of which GRKs 2, 3, 5, and 6 are ubiquitously expressed, while GRK 1 and 7 are rhodopsin kinases and GRK 4 is expressed primarily in the testis (Sallese et al., 1997, 2000; Virlon et al., 1998; Kearney et al., 2005; Hall et al., 2012; Sato et al., 2015; Pronin et al., 1998). GRK 2, 3, and 5 are abundantly expressed in the heart and play a critical role in regulating bAR function. GRK 2 and 3 are cytosolic proteins and are recruited to the bARs at the plasma membranes by the dissociated Gbg subunits, while GRK5 is tethered to the membrane by high-affinity association with phospholipids (Pitcher et al., 1998; Pronin et al., 1998). Thus, GRK-mediated phosphorylation of the C-terminal tail of the agonist-bound bAR results in binding of the receptor to b-arrestin (Madamanchi, 2007). In addition to mediating G-protein-independent signaling, b-arrestin acts as an adaptor protein for recruiting molecules in receptor endocytosis, leading to internalization of desensitized bARs (Lefkowitz and Shenoy, 2005). Oxidative stress and inflammation can also trigger bAR dysfunction potentially by altering desensitization by a distinct mechanism from the classical desensitization pathway. Proinflammatory cytokines such as TNFa, IL-1b, and IL-13 significantly predispose bARs toward desensitization in cardiomyocytes as well as in human airway smooth muscle cells (Prabhu, 2004; Gulick et al., 1989). Reactive oxygen species (ROS) also play an important role in mediating adrenergic function (Gupta et al., 2006; Donoso et al., 2011). In this context, several studies have provided evidence for oxidative stress-mediated modification in the components of the bAR desensitization pathway that underlies the altered receptor response (Whalen et al., 2007; Ozawa et al., 2008). For example, nitrosylation of GRK2 has been shown to attenuate bAR phosphorylation, thereby reducing desensitization and downregulation of bARs (Ozawa et al., 2008; Whalen et al., 2007). Given these observations, proinflammatory cytokines and ROS-dependent oxidative–nitrosylative switches may play an important role in shifting the regulation of kinases, thereby significantly impacting bAR desensitization.

Resensitization Resensitization is a process of restoration of receptor responsiveness in the presence or absence of a stimulus (Vasudevan et al., 2011). Resensitization of bARs takes place following desensitization by phosphorylation of bARs by GRKs and PKA in response to sympathetic overdrive (Lymperopoulos et al., 2012; Lefkowitz, 1998; Monto et al., 2012; Aguero et al., 2012; Zhu et al., 2012; Belmonte and Blaxall, 2011). Following phosphorylation, receptors are internalized into the endosomes via b-arrestin binding (Lefkowitz, 1998; Shenoy and Lefkowitz, 2011b; Shukla et al., 2011; Lymperopoulos, 2011; Patel et al., 2009; Rajagopal et al., 2010). Once in the endosomes, the phosphorylated bARs are dephosphorylated by protein phosphatase 2A (PP2A). This process is thought to be dependent on the acidification of the endosomes (Gardner et al., 2007). Once bARs are dephosphorylated by PP2A, the naïve receptors are recycled back to the plasma membrane. PP2A is a heterotrimeric holoenzyme characterized by a scaffolding A, regulatory B, and catalytic subunit C (Sontag, 2001; Cohen, 1989). Despite the regulation of the PP2A holoenzyme,

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resensitization, which is a key step in reestablishing receptor signaling potential, until now has been considered to be a passive homeostasis process. However, recent studies have shown that resensitization is not a passive process but a tightly regulated mechanism mediated by phosphoinositide 3-kinase g (PI3Kg). PI3Kg regulates a known endogenous modulator of PP2A function called inhibitor of PP2A (I2PP2A) (Oliver and Shenolikar, 1998; Li et al., 1995). PI3Kg phosphorylates I2PP2A on residues 9 and 93, resulting in enhanced binding of I2PP2A to PP2A, blocking PP2A activity (Nienaber et al., 2003; Naga Prasad et al., 2000). Thus, resensitization mechanisms are only coming to be appreciated, and further studies are required to identify novel regulatory mechanisms that modulate this key process. In addition, there is evidence that bARs can be activated for signaling within endosomes (Ferguson, 2001), outside of the typical pathway of recycling to the plasma membrane. These exciting observations indicate that more studies are needed to comprehensively understand resensitization and suggest a changing paradigm of resensitization mechanisms (Ferguson, 2001).

Receptor Endocytosis and Trafficking Phosphorylation of bARs in one of the key steps that initiates the process of receptor endocytosis. b-Arrestin binding to phosphorylated bARs not only mediates bAR desensitization and initiation of b-arrestin-dependent signaling but also plays a key role in recruiting molecules critical for endocytosis (Bhatnagar et al., 2001). b-Arrestin mediates its multiple activities by adopting altered confirmations with differential affinity to various proteins. Binding of b-arrestin to phosphorylated bAR results in a conformational change that exposes the C-terminal tail of b-arrestin to allow interaction with the endocytic machinery, including clathrin and adaptor subunit of AP2 (Anthony et al., 2011; Edeling et al., 2006). These interactions drive the bAR/b-arrestin complex toward clathrin-coated pits and subsequent endocytosis. It is important to note that clathrin-mediated endocytosis is a major mechanism by which GPCRs are endocytosed and trafficked in the cell. GPCRs may also use alternative pathways like caveolae for endocytosis of the receptor complex from the cell surface (Rapacciuolo et al., 2003). Although b-arrestin recruitment to the receptor complex is a key determinant in bAR endocytosis, other regulators alter the dynamics of this process. For example, proteins like b-arrestin and AP2 bind to phosphatidylinositol 4,5 bis-phosphate (PIP2) to be stabilized (Hinrichsen et al., 2006). However, b-arrestin and AP-2 have log fold higher affinity toward PIP3 (Gaidarov et al., 1999) generated by PI3K, and expression of a kinase-dead PI3K leads to significant impairment in bAR endocytosis (Patrucco et al., 2004). Once the receptor-enriched clathrin-coated vesicle is formed at the plasma membrane, it is pinched off by a scission GTPase dynamin, which is a critical step in the beginning of endosomal trafficking (Edeling et al., 2006; Warren et al., 1998; Santini et al., 1998; Orsini et al., 1999; Signoret et al., 1998). Endosomal trafficking is mediated by significant actin remodeling to provide the rails on which vesicle transport is facilitated either for recycling or lysosomal degradation. The fate of these vesicles was classically considered to be controlled by Rab GTPase family members (belonging to the family of Ras monomeric G-proteins), wherein enrichment of vesicles with specific members were sorted to lysosomes or recycled. For example enrichment of vesicles with Rab5 seem to lead to effective recycling (Seachrist et al., 2002; Zerial and McBride, 2001). However, in addition to Rab family members, receptor ubiquitination determines the fate of the endocytosed bAR (Shenoy et al., 2001, 2008). Ubiquitination is the addition of ubiquitin to a substrate protein. Agonist stimulation of bAR leads to rapid ubiquitination by the E3 ubiquitin ligase Nedd4 (neuronal precursor cell-expressed developmentally downregulated 4). Although Nedd4-directed ubiquitination directs the bAR toward lysosomal compartments (Shenoy et al., 2001, 2008), this process is dynamically regulated by deubiquitinases such as USP20 and USP33, which reverse bAR ubiquitination (Berthouze et al., 2009). The reversal of ubiquitination impairs lysosomal trafficking and shifting the process toward bAR resensitization and recycling. It is important to point out that even though bARs primarily engage and utilize b-arrestin-dependent mechanisms for endocytosis, there is evidence that other GPCRs like protease-activated receptor-1 or 5-hydroxy-tryptamine 2A serotonin receptor undergo endocytosis using b-arrestin-independent pathways (Bhatnagar et al., 2001).

Cardiac Remodeling The heart functions as a single unit performing cardiac contraction from the time of its inception to death and is composed of multiple cell types that are in perfect synchrony. A major cell type in the heart is represented by cardiomyocytes, which are the primary drivers of contraction and supported by nonmyocytes including fibroblasts, endothelial cells, mast cells, vascular smooth muscle cells, and extracellular matrix providing elasticity to the contracting heart. A key aspect of this elasticity is the innate ability of the heart to change its contractile capacity in response to increasing mechanical load either due to physiological needs like exercise or narrowing arteries in cardiovascular disease. In this context, the mechanical load on the heart could increase due to various stimulus including but not limited to stress, growth, increase in the pressure or volume, mutations in proteins, or loss of contractile tissue (Frey et al., 2004). Therefore, in order to generate greater force to supply the same amount of blood to the body, the heart undergoes remodeling. In the classic response, the heart undergoes cardiac hypertrophy, which is thickening of the myocardium resulting in decrease in size of chambers (atria and ventricles). Selective enlargement of cardiomyocytes is associated with transcriptional upregulation of contractile proteins and their accumulation in the myocytes. The left ventricle is a critical chamber in generation of contractile pumping force and also senses mechanical load/systemic pressure and may respond by left ventricular hypertrophy. Hypertrophy is one of the most common signs of cardiac remodeling and can occur in response to physiological as well as pathological responses (Gradman and Alfayoumi, 2006). The hypertrophic responses of the left ventricle are empirically classified into physiological and pathological hypertrophy (Fig. 2) (Gradman and Alfayoumi, 2006; Levy et al., 1988; Frey et al., 2004).

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Physiological Hypertrophy Left ventricular hypertrophy in response to growth signals and/or chronic exercise is considered physiological hypertrophy. A key classical component of such a hypertrophic response is its reversal following the removal of stress. For example, left ventricular changes in athletes are remodeled back to the basal state when the athlete retires. Physiological hypertrophy is associated with an increase in myocyte volume and formation of new sarcomeres (McMullen and Jennings, 2007). At the molecular level, strenuous exercise or regulation of organs during postnatal growth is associated with significant release of insulin-like growth factor 1 (IGF1) (Conlon and Raff, 1999; Serneri et al., 2001). IGF1 acts via its receptor IGF1R, which mediates a series of downstream signals that activate PI3Ka, which enhances antiapoptotic Akt/PKB (protein kinase B) signaling (Schiaffino and Mammucari, 2011). Akt/PKB activates of mTOR (target of rapamycin) signaling, which mediates cell growth and a hypertrophic response (Schiaffino and Mammucari, 2011). Consistent with activation of these pathways, cardiomyocytes-specific overexpression IGFR1 or PI3Ka leads to physiological hypertrophy in the absence of features of apoptosis. Thus, physiological hypertrophy is considered to be beneficial and provides efficient adaptation of cardiac function in response to increasing demands of the body to growth.

Pathological Hypertrophy Pathological hypertrophy is also characterized by left ventricular hypertrophy and occurs in response to stresses including systemic hypertension, ischemia, and mutations in contractile proteins leading to increased load on myocytes. However, it is not known whether this hypertrophy occurs due to the presence of intermittent unique signals, or a result of chronic stress signals (Frey et al., 2004). One of key outcomes of pathological hypertrophy is that despite management of the stress, ventricular hypertrophy is maintained, and with time can result in dilation and heart failure. In contrast to physiological hypertrophy, pathological hypertrophy is a part of an adaptive response termed “adaptive hypertrophic response” and continues to transition to “maladaptive hypertrophic response” leading to dilation characterized by cardiomyocytes apoptosis (Kehat and Molkentin, 2010; Dorn, 2009a). “Adaptive” and “maladaptive” hypertrophy are on a physiological continuum, and hearts may transition between the two, which are difficult to distinguish. Although there could be molecular signatures identifying these two seemingly similar phenotypes, comprehensive studies are still needed to define these signatures. However, a recurrent observation with pathological hypertrophy is the observation of fibrosis, apoptosis, and necrosis of myocytes (McMullen and Jennings, 2007). It is well known that many GPCRs are activated in response to cardiovascular stress, including both Gas and Gaq pathways (Smrcka et al., 1991; Taylor and Exton, 1991; Taylor et al., 1991). The Gaq initiates PLCB-mediated phospholipid hydrolysis of PIP2 to diacyl glycerol (DAG) and inositol trisphosphate (IP3) (Smrcka et al., 1991; Taylor et al., 1991; Taylor and Exton, 1991). DAG activates PKC-dependent pathways, leading to the activation of ERK, JNK, and p38. The IP3 generated also induces calcium increase, thereby activating calmodulin. Stress-induced PLC signaling also actively contributes to the development of left ventricular hypertrophy. However, a key question that remains is whether pathological responses observed in the heart due to chronic versus intermittent stress would a) manifest in similar phenotypes and b) activate different molecular signatures. In this context, studies by Perrino et al. suggest differential phenotypic and molecular responses (Perrino et al., 2006), supporting the idea that hearts could respond differently to these insults to remodel appropriately.

Signaling in Heart Failure Sympathetic overdrive is one of the key factors involved in increased cardiac output, but chronic sympathetic activation also simultaneously leads to phosphorylation of bARs. In addition, increase in catecholamines not only leads to bAR phosphorylation but is also associated with increased GRK2 expression. Thus the concomitant increase in the agonist and elevation in GRK2 results in enhanced b-arrestin binding and loss of G-protein coupling (Lefkowitz, 1998). Increased bAR phosphorylation is a key driving force for cardiac dysfunction and ensuing heart failure (Rockman et al., 2002; Bristow and Ginsburg, 1986). Therefore, impaired G-protein coupling (desensitization) and loss of surface bARs (downregulation) due to elevated GRK2 are key hallmarks of heart failure (Rockman et al., 2002; Hamdani and Linke, 2012; Bristow, 2000; Bristow et al., 1982, 1986; El-Armouche and Eschenhagen, 2009; Murphy et al., 2010; Bristow and Ginsburg, 1986). It is important to note that there is a substantial decrease in the levels of b1AR compared to b2AR in heart failure (Freedman and Lefkowitz, 2004). In addition to the classic sympathetic overdrive that underlies heart failure, many comorbid conditions such as hypertension, dyslipidemia, obesity, and diabetes are associated with significant proinflammatory cytokines including TNFa (Katsuki et al., 1998; Kenchaiah et al., 2002; Hippisley-Cox and Coupland, 2016b). TNFa is a known cardiac-depressant, and its overexpression in the rodent heart results in deleterious cardiac remodeling and heart failure (Kubota et al., 1997; Feldman et al., 2000). TNFa-dependent effects are thought to be mediated by altered Ca2 þ, sphingolipid mediators, arachidonic acid, and nitric oxide (Prabhu, 2004). In addition, a recent study showed that elevated TNFa results in increased GRK2 expression, which may noncanonically regulate bAR function by phosphorylating and desensitizing the receptor (Vasudevan et al., 2011). Thus, such a process could alter the canonical response of bARs to sympathetic hormones like epinephrine/norepinephrine. These observations explain the potential mechanistic pathways that underlie the risk factors for heart failure in comorbid conditions. Consistently, b-blockers are contraindicated in diabetes and obesity (Lee et al., 2011), supporting the idea that bARs may be desensitized through noncanonical mechanisms that need better understanding to develop therapeutic strategies in response to increased proinflammatory cytokines like TNFa.

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Drug Targets and Impact in Clinical Medicine Targeting of GPCRs constitutes over a third of all marketed drugs for the treatment of hypertension, heart disease, cancer, Alzheimer’s disease, and asthma. b-Blockers have been one of the most clinically proven classes of therapeutics in cardiovascular medicine and are used as a first line of therapy following myocardial infarction and in control of hypertension, arrhythmia, and angina (Rutten et al., 2010; De Caterina and Leone, 2011). b-Blockers bind to bARs and block endogenous catecholamines from binding, thereby regulating inotropic and chronotropic effects through b1ARs in the heart (Rohrer et al., 1996). However, use of b-blockers may impinge on the function of b2ARs in the lungs (Jacobsen, 2011) and in maintaining vascular tone (Pourageaud et al., 2005), causing deleterious side effects. Given the complexity of bAR signaling in different organs, more refined approaches are necessary to specifically target individual aspects of GPCR function. In this context, pharmacological dissection of signal transduction pathways activated by GPCRs becomes an important component as revealed by in-depth studies being performed using “biased agonists” (Marti-Solano et al., 2013). Consistent with the diverse functions mediated by GPCRs, use of biased agonist will become important as they could selectively activate or block a subset of downstream signals allowing for harnessing appropriate signaling repertoire for a specific response (Marti-Solano et al., 2013). Use of these biased agonists would allow for specific targeting of unique GPCR responses without generating off-target signals that could have adverse effects. Further, these biased agonists could selectively target a downstream signaling pathway to provide beneficial clinical outcomes.

Conclusion This article provides an overview of the current state of understanding of GPCR signaling using bARs as prototypical receptor in the context of desensitization, resensitization, and its significance in the heart. It is evident from many studies that homeostasis of bAR signaling is of utmost importance in cardiac function. Given that bAR activity/function relies on the delicate balance between desensitization and resensitization, i.e., the kinase and the phosphatase arms of maintaining receptor function, it becomes imperative to study the underlying signaling components and mechanisms as we move toward the use of biased agonists.

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Relevant Websites American heart association—http://www.heart.org/HEARTORG/Conditions/Conditions_UCM_001087_SubHomePage.jsp. World Health Organization—http://www.who.int/whosis/whostat/2011/en/, 2011.

Sinus Tachycardias: Inappropriate Sinus Tachycardia and Postural Tachycardia Syndrome BH Shaw and J Ng, University of Calgary, Calgary, AB, Canada SR Raj, University of Calgary, Calgary, AB, Canada; Vanderbilt University, Nashville, TN, United States © 2018 Elsevier Inc. All rights reserved.

Introduction Epidemiology Postural Tachycardia Syndrome Inappropriate Sinus Tachycardia Associated Conditions Chronic fatigue syndrome Ehlers–Danlos syndrome—hypermobility type Vasovagal syncope Psychiatric illnesses Pathophysiology Postural Tachycardia Syndrome Hypovolemia Partial autonomic neuropathy Hyperadrenergic state Autoimmune autoantibodies Norepinephrine transporter deficiency Mast cell activation disorder Gravitational deconditioning Inappropriate Sinus Tachycardia Clinical Evaluation Diagnostic Criteria Differential Diagnosis History and Physical Examination Investigations Autonomic Function Testing Head-up tilt test Valsalva maneuver Plasma norepinephrine levels Sweat testing Management Postural Tachycardia Syndrome Nonpharmacological Exercise-training program Fluids Avoid potentially deleterious medications Pharmacological Inappropriate Sinus Tachycardia Conclusions References

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Introduction Sinus tachycardia is a normal physiological phenomenon that is described as an appropriate heart rate (HR) increase exceeding 100 beats per minute (bpm) while in sinus rhythm. This normally occurs in response to stress that increases sympathetic nervous system activity. In contrast, there are multiple syndromes in which sinus tachycardia occurs in response to minimal stress and is deemed inappropriate in nature; these include postural tachycardia syndrome (POTS) and inappropriate sinus tachycardia (IST). POTS is defined by chronic symptoms of orthostatic intolerance that are worse with standing in conjunction with an increase in HR of
30 bpm within 10 min of standing (Sheldon et al., 2015). Additionally, orthostatic hypotension must be ruled out as a potential cause of symptoms. IST is defined by the presence of sinus tachycardia (
100 bpm) at rest or a mean 24 h HR
90 bpm (Sheldon et al., 2015) and results in symptomatic palpitations among other symptoms. To date, there is no known mortality from either of these conditions, but each condition can negatively impact quality of life.

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In this article, we will discuss the clinical approach to the patient with symptomatic sinus tachycardia of unknown cause, as well as the epidemiology, pathophysiology, and management of POTS and IST.

Epidemiology Postural Tachycardia Syndrome POTS is identified as a syndrome and not a disease with a single discrete pathophysiological mechanism. Its overall prevalence is approximately 0.2% (Sheldon et al., 2015), with an estimated 500,000–3,000,000 individuals affected in the United States alone (Robertson, 1999; Garland et al., 2007). The majority of patients that present with POTS are female, with a female to male ratio of approximately 5:1. The age of onset is typically between the ages of 13 years and 40 years. Moreover, it has been reported that 12.5% of patients have a family history of orthostatic intolerance (Thieben et al., 2007). Little is known about the long-term outcomes of POTS; it is perceived as a chronic condition with no known mortality, and with at least partial improvement in many, but not all, patients (Sheldon et al., 2015).

Inappropriate Sinus Tachycardia Including both symptomatic and asymptomatic patients, the prevalence of IST is estimated to be approximately 1.2% in a middle aged population (Still et al., 2005). There is also a recognized association between IST and health care workers (Krahn et al., 1995). It is not clear if this is representative of the overall IST population, or if this reflects a subgroup that is more likely to seek medical attention for these symptoms (Pellegrini and Scheinman, 2016). Similar to POTS, patients with IST are primarily young women (Brady et al., 2005), although it has also been reported in older individuals as well (Lopera et al., 2003). There is no known mortality associated with IST (Sheldon et al., 2015).

Associated Conditions Chronic fatigue syndrome Chronic fatigue syndrome (CFS) is characterized by persistent or recurrent unexplained fatigue and related symptoms for at least 6 months (Garland et al., 2015). According to the Centers for Disease Control and Prevention (CDC) criteria, CFS is defined as a casedefining fatigue associated with at least four of the following symptoms: impaired short-term memory or concentration, sore throat, tender lymphadenopathy, muscle pain, joint pain, headaches, sleep disturbance, and postexercise malaise (Okamoto et al., 2012). Similar to POTS, it is a clinical syndrome that is more commonly observed in females. There is a substantial overlap between POTS and CFS. POTS is associated with several symptoms seen in CFS patients, including fatigue, lightheadedness, neurocognitive deficits, and exercise intolerance; it has been identified in 19%–70% of patients with CFS (Hoad et al., 2008; Schondorf et al., 1999; Stewart et al., 1999). Moreover, there is a high prevalence of fatigue (48%–77%) and CFS diagnosis (17%–23%) in POTS patients (Lewis et al., 2013). When POTS patients were grouped according to whether or not they met the criteria for a CFS diagnosis, there were no differences between groups in the magnitude of orthostatic tachycardia or orthostatic hypotension, supine and upright plasma norepinephrine values, or plasma volume (Okamoto et al., 2012). However, CFS in POTS was associated with increased sympathetic tone when supine and greater increases in sympathetic activity during standing. The lack of distinguishing features between POTS patients with and without CFS indicates that they may not be distinct clinical entities. While almost all patients with POTS experience chronic fatigue, a subset of these patients will also meet criteria for CFS. This might represent a distinct subset of the larger CFS population. IST is also speculated to be associated with CFS (Brady et al., 2005). To date there is limited research examining this relationship.

Ehlers–Danlos syndrome—hypermobility type Ehlers–Danlos syndrome (EDS) is a heterogeneous disorder that presents in several forms (Castori et al., 2017), and is linked to sequence variations in genes encoding for fibrillary proteins and/or collagen processing enzymes (Wallman et al., 2014). It is characterized by fragile connective tissue, skin hyperextensibility, and joint hypermobility. The presence of EDS has been observed to be significantly higher in patients with POTS (18%) compared to autonomic patients without POTS (4%) and the general population (0.02%) (Wallman et al., 2014). In particular, patients with hypermobile EDS (hEDS) frequently experience symptoms of autonomic dysfunction that are prevalent in POTS patients (Hakim et al., 2017; Tinkle et al., 2017), such as lightheadedness, nausea, sweating, and chest tightness (Gazit et al., 2003). Blood pressure and HR responses consistent with POTS have been observed to be the most typical responses to tilt in patients with hEDS (De Wandele et al., 2014). In addition to standing, POTS-like symptoms and orthostatic intolerance can be triggered by physical exercise, heavy meals, and a warm environment. hEDS is the subtype that is most commonly associated with POTS (Mathias et al., 2011), although the exact mechanisms connecting the two syndromes are unknown.

Vasovagal syncope Vasovagal syncope (VVS) is a form of neurally mediated (or reflex) syncope that usually occurs with upright posture held for more than 30 s, or with exposure to emotional stress, pain, or medical settings (Sheldon et al., 2015). It is associated with hypotension

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and relative bradycardia. POTS is a common confounder of VVS and presyncope. About 25% of patients who fulfill the diagnostic criteria for POTS develop VVS during tilt table testing (Carew et al., 2009). Despite the overlap, these disorders can have distinct hemodynamic patterns during tilt table testing (Nwazue and Raj, 2013). Patients with VVS hold a steady BP for several minutes (often >10 min) prior to developing symptoms and experiencing a rapid drop in BP. In contrast, during head-up tilt, POTS patients experience an excessive increase in their HR often without a decrease in BP. VVS patients typically experience symptoms after prolonged sitting or standing, while POTS patients experience symptoms shortly after a body position change, which is then sustained. Moreover, POTS typically affects individuals between the ages of 13–50 years, while VVS can occur at any age, with the first syncopal episode usually in the second or third decade of life (Nwazue and Raj, 2013; Sheldon et al., 2006). Although both disorders predominantly affect females, POTS does so to a greater extent (85%–90%) compared to VVS (60%).

Psychiatric illnesses Given the presenting symptoms of POTS and IST, it is not uncommon for these patients to be initially mislabeled as having psychiatric disorders such as anxiety or depression. There is no increased prevalence of major depressive disorders or anxiety disorders in POTS patients in relation to the general population (Raj et al., 2009b). Symptoms of depression and anxiety do exist in this population group, but these are attributed to the underlying disease processes leading to increased sympathetic nervous system activity and sinus tachycardia rather than a primary psychiatric illness (Khurana, 2006; Masuki et al., 2007). Mental clouding, often described as “brain fog,” is a particularly common symptom described by POTS patients and may be attributed to deficits in selective attention and cognitive processing (Karas et al., 2000; Arnold et al., 2015). Sleep disturbances and fatigue are also common findings that likely contribute to the decreased quality of life that many of these patients experience (Bagai et al., 2011; BenrudLarson et al., 2002). For patients with IST, any proposed or theoretical relationship between IST and psychiatric illness has not been well described to date.

Pathophysiology Postural Tachycardia Syndrome The characteristic orthostatic tachycardia observed in POTS is known to be a “final common pathway” of multiple pathophysiologic processes; therefore, POTS is more appropriately referred to as a clinical syndrome reflecting several heterogeneous disorders rather than a disease (Garland et al., 2015; Jones et al., 2016). While the exact mechanisms that underlie POTS remain unknown, specific subtypes have been described. Due to the overlapping nature of these subtypes, it is often difficult to identify the clinical distinctions between them in individual patients.

Hypovolemia A deficit in total blood, plasma, and red cell volume is a fairly common finding in POTS patients, occurring in up to 70% of patients (Sheldon et al., 2015; Raj et al., 2005a). Normally, plasma renin activity and angiotensin II (Ang II) are expected to increase in response to hypovolemia in order to promote blood volume expansion. Compared to healthy subjects, POTS patients have significantly lower serum levels of aldosterone and inappropriately low levels of plasma renin activity (Raj et al., 2005a). It has also been reported that circulating Ang II levels are elevated without a parallel increase in angiotensin (1–7) (Stewart et al., 2009; Mustafa et al., 2011). One possible mechanism for the elevated Ang II in these POTS patients is decreased Ang II degradation as a result of blunted angiotensin-converting enzyme 2 (ACE2) activity. The cause of decreased ACE2 activity and the exact mechanism by which elevated plasma Ang II contributes to POTS remain unclear. There also seems to be blunted angiotensin II receptor type 1 (AT2R) activity, as POTS patients were found to have low levels of aldosterone despite the high levels of Ang II (Mustafa et al., 2011), and had a reduced vasopressor response to an Ang II infusion (Mustafa et al., 2012). These abnormalities in the renin–angiotensin–aldosterone system may contribute to hypovolemia and impaired sodium retention in POTS patients.

Partial autonomic neuropathy A subset of POTS patients is described to have small fiber neuropathy, usually in the lower limbs (Jacob et al., 2000). This causes sympathetic denervation and an inability to adequately vasoconstrict in response to orthostasis, leading to decreased venous return and stroke volume. This can result in a secondary increase in sympathetic tone and tachycardia in an effort to maintain cardiac output and blood pressure. The small fiber neuropathy in POTS patients is usually painless, and does not present with classic symptoms of a typical length-dependent neuropathy (Gibbons, 2014). It is estimated that approximately 50% of POTS patients may have distal small fiber neuropathy (Peltier et al., 2010; Thieben et al., 2007; Haensch et al., 2014).

Hyperadrenergic state POTS patients may have elevated levels of plasma norepinephrine, suggestive of a hyperadrenergic state. A hyperadrenergic state in POTS is observed in up to 50% of patients, and is characterized by a systolic BP increase of
10 mmHg while standing upright for 10 min, and norepinephrine levels
600 pg/mL while standing (Sheldon et al., 2015). Patients experience similar or greater HR increases than nonhyperadrenergic POTS, but have more symptoms of sympathetic activation, including palpitations, anxiety, tachycardia, and tremulousness (Low et al., 2009). This elevated sympathetic tone can be a primary underlying problem for POTS patients, although it is often secondary to a partial dysautonomia or hypovolemia (Raj, 2013). In addition, prior studies have

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shown that an increased phase IV overshoot of the Valsalva maneuver can be seen in this hyperadrenergic state (Gibbons et al., 2013).

Autoimmune autoantibodies A subset of POTS patients report an acute “viral-like” illness a few weeks to a few months prior to the onset of symptoms, suggesting a potential immune-mediated pathophysiology (Jones et al., 2016). A potential relationship has been identified between circulating autoantibodies and POTS. A low titer of ganglionic acetylcholine receptor (AChR) antibodies was detected in approximately 15% of POTS patients evaluated at the Mayo Clinic between 1993 and 2003 (Thieben et al., 2007), although this might be an overestimate by current standards (Vernino et al., 2016). More recently, autoantibodies (AAb) to a1-adrenergic receptors (a1AR) and b1/2adrenergic receptors (b1AR/b2AR) receptors have been reported (Li et al., 2014). Both a1AR and bAR AAb can have a direct stimulatory effect on adrenergic receptors. They can also exert an allosteric-mediated positive modulatory effect upon b1AR (pure agonist) and a negative modulatory effect on a1AR activity (partial agonist–antagonist) (Fedorowski et al., 2016). It is postulated that partially blocked a1AR could cause impaired vasoconstriction in response to norepinephrine (the natural ligand), resulting in greater initial hypotension with standing (Fig. 1) (Li et al., 2014). This may lead to an exaggerated sympathoneural response (with increased norepinephrine) to achieve adequate vasoconstriction. This may lead to the orthostatic tachycardia that is characteristic in POTS, as the price for BP preservation. Furthermore, the presence of b1AR/b2AR-activating AAb could further contribute to the marked tachycardia seen in POTS patients (Li et al., 2014). Autoantibodies targeting cardiac lipid raft-associated proteins have also been found in patients with POTS (Wang et al., 2013). Targets include proteins regulating cellular processes such as signaling, metabolism, chaperones, and transcription. The interaction between these autoantibodies and proteins may trigger alterations in signaling pathways, producing cardiovascular abnormalities associated with POTS. However, the specific involvement of such proteins in the pathogenesis of POTS remains unknown.

Norepinephrine transporter deficiency A rare form of hyperadrenergic POTS is caused by a loss of function mutation in the gene encoding for the norepinephrine transporter (NET) (Shannon et al., 2000). This mutation has only been found in one family. However, it has been observed that a broader group of POTS patients have decreased NET protein expression (from vein biopsies) compared to healthy subjects (Lambert et al., 2008). This deficiency increases synaptic norepinephrine through diminished clearance, and results in greater sympathetic nerve activation. Pharmacological inhibition of NET can also occur with many antidepressant and attention deficit medications, particular those in the serotonin-norepinephrine reuptake inhibitor (SNRI) class (Raj, 2006). Pharmacological NET inhibition can worsen tachycardia and symptom burden in POTS patients when standing (Green et al., 2013).

Mast cell activation disorder A subset of POTS patients has mast cell activation without an overt trigger. These patients present with severe episodic flushing during tachycardia, have abnormal increases in urine methylhistamine concentrations, and often have hyperadrenergic features accompanying orthostatic hypertension (Jones et al., 2016). It remains unclear whether sympathetic stimulation triggers mast cell activation in these patients, or whether primary mast cell activation induces the release of vasodilators and compensatory sympathetic stimulation occurs (Shibao et al., 2005).

Gravitational deconditioning Due to their disability, many POTS patients have restrictions on their activity, which can result in physical deconditioning (Garland et al., 2015). Even if this is not the primary cause of their POTS, it is often a contributing factor to their symptoms and functional limitation. When upright, patients exhibit typical indicators of deconditioning, including persistent tachycardia, reduced stroke volume, reduced left ventricular mass, and reduced peak oxygen uptake (Fu et al., 2010). Orthostatic tachycardia improves with a structured exercise program. In contrast, some patients continue to experience symptoms, suggesting that deconditioning may be a secondary mechanism in the development of POTS (Parsaik et al., 2012). For example, patients can become physically deconditioned due to another illness, or with prolonged bed rest, and develop POTS-like symptoms (Garland et al., 2015). Although it remains unclear whether deconditioning is a primary or secondary phenomenon to POTS, a program of aerobic exercise and resistance training can improve exercise tolerance and ameliorate various features of POTS (Mathias et al., 2011). When POTS patients participated in 3 months of progressive exercise training, maximal oxygen uptake increased by 11%, indicating an increase in physical fitness (Fu et al., 2010). Left ventricular mass, end-diastolic volume, blood and plasma volumes also increased after training. Most importantly to the patients, their quality of life improved if they completed the exercise-training program.

Inappropriate Sinus Tachycardia The mechanisms underlying IST are not well defined, but they are likely multifactorial and complex. Several associated pathophysiological changes can potentially result in the syndrome, including increased sinus node automaticity, beta-adrenergic receptor hypersensitivity, decreased parasympathetic activity, and impaired neurohumoral modulation (Sheldon et al., 2015; Chiale et al., 2006). The fundamental tension is between whether the underlying pathophysiology of IST results from abnormal autonomic regulation, abnormal sinus node function, or a combination of both (Olshansky and Sullivan, 2013; Nwazue et al., 2014).

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Fig. 1 Postulated mechanisms for a1-adrenergic receptor and b1/2-adrenergic receptor autoantibodies in the pathophysiological development of postural tachycardia syndrome. Serum autoantibodies may have a negative modulatory effect on a1AR activity and a positive modulatory effect on b1/2AR activity. The compensatory responses to these receptor blockades could contribute to hemodynamics of postural tachycardia syndrome. a1AR, a1-adrenergic receptor; b1AR/b2AR, b1/2-adrenergic receptor; POTS, postural tachycardia syndrome. Reproduced from the Journal of the American Heart Association, Autoimmune Basis for Postural Tachycardia Syndrome, 2014, H. Li et al., with permissions from Wiley Blackwell.

While both IST and POTS patients appear to have abnormal autonomic modulation, with elevated sympathetic tone and diminished parasympathetic tone, it is more marked in IST patients (Fig. 2) (Nwazue et al., 2014). This may indicate a stronger autonomic influence in the pathophysiology of IST compared to POTS. The exaggerated sympathetic tone in IST patients may reflect an increase in antibodies to b-adrenergic receptors. Moreover, there are no significant differences in intrinsic HR (the HR after pharmacological autonomic blockade with propranolol and atropine) between IST, POTS, and healthy subjects (Nwazue et al., 2014). This suggests that abnormal sinus node automaticity may not play an important pathophysiological role in either disorder.

Clinical Evaluation Sinus tachycardia is a normal response to exertion, but is also a common finding in clinical practice, and can be an important vital sign to help assess whether a patient may be acutely ill. Acute pathologies such as infection or dehydration can result in sinus

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Fig. 2 Spectrum of sympathetic and parasympathetic autonomic nervous system activity in postural tachycardia syndrome and inappropriate sinus tachycardia. Healthy subjects have an appropriate balance of high parasympathetic tone and low sympathetic tone. In contrast, both inappropriate sinus tachycardia and postural tachycardia syndrome patients appear to have abnormal autonomic modulation, with elevated sympathetic tone and diminished parasympathetic tone. This effect is more marked in inappropriate sinus tachycardia patients. IST, inappropriate sinus tachycardia; POTS, postural tachycardia syndrome. Reproduced from the Journal of the American Heart Association, Postural Tachycardia Syndrome and Inappropriate Sinus Tachycardia: Role of Autonomic Modulation and Sinus Node Automaticity, 2014, V.C Nwazue et al., with permissions from Wiley Blackwell.

Table 1

Diagnostic criteria for postural tachycardia syndrome and inappropriate sinus tachycardia

Postural tachycardia syndrome 1. Frequent, chronic (>6 months duration), symptoms that occur and worsen with standing 2. An increase in HR of
30 bpm (
40 bpm in patients 100 bpm at rest or a mean 24-h HR >90 bpm) 2. The absence of a primary cause of tachycardia 3. Distressing and disabling symptoms associated with the palpitations bpm, beats per minute. Definition adapted from Sheldon, R. S., Grubb, B. P., 2nd, Olshansky, B., Shen, W. K., Calkins, H., Brignole, M., Raj, S. R., Krahn, A. D., Morillo, C. A., Stewart, J. M., Sutton, R., Sandroni, P., Friday, K. J., Hachul, D. T., Cohen, M. I., Lau, D. H., Mayuga, K. A., Moak, J. P., Sandhu, R. K. and Kanjwal, K. (2015). 2015 heart rhythm society expert consensus statement on the diagnosis and treatment of postural tachycardia syndrome, inappropriate sinus tachycardia, and vasovagal syncope. Heart Rhythm 12, e41–e63.

tachycardia and will often be fairly obvious on history and examination. In contrast, those patients who presents in sinus tachycardia with no acute cause are more challenging to assess and properly diagnose. In order to know when to suspect a diagnosis of POTS or IST, it is important to first understand the diagnostic criteria for these conditions.

Diagnostic Criteria The diagnostic criteria for POTS and IST are displayed in Table 1 (Sheldon et al., 2015; Freeman et al., 2011; Garland et al., 2015). POTS is defined by three criteria: (i) an increase of HR of at least 30 bpm in response to a change in posture from supine to standing within 10 minutes; (ii) symptoms of orthostatic intolerance; (iii) orthostatic hypotension must be absent. Importantly, in order for a diagnosis of POTS to be reached, symptoms should be chronic (
6 months) in duration. In pediatric patients (age 600 pg/mL) (Raj, 2006; Wagoner et al., 2016; Okamoto et al., 2012). This finding can be supportive of an underlying hyperadrenergic pathophysiological state that may be contributing to symptoms (Benarroch, 2012). Plasma norepinephrine levels are not normally performed in the workup of IST.

Sweat testing Sweat testing is performed to assess sympathetic sudomotor axon function, and can be helpful for identifying patients with lower limb sympathetic denervation that can be characteristic in POTS patients with a neuropathic pathophysiological subtype (Low et al., 2013; Benarroch, 2012; Gibbons et al., 2013).

Management There is no gold-standard therapy available for the management of POTS or IST. Both conditions must be managed in a graded approach that should first involve conservative nonpharmacological therapies, followed by pharmacological management as needed. Overall, strong evidence-based recommendations for management are lacking (Lau et al., 2016). A multidisciplinary approach is recommended in the management of POTS, involving different types of health care team members including nursing, physiotherapy, psychology, and physicians support (Kizilbash et al., 2014). This approach can certainly be of benefit for patients with IST as well (Brady et al., 2005; Shen, 2005).

Postural Tachycardia Syndrome Management options for patients with POTS are displayed in Table 4.

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Fig. 4 Blood pressure and heart changes during head-up tilt testing for a patient with (A) vasovagal syncope and (B) postural tachycardia syndrome. Beat-to-beat blood pressure and heart rate responses are shown through the duration of testing. The patient with vasovagal syncope (A) exhibits a slight rise in heart rate over the upright phasing of testing (35 min). In contrast, the patient with postural tachycardia syndrome (B) has an exaggerated heart rate response within minutes of being tilted upright. Blood pressure is well maintained for both patients through the majority of testing. HR, heart rate; BP, blood pressure. Reproduced from Electrophysiological Disorders of the Heart: Expert Consult, Chapter 73, 2012, S.R. Raj & R.S. Sheldon, with permission from Elsevier.

Fig. 5 Valsalva maneuver in a healthy subject. The test is performed by having the patient exhale against a closed glottis generating 40 mmHg of pressure for 15 s. The resulting blood pressure and heart rate waveforms can be broken down into four phases. Phase I represents a transient rise in blood pressure that occurs during the forced expiration. Increased intrathoracic pressure forces blood out of the pulmonary circulation, resulting in increased stroke volume and blood pressure. Phase II is commonly divided into an early (IIE) and late (IIL) interval. As intrathoracic pressure remains high during forced expiration, venous return decreases. This results in reduced stroke volume and blood pressure and represents the IIE component. The reduced blood pressure that occurs during phase IIE triggers a baroreceptor mediated increase in sympathetic tone causing a rise in heart rate and blood pressure that represents phase IIL. Phase III occurs upon termination of forced expiration, resulting in a decrease in intrathoracic pressure. This allows for increased venous return and causes a sudden decrease in blood in the systemic circulation resulting in a further drop in blood pressure. This drop in blood pressure causes another baroreceptor mediated increase in sympathetic tone resulting in a blood pressure overshoot that represents phase IV of Valsalva maneuver.

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Management of postural tachycardia syndrome

Nonpharmacological

Comment

Education Exercise training Increase fluid intake (2–3 L/day) Increase dietary salt intake (10–12 g/day)

Critical Very important; not easy

Pharmacological Volume expansion 1–2 L bolus of normal saline IV Fludrocortisone (0.05–0.2 mg/day PO once daily) Desmopressin (0.2 mg PO) Antiarrhythmic medications Propranolol (10–20 mg PO QID) Ivabradine (5–7.5 mg PO once or twice daily) Pressor agents Midodrine (2.5–10 mg PO q4 hours three times daily) Clonidine (0.05–0.2 mg twice daily) Methyldopa (125–250 mg PO twice daily) Other agents Pyridostigmine (30–60 mg PO three times daily) Modafinil (100 mg PO twice daily)

Only for use for acute worsening of symptoms Only for occasional use Not well tolerated at higher doses Should not be taken within 4 h of bed Can be associated with rebound hypertension and tachycardia

Nonpharmacological Education is at the forefront of conservative management options for POTS. Patients and families should be reassured that although POTS is a chronic condition, there are no reported cases of mortality from POTS. Additionally, even though the long-term outcomes from POTS are somewhat unknown, in many patients symptoms do seem to improve over time (Sheldon et al., 2015; Kizilbash et al., 2014). Patients should also be educated to limit or avoid triggers or activities that make symptoms worse (Benarroch, 2012).

Exercise-training program Exercise is encouraged in patients with POTS, but should be undertaken in a gradual, graded approach given that it can also be an aggravating factor for symptoms, especially initially. Several studies have shown benefits from a short-term (3-month) exercise program in which patients first begin exercising in a recumbent or semirecumbent position (Fu et al., 2011; Fu and Levine, 2015). Cycling, swimming, and a rowing machine are activities that can be performed from these positions. These studies used an initial dose of 20–30 min of exercise (with a 5-min warm up and cool down), three times a week, at an intensity of 75% maximal target HR for their age (Fu and Levine, 2015). Additionally, these studies had patients perform strength training for 15–20 min, one to two times per week (Fu and Levine, 2015). Both cardio and strength sessions were increased as subjects became more fit, primarily in the second and third months. These studies found that exercise helped increase peak VO2 as well as showing echocardiographic findings of significant cardiac remodeling (Fu and Levine, 2015). Another study found that a 3-month exercise program significantly improved quality of life and decreased HR responses to standing (George et al., 2016). In fact, 71% of patients no longer met POTS HR criteria at the end of the program (George et al., 2016). An important issue raised from studies examining the therapeutic effects of exercise in POTS patients is nonadherence to therapy (Fu et al., 2010; George et al., 2016). In this regard, there are valuable clinical pearls clinicians should know to help patients be successful. Firstly, selecting an activity that can be performed in the recumbent position, such as rowing, swimming, or a cycling is important to minimize the effects of symptoms made worse in the upright position, especially initially (Raj, 2016). Secondly, patients must understand that it will take time (4–6 weeks) before the benefits of exercise being to take effect (Raj, 2016). In fact, it is not unusual for patients to feel more fatigued upon starting an exercise program. Finally, it is important to educate patients that three months of training is not a “cure” for POTS. Similar to any patient, regular physical activity should be encouraged as a lifelong activity. Overall, the Heart Rhythm Society consensus statement for the management of POTS gives exercise a class IIa recommendation (Sheldon et al., 2015).

Fluids Patients should be encouraged to increase both fluid (2–3 L) and dietary salt intake (10–12 g) per day if hypovolemia is suspected (Sheldon et al., 2015). POTS patients have been shown to have deficits in their circulating plasma volume (Raj et al., 2005a). It is believed that improved effective blood volume will help reduce the intensity of the reflex tachycardia associated with standing that may be contributing to symptoms.

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Avoid potentially deleterious medications Common medications that worsen symptoms should be avoided. These include nitrates or other diuretics, venodilators, and SNRI medications (Nwazue and Raj, 2013). Diuretics can decrease effective blood volume, and worsen symptoms driven by hypovolemia. Venodilators act to decrease preload and subsequently blood pressure leading to worsening reflex tachycardia. Selective NET inhibitors decrease the clearance of norepinephrine from synaptic terminals, which can lead to increased sympathetic activity resulting worsening symptoms secondary to increased HR.

Pharmacological There are no drugs currently approved by the US Food and Drug Administration specifically for the treatment of POTS. All agents used are done so “off-label” and few have rigorous randomized clinical trials to support their use. Additionally, there is no “shotgun” first line agent to use for the pharmacological management of POTS. It is very important to consider the clinical features of the POTS and the possible pathophysiology that is leading to symptoms. In this way, medications can be selected that will best treat these deficits. Many of the pharmacological options to treat POTS can be broadly categorized into agents that target volume expansion, antiarrhythmic medications to slow HR, and pressor agents to improve peripheral vasoconstriction. Blood volume expansion In a presentation of a POTS patient with acute worsening of their symptoms, an intravenous bolus of 1–2 L of normal saline has been shown to acutely improve orthostatic HR and symptoms (Jacob et al., 1997; Gordon et al., 2000). For a patient with known POTS presenting in an acute care setting, like the emergency department, a normal saline infusion can be an effective option in such a scenario. This treatment modality acts to reduce hypovolemia in these patients. Essentially it follows a similar mechanism, but makes a much more acute impact, as increasing dietary fluid and salt intake. The long-term use of normal saline infusions as a means of treatment is not recommended (Sheldon et al., 2015). Significant risks include complications associated with central intravenous line insertion such as thrombosis and infection. Fludrocortisone is a modified corticosteroid, which, at low doses (0.05–0.2 mg PO once daily), has predominantly mineralocorticoid activity resulting in sodium and water retention. This can be considered an adjunct to help boost plasma volume in addition to increasing dietary salt and water intake. There are no randomized controlled trials testing the use of fludrocortisone in POTS patients. A trial in patients with CFS and orthostatic intolerance did not find a significant improvement in symptoms, however this study focused on global symptoms rather than those secondary to orthostatic stress (Rowe et al., 2001). In patients with VVS, fludrocortisone may offer benefit in syncope recurrence in patients who reach a stabilized dose (Sheldon et al., 2016). Potential side effects of fludrocortisone include hypertension, fatigue, nausea, and hypokalemia (Lee and Krahn, 2016). The Heart Rhythm Society consensus statement suggests that despite limited evidence for the use of fludrocortisone in POTS patients, the potential benefits likely outweigh the risks (Sheldon et al., 2015). Desmopressin (DDAVP) is a synthetic version of antidiuretic hormone and promotes free water retention. This has been tested in POTS patients with the hypothesis of eliciting blood volume expansion for POTS patients who are hypovolemic. One study found that DDAVP improved standing HR and symptoms in POTS patients upon acute administration (Coffin et al., 2012). Potential effects of its administration include hyponatremia (especially with the increased water intake advised for POTS patients), headache, and peripheral edema (Nwazue and Raj, 2013). Antiarrhythmic medications Propranolol, when used at low doses (10–20 mg PO four times daily), reduces supine and standing HR, and improves symptoms acutely (Raj et al., 2009a). Higher doses were found to make symptoms worse. Quality of life after three months of exercise training has been found to provide superior improvement in quality of life in comparison to long-acting propranolol despite both providing significant reductions in HR (Fu et al., 2011). To date, other beta blockers have not actively studied (Sheldon et al., 2015). Similar to fludrocortisone, the Heart Rhythm Society suggests propranolol can be considered for the treatment of POTS in the absence of evidence contraindicating its use (Sheldon et al., 2015). Some centers consider propranolol as first line treatment for POTS (Garland et al., 2015). Ivabradine is a selective funny current (If) channel blocker that can be used to slow HR (DiFrancesco, 2010). It has been more extensively tested in the treatment of IST, but a retrospective case series of POTS patients prescribed ivabradine found that 60% of patients reported a symptomatic improvement with its use (McDonald et al., 2011). The major downside to this medication is a lack of availability in some countries, although this may change in the near future (Sheldon et al., 2015). Dosing is recommended at 5–7.5 mg once or twice daily. Pressor agents Midodrine is a pro-drug that is an alpha-1 adrenergic receptor agonist when converted to its active form. It can increase vascular resistance and venous return through peripheral constriction of arteries and veins. The improved venous return is believed to reduce the reflex tachycardia that accompanies standing. Midodrine may be more useful with the peripheral neuropathy seen in neuropathic POTS, where peripheral vasoconstriction may be impaired (Ross et al., 2014). Several studies in POTS patients have found the effects of midodrine to decrease supine and upright HR and improve symptoms acutely (Jacob et al., 1997; Gordon et al., 2000). Midodrine has several challenges associated with its use including the need for frequent dosing, its brief effect (4 h), and

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side effect of supine hypertension (Raj and Sheldon, 2016). As such, it is not recommended to be taken within 4–5 h of sleep (Jones et al., 2016). Other side effects of midodrine that may contraindicate its use include urinary retention in older men, and possible teratogenic effects when used in pregnant females (Raj and Sheldon, 2016). Expert opinion suggests that midodrine can be attempted for the management of POTS given the absence of contraindications against its use (Sheldon et al., 2015). Clonidine and methyldopa are centrally acting sympatholytic agents that may be useful in patients with hyperadrenergic POTS. Clonidine is an alpha-2 receptor agonist that may be helpful in reducing symptoms in patients with prominent hyperadrenergic features (Gaffney et al., 1983). Methyldopa is a false neurotransmitter that exudes a similar effect, and has also been suggested for use in patients with a hyperadrenergic state (Shibao et al., 2005). It is thought to be easier to titrate in POTS patients in comparison to clonidine due to its longer half-life (Jacob and Biaggioni, 1999). The tolerability of these medications may be limited due to side effects including worsening drowsiness, fatigue, and mental clouding, all of which can be presenting complaints in POTS patients (Raj, 2013). Additionally, both medications may be less beneficial in POTS patients with significant neuropathic features, although data is lacking. Droxidopa is a synthetic amino acid precursor for norepinephrine, and acts to increase synaptic levels of the neurotransmitter, enhancing the effects of vasoconstriction. It is postulated to act as an alternative to midodrine in POTS patients with symptoms refractory to treatment. One retrospective study found droxidopa to improve symptoms in POTS patients, but induced no significant reduction in standing HR and did not seem to improve quality of life in these patients (Ruzieh et al., 2017). Given that droxidopa is a norepinephrine precursor, it has the potential side effect of increasing sympathetic activity resulting in further increased HR, possibly worsening symptoms. Overall, there is a fundamental lack of data assessing the efficacy of droxidopa in POTS patients. Other pharmacological agents Pyridostigmine is a peripherally acting acetylcholinesterase inhibitor. The mechanism of action of pyridostigmine is to increase transmission of acetylcholine at synaptic junctions equipped with nicotinic or muscarinic AChR. This results in increased cardiovagal tone, helping reduce HR. It has been shown to reduce tachycardia and improve symptoms acutely in POTS patients (Raj et al., 2005b). Unfortunately, there are significant gastrointestinal side effects that limit the efficacy of this medication including severe cramping, nausea, and diarrhea in about 20% of POTS patients (Kanjwal et al., 2011). In patients who can tolerate the drug longterm, it does continue to help control tachycardia and symptoms (Kanjwal et al., 2011); the Heart Rhythm Society provides a modest recommendation for its use (Sheldon et al., 2015). In patients in whom mental clouding is a predominant symptom, modafinil has anecdotally been used to improve concentration and alertness in POTS patients (Raj, 2013). It is a psychostimulant with similar actions to amphetamine and methylphenidate (Taneja et al., 2004). Additionally, it does not appear to worsen symptoms of orthostatic tachycardia when tested in POTS patients (Kpaeyeh et al., 2014).

Inappropriate Sinus Tachycardia The treatment of IST is a challenge. A rate control strategy to eliminate the presence of the sinus tachycardia does not always eradicate symptoms (Olshansky and Sullivan, 2013; Sheldon et al., 2015). Additionally, there is little concrete evidence in the literature to develop strong recommendations for the management of IST (Sheldon et al., 2015). With that being said, conservative management with good patient education is key in the initial management. Patients can often be in great distress about their symptoms. Similar to the treatment of POTS, it is important to reassure patients that the disease course is thought to be benign (Abed et al., 2016) and that no known mortality is known to be caused from this condition (Sheldon et al., 2015; Olshansky and Sullivan, 2013). The use of beta blockers or other negative chronotropic agents for the treatment of IST has been proposed as a means of reducing HR. Experts believe that symptoms often do not disappear while on beta blockers (Sheldon et al., 2015; Olshansky and Sullivan, 2013). Nondihydropyridine calcium channel blockers and amiodarone have also been suggested as potential therapeutic agents, but the benefits of HR reduction are likely outweighed by the adverse effects of these medications (Ptaszynski et al., 2013). Finally, no prospective studies or randomized controlled trials have been conducted to show any benefit for the use of these medications. Ivabradine has been tested as an off-label product for the treatment of IST (Annamaria et al., 2015). It has been the most vigorously tested medication in the treatment of IST, including having one randomized control trial testing its efficacy. This trial found ivabradine was well tolerated, eliminated 75% of baseline symptoms in its cohort (n ¼ 21) and fully eliminated symptoms in approximately 50% of patients (Cappato et al., 2012). In comparison to the beta blocker metoprolol, ivabradine exerts a similar decrease in HR, is better tolerated, and is more effective at relieving symptoms associated with IST (Ptaszynski et al., 2013). A dose of 5–7.5 mg twice daily can slow HR by 14%–31% of baseline (Annamaria et al., 2015). Sinus node ablation or modification has been explored as a therapeutic option to treat patients with IST. Both radiofrequency and surgical techniques have been tried (Olshansky and Sullivan, 2013). Sinus rate can be significantly improved by these techniques, but there is limited evidence that clinical symptoms are vastly improved (Shen et al., 2001; Olshansky and Sullivan, 2013). Additionally, there are rather significant potential complications secondary to these permanent procedures including surgical risks and making the patient pacemaker dependent (Lee et al., 1995; Man et al., 2000). The Heart Rhythm Society consensus statement strongly recommends against the use of these treatments for patients with IST (Sheldon et al., 2015).

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Conclusions POTS and IST represent etiologies for a patient presenting in sinus tachycardia without any clear primary cause. Neither condition is believed to be linked to an increased risk of mortality, but each can substantially negatively impact a patient’s quality of life if not treated. There is no gold-standard treatment for POTS or IST, and there is limited high quality evidence for management of these conditions. Experts agree that a multidisciplinary approach that considers the individual patient’s presentation, underlying pathophysiology of the disease, and associated conditions allows for available treatment strategies to be selected and tailored to the patient at hand. Much remains unknown about these conditions and considerable effort is still required to fully understand the pathophysiology and optimal treatment of these conditions.

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Skeletal Muscle in Heart Failure S Scheetz, The Ohio State University College of Medicine, Columbus, OH, United States R Baliga, The Ohio State University Wexner Medical Center, Columbus, OH, United States; Davis Heart and Lung Research Institute (HLRI), Columbus, OH, United States © 2018 Elsevier Inc. All rights reserved.

Heart Failure Skeletal Muscle in Heart Failure Skeletal Muscle Tissue and Muscle Fiber Changes Metabolic Changes Mitochondrial Content Oxidative Capacity Enzyme Abnormalities Oxidative Stress ECC and Calcium Inflammation and Cytokines Neurologic Response and Muscle Reflexes Muscle Atrophy Atrophy and Cardiac Cachexia Sarcopenia Deconditioning Muscle Cell Apoptosis Growth Hormone/IGF-1 Axis Biochemical Pathways Circulating Factors Nutrition Clinical Muscle Weakness Blood Flow to Skeletal Muscle Exercise Other Approaches to Treatment References

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Heart Failure Congestive heart failure (CHF) is defined as “a pathophysiological state in which an abnormality of cardiac function is responsible for the failure of the heart to pump blood at a rate commensurate with the requirements of the metabolizing tissues (Francis et al., 2011).” In other words, the heart is unable to adequately perfuse peripheral tissue unless cardiac filling pressures are abnormally high (Lilly and Harvard Medical School, 2011). In the United States, the incidence of CHF is 550,000 cases per year and the prevalence is 5.8 million cases (Lilly and Harvard Medical School, 2011). CHF, which mostly affects older adults, is the most common diagnosis of hospitalized patients 65 years and older (Lilly and Harvard Medical School, 2011; Rich et al., 2016). The prevalence is expected to increase significantly due to associations with age and interventions that increase survival after CHF (Lilly and Harvard Medical School, 2011). CHF presents as a clinical syndrome (Lilly and Harvard Medical School, 2011). One of the primary features of CHF is exercise intolerance (Fletcher et al., 2011). Patients also present with fatigue, volume overload, shortness of breath, dyspnea, impaired urine output, paroxysmal nocturnal dyspnea, orthopnea, nocturnal cough, dulled mental status, and edema (Lilly and Harvard Medical School, 2011). Patients are progressively restricted in daily activities (Minotti et al., 1992). The severity of physical limitations correlates more closely with prognosis than hemodynamics (Mettauer et al., 2006). CHF may be classified as either heart failure with reduced ejection fraction (HFrEF) or heart failure with preserved ejection fraction (HFpEF). Most patients diagnosed with CHF have decreased systolic function, which is a form of HFrEF (Sarma and Levine, 2015). Research has historically focused on exercise intolerance in patients with HFrEF (Maurer and Schulze, 2012). The most common type of CHF in older patients, however, is HFpEF (Sarma and Levine, 2015). HFpEF is also more common in women (Sarma and Levine, 2015; Taub, 2016). Patients with HFpEF have similar mortality and rehospitalization rates (Sarma and Levine, 2015). With growing recognition of patients with HFpEF and a lack of specific therapies, researchers are now working to further characterize peripheral abnormalities in HFpEF (Maurer and Schulze, 2012).

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Skeletal Muscle in Heart Failure In CHF, many bodily responses to maintain circulatory function ultimately become maladaptive, contributing to progression over time (Francis et al., 2011). Decreased cardiac performance leads to problems in peripheral circulation, the kidney, and many other organs (Francis et al., 2011). As in other chronic conditions, such as chronic pulmonary or renal disease, CHF leads to skeletal muscle abnormalities (Zizola and Schulze, 2013). Skeletal muscle changes are clearly identifiable from an early stage in CHF and contribute to disease progression (Tomono et al., 2016; Georgiadou and Adamopoulos, 2012). The changes impact both peripheral and ventilatory muscles (Georgiadou and Adamopoulos, 2012). Alterations are present at rest, but they are exacerbated during exercise (Georgiadou and Adamopoulos, 2012). Even though changes in CHF are induced by cardiac abnormalities, symptoms like exercise intolerance are often independent of central hemodynamic alterations and reduced blood flow to muscle (Georgiadou and Adamopoulos, 2012; Cicoira et al., 2001). Similarly, hemodynamic improvement does not necessarily reverse symptoms (Georgiadou and Adamopoulos, 2012). These observations suggest that circulatory changes are not primarily responsible for changes in skeletal muscle metabolism. This is in contrast to healthy patients, in whom exercise tolerance is related to cardiac output (Georgiadou and Adamopoulos, 2012). Instead, exercise tolerance in CHF patients with HFrEF and HFpEF is more related to biochemical, metabolic, and histologic changes in skeletal muscle that lead to skeletal muscle dysfunction (Georgiadou and Adamopoulos, 2012; Cicoira et al., 2001; Bowen et al., 2015). Consequently, training improves exercise tolerance through peripheral adaptations without impacting central hemodynamics. This implies that peripheral skeletal muscle plays a significant role in CHF symptoms. Researchers have suggested that the role of circulation may be dependent on the disease stage, with peripheral alterations playing greater roles later in the progression (Piepoli et al., 2001). Studies have shown that peripheral factors play a role in patients with HFrEF and HFpEF. Many of these factors, which will be explained in depth in this paper, are shown below (Fig. 1, Tables 1 and 2). Patients with HFrEF and HFpEF have similar levels of exercise intolerance and dyspnea (Sarma and Levine, 2015). A study using soleus tissue in animal models suggested, however, that skeletal muscle alterations are exacerbated in HFrEF compared to HFpEF (Seiler et al., 2016). Diaphragm muscle, on the other hand, was not significantly different between the two groups (Seiler et al., 2016).

Skeletal Muscle Tissue and Muscle Fiber Changes Skeletal muscle tissue is characterized by strong, quick, discontinuous, and voluntary contractions. The structural unit of skeletal muscle tissue is called a sarcomere. The composition of muscle fibers depends on activity, mechanical load, hormones, and age (Mettauer et al., 2006). Cardiac tissue, on the other hand, is characterized by continuous and involuntary contractions. Significant

Fig. 1 Skeletal muscle abnormalities in CHF (Zizola and Schulze, 2013).

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Skeletal Muscle in Heart Failure Table 1

Skeletal muscle changes in heart failure (Piepoli et al., 2001)

Function Morphology Blood flow Metabolism

Ultrastructural 1. Fiber type 2. Mitochondrial 3. Endothelial dysfunction

Table 2

" Weakness " Fatigability 1. Quantity: Loss of muscle mass (bulk) 2. Quality: Atrophy, damage and/or necrosis # Capillary density (endothelial cell/fiber) # mL min1 # Vasodilatation " Glycolytic # Oxidative " Phosphocreatinine depletion " Intracellular acidosis # Type I oxidative slow-twitch " Type IIb glycolytic fast-twitch # Volume density # Surface density of cristae

Skeletal Muscle Abnormalities in Heart Failure (HF) (Liu and Marcinek, 2016)

Author, year (no.)

Population character

Key measurement

Outcome and conclusion

Mancini et al. (1988)

HF and age-matched healthy control male (54 years)

HF peak VO2 13.6  5 mL/min/kg In vivo P31-NMR

Southern et al. (2015) Mancini et al. (1994) Wiener et al. (1986)

HF and age-matched control (64 years)

Near-infrared spectroscopy

HF and control (58 years)

Ventilatory capacity: progressive isocapnic hyperpnea respiratory muscle deoxygenation near-infrared spectroscopy Forearm blood flow with plethysmography Metabolism 31P NMR

Lower leg muscle mass loss in HF Calf metabolic abnormality part due to muscle atrophy During exercise Pi/PCr, HF > control Recovery time post Ex, HF > control Impaired metabolic profile suggests intrinsic changes not only due to muscle loss Oxidative capacity lower in HF and exercise training improved oxidative capacity only in control, suggested reduced oxidative capacity and impaired training adaptation in HF Reduced respiratory ventilator capacity without respiratory muscle deoxygenation in HF

Mancini et al. (1989)

HF and age-matched control (57 years)

31

Toth et al. (2012)

HF and control, age and physical activity matched

18-Week resistance training (RE) Muscle biopsy, in vitro analysis

MiddleKauff et al. (2013)

HF and control (50 year, peak VO2 11.6 mL/kg/min)

Muscle biopsy and in vitro biochemistry analysis; fiber typing and mitochondria enzyme activity

Zizola et al. (2015)

Myocardial infarction induced mice

In vitro muscle biopsy: fiber typing and enzyme activity assay; ATP content

Schrepper et al. (2012) Dai et al. (2011)

Pressure overload hypertrophy in rat heart Ang II induced cardiomyopathy in mice treated with SS-31 HF with preserved ejection fraction (HFpEF)

In vitro assay from muscle biopsy; isolation of fresh mitochondria mRNA and protein assay

Kitzman et al. (2014)

HF and age-matched control (60 years)

P NMR; Pi/PCr and PH changes In vitro muscle biopsy; enzyme activity fiber type

Flow cytometric access MitoSOX and DCFDA signal Peak VO2 Fiber type Capillary-to-fiber ratio

Forearm blood flow was similar, but increased Pi/PCr upon exercise suggested that abnormal metabolism in HF was not due to decreased muscle blood flow rather intrinsic changes in mitochondria or substrate utilization HF fiber shift to increased fast, glycolytic type IIb fibers; decreased fatty acid oxidation enzyme activity; 31P NMR also showed higher Pi/PCr; no correlation between Pi/PCr to VO2 and enzyme activity suggested intrinsic changes not due to metabolic response (Pi/ PCr changes) Larger but fewer mitochondria per fiber without difference in content between HF and control; no difference in mitochondria enzyme activity and mRNA level of cytochrome oxidase RE increased mitochondrial transcription factor A and muscle strength for both HF and control but did not alter mitochondrial size/content, enzyme, or transcriptional regulator HF fibers shift to fast twitch; no difference in vascular index or many of mitochondrial enzyme activities; clonidine revealed no impact for HF suggested skeletal myopathy is not caused by neuroendocrine disuse Muscle dysfunction associated with impaired PPARd signaling; upon treating MI mice with PPARd agonist corrected diminished oxidative capacity and FA metabolism (CPT1) and improved exercise capacity Complexes I and II early increase and then later decline (I, II, and III) in respiratory capacity not due to differences in gene expression or supercomplex assembly SS-31 reduced Ang II-induced ROS signal (mitochondrial superoxide and total cellular ROS) Reduced type I fiber and capillary to fiber ratio contribute to exercise intolerance among HF

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similarities and differences between skeletal and cardiac muscle tissue are shown below (Table 3). Skeletal muscle tissue, along with vessels, nerve fibers, and connective tissue, forms the skeletal muscle organ. Skeletal muscle accounts for 40%–45% of body weight, which is more than any other organ of the body (Mohrman and Heller, 2014). Based on functional demands, muscles may be composed of different types of fibers with different capabilities (Table 4). Skeletal muscle has high capacity for regeneration and remodeling, making it a good target for therapeutic approaches (Rich et al., 2016). In patients with CHF, muscle fibers are characterized by abnormalities. Changes are related to different isoforms of myosin heavy chain (MHC), which is the motor protein in the muscle thick filament myosin (Mettauer et al., 2001; Nicoletti et al., 2003). Muscle biopsies and ultrastructural analyses have shown that there are fewer slow fibers and more fast fibers in patients with CHF. The change is due to an increase in the relative content of MHC 2X from active healthy patients to sedentary healthy patients to CHF patients (Mettauer et al., 2001). In other words, patients with CHF have a higher proportion of fast-twitch, type II fibers relative to type I fibers (Georgiadou and Adamopoulos, 2012). These changes in muscle fibers have been confirmed in patients with HFpEF as well (Maurer and Schulze, 2012). This has been supported by observation of splitting of the inorganic phosphate (Pi) peak in patients with CHF, which implies the presence of two types of muscle fibers (Minotti et al., 1992). Some studies have suggested that no significant fiber difference exists between sedentary controls and CHF patients (Mettauer et al., 2001). This would support the idea that fiber type changes are due to muscle disuse rather than specific effects of CHF. This was supported in studies that showed no fiber type shift compared to deconditioned controls with similar VO2 max (see the “Exercise” section for a further discussion on VO2 max) (Nicoletti et al., 2003). It has been shown, however, that angiotensinconverting enzyme inhibitor (ACEi) treatment normalizes myosin isoform abnormalities in muscle fibers in CHF patients (Mettauer et al., 2006). This may account for discrepancies between studies. Muscle fiber type directly impacts metabolism (see “Metabolic Changes” section for further discussion). Mitochondrial respiration in active controls favors slow-oxidative muscle (Mettauer et al., 2001). This is characterized by high oxidative capacity, low sensitivity to external adenosine diphosphate (ADP), and control by mitochondrial creatine kinase (CK) (Mettauer et al., 2001). Respiration in sedentary controls and CHF patients, on the other hand, is closer to fast-glycolytic muscle in rodents (Mettauer et al., 2001). Some groups showed that muscle fibers in patients with CHF show decreased activity of oxidative enzymes while activity of glycolytic enzymes is maintained (Minotti et al., 1992). Type II fibers, which have higher oxygen and adenosine triphosphate (ATP) consumption, transition to anaerobic metabolism sooner (Vescovo et al., 2000). Muscle biopsies in patients with CHF showed reduced activity of both lipolytic and oxidative enzymes (Zizola and Schulze, 2013) .Fiber changes cause metabolic signaling to favor replenishment of energy stores instead of modification of energy production based on demands (Mettauer et al., 2006). The fibers also lead to a lower pH during exercise (Minotti et al., 1992). Muscle fibers in patients with CHF may also be characterized by atrophy, decreased maximal strength, and reduced electromyographic activity (see “Muscle Atrophy” section for further discussion) (Georgiadou and Adamopoulos, 2012). Some studies have shown that all fibers have reduced size, whereas some studies suggest that only type II fibers have reduced diameter (Georgiadou and Adamopoulos, 2012). In skeletal muscle from a mouse model of dilated cardiomyopathy, the shift to more fatigable fibers was associated with activation of Wnt (Okada et al., 2015). Through b-catenin, Wnt activates Forkhead box O (FoxO) (Okada et al., 2015). FoxO signaling plays a critical role in the development of skeletal myopathy in CHF (Okada et al., 2015). Overexpression of FoxO1 increases shifts to fatigable fibers, whereas suppression of FoxO1 activity inhibits these changes (Okada et al., 2015). This supports the role of Wnt signaling as a potential target for new therapies against skeletal myopathy in CHF (Okada et al., 2015). Clinically, muscle fiber changes in CHF are related to exercise intolerance and shortness of breath. There is a positive correlation between the percentage of MHC I and VO2, ventilator threshold, and oxygen pulse (Nicoletti et al., 2003). Similarly, there is a negative correlation between MHC II and these measures of exercise capacity (Nicoletti et al., 2003). These relationships have been demonstrated in patients with HFpEF as well (Kitzman et al., 2014). Exercise may reverse fiber composition abnormalities, increasing slow-twitch fibers and decreasing fast-twitch glycolytic fibers in skeletal muscle (Piepoli et al., 2001). It may also increase muscle fiber size (Piepoli et al., 2001). Various other changes in muscle fibers have been identified in patients with CHF. Fibers may be altered due to changes in regulatory components of thin filaments, including troponin, and proteins involved in calcium transport, including Ca2þ-ATPase (Georgiadou and Adamopoulos, 2012). There is also a reduction in capillary-to-fiber ratio (Kitzman et al., 2014). Researchers have suggested that there is a decrease in capillary density, although these findings have been controversial (Sarma and Levine, 2015; Mettauer et al., 2001; Georgiadou and Adamopoulos, 2012; Minotti et al., 1992; Mettauer et al., 2006). The decreased capillary density around skeletal myofibrils is related to decreased peak VO2 (Sarma and Levine, 2015).

Metabolic Changes Mitochondrial Content Mitochondria are altered in skeletal muscle in patients with CHF. One study suggested that there is some parallelism between cardiac and skeletal muscle mitochondrial alterations in patients with CHF, and that these alterations begin before the major clinical Framingham criteria are installed (Guzman Mentesana et al., 2014). Ultrastructural analysis showed fewer, smaller mitochondria in patients compared to controls (Guzman Mentesana et al., 2014). Specifically, there are fewer mitochondria per muscle fiber (Zizola and Schulze, 2013). Mitophagy may be enhanced by hypoxia, inflammation, and muscle inactivity (Zizola and Schulze, 2013). In older patients with HFpEF, mitochondrial reductions in skeletal muscle have been demonstrated based on levels of porin expression (Molina et al., 2016). Morphometric analysis of vastus lateralis muscles from patients with CHF showed reduced volume

408 Table 3

Skeletal Muscle in Heart Failure Similarities and differences between skeletal and cardiac muscle (Kennelly and Murray, 2015)

Skeletal muscle

Cardiac muscle

Striated No syncytium Small T tubules Sarcoplasmic reticulum well developed and Ca2þ pump acts rapidly Plasmalemma contains few hormone receptors Nerve impulse initiates contraction Extracellular fluid Ca2þ not important for contraction Troponin system present Caldesmon not involved Very rapid cycling of the cross-bridges

Striated Syncytial Large T tubules Sarcoplasmic reticulum present and Ca2þ pump acts relatively rapidly Plasmalemma contains a variety of receptors (e.g., a- and b-adrenergic) Has intrinsic rhythmicity Extracellular fluid Ca2þ important for contraction Troponin system present Caldesmon not involved Relatively rapid cycling of the cross-bridges

Table 4 Similarities and differences between type I and type II muscle fibers (Kennelly and Murray, 2015; Kibble and Halsey, 2015) Characteristic

Slow twitch (type I)

Fast twitch (type II)

Color Metabolism Mitochondria Glycogen content Duration Fatigability Myosin ATPase Energy utilization Contraction rate

Red (myoglobin) Oxidative Abundant Low Prolonged Low Low Low Slow

White (low myoglobin) Glycolytic Few High Short High High High Fast

density of mitochondria (Mettauer et al., 2006). In a rat model of right ventricular heart failure induced by monocrotaline (MCT) injection, MCT treatment was related to lower mitochondrial volume density and quality (Wust et al., 2012). Remaining mitochondria have fewer cristae (Mettauer et al., 2006; Zizola and Schulze, 2013). It has been noted, however, that skeletal muscle has less clear mitochondrial changes compared to cardiomyocytes (Mettauer et al., 2006). Moreover, a study comparing 13 CHF patients with 14 age- and activity-matched controls suggested that mitochondrial changes in CHF are primarily related to muscle disuse and other disease-related factors (Toth et al., 2012). Exercise training is typically thought to alleviate quantitative and structural mitochondrial changes in patients with CHF. Exercise has been shown to increase the number of mitochondria in skeletal muscle (Maurer and Schulze, 2012). It also significantly increases the total volume density of mitochondria (Nicoletti et al., 2003). In one study, however, resistance training did not alter mitochondrial size and content in patients with CHF, leading the authors to suggest that impaired oxidative capacity is not related to mitochondrial dysfunction (Toth et al., 2012).

Oxidative Capacity In addition to structural changes, mitochondria in skeletal muscles from patients with CHF also have impaired function. As in many diseases, mitochondrial alterations contribute to a reduction in oxidative metabolic capacity. Oxidative capacity is defined as the maximal rate at which oxidative phosphorylation may be performed (Leermakers and Gosker, 2016). Reduced oxidative capacity contributes to decreased skeletal muscle oxygen consumption (Sarma and Levine, 2015). Reduced oxygen consumption is further caused by impaired cardiac function in patients with HFrEF and by impaired oxygen diffusion (Sarma and Levine, 2015). Despite these changes, muscles typically are adequately supplied with oxygen during abnormalities, suggesting an intrinsic cause within skeletal muscle (Zizola and Schulze, 2013). As oxidative metabolism fails, there is a shift to anaerobic, glycolytic energy production. This shift occurs in both patients with HFrEF and HFpEF (Kitzman et al., 2014). Increased anaerobic metabolism causes an earlier increase in the concentration of lactate in the blood, especially during exercise (Schulze et al., 2002). This occurs even in patients with chronic CHF with normal leg blood

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flow (Nicoletti et al., 2003). The shift to glycolytic metabolism has been demonstrated in patients with CHF using 31P magnetic resonance spectroscopy (Zizola and Schulze, 2013). Glycolytic metabolism also leads to earlier intramuscular acidosis (Georgiadou and Adamopoulos, 2012). In a rat model of CHF, skeletal muscle metabolic capacity was reduced in both oxidative and glycolytic muscles (Mettauer et al., 2006). Quantitative, structural, and metabolic changes in mitochondria contribute to exercise intolerance. Mitochondrial alterations affect factors such as peak aerobic exercise capacity (Zizola and Schulze, 2013). In one study, levels of porin and mitofusin-2 (Mfn2) expression were positively correlated with peak VO2 and 6-min walk distance (see “Exercise” section for further discussion) (Molina et al., 2016). Mitochondrial volume density and cristae reductions are proportional to declines in peak VO2 (Mettauer et al., 2006). Exercise may restore oxidative capacity in patients with CHF. Mitochondrial improvements from exercise training are significantly correlated with increased peak VO2 (Piepoli et al., 2001). Exercise also improves metabolic function through slowing utilization of muscle glycogen, increasing reliance on fat oxidation and utilization, and decreasing production of lactate during exercise (Nicoletti et al., 2003). In one study, however, wrist-flexor training induced a 50% improvement in oxidative capacity in patients without CHF but did not induce improvement in patients with CHF (Southern et al., 2015). The authors suggested that CHF patients have impaired oxidative adaptations to endurance exercise compared to healthy controls (Southern et al., 2015). Changes in oxidative capacity are controversial. Some studies suggest that oxidative capacity in patients with CHF is similar to oxidative capacity in sedentary controls (Mettauer et al., 2001). Further research is required to determine the contributions from atrophy, fibrosis, and inflammation (Zizola and Schulze, 2013). Moreover, mitochondrial abnormalities, reduced blood flow, and decreased oxygen extraction often reverse after administration of ACEi (Minotti et al., 1992). The more recent application of ACEi and b-blocker treatments may account for older studies observing intrinsic skeletal muscle mitochondrial defects while newer studies observe normal mitochondrial function (Mettauer et al., 2006).

Enzyme Abnormalities In patients with CHF, impaired CK function in skeletal muscle is likely related to abnormal production and handling of high-energy phosphates (Mettauer et al., 2006; Schulze et al., 2002; Hambrecht et al., 1999). CK is an enzyme that adds a phosphate from ATP to creatine to produce phosphocreatine (PCr) (Mettauer et al., 2006). PCr functions as an energy buffer for ATP homeostasis in skeletal muscle (Greenhaff, 2001). Three isoforms of muscle CK are the dimers MM-CK, BB-CK, and MB-CK (Mettauer et al., 2006). There is also a mitochondrial isoform (mi-CK) (Mettauer et al., 2006). In patients with CHF, levels of total cytosolic CK, MM-CK, and mi-CK decrease (Mettauer et al., 2006). Reduced CK function is exacerbated by reduced oxidative capacity, which increases use of PCr as a source of energy. Many studies using 31P magnetic resonance spectroscopy have shown that patients with CHF have increased rates of PCr utilization (Zizola and Schulze, 2013; Schulze et al., 2002; Hambrecht et al., 1999). PCr depletion is accompanied by increased levels of Pi (Minotti et al., 1992). Moreover, a study using 31P magnetic resonance spectroscopy revealed that patients with HFpEF have longer recovery times to regenerate PCr compared to healthy, sedentary, age-matched controls (Sarma and Levine, 2015). Long recovery of high-energy phosphates is proportional to the severity of CHF (Mettauer et al., 2006). In addition, during exercise in patients with CHF, levels of ADP increase faster while pH falls significantly more compared to healthy controls (Nicoletti et al., 2003). Abnormal CK function is independent of peripheral blood flow, histologic changes, muscle mass, and hypoxia (Zizola and Schulze, 2013; Hambrecht et al., 1999). Impaired CK function and lower levels of ATP contribute to early fatigue and muscle intolerance in patients with CHF (Piepoli et al., 2001; Hambrecht et al., 1999). Since these changes may occur prior to atrophy, patients often present with fatigue prior to decreased contractile force (Schulze et al., 2002). Reduced enzyme activity in the Krebs cycle and electron transport chain is related to energy depletion in patients. In a rat model of CHF induced by MCT injection, succinate dehydrogenase (SDH, complex II) activity and maximal respiratory rate were 15% lower in all muscle fibers (Wust et al., 2012). In patients with HFrEF but not HFpEF, soleus tissue muscle showed a reduced SDH to lactate dehydrogenase (LDH) ratio, which is further impacted by reduced levels of LDH in patients with CHF (Seiler et al., 2016). In the rat model, complex I/IV activity was also 20% lower (Wust et al., 2012). In general, the percentage of mitochondria stained for cytochrome oxidase (complex IV) is reduced in patients with CHF but improves with exercise (Mettauer et al., 2006). Changes in citrate synthase levels are more variable. Some studies have suggested that citrate synthase activity is reduced in skeletal muscle from patients with CHF, including older patients with HFpEF. Other studies, however, state that levels of citrate synthase are unchanged (Mettauer et al., 2001, 2006; Zizola and Schulze, 2013; Molina et al., 2016). Other proteins are also affected. Reductions in fatty acid metabolism are characterized by low concentrations of skeletal muscle long chain acylcarnitine, increased lipid droplets, and decreased activity of b-hydroxyacyl coenzyme A dehydrogenase, an enzyme involved in b-oxidation of fatty acids (Nicoletti et al., 2003). Reductions in Mfn2 and porin, both of which are proteins that are present on the outer mitochondrial membrane, are correlated to measures of exercise tolerance in patients with HFpEF (Molina et al., 2016). Peroxisome proliferator-activated receptor-g expression was reduced in soleus tissue from patients with HFrEF but not HFpEF (Seiler et al., 2016). Deactivation of the PPARa/AMPK pathway, which consequently downregulates many enzymes for glucose and free fatty acid metabolism, is also related to skeletal muscle metabolic dysfunction (Sente et al., 2016a). Exercise may improve enzymatic abnormalities. In an animal model of CHF, exercise training decreased PCr depletion and increased levels of ATP (Piepoli et al., 2001; Nicoletti et al., 2003). In patients with CHF, 31P nuclear magnetic resonance spectroscopy after submaximal exercise showed reduced acidosis, reduced PCr depletion, and increased levels of ADP (Minotti et al., 1992). Moreover, exercise reduced the recovery half-time for PCr (Schulze et al., 2002). Needle biopsies from patients after exercise have shown a significant increase in oxidative enzyme activity along with reduced or unaltered glycolytic enzyme activity

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(Piepoli et al., 2001). In a study on rats with CHF, exercise training increased spinotrapezius muscle citrate synthase activity more than it did in sedentary counterparts (Hirai et al., 2014). Exercise has also been shown to increase the concentration of enzymes involved in lipid metabolism (Fletcher et al., 2011).

Oxidative Stress Oxidative stress is defined as an excess production of reactive oxygen species (ROS) relative to antioxidant defense (Tsutsui et al., 2011). Sources of ROS include mitochondria, NAD(P)H oxidase, xanthine oxidase, and uncoupled nitric oxide synthase (NOS) (Fig. 2A; Guzman Mentesana et al., 2014; Tsutsui et al., 2011; Koba et al., 2009). Levels of ROS may also increase due to decreased antioxidative capacity, which may be caused by decreased function of radical scavenger enzymes including superoxide dismutase (SOD) and catalase (Fig. 2B; Koba et al., 2009). Increased ROS in mitochondria will damage mitochondrial DNA, which impairs mitochondrial function and further augments generation of ROS (Tsutsui et al., 2011). ROS may also mediate apoptosis (Tsutsui et al., 2011). Heart failure increases oxidative stress. In patients, levels of ROS, such as superoxide, are increased (Koba et al., 2009). One study, however, found significant changes in markers of oxidative stress, including increased nicotinamide adenine dinucleotide phosphate oxidase and decreased antioxidative enzyme activity, in soleus tissue from patients with HFrEF but not HFpEF (Seiler et al., 2016). Superoxide may partially contribute to symptoms by sensitizing muscle afferents involved in the mechanoreflex (see the “Neurologic Response and Muscle Reflexes” section for further discussion) (Koba et al., 2009). Patients with CHF may maintain some antioxidant defense mechanisms. An nitrous oxide (NO)-dependent antioxidant defense may increase skeletal muscle resistance to catabolic processes (Okutsu et al., 2014). In a genetic mouse model of CHF, muscle CK extracellular superoxide dismutase (MCK-EcSOD) significantly attenuated cachexia and exercise intolerance (Okutsu et al., 2014). It also ameliorated MAFbx/Atrogin-1 mRNA expression, loss of mitochondria, and reduction of capillary density in skeletal muscle (Okutsu et al., 2014). Oxidative stress contributes to the CHF syndrome in many ways. It is related to cachexia, insulin resistance, and exercise intolerance. ROS impair contractile function through modification of proteins related to excitation–contraction coupling (ECC) (see “ECC and Calcium” section for further discussion) (Tsutsui et al., 2011). Although muscle contraction increases ROS production in healthy subjects, active muscle in patients with CHF releases higher levels of cyclooxygenase products and bradykinin (BK), which are a source of superoxide generation (Koba et al., 2009). ROS also decrease peripheral perfusion due to endothelial dysfunction (Koba et al., 2009). Clinically, increased oxidative stress in the skeletal muscle is related to fatigue and dyspnea in patients with CHF (Guzman Mentesana et al., 2014). Exercise training may decrease oxidative stress in skeletal muscles (Maurer and Schulze, 2012; Cunha et al., 2012).

ECC and Calcium Skeletal muscle function relies on intact ECC. The normal steps of this process are shown below (Fig. 3). In patients with CHF, ECC in skeletal muscle is abnormal. Abnormalities in ECC may be due to problems in the neuromuscular junction. In lower limbs of patients with CHF, extension and flexion time-to-peak torque was longer (Brunjes et al., 2016). Furthermore, acceleration and deceleration times in the lower limbs were prolonged (Brunjes et al., 2016). CHF patients had increased adiposity, decreased lean muscle mass, decreased circulating unsaturated fatty acids, and increased ceramides (Brunjes et al., 2016). The researchers suggested that delayed torque development indicates skeletal muscle impairments that may reflect abnormal neuromuscular functional coupling (Brunjes et al., 2016). There may also be abnormalities with intracellular calcium handling, causing an “intracellular calcium-overload state (Zizola and Schulze, 2013).” In CHF, the muscle-specific type 1 ryanodine receptor (RyR1), which exists on the sarcoplasmic reticulum (SR), becomes leaky (Zizola and Schulze, 2013). This occurs because chronic adrenergic stimulation results in

Fig. 2 (A) Sources of ROS (Tsutsui et al., 2011); (B) reactions underlying generation and degradation of ROS (Tsutsui et al., 2011).

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Fig. 3 Excitation–contraction coupling (Heiny and Meissner, 2012).

hyperphosphorylation of the channel (Zizola and Schulze, 2013). Channel hyperphosphorylation causes dissociation of calstabin1, which is necessary to maintain the closed state of the RyR1 channel (Zizola and Schulze, 2013). A study of eight sedentary HF patients compared to seven age-matched, healthy but sedentary controls further showed that skeletal muscle RyR1 from human heart failure is posttranslationally modified (Rullman et al., 2013). Modifications included excessive phosphorylation, S-nitrosylation, and oxidation (Rullman et al., 2013). RyR1 from HF patients had depleted levels of calstabin1 (Rullman et al., 2013). Changes in RyR1 in CHF impair muscle function and exercise tolerance, most significantly via altered SR Ca2þ pumping in slow-twitch muscles (Zizola and Schulze, 2013). A leaky SR with decreased Ca2þ content may impair ECC through altered action potential (AP)-evoked Ca2þ release, which may be called a “calcium spark (Zizola and Schulze, 2013; DiFranco et al., 2014).” In a study of four patients with CHF, excitability mechanisms seemed to be intact since single APs did not vary between CHF patients and healthy controls (DiFranco et al., 2014). AP-evoked Ca2þ release flux in single fibers, however, was significantly reduced compared to fibers from healthy controls (DiFranco et al., 2014). In a different study, skeletal muscle from animals with heart failure exhibited increased Ca2þ spark frequency, decreased Ca2þ spark amplitude, and increased Ca2þ spark duration (Zizola and Schulze, 2013). Skeletal muscle expression of SR Ca2þ-ATPase (SERCA) 1a, the skeletal muscle specific isoform, differ in relation to muscle fiber composition, the degree of functional impairment, and the type of CHF model (Zizola and Schulze, 2013). Expression of SERCA was reduced in rats with post-infarction heart failure, which may explain abnormal calcium handling and accelerated muscle fatigue in CHF (Piepoli et al., 2001). The sarcolemma may also be abnormal (Maurer and Schulze, 2012).

Inflammation and Cytokines Immune responses and inflammation play a significant role in CHF. Proinflammatory factors involved in CHF include tumor necrosis factor a (TNF-a), interleukin (IL) 1b (IL-1b), IL-1, IL-6 and interferon g (IFN-g) (Sente et al., 2016a). Levels of chemokines,

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such as IL-8, also increase (Sente et al., 2016a). Biopsy-derived primary skeletal muscle myoblasts from patients with HFrEF also showed loss of antiinflammatory and proliferative activity (Sente et al., 2016b). Cytokines are associated with poor prognosis and recurrent hospitalization (Schulze et al., 2002). Low-level systemic inflammation in CHF may cause changes in skeletal muscle (Zizola and Schulze, 2013). Plasma levels of circulating inflammatory cytokines differ between patients with HFrEF and HFpEF (Seiler et al., 2016). In HFrEF, plasma concentration of TNF-a was significantly greater (Seiler et al., 2016). In HFpEF, on the other hand, plasma concentrations of IL-1b and IL-12 were significantly greater (Seiler et al., 2016). This may partially explain differences between changes in skeletal muscle in HFrEF and HFpEF (Seiler et al., 2016). Even when circulating concentrations of cytokines are unaltered, CHF increases levels of TNF-a and IL-1b and decreases levels of antiinflammatory IL-10 in skeletal muscle and other tissue (Poole et al., 2012). Cytokines influence the expression of proteins in muscle (Schulze et al., 2002). For example, IL-1b may decrease expression of SERCA and phospholamban mRNA and protein in neonatal myocytes (Schulze et al., 2002). This prolongs the calcium transient (Schulze et al., 2002). TNF-a may initiate a similar effect (Schulze et al., 2002). In advanced CHF, systemic cytokines may significantly upregulate skeletal muscle expression of inducible nitric oxide synthase (iNOS, NOS II). Increased iNOS was confirmed in skeletal muscle biopsies from patients with CHF (Gielen et al., 2003). NOS II is a calcium-independent enzyme that is expressed in immunologically activated cells in response to TNF-a, IFN-g, and IL-1b (Riede et al., 1998). These cytokines work through activation of NF-kB (Zizola and Schulze, 2013). NOS II is a source of intracellular NO (Hambrecht et al., 1999). Toxic levels of NO may inhibit enzymes related to oxidative phosphorylation, such as cytochrome c oxidase (COX), and reduce peak oxygen uptake (Gielen et al., 2003). This process may attenuate skeletal muscle contraction and mediate muscle wasting through altered metabolism (Gielen et al., 2003). As a result, increased expression of NOS II is inversely correlated with oxidative capacity, functional work capacity, and exercise tolerance in patients with CHF (Hambrecht et al., 1999). Local inflammation in skeletal muscle with increased levels of IL-1b, TNF-a, and NOS II might further contribute to the progressive deterioration of skeletal muscle structure, function, and metabolism (Maurer and Schulze, 2012). Exercise training for 6 months was shown to reduce skeletal muscle concentration of IL-1b by 27% and TNF-a by 28%, consequently decreasing iNOS expression by 32% (Adams et al., 2001; Schulze et al., 2001). A separate study on 20 male patients with stable CHF showed that exercise training did not affect serum levels of TNF-a, IL-6, and IL-1b, but did decrease skeletal muscle TNF-a, IL-6, and IL-1b (Gielen et al., 2003). In this study, exercise training reduced skeletal muscle iNOS expression by 52%. Exercise training also restores levels of the antiinflammatory mediator IL-10 (Gielen et al., 2003). Disuse-induced atrophy promotes skeletal muscle inflammation through multiple pathways (see “Muscle Atrophy” section for further discussion). Skeletal muscle inflammation reduces O2 delivery, decreases local insulin-like growth factor-1 (IGF-1) levels, and increases oxidative stress (Zizola and Schulze, 2013). Muscle inflammation induces cytokines, including IL-6 and TNF-a, which contribute to muscle wasting through activation of the NF-kB pathway (Zizola and Schulze, 2013). In rats, IL-6 increases skeletal and diaphragmatic muscle atrophy (Zizola and Schulze, 2013). It also activates the JAK-STAT and cAMP activated protein kinase (AMPK) pathways (Zizola and Schulze, 2013). Skeletal muscle inflammation increases FoxO activity, causing muscle protein degradation and atrophy through the ubiquitin-proteasome pathway (Zizola and Schulze, 2013). Systemic inflammation may also contribute to muscle atrophy. Local antiinflammatory effects of exercise may attenuate catabolic wasting associated with the progression of CHF (Gielen et al., 2003). In patients with HFrEF, increased inflammation corresponds with increased levels of adiponectin (Sente et al., 2016a). It has been shown that increased adiponectin has a protective role through antiinflammatory mechanisms (Sente et al., 2016a).

Neurologic Response and Muscle Reflexes The autonomic nervous system may be divided into the sympathetic and parasympathetic branches. In healthy subjects, exercise generally reduces parasympathetic activity and augments sympathetic activity (Fletcher et al., 2011). Sympathetic activation causes the release of norepinephrine and increases plasma concentrations of epinephrine (EPI) (Fletcher et al., 2011). In patients with CHF, there is abnormally high sympathetic activation and a withdrawal of parasympathetic activity at rest (Piepoli et al., 2001). Skeletal muscle receptors that are stimulated by work are called ergoreceptors. The two types of ergoreceptors are mechanoreceptors and metaboreceptors (Georgiadou and Adamopoulos, 2012). Mechanoreceptors are myelinated type III afferents that respond to mechanical stimuli (Georgiadou and Adamopoulos, 2012). Metaboreceptors are chemically activated unmyelinated type IV afferents that respond to metabolites (Georgiadou and Adamopoulos, 2012). Metabolites that may stimulate metaboreceptors include acidosis, prostaglandins, BK, potassium, adenosine, and lactate (Georgiadou and Adamopoulos, 2012). One study, however, suggested that K þ and phosphate stimulate muscle afferents while H þ and lactate do not (Khan and Sinoway, 2000). Some studies have challenged the distinction between the two types of ergoreceptors. The response initiated by ergoreceptors is called the ergoreflex (Georgiadou and Adamopoulos, 2012). Specifically, during exercise, the response may be called the exercise pressor reflex (Wang et al., 2012). Ergoreceptors are the basis of the muscle theory of sympathetic drive in CHF (Georgiadou and Adamopoulos, 2012). In normal patients, muscle contraction stimulates thin fiber afferents to evoke a change in blood pressure (BP) (Koba et al., 2009). The overall ergoreflex is more strongly stimulated in patients with CHF (Koba et al., 2009). Some studies have shown that responses of both mechanoreceptors and metaboreceptors are increased in CHF (Georgiadou and Adamopoulos, 2012). Others, however, have suggested that the metaboreceptor contribution to increased muscle sympathetic nerve activity is minimal or decreased in CHF

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(Koba et al., 2009). Even if metaboreceptor responses are reduced, higher accumulation of metabolites due to slower oxygen uptake, lower VO2, and other changes will still stimulate the metaboreceptors (Poole et al., 2012). In a study on rats with heart failure induced by coronary artery ligation, it was shown that continuous contraction stimulates both mechanically and metabolically sensitive muscle afferents whereas short, intermittent contraction stimulates predominantly mechanosensitive afferents (Koba et al., 2009). The ergoreflex causes global sympathetic activation (Poole et al., 2012). This includes activation of cardiovascular pathways in the central nervous system (Koba et al., 2009). Increased responses cause neurohumoral derangement, altered autonomic state, exaggerated ventilatory responses, increased circulatory responses, and exercise intolerance (Georgiadou and Adamopoulos, 2012). Specifically, sympathetic activation reduces blood flow to resting muscle to less than one-fourth of the normal value (Mohrman and Heller, 2014). Since there is usually more blood flow to skeletal muscle at rest than necessary, resting tissue metabolic processes may not be impacted by this (see “Blood Flow to Skeletal Muscle” section for further discussion) (Mohrman and Heller, 2014). Due to the large amount of skeletal muscle tissue in the body, however, changes in blood flow due to sympathetic activity play a large role in regulation of BP (Mohrman and Heller, 2014). Although changes are induced to meet metabolic needs of skeletal muscle, they become maladaptive in CHF (Francis et al., 2011). The decrease in blood flow to the periphery further increases skeletal muscle abnormalities (Francis et al., 2011). Enhanced sympathetic activity may be a factor in skeletal muscle breakdown. This shows that the reflex contributes not only to initiation of symptoms but also to CHF progression. Neural alterations of vasomotor tone impact blood flow to exercising muscle (Fletcher et al., 2011). These changes are partially induced by the ergoreflex. In healthy subjects, exercise induces sympathetic activation (Fletcher et al., 2011). Sympathetic activation causes most vascular beds to constrict to restrict blood flow to nonexercising muscles (Fletcher et al., 2011). Though sympathetic activation may cause vascular beds for exercising muscle to constrict, the effect is outweighed by vasodilatation due to metabolites (Fletcher et al., 2011). Sympathetic activation serves to prevent peripheral vasculature from dilating beyond the capabilities of maximal cardiac output in order to maintain BP (Khan and Sinoway, 2000). In patients with CHF, earlier and increased acidification and accumulation of exercising muscle metabolites increase involvement of the ergoreflex (Poole et al., 2012). Increased neurohumoral activation has been confirmed by higher plasma levels of catecholamines, renin activity, and aldosterone in patients with CHF (Piepoli et al., 2001). This increases peripheral vasoconstriction, thereby decreasing blood flow to skeletal muscle. Ergoreflex activation is significantly correlated with exercise capacity through variables including peak VO2 and the ventilation/carbon dioxide production ratio (Nicoletti et al., 2003). The correlations suggest that increased muscle afferent activity contributes to reduced exercise tolerance (Nicoletti et al., 2003). One study suggested that muscle reflexes in CHF are different in rhythmic exercise compared to static exercise (Khan and Sinoway, 2000). Using vascular resistance in the calf as a measure of sympathetic activation, it was shown that CHF patients have increased calf vascular resistance and BP during post-ischemia exercise, whereas values in controls decreased to baseline levels (Khan and Sinoway, 2000). The magnitude of the ventilatory response was also greater in patients with CHF (Khan and Sinoway, 2000). Patients with CHF had increased muscle acidosis and accumulation of Pi, which may cause increased activation of the muscle metaboreflex (Khan and Sinoway, 2000). Data also suggest that purinergic P2X receptors of muscle afferent nerves contribute to enhanced sympathetic activation and BP changes during static exercise in patients with CHF (Xing and Li, 2016). In CHF, there is increased P2X current activity and increased expression of P2X3 and kinin B2 receptors (Xing and Li, 2016). BK at least partially causes modulation of the P2X-driven responses (Xing and Li, 2016). In accordance with this, in rats with heart failure, injection of BK into the arterial blood supply of hindlimb muscles more greatly heightened responses induced by P2X activation (Xing and Li, 2016). Exercise may benefit patients with CHF by reducing the magnitude of the ergoreflex response. Positive effects may be mediated through a direct mechanism or through indirect effects on concentrations of stimulatory metabolites. In rats with CHF, exercise training prevented the sensitization of group III responses to contraction and stretch and partially prevented the decreased group IV responses to contraction and capsaicin (Wang et al., 2012). Conditioning also increases blood flow to skeletal muscle and increases the capacity for aerobic skeletal muscle metabolism, thereby decreasing anaerobic metabolism (Khan and Sinoway, 2000). As a result, acidification and concentrations of metabolites that stimulate the ergoreflex are decreased (Khan and Sinoway, 2000). These changes reduce ventilatory drive, vasoconstriction, and sympathetic activation (Piepoli et al., 2001). With exercise, the ergoreflex response in patients with CHF may be attenuated toward the level of activation in healthy subjects (Khan and Sinoway, 2000). Exercise training should be started early in CHF progression to maximally limit changes in the ergoreflex. Over-activation of the sympathetic nervous system from skeletal muscle afferents may contribute to inflammation and cytokine activation. Increased levels of TNF-a and insulin resistance may contribute to catabolic muscle wasting (Nicoletti et al., 2003). These changes may also reduce anabolic function (Nicoletti et al., 2003).

Muscle Atrophy Atrophy and Cardiac Cachexia As in many systemic diseases, skeletal muscle atrophy may be observed in patients with CHF. Atrophy occurs early in the progression of CHF prior to documented loss of weight (Georgiadou and Adamopoulos, 2012). Atrophy is indicated by decreased fiber cross-sectional area (CSA) and decreased muscle bulk, especially in the quadriceps (Nicoletti et al., 2003). One paper noted

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controversy regarding the effect of clinical status on muscle atrophy in CHF (Zizola and Schulze, 2013). Many studies have suggested that muscle protein metabolism is not impaired in stable patients, suggesting that initiation and progression of atrophy are related to events of disease exacerbation (Zizola and Schulze, 2013). Atrophy probably only plays a minor role in impairment of skeletal muscle energetics in CHF (Mettauer et al., 2006). Changes in skeletal muscle occur due to suppression of whole-body protein synthesis and augmentation of myofibrillar protein degradation (Francis et al., 2011). In patients with systolic heart failure, skeletal muscle expression of the atrophypromoting genes FoxO1 and FoxO3 was increased compared to controls (Forman et al., 2014). However, expression of other atrophy-related genes (atrogin-1 and MuRF-1), growth promoting genes (IGF-1), and inflammatory cytokines (TNF-a, C-reactive protein, IL-1b, and IL-6) was similar between groups (Forman et al., 2014). In one study, soleus tissue from patients with HFrEF, but not patients with HFpEF, showed a significant increase in markers of muscle atrophy (MuRF1, calpain, and ubiquitin proteasome) (Seiler et al., 2016). An additional mechanism may include selective atrophy of oxidative fibers (Francis et al., 2011). Eventually, atrophy transitions to the severe muscle wasting that is characteristic of cardiac cachexia. Cachexia is defined as “nonintentional documented weight loss of at least 7.5% of a previously normal weight (Francis et al., 2011).” Skeletal muscle wasting is a well-known feature of late-stage heart failure (Minotti et al., 1992). Muscle wasting in cardiac cachexia affects all tissue compartments, but it may be more apparent in the legs (Francis et al., 2011; Mettauer et al., 2006). Clinically, muscle wasting is associated with exercise intolerance. Limb and respiratory muscle weakness contribute to increased morbidity and mortality (Mangner et al., 2015). Various factors are involved in skeletal muscle atrophy and wasting.

Sarcopenia Sarcopenia refers to the normal progressive decline in muscle mass, strength, and function that occurs with aging (Maurer and Schulze, 2012). In research, it may be defined as appendicular skeletal mass (ASM) two standard deviations below the mean of a healthy reference group (Saitoh et al., 2016). As a systemic skeletal muscle disease, it impairs the function of limb skeletal muscles and respiratory muscles (Kinugasa and Yamamoto, 2016). There is a high prevalence of sarcopenia among the elderly and women (Sarma and Levine, 2015). Sarcopenia is characterized by changes involving skeletal muscle dysfunction, oxidative protein damage, cytokines, and IGF-1 (Maurer and Schulze, 2012). Since these problems are also present in CHF, sarcopenia has been identified as a serious comorbidity in patients with CHF (Dos Santos et al., 2016). Sarcopenia is an independent risk factor for mortality in patients with cardiovascular diseases (Onoue et al., 2016). With this in mind, it was shown that a sarcopenia screening test involving age, grip strength, and calf circumference can predict future adverse events in patients with CHF (Onoue et al., 2016). A Kaplan–Meier curve showed that CHF event-free survival rate was significantly lower in patients with sarcopenia (Onoue et al., 2016). In regard to CHF, sarcopenia is most often associated with HFpEF, especially in frail patients (Kinugasa and Yamamoto, 2016). Sarcopenia may contribute to the development of HFpEF through different metabolic and endocrine changes (Kinugasa and Yamamoto, 2016). Compared to symptomatic HFpEF patients without sarcopenia, those with sarcopenia performed worse during 6-min walk testing and showed lower absolute peak oxygen consumption (Bekfani et al., 2016). ASM was independently associated with reduced distance during the walk testing (Bekfani et al., 2016). Higher muscle strength and ASM values were associated with higher quality of living (Bekfani et al., 2016).

Deconditioning Physical deconditioning due to decreased physical activity likely contributes to skeletal muscle wasting in patients with CHF. Deconditioning is typically associated with muscle disuse. Overall, changes in CHF are similar to changes due to deconditioning. It has been observed that biochemical and histological alterations in skeletal muscle in CHF are similar to those caused by deconditioning (Minotti et al., 1992). Specifically, both involve atrophy, metabolic alterations with decreased oxidative enzymes, sympathetic over-activation, and decreased muscle fiber size (Nicoletti et al., 2003). In terms of exercise intolerance, deconditioning and CHF are correlated with decrements in peak systemic VO2, muscle strength, and endurance (Minotti et al., 1992). Exercise training improves both conditions. Since benefits of exercise training are nonspecific, however, improvements from exercise do not prove that deconditioning is the primary mechanism of skeletal muscle changes in CHF (Minotti et al., 1992). The similarities between CHF and deconditioning are summarized below (Table 5). Although deconditioning may contribute to skeletal muscle alterations in CHF, it does not fully explain changes in muscle structure, metabolism, and function. Some components of the CHF syndrome suggest a generalized metabolic myopathy caused by CHF (Mettauer et al., 2006). In experimental models of CHF, all muscles including the diaphragm are characterized by abnormal enzymatic and mitochondrial function (Mettauer et al., 2006). In deconditioning, only postural oxidative muscles are affected (Mettauer et al., 2006). Moreover, enzymatic changes involving CK and glycolytic systems are present in CHF but not deconditioning (Mettauer et al., 2006). Disuse atrophy causes a shift toward the slow type of MHC, which is the opposite of what occurs in patients with CHF (Nicoletti et al., 2003). Further studies are needed to fully determine the extent to which deconditioning impacts the syndrome of CHF. Regardless, localized and systemic exercise training and reconditioning may significantly alleviate changes in patients with CHF (Mettauer et al., 2006).

Skeletal Muscle in Heart Failure Table 5 2001)

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Similarities between muscular deconditioning and heart failure (Piepoli et al.,

Hemodynamics Vascular resistance Resting heart rate Max A-VO2 differences Function Exercise tolerance VO2 max Neuroendocrine/autonomic Renin/angiotensin Sympathetic Vagal activity Baroreflex sensitivity HRV Skeletal muscle Muscle mass/bulk Mitochondrial enzymes Oxidative Glycolytic Fiber type IIb/IIa ratio Psychological Well-being Activity scores

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Muscle Cell Apoptosis Apoptosis often occurs in skeletal muscle of patients with CHF. This has been confirmed in skeletal muscle biopsies (Hambrecht et al., 2002). Ultrastructural analysis reveals a higher number of apoptotic myocytes (Nicoletti et al., 2003). Though there are over 100 nuclei in each muscle fiber, only a minority of the nuclei display DNA fragmentation, which indicates cell death (Schulze et al., 2002). Impaired endothelial nitric oxide synthase (eNOS) expression is one factor associated with increased skeletal muscle apoptosis (Georgiadou and Adamopoulos, 2012). Apoptosis leads to decreased muscle bulk, decreased contractility, and increased muscle atrophy (Schulze et al., 2002). As a result, it is also associated with reduced exercise tolerance. It has been suggested, however, that apoptosis may minimally contribute to decreased muscle mass (Mettauer et al., 2006). Many genes that regulate apoptosis are altered in CHF. Oncogenes including c-myc and bcl2 are reduced (Nicoletti et al., 2003). Tumor suppressor genes, including p53, and other factors that increase apoptosis, including NOS, nitric oxide, caspase-3, and ubiquitin, are increased (Nicoletti et al., 2003).

Growth Hormone/IGF-1 Axis Many factors influence expression of IGF-1 in skeletal muscle. Serum levels of IGF-1 and growth hormone (GH) influence skeletal muscle expression of IGF-1. Nonhumoral stimuli may also stimulate IGF-1 expression (Schulze et al., 2002). One study showed that 4 days of muscle stretch, the strongest nonhumoral stimulus, induced upregulation of IGF-mRNA as soon as 12 h later (Schulze et al., 2002). Skeletal muscle IGF-1 levels are modified by muscle use (Schulze et al., 2002). In neonatal rats, muscle unloading by zero gravity caused decreased expression of IGF-1 in skeletal muscle (Schulze et al., 2002). The GH/IGF-1 axis is a regulator of normal growth, hypertrophy, and atrophy (Hambrecht et al., 2002). Binding of IGF-1 to receptors induces cellular proliferation and protection from apoptosis. It also prevents TNF-a induced cell death (Hambrecht et al., 2002). Patients with CHF may have increased levels of GH with unusually normal or low serum levels of IGF-1 (Hambrecht et al., 2002). These findings suggest the development of GH resistance in CHF patients (Hambrecht et al., 2002). Local levels of IGF-1 are reduced before systemic changes are apparent (Hambrecht et al., 2002). Skeletal muscle biopsies from noncachectic patients with CHF had downregulated skeletal muscle expression of IGF-1 but normal serum concentrations of IGF-1 (Schulze et al., 2002). Changes in the GF/IGF-1 axis contribute to the loss of muscle bulk, muscle wasting, and eventually clinically recognizable cachexia (Hambrecht et al., 2002). Pathophysiological changes related to alterations in the GH/IGF-1 axis in patients with CHF have been characterized. Insulin resistance in CHF may be caused by proinflammatory cytokines and oxidative stress (Georgiadou and Adamopoulos, 2012). Combined with decreased levels of IGF-1, this decreases activation of protein kinase B (Akt) in skeletal muscle (Georgiadou and Adamopoulos, 2012). Decreased Akt activation decreases phosphorylation of mammalian target of rapamycin (mTOR) and

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glycogen synthase kinase, thereby decreasing protein synthesis (Georgiadou and Adamopoulos, 2012). Moreover, decreased Akt activation upregulates FoXO transcription factors (Georgiadou and Adamopoulos, 2012). FOXO transcription factors activate the ubiquitin proteasome pathway of protein degradation by activating ubiquitin-protein ligase atrogin-1/MAFbx (Georgiadou and Adamopoulos, 2012). Decreased levels of IGF-1 also activate caspase-3, which also contributes to protein degradation through the ubiquitin proteasome (Georgiadou and Adamopoulos, 2012). In a murine heart failure model with whole body insulin resistance, serine phosphorylation of Akt and glucose transporter 4 (GLUT4) in skeletal muscle is impaired by NAD(P)H oxidase-derived superoxide (Tsutsui et al., 2011). NAD(P)H oxidase inhibitor alleviated insulin resistance and signaling deficiencies in skeletal muscle (Tsutsui et al., 2011). Similarly, in skeletal muscle from post-infarction mice, it was shown that insulin-stimulated serinephosphorylation of Akt decreased by 57% and GLUT4 translocation decreased by 69% (Fukushima et al., 2016). In this study, aliskiren, a direct renin inhibitor, alleviated changes, inhibited plasma renin, and decreased angiotensin II (Ang II) levels (Fukushima et al., 2016). Increased levels of Ang II suppress IGF-1 signaling through the Akt/mTOR/p70S6k pathway (Zizola and Schulze, 2013). Ang II also activates caspase-3, actin cleavage, ubiquitination, and apoptosis (Zizola and Schulze, 2013). Renin inhibitors may reduce insulin resistance (Fukushima et al., 2016). It has not yet been determined if ACEi improve skeletal muscle in patients with CHF through the IGF-1 pathway or through direct effects on vascular endothelial function (Zizola and Schulze, 2013). Skeletal muscle changes due to alterations in the GH/IGF-1 pathway have also been characterized. In noncachectic patients, low levels of systemic IGF-1, which occur in advanced stages of CHF, are associated with decreased leg muscle CSA and strength (Hambrecht et al., 2002). Even when serum IGF-1 levels are not significantly altered in patients with CHF, quadriceps skeletal muscle may have reduced IGF-1 mRNA expression and increased IGF-1 receptor mRNA expression (Hambrecht et al., 2002). Increased receptor expression, however, is unable to compensate for IGF-1 deficits that lead to atrophy (Hambrecht et al., 2002). Atrophy is accompanied by fatigability and reduced total muscle CSA that closely correlates with local IGF-1 expression (Hambrecht et al., 2002). Exercise training, which serves as a natural cause of muscle stretch, may alleviate CHF symptoms through the GH/IGF-1 pathway (Schulze et al., 2002). One study showed that local IGF-1 expression more than doubled after 6 months of exercise training in patients with CHF (Schulze et al., 2002). Specifically, long-term aerobic exercise training (AET) has been recommended as an intervention for the IGF-1 deficient, catabolic state (Schulze et al., 2002). In mice, AET activated the IGF-1/Akt/mTOR pathway (Bacurau et al., 2016). This reduced exercise intolerance, soleus atrophy, and 26S proteasome hyperactivity (Bacurau et al., 2016). It also decreased levels of myostatin and Smad2 while preventing reduction of IGF-1, pAkt, p4E-BP1, and pP70 (Bacurau et al., 2016). Rapamycin treatment prior to AET limited beneficial effects of AET, showing that AET-mediated benefits may involve the IGF-1 pathway (Bacurau et al., 2016). Alternatively, therapies may focus on reducing GH resistance in patients with skeletal muscle wasting (Nicoletti et al., 2003). Cytokine antagonists, catabolic hormone antagonists, and amino acid supplementation may all reduce problems related to the GH/IGF-1 axis (Pasini et al., 2003).

Biochemical Pathways Impaired energy metabolism contributes to skeletal muscle wasting. In mice, CK deficiency induced skeletal muscle wasting through activation of AMP-activated protein kinase (Mettauer et al., 2006). In a Wistar Kyoto rat model of CHF, muscle wasting was related to changes in antioxidative capacity (Mangner et al., 2015). In the quadriceps, antioxidative capacity was reduced, as shown by reduced glutathione peroxidase and manganese SOD activity (Mangner et al., 2015). COX activity decreased and LDH activity increased (although other studies have shown that LDH activity decreases—see “Metabolic Changes” section for further discussion) (Mangner et al., 2015). On the contrary, in the diaphragm, antioxidative capacity increased, as shown by increased glutathione peroxidase and manganese SOD activity (Mangner et al., 2015). Metabolic enzymes in the diaphragm were unaltered (Mangner et al., 2015). In both quadriceps and the diaphragm, catabolic responses and myopathy were increased, as shown by increased protein expression of the E3 ligase muscle ring finger 1 and proteasome activity (Mangner et al., 2015). Long-term exercise training may improve skeletal muscle COX activity (Schulze et al., 2002). Protein degradation pathways play a role in muscle wasting. One major protein degradation pathway is the ubiquitinproteasome pathway. In this pathway, proteins tagged with ubiquitin are degraded through a 26S proteasome in an ATP-dependent manner (Zizola and Schulze, 2013). The ubiquitin-proteasome pathway may be activated by factors in CHF, including Ang II and cytokines (TNF-a and IL-1) (Zizola and Schulze, 2013). A study on skeletal muscle in 4-week old Wistar rats with heart failure induced by MCT showed that the ubiquitin-proteasome and macroautophagolysosome pathways were activated even before morphological changes were present in skeletal muscle (Fujita et al., 2015). Skeletal muscle from mice with left ventricular dysfunction revealed activation of the ubiquitin-proteasome pathway with increased protein ubiquitination, FoxO transcription factor activation, increased expression of muscle-specific atrogenes and overall muscle atrophy (Zizola and Schulze, 2013). Increased activation of the ubiquitin-proteasome system in skeletal muscle was further shown in a sympathetic hyperactivity mouse model of CHF (Cunha et al., 2012). In this study, AET normalized levels of lipid hydroperoxides, carbonylated proteins, and E3 ligase mRNA (Cunha et al., 2012). Moreover, it restored chymotrypsin-like proteasome activity, which has also been observed in human skeletal muscle (Cunha et al., 2012). Studies suggest that physical exercise, especially prior to recognizable skeletal muscle atrophy, should be implemented to reduce over-activation of protein degradation pathways (Fujita et al., 2015). In CHF, increased PGC-1a, which is related to mitochondrial function and moderation of FoxO activity, may also reduce declines due to the ubiquitin pathway (Forman et al., 2014).

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Circulating Factors Patients with advanced CHF and cachexia have increased Ang II levels (Yoshida and Delafontaine, 2016). Ang II, via its type 1 receptor, causes muscle protein breakdown and apoptosis (Yoshida and Delafontaine, 2016). It also inhibits satellite cell proliferation and muscle regeneration (Yoshida and Delafontaine, 2016). Via the type 2 receptor (AT2R), however, Ang II potentiates muscle regeneration (Yoshida and Delafontaine, 2016). In a mouse model of CHF, muscle regeneration was reduced and AT2R expression was slightly increased (Yoshida and Delafontaine, 2016). The researchers suggested that an intronic enhancer (specifically AT2R intron 2) that regulates AT2R expression during stem cell (SC) differentiation is suppressed in CHF, thereby decreasing muscle regeneration (Yoshida and Delafontaine, 2016). Skeletal muscle biopsies from patients with HFrEF indicate increased local concentrations of adiponectin in addition to circulating levels (Sente et al., 2016a). In patients with HFrEF, circulating adiponectin levels increase relative to the severity of the disease (Sente et al., 2016a). Adiponectin resistance in skeletal muscle may be related to increased free fatty acid availability and skeletal muscle wasting (Sente et al., 2016a). Various other factors may be involved. Studies have shown an elevated cortisol to dehydroepiandrosterone ratio in patients with CHF (Schulze et al., 2002). In male patients with CHF, deficiencies in anabolic hormones, such as testosterone and dehydroepiandrosterone, correlate with a poor prognosis (Zizola and Schulze, 2013). Studies have also shown high levels of catecholamines, which would influence resting metabolic rate (Schulze et al., 2002; Hambrecht et al., 2002). One abstract focusing on 53 CHF patients with severely impaired exercise intolerance suggested that significantly increased serum concentrations of leptin, a hormone related to energy expenditure and weight loss, may be involved in catabolic alterations in patients with severe left ventricular dysfunction (Adams et al., 2001; Schulze et al., 2001) Many studies have shown that increased levels of circulating myostatin, a factor secreted by skeletal muscle, may contribute to muscle atrophy in CHF through antianabolic and antihypertrophic mechanisms (Zizola and Schulze, 2013). Studies related to changes in the concentration of circulating myostatin in patients with CHF, however, show conflicting results. Alterations involving aldosterone, renin, melanocortins, neuropeptide Y, and ghrelin have been observed (Georgiadou and Adamopoulos, 2012). Finally, sympathetic activation and cytokines (TNF-a, IL-6, IL-1b) contribute to muscle wasting.

Nutrition Skeletal muscle plays an important role in metabolism. It exchanges amino acids with the liver (Pasini et al., 2003). These amino acids are used to produce glucose through gluconeogenesis during malnutrition (Pasini et al., 2003). Malnutrition has been shown to be related to muscle wasting and cachexia in patients with CHF. One study showed that 24% of patients with CHF are malnourished, whereas 68% have muscle atrophy (Pasini et al., 2003). Another study involving 130 ambulatory patients with CHF showed that poor nutritional status is related to poor clinical outcomes (Saitoh et al., 2016). In the study, patients with muscle wasting had significantly lower values of peak VO2, 6-minute walk distance, and Mini-Nutritional Assessment-Short Form (MNA-SF) score (Saitoh et al., 2016). In multivariate analysis, MNA-SF remained an independent predictor of muscle wasting and mortality, leading the researchers to suggest that nutritional screening should be included as a fundamental part of patient assessment (Saitoh et al., 2016). Exogenous amino acid supplementation may serve as an alternative therapy for patients with CHF and poor nutritional status (Pasini et al., 2003). Amino acids may increase anabolic processes and reduce catabolic processes (Pasini et al., 2003).

Clinical Muscle Weakness Reduced skeletal muscle mass, especially at the stage of cachexia, contributes to exercise intolerance in patients with CHF. Patients consistently show a reduction in muscle bulk and endurance. In one study, static and dynamic endurance were markedly decreased in patients with CHF (Minotti et al., 1992). There was a relationship between dynamic endurance and peak systemic VO2 in patients with CHF (Minotti et al., 1992). In another study, CHF patients underwent localized unilateral arm training (Minotti et al., 1992). The training doubled or tripled wrist flexor endurance although the muscle size did not change (Minotti et al., 1992). The changes were associated with improvements in muscle oxidative metabolism, as shown by a slower increase of Pi and decrease of PCr (Minotti et al., 1992). Some studies have suggested that muscle strength is not impaired in patients with CHF, although others have reported reduced muscle strength (Nicoletti et al., 2003). A study on patients with severe CHF showed that patients only had 55% of the predicted strength (Minotti et al., 1992). A different preliminary study comparing quadriceps strength and endurance in nine patients with CHF to five sedentary controls found that isometric strength was similar between the groups, although they suggested that this might be due to a wide range of clinical severity (Minotti et al., 1992). After normalizing work load to an individual’s maximal strength, a group showed that the maximum load in patients with CHF was 30% lower compared to controls (Minotti et al., 1992). Muscle contractility may also be altered by atrophy. One study focused on contractility in the soleus because it is a primary site of muscle atrophy (Panizzolo et al., 2016). Compared to age- and activity-matched controls, CHF patients had reduced passive soleus force at the same relative levels of muscle stretch (though the results were not statistically significant) (Panizzolo et al., 2016). The reduction was eliminated when normalized by CSA, showing that force output reduction may be most strongly associated with muscle size (Panizzolo et al., 2016). Passive force was also significantly higher in CHF patients at an absolute muscle length, which

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could potentially be explained by shorter muscle slack lengths (Panizzolo et al., 2016). A second study related to muscle shortening showed decreased maximal force, speed, and power (Coggan and Peterson, 2016). This study, however, suggested the changes may be related to decreased NO availability (Coggan and Peterson, 2016).

Blood Flow to Skeletal Muscle Blood flow to tissue is related to the level of metabolic activity. Cardiovascular hemodynamics are impacted by skeletal muscle due to its large mass (Mohrman and Heller, 2014). At rest, skeletal muscle receives 15%–20% of cardiac output (Fletcher et al., 2011; Mohrman and Heller, 2014). This is partially due to a high basal vascular tone (Mohrman and Heller, 2014). Resting skeletal muscles normally extract only 25%–30% of the oxygen delivered through blood flow (Mohrman and Heller, 2014). This means that, although blood flow to skeletal muscle is relatively low, it is still significantly greater than the flow necessary for metabolic requirements (Mohrman and Heller, 2014). During strenuous exercise, skeletal muscle may receive greater than 80%–85% of cardiac output (Fletcher et al., 2011; Mohrman and Heller, 2014). Specifically, this may be a change from 4–7 mL/min of blood per 100 g of skeletal muscle during rest to 50–75 mL/min of blood per 100 g of muscle during exercise (Fletcher et al., 2011). Blood flow in active skeletal muscle is mostly directed to oxidative portions rather than glycolytic portions (Fletcher et al., 2011). Patients with CHF have reduced blow flow to skeletal muscle. Due to reduced cardiac output in CHF, circulatory regulation must decrease blood supply to exercising skeletal muscle in order to prevent dangerous changes in BP (Poole et al., 2012). Reduced blood flow impairs peripheral perfusion, causing reduced oxygen supply to skeletal muscle despite increased oxygen demands (Poole et al., 2012). Researchers are unsure if skeletal muscle changes in CHF are related to a CHF-specific myopathy or secondary effects of reduced blood flow in exercising muscle (Nicoletti et al., 2003). Changes secondarily affect respiratory, vascular, and locomotor muscle function (Poole et al., 2012). Skeletal muscle in patients with CHF has changes related to capillaries. Many studies have shown that capillary density is reduced in the skeletal muscle. In a rat model of heart failure induced by MCT injection, capillary-to-fiber ratio was lower in the oxidative plantaris region but not in the glycolytic region (Wust et al., 2012). Some researchers suggest that, due to fiber atrophy, the number of capillaries per fiber area is unchanged (Mettauer et al., 2006). Post-capillary resistance is increased, which impairs blood flow (Poole et al., 2012). The combination of slowed capillary hemodynamics and reduced blood flow velocity helps to maintain normal levels of oxygen extraction (Mettauer et al., 2006). As a result, arteriovenous oxygen difference is typically normal during exercise in patients with CHF (Mettauer et al., 2006). Changes in skeletal muscle blood flow are strongly related to alterations in vascular tone. Patients with CHF have increased peripheral vasoconstriction along with defective vasodilatation. Increased vasoconstriction may be caused by increased plasma concentrations of catecholamines, renin, Ang II, vasopressin, and endothelin-1 (Poole et al., 2012). Peripheral chemoreceptors and metaboreflexes also contribute to vasoconstriction through increased sympathetic activation of a-adrenergic tone (Poole et al., 2012). Experimental and clinical studies suggest that decreased vasodilatation, on the other hand, may be caused by vascular stiffness and resistance from alterations in arterial wall sodium content (Minotti et al., 1992). Vasodilatation is impaired by salt and water retention and improved by diuresis (Poole et al., 2012). In a study comparing dynamic, single leg knee-extensor exercise in patients with HFpEF compared to healthy controls, HFpEF patients showed significant attrition during more intensive exercise related to a marked reduction in leg blood flow and leg vascular conductance that was not attributed to disease-related changes in central hemodynamics (Lee et al., 2016). This suggested that impaired vasodilatation in exercising skeletal muscle vasculature impacts exercise intolerance in patients with HFpEF (Lee et al., 2016). Lower vasodilatation capability particularly impacts exercise tolerance in patients with sarcopenia (Dos Santos et al., 2016). Altered vascular tone also decreases flow of nutrients to skeletal muscle during exercise (Mettauer et al., 2006). This decreases oxygen and substrate supply to myocytes and reduces the increase in oxygen uptake at the beginning of exercise (Mettauer et al., 2006). Vasodilatation may also be impaired through endothelial dysfunction. A study in 228 patients with CHF and sarcopenia confirmed the presence of impaired endothelial function (Dos Santos et al., 2016). Endothelial dysfunction may be augmented by endothelial cell damage and decreased capacity for repair due to low circulating levels of endothelial progenitor cells (Poole et al., 2012). In patients with CHF, there is reduced production and release of endothelium-derived vasodilator factors, such as NO, in response to acetylcholine (Piepoli et al., 2001). Basal release of NO, however, may be preserved or enhanced as a compensatory mechanism (Francis et al., 2011). NO has general antiatherogenic and antithrombotic effects (Fletcher et al., 2011). Decreased NO levels reduce the ability to oppose a-adrenergic vasoconstriction and reduce vasodilatation caused by shear stress (Poole et al., 2012). This causes oxygen delivery-utilization mismatch, in which microvascular oxygenation falls faster during increased metabolic demand (Hirai et al., 2014). It also reduces exercise tolerance in patients with HFrEF (Hirai et al., 2017). Endothelial dysfunction may be partially related to deconditioning, and it may be reversed through exercise (Francis et al., 2011). Exercise may alleviate changes in skeletal muscle blood flow in patients with CHF. Exercise may increase muscle capillarity in patients with CHF through preservation of vascular endothelial growth factor pathways (Poole et al., 2012). In a study comparing stable patients with CHF to healthy controls, it was shown that acute exercise affects microcirculation in peripheral, nonexercising muscles in a different way in patients with CHF (Tzanis et al., 2016). Specifically, patients with CHF had lower muscle oxygen saturation (StO2) and reperfusion rate at rest (Tzanis et al., 2016). Oxygen consumption rate increased after exercise in both patients with CHF and healthy controls (Tzanis et al., 2016). StO2 decreased significantly after maximal exercise in patients with CHF, whereas it returned to preexercise values in healthy subjects (Tzanis et al., 2016). In a study on rats with CHF, exercise training

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slowed the overall fall in microvascular oxygenation during contractions (Hirai et al., 2014). This effect was not abolished by N(G)nitro-L-arginine methyl ester (Hirai et al., 2014). Moreover, sodium nitroprusside increased mean response time in both groups, thereby slowing kinetics in trained CHF rats (Hirai et al., 2014). The researchers concluded that improved NO-mediated function is not obligatory for training-induced improvements in skeletal muscle microvascular oxygenation in rats with CHF (Hirai et al., 2014). In a third study, it was shown that exercise training enhances endothelium-dependent coronary and peripheral arterial vasodilatation in patients with CHF (Fletcher et al., 2011). Exercise may improve vascular function through increasing arterial wall shear stress, which promotes enhanced expression and activation of eNOS through Akt-dependent phosphorylation (Fletcher et al., 2011). Exercise may also improve vascular endothelial function through elevation of circulating endothelial progenitor cells and improved endothelial repair (Poole et al., 2012).

Exercise Exercise intolerance is one of the primary features of CHF. It is often accompanied by fatigue. Patients are often categorized based on results from cardiopulmonary exercise testing (Fletcher et al., 2011). Treadmill exercise time with the Naughton protocol is an alternative method of testing that is simple and accessible (Fletcher et al., 2011). Exercise intolerance is highly related to mortality in patients with CHF (Mettauer et al., 2001). Exercise intolerance is not correlated with left ventricular ejection fraction, which suggests that it may be instead related to peripheral abnormalities including blood flow to muscles and skeletal muscle dysfunction (Francis et al., 2011; Maurer and Schulze, 2012; Nicoletti et al., 2003). As mentioned throughout this paper, many factors contribute to reduced exercise capacity. Many maladaptive changes related to exercise intolerance are reversible. Systemic exercise capacity is most commonly described in terms of peak oxygen uptake (VO2 max). In healthy subjects, exercise capacity is related to cardiac output and peripheral oxygen delivery in response to metabolic demands (Minotti et al., 1992). At maximal exercise, VO2 max is achieved and oxygen uptake plateaus (Minotti et al., 1992). In patients with CHF, however, there is only a weak relationship between VO2 max and ejection fraction (Minotti et al., 1992). Skeletal muscle CSA, though, is an independent predictor of VO2 max (Harrington et al., 1997). A study showed that patients with HFpEF had reduced VO2 max and 6-min walk distances (Kitzman et al., 2014). In another study, addition of arm exercise to maximal leg exercise increased VO2 max, showing that the decline in VO2 max is not related to decreased cardiac output (Mettauer et al., 2006). In CHF patients, fatigue occurs prior to reaching VO2 max (Minotti et al., 1992). These observations suggest that VO2 max alterations, like other factors in exercise intolerance, are due to skeletal muscle abnormalities. Exercise capacity may also be characterized by other variables. VO2 kinetics are related to the speed of adjustments in oxygen uptake (Poole et al., 2012). Kinetics are slowed to several minutes in patients with CHF (Poole et al., 2012). This means that, for any metabolic transition, patients with CHF incur a greater oxygen deficit and more extreme intracellular perturbation of high-energy phosphagens (Poole et al., 2012). Slowed kinetics also accelerate glycogenolysis and contribute to fatigue and exercise intolerance (Poole et al., 2012). Anaerobic threshold (AT), also called lactate threshold, is the level of exercise beyond VO2 max at which increased anaerobic metabolism results in lactate accumulation (Minotti et al., 1992). Typically, AT occurs at 50%–60% of peak exercise (Tomono et al., 2016). In patients with CHF, however, AT occurs at low absolute VO2 levels (Poole et al., 2012). This means that patients with the most compromised oxygen delivery to muscle may have the highest oxygen requirements during exercise (Poole et al., 2012). In a study on 194 stable, optimally treated patients with CHF, the ratio of AT to VO2 max (%AT/peak) showed a significant negative correlation with VO2 max but not AT (Tomono et al., 2016). Although this showed that decreased VO2 max is the primary mechanism of decline, AT is still a well-known factor in evaluating patients (Tomono et al., 2016). Lastly, patients with CHF have an increased ventilation response (VE/VCO2) (Cicoira et al., 2001). This means that patients ventilate at a higher level for a given rate of carbon dioxide production (Cicoira et al., 2001). Ventilation is partially stimulated by the muscle metaboreflex. A study showed that skeletal muscle mass independently predicts VE/VCO2 (Cicoira et al., 2001). Changes in ventilation may be related to alterations in respiratory muscle (Nicoletti et al., 2003). Appropriate exercise training is safe in patients with CHF. It may improve exercise tolerance through noncardiac factors including skeletal muscle structure and function, metabolic changes, peripheral blood flow, oxygen utilization, and endothelial function. In a study on patients with CHF, isolated quadriceps training improved maximal exercise capacity (Esposito et al., 2011). Exercise training also increases VO2 max. In a meta-analysis of trials by the European Heart Failure Training Group, exercise improved VO2 max by up to 2 mL/kg/min1, which is similar to the most effective pharmaceutical treatments, such as ACE inhibitors (Schulze et al., 2002). In a study on 20 male patients with stable CHF, training improved VO2 max by 29% (Gielen et al., 2003). Improvements in all of these factors positively contribute to quality of life. Some of the benefits of exercise are summarized below (Tables 6 and 7). Exercise training increases skeletal muscle bulk and CSA in patients with CHF (Piepoli et al., 2001). In male Wistar rats with ascending aortic stenosis that induced CHF, exercise prevented catabolic processes and muscle wasting (Souza et al., 2014). It did not, however, impact expression of anabolic factors (Souza et al., 2014). Similar changes are observed in patients with CHF. Improvements in muscle bulk and CSA lead to improved function in terms of strength, peak work rate, endurance, and fatigability (Piepoli et al., 2001). Although aerobic exercise is the most often suggested form of exercise, other forms of exercise may have specific effects and benefits. Resistance training may target muscle hypertrophy and lengthening through generation of new sarcomeres (Panizzolo et al., 2016). This was confirmed in one study on patients with CHF with reduced soleus size and passive force

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Exercise training in CHF (Schulze et al., 2002)

Exercise training in chronic heart failure Skeletal muscle

Endothelial function

Oxidative enzymes " Fiber type shift (type II–type I) Local IGF-1 expression " iNOS expression # Skeletal muscle mass "?

Agonist-mediated endothelium-dependent peripheral vasodilation " Afterload reduction

Table 7

Skeletal muscle benefit of exercise training (Piepoli et al., 2001)

1. Morphology 2. Function

3. Blood flow 4. Metabolism

5. Ultrastructural

" Cross sectional area " Peak work rate " Strength " Endurance # Fatigability " Leg oxygen delivery # Leg vascular resistance " O2 arterio-venous differences " Oxidative metabolism " Adenosine triphosphate re-synthesis #/$ Anaerobic metabolism # Lactate accumulation, acidosis # Phosphocreatinine depletion " Mitochondria size " Aerobic enzyme activity " Fiber size " Capillary density " Endothelium function " NO release

(Panizzolo et al., 2016). In another study, nondominant wrist flexor training improved oxidative capacity in skeletal muscles during submaximal work load (Volaklis and Tokmakidis, 2005). Further studies have shown that resistance training increases CSA of the quadriceps femoris, muscle fiber area, and oxidative capacity (Volaklis and Tokmakidis, 2005). Improvements due to resistance training are related to functional improvements demonstrated in 6-min walking tests (Volaklis and Tokmakidis, 2005). Highintensity interval training (HIIT) is a specific form of AET. In one study on 13 males with CHF, HIIT increased type I fibers, fiber CSA, capillary to fiber ratio, and expression of IGF-1 and insulin-like growth factor binding protein (IGFBP)-3 (Tzanis et al., 2016). In a second study on 26 patients with CHF, 12 weeks of HIIT at 85%–95% of peak VO2 improved maximal exercise capacity and exercise hemodynamics (Spee et al., 2016). Improvements in recovery were related to attenuated skeletal muscle deoxygenation rather than cardiac output (Spee et al., 2016). HIIT may specifically reduce skeletal muscle myopathy and improve microvascular delivery and utilization (Spee et al., 2016).

Other Approaches to Treatment This section will briefly list various programs, treatments, and potential therapies that have been suggested in addition to exercise. Cardiac rehabilitation is increasingly applied to patients with CHF (Taub, 2016). It is newly indicated for patients with stable CHF with an ejection fraction below 35% (Taub, 2016). It may also be helpful in cases of HFpEF, which has limited treatment options (Taub, 2016). Exercise training is still a primary focus in cardiac rehabilitation, but it is combined with nutrition, BP management, and lipid management (Taub, 2016). Two intensive 72-h cardiac rehabilitation approaches include the Ornish and Pritikin programs (Taub, 2016). The Ornish program involves a 100% plant-based diet and live instructors (Taub, 2016). Patients in this program showed regression in coronary atherosclerosis (Taub, 2016). The Pritikin program involves some lean meat and fish, inclusion of video instruction and customizable steps (Taub, 2016). Patients in this program showed improvement in biomarkers like HbA1c (Taub, 2016). Cardiac rehabilitation improves mitochondrial function and nitric oxide function while also inducing antiinflammatory effects (Taub, 2016). Patients who participate in these programs have decreased levels of all-cause mortality, risk of reinfarction, and readmission (Taub, 2016).

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A combination of physical training and certain drug therapies, such as administration of ACEi and Ang II-receptor blockers, may better improve exercise tolerance and characteristics of skeletal muscles (Georgiadou and Adamopoulos, 2012). One study showed than irbesartan, an Ang II type I receptor blocker, prevents myocyte apoptosis, muscle atrophy, and changes in MHCs in experimental CHF (Nicoletti et al., 2003). The researchers suggested that irbesartan limits activity of TNF-a and Ang II to reduce levels of apoptosis (Nicoletti et al., 2003). Beta blockers may also be used to reduce sympathetic activation in patients with CHF. It is yet to be determined if pharmacologic interventions including beta blockers and inhibition of the renin-angiotensin-aldosterone system have an impact on maladaptive changes in skeletal muscle (Maurer and Schulze, 2012). Patients with CHF have elevated GH but reduced IGF-1 and IGFBP-3 (Khawaja et al., 2014). It has been shown that IGF-1 inversely modulates key atrophy induced genes via the PI3K/Akt/mTOR pathway, meaning this pathway may be potentially useful as a target for antiatrophic therapies (Georgiadou and Adamopoulos, 2012). In one study of patients with advanced heart failure, ventricular assist device (VAD) implantation increased skeletal muscle expression of IGF-1 10-fold and IGFBP-3 5-fold (Khawaja et al., 2014). Moreover, implantation enhanced oxidative gene expression (CD36, CPT1, and PGC1a) and oxidation rates (Khawaja et al., 2014). VAD implantation also increased the oxidative muscle fiber proportion, fiber CSA, and hand grip strength (Khawaja et al., 2014). Studies on the impact of a nitrate-rich diet in patients with CHF have had varied results. In one study on patients with HFrEF, even though nitrate-rich supplementation resulted in a significantly higher plasma nitrite concentration, there was no significant difference in the time to exercise intolerance between nitrate and placebo groups (Hirai et al., 2017). Moreover, there were no significant differences in central hemodynamics, arterial BP, pulmonary oxygen uptake kinetics, skeletal muscle oxygenation, or blood lactate concentrations (Hirai et al., 2017). Other studies, however, have endorsed positive effects of a nitrate-rich diet. One study suggested that dietary nitrate supplementation improves skeletal muscle vascular function during exercise in rats with CHF (Ferguson et al., 2016). Another study on patients with CHF suggested that acute ingestion of nitrate-rich beetroot juice, a source of NO via the NO synthase-independent enterosalivary pathway, increased maximal muscle speed and power (Coggan and Peterson, 2016). A third study on nine patients with systolic heart failure showed that acute dietary nitrate intake is well tolerated, enhances NO bioavailability, and increases muscle power. The treatment did not alter BP or incite adverse clinical events. These three studies support nitrate-rich diet supplementation, especially with beetroot juice, as a novel therapeutic modality for the treatment of patients with CHF (Coggan et al., 2015). Other potential therapies include enhanced external counterpulsation (Melin et al., 2016), therapeutic ultrasound to modulate inflammation (Rossato et al., 2015), autologous transplantation of satellite cells to reduce myopathy (Castellani et al., 2013), and activation of peroxisome proliferator-activated receptor delta (Myers and Yoshioka, 2015).

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Sleep and Circadian Cardiovascular Medicine K Kario, Jichi Medical University School of Medicine, Shimotsuke, Tochigi, Japan © 2018 Elsevier Inc. All rights reserved.

Sleep Disturbance and Cardiovascular Disease Obstructive Sleep Apnea Syndrome Sleep Deprivation and Insomnia Sleep Duration and Cardiovascular Disease Sleep Quality and Cardiovascular Disease Sleep and Subclinical Cardiovascular Disease Sleep and Diabetes Sleep and Sympathetic Nervous System Sleep and Blood Pressure Sleep Duration Adults Elderly Sex-difference Adolescents Sleep Quality Sleep and Circadian Rhythm Circadian Rhythm Nocturnal Blood Pressure During Sleep Disrupted Circadian Rhythm in Blood Pressure Office and Home BP Variability The Trigger Technique, a Novel Method of Nocturnal Blood Pressure Monitoring at Home Sleep Hygiene and Medication References

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Sleep Disturbance and Cardiovascular Disease Recent studies have demonstrated that sleep disturbance is closely associated with hypertension, metabolic disease, and various types of cardiovascular disease (CVD) (Fig. 1) (Shimamoto et al., 2014; Kario, 2015a, 2016; St-Onge et al., 2016; Grandner et al., 2016). Sleep disturbance includes sleep deprivation, shift-working, insomnia, obstructive sleep apnea syndrome (OSAS), restless leg syndrome, narcolepsy, etc.

Obstructive Sleep Apnea Syndrome OSAS is the most common sleep-related breathing disorder. In OSAS, the throat narrows or collapses repeatedly during sleep, causing apnea events; in addition, intermittent hypoxia and hypercapnia, recurrent arousals, and increase in respiratory efforts lead to secondary sympathetic activation, an increase in intrathoracic pressure, oxidative stress, and systemic inflammation (Fig. 1) (Kario, 2009, 2016; Lévy et al., 2015; Malhotra et al., 2015; Bradley and Floras, 2009). OSAS is associated with metabolic syndrome, hypertension, and CVDs including stroke, coronary artery disease (CAD), arrhythmias, heart failure (HF), and aortic dissection. Several population-based studies have demonstrated an increased incidence of baseline and future hypertension in subjects with OSAS (Lévy et al., 2015; Malhotra et al., 2015; Bradley and Floras, 2009). In addition, OSAS is the most common secondary cause of resistant hypertension.

Sleep Deprivation and Insomnia There is increasing evidence that poor quantity and/or quality of sleep due to causes other than SAS, such as poor sleep hygiene (sleep deprivation, irregular falling asleep time, shift working) and insomnia, are closely associated with cardiometabolic risk factors, hypertension, and various CVDs and poor prognosis (Fig. 1) (Shimamoto et al., 2014; Kario, 2015a; St-Onge et al., 2016; Grandner et al., 2016). Sleep deprivation has become an important health problem in our modern 24-h society, with evidence showing that people in Western countries are sleeping on average only 6.8 h per night, 1.5 h less than a century ago (Nagai et al., 2010). Chronic insomnia is disrupted sleep that occurs at least three nights per week and lasts at least 3 months. People with insomnia tend to have difficulty falling asleep (onset) or staying asleep (maintenance), and/or they wake up too early in the morning. People with insomnia can feel dissatisfied with their sleep and usually experience one or more of the following symptoms: fatigue, low energy, difficulty concentrating, mood disturbances, and decreased performance in work or at school. Chronic

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Fig. 1 Sleep disturbance and its relation to the mechanism of cardiovascular disease. BP, blood pressure.

insomnia disorders can have many causes. Changes in the environment, unhealthy sleep habits, shift work, other clinical disorders, and certain medications can lead to a long-term pattern of insufficient sleep. Recent guidelines and/or statements from health organizations stress the importance of sleep hygiene for the management of hypertension and CVD prevention (Shimamoto et al., 2014; St-Onge et al., 2016).

Sleep Duration and Cardiovascular Disease Both shorter and longer sleep durations are associated with the risk of future CVD events. In a cross-sectional study of 30,397 individuals > 18 years of age who responded to the 2005 National Health Interview Survey, the adjusted odds ratios (ORs) of CVD were 2.20, 1.33, 1.23, and 1.57 for a sleep duration of < 5, 6, 8, and > 9 h compared with a sleep duration of 7 h (referent). Thus, compared with sleep duration of 7 h, shorter and longer sleep durations are independently related to CVD (Sabanayagam and Shankar, 2010). In a metaanalysis of multiple prospective studies (24 cohorts; n ¼ 474684; follow-up: 6.9–25 years) that included 16,067 events (4169 CAD, 3478 stroke, and 8420 CVD events), self-reported short sleep duration was associated with a greater risk of CAD (relative risk 1.48) and stroke (1.15), but not total CVD (1.03). Long sleep duration has also been associated with a greater risk of CAD (1.38), stroke (1.65), and total CVD (1.41) (Cappuccio et al., 2011). In a case-control study of middle-aged men, long working hours and short sleep duration contributed independently to the risk of CVD in men. Men whose average number of working hours was >60 h/week were found to have significantly increased risks for CAD (OR 2.2) as compared to those with weekly working hours in the range of 40–48 h, and those with daily sleep duration 70,000 elderly individuals aged > 60 years), long and short sleep duration were associated with increased risk for all-cause mortality. Long sleep duration has also been associated specifically with CVD mortality (da Silva et al., 2016). In a prospective cohort study of 392,164 adults aged > 20 years who attended a health checkup program, when compared to those who slept 6–8 h per night, the risk of CAD death was increased by 34% and 35% in those who slept 8 h, respectively. Thus, adequate sleep duration should be considered an important component of a healthy lifestyle (Strand et al., 2016). In our Jichi Medical School Cohort Study, a nationwide population-based prospective study of 11,367 Japanese with an average follow-up of 10.7 years, the incidences of CVD for individuals sleeping 9 h were 2.14 and 1.33 in men, and 1.46 and 1.28 in women, respectively, relative to those who reported sleeping 7–7.9 h per day (Amagai et al., 2010). Short sleep is associated with particularly high risk of developing HF in men with CVD, and daytime napping is also associated with greater HF risk in older men. In a population-based prospective study of general practices in 24 British towns, which enrolled men aged 60–79 years without prevalent HF followed for 9 years (n ¼ 3723), self-reported daytime sleep duration >1 h was

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independently associated with significantly greater HF risk (hazard rate (HR) 1.69) than in those who reported no daytime napping. Self-reported shorter nighttime sleep duration 6 to 8 h) after adjusting for confounding factors (Yaffe et al., 2016). In a prospective cohort study of 4238 participants from the Nurses’ Health Study, self-reported sleep duration was significantly associated with a decline in renal function over an 11-year period. Compared with sleeping 7–8 h per night, the adjusted ORs for a rapid decline in renal function (30% or greater reduction in the estimated glomerular filtration rate) were a significant 1.79 for 9 h. Thus, shorter sleep duration was prospectively and independently associated with faster decline in renal function (McMullan et al., 2016). These data are consistent with the hypothesis that the CVD consequences of short sleep may begin as early as adolescence and persist until older age.

Sleep and Diabetes Sleep loss is associated with obesity, metabolic syndrome, and diabetes. An increasing number of epidemiological studies show an association between adverse metabolic traits, particularly obesity and type 2 diabetes, and each of short sleep duration, sleep disturbances, and circadian desynchronization of sleep (Schmid et al., 2015; Kawakami et al., 2004; Gottlieb et al., 2005; Tasali et al., 2008; Chao et al., 2011). U-shaped patterns have been observed for the relationship between sleep duration and diabetes. In conclusion, both short and long sleep durations have been independently associated with newly diagnosed diabetes. In a total of 3470 adults recruited from a health checkup center, the multinomial regression model demonstrated that both short ( 140/90 mmHg with > 3 antihypertensive drugs or controlled BP with > 4 drugs) in women (OR 5.3), but not in men (Bruno et al., 2013).

Sleep and Circadian Rhythm The sleep and circadian rhythm of the cardiovascular system have physiological effects on the diurnal variation of hemodynamics, and they are also thought to effect the pathophysiology of CVD.

Circadian Rhythm The onset of CVD shows a circadian rhythm, and the incidence of CVD events such as stroke and myocardial infarction is greater in the early morning than at other times of day. BP also shows a circadian rhythm, decreasing by 10%–20% during sleep. This circadian rhythm in BP is the result of modifications in the clock gene-regulated endogenous sleep–wake rhythm with a cardiovascular response to living environment-based mental and physical activities (Kario, 2015a, 2016). Short-term BP variabilities such as morning BP surge, physical or psychological stress-induced changes in daytime BP, and nocturnal BP surge triggered by hypoxic episodes in OSAS modulate this circadian rhythm of BP, leading to individual differences in the circadian variability of 24-h ambulatory BP and cardiovascular risk (Kario, 2015b; Kario et al., 2003).

Nocturnal Blood Pressure During Sleep Sleep is the major determinant of the nocturnal dipping status of BP. The sleep architecture (sleep stage) is closely associated with the nocturnal BP level (Figs. 2 and 3). Nocturnal BP gradually decreases along with the advance in non-REM sleep stages (from N1, N2, to N3) (Somers et al., 1993). Nocturnal BP surges with an exaggerated peak are frequently found during REM sleep. The basal BP, which is the lowest BP level with the minimal amplitude and frequency of BP surges, is usually found during Stage N3 (SWS) (Fig. 2). The basal BP is predominantly determined by the circulating blood volume and cardiovascular structure without any effect of neurohumoral activation (Kario, 2015a). In addition to the BP surges generated during REM sleep, microarousals (unconscious arousals) detected by PSG induce BP surges during non-REM sleep. At the time of apnea episodes, arousals frequently occur. Spontaneous non-SAS arousals increase with aging, and these events induce BP surge independently of apnea (Fig. 4). Arousals experimentally induced by auditory tones (range: 40–80 dB; duration: 0.5 s) increase BP by 15%–20% (Bangash et al., 2008).

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Fig. 2 Beat-by-beat sleep blood pressure continuously monitored by the newly developed tonometry-type wrist surge pressure monitoring-1 (WSP-1) system (The prototype model which is jointly developed by Omron Healthcare Co., Ltd. and Jichi Medical University School of Medicine ) in different sleep stages defined by simultaneous polysomnography. The data were obtained from 43-year-old healthy woman. REM, rapid-eye movement.  This research is partially supported by the Research and development of supportive device technology for medicine using ICT from Japan Agency for Medical Research and development, AMED.

Fig. 3 Beat-by-beat short-term sleep blood pressure variability continuously monitored by the newly developed tonometry-type wrist surge pressure monitoring-1 (WSP-1) system (The prototype model which is jointly developed by Omron Healthcare Co., Ltd. and Jichi Medical University School of Medicine ) in the different sleep stages shown in Fig. 2. REM, rapid-eye movement. The blood pressure surges during awake or REM sleep are more pronounced than those during slow-wave sleep (N3). The basal BP, the lowest BP, is usually found during N3 sleep.  This research is partially supported by the Research and development of supportive device technology for medicine using ICT from Japan Agency for Medical Research and development, AMED.

Disrupted Circadian Rhythm in Blood Pressure Disrupted circadian BP rhythm (i.e., the absence of a nocturnal-BP fall in a nondipper, or a nocturnal BP greater than daytime BP in a riser) (Fig. 5) is linked to a cardiovascular risk independent of a high BP level. Abnormality in the circadian rhythm of BP can be evaluated by 24-h ambulatory BP monitoring (ABPM) or home nocturnal BP monitoring (Kario, 2015a, 2016; Kario et al., 2015a).

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Fig. 4 Nocturnal blood pressure surges triggered by arousal (upper panel: data from 36-year-old healthy man) and apnea/hypopneas (lower panel: data from 50-year-old man with severe obstructive sleep apnea). Beat-by-beat sleep blood pressure was continuously monitored by the newly developed tonometry-type wrist surge pressure monitoring-1 (WSP-1) system (The prototype model which is jointly developed by Omron Healthcare Co., Ltd. and Jichi Medical University School of Medicine ).  This research is partially supported by the Research and development of supportive device technology for medicine using ICT from Japan Agency for Medical Research and development, AMED.

Fig. 5 Four different dipping statuses of nocturnal blood pressure in hypertension. The data shown were evaluated by ambulatory blood pressure monitoring. Reproduced from Kario K, Pickering TG, Matsuo T, Hoshide S, Schwartz JE, and Shimada K (2001) Stroke prognosis and abnormal nocturnal blood pressure falls in older hypertensives. Hypertension 38: 852–857.

Although the fall in nocturnal BP tends to disappear with aging, our ABPM studies in elderly patients with hypertension revealed that risers have a risk of developing SCI or symptomatic stroke (Kario et al., 1996, 2001). The riser pattern is an independent predictor of prognosis in HF patients with a preserved ejection fraction (Komori et al., 2017). A rise in nocturnal BP and being a nondipper/riser are also linked not only to cardiovascular risk but also to brain atrophy (Nagai et al., 2008) and decreased cognitive function/physical activity in elderly patients with hypertension (Yano et al., 2011). On the other hand, although the heart rate also decreases during nocturnal sleep, heart rate nondippers exhibit higher plasma BNP levels than heart rate dippers (Oba et al., 2017). In addition, the risk of stroke in nondippers who show neither a decrease in BP nor a decrease in heart rate during the nighttime

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reached 8.9 times that in normal dippers for both parameters, and the risk increased synergistically (Kabutoya et al., 2010). In nondipper/riser subjects with a normal 24-h BP below 125/80 mmHg in a community-dwelling population, increased plasma blood BNP level and increased left ventricular mass on echocardiography were observed with progressive concentric cardiac hypertrophy (Hoshide et al., 2003). Even in normotensive young adults, disrupted circadian rhythms in BP (both a nondipper/ riser pattern and an extreme-dipper pattern) are closely associated with the presence of CAC detected by coronary CT after a 10–15 year follow-up period (Viera et al., 2012). The cardiovascular risk of risers may be synergistically augmented by shorter sleep duration. In our prospective study on 1255 elderly hypertensive patients (mean 70.4 years), short sleep duration (6 h and good sleep quality are essential components in the reduction of BP and cardiovascular risk.

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Tamura K, Tanahashi N, Tsuchihashi T, Uchiyama M, Ueda S, and Umemura SJapanese Society of Hypertension Committee for Guidelines for the Management of Hypertension (2014) The Japanese Society of Hypertension guidelines for the management of hypertension (JSH 2014). Hypertension Research 37(4): 253–390. Somers VK, Dyken ME, Mark AL, and Abboud FM (1993) Sympathetic-nerve activity during sleep in normal subjects. New England Journal of Medicine 328(5): 303–307. St-Onge MP, Grandner MA, Brown D, Conroy MB, Jean-Louis G, Coons M, and Bhatt DLAmerican Heart Association Obesity, Behavior Change, Diabetes, and Nutrition Committees of the Council on Lifestyle and Cardiometabolic HealthCouncil on Cardiovascular Disease in the YoungCouncil on Clinical CardiologyStroke Council (2016) Sleep duration and quality: impact on lifestyle behaviors and cardiometabolic health: a scientific statement from the American Heart Association. Circulation 134(18): e367–e386. Strand LB, Tsai MK, Gunnell D, Janszky I, Wen CP, and Chang SS (2016) Self-reported sleep duration and coronary heart disease mortality: a large cohort study of 400,000 Taiwanese adults. International Journal of Cardiology 207: 246–251. Tasali E, Leproult R, Ehrmann DA, et al. (2008) Slow-wave sleep and the risk of type 2 diabetes in humans. Proceedings of the National Academy of Sciences of the United States of America 105: 1044–1049. Taylor KS, Murai H, Millar PJ, Haruki N, Kimmerly DS, Morris BL, Tomlinson G, Bradley TD, and Floras JS (2016) Arousal from sleep and sympathetic excitation during wakefulness. Hypertension 68(6): 1467–1474. Epub 2016 Oct 3. Tochikubo O, Ikeda A, Miyajima E, et al. (1996) Effects of insufficient sleep on blood pressure monitored by a new multibiomedical recorder. Hypertension 27: 1318–1324. van den Berg JF, Tulen JH, Neven AK, Hofman A, Miedema HM, Witteman JC, and Tiemeier H (2007) Sleep duration and hypertension are not associated in the elderly. Hypertension 50(3): 585–589. Epub 2007 Jul 16. Viera AJ, Lin FC, Hinderliter AL, Shimbo D, Person SD, Pletcher MJ, and Jacobs DR (2012) Nighttime blood pressure dipping in young adults and coronary artery calcium 10–15 years later. Hypertension 59: 1157–1163. Wang Y, Mei H, Jiang YR, Sun WQ, Song YJ, Liu SJ, and Jiang F (2015) Relationship between duration of sleep and hypertension in adults: a meta-analysis. Journal of Clinical Sleep Medicine 11: 1047–1056. Wannamethee SG, Papacosta O, Lennon L, and Whincup PH (2016) Self-reported sleep duration, napping, and incident heart failure: prospective associations in the British Regional Heart Study. Journal of American Geriatrics Society. https://doi.org/10.1111/jgs. Wong PM, Manuck SB, DiNardo MM, Korytkowski M, and Muldoon MF (2015) Shorter sleep duration is associated with decreased insulin sensitivity in healthy white men. Sleep 38: 223–231. Yaffe K, Nasrallah I, Hoang TD, Lauderdale DS, Knutson KL, Carnethon MR, Launer LJ, Lewis CE, and Sidney S (2016) Sleep duration and white matter quality in middle-aged adults. Sleep 39(9): 1743–1747. pii: sp-00040-16. [Epub ahead of print]. Yano Y, Inokuchi T, Hoshide S, Kanemaru Y, Shimada K, and Kario K (2011) Association of poor physical function and cognitive dysfunction with high nocturnal blood pressure level in treated elderly hypertensive patients. American Journal of Hypertension 24: 285–291. Yoshida T, Kuwabara M, Hoshide S, and Kario K (2016) Recurrence of stroke caused by nocturnal hypoxia-induced blood pressure surge in a young adult male with severe obstructive sleep apnea syndrome. Journal of the American Society of Hypertension 10(3): 201–204. Zhang J, Ma RC, Kong AP, So WY, Li AM, Lam SP, Li SX, Yu MW, Ho CS, Chan MH, Zhang B, and Wing YK (2011) Relationship of sleep quantity and quality with 24-hour urinary catecholamines and salivary awakening cortisol in healthy middle-aged adults. Sleep 34(2): 225–233.

Sleep-Disordered Breathing and Heart Failure Interactions and Controversies WJ Healy and R Khayat, The Ohio State University Sleep Heart Program, Columbus, OH, United States © 2018 Elsevier Inc. All rights reserved.

Introduction Definitions Pathophysiology—Cause and Effect Presentation and Risk Factors of Sleep-Disordered Breathing Diagnostic Testing Treatment of SDB Including OSA Treatment of OSA and CSA Including Controversies in Treatment of CSA SDB and Cardiac Surgery Summary References

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Introduction Every day over 2200 Americans die of cardiovascular disease (Mozaffarian et al., 2016). It has been estimated that up to 287,000 annual deaths may be attributable to heart failure (HF) (Mozaffarian et al., 2016). Sleep-disordered breathing (SDB), a term that denotes all respiratory disorders of sleep, is broadly categorized into obstructive sleep apnea (OSA) and central sleep apnea (CSA). SDB is independently associated with increased mortality and morbidity in HF patients (Khayat et al., 2012, 2015). The prevalence of SDB is estimated to exceed 60% in patients with systolic HF (heart failure with reduced left ventricular ejection fraction) (Khayat et al., 2009; Oldenburg et al., 2007). The association between SDB and increased mortality and readmission in HF patients supports the need for surveillance and expedited treatment of SDB cases in patients with known HF.

Definitions SDB is defined by the presence of five or more abnormal respiratory events per 1 h of sleep. These respiratory events are generally divided into apneas and hypopneas (Berry et al., 2017). Apneas indicate absence of airflow defined as a period >10 s with >90% drop in oronasal thermal sensor flow (Berry et al., 2017). The oronasal sensor is placed over the mouth during a polysomnogram (PSG) or sleep study. Apneas are further differentiated into obstructive and central apneas (CA). Obstructive apneas (OA) are associated with persistent effort to breathe as measured by chest and abdomen effort belts that are ineffective in overcoming the upper airway collapse. In CA, there are absent inspiratory efforts caused by a temporary failure of the pontomedullary pacemaker (Javaheri and Dempsey, 2013). In hypopneas, there is a drop of >30% of the nasal pressure signal for that lasts longer than 10 s and there is a
4% desaturation from baseline (Berry et al., 2017).

Pathophysiology—Cause and Effect There are multiple mechanisms of abnormal physiology in SDB that are deleterious to the HF patient including intermittent hypoxia, sympathetic overdrive, and endothelial dysfunction accompanied by oxidative stress. HF patients have instability in their respiratory control centers that can cause both obstructive and CSA (Dempsey, 2005). During both central and OA, there are periods of hypoxemia and hypercapnia that cause sympathetic activation. Particularly at the end of these apneic events, there are arousals where there are surges in the systolic and diastolic blood pressure of approximately systolic 20 mmHg and diastolic 15 mmHg (Morgan et al., 1985) accompanied by a rebound in oxygenation as patients frequently desaturate during these events. Not only are these sympathetic activations greater at night when the apneas are occurring, but also the elevated sympathetic tone persists into the waking hours (Somers et al., 1995). Stimuli from these hypoxemic and hypercapnic events change the sensitization of peripheral and central chemoreceptors triggering changes in how the body responds with sympathetic tone and ventilation (Smith and Muenter, 2000; Peng et al., 2003). Aside from considerations of oxygenation, OSA is correlated with oxidant-mediated vascular endothelial dysfunction (Varadharaj et al., 2015). This endothelial dysfunction has been linked to atherosclerosis and also felt to play a role in stroke (Varadharaj et al., 2015). Although CSA and OSA present differently, they are both associated with a similar pattern of recurrent respiratory events and intermittent hypoxia during the night. Sympathetic activation and blood pressure surges occur similarly in these two types of SDB (Morgan et al., 1993).

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Presentation and Risk Factors of Sleep-Disordered Breathing Patient with SDB may or may not be symptomatic upon presentation. However, symptoms may include excessive daytime sleepiness due to poor sleep quality from respiratory events interrupting sleep. Patients may also present with insomnia as the patient has frequent awakenings from respiratory events and is unable to go to sleep. Querying the bedpartner is relevant as the patient may have been witnessed to have apneas which support the presence of SDB. Snoring is an important symptom that is often reported by bedpartners. known risk factors for OSA include obesity, neck circumference >17 in. (43 cm) in men or >15 in. (38 cm) in women, narrowed airway, male gender, age, family history, alcohol use, tobacco use, and nasal congestion. Further, there are risk stratification tools that can help predict the patient’s risk of OSA, such as the Flemmons score. This simple tool uses three risk factors: neck circumference in centimeter, presence of hypertension (four points), and witnessed apneas/gasping most nights (three points) (Flemons, 2002). If the cumulative score is >48, then the patient is high probability for sleep apnea, or 20 times as likely as a low risk patient (34 mL/m2). Much of the data on cardiac structure and function in HFpEF originate from imaging substudies of HFpEF clinical trials, which allow for the accrual of large numbers of cases, robust clinical phenotyping, and prospective assessments. Given the inclusion and exclusion criteria necessarily imposed by such trials, these studies are clearly not reflective of HFpEF epidemiology, and identify specific subsets of patients within the HFpEF syndrome. Across seven major phase 2 and 3 HFpEF clinical trial imaging studies (Cleland et al., 2006; Zile et al., 2011; Solomon et al., 2012; Persson et al., 2007; Shah et al., 2014a; Edelmann et al., 2013; Redfield et al., 2013), mean LV size tended to be normal but with appreciable within trial and between trial variability. Similar variability was noted in LV wall thickness and the prevalence of both increased concentricity (wall thickness relative to chamber diameter) and LV hypertrophy, with values ranging from 14% to 49% and 21% to 59% respectively. For example, in the two largest and most comprehensive studies to date, the echocardiographic substudies of the I-PRESERVE and TOPCAT trials (Zile et al., 2011; Shah et al., 2014a), concentric hypertrophy was present in 29% and 43% of subject respectively, while normal LV geometry was present in 46% and 14% respectively. These observations highlight the marked heterogeneity of ventricular morphology found within this syndrome. The prognostic relevance of greater LV mass in HFpEF, independent of conventional clinical risk factors, has been well documented in several studies (Zile et al., 2011; Shah et al., 2014b; Burke et al., 2014). Although concentric LVH has classically

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characterized HFpEF, no significant differences in event rates have been noted between HFpEF patients with concentric compared to eccentric hypertrophy (Katz et al., 2013; Shah et al., 2014b). In contrast to HFrEF, neither LVEF nor LV size have demonstrated prognostic importance in HFpEF, possibly due to the restricted distribution of values in this syndrome. Importantly, measures of LV diastolic function also provide independent prognostic value in HFpEF (Shah et al., 2014b). These include left atrial enlargement, likely a marker of LV diastolic dysfunction and chronically elevated filling pressure (Zile et al., 2011; Shah et al., 2014b), and E/e’, an index of instantaneous LV filling pressure (Shah et al., 2014b). Although attention has largely focused on alterations in LV structure and diastolic performance, HFpEF is also characterized by abnormal systolic function, detectable by strain (Kraigher-Krainer et al., 2014; Yip et al., 2011; Tan et al., 2009), but also by M-mode echocardiography (Petrie et al., 2002; Yip et al., 2002) tissue Doppler imaging (Yu et al., 2002; Cioffi et al., 2012; Vinereanu et al., 2005). In the echocardiographic study of the TOPCAT trial in HFpEF, strain was impaired in 52% of participants, was the strongest echocardiographic predictor of cardiovascular death or HF hospitalization, and provided incremental value beyond clinical risk factors, LVEF, and measures of LV structure and diastolic function (Shah et al., 2015).

Conclusions LV remodeling refers to changes in LV structure in response to physiologic and pathologic hemodynamic stress. Patterns of LV remodeling vary depending on the nature of the insult, but are closely linked to alterations in LV systolic and diastolic performance that underlie the HF syndrome. HFrEF is characterized by ventricular enlargement and spherical remodeling. The cardiac phenotype in HFpEF, while classically associated with LV concentric hypertrophy, is diverse and likely mirrors the clinical and pathophysiologic heterogeneity of this syndrome. Detailed quantification of LV structure and function offers a promising foundation for identifying pathophysiologically relevant subgroups within the HFpEF syndrome.

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Burke MA, Katz DH, Beussink L, Selvaraj S, Gupta DK, Fox J, Chakrabarti S, Sauer AJ, Rich JD, Freed BH, and Shah SJ (2014) Prognostic importance of pathophysiologic markers in patients with heart failure and preserved ejection fraction. Circulation. Heart Failure 7: 288–299. Cheng S, Fernandes VR, Bluemke DA, McClelland RL, Kronmal RA, and Lima JA (2009) Age-related left ventricular remodeling and associated risk for cardiovascular outcomes: the Multi-Ethnic Study of Atherosclerosis. Circulation. Cardiovascular Imaging 2: 191–198. Cheng S, Xanthakis V, Sullivan LM, Lieb W, Massaro J, Aragam J, Benjamin EJ, and Vasan RS (2010) Correlates of echocardiographic indices of cardiac remodeling over the adult life course: longitudinal observations from the Framingham Heart Study. Circulation 122: 570–578. Cioffi G, Senni M, Tarantini L, Faggiano P, Rossi A, Stefenelli C, Russo TE, Alessandro S, Furlanello F, and de Simone G (2012) Analysis of circumferential and longitudinal left ventricular systolic function in patients with non-ischemic chronic heart failure and preserved ejection fraction (from the CARRY-IN-HFpEF study). American Journal of Cardiology 109: 383–389. Cleland JG, Tendera M, Adamus J, Freemantle N, Polonski L, Taylor J, and PEP-CHF Investigators (2006) The perindopril in elderly people with chronic heart failure (PEP-CHF) study. European Heart Journal 27: 2338–2345. Davis BR, Kostis JB, Simpson LM, Black HR, Cushman WC, Einhorn PT, Farber MA, Ford CE, Levy D, Massie BM, Nawaz S, and ALLHAT Collaborative Research Group (2008) Heart failure with preserved and reduced left ventricular ejection fraction in the antihypertensive and lipid-lowering treatment to prevent heart attack trial. Circulation 118: 2259–2267. Desai RV, Ahmed MI, Mujib M, Aban IB, Zile MR, and Ahmed A (2011) Natural history of concentric left ventricular geometry in community-dwelling older adults without heart failure during seven years of follow-up. American Journal of Cardiology 107: 321–324. Devereux RB, Roman MJ, Liu JE, Welty TK, Lee ET, Rodeheffer R, Fabsitz RR, and Howard BV (2000) Congestive heart failure despite normal left ventricular systolic function in a population-based sample: the Strong Heart Study. American Journal of Cardiology 86: 1090–1096. Devereux RB, Wachtell K, Gerdts E, Boman K, Nieminen MS, Papademetriou V, Rokkedal J, Harris K, Aurup P, and Dahlof B (2004) Prognostic significance of left ventricular mass change during treatment of hypertension. JAMA 292: 2350–2356.

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Doughty RN, Whalley GA, Gamble G, MacMahon S, and Sharpe N (1997) Left ventricular remodeling with carvedilol in patients with congestive heart failure due to ischemic heart disease. Australia-New Zealand Heart Failure Research Collaborative Group. Journal of the American College of Cardiology 29: 1060–1066. Drazner MH, Rame JE, Marino EK, Gottdiener JS, Kitzman DW, Gardin JM, Manolio TA, Dries DL, and Siscovick DS (2004) Increased left ventricular mass is a risk factor for the development of a depressed left ventricular ejection fraction within five years: the Cardiovascular Health Study. Journal of the American College of Cardiology 43: 2207–2215. Edelmann F, Wachter R, Schmidt AG, Kraigher-Krainer E, Colantonio C, Kamke W, Duvinage A, Stahrenberg R, Durstewitz K, Loffler M, Dungen HD, Tschope C, Herrmann-Lingen C, Halle M, Hasenfuss G, Gelbrich G, Pieske B, and Aldo DHF Investigators (2013) Effect of spironolactone on diastolic function and exercise capacity in patients with heart failure with preserved ejection fraction: the Aldo-DHF randomized controlled trial. JAMA 309: 781–791. Folsom AR, Shah AM, Lutsey PL, Roetker NS, Alonso A, Avery CL, Miedema MD, Konety S, Chang PP, and Solomon SD (2015) American Heart Association’s Life’s Simple 7: avoiding heart failure and preserving cardiac structure and function. American Journal of Medicine 128: 970–976. e2. Fonseca CG, Dissanayake AM, Doughty RN, Whalley GA, Gamble GD, Cowan BR, Occleshaw CJ, and Young AA (2004) Three-dimensional assessment of left ventricular systolic strain in patients with type 2 diabetes mellitus, diastolic dysfunction, and normal ejection fraction. American Journal of Cardiology 94: 1391–1395. Fouad FM, Slominski JM, and Tarazi RC (1984) Left ventricular diastolic function in hypertension: relation to left ventricular mass and systolic function. Journal of the American College of Cardiology 3: 1500–1506. Ganau A, Devereux RB, Roman MJ, de Simone G, Pickering TG, Saba PS, Vargiu P, Simongini I, and Laragh JH (1992) Patterns of left ventricular hypertrophy and geometric remodeling in essential hypertension. Journal of the American College of Cardiology 19: 1550–1558. Ghali JK, Liao Y, and Cooper RS (1998) Influence of left ventricular geometric patterns on prognosis in patients with or without coronary artery disease. Journal of the American College of Cardiology 31: 1635–1640. Greenberg B, Quinones MA, Koilpillai C, Limacher M, Shindler D, Benedict C, and Shelton B (1995) Effects of long-term enalapril therapy on cardiac structure and function in patients with left ventricular dysfunction. Results of the SOLVD echocardiography substudy. Circulation 91: 2573–2581. Grossman W, Jones D, and McLaurin LP (1975) Wall stress and patterns of hypertrophy in the human left ventricle. Journal of Clinical Investigation 56: 56–64. Gupta DK, Shah AM, Castagno D, Takeuchi M, Loehr LR, Fox ER, Butler KR, Mosley TH, Kitzman DW, and Solomon SD (2013) Heart failure with preserved ejection fraction in African Americans: the ARIC (Atherosclerosis Risk in Communities) study. JACC: Heart Failure 1: 156–163. Hammermeister KE, Fisher L, Kennedy W, Samuels S, and Dodge HT (1978) Prediction of late survival in patients with mitral valve disease from clinical, hemodynamic, and quantitative angiographic variables. Circulation 57: 341–349. Hammermeister KE, DeRouen TA, and Dodge HT (1979) Variables predictive of survival in patients with coronary disease. Selection by univariate and multivariate analyses from the clinical, electrocardiographic, exercise, arteriographic, and quantitative angiographic evaluations. Circulation 59: 421–430. Hare JL, Brown JK, and Marwick TH (2008) Association of myocardial strain with left ventricular geometry and progression of hypertensive heart disease. American Journal of Cardiology 102: 87–91. Hayashi SY, Rohani M, Lindholm B, Brodin LA, Lind B, Barany P, Alvestrand A, and Seeberger A (2006) Left ventricular function in patients with chronic kidney disease evaluated by colour tissue Doppler velocity imaging. Nephrology, Dialysis, Transplantation 21: 125–132. Haykowsky MJ, Brubaker PH, John JM, Stewart KP, Morgan TM, and Kitzman DW (2011) Determinants of exercise intolerance in elderly heart failure patients with preserved ejection fraction. Journal of the American College of Cardiology 58: 265–274. He KL, Burkhoff D, Leng WX, Liang ZR, Fan L, Wang J, and Maurer MS (2009) Comparison of ventricular structure and function in Chinese patients with heart failure and ejection fractions >55% versus 40% to 55% versus 120 msec) rhythm with a rate exceeding 100 beats per minute. Sustained VT is that which lasts for more than 30 s or that which requires early intervention due to hemodynamic instability (Kusumoto, 2008). Nonsustained VT is sometimes defined as that which lasts for five or more beats at a rate exceeding 100 beats per minute but does not otherwise meet criteria as being sustained. When this definition of nonsustained VT is used, three consecutive QRS complexes of ventricular origin are referred to as a ventricular triplet and four consecutive QRS complexes of ventricular origin are referred to as a ventricular salvo. Others simply define nonsustained VT as that which lasts for three or more beats at a rate exceeding 100 beats per minute but does not otherwise meet criteria as being sustained. Monomorphic VT presents wide QRS complexes that have a single QRS morphology and usually a stable rate and QRS axis. Polymorphic VT presents wide QRS complexes that have varying QRS morphologies, coupling intervals, and axis (Zipes et al., 2006). Some distinguish monomorphic VT and polymorphic VT from pleomorphic VT that presents wide QRS complexes of two or more morphologies each present for a period of time, including two morphologies that are alternating (bidirectional VT). VTs may also be classification according to the patient’s clinical presentation as hemodynamically stable VT (that with minimal symptoms such as palpitations) or as hemodynamically unstable VT (that with symptoms and/or signs of systemic hypotension, pulmonary venous hypertension, myocardial ischemia, cerebral hypoperfusion, or cardiac arrest/death). Three or more episodes of sustained VT within a 24-h period defines a VT storm (Kusumoto, 2008; Israel and Barold, 2007). Approximately 10% of patients who receive an implantable cardioverter defibrillator will experience a VT storm within two years (Raymond et al., 2009). Sustained VT is distinguished from two other sustained ventricular tachydysrhythmias (Table 1). Ventricular flutter presents wide QRS complexes without intervening isoelectric periods (like a sine wave) usually at a rate of approximately 300 beats per minute suggesting that the mechanism of the ventricular tachydysrhythmia is macro reentry following a stable reentrant route. Ventricular fibrillation presents wide QRS complexes that are ultrarapid (>300 beats per minute) in the form of baseline undulations varying in morphology and timing.

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Ventricular Tachycardia in Ischemic and Dilated Cardiomyopathy: Mechanisms and Diagnosis Table 1

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Classification of Ventricular tachycardia

Classification by electrocardiography Nonsustained VT

Sustained VT

Bundle-branch re-entrant tachycardia Bidirectional VT Torsades de pointes

Monomorphic Polymorphic Monomorphic Polymorphic

Ventricular flutter Ventricular fibrillation

Three or more beats in duration, terminating spontaneously in less than 30 s VT is a cardiac arrhythmia of three or more consecutive complexes in duration emanating from the ventricles at a rate of greater than 100 bpm (cycle length less than 600 ms) Nonsustained VT with a single QRS morphology Nonsustained VT with a changing QRS morphology at cycle length between 600 and 180 ms VT greater than 30 s in duration and/or requiring termination due to hemodynamic compromise in less than 30 s Sustained VT with a stable single QRS morphology Sustained VT with a changing or multiform QRS morphology at cycle length between 600 and 180 ms VT due to reentry involving the His-Purkinje system, usually with LBBB morphology; this usually occurs in the setting of cardiomyopathy VT with a beat-to-beat alternans in the QRS frontal plane axis, often associated with digitalis toxicity Characterized by VT associated with a long QT or QTc, and electrocardiographically characterized by twisting of the peaks of the QRS complexes around the isoelectric line during the arrhythmia: • “Typical,” initiated following “short-long-short” coupling intervals. • Short coupled variant initiated by normal-short coupling A regular (cycle length variability 30 ms or less) ventricular arrhythmia approximately 300 bpm (cycle length—200 ms) with a monomorphic appearance; no isoelectric interval between successive QRS complexes Rapid, usually more than 300 bpm/200 ms (cycle length 180 ms or less), grossly irregular ventricular rhythm with marked variability in QRS cycle length, morphology, and amplitude

(7) (7) (7) (7) (7) (7) (7) (7) (7)

(7) (7)

From Zipes et al. (2006).

Mechanisms and Substrates The characteristics of sustained monomorphic VT indicate that the mechanism of monomorphic VT is either reentry with a stable conduction pathway and exit site or automaticity with a stable origin and subsequent conduction route. The former is most common in patients with structural heart disease that includes a ventricular scar while the latter is most common in patients with idiopathic VT in the absence of identifiable structural heart disease (Roberts-Thomson et al., 2011). The ventricular scar forming the substrate for reentrant VT may be the result of ischemic heart disease, nonischemic dilated cardiomyopathy, prior cardiac surgery (often in the setting of corrected congenital heart disease), arrhythmogenic right ventricular cardiomyopathy, cardiac sarcoidosis, or hypertrophic cardiomyopathy (Roberts-Thomson et al., 2011). The substrate regions usually consist of dense fibrosis with some surviving myocardial bundles that help to create conducting channels (Roberts-Thomson et al., 2011). These conducting channels may have reduced cell-to-cell coupling resulting in slow conduction and may be adjacent to anatomical obstacles due to dense fibrosis (Roberts-Thomson et al., 2011). Accordingly, areas of slow conduction, areas of fixed conduction block due to fibrosis, and areas of functional conduction block due to anisotropy represent ideal physiological conditions for reentry initiated by premature beats or cycle length fluctuations (Fig. 1). This VT is monomorphic because ventricular activation outside the scar proceeds from a stable location, which is typically the exit of a group of surviving myocyte bundles, which form a channel for conduction through the scar. A single area of scar is often able to support multiple different circuits. Hence, multiple VTs may be induced with programmed stimulation in patients with structural heart disease (Roberts-Thomson et al., 2011).

Mechanisms for VT in Ischemic Cardiomyopathy The link between ventricular scar and arrhythmia risk suggests that identification and characterization of scar with imaging may allow prediction of arrhythmia risk. In magnetic resonance images (MRI), scar is identified by delayed washout of gadolinium contrast (Nazarian et al., 2005; Kwong et al., 2006). In myocardial infarction survivors, the scar typically extends along a vascular territory supplied by the infarct-related artery (Fig. 2). The central zone of the scar is typically transmural with fewer surviving myocytes. The peripheral part of the scar, the “border zone,” is typically more heterogeneous and has a mixture of fibrous tissue and surviving myocytes, and may play a more important role in permitting reentry. This has been confirmed by three-dimensional MRIderived scar reconstruction (Piers et al., 2014), and the size of the border zone has been shown to be a marker for late mortality (Kwong et al., 2006). The burden of scar and its characteristics has also been shown to be related with the presence of both spontaneous and inducible ventricular tachycardia (Gouda et al., 2015; Schmidt et al., 2007). Computer simulations using MRIderived scar mapping were recently shown to be feasible to predict the existence of VT circuits in animal models (Ng et al., 2012) and in humans (Arevalo et al., 2013). Furthermore, such maps could also predict optimal VT ablation targets within the scar (Ashikaga et al., 2013).

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Fig. 1 Theoretical reentry circuits as they relate to areas of block and isthmuses are shown. In the schematics on the left the reentry circuit is indicated by the arrows. Gray regions indicate conduction block that might be from fibrosis, collision of wave fronts, or refractoriness. (A) A simple circuit consisting of a single loop around a region of block. If the loop is broad, ablation in the loop (dotted black line) may increase the reentry path but fail to interrupt reentry. (B) A figure-of-eight type of reentry circuit defined by wave fronts propagating around 2 regions of block and sharing a common isthmus and a common pathway (CP) through which conduction is slowed, creating a “figure-of-eight” configuration. Ablation across the common isthmus (dotted black line) would interrupt reentry. Ablation in either loop alone leaves the other loop to continue reentry. (C) A complex circuit with several regions of conduction block along a valve annulus that creates multiple potential channels. (D) Ablation (RF) that interrupts 1 channel and leaves the other potential channels that may support reentry. (E) Photograph of an explanted heart from a patient who had incessant VT and failed VT ablation with a theoretical reentry circuit (yellow arrows) is shown. Areas of dense scar, that may form electrically unexcitable scar (EUS), is indicated. A hypothetical channel/isthmus is present between two EUS areas. The circulating reentry wave front propagates through the channel, emerging at the exit to propagate across the ventricles producing the QRS complex. The circulating wave front propagates along the border of the scar (outer loop) to reenter the channel. A bystander area (black arrow) is also shown. RF lesions failed to interrupt VT, likely related to the location of the re-entry circuit deep to the endocardium. From Raymond, J. M., Sacher, F., Winslow, R., Tedrow, U. and Stevenson, W. G. (2009). Catheter ablation for scar-related ventricular tachycardias. Current Problems in Cardiology 34, 225–270.

Mechanisms for VT in Nonischemic Cardiomyopathy In patients with nonischemic cardiomyopathy (NICM), subendocardial scarring and patchy fibrosis may occur and may contribute to decreased cellular coupling and regional slow conduction, thus providing an anatomic substrate for reentrant VT. However, the extent and degree of fragmented and abnormal endocardial electrograms appear to be significantly less than in patients with ischemic cardiomyopathy (Hsia et al., 2003). In addition, the distribution of scar is more commonly basal, in anatomic relationship with the mitral annulus. In contrast, epicardial patchy fibrosis and abnormal conduction may be detected in 30%–50% of patients with NICM at the time of open heart surgery (de Bakker et al., 1996; Pogwizd et al., 1998) (Fig. 2). Several experimental and clinical reports indicate that focal nonreentrant mechanisms may be common in patients with NICM (Pogwizd et al., 1998; Delacretaz et al., 2000). In this population, myocardial macroreentrant circuits may account for only 50%–70% of VT, with focal mechanisms and bundle branch reentry comprising the remainder (Delacretaz et al., 2000). Most patients have multiple distinct QRS morphologies, often with different mechanisms. Given the different mechanisms, it is not surprising that programmed stimulation frequently fails to induce the VT observed clinically.

Bundle Branch Reentry as a Mechanism of VT Bundle branch reentry VT is a VT that occurs most commonly in patients with nonischemic dilated cardiomyopathy. These patients usually have evidence of conduction system disease that provides the zone of slow conduction. The Purkinje network is integral to this macro reentrant VT (Roberts-Thomson et al., 2011). Most commonly, the right bundle branch is the antegrade limb and the left

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Fig. 2 Representative examples of scar distribution in various types of scar-related ventricular tachycardias. Contact bipolar voltage maps with reduced bipolar voltage (120 msec) tachycardia at a rate greater than 100 beats per minute should be considered to be VT unless proven otherwise. This admonition reflects the fact that therapy for supraventricular tachycardia may worsen the state of a patient with VT whereas the converse is unlikely.

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Recalling that a narrow QRS complex is the result of simultaneous activation of the two ventricles, wide QRS complex rhythms result from sequential activation of the two ventricles—one ventricle being activated early (a ventricular rhythm or a supraventricular rhythm with ventricular preexcitation) or one ventricle being activated late (a paced ventricular rhythm or a supraventricular rhythm with aberrant AV conduction (right bundle branch block, left bundle branch block, or an intraventricular conduction defect)). Atrioventricular (AV) dissociation is the only ECG feature that is diagnostic for VT (Wellens, 2001). On an ECG recording VA dissociation is manifest as evident P-waves at a rate that is unrelated to the QRS rate and that is generally slower than the QRS rate. Such P-waves may intermittently conduct to the ventricles resulting in a “capture beat” that has the same QRS morphology as that patient’s normal rhythm or a “fusion beat” that has a QRS complex morphology representing the sum of that patient’s normal QRS morphology and the QRS morphology of the VT (Wellens, 2001) (Fig. 4). Unfortunately, AV dissociation during VT is uncommonly seen on the ECG recording because slower VTs may conduct retrogradely to the atrium, preserving a 1:1 relationship between atrial and ventricular activation, and faster VTs obscure the pattern of background P-waves, precluding recognition of AV dissociation (Roberts-Thomson et al., 2011). Other ECG findings are not diagnostic but may contribute to the differential diagnosis of a wide QRS complex tachycardia. In general, if the ECG QRS complex pattern is that of typical right or left bundle branch block then a supraventricular tachydysrhythmia with aberrant AV conduction is favored. The less the QRS complex is typical of right or left bundle branch block, the more likely it is a VT. VT is likely if a wide QRS complex tachycardia presents QRS complexes with a right superior axis, precordial concordance (implying early basal or apical activation), and a very wide QRS (left bundle branch block like pattern with a QRS duration >160 ms or a right bundle branch block like pattern with a QRS duration >140 ms) (Roberts-Thomson et al., 2011). Comparison of the relative time courses of ventricular activation at the beginning of the QRS complex and at the end of the QRS complex may be helpful in the differential diagnosis of a wide QRS complex tachycardia. When ventricular activation involves the Purkinje system, voltage changes are rapid. When ventricular activation depends upon ventricular myocyte conduction, voltage changes are slower. Accordingly, a slurry initial QRS complex associated with a sharp terminal QRS complex suggests VT or ventricular preexcitation while the reverse suggests a supraventricular tachycardia conducted with aberrancy. These ECG features have been incorporated into formal algorithms designed to assist the differential diagnosis. A four-step algorithm developed by Brugada was reported to have a sensitivity of 98.7% and specificity of 96.5% for the diagnosis of VT (Fig. 5) (Brugada et al., 1991). The initial step was to assess the absence of RS complexes in all the precordial leads, a finding that suggests VT. When there was a precordial lead with an RS morphology, an onset of R to a nadir of S interval greater than 100 msec suggests VT provided that the patient was not receiving an antiarrhythmic drug that slows intraventricular conduction. The third step identified AV dissociation. The final step examined morphology criteria in ECG leads V1 and V6 that basically assessed whether the morphology in these leads deviated from a typical left or right bundle branch block pattern as this would also suggest VT. Another algorithm, derived from a patient population that included preexcited supraventricular tachycardias, suggested by Vereckei et al., examined ECG lead aVR for the presence of an initial R wave (Vereckei et al., 2008). This stepwise algorithm suggests that the presence of an initial dominant R wave, the presence of a nondominant r or q wave lasting more than 40 ms, the presence of a notch on the descending limb of a negative onset and predominantly negative QRS, and a ventricular activation velocity ratio, vi/vt (vi is the vertical excursion during the initial part of the QRS and vt is during the terminal part of the QRS) all suggest VT (Vereckei et al., 2008) (Fig. 6). A VT that emerges from the interventricular septum usually presents QRS complexes that are less wide than those of VT arising from other regions. In patients that already have an underlying wide QRS complex during supraventricular rhythm, a less wide QRS complex during tachycardia should raise suspicion that the tachycardia is VT because a supraventricular tachycardia would have no mechanism to produce a QRS complex less wide than a slower supraventricular rhythm (Wellens, 2001). The 12-lead ECG may be used to localize the site of origin of VT, useful information for the diagnosis of idiopathic VT (the most common site of origin of which is the right ventricular outflow tract), or when VT ablation is planned. Here the site of origin refers to the site of abnormal automaticity in the case of an automatic VT or the site of exit from the zone of slow conduction in the case of a

Fig. 4 Simultaneously recorded ECG leads aVL, aVF, and V1 during a regular wide QRS complex tachycardia with left bundle branch block like and superior axis morphology and a ventricular rate of 143 beats per minute with AV dissociation, fusion beats, and a capture beat. P-waves are best seen in lead aVF. The arrows denote evident P-waves including one distorting the onset of the QRS complex (second arrow) and one distorting the downslope of the T-wave (forth arrow). The asterisks indicate where other P-waves must be although they are obscured by the background rhythm. The atrial rate is 103 beats per minute. C denotes a narrow QRS complex capture beat with normal QRS morphologies in each lead. F denotes three fusion beats with morphologies that are variably intermediate between that of the underlying rhythm and that of the capture beat. The third fusion beat is the least fused with morphology change evident only in V1.

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Fig. 5 Algorithm from Brugada et al. for diagnosis of a tachycardia with a widened QRS complex. When an RS complex cannot be identified in any precordial lead, the diagnosis of ventricular tachycardia (VT) is made. If an RS complex is present in one or more precordial leads, the longest RS interval is measured. If the RS interval is longer than 100 msec, the diagnosis of VT is made. If shorter than 100 msec, the next step of the algorithm is considered: whether atrioventricular dissociation is present. If present, the diagnosis of VT is made. If absent, the morphology criteria for VT are analyzed in leads V, and V6. If both leads fulfill the criteria for VT, the diagnosis of VT is made. If not, the diagnosis of supraventricular tachycardia (SVT) with aberrant conduction is made by exclusion of VT. From Brugada, P., Brugada, J., Mont, L., Smeets, J. and Andries, E. W. (1991). A new approach to the differential diagnosis of a regular tachycardia with a wide QRS complex. Circulation 83, 1649–1659.

Fig. 6 Algorithm developed by Vereckei et al. for diagnosis of VT from a wide complex tachycardia using aVR. If an initial R wave is seen then VT is diagnosed. If not then presence of r or q wave >40 ms diagnoses VT. If not presence of a notch on the descending limb of a negative onset and predominantly negative QRS suggests VT. Otherwise vi/vt < 1 suggests VT. From Vereckei, A., Duray, G., Szenasi, G., Altemose, G.T., and Miller, J. M. (2008). New algorithm using only lead aVR for differential diagnosis of wide QRS complex tachycardia. Heart Rhythm 5, 89–98.

reentrant VT. In patients without structural heart disease, using the ECG for localization is reasonably accurate. In patients with structural heart disease, the ECG morphology identifies the zone of epicardial breakthrough, which may be distant from the site of origin when intraventricular conduction is disturbed. VT that originates from the right ventricle or the anterior portion of the interventricular septum usually has a left bundle branch block like morphology in lead V1. VT originating from the left ventricle tends to have a right bundle branch block like morphology in lead V1. VT that presents QRS complexes that are negative in all of the precordial leads (negative concordance) is likely originating from near the apex; VT that presents QRS complexes that are positive in all of the precordial leads (positive concordance) is likely originating from the posterior portion of the left ventricle (Wellens, 2001).

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Fig. 7 Left ventricular endocardial mapping grid. The grid is divided into three sections in each of three planes, determined from two fixed fluoroscopic planes. A, anterior; C, central; I, inferior; L, lateral; LAO, left anterior oblique projection; M, middle; RAO, right anterior oblique projection; S, septal; 1,2,3, three regions along the long axis of the left ventricle (LV): apical, mid-ventricular and basal. From Kuchar, D. L., Ruskin, J. N. and Garan, H. (1989). Electrocardiographic localization of the site of origin of ventricular tachycardia in patients with prior myocardial infarction. Journal of the American College of Cardiology 13, 893–900.

Fig. 8 Flow chart used for predicting site of origin of ventricular tachycardia: a three-step flowchart for predicting each of the three axis coordinates. To determine these sites, begin with the designated electrocardiographic lead and, depending on the QRS morphology in that lead, follow the arrows to the bottom of the diagram. The electrocardiographic leads are enclosed by boxes, whereas endocardial sites are indicated in bold type. Abbreviations as in Fig. 6. From From Kuchar, D. L., Ruskin, J. N. and Garan, H. (1989). Electrocardiographic localization of the site of origin of ventricular tachycardia in patients with prior myocardial infarction. Journal of the American College of Cardiology13, 893–900.

VT with an Inferior axis in the frontal plane suggests an origin in the right or left ventricular outflow tract; VT with a superior axis suggests an origin in the inferior wall. Kuchar et al. developed an algorithm using the QRS morphology resulting from endocardial pacing (Kuchar et al., 1989) as shown in Figs. 7 and 8. When this algorithm was tested in patients with VT after remote MI the correct location of VT origin was predicted in 39% of patients and an adjacent location of VT origin was predicted in an additional 36% of patients.

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An epicardial origin of VT is suggested by a pseudo delta wave (measured from earliest ventricular activation to earliest fast deflection in any precordial lead) with a duration greater than or equal to 34 ms, by an RS complex duration (measured from earliest ventricular activation to nadir of first S wave in any precordial lead) >121 ms, or by an intrinsicoid deflection time (earliest ventricular activation to peak of R wave in V2) greater than or equal to 85 ms (Berruezo et al., 2004). Not infrequently, an epicardial origin of VT is surmised after failed endocardial VT mapping and/or ablation. Some patients, particularly those with advanced structural heart disease, will already have an ICD when their first VT occurs. In such patients, an ECG documenting the VT will be difficult to obtain and use of device recorded electrograms will be necessary to diagnose VT (Hook et al., 1993).

Investigations When a patient has been diagnosed as having VT initial investigations are focused on identification of the etiology of and the magnitude of the patient’s underlying structural heart disease. These investigations will be guided by the patient’s demographics, family history, cardiac risk factors, history, and clinical examination. If no evidence of structural heart disease is found, the VT is likely an idiopathic VT or the result of an inherited channelopathy. When structural heart disease is documented, it is usually the result of ischemic heart disease or a nonischemic congestive cardiomyopathy. Monomorphic VT in these settings usually originates from a preexisting ventricular myocardial scar. Polymorphic VTs in such patients usually indicate myocardial ischemia and/or decompensated congestive heart failure (Priori et al., 2015). Cardiac enzymes may be elevated in a patient with VT due to a prolonged episode of VT resulting in myocardial supply and demand mismatch, due to resuscitation, and/or due to defibrillator shocks. Accordingly, elevations of cardiac enzymes must be interpreted with caution in a patient presenting with VT. Patients presenting with VT will usually start their investigations with laboratory investigations and with a transthoracic echocardiogram (Roberts-Thomson et al., 2011). Laboratory investigations include evaluations of electrolytes, renal function, blood counts, liver function, and thyroid function. Abnormalities in these tests are rarely the principle cause for monomorphic VT, but will inform subsequent treatment, particularly with antiarrhythmic drugs. Abnormalities on the transthoracic echocardiogram will prompt further testing which will usually take the form of cardiac catheterization and coronary angiography and cardiac magnetic resonance imaging for infiltrative disorders. If a nonischemic congestive cardiomyopathy is suspected, a workup for cause of such a cardiomyopathy is indicated. The details of this workup will depend on both patient and environmental characteristics and will consider Chagas disease in South America and cardiac sarcoidosis in the presence of coexisting conduction system disease. Arrhythmogenic right ventricular cardiomyopathy is considered when testing reveals no clear left ventricular structural heart disease especially when the VT had a left bundle branch block like morphology (Zipes et al., 2006). Signal-averaged electrocardiography and endomyocardial biopsy may also be necessary in selected patients (Roberts-Thomson et al., 2011). Patients presenting with VT who already have received an ICD will likely have already had all the required testing performed. Nevertheless, such patients usually have laboratory tests and a transthoracic echocardiogram repeated to assess for contributing electrolyte or metabolic factors and to reassess their structural heart disease, particularly their left ventricular systolic function.

Conclusion Ventricular tachycardia can portend a poor prognosis in patients with structural heart disease. The mechanism for VT in such patients is usually reentry. Symptoms such as palpitations or syncope should raise suspicion of VT and further investigation and monitoring may need to be performed. Developing technologies include smart phone apps, implantable loop recorders, other ambulatory monitoring devices that will facilitate the diagnosis of VT in patients with structural heart disease, and developments in imaging that may also aid in diagnosis and risk stratification.

References Arevalo H, Plank G, Helm P, Halperin H, and Trayanova N (2013) Tachycardia in post-infarction hearts: Insights from 3D image-based ventricular models. PLoS ONE 8: e68872. Ashikaga H, Arevalo H, Vadakkumpadan F, Blake RC 3rd., Bayer JD, Nazarian S, Muz Zviman M, Tandri H, Berger RD, Calkins. H, Herzka DA, Trayanova NA, and Halperin HR (2013) Feasibility of image-based simulation to estimate ablation target in human ventricular arrhythmia. Heart Rhythm 10: 1109–1116. Berruezo A, Mont L, Scalise A, and Brugada J (2004) Orthodromic pacemaker-mediated tachycardia in a biventricular system without an atrial electrode. Journal of Cardiovascular Electrophysiology 15: 1100–1102. Brugada P, Brugada J, Mont L, Smeets J, and Andries EW (1991) A new approach to the differential diagnosis of a regular tachycardia with a wide QRS complex. Circulation 83: 1649–1659. De Bakker JM, Van Capelle FJ, Janse MJ, Tasseron S, Vermeulen JT, De Jonge N, and Lahpor JR (1996) Fractionated electrograms in dilated cardiomyopathy: Origin and relation to abnormal conduction. Journal of the American College of Cardiology 27: 1071–1078. Delacretaz E, Stevenson WG, Ellison KE, Maisel WH, and Friedman PL (2000) Mapping and radiofrequency catheter ablation of the three types of sustained monomorphic ventricular tachycardia in nonischemic heart disease. Journal of Cardiovascular Electrophysiology 11: 11–17. Garratt CJ, Griffith MJ, Young G, Curzen N, Brecker S, Rickards AF, and Camm AJ (1994) Value of physical signs in the diagnosis of ventricular tachycardia. Circulation 90: 3103–3107.

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Goldenberg I, Zareba W, and Moss AJ (2008) Long QT Syndrome. Current Problems in Cardiology 33: 629–694. Gouda S, Abdelwahab A, Salem M, and Hamid MA (2015) Scar characteristics for prediction of ventricular arrhythmia in ischemic cardiomyopathy. Pacing and Clinical Electrophysiology 38: 311–318. Hook BG, Callans DJ, Kleiman RB, Flores BT, and Marchlinski FE (1993) Implantable cardioverter-defibrillator therapy in the absence of significant symptoms. Rhythm diagnosis and management aided by stored electrogram analysis. Circulation 87: 1897–1906. Hsia HH, Callans DJ, and Marchlinski FE (2003) Characterization of endocardial electrophysiological substrate in patients with nonischemic cardiomyopathy and monomorphic ventricular tachycardia. Circulation 108: 704–710. Israel CW and Barold SS (2007) Electrical storm in patients with an implanted defibrillator: A matter of definition. Annals of Noninvasive Electrocardiology 12: 375–382. Kuchar DL, Ruskin JN, and Garan H (1989) Electrocardiographic localization of the site of origin of ventricular tachycardia in patients with prior myocardial infarction. Journal of the American College of Cardiology 13: 893–900. Kuriachan VP, Sumner GL, and Mitchell LB (2015) Sudden cardiac death. Current Problems in Cardiology 40: 133–200. Kusumoto F (2008) A comprehensive approach to management of ventricular arrhythmias. Cardiology Clinics 26(481–96): vii. Kwong RY, Chan AK, Brown KA, Chan CW, Reynolds HG, Tsang S, and Davis RB (2006) Impact of unrecognized myocardial scar detected by cardiac magnetic resonance imaging on event-free survival in patients presenting with signs or symptoms of coronary artery disease. Circulation 113: 2733–2743. Morady F, Baerman JM, Dicarlo LA Jr., Debuitleir M, Krol RB, and Wahr DW (1985) A prevalent misconception regarding wide-complex tachycardias. JAMA 254: 2790–2792. Nazarian S, Bluemke DA, Lardo AC, Zviman MM, Watkins SP, Dickfeld TL, Meininger GR, Roguin A, Calkins H, Tomaselli GF, Weiss RG, Berger RD, Lima JA, and Halperin HR (2005) Magnetic resonance assessment of the substrate for inducible ventricular tachycardia in nonischemic cardiomyopathy. Circulation 112: 2821–2825. Ng J, Jacobson JT, Ng JK, Gordon D, Lee DC, Carr JC, and Goldberger JJ (2012) Virtual electrophysiological study in a 3-dimensional cardiac magnetic resonance imaging model of porcine myocardial infarction. Journal of the American College of Cardiology 60: 423–430. Piers SR, Tao Q, De Riva Silva M, Siebelink HM, Schalij MJ, Van Der Geest RJ, and Zeppenfeld K (2014) CMR-based identification of critical isthmus sites of ischemic and nonischemic ventricular tachycardia. JACC. Cardiovascular Imaging 7: 774–784. Pogwizd SM, McKenzie JP, and Cain ME (1998) Mechanisms underlying spontaneous and induced ventricular arrhythmias in patients with idiopathic dilated cardiomyopathy. Circulation 98: 2404–2414. Priori SG, Blomstrom-Lundqvist C, Mazzanti A, Blom N, Borggrefe M, Camm J, Elliott PM, Fitzsimons D, Hatala R, Hindricks G, Kirchhof P, Kjeldsen K, Kuck KH, Hernandez-Madrid A, Nikolaou N, Norekval TM, Spaulding C, and Van Veldhuisen DJ (2015) 2015 ESC Guidelines for the management of patients with ventricular arrhythmias and the prevention of sudden cardiac death: The Task Force for the Management of Patients with Ventricular Arrhythmias and the Prevention of Sudden Cardiac Death of the European Society of Cardiology (ESC). Endorsed by: Association for European Paediatric and Congenital Cardiology (AEPC). European Heart Journal 36: 2793–2867. Raymond JM, Sacher F, Winslow R, Tedrow U, and Stevenson WG (2009) Catheter ablation for scar-related ventricular tachycardias. Current Problems in Cardiology 34: 225–270. Roberts-Thomson KC, Lau DH, and Sanders P (2011) The diagnosis and management of ventricular arrhythmias. Nature Reviews. Cardiology 8: 311–321. Schmidt A, Azevedo CF, Cheng A, Gupta SN, Bluemke DA, Foo TK, Gerstenblith G, Weiss RG, Marban E, Tomaselli GF, Lima JA, and Wu KC (2007) Infarct tissue heterogeneity by magnetic resonance imaging identifies enhanced cardiac arrhythmia susceptibility in patients with left ventricular dysfunction. Circulation 115: 2006–2014. Solomon SD, Zelenkofske S, Mcmurray JJ, Finn PV, Velazquez E, Ertl G, Harsanyi A, Rouleau JL, Maggioni A, Kober L, White H, Van De Werf F, Pieper K, Califf RM, Pfeffer MA and Valsartan in Acute Myocardial Infarction Trial (2005) Sudden death in patients with myocardial infarction and left ventricular dysfunction, heart failure, or both. New England Journal of Medicine 352: 2581–2588. Vereckei A, Duray G, Szenasi G, Altemose GT, and Miller JM (2008) New algorithm using only lead aVR for differential diagnosis of wide QRS complex tachycardia. Heart Rhythm 5: 89–98. Wathen MS, Sweeney MO, Degroot PJ, Stark AJ, Koehler JL, Chisner MB, Machado C, Adkisson WO, and Pain FI (2001) Shock reduction using antitachycardia pacing for spontaneous rapid ventricular tachycardia in patients with coronary artery disease. Circulation 104: 796–801. Wellens HJ (2001) Electrophysiology: Ventricular tachycardia: Diagnosis of broad QRS complex tachycardia. Heart 86: 579–585. Zipes DP, Camm AJ, Borggrefe M, Buxton AE, Chaitman B, Fromer M, Gregoratos G, Klein G, Moss AJ, Myerburg RJ, Priori SG, Quinones MA, Roden DM, Silka MJ, Tracy C, Smith SC Jr., Jacobs AK, Adams CD, Antman EM, Anderson JL, Hunt SA, Halperin JL, Nishimura R, Ornato JP, Page RL, Riegel B, Priori SG, Blanc JJ, Budaj A, Camm AJ, Dean V, Deckers JW, Despres C, Dickstein K, Lekakis J, Mcgregor K, Metra M, Morais J, Osterspey A, Tamargo JL, Zamorano JL and American College of Cardiology/American Heart Association Task Force and the European Society of Cardiology Committee for Practice (2006) ACC/AHA/ESC 2006 guidelines for management of patients with ventricular arrhythmias and the prevention of sudden cardiac death: A report of the American College of Cardiology/American Heart Association Task Force and the European Society of Cardiology Committee for Practice Guidelines (Writing Committee to Develop Guidelines for Management of Patients With Ventricular Arrhythmias and the Prevention of Sudden Cardiac Death). 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Further Reading Connolly SJ, Hallstrom AP, Cappato R, Schron EB, Kuck KH, Zipes DP, Greene HL, Boczor S, Domanski M, Follmann D, Gent M, and Roberts RS (2000b) Meta-analysis of the implantable cardioverter defibrillator secondary prevention trials. AVID, CASH and CIDS studies. Antiarrhythmics vs Implantable Defibrillator study. Cardiac Arrest Study Hamburg. Canadian Implantable Defibrillator Study. European Heart Journal 21: 2071–2078. Priori SG, Blomstrom-Lundqvist C, Mazzanti A, Blom N, Borggrefe M, Camm J, Elliott PM, Fitzsimons D, Hatala R, Hindricks G, Kirchhof P, Kjeldsen K, Kuck KH, Hernandez-Madrid A, Nikolaou N, Norekval TM, Spaulding C, and Van Veldhuisen DJ (2015b) 2015 ESC Guidelines for the management of patients with ventricular arrhythmias and the prevention of sudden cardiac death: The Task Force for the Management of Patients with Ventricular Arrhythmias and the Prevention of Sudden Cardiac Death of the European Society of Cardiology (ESC). Endorsed by: Association for European Paediatric and Congenital Cardiology (AEPC). European Heart Journal 36: 2793–2867. Raymond JM, Sacher F, Winslow R, Tedrow U, and Stevenson WG (2009b) Catheter ablation for scar-related ventricular tachycardias. Current Problems in Cardiology 34: 225–270. Roberts-Thomson KC, Lau DH, and Sanders P (2011b) The diagnosis and management of ventricular arrhythmias. Nature Reviews. Cardiology 8: 311–321.

Ventricular Tachycardia in Structurally Normal Hearts AG Bhatt and S Mittal, Valley Health System, Paramus, NJ, United States © 2018 Elsevier Inc. All rights reserved.

Introduction Epidemiology Prevalence Among Treated VT Gender Differences Age Distribution Prognostic Implications Clinical Presentation Symptoms Triggers Arrhythmia Patterns Anatomic Substrate Malignant Consequences Cardiomyopathy Malignant Arrhythmias Clinical Evaluation History Physical Examination Electrocardiogram Echocardiogram Holter Exercise Stress Testing Advanced Cardiac Imaging Mechanisms of Arrhythmogenesis Adenosine-Sensitive Verapamil Sensitive Propranolol Sensitive Management Strategies Observation Avoidance of Triggers Pharmacotherapy: Beta-Blockers and Calcium Channel Blockers Pharmacotherapy: Antiarrhythmic Drugs (AADs) Catheter Ablation Conclusion Challenges References

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Introduction The clinical spectrum of ventricular tachycardia (VT) in structurally normal hearts, “idiopathic VT,” ranges from isolated premature ventricular complexes (PVCs) to sustained VT, and in general portends a benign prognosis. The prognosis is unclear at initial presentation as the arrhythmias are indistinguishable from VT with structural heart disease (SHD) or a reversible cardiomyopathy may be present. The pathophysiology, epidemiology, prognosis, and treatment of VT with SHD have been extensively characterized with welldeveloped guidelines for risk stratification and treatment that are generalizable to large populations. On the other hand, idiopathic VT has not been systematically assessed with large population-based studies due to low prevalence. Elucidating the pathophysiology and developing treatment strategies is confounded by the fact that the definition of a structurally normal or abnormal heart is not rigorously defined. The connotation of this classification differs in among subspecialties of cardiovascular medicine. The absence of obvious ischemic or nonischemic cardiomyopathy implies a structurally normal heart but relies on conventional angiographic and echocardiographic assessment. However, this does not account for microvascular, ultrastructural (i.e., fibrosis or inflammation), molecular, or genetic abnormalities that have become increasingly recognized with advanced imaging techniques, biomarkers, and genetic testing.

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The prevailing clinical gestalt suggests that idiopathic VT is benign; however, numerous epidemiologic studies over the previous 50 years have demonstrated that ambient ventricular ectopy is associated with heightened risk of cardiovascular morbidity and mortality and may represent subclinical disease not discernible with conventional assessment. There are several recognized types of idiopathic VT that have been classified and categorized based on clinical presentation, site of origin, electrocardiographic pattern, response to medication testing, and mechanism. Pharmacologic and ablative treatment strategies targeting ventricular ectopy with or without SHD suggest clinical benefit and also suggests that ventricular ectopy is a modifiable risk factor for cardiovascular morbidity and mortality.

Epidemiology In 1962 the incidence of PVCs or nonsustained ventricular tachycardia (NSVT) on screening electrocardiograms (ECGs) among apparently healthy United States Air Force flight personnel was estimated at 0.8% (Hiss and LAMB, 1962). Large population studies, such as the Framingham Heart Study (Bikkina et al., 1992) and Atherosclerosis Risk in Communities (Simpson et al., 2002) study, estimate that the prevalence of PVCs or complex ventricular ectopy ranges from 6% to 12% based on ECG. The definition of complex ventricular ectopy includes more than 30 PVCs per hour or multiform PVCs, ventricular couplets, VT, or R-on-T phenomenon (Bikkina et al., 1992). PVC prevalence increases with advancing age, male gender, African-American ethnicity, and hypertension (HTN); HTN is associated with a 23% increase in the prevalence of PVCs (Simpson et al., 2002). Ambient ventricular ectopy was found in 50% of healthy medical students on 24-hour ambulatory monitoring but only 2% had greater than 50 PVCs (Brodsky et al., 1977). Multiple other studies with 24-h ambulatory monitoring between 1977 and 1982 demonstrated the prevalence of PVCs or complex ventricular ectopy ranging from 40% to 75% (Kennedy et al., 1985). Hingorani et al. recently demonstrated the incidence of PVCs and complex ventricular ectopy as 43% and 16%, respectively, on 24-hour ambulatory monitoring in healthy drug-free participants of phase I clinical trials (Hingorani et al., 2016). Exercise-induced PVCs has been observed in 2%–27% of healthy patients undergoing exercise stress testing in an assessment of Parisian civil service employees and the Framingham Offspring Study (Jouven et al., 2000; Morshedi-Meibodi et al., 2004). Exerciseinduced NSVT occurred in 4% of the Baltimore Longitudinal Study of Aging. PVCs are commonly encountered in clinical practice; however, the incidence of idiopathic PVCs may be lower since these studies did not fully exclude the presence of SHD.

Prevalence Among Treated VT Early case series of patients referred for management and treatment of VT estimated the prevalence of idiopathic VT in the range of 7%–38% (Hoffmayer and Gerstenfeld, 2013). More contemporary estimates suggest a prevalence of 10% in the United States (Lerman et al., 1997) and 20% in Japan (Okumura and Tsuchiya, 2002). This may underestimate the true prevalence as the generally benign prognosis of idiopathic VT may limit referral for electrophysiologic evaluation.

Gender Differences There are well-recognized gender differences in the prevalence and presentation of arrhythmias owing to gender-related variation of ion channels (genetic or molecular), autonomic tone, and modulation of myocardial electrophysiologic properties with sex hormones. The anatomic distribution and presentation differs between men and women. Idiopathic VT arising from the right ventricular outflow tract (RVOT) has a 1.5–2:1 female predominance, left ventricular outflow tract (LVOT) VT 1.4:1 male predominance, and fascicular VT 3:1 male predominance (Nakagawa et al., 2002; Tanaka et al., 2011). Marchlinski et al. observed that cyclic and age-related hormonal variation due to menses, pregnancy, and menopause triggers VT from the RVOT (RVOT-VT) in women, whereas exercise or stress more commonly triggers RVOT-VT in men (Marchlinski et al., 2000). Ventricular arrhythmias triggered during pregnancy subside postpartum (M. Nakagawa et al., 2004). Ovulatory peak estradiol and hormone replacement therapy (HRT) both attenuate PVCs (DOGAN et al., 2016; Hu et al., 2011).

Age Distribution Multiple population studies, as mentioned above, demonstrated that the prevalence of PVCs increase with age (Bikkina et al., 1992; 1993; Hiss and LAMB, 1962; Simpson et al., 2002) (Fig. 1). RVOT-VT frequently occurs between the age of 30 and 50 (M. Nakagawa et al., 2002), whereas VT arising from the LVOT (LVOTVT) increases with age and frequently occurs between the age of 50 and 70 (Tanaka et al., 2011) (Fig. 2). Fascicular VT frequently occurs between the age of 20 and 40 with male predominance; however, women present at an earlier age(M. Nakagawa et al., 2002; Tanaka et al., 2011).

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Fig. 1 Age distribution of outflow tract ventricular arrhythmias based on gender. Woman have bimodal age distribution with peaks at 20–30 and 50–60 years of age whereas for men the prevalence linearly increase with age (Tanaka et al., 2011).

Fig. 2 Age distribution of the most common idiopathic ventricular arrhythmias. Right ventricular outflow tract (RVOT) ventricular arrhythmias are most common and present at an earlier age than either left ventricular outflow tract (LVOT) or annular ventricular arrhythmias (Tanaka et al., 2011).

Prognostic Implications Initial studies attempted to define the prognostic significance of ventricular ectopy following myocardial infarction (MI) and determined that complex ventricular ectopy after MI increased mortality by a factor of 3 but antiarrhythmic drugs (AADs) worsened outcomes (Kotler et al., 1973; Ruberman et al., 1977). Multiple population studies demonstrated that PVCs without evidence of cardiac disease similarly increased cardiovascular morbidity and mortality:

• • • •

Multiple Risk Factor Intervention Trial found that PVCs conferred a threefold increased risk of sudden cardiac death (SCD) with the effect more pronounced with complex ventricular ectopy (Abdalla et al., 1987). Framingham Heart Study found that complex ventricular ectopy without coronary artery disease (CAD) increased MI and mortality in men but not in women (Bikkina et al., 1992). In the same cohort, complex ventricular ectopy with underlying left ventricular hypertrophy (LVH) increased mortality (Bikkina et al., 1993). Cardiovascular Health Study found the highest quartile of PVC burden was associated with a 3-fold increase of LV dysfunction over 5 years, 48% increased risk of congestive heart failure (CHF), and 31% increased risk of death (Dukes et al., 2015) (Fig. 3). Lin et al. demonstrated that PVCs and NSVT conferred a higher risk of mortality and incident CHF while identifying both as independent risk factors for transient ischemic attack and atrial fibrillation (AF) (Lin et al., 2015, 2016).

Exercise-induced PVCs in the absence of SHD is associated with an increased risk of death (Jouven et al., 2000; Morshedi-Meibodi et al., 2004), however, exercise-induced NSVT does not independently increase mortality (Marine et al., 2013) (Fig. 4).

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Fig. 3 The population-based risk of disease-free survival from all-cause mortality or incident congestive heart failure (CHF) associated with burden of premature ventricular complexes stratified by quartiles. Quartiles 1–4 represent PVC burden of 0–0.002%, 0.002–0.011%, 0.011–0.123%, and 0.123–17.7%. There is a gradient of risk for all-cause mortality across all four quartiles; however, the risk of CHF similar amongst quartiles 1–3 and lowest with quartile 4.

Fig. 4 Exercise-induced idiopathic ventricular tachycardia during exercise tolerance testing in a 26-year old with a structurally normal heart based performed due to exercise-induced chest discomfort and dizziness.

Clinical Presentation Symptoms The most frequent reported clinical symptoms in patients presenting for ablation are palpitations (80%), chest pain (26%), and syncope (24%) (Kim et al., 2007). Exercise- or stress-triggered palpitations are more frequent with sustained monomorphic VT (53%) when compared to NSVT (30%) or PVCs (18%). Other common symptoms include presyncope, dyspnea, fatigue, exercise intolerance, cough, or dysphagia (Laplante and Benzaquen, 2016). A significant proportion are asymptomatic and diagnosed incidentally when an irregular or slow pulse is noted or an ECG is performed for other reasons.

Triggers The most common triggers for idiopathic VT are exercise, emotional stress, and stimulants (Table 1). Other triggers include hormonal variation, as discussed above, medications, and metabolic abnormalities. Circadian variation in autonomic tone results in peak sympathetic tone in the morning, which coincides with the observed early morning risk of VT and SCD. Idiopathic PVCs follow the same circadian pattern (Hayashi et al., 1999). These observations implicate sympathetic tone as a trigger or promoter of ventricular arrhythmias and provide mechanistic insight for the common triggers. A small proportion of patients are paradoxically observed to have PVCs intensify during periods of heightened vagal tone (rest or sleep) and attenuate with increase in sympathetic tone, which may portend a benign prognosis.

Arrhythmia Patterns Idiopathic VT commonly manifests as frequent monomorphic or pleomorphic PVCs, salvos of NSVT also known as repetitive monomorphic VT (MMVT), and sustained VT (Fig. 5). Kim et al. observed that sustained MMVT occurred in 28%, NSVT in 36%, and PVCs in 35% among patients with idiopathic VT presenting for ablation (Kim et al., 2007). Sustained VT was elicited during exercise testing in 67%, 10%, and 10% of patients presenting with sustained VT, NSVT, and PVCs, respectively. VT was induced during electrophysiologic testing in 78%, 48%, and 4% across the three groups.

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Ventricular Tachycardia in Structurally Normal Hearts Table 1

Common triggers for ventricular arrhythmias without structural heart disease

Clinical history Physical activity Exercise Sexual intercourse Anxiety Toxic effects Caffeine Alcohol toxicity and withdrawal Tobacco Exogenous catecholamines (isoproterenol, dopamine, norepinephrine, etc.) Drugs (i.e., digoxin, tricyclics, macrolides, fluoroquinolones, etc. Illicit drugs (i.e., cocaine, cannabis, amphetamine, etc.) Hormonal effects Menses Gestational Perimenopausal Hormone replacement therapy or oral contraceptives Other Hyperthyroidism Pheochromocytoma Hypoxemia Acidemia Ischemia Occult structural heart disease

Fig. 5 Idiopathic ventricular arrhythmias may clinically present as occasional isolated premature ventricular complexes, ventricular bigeminy (A), salvos of repetitive monomorphic ventricular tachycardia (B), and sustained ventricular tachycardia (C).

Anatomic Substrate Idiopathic VT classically refers to outflow tract or fascicular VT; however, other common endocardial or epicardial sites of origin include the mitral or tricuspid annulus, aortomitral continuity (AMC), and papillary muscles (Table 2). Understanding the complex anatomy of these sites and the adjacent structures prone to collateral damage is critically important to optimize efficacy and safety of ablation. Real-time integration of multimodality imaging including fluoroscopy, cardiac computed tomography (CCT), cardiac magnetic resonance (CMR) imaging, electroanatomic mapping, and ultrasound further facilitates understanding of the anatomic relationships and procedural outcomes. RVOT-VT accounts for 50%–80% and LVOT-VT for 15%–25% of all idiopathic VTs (Callans et al., 1997; Kim et al., 2007; Tanaka et al., 2011). The posterior aspect of the RVOT is the most common site for RVOT-VT; LVOT-VT commonly arises from aortic root or coronary cusps (Yamada, 2016). RVOT or infundibulum is a superiorly located conical structure, extending leftward from the tricuspid annulus to the pulmonic annulus, anteriorly overriding the LVOT (Fig. 6). The distal extent at the pulmonic annulus is superior, leftward, and orthogonal to

Ventricular Tachycardia in Structurally Normal Hearts Table 2

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Anatomic classification of idiopathic ventricular arrhythmias

Outflow tract ventricular arrhythmias Right ventricular outflow tract Left ventricular outflow tract Sinuses of Valsalva or coronary cusps Fascicular ventricular arrhythmias Left posterior fascicle Left anterior fascicle Septal fascicle Annular ventricular arrhythmias Mitral annulus Aortomitral continuity Tricuspid annulus Other ventricular arrhythmias Epicardial (LV crux and summit) Papillary muscle Moderator band

Fig. 6 Anatomic relationship of the right ventricular outflow tract (RVOT) to the left ventricular outflow tract (LVOT): (A) An endocardial cast of the right ventricle (RV) and left ventricle (LV) displayed in an anteroposterior projection. The dotted circles represent the annuli of the aortic and pulmonary valves. RVOT anteriorly overrides the LVOT from right to left. (B) The aortic valve is a central structure that is located anterior and superior to the mitral valve (MV) and tricuspid valve (TV) but posterior to the pulmonary trunk (PT). The dotted line represents the interatrial septum. The non-coronary cusp (N) is posterior and adjacent to the atria and the left (L) and right (R) coronary cusps. (C) The dotted line delineates the junction between the RV and the pulmonary artery; the pulmonic valve is orthogonal and superiorly located to the aortic valve. The septal and posterior RVOT are in proximity to the left main (LCA) coronary artery whereas the right coronary artery (RCA) is separated by more distance and epicardial fat. From Ho, S.Y., 2009. Anatomic insights for catheter ablation of ventricular tachycardia. Heart Rhythm: The Official Journal of the Heart Rhythm Society 6(8 Suppl), S77–80, with permission.

the aortic valve (Asirvatham, 2009; Lerman, 2015). The proximal and rightward extent at the level of the tricuspid annulus is adjacent to the His bundle and noncoronary cusp (NCC) of the aortic valve. RVOT is subdivided into septal (posterior and leftward) and free wall (anterior and rightward) segments with the posterior RVOT immediately anterior to the right (RCC) and left (LCC) coronary cusps of the aortic valve and in proximity to the left main coronary artery (LMCA) (Fig. 7). The anterior free wall is generally thinner and at increased risk of perforation than posterior or proximal segments. Myocardial sleeves extending up to and beyond the pulmonary artery or sinuses of Valsalva are implicated as the source of automaticity or triggered activity (Gami et al., 2011; Liu et al., 2014) (Fig. 8). RVOT and LVOT are intimately involved structures derived from a common embryologic outflow tract with slow conduction properties before incorporating into the embryologic RV and developing rapid conduction properties;

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Fig. 7 Intracardiac echocardiography (ICE) of the sinus of Valsalva delineating the non-coronary cusp (NCC), right coronary cusp (RCC), and left coronary cusp (LCC). The two solid lines delineate the course of the left main coronary artery from the LCC and the dotted red line represents a mapping and ablation catheter positioned at the site of earliest ventricular activation in the left coronary cusp.

Fig. 8 A longitudinally dissected aortic annulus revealing the cusps of the aortic valve with visible myocardium extending to the right cusp. The adjacent illustration the extension of myocardial tissue above and into the cusps. From Gami, A.S. et al., 2011. Anatomical correlates relevant to ablation above the semilunar valves for the cardiac electrophysiologist: a study of 603 hearts. Journal of Interventional Cardiac Electrophysiology: An International Journal of Arrhythmias and Pacing 30(1) 5–15, with permission.

persistent remnants of slow conducting tissue may represent the substrate for arrhythmia, the myocardial sleeves (Boukens et al., 2009). Fascicular VT accounts for approximately 10%–15% and originates from the left-sided Purkinje network including the left posterior (
90%), left anterior, and septal fascicles. The left anterior fascicle traverses the anterior mitral annulus and arborizes to the anterolateral wall and anterolateral papillary muscle. The left posterior fascicle extends from the His bundle through the inferoseptum and arborizes to the inferolateral wall and posteromedial papillary muscle; a septal fascicle is present in approximately 65%. VT arising from the mitral or tricuspid annulus accounts for approximately 10% of idiopathic VT (Tanaka et al., 2011). Mitral annular VT most commonly originates from the anterolateral followed by the posteromedial aspects (Figs. 9 and 10). PVCs may arise from the confluence of the subaortic apparatus and anteromedial aspect of the mitral annulus below the left and NCC, referred as the AMC (Fig. 11). Tricuspid annular VT more commonly originates from the anteroseptal region compared to the free wall (Yamada, 2016). Idiopathic VT of epicardial origin typically arises from the crux or LV summit, basal structures in proximity to the coronary venous and arterial systems. The crux is the confluence of the atrioventricular and posterior interventricular grooves near the posterior descending artery and middle cardiac vein. The LV summit region is the triangular space delineated by the bifurcation of the LMCA and the great cardiac vein. A significant layer of epicardial fat and risk of coronary artery damage limits mapping and ablation in this region.

Ventricular Tachycardia in Structurally Normal Hearts

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Fig. 9 Sustained monomorphic ventricular tachycardia in a patient with a structurally normal heart with right bundle branch block (RBBB) morphology with inferior and rightward axis. Electroanatomic mapping revealed that the anterolateral mitral annulus was the site of earliest activation with excellent bipolar and unipolar presystolic electrograms where the tachycardia was successfully ablated.

Fig. 10 Bigeminal premature ventricular complexes with right bundle branch block (RBBB) pattern, positive concordance, and superior axis that was mapped and successfully ablated at the inferior mitral annulus.

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Ventricular Tachycardia in Structurally Normal Hearts

Fig. 11 Premature ventricular complexes with qR complex in lead V1 and Rs in lead I indicative of origin from the aortomitral continuity.

Malignant Consequences Cardiomyopathy Development of reversible PVC-induced cardiomyopathy and heart failure was first described by Duffee et al. (1998). The estimated incidence is 7%–8% among all patients with idiopathic VT (Hasdemir et al., 2011; Kim et al., 2007) with a male predominance (Yokokawa et al., 2012a). Differentiating between primary and secondary cardiomyopathies at presentation is difficult and empiric treatment is performed. The time course for developing LV dysfunction is variable with recovery typically in 4–6 months though up to 4 years was reported. Numerous factors including PVC burden, QRS duration (QRSd) and contour, interpolation, coupling interval, symptoms, and site of origin are associated with heightened risk and suggest a complex interplay of factors including an underlying genetic susceptibility. Multiple studies demonstrated that PVC burden correlates with incidence and severity of LV dysfunction but without a clear threshold for risk. Kanei et al. observed a graded risk of LV dysfunction based on PVC burden: 4% with 10,000 on 24-h ambulatory monitoring (Kanei et al., 2008) (Fig. 12). Dukes et al. similarly observed a graded risk of cardiomyopathy and heart failure with PVC burden stratified quartiles (Dukes et al., 2015). More than 20,000 PVCs in 24 h were associated with LV dysfunction (Niwano et al., 2009) but with less than 15%–20% there was neither difference in LV dysfunction nor improvement with ablation (Hasdemir et al., 2011; Takemoto et al., 2005). PVC burden of 24% is 79% sensitive and 78% specific for PVC-induced cardiomyopathy (Baman et al., 2010). In general, >10,000–20,000 or 20% PVCs in 24 h are considered clinically significant but only a minority is affected in the setting of persistent ventricular bigeminy, whereas reversible cardiomyopathy has been described with less frequent PVCs (Shanmugam et al., 2006). Circadian variability of PVCs impacts the long-term burden and less variability predicts cardiomyopathy independent of PVC burden (Bas et al., 2016). NSVT and pleomorphic PVCs increase the risk of cardiomyopathy (del Carpio Munoz et al., 2011; Kanei et al., 2008). QRSd and contour predicts underlying heart failure and cardiomyopathy: PVCs with QRSd >160 ms and broad (>40 ms) notching are reliable markers of cardiomyopathy (Moulton et al., 1990). Yokokawa et al. established that PVC QRSd >150 predicts reversible cardiomyopathy and the required burden needed to develop cardiomyopathy was lower at this threshold (Yokokawa et al., 2012b). Further increases in QRSd predict irreversible cardiomyopathy (Deyell et al., 2012). Interestingly, fascicular PVCs are narrower but do not have a lower incidence of cardiomyopathy. PVCs that do not alter the surrounding sinus rate (R-R interval) are interpolated (Fig. 13). Interpolation allows more sinus beats and PVCs due to the coupled relationship to the preceding sinus beat. One study suggested that interpolation independently

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Fig. 12 Association of premature ventricular complex (PVC) frequency during 24-hour ambulatory monitoring with left ventricular systolic function. Adapted from Kanei et al., 2008. Frequent premature ventricular complexes originating from the right ventricular outflow tract are associated with left ventricular dysfunction. Annals of Noninvasive Electrocardiology 13: 81–85. https://doi.org/10.1111/j.1542-474X.2007.00204.x.

Fig. 13 Interpolated premature ventricular complexes (PVCs) do not alter the underlying sinus rate and are associated with a higher burden of PVCs. Interpolation has been suggested as a marker of risk for developing a PVC-induced cardiomyopathy independent of PVC burden.

predicted PVC induced cardiomyopathy (Olgun et al., 2011); however, other studies did not find relationship (Ban et al., 2013; Bas et al., 2016). Duration or absence of symptoms correlates with the accumulative PVC burden and both are independently associated with PVC-induced cardiomyopathy (Blaye-Felice et al., 2016; Yokokawa et al., 2012a). Lack of symptoms is associated with a higher 24-hour PVC burden and is 3 times more likely with than without cardiomyopathy (Yokokawa et al., 2012a). Initially, the mechanism was considered analogous to tachycardia-mediated cardiomyopathy prototypically due to AF but multiple studies demonstrated that heart rate remains unchanged regardless of PVC burden (Olgun et al., 2011; Takemoto et al., 2005). The putative mechanism is considered to be due to dyssynchronous ventricular activation similar to pacing-induced cardiomyopathy or manifest right-sided accessory pathways (Udink ten Cate et al., 2010). Though conceptually appealing, several clinical insights suggest greater complexity. First, LV dysfunction is not triggered by LV only pacing or with left-sided accessory pathways. Second, anatomic origin of PVCs should have differential effects if dyssynchrony was fully explicative; however, both right- and left-sided PVCs trigger cardiomyopathy. The rates of cardiomyopathy are independent of endocardial site of origin (del Carpio Munoz et al., 2011; Yokokawa et al., 2012b) but Del Carpio Munoz et al. observed that fascicular VT was associated with higher LVEF and the critical burden for developing cardiomyopathy was different: >10% for RVOT and >20% for LVOT (del Carpio Munoz et al., 2011). Potfay et al. with multisite pentageminal ventricular pacing demonstrated that markers of dyssynchrony are not associated with anatomic location but rather a longer coupling interval (Potfay et al., 2015). Neither burst ventricular pacing nor pentageminal atrial pacing produced the same degree of dyssynchrony and if causative likely relies on a complex interaction between site of origin and coupling interval. Multiple studies demonstrated that epicardial PVCs are associated with greater QRSd prolongation and PVC-induced cardiomyopathy (Blaye-Felice et al., 2016; Hamon et al., 2016; Yokokawa et al., 2012b). PVC-induced cardiomyopathy develops after 12 weeks in a canine model of ventricular bigeminy and rapidly reverses in 2–4 weeks upon cessation of PVCs (Huizar et al., 2011). PVCs result in volumetric and electrical remodeling as is evident from developing of systolic dysfunction, dilation, and increased effective refractory period. Interestingly, there was no histopathologic evidence or change in inflammation, fibrosis, apoptosis, or levels of oxidative stress suggesting a functional cardiomyopathic process. The associated electrical remodeling was further characterized by Wang et al. who demonstrated that dispersion of action potential duration (APD) increased with wider beat-to-beat variation establishing a potentially proarrhythmic substrate (Wang et al., 2014). The densities of outward potassium (Ito, IK1) and inward calcium (L-type) currents decreased without change in other potassium currents (IKr or IKs). Furthermore, impairment of sarcoplasmic reticulum (SR) calcium-induced calcium release and

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alterations in protein expression (juntophilin-2) responsible for maintaining the optimal interface between the cell membrane and SR may account for contractile dysfunction.

Malignant Arrhythmias Focal triggers of ventricular fibrillation (VF) arising from the Purkinje network of the RVOT were described by Haïssaguerre et al. (2003) followed by rare case reports of polymorphic ventricular tachycardia (PMVT) or VF triggered by closely coupled RVOT PVCs with ablation mitigating the risk (Noda et al., 2005; Viskin et al., 2005) (Fig. 14). The aforementioned electrical remodeling facilitates arrhythmogenesis. The coupling interval for triggering PVCs is longer than observed in idiopathic VF but shorter than benign PVCs; triggering coupling intervals are longer for MMVT than PMVT (Shimizu, 2009). MMVT with shorter cycle lengths are associated with a more malignant prognosis.

Clinical Evaluation Idiopathic VT is a diagnosis of exclusion and the principle goal of clinical evaluation is to rule out SHD or heritable arrhythmia syndromes associated with increased risk of SCD or heart failure that persists despite treatment. Initial evaluation should include a comprehensive history and physical examination, 12-lead ECG, and echocardiogram.

History The history establishes the severity, duration, frequency, and triggers of symptoms and impact on quality of life. High-risk features such as syncope or prior cardiac disease significantly modify the prognosis, diagnostic approach, and treatment. A careful review of symptoms to evaluate for signs or symptoms of angina or CHF as well as excluding secondary causes such as endocrine (thyroid, adrenal, or pituitary) and pulmonary disease is paramount. Medications including caffeine, prescription drugs, herbal supplements, or illicit drugs need to be reviewed for potential electrophysiologic effects. Family history should thoroughly evaluate for premature CAD, SCD among first-degree relatives, and heritable cardiomyopathies or electrical disorders.

Physical Examination The physical examination is focused on evaluating the signs of CHF such as elevated jugular venous pressure, pulmonary rales, and pathologic murmurs or gallops suggestive of elevated filling pressures or valvular disease. Evaluation for other systemic manifestations of thyroid (hyperthyroidism), adrenal (pheochromocytoma), or pituitary (acromegaly) disorders as well as diseases with cardiac manifestations (i.e., muscular dystrophy, hemochromatosis, etc.,) is helpful. There are numerous other obvious or subtle findings that may suggest occult cardiopulmonary disease such as xanthelasma, abnormal peripheral pulses or bruits, clubbing, psoriasis, or signs for rheumatoid arthritis.

Electrocardiogram Twelve-lead ECG is generally specific but not sensitive for manifestations of SHD or primary electrical disorders such as q-waves, hypertrophy, conduction delay or block, Brugada pattern, T-wave abnormalities, Epsilon waves, preexcitation, and prolonged QTc. Morphologic assessment of ventricular ectopy allows anatomic localization and assessing complexity of ablation. Outflow tract VT demonstrates left bundle branch block (LBBB) morphology and inferior axis (positive in lead II, III, and aVF) generally with QRSd RCC

Rs

rS or R

II/III R wave ratio > 1

V2-V3 Earlier than sinus rhythm V2 transition ratio 0.6

V1-V3

Earlier than V2

Superior axis Inferior axis

Papillary Concordance

Superior axis-posteromedial Inferior axis-anterolateral

RCC, Right coronary cusp; LCC, Left coronary cusp; AMC, Aortomitral continuity; MA, Mitral annulus. Al’Aref et al. (2015). Circulation: Arrhythmia and Electrophysiology 8, 616–624; Yamada et al. (2010). Circulation: Arrhythmia and Electrophysiology 3, 324–331; Yamada et al. (2008). Journal of the American College of Cardiology 52, 139–147; Kuo et al. (2003). PACE 26, 1986–1992; Kamakura et al. (1998). 98, 1525–1533; Betensky et al. (2011). Journal of the American College of Cardiology 57, 2255–2262; Jadonath et al. (1995). American Heart Journal 130, 1107–1113; Ouyang et al. (2002). Journal of the American College of Cardiology 39, 500–508; Steven et al. (2009). Circulation: Arrhythmia and Electrophysiology 2, 660–666; Hoffmayer et al. (2013). Current Problems in Cardiology 38, 131–158; Dixit, S., et al. (2003). Journal of Cardiovascular Electrophysiology 14,1–7.

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ECG Lead

Other

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Fig. 18 V2 transition ratio of 0.60 is a highly sensitive (95%) and specific (100%) marker for origin from the left ventricular outflow tract. The transition ratio is calculated with the following formula: [B/(B þ C)  E/(E þ F)]. A ¼ PVC R-wave duration (ms); B ¼ PVC R-wave amplitude (mV); C ¼ PVC S-wave amplitude (mV); D ¼ PVC QRS duration (ms); E ¼ sinus rhythm R-wave amplitude (mV); and F ¼ sinus rhythm S-wave amplitude (mV). With permission (Betensky et al. 2011). Table 4

Electrocardiographic markers indicative of epicardial origin

Criteria

Sensitivity and Specificity

Pseudodelta wave 34 ms V2 intrinsicoid deflection 85 Shortest RS complex 121 Maximum deflection index 0.55 Q wave in I or inferior leads

83% and 95% 87% and 90% 76% and 85% 100% and 98.7% 88% and 88%

Berruezo et al. (2004). Circulation. 109, 1842–1847; Daniels et al. (2006). Circulation 113, 1659–1666; Vallès et al. (2010). Circulation: Arrhythmia and Electrophysiology 3, 63–71.

Fig. 19 Maximal deflection index (MDI) is the fraction of the QRS duration represented by the initial forces. The time from onset to maximal deflection (dotted line) is 154 msec and overal QRS duration is 212 msec. MDI is 154/212 or 0.73. MDI 0.55 is a highly sensitive and specific marker for origin from the epicardium.

Advanced Cardiac Imaging Advanced cardiovascular imaging techniques such as CCT, CMR, and positron emission tomography (PET) allow for highly detailed anatomic evaluation of cardiac structures and coronary anatomy as well as assessment of microvascular perfusion and tissue characterization for myocardial fibrosis, fibrofatty replacement, and inflammation. In particular, attention has focused on the relationship between idiopathic outflow tract VT and ARVC. ARVC is a progressive disease with sites for VT from the outflow tract, apex, and sub-tricuspid area (triangle of dysplasia) associated with RV dilation and

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Fig. 20 Fascicular premature ventricular complex (PVC) morphology from both the posterior (A) and anterior (B) fascicles. Left posterior fascicular PVCs have right bundle branch block (RBBB) morphology and left superior axis. Left anterior fascicular PVCs have RBBB morphology and right inferior axis.

aneurysms (Fig. 21). The overlap of VT from the outflow tract raises the question of whether idiopathic outflow tract VT is an early manifestation or forme fruste of ARVC. Mehta et al. demonstrated approximately 40% of patients with idiopathic RVOT-VT had abnormal endomyocardial biopsies of which 73% had abnormal echocardiograms; echocardiogram was abnormal in 6% with a normal biopsy. Sustained VT with LBBB morphology and superior axis suggests occult RV cardiomyopathy (Mehta et al., 1989, 1994) (Fig. 22). Interestingly, Carlson et al. demonstrated that RVOT-VT is associated with focal RV structural abnormalities only detected on CMR including focal wall thinning, decreased systolic thickening, and abnormal wall motion (Carlson et al., 1994). This finding was confirmed by multiple other studies that additionally observed mild fibrofatty infiltration in RVOT-VT (Globits et al., 1997; O’Donnell et al., 2003; Proclemer et al., 1997). Gaita et al. reevaluated 61 patients with idiopathic RVOT-VT after a mean follow-up of 15 years and found that none experienced SCD or developed ARVC but 8 of 11 (73%) patients who underwent CMR displayed focal fibrofatty replacement (Gaita et al., 2001). 18-fluorodeoxyglucose (FDG) PET combines different imaging modalities including myocardial FDG avidity as a marker of metabolic activity, rubidium-82 perfusion imaging, and morphologic assessment with CCT where a mismatch between metabolic and perfusion imaging suggests regions of scar due to active myocardial inflammation. PET is helpful when cardiac sarcoidosis is suspected as there is no specific cardiac presentation pattern and may mimic other diseases such as ARVC. Nery et al. found that 42% of all patients presented with sustained MMVT had abnormal FDG-PET scans suggesting myocardial inflammation and 28% were confirmed to have cardiac sarcoidosis (Nery et al., 2014). FDG-avidity without evidence of sarcoidosis may represent myocarditis or is nonspecific. Variability in QRS morphology and cycle length may distinguish VT associated with cardiac sarcoidosis from idiopathic VT (Panda et al., 2015). CCT, CMR, or FDG-PET is not routinely indicated in the presence of a normal 12-lead ECG, monomorphic ventricular ectopy, normal echocardiogram, and in the absence of high risk features such as syncope or family history of sudden death. These imaging modalities are generally reserved for case when the history, ECG, and echocardiogram raise the specter of congenital heart disease, infiltrative disease, hypertrophic cardiomyopathy, or ARVC. Other imaging modalities with limited utility are routine coronary angiography, RV angiography, myocardial perfusion scintigraphy, and endomyocardial biopsy.

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Fig. 21 Morphological changes of the right ventricle consistent with arrhythmogenic right ventricular (RV)cardiomyopathy. The two echocardiographic panels on the left show a dilated RV with a thin walled apical aneurysm wrapping around the left ventricular apex (LV) on parasternal long axis views. The two cardiac magnetic resonance imaging panels on the right confirm severe RV dilation and a RV apical aneurysm.

Fig. 22 Sustained monomorphic ventricular tachycardia with left bundle branch block morphology, negative concordance, and superior axis suggestive of origin from the inferoapical right ventricle suggestive of arrhythmogenic right ventricular cardiomyopathy.

Ventricular Tachycardia in Structurally Normal Hearts Table 5

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Electropharmacologic classification of idiopathic ventricular arrhythmias Adenosine-sensitive

Verapamil-sensitive

Propranolol-sensitive

Mechanism

Triggered activity cAMP-mediated calcium overload leading to DADs

Intrafascicular reentry

Enhanced automaticity

Pattern

Monomorphic PVCs, salvos, sustained VT

Monomorphic PVCs, salvos, sustained VT

ECG Morphology Anatomic Origin Induction PES (rapid pacing) Catecholamines Exercise Entrainment Drug response Adenosine Verapamil Propranolol

LBBB with inferior axis RVOT or LVOT

RBBB with left-superior axis RBBB with rightinferior axis LAF or LPF

Monomorphic or polymorphic Incessant RBBB, LBBB, polymorphic

(þ)

(þ)

()

(þ) (þ) Absent

(þ) (þ) Present

(þ) (þ) Absent

Termination Termination Termination

No response Termination No response

Termination

No effect

Transient suppression No response Termination or transient suppression Transient suppression

Acetylcholine

RV and LV

cAMP, Cyclic adenosine monophosphate; DADs, Delayed afterdepolarization; PVCs, Premature ventricular complexes; VT, Ventricular tachycardia; LBBB, Left bundle branch block; RBBB, Right bundle branch block; RVOT, Right ventricular outflow tract; LVOT, Left ventricular outflow tract; LAFB, Left anterior fascicle; LPF, Left posterior fascicle; RV, Right ventricle; LV, left ventricle; (þ), Induced or facilitates; (), No effect

Mechanisms of Arrhythmogenesis The clinical presentation and electropharmacologic profiles of idiopathic VT are variable but classification is possible by differences in electrocardiographic pattern, anatomic origin, response to exercise or catecholamines, response to programmed electrical stimulation (PES), or medications including adenosine, verapamil, or propranolol. The most common classification framework is based on response to adenosine, verapamil, or propranolol as drug response provides mechanistic insight: triggered activity, reentry, and automaticity, respectively (Table 5).

Adenosine-Sensitive Lerman et al. first characterized the response of idiopathic VT with LBBB morphology and inferior axis, now recognized as outflow tract VT, to pharmacologic agents and PES (Lerman, 1993; Lerman et al., 1986; Wilber et al., 1993). Burst pacing reliably induces and terminates VT; isoproterenol facilitates induction; beta-blockade suppresses induction; and VT terminates with adenosine, verapamil, beta-blockers, Valsalva maneuver, or carotid sinus massage. Kim et al. demonstrated that the clinical presentation, electrophysiologic provocation, and drug response are similar across the spectrum of outflow tract VTs suggesting a common mechanism of arrhythmogenesis (Kim et al., 2007). The sensitivity to adenosine provided the central insight to understand the clinical observations and mechanism. Adenosine (A1) receptors are found in atrial and ventricular myocardium with greater density in atrial versus ventricular myocardium (Lerman and Belardinelli, 1991). A1 receptors couple to an inhibitory G protein with two principal signal transduction pathways: cAMP and phosphatidylinositol. The response of supraventricular tachycardia to adenosine is due to cAMP-independent activation of the outward potassium current with resultant decrease in APD; however, this is not observed in ventricular myocardium. Adenosine inhibits adenylate cyclase- and cAMP-mediated activation of the inward calcium current (L-type) resulting in negative chronotropic and inotropic effects. Acetylcholine, via cardiac muscarinic receptors, yields identical effects explaining the unusual response to vagal maneuvers. Calcium channel blockers (CCBs) directly inhibit the L-type calcium current (Fig. 23). The findings are consistent with a mechanism dependent on cAMP-mediated calcium overload. cAMP activates protein kinase A leading to phosphorylation of the L-type calcium channel and ryanodine receptor resulting in increased inward calcium current and calcium release from the SR that feeds back to further stimulate calcium-induced calcium release. Intracellular calcium overload results in an increase in the transient inward sodium current due to the activation of the sodium-calcium exchanger during phase 4 of the action potential (AP), triggering delayed afterdepolarizations (DADs). DADs reaching the critical threshold will trigger another AP that may result in development of successive APs leading to triggered VT. Accordingly, adenosine sensitivity is the sine qua non of cAMP-mediated triggered activity.

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Fig. 23 Signal transduction pathway for cAMP-mediated triggered ventricular tachycardia. AC ¼ adenylate cyclase; Ach ¼ acetylcholine; ADO ¼ adenosine; A1R ¼ A1-adenosine receptor; b-AR ¼ b-adrenergic receptor; CCB ¼ calcium channel blocker; DAD ¼ delayed after depolarization; Iti ¼ transient inward current; M2R ¼ muscarinic receptor; NCX ¼ Naþ/Ca2þ exchanger; PLB ¼ phospholamban; PKA ¼ protein kinase A; RyR ¼ ryanodine receptor; SR ¼ sarcoplasmic reticulum. From Lerman, B.B., 2007. Mechanism of outflow tract tachycardia. Heart Rhythm : The Official Journal of the Heart Rhythm Society 4(7) 973–976, with permission.

Verapamil Sensitive Zipes et al. in 1979 first described idiopathic VT with RBBB morphology and left axis deviation that was induced with atrial pacing (Zipes et al., 1979) and later described by Belhassen et al. to be sensitive to verapamil (Belhassen et al., 1981). Multiple studies suggested intrafascicular reentry as the mechanism due electrocardiographic morphology, response to PES with entrainment, early retrograde His potential suggesting fascicular origin and identification of an area of slow in the region of the fascicles (Belhassen et al., 1981; German et al., 1983; Lin et al., 1983; Ohe et al., 1988; Okumura et al., 1987, 1996; Zipes et al., 1979). Common triggers include exercise or catecholamines. The antegrade limb extends from the basal to mid apical septum and slowly conducting verapamil-sensitive fascicular fibers with decremental conduction properties are implicated as the retrograde limb of the reentrant circuit (Lin et al., 1983). It was postulated that presystolic Purkinje potentials would be appropriate targets for ablation and was confirmed by Nakagawa et al. (1993) (Fig. 24). Diastolic Purkinje potentials have been observed (Nogami et al., 2000). Targeting Purkinje potentials for ablation during sinus rhythm has proved successful (Ouyang et al., 2002a). Interestingly, successful ablation of the left posterior fascicle for fascicular VT does not result in QRS widening or fascicular block, suggesting that the fascicles are not critical substrate (Kuo et al., 2003). Two studies suggest that the fascicle is in fact a bystander and that the retrograde limb is LV myocardium (Maeda et al., 2014; Morishima et al., 2012). The optimal site of ablation therefore cannot be identified if VT is not induced and an anatomic linear ablation to transect the region of the posterior fascicle is necessary to sufficiently modify the substrate.

Propranolol Sensitive The clinical characteristics and mechanisms of propranolol-sensitive VT are poorly defined but may present as MMVT or PMVT that is modulated by catecholamines (Lerman et al., 1997; Sung et al., 1988). VT may be induced with exercise or isoproterenol and conversely suppressed with beta-blockers. PES characteristically is unable to initiate or terminate VT. Adenosine suppresses, not terminates, VT. These characteristics suggest an automatic mechanism arising from fully repolarized myocardium (normal, 90 mV) not abnormal automaticity (60 mV).

Management Strategies Observation In the absence of symptoms and underlying cardiomyopathy there is no immediate need for intervention if the burden of PVCs is 20,000 PVCs.

Avoidance of Triggers A common recommendation is to avoid potential triggering substances, medications, food, or illicit drugs including caffeine, alcohol, tobacco, chocolate, beta-agonists, marijuana, cocaine, amphetamines, and other stimulants. While recommendations to avoid illicit stimulants, alcohol, or tobacco are beneficial for a myriad of reasons, there is little data supporting avoidance or behavioral modification for caffeine, alcohol, and tobacco in regard to ventricular arrhythmias (Glatter et al., 2012). In fact, Debacker et al. did not find any benefit from cessation or reduction of caffeine, tobacco, or alcohol (DeBacker et al., 1979).

Pharmacotherapy: Beta-Blockers and Calcium Channel Blockers Beta-blockers and CCBs are generally first-line therapy for asymptomatic or symptomatic idiopathic VT but overall efficacy is not well established. Generally, the effectiveness of beta-blockers and CCBs are considered to be modest and limited by potential side effects encountered in doses sufficient for arrhythmia suppression. Beta-blockers inhibit activation of adenylate cyclase thus reduce cAMP-dependent phosphorylation of L-type calcium channels and ryanodine receptors leading to reduced intracellular calcium thus suppressing automaticity and afterdepolarizations. Atenolol significantly reduced PVC burden by 33% and reduced symptoms but placebo resulted in a similar degree of symptom reduction without change in PVC burden (Krittayaphong et al., 2002). Verapamil reduces PVC burden by 35% (Gill et al., 1992). A retrospective analysis found that beta-blockers and calcium channel blockers resulted in 36% and 43% reduction in PVC burden, respectively (Zhong et al., 2014). Intravenous adenosine and verapamil both have been used for the acute treatment of idiopathic VT as well as sympatholytic maneuvers (Valsalva or carotid sinus massage). The vasodilatory and electrophysiologic effects of adenosine or verapamil may lead to hemodynamic compromise or rhythm degeneration, especially in the presence of SHD, which is rarely known at the time of presentation.

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Pharmacotherapy: Antiarrhythmic Drugs (AADs) The clinical response to AADs has been evaluated in several small studies and included mexiletine, tocainide, flecainide, disopyramide, and sotalol (Capucci et al., 1989, 1991; Gill et al., 1992; Masotti et al., 1984; Tanabe et al., 1991). Amiodarone, mexiletine, flecainide, sotalol, and propafenone result in 70%–89% reduction in PVC burden (Zhong et al., 2014). Of these medications, sotalol and flecainide are most commonly used. Sotalol has been used safely in the presence of SHD and appears to be greater than 89% effective for the treatment of RVOT-VT (Gill et al., 1992). These medications are generally well tolerated but care must be taken when administering to patients at risk for or with cardiomyopathy due to negative inotropic effects, QT prolongation, and proarrhythmia. AADs are generally reserved for risk averse or frail patients or for specific anatomic sites of origin (i.e., epicardial) that suggest lower ablation success with higher complication rates.

Catheter Ablation Chugh et al. first described a patient with cardiomyopathy and high burden of PVCs in whom successful catheter ablation resulted in reversal of cardiomyopathy (Chugh et al., 2000). Takemoto et al. in 2005 systematically evaluated the role of ablation for RVOT PVCs and found that the success rate was 93% with 3% complication and 3% recurrence rates (Takemoto et al., 2005). Ablation of patients with a high burden (>20%) of PVCs was associated with improvement in LVEF and LV dimensions. Yarlagadda et al. confirmed this finding with an 85% success rate of ablation (Yarlagadda et al., 2005). Multiple subsequent single-center experiences have demonstrated that ablation is successful in 66%–92% all associated with significant reduction in PVC burden and improvement in LVEF and dimensions (Ban et al., 2013; Bogun et al., 2007; Penela et al., 2013; Sarrazin et al., 2009; Yokokawa et al., 2012a; 2013). Ablation was further associated with improvement in functional class and decrease in brain natriuretic peptide levels (Penela et al., 2013). Ineffective ablation was associated with a further decline in LVEF (Bogun et al., 2007). The time to recovery was generally within 4–6 months (Bogun et al., 2007; Yokokawa et al., 2013) but a significant minority (32%) of patients experienced more delayed improvement (Yokokawa et al., 2013). Epicardial PVCs or wider QRSd are independently associated with delayed recovery (Yokokawa et al., 2013). The recurrence rate of PVCs following an initially successful ablation appears to range from 9% to 17%. Tanaka et al. (2011) found that the success of ablation was 88% for RVOT origin but only 58% for LVOT origin. Latchamsetty et al. published an extensive retrospective multicenter outcomes study for catheter ablation of idiopathic PVCs from eight high volume ablation centers with mean PVC burden of 20% and LVEF 55% in which the acute success of ablation was 84% (Latchamsetty et al., 2015). The success rate was as high as 93% for RVOT origin and as low as 67% for epicardial origin (Fig. 25). 71% experienced a durable decline in PVC burden (80% reduction) over 20 months of follow-up; 19% were on antiarrhythmic medications at follow-up. Among patients with cardiomyopathy, LVEF improved  10% in 67%, 100 ms in one or more precordial leads (Brugada et al., 1991)). - Vi/Vt ratio 50 ms (Pava et al., 2010). – Ventricular flutter: continuous, oscillatory monomorphic waveform, with no isoelectric line and T waves may not be clearly visible (Fig. 6). The diagnostic utility of these features will be covered in more detail in the discussion of how they help to differentiate VT from other etiologies.

Differential Diagnosis When attempting to make a diagnosis of the mechanism of any tachycardia on ECG, it is useful to start by asking two simple questions:

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Fig. 3 Chest leads of a WCT showing negative concordance, with predominantly negative QRS complexes across all the leads. Since the complexes in V1 are predominantly negative (in this case, rS waves), this tachycardia would be described as having a “left bundle branch block (LBBB) morphology,” even though the appearances are not typical for actual block in the left bundle. The ECG suggests VT with an apical exit. ECG recorded at 25 mm s1.

Fig. 4 ECG leads I, II, III, V1, recorded at 25 mm s1, showing dual-chamber pacing followed by irregular, polymorphic VT. On the first two beats the ST segments appear abnormal in lead I and V1, even given the fact that the rhythm is paced. In this case the polymorphic VT was occurring in the setting of acute ischemia.

• •

Is the rhythm visibly regular or irregular? Are the QRS complexes narrow (35 years as a predictor of VT was lower at 85%. There were no strong predictors of SVT, with the best predictor being age 160 ms (Wellens et al., 1978). Therefore, in these cases, VT should be suspected. Some caveats are that: (1) in the presence of drugs which prolong the QRS duration (particularly Class 1C agents like flecainide) the aberrantly conducted beats can be wider than usual; (2) preexcited tachycardias can have markedly widened QRS complexes, especially when conduction is over a right or left free wall accessory pathway; (3) some patients with congenital heart disease may have RBBB with a markedly widened QRS (Fig. 14). QRS axis Analysis of the QRS in the frontal plane (I, II, III, aVL, aVR, aVF) can also be helpful in differentiating SVT from VT. The QRS axis can easily be measured and can be quite useful if the axis is between 90 and 180 degrees otherwise known as the “northwest quadrant” or “right superior” axis (Fig. 15). Typical fascicular blocks range between 30 and 90 degrees for left anterior fascicular block, and 110 and 150 degrees for left posterior fascicular block. Therefore, a marked deviation from these suggests VT (Wellens et al., 1978). This observation is true for VT with a RBBB configuration but has been questioned in VT with a LBBB configuration (Kindwall et al., 1988). QRS concordance Analysis of the precordial leads (V1–V6) is useful as it may show abnormal progression of the QRS complexes. If the QRS is predominantly positive or negative in leads V1–V6, it is said to have positive or negative concordance, respectively, which favors VT with a specificity of 90%–95% (Miller et al., 2006), see Figs. 2 and 3). A rhythm with negative concordance suggests an origin at the apex of the heart (e.g., consider the morphology of RV apical pacing), while positive concordance suggests an origin from the base or posterior wall of the left ventricle. The latter would include VT from this site or conduction over a left posterior accessory pathway, so it is not 100% specific for VT. QRS morphology Morphological criteria suggesting VT or BBB can be subtle and depend largely on a clinician’s familiarity with typical bundle branch block patterns. In general, these criteria rely on identifying how closely the QRS morphology of the tachycardia matches the

Fig. 14 Baseline ECG in a patient with congenital heart disease (Uhl’s anomaly) demonstrating right bundle branch block with markedly widened QRS complexes (QRS duration 200 ms). ECG recorded at 25 mm s1.

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Fig. 15 ECG limb leads, recorded at 25 mm s1, showing right superior or “Northwest” axis deviation, and wide, bizarre QRS complexes, in a patient with ventricular tachycardia.

Fig. 16 QRS morphology patterns in leads V1 and V6 which may help differentiate SVT with aberrant conduction from VT. In the case of SVT with aberration, the QRS morphology shows the typical appearances for left or right bundle branch block, generally with rapid initial forces and delay later in the QRS. In the case of VT, the QRS morphology is more atypical, often with delay at the start of the QRS complex. LBBB: left bundle branch block; RBBB: right bundle branch block; SVT: supraventricular tachycardia; VT: ventricular tachycardia. Reproduced, with permission, from Miller, J. M., Das, M. K., Yadav, A. V., Bhakta, D., Nair, G., Alberte, C. (2006). Value of the 12-lead ECG in wide QRS tachycardia. Cardioliology Clinics 24, 439–451 (their Fig. 5).

expected typical findings for BBB, where the closer the match, the more likely it is to be SVT with BBB, and the more disparate the appearances, the more likely it is to be VT. Within these criteria, attention is also focused on the initial portion of the QRS since in BBB the activation here is generally rapid (since it uses the normal conduction system of the working bundle) while in VT it is slowed (since it occurs by cell-to-cell conduction). Fig. 16 summarizes some of these criteria.

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Wide QRS Complex Tachycardia: What is the Diagnosis?

WCT with “RBBB-morphology” QRS In an SVT with typical RBBB, one should note:

• • •

The QRS duration exceeds 120 ms. The QRS in V1 is described as triphasic with an rsr’, rsR’, or rSR’ pattern. The initial r reflects normal septal activation; the S reflects LV activation and the R’ reflects late activation of the RV. Whereas in leads I, aVL and the left precordial leads, the S wave is wider than the preceding R wave due to the late depolarization of the right ventricle via slow conduction from myocyte-to-myocyte (Wellens and Conover, 2006; Mirvis and Goldberger, 2015). In the absence of coexisting left fascicular block, the axis is typically normal in the limb leads.

“RBBB” QRS patterns that are highly suggestive of VT include a monophasic (R), or biphasic (qR, QR) in V1 (Marriott, 1970). It is important to note that there are limitations to these generalizations as large Q waves on baseline ECGs can make an SVT look biphasic. When these characteristics were assessed by Brugada et al., they noted 84% specificity for VT for the monophasic R, 98% specificity for a QR or RS, and 91% specificity for the triphasic configuration (Brugada et al., 1991). Therefore, looking at additional leads can help provide consistency in findings. The QRS morphology in lead V6 suggests VT if the R:S ratio is 60 ms. 4. Notching on the downstroke of the S wave in V1 or V2. All four criteria were found to be specific for VT in the original paper (ranging from 94% to 100%), but less so in subsequent papers, including Miller et al. who reported that the specificity of QRS onset to nadir of the S wave >60 ms was 85% (Miller et al., 2006). Where Kindwall et al. had suggested that onset of the R to the deepest part of the S in V1 and V2 in LBBB WCT could be used to differentiate VT from SVT, Brugada et al. suggested that the longest RS interval in any precordial lead exceeding 100 ms would be suggestive of VT (Brugada et al., 1991). This removes the complexity of having the observers be comfortable with recognizing the bundle branch block morphology and their individual nuances. Brugada et al. observed that RS intervals of >100 ms were only seen in VT, and that absence of any RS complex in any of the precordial leads was seen only in VT. They concluded these findings were 100% specific. Absence of RS was only seen in 21% of VTs, and an RS interval >100 ms was seen in 66% of VTs in the original report. Subsequent reports found these to be 93% specific (Vereckei et al., 2007; Vereckei et al., 2008). As a measure of slow conduction through myocardium, Verekei et al. proposed that a ratio of the amplitude of the initial 40 ms of the QRS to the terminal 40 ms of the QRS (Vi/Vt) of 40 ms as a marker for VT (Vereckei et al., 2008). While this was insensitive, with only 28% of VTs having a q or r wave in aVR, it was fairly specific with a reported specificity of approximately 92%. Another group proposed using lead II to assess slow ventricular depolarization in VT, using the R-wave peak time (RWPT) >50 ms to detect VT (Pava et al., 2010). RWPT was defined as onset of the QRS to the first change of polarity, independent of whether the QRS deflection was positive or negative. They looked at 218 patients who had undergone EP studies for different reasons and reported an initial sensitivity of 93% and specificity of 99%. Its main benefit over the previous algorithms is simplicity. RWPT was assessed by another group, comparing it to the Verekei aVR algorithm and found it did surprisingly well despite its apparent simplicity, with 74%–85% specificity (Szelényi et al., 2013). However, its sensitivity was quite low at 62%–79% versus the Verekei aVR algorithm which had sensitivities in the 91%–93% range. The presence of multiple WCT morphologies also suggests VT. Scar tissue can result in circuits with different exit points and thus different morphologies in VT. Miller and Das analyzed 861 patients assessed for WCT with an EP study and found that 266/524 (50%) of patients with VT had multiple WCT morphologies whereas only 31/392 (8%) of patients in SVT did (Miller and Das, 2009).

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Fig. 17 (A) Stepwise algorithm from Brugada et al for differentiating VT from SVT with aberrant conduction. (B) Table outlining the criteria referred to in the last step of the algorithm. Reproduced, with permission, from Brugada, P., Brugada, J., Mont, L., Smeets, J., Andries, E. W. (1991). A new approach to the differential diagnosis of a regular tachycardia with a wide QRS complex. Circulation 84,1649-59 (their Fig. 1 and Table 1).

Fig. 18 (A) Stepwise algorithm from Vereckei et al for differentiating VT from SVT with aberrant conduction. (B) Method for calculating Vi/Vt for step 4 of the algorithm. Vi is the voltage change, in mV, of the initial 40 ms of the QRS complex, while Vt is the same measurement made for the terminal 40 ms of the QRS complex. A-V: atrioventricular; BBB: bundle branch block; FB: fascicular block; SVT: supraventricular tachycardia; VT: ventricular tachycardia. Reproduced, with permission, from Vereckei, A., Duray, G., Szénási, G., Altemose, G. T., Miller, J. M. (2007). Application of a new algorithm in the differential diagnosis of wide QRS complex tachycardia. European Heart Journal 28, 589–600 (their Fig. 3); Vereckei, A., Duray, G., Szénási, G., Altemose, G. T., Miller, J.M. (2008). New algorithm using only lead aVR for differential diagnosis of wide QRS complex tachycardia. Heart Rhythm 5, 89–98 (their Figs. 1 and 3).

Stepwise algorithms for distinguishing VT from SVT with BBB Several algorithms have been published to improve the sensitivity and specificity by combining multiple ECG findings. The most popular of these were published by Brugada et al. (1991), see Fig. 17) and the two algorithms by Verekei et al. (2007); Vereckei et al. (2008), see Figs. 18 and 19). Initial sensitivities and specificities were >90%, but real-world application by cardiologists and emergency doctors tends to yield poorer results (Isenhour et al., 2000; Jastrzebski et al., 2012; Szelényi et al., 2013).

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Wide QRS Complex Tachycardia: What is the Diagnosis?

Fig. 19 (A) Simplified stepwise algorithm from Vereckei et al for differentiating VT from SVT with aberrant conduction, using Lead aVR alone. (B) Method for calculating Vi/Vt for step 4 of the algorithm. Vi is the voltage change, in mV, of the initial 40 ms of the QRS complex, while Vt is the same measurement made for the terminal 40 ms of the QRS complex. SVT: supraventricular tachycardia; VT: ventricular tachycardia. Reproduced, with permission, from Vereckei, A., Duray, G., Szénási, G., Altemose, G. T., Miller, J. M. (2008). New algorithm using only lead aVR for differential diagnosis of wide QRS complex tachycardia. Heart Rhythm 5, 89–98 (their Figs. 1 and 3).

One of these studies assessed the performance of several algorithms/methods: Brugada, Bayesian, Griffith, Verekei aVR and RWPT (Jastrzebski et al., 2012). All five methods had only moderate accuracy (69%–77%). Overall, the Brugada algorithm had the best balance of sensitivity (89%) and specificity (59%) compared to the other criteria. A Bayesian approach involving 19 features (Lau et al., 2000) did not perform better than the much simpler Brugada algorithm. The Griffith approach yields slightly better sensitivity (94%) as it presumes all WCT to be VT until proven otherwise. However, this is at the expense of specificity (39%). The lead II RWPT had the highest specificity (83%) but at the expense of sensitivity (60%). Despite the advances and further refinements in ECG interpretation, there is no single algorithm that can reliably differentiate SVT from VT. The most specific finding for VT, AV dissociation, is found only in a small proportion of VTs (approximately 30%). Attempts to increase the sensitivity unfortunately decrease the specificity. The more tools a clinician has in his toolbox, the greater the chance of an accurate diagnosis, although sometimes assuming that the WCT is VT can be the safest approach, particularly if the diagnostic criteria give disparate results. Cardiac imaging Most of the literature on the differentiation of SVT from VT aims at interpretation of the ECG. However, imaging may also prove useful in assessing the likelihood the arrhythmia is VT, by providing an assessment for structural heart disease. While a normal echo or magnetic resonance imaging (MRI) cannot rule out VT, an abnormal study would increase the likelihood of VT (Tandri et al., 2004). Reduced LV ejection fraction is a crude measure which correlates with the risk of VT and sudden cardiac arrest (Vest and Gold, 2010). Some imaging studies have tried to provide a more refined estimate of the risk of ventricular arrhythmias. Cardiac MRI studies suggest that the extent of the ventricular scar, as well as tissue heterogeneity may be correlated to an increased likelihood of ventricular arrhythmia in ischemic heart disease (Schmidt et al., 2007). Cardiac MRI has also been shown to predict VT in other patient groups including hypertrophic cardiomyopathies (Nojiri et al., 2011; O’Hanlon et al., 2010), dilated cardiomyopathies (Gao et al., 2012), ARVC (Mavrogeni et al., 2012; Jain et al., 2008; Sen-Chowdhry et al., 2007), Tetralogy of Fallot (Tsai et al., 2010)), and chronic Chagas’ disease (Rochitte et al., 2005). Cardiac implantable device interrogation It is becoming more and more common for patients to present with an undifferentiated arrhythmia in the presence of a cardiac device. Proper interpretation of stored device episodes and electrograms may aid in the differentiation of VT from SVT and lead to the appropriate clinical management. The amount of information available will depend on the type of device (implantable loop recorder, pacemaker, or ICD), manufacturer of the device, and number of leads (single versus dual chamber).

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The first consideration is that any patient with an ICD in place will either have had prior ventricular arrhythmias (secondary prevention ICDs) or have been judged to be at higher risk of ventricular arrhythmias (primary prevention ICDs). Thus, their pretest probability of VT will already be significantly elevated. However, such patients may also have BBB and coexisting arrhythmias, including SVT and other atrial arrhythmias, so it is not unusual for them to have other mechanisms for a WCT. Some device findings may be diagnostically useful. The ventricular rate of an episode alone is a fairly poor discriminator and can lead to inappropriate therapy for SVT in up to 45% of cases at 1 year (Dorian et al., 1999). The MADIT-RIT trial noticed a very high rate of inappropriate therapies with frequent atrial tachyarrhythmias occurring in the range of 170–199 bpm and failure of the device to discriminate between atrial and ventricular tachyarrhythmias (Moss et al., 2012). ATs were significantly less frequent at higher rates (over 200 bpm). Changes in local or farfield electrogram morphology compared to the baseline rhythm are also poor discriminators for VT versus SVT with BBB, since differences may occur in both cases. In a dual-chamber device, the most useful diagnostic information can come from examining the AV relationship during an episode of WCT. In contrast to ECG interpretation, where P waves can be difficult to discern, up to 90% of VTs have been reported to show AV dissociation on dual-chamber ICDs (Swerdlow, 2001). In approximately 3% of patients with ICDs, VT occurs in the setting of AF (Stein et al., 1999). The combination of regularity of the ventricular rhythm and AF (not AFL) in the atrium is highly successful in distinguishing VT. Invasive EP study For many of the published studies on differentiation of SVT from VT, the EP study was used as the gold standard for diagnosis, and this can also be the case in clinical practice. Pacing protocols can allow the induction of tachycardia, which can be compared to the clinical WCT. Intracardiac recordings and pacing maneuvers can identify substrates for SVT or confirm that the rhythm is ventricular. There is also the opportunity for curative ablation of SVT circuits. Ablation would not typically be employed as first-line therapy for VT in the setting of ischemic or nonischemic cardiomyopathy but could be considered for outflow tract VT, fascicular (Belhassen) VT, and bundle branch reentry VT.

Particular Types of WCT With Classic Electrocardiographic Features Table 1 outlines several forms of WCT which may be recognized from their classic ECG appearances. Identification of these mechanisms is important since they may be treated with ablation (also reviewed in Issa et al., 2012).

Identification of Preexcited Tachycardias Access to an ECG in sinus rhythm greatly aids in the identification of preexcited tachycardias, especially when the preexcitation is readily apparent and can be compared to the WCT being considered. It is important to remember that ventricular activation in sinus rhythm will usually involve fusion between activation over the normal conduction system and activation over the accessory pathway. Often in a regular preexcited tachycardia, ventricular activation occurs exclusively over the accessory pathway (the ECG shows maximal preexcitation), so there can be significant differences in the overall QRS morphology between these two situations. ECG clues may be used to help differentiate between VT and SVT with antegrade conduction over an accessory pathway. Brugada and coworkers developed some criteria for distinguishing preexcited tachycardias (Antunes et al., 1994). These focused on the following features:

• • •

Preexcited tachycardias activate from base to apex, therefore leads V4–V6 are predominantly positive. Negative complexes in V4–V6 therefore favor the diagnosis of VT. In the absence of structural heart disease, QR complexes should not be observed during preexcited tachycardia; therefore this favors the diagnosis of VT. AV dissociation, as this is nearly 100% specific for VT.

Based on these criteria, they found that preexcited tachycardias were all appropriately identified. However, 25% of VTs were misdiagnosed as preexcited tachycardias, signifying caution when applying these criteria. This is not surprising, since VT with an exit near the mitral or tricuspid annulus could look identical to a preexcited tachycardia with the ventricular insertion of the accessory pathway at this site.

Approach to Irregular WCT As listed earlier, the main differential diagnosis of an irregular WCT includes atrial dysrhythmias (AF, AFL with variable AV conduction, AT with variable AV conduction, MAT) conducted with BBB or over an accessory pathway, polymorphic VT, VF, and artifact. In keeping with the approach to regular WCT, the patient’s prior medical history (including medications) and current clinical context can aid in making the rhythm diagnosis. Baseline ECGs should be examined in particular for the atrial rhythm, any evidence of ischemia, infarction, or preexcitation, and any QT prolongation or other abnormalities suggesting a cardiomyopathy. The serum potassium level should be checked since hypokalemia can induce or exacerbate QT prolongation and increase the risk of torsades de pointes VT.

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Table 1

Selected wide complex tachycardia diagnoses with classic electrocardiographic features

Tachycardia

WCT type

Right ventricular outflow tract (RVOT) VT

VT

Left ventricular outflow tract (LVOT) VT

VT

Idiopathic LV VT (also referred to as “Belhassen VT” and LV fascicular VT)

VT

Bundle branch reentry VT

VT

Classic ECG findings

Notes and references

• • • • • • • • • • • •

Lerman (2015)

•

LBBB-morphology QRS Inferior frontal axis V3 R/S < 1 LBBB-morphology QRS Inferior frontal axis V3 R/S > 1 V3 R ¼ S RBBB-morphology QRS QRS duration 100–140 ms Left axis deviation R/S < 1 in V1–V2 BBB pattern matching conducted rhythm AV dissociation may be apparent

Bidirectional VT

VT

•

Alternating QRS axis

Atriofascicular reentry tachycardia

SVT

• •

LBBB-morphology QRS Frontal axis can be normal, horizontal, or leftward QRS duration often minimally prolonged or normal

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Origin can be below or above the aortic valve. Nogami (2002) and Lerman (2015) “Common type” of idiopathic LV VT has left-axis deviation; other types can have rightward or normal axis Nogami (2002) Generally seen in the context of significant baseline conduction system disease  structural heart disease LBBB morphology is the most common (normal or left-axis deviation) Bundle branch reentry with a RBBB morphology usually has a normal or right axis deviation Associated with CPVT, digitalis toxicity, and Anderson–Tawil syndrome Wellens and Canover (2006) and Smith et al. (2006) Gandhavadi et al. (2013)

AV: atrioventricular; BBB: bundle branch block; CPVT: catecholaminergic polymorphic ventricular tachycardia; LBBB: left bundle branch block; LV: left ventricular; RBBB: right bundle branch block; SVT: supraventricular tachycardia; VT: ventricular tachycardia; WCT: wide complex tachycardia. References: Gandhavadi, M., Sternick, E. B., Jackman, W. M., Wellens, H. J., Josephson, M. E. (2013). Characterization of the distal insertion of atriofascicular accessory pathways and mechanisms of QRS patterns in atriofascicular antidromic tachycardia. Heart Rhythm 10, 1385–1392; Lerman, B. B. (2015). Mechanism, diagnosis, and treatment of outflow tract tachycardia. Nature Reviews Cardiology 12, 597–608; Nogami, A. (2002). Idiopathic left ventricular tachycardia: assessment and treatment. Cardiac Electrophysiology Review 6, 448–457; Smith, A. H., Fish, F. A., Kannankeril, P. J. (2006). Andersen-Tawil syndrome. Indian Pacing and Electrophysiology Journal 6, 32–43; Wellens, H. J. J., Conover, M. (2006). The ECG in emergency decision making. (2nd edn.). Philadelphia, PA: Saunders Elsevier.

Some types of irregular WCT have very characteristic ECG appearances and are often easily recognized. Irregular VT with continuously varying QRS morphology is termed polymorphic VT. When this is associated with baseline QT prolongation and displays a typical “twisting” appearance of the QRS axis around the baseline, it is termed torsades de pointes VT (Fig. 20). The other circumstance where polymorphic VT is typically seen is in the context of acute ischemia (Fig. 21). In this case the baseline QT interval is generally normal and the QRS morphology of the tachycardia tends to vary in a more unpredictable manner than it does with torsades de pointes VT. Ventricular fibrillation (VF) also displays irregularity of ventricular activity in terms of cycle length, amplitude and axis, with a chaotic continuous waveform on the ECG (Fig. 22). “Coarse” VF, with larger average amplitudes, may be indistinguishable from polymorphic VT, and both can have the same hemodynamic consequences. In cases where the QRS complexes are uniform in appearance but occur at an irregularly irregular rate, it should be suspected that the underlying rhythm is AF and that the widening of the QRS complex is due to BBB (Fig. 23). The ECG should then be analyzed for the typical appearances of left or right bundle branch block, as described earlier. In the presence of tachycardia and wide QRS complexes it can be hard to determine on the ECG whether the atrial rhythm is AF, AFL, or MAT; however the relative prevalence of each condition means that AF is by far the most likely rhythm. Often the atrial activity can only be determined with certainty when the ventricular rate has been slowed, for example, by medication. Also, if the bundle branch block is functional (rate-related), it may resolve at slower ventricular rates or not be present with every beat, facilitating diagnosis of the atrial rhythm. AF with preexcitation (Fig. 24) is an important diagnosis to make since it has immediate consequences for the acute care of the patient and also strongly suggests that subsequent management should include an ablation procedure. The hallmarks of this dysrhythmia are:

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An irregularly irregular rhythm (which should always raise the suspicion of AF, irrespective of the QRS morphology) Variable QRS morphology, typically with differing QRS duration and often the presence of some narrow QRS complexes The wide QRS beats show a slurred onset and do not resemble typical left or right bundle branch block

Wide QRS Complex Tachycardia: What is the Diagnosis?

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Fig. 20 (A) Lead II rhythm strip, recorded at 25 mm s1, from a 51-year-old female with chronic nausea and diarrhea, after bowel preparation for colonoscopy. After an initial conducted sinus beat there is an irregular wide complex tachycardia with a characteristic “twisting” of the axis, indicating torsades de pointes VT. (B) Baseline rhythm strip, showing marked QT prolongation (around 600 ms). Her serum potassium was 2.6 mmol L1, and her medications included fluoxetine and hydrochlorothiazide.

Fig. 21 ECG recorded from a 60-year-old male with chest pain. There are repeated bursts of irregular, polymorphic VT, and the inferior leads show around 1 mm of ST elevation. This ECG was taken shortly after reperfusion of an inferior ST elevation myocardial infarction. ECG recorded at 25 mm s1.

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Very short coupling intervals may be seen ( 1 means that a positive test increases the chance that the condition is present, while a LR 250 ms in control state and >200 ms after isoproterenol) was noted. Recent papers have looked at labeling a patient as being considered high-risk (malignant) only using minimal cycle length of preexcitation in the absence of inducible AF: in the PACES/HRS 2012 Management of Asymptomatic Preexcitation Recommendations it was recommended that in the absence of inducible AF the minimal cycle length of preexcitation should be used as an alternative (Cohen et al., 2012).

General Results of Electrophysiological Studies The exact nature of the preexcitation syndrome is assessed. Most preexcitations are related to an AV AP (Kent bundle): the degree of preexcitation increases during premature atrial stimulation until the refractory period of AP is reached, because the conduction does not change in AP with the shortening of atrial cycle length and increases in the AV node. Rarely preexcitation is related to a nodoventricular AP or Mahaim bundle; the degree of preexcitation remains unchanged during premature atrial stimulation. Furthermore, atrial pacing also is an important method to detect or confirm or infirm the presence of a preexcitation syndrome when delta wave is not evident. In symptomatic patients it is easy to reproduce the spontaneous tachycardia. Reentrant tachycardias are easily induced by stimulation (Fig. 3): orthodromic tachycardia which is a reciprocating tachycardia using the normal AV conduction system for the anterograde conduction and the AP for the retrograde conduction is rarely induced in asymptomatic patients (