The Cleveland Clinic Cardiology Board Review, 3e (Dec 24, 2021)_(1496399188)_(LWW) 9781496399182, 9781496399199

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The Cleveland Clinic

Cardiology Board Review THIRD EDITION

THE CLEVELAND CLINIC CARDIOLOGY BOARD REVIEW

THE CLEVELAND CLINIC CARDIOLOGY BOARD REVIEW THIRD EDITION EDITORS Brian P. Griffin, MD, FACC John and Rosemary Brown Chair in Cardiovascular Medicine Section Head, Cardiovascular Imaging Department of Cardiovascular Medicine Heart, Thoracic and Vascular Institute Cleveland Clinic Cleveland, Ohio

Samir R. Kapadia, MD, FACC Professor of Medicine Chairman, Department of Cardiovascular Medicine Cleveland Clinic Cleveland, Ohio

Venu Menon, MD, FACC, FAHA, FESC Mehdi Razavi MD, Education Endowed Chair Director of Cardiac Intensive Care Unit Director, Cardiovascular Fellowship Associate Director C5 Professor of Medicine Cleveland Clinic Lerner College of Medicine Case Western Reserve University School of Medicine Cleveland Clinic Cleveland, Ohio

,_,,~ Wolters

Kluwer

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Senior Acquisitions Editor: Keith Donnellan Senior Development Editor: Ashley Fischer Editorial Coordinator: Christopher Rodgers Marketing Manager: Kirsten Wartrud Production Project Manager: Bridgett Dougherty Manager, Graphic Arts & Design: Stephen Druding Senior Manufacturing Coordinator: Beth Welsh Prepress Vendor: Straive Third Edition Copyright © 2022 Wolters Kluwer Copyright © 2013 by LIPPINCOTT WILLIAMS & WILKINS, a WOLTERS KLUWER business. First Edition © 2007 by LIPPINCOTT WILLIAMS & WILKINS. All rights reserved. This book is protected by copyright. No part of this book may be reproduced or transmitted in any form or by any means, including as photocopies or scanned-in or other electronic copies, or utilized by any information storage and retrieval system without written permission from the copyright owner, except for brief quotations embodied in critical articles and reviews. Materials appearing in this book prepared by individuals as part of their official duties as U.S. government employees are not covered by the abovementioned copyright. To request permission, please contact Wolters Kluwer at Two Commerce Square, 2001 Market Street, Philadelphia, PA 19103, via email at [email protected], or via our website at shop.lww.com (products and services). 987654321 Printed in China Library of Congress Cataloging-in-Publication Data Names: Griffin, Brian P., 1956-editor. | Kapadia, Samir R., editor. | Menon, Venu, editor. Title: The Cleveland Clinic cardiology board review / editors, Brian P. Griffin, Samir R. Kapadia, Venu Menon.Other titles: Cardiology board review Description: Third edition. | Philadelphia : Wolters Kluwer, [2022] | Includes bibliographical references and index. | Summary: “Providing a comprehensive, state-of-the-art review of every area of contemporary cardiovascular medicine, The Cleveland Clinic Cardiology Review is an excellent tool for learning and reviewing key concepts in major areas of cardiology. The ThirdEdition contains fully revised content, review questions used on the board exam. A new, easy-to-follow chapter template facilitates quick review and retention of the material. Emphasizes board-relevant clinical material and accurate, real-world clinical decision making.Covers every major topic you’ll encounter on certification and recertification exams, including congenital heart disease, electrophysiology, valvular heart disease, vascular disease, and pharmacology, and more. Presents review questions with each chapter for thorough exam preparation and self-assessment. Uses a new, consistent format for most chapters: introduction, clinical presentation, diagnosis, algorithm, treatment, suggested readings, and questions/answers.Written by distinguished clinicians from the Cleveland Clinic Foundation’s Department of Cardiovascular Medicine and based on the Cleveland Clinic Foundation’s popular annual Intensive Review of Cardiology course. Enrich Your eBook Reading ExperienceRead directly on your preferred device(s), such as computer, tablet, or smartphone. Easily convert to audiobook, powering your content with natural language text-to-speech”—Provided by publisher.

Identifiers: LCCN 2021041912 (print) | LCCN 2021041913 (ebook) | ISBN 9781496399182 (casebound) | ISBN 9781496399199 (epub) Subjects: MESH: Cardiovascular Diseases | Examination Questions | Outline | BISAC: MEDICAL / Cardiology | MEDICAL / Education & Training Classification: LCC RC667 (print) | LCC RC667 (ebook) | NLM WG 18.2 | DDC 616.10076—dc23 LC record available at https://lccn.loc.gov/2021041912 LC ebook record available at https://lccn.loc.gov/2021041913 This work is provided “as is,” and the publisher disclaims any and all warranties, express or implied, including any warranties as to accuracy, comprehensiveness, or currency of the content of this work. This work is no substitute for individual patient assessment based upon healthcare professionals’ examination of each patient and consideration of, among other things, age, weight, gender, current or prior medical conditions, medication history, laboratory data and other factors unique to the patient. The publisher does not provide medical advice or guidance and this work is merely a reference tool. Healthcare professionals, and not the publisher, are solely responsible for the use of this work including all medical judgments and for any resulting diagnosis and treatments. Given continuous, rapid advances in medical science and health information, independent professional verification of medical diagnoses, indications, appropriate pharmaceutical selections and dosages, and treatment options should be made and healthcare professionals should consult a variety of sources. When prescribing medication, healthcare professionals are advised to consult the product information sheet (the manufacturer’s package insert) accompanying each drug to verify, among other things, conditions of use, warnings and side effects and identify any changes in dosage schedule or contraindications, particularly if the medication to be administered is new, infrequently used or has a narrow therapeutic range. To the maximum extent permitted under applicable law, no responsibility is assumed by the publisher for any injury and/or damage to persons or property, as a matter of products liability, negligence law or otherwise, or from any reference to or use by any person of this work. shop.lww.com

To our families

CONTRIBUTING AUTHORS Philip Aagaard, MD Cardiovascular Medicine Fellow Department of Cardiovascular Medicine Cleveland Clinic Cleveland, Ohio

Haitham Ahmed, MD Cardiovascular Medicine Fellow Department of Cardiovascular Medicine Cleveland Clinic Cleveland, Ohio

Chonyang L. Albert, MD, FACC Assistant Professor of Medicine Cleveland Clinic Lerner College of Medicine Case Western Reserve University School of Medicine Staff, Advanced Heart Failure and Transplant Cardiology Cleveland Clinic Cleveland, Ohio

Craig R. Asher, MD, FACC, FASE Department of Cardiology Cleveland Clinic Florida Weston, Florida

Ajay Bhargava, MD Section of Clinical Cardiology Department of Cardiovascular Medicine

Cleveland Clinic Cleveland, Ohio

Mandeep Bhargava, MD Staff Physician Department of Cardiovascular Medicine Cleveland Clinic Cleveland, Ohio

Pavan Bhat, MD, FACC Advanced Heart Failure and Transplantation Staff Section of Heart Failure and Transplantation Medicine Department of Cardiovascular Medicine Cleveland Clinic Cleveland, Ohio

Sanjeeb Bhattacharya, MD, FACC Section of Heart Failure and Cardiac Transplant Medicine Department of Cardiovascular Medicine Cleveland Clinic Cleveland, Ohio

Ashley Bock, MD Advanced Heart Failure Cardiologist TriStar Centennial Heart and Vascular Center TriStar Centennial Medical Center Nashville, Tennessee

Michael A. Bolen, MD Associate Professor of Radiology Cleveland Clinic Lerner College of Medicine Case Western Reserve University School of Medicine Staff Radiologist Cardiovascular and Thoracic Sections Imaging Institute

Cleveland Clinic Cleveland, Ohio

Nyal E. Borges, MD Chief Fellow, Intervention Cardiology Cleveland Clinic Cleveland, Ohio

Thomas D. Callahan IV, MD, FACC, FHRS Director of Inpatient Services Section of Electrophysiology and Pacing Department of Cardiovascular Medicine Family Heart, Vascular and Thoracic Institute Cleveland Clinic Cleveland, Ohio

Joseph D. Campbell, MD Staff Physician Department of Cardiovascular Medicine Cleveland Clinic Cleveland, Ohio

Daniel J. Cantillon, MD Associate Section Head of Cardiac Electrophysiology and Pacing Medical Director Central Monitoring Unit Heart, Thoracic and Vascular Institute Cleveland Clinic Cleveland, Ohio

Michael Chetrit, MD, FRCPC, FACC Assistant Professor of Medicine McGill University Cardiologist McGill University Health Centre

Co-Director McGill Amyloidosis Project Montreal, Quebec, Canada

Leslie Cho, MD, FACC, FSCAI, FESC Professor of Medicine Cleveland Clinic Lerner College of Medicine Case Western Reserve University School of Medicine Section Head, Preventive Cardiology and Rehabilitation Director, Women's Cardiovascular Center Cleveland, Ohio

Patrick Collier, MD, PhD, FASE, FESC, FACC Staff, Cardiovascular Medicine Co-Director of Cardio-Oncology Center Deputy Director Echo Lab Associate Professor of Medicine Cleveland Clinic Lerner College of Medicine Case Western Reserve University School of Medicine Cleveland Clinic Cleveland, Ohio

Paul C. Cremer Associate Director Cardiovascular Training Program and Cardiac Intensive Care Unit Cleveland Clinic Cleveland, Ohio

Thomas M. Das, MD Fellow Department of Cardiovascular Medicine Cleveland Clinic Cleveland, Ohio

Kara Denby, MD

Fellow Department of Cardiovascular Medicine Heart, Vascular and Thoracic Institute Cleveland Clinic Cleveland, Ohio

Milind Y. Desai, MD, MBA, FACC, FAHA, FESC Haslam Family Endowed Chair in Cardiovascular Medicine Professor of Medicine Cleveland Clinic Lerner College of Medicine Case Western Reserve University School of Medicine Director, Clinical Operations Director, HCM Center Medical Director, Aorta Center Department of Cardiovascular Medicine Heart, Thoracic and Vascular Institute Cleveland Clinic Cleveland, Ohio

Eoin Donnellan, MD Fellow in Cardiac Electrophysiology Department of Cardiovascular Medicine Cleveland Clinic Cleveland, Ohio

Stephen G. Ellis, MD Director, Interventional Cardiology Cleveland Clinic Cleveland, Ohio

Jerry D. Estep, MD, FACC, FASE Section Head of Heart, Failure and Transplantation Department of Cardiovascular Medicine Cleveland Clinic Cleveland, Ohio

Michael D. Faulx, MD, FACC Associate Professor of Medicine Cleveland Clinic Lerner College of Medicine Case Western Reserve University Staff Cardiologist Section of Clinical Cardiology Heart, Vascular and Thoracic Institute Cleveland Clinic Cleveland, Ohio

J. Emanuel Finet, MD, FACC, FHFSA Clinical Assistant Professor of Medicine Cleveland Clinic Lerner College of Medicine Case Western Reserve University School of Medicine Staff, Section of Heart Failure and Transplantation Medicine Medical Director, Metabolic Exercise Testing Center Department of Cardiovascular Medicine Heart, Vascular and Thoracic Institute Cleveland Clinic

James L. Gentry III, MD Fellow Department of Cardiovascular Medicine Cleveland Clinic Foundation Cleveland, Ohio

Joanna Ghobrial, MD, MSc Director of Adult Congenital Heart Disease Department of Cardiovascular Medicine Heart, Vascular and Thoracic Institute Cleveland Clinic Cleveland, Ohio

Marcelo Gomes, MD, FSVM, RPVI

Co-Associate Section Head—Vascular Medicine Department of Cardiovascular Medicine Heart, Vascular and Thoracic Institute Cleveland Clinic Cleveland, Ohio

Matthew Gonzalez, MD Fellow Department of Cardiovascular Medicine Cleveland Clinic Cleveland, OH

Steven M. Gordon, MD Professor of Medicine Cleveland Clinic Lerner College of Medicine Case Western Reserve University School of Medicine Chairman, Department of Infectious Diseases Respiratory Institute Cleveland Clinic Foundation Cleveland, Ohio

Brian P. Griffin, MD, FACC John and Rosemary Brown Chair in Cardiovascular Medicine Section Head, Cardiovascular Imaging Department of Cardiovascular Medicine Heart, Vascular and Thoracic Institute Cleveland Clinic Cleveland, Ohio

Adam Grimaldi, MD Department of Cardiovascular Medicine Heart and Vascular Institute Cleveland Clinic Cleveland, Ohio

Jonathan D. Hansen, MD, MPH

Fellow, Interventional Cardiovascular Medicine Department of Cardiovascular Medicine Cleveland Clinic Cleveland, Ohio

Serge C. Harb, MD, FACC Assistant Professor of Medicine Cleveland Clinic Lerner College of Medicine Case Western Reserve University School of Medicine Staff, Section of Cardiovascular Imaging Department of Cardiovascular Medicine Heart, Vascular and Thoracic Institute Cleveland Clinic Cleveland, Ohio

Jeffrey S. Hedley, MD, MSc Fellow, Clinical Cardiac Electrophysiology Department of Cardiovascular Medicine Cleveland Clinic Cleveland, Ohio

Grant Henderson, MD Fellow Department of Cardiovascular Medicine Cleveland Clinic Cleveland, Ohio

Andrew R. Higgins, MD Fellow Department of Cardiovascular Medicine Cleveland Clinic Cleveland, Ohio

Eileen Hsich, MD

Medical Director for Heart Transplant at Cleveland Clinic Department of Cardiology Cleveland Clinic Lerner College of Medicine Case Western Reserve University School of Medicine Cleveland, Ohio

Peter T. Hu, MD Fellow Department of Cardiovascular Medicine Cleveland Clinic Cleveland, Ohio

Chetan P. Huded, MD, MSc, FACC, FSCAI Cardiovascular Consultant Interventional and Structural Cardiology Saint Luke's Mid America Heart Institute University of Missouri–Kansas City School of Medicine Kansas City, Missouri

Muzna Hussain, MD Research Fellow Department of Cardiovascular Medicine, Imaging Section Cleveland Clinic Cleveland, Ohio

Ayman A. Hussein, MD Fellow Department of Cardiovascular Medicine Cleveland Clinic Cleveland, Ohio

Erika Hutt-Centeno, MD Fellow Department of Cardiovascular Medicine

Cleveland Clinic Cleveland, Ohio

Zachary J. Il'Giovine, MD Fellow Department of Cardiovascular Medicine Heart, Vascular and Thoracic Institute Cleveland Clinic Cleveland, Ohio

Wael A. Jaber, MD, FACC, FESC Professor of Medicine Cleveland Clinic Lerner College of Medicine Case Western Reserve University School of Medicine Fuad Jubran Endowed Chair in Cardiovascular Medicine Heart, Thoracic and Vascular Institute Cleveland Clinic Cleveland, Ohio

Miriam Jacob Staff Physician, Program Director Cardiovascular Medicine Section of Advances Heart Failure and Transplantation Cleveland Clinic Cleveland, Ohio

Christine Jellis, MD, PhD, FACC, FASE Associate Professor of Medicine Staff Cardiologist Department of Cardiovascular Medicine Heart, Vascular and Thoracic Institute Cleveland Clinic Cleveland, Ohio

Vidyasagar Kalahasti, MD, FACC

Staff, Department of Cardiovascular Imaging Assistant Professor of Medicine Cleveland Clinic Lerner College of Medicine Case Western Reserve University School of Medicine Associate Director Clinical Endpoints Committee Heart, Thoracic and Vascular Institute Cleveland Clinic Cleveland, Ohio

Mohamed Kanj, MD Co-Director, Electrophysiology Laboratories Department of Cardiovascular Medicine Cleveland Clinic Cleveland, Ohio

Samir R. Kapadia, MD, FACC Professor of Medicine Chairman, Department of Cardiovascular Medicine Cleveland Clinic Cleveland, Ohio

Deborah Kerrigan, MD, MA Assistant Professor of Medicine Department of Neurology Vanderbilt University School of Medicine Vanderbilt University Medical Center Nashville, Tennessee

Jimmy Kerrigan, MD, FACC, FSCAI Assistant Professor of Medicine Division of Cardiology University of Tennessee College of Medicine Interventional Cardiologist Ascension Saint Thomas Heart

Co-Director, Advanced Coronary Therapeutics Program Ascension Saint Thomas West Hospital Co-Director, Pulmonary Embolism Response Team Ascension Saint Thomas West Hospital Chair, Ascension Chronic Total Occlusion Interventional Cardiology Affinity Group University of Tennessee Health Science Center Ascension St. Thomas West Hospital Nashville, Tennessee

Allan L. Klein, MD, FRCP(C), FACC, FAHA, FASE, FESC Professor of Medicine Cleveland Clinic Lerner College of Medicine Case Western Reserve University School of Medicine Director, Center for the Diagnosis and Treatment of Pericardial Diseases Section of Cardiovascular Imaging Department of Cardiovascular Medicine Heart, Vascular and Thoracic Institute Past-President, American Society of Echocardiography Cleveland Clinic Cleveland, Ohio

Robert A. Koeth, MD, PhD Clinical Assistant Professor of Molecular Medicine Cleveland Clinic Lerner College of Medicine Case Western Reserve University School of Medicine Fellow, Cardiac Electrophysiology Department of Cardiovascular Medicine, Section of Cardiac Pacing and Electrophysiology Heart, Thoracic and Vascular Institute Cleveland Clinic Cleveland, Ohio

Amar Krishnaswamy, MD Section Head, Interventional Cardiology Director, Sones Cardiac Catheterization Laboratories

Program Director, Interventional Cardiology Fellowship Cleveland Clinic Cleveland, Ohio

Anirudh Kumar, MD, MSc Fellow, Interventional Cardiology Heart, Thoracic and Vascular Institute Cleveland Clinic Cleveland, Ohio

Luke J. Laffin, MD, FACC Co-Director, Center for Blood Pressure Disorders Medical Director of Cardiac Rehabilitation Department of Cardiovascular Medicine Cleveland Clinic Cleveland, Ohio

Cameron T. Lambert, MD Fellow, Cardiac Electrophysiology Heart, Vascular and Thoracic Institute Cleveland Clinic Cleveland, Ohio

Harry M. Lever, MD Staff Physician Department of Cardiovascular Medicine Cleveland Clinic Cleveland, Ohio

A. Michael Lincoff, MD Professor of Medicine Cleveland Clinic Lerner College of Medicine Case Western Reserve University School of Medicine Vice Chairman for Research Department of Cardiovascular Medicine

Heart, Vascular and Thoracic Institute Cleveland Clinic Cleveland, Ohio

Kyle Mandsager, MD, FACC Cardiac Electrophysiologist Centennial Heart Centennial Hospital Nashville, Tennessee

Preethi Mani, MD, MPH Fellow, Advanced Cardiac Imaging Department of Cardiovascular Medicine Cleveland Clinic Cleveland, Ohio

Kenneth A. Mayuga, MD, FHRS, FACC, FACP Staff Physician in Cardiac Electrophysiology Director of the Syncope Center Cleveland Clinic Assistant Professor of Medicine Cleveland Clinic Lerner College of Medicine Case Western Reserve University Cleveland, Ohio

Venu Menon, MD, FACC, FAHA, FESC Mehdi Razavi MD, Education Endowed Chair Director of Cardiac Intensive Care Unit Director, Cardiovascular Fellowship Associate Director C5 Professor of Medicine Cleveland Clinic Lerner College of Medicine Case Western Reserve University Cleveland Clinic Cleveland, Ohio

Richard D. Meredith, MD Cleveland Clinic Foundation Cleveland, Ohio

Michael A. Militello, PharmD, BCPS Pharmacotherapy Residency Program Director Department of Pharmacy Cleveland Clinic Cleveland, Ohio

Maria M. Mountis, DO Staff Cardiologist Section of Heart Failure and Transplant Heart, Vascular and Thoracic Institute Cleveland Clinic Cleveland, Ohio

Vinayak Nagaraja, MBBS, MS, MMed (Clin Epi), FRACP Department of Cardiovascular Medicine Cleveland Clinic Foundation Cleveland, Ohio

Shady Nakhla, MD Fellow, Department of Cardiovascular Medicine Clinical Instructor of Medicine Cleveland Clinic Cleveland, Ohio

David M. Nemer, MD Fellow Cleveland Clinic Cleveland, Ohio

Andrew E. Noll, MD

Section of Electrophysiology Department of Cardiovascular Medicine Cleveland Clinic Foundation Cleveland, Ohio

Divyang Patel, MD Fellow, Department of Cardiovascular Medicine Cleveland Clinic Foundation Cleveland, Ohio

Dermot Phelan, MD, PhD, FASE, FACC Medical Director, Cardiovascular Imaging Director, Sports Cardiology Program Co-Director, Hypertrophic Cardiomyopathy Program Sanger Heart & Vascular Institute Atrium Health Charlotte, North Carolina

Varinder Kaur Randhawa, MD, PhD Research Fellow Section of Heart Failure and Transplantation Medicine Department of Cardiovascular Medicine Heart, Vascular and Thoracic Institute Cleveland Clinic Cleveland, Ohio

Claire E. Raphael, MBBS MA. PhD Interventional Cardiologist Heart, Vascular and Thoracic Institute Cleveland Clinic Main Campus

Russell E. Raymond, DO Interventional Cardiology Cleveland Clinic Cleveland, Ohio

Grant W. Reed, MD, MSc, FACC, FSCAI Associate Program Director Cardiovascular Medicine Fellowship Director, STEMI Program Department of Cardiovascular Medicine Cleveland Clinic Cleveland, Ohio

John Rickard, MD Fellow Department of Cardiovascular Medicine Cleveland Clinic Cleveland, Ohio

Christina Rigelsky, MS, CGC Lead Cardiovascular Genetic Counselor Center for Personalized Genetic Healthcare Cleveland Clinic Cleveland, Ohio

L. Leonardo Rodriguez, MD, FACC, FASE, FESC Program Director of Advanced Cardiovascular Imaging Fellowship Associated Director of Echocardiography Laboratory Department of Cardiovascular Medicine Heart, Thoracic and Vascular Institute Cleveland Clinic Cleveland, Ohio

Jeffrey E. Rossi, MD Fellow Department of Cardiovascular Medicine Cleveland Clinic Cleveland, Ohio

Joshua Saef, MD

Fellow, Adult Congenital Heart Disease Perelman School of Medicine at the University of Pennsylvania Philadelphia, Pennsylvania

Walid Saliba, MD Director, Atrial Fibrillation Center Department of Cardiovascular Medicine Cleveland Clinic Cleveland, Ohio

Aldo L. Schenone, MD Chief Non-Invasive Cardiovascular Imaging Fellow Brigham and Women's Hospital Harvard Medical School Boston, Massachusetts

Nishant P. Shah, MD Fellow Department of Cardiovascular Medicine Cleveland Clinic Cleveland, Ohio

Zarina M. Sharalaya, MD Fellow, Interventional Cardiology Department of Cardiovascular Medicine Cleveland Clinic Cleveland, Ohio

Abhinav Sharma, MD Assistant Professor Department of Cardiovascular Medicine Medical College of Wisconsin Wauwatosa, Wisconsin

Calvin Chen Sheng, MD Fellow Department of Cardiovascular Medicine Heart, Vascular and Thoracic Institute Cleveland Clinic Cleveland, Ohio

Conrad C. Simpfendorfer, MD Fellow Department of Cardiovascular Medicine Cleveland Clinic Cleveland, Ohio

Nikolaos Spilias, MD Fellow Department of Cardiovascular Medicine Cleveland Clinic Cleveland, Ohio

Khaldoun G. Tarakji, MD, MPH Associate Section Head, Cardiac Electrophysiology Associate Professor Cleveland Clinic Lerner College of Medicine Case Western Reserve University School of Medicine Heart, Vascular and Thoracic Institute Cleveland Clinic Cleveland, Ohio

Patrick J. Tchou, MD Section of Cardiac Electrophysiology and Pacing Department Cardiovascular Medicine Heart, Thoracic and Vascular Institute Cleveland Clinic Cleveland, Ohio

Kartik S. Telukuntla, MD Fellow, Advanced Heart Failure and Transplant Cardiology Heart, Vascular and Thoracic Institute Cleveland Clinic Cleveland, Ohio

Albree Tower-Rader, MD, FACC Division of Cardiology Department of Medicine Harvard Medical School Massachusetts General Hospital Boston, Massachusetts

Kevin M. Trulock, MD Fellow Department of Cardiovascular Medicine Cleveland Clinic Cleveland, Ohio

Rayji S. Tsutsui, MD, ChB, MPH Structural Interventional Cardiologist Department of Cardiology Straub Medical Centre Hawaii Pacific Health Honolulu, Hawaii

Sneha Vakamudi, MD Ascension Seton Heart & Vascular Assistant Professor Dell Medical School The University of Texas at Austin Austin, Texas

Oussama Wazni, MD

Section Head, Cardiology Department of Cardiovascular Medicine Cardiology Cleveland Clinic Cleveland, Ohio

Bruce L. Wilkoff, MD Cardiovascular Medicine Fellow Department of Cardiovascular Medicine Cleveland Clinic Foundation Cleveland, Ohio

Bo Xu, MD Imaging Cardiologist Section of Cardiovascular Imaging Department of Cardiovascular Medicine Heart, Vascular and Thoracic Institute Cleveland, Ohio

Laura Young, MD Fellow, Interventional Cardiology Department of Cardiovascular Medicine Clinical Instructor Cleveland Clinic Lerner College of Medicine Case Western Reserve University School of Medicine Cleveland, Ohio

Kenneth G. Zahka, MD, FACC, FAAP, FAHA Professor of Pediatrics Cleveland Clinic Lerner College of Medicine Case Western Reserve University School of Medicine Department of Pediatric Cardiology Adult Congenital Heart Disease Center Cleveland Clinic Cleveland, Ohio

PREFACE The aim of this edition of the book is unchanged in its essence and is to provide a comprehensive topical overview of cardiovascular medicine in a concise and readable format. The needs of those seeking to revise the practice of cardiology broadly with a view to undertaking certification and recertification examinations were very much to the fore as we revised the book and led to the inclusion of new material and questions. We hope that this book will be useful not only to exam takers but also to cardiology fellows, cardiologists, and other providers seeking a targeted review of the current scope of cardiovascular medicine. We wish to acknowledge the support and assistance of both faculty and fellows in cardiovascular medicine and related disciplines at Cleveland Clinic who wrote the individual chapters and questions. We particularly want to dedicate this book to our colleagues and fellows and of course to our families. We hope you find this updated edition easy to use and helpful. Brian P. Griffin Samir R. Kapadia Venu Menon

CONTENTS Contributing Authors Preface

I FUNDAMENTALS 1 How to Pass the Cardiovascular Disease Board Examination

John Rickard and Grant W. Reed

2 Cardiac Physical Examination Craig R. Asher

3 Cardiac Anatomy

Samir R. Kapadia and Nishant P. Shah

4 Cardiovascular Physiology: Flow–Volume Loops Richard D. Meredith and Michael D. Faulx

5 Basic Cardiac Electrophysiology Patrick J. Tchou

6 Cardiac Biochemistry

Robert A. Koeth and Venu Menon

7 Clinical Epidemiology and Biostatistics Sneha Vakamudi and Paul C. Cremer

II CARDIOVASCULAR IMAGING AND STRESS TESTING 8 Chest Radiography for the Cardiovascular Medicine Boards

Albree Tower-Rader and Michael A. Bolen

9 Doppler Echocardiography Bo Xu and Christine Jellis

10

Electrocardiographic Stress Testing

11

Stress Echocardiography

12

Nuclear Cardiac Imaging: A Primer

13

Cardiac MRI and CT

Philip Aagaard and Haitham Ahmed

Abhinav Sharma and L. Leonardo Rodriguez

Aldo L. Schenone, Paul C. Cremer, and Wael A. Jaber

James L. Gentry III and Milind Y. Desai

III CONGESTIVE HEART CARDIOMYOPATHY

FAILURE

14

Pathophysiology of Heart Failure

15

Medical Treatment of Heart Failure

Varinder Kaur Randhawa, Ashley Bock, and J. Emanuel Finet

AND

Chonyang L. Albert and Jerry D. Estep

16

Heart Transplantation

17

Devices for Heart Failure

18

Myocarditis and Dilated Cardiomyopathy

19

Pulmonary Hypertension

20

Heart Failure with Preserved Ejection Fraction

21

Hypertrophic Cardiomyopathy

Kartik S. Telukuntla, Matthew Gonzalez, and Eileen Hsich

Pavan Bhat and Maria M. Mountis

Zachary J. Il’Giovine and Sanjeeb Bhattacharya

Kartik S. Telukuntla and Miriam Jacob

Albree Tower-Rader and Allan L. Klein

Sneha Vakamudi and Harry M. Lever

IV CONGENITAL HEART DISEASE 22

Congenital Heart Disease in the Adult

23

Echocardiography in Congenital Heart Disease

Joshua Saef and Joanna Ghobrial

Serge C. Harb and Christine Jellis

V CARDIAC ELECTROPHYSIOLOGY

24

Twelve-Lead Electrocardiography

25

Electrophysiologic Testing, Including His Bundle and Other Intracardiac Electrograms

Peter T. Hu and Ajay Bhargava

Kevin M. Trulock and Thomas D. Callahan IV

26

Sudden Cardiac Death and Ventricular Tachycardia

27

Atrial Fibrillation and Flutter

28

Supraventricular Tachycardias

29

Wide Complex Tachycardia: Ventricular Tachycardia versus Supraventricular Tachycardia

Cameron T. Lambert, Daniel J. Cantillon, and Oussama Wazni

Ayman A. Hussein and Mohamed Kanj

Andrew E. Noll and Mandeep Bhargava

Adam Grimaldi and Walid Saliba

30

Pacemakers and Defibrillators

31

Syncope

Divyang Patel, Bruce L. Wilkoff, and Khaldoun G. Tarakji

Erika Hutt-Centeno, Jeffrey S. Hedley, and Kenneth A. Mayuga

VI VALVULAR HEART DISEASE 32

Aortic and Pulmonary Valve Disease Richard D. Meredith, Amar Krishnaswamy, and Brian P. Griffin

33

Mitral Valve and Tricuspid Valve Disease

34

Infective Endocarditis

35

Prosthetic Valve Disease

Bo Xu and Serge C. Harb

Andrew R. Higgins and Steven M. Gordon

Preethi Mani and Paul C. Cremer

VII CORONARY ARTERY DISEASE CARDIAC CATHETERIZATION

AND

36

Evaluation of Chest Discomfort

37

Coronary Artery Disease: Epidemiology

38

Stable Angina: Diagnosis, Risk Stratification, Medical Therapy, and Revascularization Strategies

David M. Nemer and Wael A. Jaber

Calvin Chen Sheng and Leslie Cho

Chetan P. Huded and Conrad C. Simpfendorfer

39

Unstable Coronary Syndrome

40

Acute Myocardial Infarction

41

Complications of Myocardial Infarction

Jonathan D. Hansen and A. Michael Lincoff

Venu Menon and Chetan P. Huded

Thomas M. Das and Venu Menon

42

Risk Stratification and Post–Myocardial Infarction Therapy Nyal E. Borges and Samir R. Kapadia

43

Radiation Safety Laboratory

in

the

Cardiac

Catheterization

Rayji S. Tsutsui and Samir R. Kapadia

44

Hemodynamic Measurements

45

Catheterization Laboratory Imaging and Functional Assessment

Jeffrey E. Rossi and Amar Krishnaswamy

Anirudh Kumar and Samir R. Kapadia

46

Percutaneous Coronary Intervention Claire E. Raphael and Stephen G. Ellis

VIII AORTA/PERIPHERAL DISEASE 47

Diseases of the Aorta

48

Venous Thromboembolism

49

Peripheral Artery Disease

VASCULAR

Grant Henderson and Vidyasagar Kalahasti

Erika Hutt-Centeno and Marcelo Gomes

Nikolaos Spilias and Joseph D. Campbell

HEART

50

Carotid Disease Jimmy Kerrigan, Deborah Kerrigan, and Joseph D. Campbell

IX CLINICAL CARDIOLOGY

AND

PREVENTATIVE

51

Hallmarks of Primary and Secondary Hypertension

52

The Dyslipidemias

53

Preoperative Evaluation Noncardiac Surgery

Luke J. Laffin and Leslie Cho

Nishant P. Shah and Leslie Cho

of

Cardiac

Patients

for

Laura Young and Ajay Bhargava

54

Pregnancy and Heart Disease

55

Women and Heart Disease

56

Pericardial Diseases

57

Effects of Systemic Diseases on the Cardiovascular System

Zarina M. Sharalaya and Russell E. Raymond

Ashley Bock and Leslie Cho

Michael Chetrit and Allan L. Klein

Jeffrey S. Hedley and Michael D. Faulx

58

Cardiac Neoplasms Eoin Donnellan and Brian P. Griffin

Heart and

X PHARMACOLOGY 59

Cardiovascular Drug Interactions

60

XI MISCELLANEOUS901Patent Foramen Ovale and Atrial Septal Defect Closure

Aldo L. Schenone and Michael A. Militello

Kara Denby, Anirudh Kumar, and Joanna Ghobrial

61

Transcatheter Aortic Valve Replacement

62

Percutaneous Mitral Interventions

63

Genetics and Heart Disease

64

Summary of Important Guidelines

65

Sports Cardiology

66

Cardio-oncology

Grant W. Reed, Samir R. Kapadia, and Amar Krishnaswamy

Vinayak Nagaraja and Samir R. Kapadia

Kartik S. Telukuntla, Christina Rigelsky, and Kenneth G. Zahka

Vinayak Nagaraja and Samir R. Kapadia

Kyle Mandsager and Dermot Phelan

Eoin Donnellan, Muzna Hussain, and Patrick Collier

Appendix (Common Formulae) Shady Nakhla and Venu Menon Index

I FUNDAMENTALS

CHAPTER 1

How to Pass the Cardiovascular Disease Board Examination JOHN RICKARD AND GRANT W. REED

GENERAL INFORMATION Board certification in Cardiovascular Disease is an attainable goal made possible with careful planning and preparation. Each year, the American Board of Internal Medicine (ABIM) Certifying Examination is offered in the fall, typically in October. The initial certification exam is given over 1.5 days. The first day consists of multiple choice questions, and the second half day includes an ECG examination and an imaging studies section comprising echocardiograms and coronary angiograms, focused on proper coding of studies. Registration dates are specified by the ABIM. In general, registration for the standard examination occurs from December 1 of the prior year through June 15 of the examination year, and late registration dates are typically June 16 through June 28. However, there may be exceptions, as in 2020 when late fees were waved in light of the COVID-19 pandemic. Applications with a disability may be eligible for the Special Accommodation Examination, which has the same registration periods but is usually offered a few weeks after the standard examination. The initial certification examination fee for 2020 was $2,480. In addition, a nonrefundable fee of $400 is added for late registration, and a $500 fee is added for international testing centers. A 70% refund will be given if the examination is cancelled at least 48 hours prior to the examination, and a 55% refund given for cancellation within 48 hours. As

registration test centers often fill up rapidly, early registration is key to assure the ability to take the examination at a nearby test center. Applicants can register for the examination at the official ABIM Web site: www.abim.org/certification/exam-information/. All applicants should become familiar with the ABIM Web site, which provides detailed policies, information about the examination, and a practice test using the same software used on the day of the examination. Test results are typically first available on the ABIM Web site approximately 3 months after the examination. After initial certification, for certification to be considered current, one must be active in the ABIM Maintenance of Certification (MOC) program. In 2020, the MOC program requirements were as follows: 1. Participate in at least 1 activity every 2 years to earn “MOC Points”. The activity can be of any point value. 2. Earn at least 200 MOC points every 5 years. 3. Pass a separate MOC Assessment (detailed below). As of 2020, the options for the MOC Assessment are to 1. Take a recertification examination every 10 years. 2. Take a “Knowledge Check-In (KCI)” assessment every 2 years instead of a 10-year examination. 3. Participate in the “Collaborative Maintenance Pathway (CMP),” which consists of shorter annual performance assessments administered through the ACC Adult Clinical Cardiology SelfAssessment Program (ACCSAP). There have been several recent changes to the recertification process in Cardiovascular Diseases, and as such applicants should visit the ABIM Web site for full up-to-date details: https://www.abim.org/maintenance-ofcertification/assessment-information/assessment-options.aspx In addition, examinees are now permitted to use UpToDate as a reference during the examination. Examinees are encouraged to visit the UpToDate User Academy for ABIM Exam preparation to learn how to make the most of this resource: https://www.uptodate.com/home/uptodate-user-academyabim-exam.

FORMAT As of 2020, the Cardiovascular Diseases Board examination is taken over the course of 1.5 days for first-time takers and 1 day for those taking it to recertify and opting for the 10-year examination option (those recertifying are exempt from the ECG and imaging sections). The first day is a full day lasting up to 10 hours. Day 1 consists of four 2-hour blocks consisting up to 60 multiple choice questions each. Break time between sessions is limited to 100 minutes total but can be divided between breaks however the examinee chooses. The second day is a half-day consisting of an ECG section of 35 to 40 tracings lasting 2 hours 15 minutes and an imaging section lasting 2 hours consisting of 35 to 40 video images that include echocardiograms, ventriculograms, aortograms, and angiograms. Table 1.1 delineates the weighted subject content for the examination. Many cardiology trainees do not have sufficient exposure to peripheral vascular disease, pharmacology, and congenital heart disease during their training and must overcome this deficiency during their preparation for the examination. For the ECG section, a brief one- or two-line clinical vignette is provided with each ECG tracing. The test taker then must code relevant findings using a coding sheet, available in advance for review at the ABIM Web site. Similarly, for the imaging section, coding sheets are provided to capture the various findings. Test takers must make sure they review the coding sheet prior to the test. Sample cases and practice coding sheets could be found on the ABIM Web site.

Table 1.1 Breakdown in Content of the Cardiology Board Examination

Examination questions in the content areas above may also address topics in preventative and rehabilitative cardiology, cardiovascular disease in women, geriatric cardiovascular disease, preoperative assessment of noncardiac surgery, postoperative cardiac care, critical care medicine, cardiovascular surgery, and general internal medicine as encountered in the practice of cardiology.

HOW YOU ARE SCORED For first-time test takers, the multiple choice components and the ECG and imaging sections are scored separately. The ECG and imaging sections are combined for scoring purposes. For a passing score, both the multiple choice and the ECG and imaging components must be passed. While the imaging section can be challenging, due to the combination of scoring with the ECG section, a poor performance on the imaging section can be balanced out by a stronger score on the ECG section (or vice versa). While there is no penalty for guessing on the multiple choice section, overcoding on the ECG and imaging sections leads to point deductions. The strategy we advocate is to code the 2 to 3 main diagnoses per ECG or image and any obvious minor diagnoses and omit any borderline or uncertain codes. For first-time takers, pass rates for the examination from 2004 to 2019 are listed in Table 1.2. The ultimate pass rate within 3 subsequent years from 2009 to 2019 was 97%.

Table 1.2 First-Time Taker Pass Rates

TIPS A 3-month study period prior to the test is a reasonable amount of time to prepare for the examination. Reviewing information in a scheduled way over this time period is important. The examination encompasses a large quantity of information making a last-minute approach ill advised. Fellows who are enrolled in busy advanced fellowship programs such as electrophysiology and intervention must be realistic about the need to study for the examination. Too often, these trainees do not allow themselves sufficient time to prepare. They may consider signing up for a dedicated course, which would force them to focus on the material covered on the examination. The multiple choice section of the boards is structured such that a clinical vignette is presented and typically five answer choices are provided. While the clinical vignettes are often long, each block of 60 questions is allotted 2 hours of time (2 minutes/question). Very few questions on the boards simply ask a question on a medical fact. The large majority of questions make the test taker read through a patient scenario complete with a past medical history, current symptomatology, in-depth physical examination findings, and imaging and laboratory data prior to asking how to proceed with the patient’s management. In addition, the examination will often challenge the test taker to determine the most likely condition from the physical examination and then determine the treatment options based on other information given. Therefore, knowing the physical examination findings of common cardiovascular conditions is imperative. A good strategy is to make sure each question is answered to avoid missing easy questions by getting hung up by long ones, and then returning to tougher questions to check one’s work after. The board examination will not ask questions on any areas that are controversial or not supported by evidence. The majority of questions will focus on information obtained from guidelines—most notably class I and III recommendations. In preparing, it is important to focus on common therapeutic and diagnostic conditions rather than rare conditions. Anticipate questions regarding common conditions structured in complex ways. In addition, the results of major, practice-changing clinical trials are favorite board topics. Examinees are encouraged to remember that clinical trials or major guideline changes published within 1 to 2 years are typically not

included and thus should answer questions accordingly. Some board questions may strike the test taker as strange or potentially even unfair. It is important not to get stressed out by such questions as the board pilots new questions every year. These new questions will not be included in the final score. Lastly, the imaging section of the boards can be difficult due to variable image quality. One should ensure not to waste time overcoding but simply code the major findings that are clearly identifiable, as above. It is also critical to make sure that all the available images have been viewed. It is vitally important not to underestimate the ECG section. The majority of test takers who failed the boards in the past have done so by failing this section. Knowing the coding sheet cold prior to sitting for the test is vital (the coding sheet is available online from the ABIM). Many test takers run into time issues with this section. Searching for the correct codes on the sheet can waste a significant amount of time and may cause some examinees not to finish. Secondly, the board examination commonly tests clinical syndromes on the ECG section. The test taker should be very familiar with the clinical syndromes on the code sheet and be able to identify such conditions rapidly. While electronic calipers are provided, they are rarely required to obtain the correct answer. Overuse of calipers can waste valuable time. It is also important not to overcode the ECG portion of the test. The board examiners want to ensure that the examinee can identify the major findings on each tracing. Taking time to code small, somewhat questionable ECG findings will waste time and possibly cause point deductions. Examinees are encouraged to start preparing early, and obtain several books or online resources containing practice multiple choice questions. One should then focus one’s study on completing the resources that emphasize one’s weaknesses. Examinees are also encouraged to practice ECG and image coding with one of several books or online services available. Lastly, it is important to get a good night sleep prior to the examination as the test is lengthy and can be fatiguing, especially toward the end of the examination session. Taking the examination at the first opportunity after completion of your fellowship is strongly advised as the material learned in training will be the freshest at that time. Use in-service scores to identify areas you need to work on the most. The examination typically rewards tests takers who are well rounded without major deficiencies in knowledge rather than individuals who are experts in a few areas and deficient in others.

Finally, and as mentioned previously, early registration is important to secure a nearby test location. Having to travel large distances or staying in a hotel prior to the test will only cause unneeded stress and distraction.

TEN PITFALLS TO AVOID 1. Underestimating the ECG and imaging sections 2. Not being familiar with the coding sheets for the ECG and imaging sections prior to the test 3. Not being able to identify common cardiovascular conditions based on physical examination findings 4. Overcoding the ECG and imaging sections 5. Spending a disproportionate time on one or two questions at the expense of other easier questions 6. Getting upset by what appears to be very strange, “out of left field”– type questions that are probably pilot questions that are not factored into the final score 7. Wasting too much time with the electronic calipers on the ECG section 8. Cramming for the test at the last minute 9. Registering late forcing the test to be administered a distance away from home 10. Not reviewing the tutorial on the ABIM Web site

CHAPTER 2

Cardiac Physical Examination CRAIG R. ASHER

INTRODUCTION EXAMINATION

TO

PHYSICAL

Over the years, the bedside skills of the cardiologist have diminished, due in part to the readily available access to echocardiography. However, the Cardiology Board examination expects a high level of understanding of physical diagnosis. Most of the testing of physical diagnosis is indirect. Many of the questions are structured with a brief history and physical examination that provide clues about the diagnosis or answer. Often these are subtle hints that will not be appreciated by the unprepared. This chapter provides many of the pearls of physical diagnosis that are important for taking the boards.

INSPECTION Basic principles (these descriptors may correlate with a specific diagnosis): General appearance: Distress, diaphoresis, tachypnea, cyanosis, pallor Posture: Orthopnea, platypnea/orthodeoxia (dyspnea and O2 desaturation in the upright position such as seen in patients with patent foramen ovale [PFO] and atrial septal defect [ASD] with R-to-L shunt), trepopnea (dyspnea lying on one side but not the other such as with

large pleural effusions), bendopnea (dyspnea with bending as seen with congestive heart failure) Stature: Tall (Marfan syndrome, acromegaly), short (Turner and Noonan syndromes, Down syndrome), dwarfism (Ellis–van Creveld syndrome associated with ASD) Nutritional status: Obese (sleep apnea, metabolic syndrome), cachexia (end-stage systolic heart failure, chronic disease, malignancy), athletic or muscular (anabolic steroid use) Abnormal movements: Chorea (Sydenham chorea as seen with rheumatic fever), ataxia (Friedreich ataxia associated with hypertrophic cardiomyopathy [HCM] or tertiary syphilis associated with aortic aneurysms), head bobbing (aortic regurgitation [AR] or tricuspid regurgitation [TR]), Cheyne–Stokes respirations See Table 2.1 for additional associated conditions and specific diseases found with various skin, head and neck, eye, chest and abdomen, extremity findings.

Table 2.1 Physical Examination Findings with Associated Conditions and Disease States

Physical Finding

Associated Conditions (Specific Diseases)

Eyes Rorh spo rs, conjuncriva l perechiae

Endocardiris

Xanthelasmas

Dyslipidemia (fami lial hypercholesrerolemia)

Blue sclera

(O steogenesis imperfecta with aortic disease, AR , MVP)

lcre ric sclera

Cardiac cirrhosis

Ectopia lentis (upward disp lacement)

(Marfan syndrome)

Ecropi a lentis (do wnwa rd displacement)

(Ho mocystinuria and premature CAD, stroke, PVD)

Co njuncti vitis

(Reiter syndrome with aortic disease, AR)

Corneal opacities

(Fa bry disea se with H CM )

Arcus senilis

(Corona ry a rtery di sease)

Retina l occlusion

Embolic disease

Chest and Abdomen Pectus excavarum (funn el chest )

(Marfan syndrome with aortic aneurysm, MVP)

Pecrus carinarum (pigeon chest)

(Marfan syndrome; N oo na n syndrome)

Straight back syndrome

(MVP; Ankylosing spo nd ylitis w ith AR)

lntercosta l arteries coll aterals

(Coa rctation of the aorta and bicuspid aortic valve)

Extremities Rudimentary or a bsenr thumbs

(Ho lt- Oram syndrome with ASD)

O sle r nodes, Janeway lesio ns, splinter hemo rrhage

Endocarditis

Hyperextensible joints

(Ehlers-Danlos syndro me)

Rayna ud phenomenon

Connecti ve rissue disorder; Vasculiris

Skin Ja undice

Rig ht heart fa ilure; Hemolysis

Xa nthomas

Dyslipidemia (Fa milia l h ypercho lesterolemia)

Central cyanosis

Rig hr-ro-left shunts (Eisenmenger syndrome); methemoglo binemia

Differentia l cyanosis

Rig ht-to-left shunt wirh (PDA)

Peri phera I cya nosis

Ca rdiogenic shock, severe peripheral vascula r disease

Tela ngiectasias (dilated blood vessels)

(Hereditary hemo rrhagic telangiectasias with pulmonary AV fistula; scleroderma)

Lentigines (brown skin lesio ns)

(LEOPARD syndrome; Carney syndrome w ith a tria l myxomas)

Lupu s pernio (purple skin lesion ), erythema nodosum

(Sarcoidosis with pulmo nary HTN, arrhythmi as, myopathic disease)

Angio fibromas (shiny papules-on face adeno ma sebaceum)

(Tubero us sclerosis w ith rhabdo myomas)

Stria e atro phicae

(M arfan syndro me with aortic aneurysm, MVP)

Bro nze pigmentatio n

(Hemochro matosis with supraventricula r a rrhythmias, cardio myo pathy)

H yperextensible skin, bruising, fragile

(Ehlers-Danlos syndro me w irh aortic aneurysm)

Ma la r rash

(Lupus erythema tosus with endo -, myo-, pericarditis)

ARTERIAL PULSE Basic Principles Described by upstroke, magnitude, and contour Central aortic or carotid pulse composed of percussion (ejection, early portion) and tidal waves (reflected wave from periphery, mid to later portion) Graded 0 to 4. Grade 0 is absent; grade 1 is barely palpable; grade 2 is normal; grade 3 is increased; and grade 4 is bounding. Normal pulse pressure approximately 30 to 40 mm Hg (systolic minus diastolic blood pressure) Anacrotic notch is present at the systolic upstroke in the arterial pulse (ascending limb). Dicrotic notch is present in the diastolic downstroke in the arterial pulse (descending limb) at aortic valve closure.

Disease States See Figure 2.1.

FIGURE 2.1 Carotid pulse findings in normal and disease states. A:The normal carotid pulse. There is a rapid ascending and descending limb. The descending limb is slower than the ascending limb and has a dicrotic notch that occurs during aortic valve closure. The dicrotic notch is generally not palpable on examination. B:Hyperdynamic pulse. There is a rapid, highvolume ascending and descending limb. C:Parvus/tardus pulse with anacrotic notch refers to a small-amplitude pulse with a delayed systolic peak associated with AS. The anacrotic notch on the ascending limb may be appreciated on examination. D:Pulsus alternans is the beat-to-beat variation in the arterial pulse amplitude that is seen with left ventricular dysfunction and low

stroke volume. E:Pulsus bisferiens is characterized by two systolic peaks during systole. The amplitude of the pulse is high. The initial peak is due to the ejection or percussion wave, and the second peak is due to a reflected or tidal wave in the periphery. This type of pulse is most often seen with isolated AR or combined AR and stenosis. F:Dicrotic pulse is another form of double-peaked pulse where the dicrotic notch is present in diastole just after S2. The dicrotic pulse usually occurs in patients with hypotension due to low CO or low SVR. G:Spike and dome pulse is another form of double-peaked pulse that occurs with HOCM. There is an initial rapid systolic peak followed by a lower-amplitude systolic peak.

Pulsus Alternans Alternating beat to beat pulse amplitude with strong and weak pulsations in sinus rhythm Most often reflects left ventricular myocardial failure due to alterations in preload, afterload, and contractility with each beat Also described with HCM with obstruction

Pulsus Paradoxus Exaggeration of normal inspiratory fall of systolic blood pressure (SBP) > 10 mm Hg Causes include cardiac tamponade, chronic lung disease/acute asthma, pulmonary embolism (PE), right ventricular infarction, congestive heart failure, tension pneumothorax, pregnancy, obesity, and rarely constrictive pericarditis (only effusive form) Major mechanisms include (a) ↑ venous return to the right heart during inspiration with shift of the septum to the left resulting in ↓ left ventricle (LV) stroke volume and therefore ↓ SBP (reverse Bernheim effect) and (b) ↑ pulmonary venous reservoir with inspiration resulting in ↓ leftsided filling (lower pulmonary vein to left ventricular gradient). Cardiac tamponade may occur without pulsus paradoxus due to loss of interventricular dependence with high LV end-diastolic pressure (AR or

LV dysfunction), ASD (volume of shunted blood exceeds change in volume of blood between inspiration and expiration), or right ventricular hypertrophy (RVH) and pulmonary hypertension (PH). The paradox is that heart sounds can be heard during inspiration, while the pulse weakens and may not be palpable. Reversed pulsus paradoxus may occur with HCM or in mechanically ventilated patients.

Double-Peaked Pulse ↑ amplitude pulse with two systolic peaks and midsystolic dip Results from accentuated percussion wave and tidal wave Most common cause is severe AR (bisferiens) with or without aortic stenosis (AS), but may also occur with hypertrophic obstructive cardiomyopathy (HOCM, bifid or “spike and dome”) and hyperdynamic states (patent ductus arteriosus [PDA], arteriovenous malformations)

Pulsus Tardus and Parvus Carotid pulse with tardus (delayed peak and slower upstroke) and parvus (low amplitude) Caused by AS, though may be absent even in the setting of severe AS in elderly with noncompliant carotid vessels Associated with an anacrotic pulse and carotid shudder (thrill)

Anacrotic Pulse Notch on the upstroke of the carotid pulse (anacrotic notch) may be palpable Two distinct waves can be seen (slow initial upstroke and delayed peak, which is close to S2). Present in AS

Dicrotic Pulse

Accentuated upstroke with second peak, the dicrotic notch in diastole (after S2) Second peak in diastole differentiates the dicrotic pulse from a bisferiens pulse. Occurs in patients with low cardiac output (CO) and high systemic vascular resistance (SVR) or high CO and low SVR (in both cases the SBP is low) Other miscellaneous signs/findings related to arterial pulse include the following:

Osler Sign or Maneuver Obliteration of brachial pulse by BP cuff with sustained palpable and rigid radial artery Invasive BP measurements are lower than the cuff pressures (pseudohypertension). Due to atherosclerotic, stiffened, calcified blood vessels

Pulse Deficit Difference in the heart rate by direct cardiac auscultation and by palpation of the peripheral arterial pulse rate when in atrial fibrillation (AF) Due to short diastoles (short RR interval), ventricular contraction may not be strong enough to generate enough stroke volume to the periphery and thus the peripheral pulse may underestimate the heart rate.

Radial-to-Femoral Delay Generally radial and femoral pulses occur at nearly the same time (femoral slightly earlier ~5 ms). Due to obstruction of arterial flow in coarctation, the femoral pulse is delayed.

Confirmed by (>20 mm Hg) in upper-extremity pressure compared to lower-extremity pressure in the supine position

Pressure/Pulse Difference in Two Arms (>10 mm Hg Systolic) Due to obstruction involving the aorta, innominate and subclavian arteries due to the following etiologies: congenital, arteriosclerosis, embolism, arteritis, dissection, postsurgical (subclavian flap repair for coarctation) or external obstruction (thoracic outlet syndrome)

Asymmetric Right Greater Than Left Pulses and Pressures Supravalvular AS: The blood flow is directed toward the right side of the aorta in greater proportion to the left side (due to the Coanda effect) resulting in a disparity with ↑ right-sided pulse amplitude and pressures, including inequality of carotid pulses. Historical signs of severe AR due to high stroke volume detected by pulse abnormalities include the following:

Hill Sign Extreme augmentation of systolic BP in the popliteal artery compared with the brachial artery (>40 mm Hg with severe AR) Results from a summation of reflected pressure waves traveling distally in the aorta

Mayne Sign ↓ in diastolic BP with arm elevation of >15 mm Hg compared to standard arm position Seen with severe AR

Traube Sign “Pistol Shot”

Loud systolic sound heard over the femoral artery

Corrigan Pulse: “Water-Hammer” Pulse Large-amplitude, rapid upstroke followed by rapid collapse of the peripheral pulse Due to high left ventricular stroke volume and low SVR Most commonly seen with chronic severe aortic regurgitation

Duroziez Sign Systolic and diastolic bruit heard over the femoral artery with gentle compression with the bell of the stethoscope

JUGULAR VENOUS PULSE Basic Principles Pressure and waveforms should be evaluated Adjust level of head/torso until pulsations optimally visualized, generally around 45 degrees Internal jugular vein preferable to external jugular vein and right internal jugular vein preferable to left internal jugular vein Jugular venous pulse (JVP) ↓ with inspiration in normal patients

Jugular Venous Pressure Measure the vertical height above the sternal angle or angle of Louis (junction of manubrium and sternum), which is considered to be 5 cm above the mid–right atrium (RA) in all positions. However, this distance may not be constant for all patients and may vary in some patients (especially based on size) and with different positions.

5 cm + height of jugular venous pressure above the sternal angle = right atrial pressure Above 9 cm H2O is considered elevated. Conversion: 1.36 cm H2O = 1 mm Hg (or 1 cm H2O = 0.74 mm Hg) Abdominojugular reflux (previously referred to as the hepatojugular) can be performed to confirm or determine elevated venous pressure. Application of pressure >10 to 30 seconds over the right upper quadrant (RUQ) results in sustained elevation of jugular pressure 4 cm above the sternal angle for >10 seconds following release of pressure. Straining (Valsalva maneuver) must be avoided since it will cause a false reading.

Jugular Venous Waveforms See Figure 2.2.

FIGURE 2.2 Internal jugular pulsations in normal individuals and during AF. The physiology attributed to each wave is noted. Typically, there are two positive waves (“a” and “v” waves) and two negative waves (“x” and “y” descents) in normal individuals.

The “a” wave is lost with AF. The “c” wave is not appreciable on physical examination. RA, right atrium; RV, right ventricle.

Disease States See Figure 2.3.

FIGURE 2.3 Internal jugular pulsations during various disease states. A:Large “v” or “cv” wave characteristic of TR along with a rapid “y” descent. B:Large “a” wave as seen with obstruction to right ventricular filling with TS. The “y” descent is slow when TS is present. A large “a” wave without a blunted “y” descent may occur with RVH or PH. C:Cannon “a” waves are present with AV dissociation and describe the presence of intermittent prominent “a” waves that occur during contraction against a closed AV valve during ventricular systole. It should not be confused with a prominent “v” wave. D:Loss or blunting of the “y” descent is an important feature of cardiac tamponade that corresponds with impairment of diastolic filling. E:A prominent “x” and “y” descent is present with constrictive pericarditis. The rapid “y” descent is a marker of early rapid filling due to an abnormality of compliance. F: With restrictive cardiomyopathy a blunted “x” descent is present with a rapid “y” descent. AF: loss of “a” wave resulting in just one major positive and prominent “v” wave Complete heart block, atrioventricular (AV) dissociation/ventricular tachycardia—cannon “a” wave due to contraction against a closed tricuspid valve

Tricuspid stenosis (TS), RVH, PH, severe left ventricular hypertrophy (LVH) with hypertrophied septum (Bernheim effect)—large or giant “a” waves Severe TR: large “v” wave and rapid “y” descent ASD: prominent and equal “a” and “v” waves Constrictive pericarditis: prominent “y” descent (predominant filling during early diastole) and prominent “x” descent giving “w” shape waveform along with elevated jugular venous pressure and Kussmaul sign Restrictive cardiomyopathy: Blunted “x” descent and prominent “y” descent with elevated jugular venous pressure and Kussmaul sign. Cardiac tamponade: prominent “x” wave and loss of the “y” descent representing loss of filling in diastole along with elevated jugular venous pressure Superior vena cava (SVC) obstruction— elevated but nonpulsatile JVP

Other Miscellaneous Signs/Findings Kussmaul sign: paradoxical rise in JVP during inspiration due to increased resistance of RA filling during inspiration. The opposite of the normal fall in JVP with inspiration due to negative intrathoracic pressure Due to right ventricular increased volume and reduced compliance, and restricted flow from SVC Classical finding in constrictive pericarditis. May also occur with RV infarct, severe TR or TS, PE, and restrictive cardiomyopathy, but is absent with cardiac tamponade except for the effusive constrictive form

PRECORDIAL MOTION Basic Principles

The normal left ventricular apex moves toward the chest wall during isovolumic contraction/as the heart rotates counterclockwise. The normal LV impulse is best palpated in the fourth or the fifth left intercostal space just medial to the midclavicular line in the left lateral decubitus position. It is about 1 to 3 cm in size and lasts less than one-third of systole. The apical pulsation is not always the point of maximal impulse (PMI) (e.g., in rheumatic mitral stenosis [MS], the PMI may be produced by the right ventricle or pulmonary artery).

Hypertrophy LVH results in an apical impulse that is sustained and not diffuse. RVH or PH results in a left parasternal heave or lift that is sustained and not diffuse.

Dilation LV enlargement results in a diffuse, laterally displaced apical impulse. RV enlargement results in a diffuse impulse occurring in the parasternal region.

Disease States LV aneurysms may produce diffuse outward bulging and a rocking effect. Constrictive pericarditis may be characterized by systolic (inward) retraction of the chest instead of outward motion (Broadbent sign) with absent palpable apical impulse. Hyperactive precordium occurs in volume overload (severe aortic and mitral regurgitation [MR], large left-to-right shunt). HCM causes a double systolic outward motion. This is due to a palpable “a” wave (increased atrial filling wave) and a sustained outward movement of the apex. In some patients, there are two systolic

motions as well as the motion during atrial systole resulting in a triple apical impulse (triple ripple).

FIRST HEART SOUND Basic Principles Ventricular systole begins with closure of the mitral (first) and tricuspid (second) valves. S1 is best heard with the diaphragm of the stethoscope at the apex for the mitral and the left sternal border for the tricuspid valve. Opening sounds of the mitral and tricuspid valves are pathologic sounds.

Intensity Mitral closure is generally louder than tricuspid closure. S1 is generally louder than S2 at the apex and the left sternal border and softer than S2 at the left and the right second interspaces. S1 (particularly M1) is ↑ with Short PR interval (due to wide separation of leaflets at onset of ventricular systole) or preexcitation syndromes MS with mobile leaflets Hyperdynamic LV function or ↑ transvalvular flow due to shunts (↑ force of leaflet closure) TS or ASD (T1 ↑) S1 is ↓ with Long PR interval (leaflets close together at onset of ventricular systole) MS with immobile or calcified leaflets

Severe AR (due to mitral preclosure from the jet hitting the mitral valve and high left ventricular end diastolic pressure [LVEDP]) MR due to prolapse or flail (poor coaptation of leaflets) Severe LV dysfunction with poor CO (↓ force of leaflet closure) S1 is variable with Atrial fibrillation Complete heart block and AV dissociation

Splitting Split S1 must be differentiated from an S4 gallop heard best at the apex with the bell of the stethoscope and an ejection sound (ES) (pulmonic or aortic) heard at the base of the heart.

Persistent Splitting Late T1 closure due to severe TS, ASD or right bundle branch block (RBBB) Late T1 closure due to Ebstein anomaly (S2 also split) with associated multiple systolic and diastolic clicks “sail-like sounds” Early M1 closure due to LV preexcitation

Reverse Splitting (Rare) Late M1 closure due to severe MS (usually associated with TR), left bundle branch block (LBBB), RV pacing

SECOND HEART SOUND Basic Principles

Ventricular systole ends at the dicrotic notch with closure of the aortic (first) and pulmonic (second) valves S2 closure sounds are heard best with the diaphragm of the stethoscope

Intensity Aortic closure heard best at the second right intercostal space adjacent to the sternum is generally louder than pulmonic closure heard best at the second left intercostal space adjacent to the sternum. S2 (A2) is ↑ with hypertension (HTN) or a dilated, anteriorly positioned or aneurysmal aorta (may have tambour quality) S2 (A2) is ↓ with AS, AR, and hypotension. S2 (P2) is ↑ with pulmonary HTN, dilated pulmonary artery (PA) or ASD. S2 (P2) is ↓ with pulmonary stenosis (PS) either valvular or subvalvular or pulmonary regurgitation (PR).

Single S2 A2 is absent with severe AS or AR. P2 is absent with chronic obstructive pulmonary disease (COPD) and obesity (inaudible sound due respiratory noise) or PS, pulmonary atresia, right ventricular outflow tract (RVOT) obstruction, and tetralogy of Fallot. A2-P2 occur together with aging due to decreased inspiratory delay of P2.

Splitting Normally A2 and P2 separate during inspiration and come together during expiration (physiologic splitting) (Fig. 2.4). This occurs due to ↓ pulmonary vascular impedance and a relatively longer RV ejection period relative to LV ejection period

FIGURE 2.4 Illustration of normal S2 (physiologic) splitting and pathologic S2 splitting (persistent, fixed, paradoxical) with the changes that occur as a result of the respiratory cycle. With normal physiologic splitting, P2 closure occurs later than does A2 closure during inspiration with associated increased preload and a longer right ventricular ejection period. During expiration, a single S2 sound is heard. With persistent splitting, A2 and P2 are heard throughout the respiratory cycle but separated by a wider distance during inspiration. This is due either to a delay in the closure of P2 or an early closure of A2. Fixed splitting may occur with hemodynamically significant ASDs and describes the equal and persistent separation of A2 and P2 during the respiratory cycle. Paradoxical splitting is the opposite of normal splitting (P2 precedes A2) during expiration, and a single sound is heard during inspiration. This is due to either a delay in A2 closure or an early P2 closure.

Splitting of the S2 may be physiologic or pathologic.

Pathologic Splitting Fixed splitting: wide and persistent splitting that remains unchanged throughout the respiratory cycle (defined as ≤20 ms of variation) Mechanism: With ASD and left-to-right shunt, this occurs due to prolonged RV ejection due to increased stroke volume that delays P2 during inspiration. During expiration there is decreased caval inflow and so increased left to right shunt. Therefore, the total preload stays the same during inspiration and expiration and S2 split is fixed. Conditions: ASD (~70% secundum ASD when hemodynamically significant), RV failure (most common cause in adults) Persistent splitting: Splitting occurs with both inspiration and expiration but is not fixed with a further widening occurring with inspiration. Mechanism: This type of splitting occurs when there is an electromechanical delay in P2 closure or early A2 closure. Conditions: P2 delayed—RBBB, pulmonary HTN, RV dysfunction, PS, dilated PA A2 early—severe MR, VSD, Wolff–Parkinson–White (WPW) (LV preexcitation) Paradoxical splitting: The normal sequence of A2 followed by P2 closure is reversed so that with expiration P2 precedes A2 and with inspiration the sounds come together. Mechanism: This type of splitting occurs either when there is an electromechanical delay in A2 closure or if P2 closure occurs early. Conditions: A2 delayed—LBBB or RV pacing, AS or AR, LV dysfunction, HCM, dilated aorta, or myocardial ischemia P2 early—WPW (RV preexcitation)

THIRD HEART SOUND Basic Principles Physiologic diastolic sound in young adults though may disappear with standing. Almost all adults lose S3 after 40 years of age. It is normal during the third trimester of pregnancy. Best heard with light pressure of the bell of stethoscope (low frequency) in the left lateral decubitus position at the apex Right-sided S3 can be heard at left sternal border and may ↑ with inspiration. Most commonly heard in conditions of high flow across an AV valves S3 follows an opening snap (OS) and pericardial knock (PK) in timing. S3 corresponds with the “y” descent of the central venous or atrial waveform or the Doppler e wave on an echocardiogram. An S3 is not expected with severe MS.

FOURTH HEART SOUND Basic Principles S4 is usually pathologic (atrial gallop). S4 is heard best with the bell of the stethoscope and occurs just before S1, after the P wave on the EKG and is equivalent to the Doppler a wave on an echocardiogram. A left-sided S4 is heard best in the left lateral decubitus position at the apex during expiration, and a right-sided S4 is heard at the left sternal border to midsternum best with inspiration. Common pathologic states associated with a left-sided S4 include AS, HTN, HCM, and ischemic heart disease. A right-sided S4 is heard with

PH and PS. S4 gallop is not heard with AF. When S3 and S4 are heard simultaneously such as may occur with tachycardia and prolonged PR intervals, a loud “summation gallop” (SG) is present. A quadruple rhythm with a distinct S3 and S4 may be heard with tachycardia.

EXTRA HEART SOUNDS Diastole See Figure 2.5.

FIGURE 2.5 The relative timing of heart sounds heard during diastole is shown. The earliest sound audible is an OS. A pericardial knock (PK) present with constrictive pericarditis occurs later than an OS but slightly earlier than an S3 gallop. The PK can be distinguished from an S3 since it is louder and higher pitched. An S4 occurs before the onset of ventricular systole. Sometimes with rapid heart rates, there is a fusion of S3 and S4 to create a summation gallop (SG).

Opening Snap Pathologic sound generated by abrupt movement of the body of the mitral leaflets in early diastole due to MS or tricuspid stenosis (TS) OS is a high-pitched sound best heard medial to the apex with the diaphragm of the stethoscope. If the valve is calcified and not mobile or MR is present, an OS may not occur. A S2 to OS interval of 95%) blood when a sample is drown from the distal port 3. Stagnation of injected dye in the pulmonary artery

When in doubt, the threshold to perform a left heart catheterization (for direct measurement of LVEDP) should be low. These pressures can then be used to calculate TPG and PVR. In addition, volume challenge during RHC can be useful if resting hemodynamic data are inconclusive to make a diagnosis of PAH. 500 cc of normal saline is infused over 5 to 10 minutes if the resting right atrial pressure is 50% of the variables (noted above) are abnormal. This algorithm is usually applied to a fairly normal group of patients. In patients likely to have diastolic dysfunction (myocardial pathology), recommendations are to estimate LV filling pressures and grade diastolic function into grades I, II, and III (Fig. 20.3). If grade II cannot be assessed due to missing variables, then this will be called indeterminate diastolic function. If the patient has shortness of breath, and there is grade I diastolic function, a diastology stress test is recommended.

FIGURE 20.2 An algorithm for assessment of diastolic dysfunction in patients with normal left ventricular function. LV, left ventricular; EF, ejection fraction; TR, tricuspid regurgitation; LA, left atrial. (From Nagueh SF, Smiseth OA, Appleton CP, et al. Recommendations for the evaluation of left ventricular diastolic function by echocardiography: an update from the American Society of Echocardiography and the European Association of Cardiovascular Imaging. J Am Soc Echocardiogr. 2016;29:277314, with permission from Elsevier.)

FIGURE 20.3 Algorithm for estimation of LV filling pressures and grading LV diastolic function in patients with depressed LVEFs and patients with myocardial disease and normal LVEF after consideration of clinical and other 2-D data. TR, tricuspid regurgitation; LA, left atrial; Vol, volume; LAP, left atrial pressure; CAD, coronary artery disease. (From Nagueh SF, Smiseth OA, Appleton CP, et al. Recommendations for the evaluation of left ventricular diastolic function by echocardiography: an update from the American Society of Echocardiography and the European Association of Cardiovascular Imaging. J Am Soc Echocardiogr. 2016;29:277-314, with permission from Elsevier.) This algorithm should not be applied to special populations, and different criteria should be used (Table 20.2).

Table 20.2 Assessment of LV Filling Pressures in Special Populations

Disease Atrial fibrillation

Echocardiographic Measurements (Cut-off Values) Pea k acceleration rate o f mitral E velocity (2:1,900 cmls2 ) IVRT

( ~65

ms)

DT o f pulmo nary venous diasto lic velocity ( ~220 ms) ENp ra tio (2:1.4) Septa l Ele' ratio (2:11 ) Sinus tachycardia

Mirra) inflow pa ttern with predominant early LV filling in patients with LVEF < 50% IVRT

~ 70

ms

Pulmonary vein systolic filling fractio n ~40 % Average Ele' > 14 Diastolic function ca n be assessed if E and A velocities separate during a compensatory period after a premature beat Hypertrophic cardiomyopathy

Average Ele' (>14) Ar-A (;::30 ms) TR peak velocity (>2.8 m is) LA volume (> 34 mL/m2 )

Restrictive cardiomyopathy

DT (2.5) IVRT ( 13 indica tive of a cardiac etiology for increased pulmonary pressures; < 8 indicative of a noncardiac etiology

Mitral stenosis

IVRT ( :.... 200

....cCl> J:

ct

150 100 50

B

AVN Slow Pathway ERP 420 ms

•

•

Baseline

• •••

AVN Fast Pathway ERP 420 ms

AVNRT 300 350 400 450 A 1- A2 Coupling Interval (ms)

500

FIGURE 25.15 AH jump and AVN echo beat. A:Single atrial premature extrastimuli are delivered after eight-beat paced drive cycles. The AH interval is 140 ms with a coupling interval of 290 ms. After a coupling interval of 280 ms, the AH interval “jumps” to 470 ms, indicating the presence of dual AVN pathway physiology. The atrial EGMs evident in the CS leads (arrows) indicate the AVN echo beat with retrograde conduction to the atria. B:AVN conduction curve demonstrating an AH jump at the fast pathway ERP of 420 ms and induction of echo beats and AVNRT. AV Nodal Refractory Periods. The AV Nodal Effective Refractory Period (AVN ERP) is the longest A1A2 interval that fails to conduct through the AVN (Fig. 25.16). Prolongation may occur with high vagal tone or concomitant medications. Other refractory periods that can be measured include the AV nodal relative refractory period (AVN RRP), which represents the longest A1A2, which results in an H1H2 > A1A2 during atrial extrastimulus testing. The AV nodal functional refractory period (AVN FRP) is the shortest H1H2 interval (AVN output) observed during extrastimulus testing.

FIGURE 25.16 AV node effective refractory period (AVN ERP).

INCREMENTAL PACING

VENTRICULAR

While not a component of EP testing that directly assesses anterograde AV conduction, incremental ventricular pacing (pacing in the ventricle at faster and faster cycle lengths) can help determine whether retrograde conduction occurs via the AVN (Fig. 25.17) or an accessory pathway (Fig. 25.18). Atrial activation occurring with a midline activation pattern that decrements with more rapid pacing rates or a shorter premature extrastimulus coupling interval suggests conduction via the His–Purkinje–AVN system. In this pattern, concentric activation is seen in the CS leads with earliest atrial activation occurring at the AVN, septal region, and later activation occurring

at more lateral atrial sites (Fig. 25.17). In contrast, retrograde conduction via a left lateral free wall accessory pathway (Fig. 25.18) would cause an eccentric activation pattern with earliest ventricular activation occurring near the accessory pathway in the lateral CS leads and earliest retrograde atrial activation in the distal CS as well.

FIGURE 25.17 Normal anterograde and retrograde activation.

FIGURE 25.18 Abnormal anterograde and retrograde activation: left-sided accessory pathway. PCL of VA Block. The longest ventricular PCL associated with failure of retrograde VA conduction is determined by decremental ventricular pacing. Pacing is performed at shorter and shorter cycle lengths. During retrograde AV nodal conduction, VA intervals gradually increase as pacing cycle length shortens. PCL is shortened until VA block occurs (e.g., retrograde Wenckebach or 2:1 VA block). In the presence of a typical accessory pathway, a constant VA interval is usually observed, and VA block occurs when the accessory pathway refractory period is reached. This usually occurs with a 2:1 VA block pattern, rather than in a retrograde Wenckebach pattern.

Ventricular Extrastimulus Testing. Analogous to atrial extrastimulus testing, single premature ventricular extrastimuli (V2) are delivered after eight-beat trains of ventricular pacing (V1) at several ventricular PCLs (e.g., PCL 600, 500, 400 ms). The coupling interval of the extrastimulus (V1V2) is shortened by 10 to 20 ms with each succeeding drive train. In this manner, retrograde VA conduction can be assessed. Decremental retrograde conduction suggests that conduction is occurring via the His–Purkinje–AVN system. Retrograde conduction via a typical accessory pathway is generally nondecremental, unless the accessory pathway is an atypical, decremental pathway. In addition, retrograde atrial activation patterns are examined to determine if atrial activation occurs with a typical AV nodal midline activation pattern (Fig. 25.17).

TACHYARRHYTHMIA EVALUATION BY EPS Ventricular Tachycardia Most patients undergoing EP study for assessment of ventricular arrhythmias have CAD or dilated cardiomyopathy and reduced left ventricular function. In selected patients, EP study may be useful for assessment of risk and need for ICD implantation, drug testing, assessment of device/antitachycardia pacing function, or mapping for ablation. EP testing has limited sensitivity and specificity in the prediction of arrhythmic events in nonischemic disease. EP studies have been more useful in risk stratification of patients with CAD after MI. Based on data from Multicenter Unsustained Tachycardia Trial (MUSTT) (4) and Multicenter Automatic Defibrillator Implantation Trial (MADIT) (5), survival is improved with ICD implantation in patients with CAD, prior MI, nonsustained VT, and LVEF ≤ 40%, and inducible sustained VT or reproducibly inducible VF with double ventricular extrastimuli that is not suppressible with an antiarrhythmic drug (MADIT) (5). These studies provide a rationale for performing EP studies for risk stratification in these patient groups. MADIT II (6) demonstrated the value of prophylactic ICD

implantation without EP testing in patients with CAD and LVEF ≤ 30%. DEFiNITE (7) and SCDHeFT (8) studied the value of prophylactic ICD implantation and included patients with nonischemic cardiomyopathy. SCDHeFT demonstrated survival benefits for ICD implantation in ischemic or nonischemic cardiomyopathy patients with heart failure and LVEF ≤ 35% without the need for EP testing. EP testing is generally not necessary in patients who have criteria that already meet approved ICD indications. Patients with normal LV function and VT usually have special types of ventricular arrhythmias that may be studied by EP testing, particularly in conjunction with mapping and ablation.

Ventricular Programmed Stimulation Protocols Several stimulation protocols have been of utility in stratifying risk for sustained ventricular arrhythmias. Some of the most common are summarized below:

Ventricular overdrive burst pacing.

Ventricular Effective Refractory Period (VERP). Single ventricular premature extrastimuli are delivered with shortening coupling intervals until the stimulus fails to capture the ventricle (Fig. 25.19). The VERP is the longest ventricular extrastimulus V1V2 that fails to capture the ventricle during ventricular extrastimulus testing. It is measured from pacing stimulus to pacing stimulus and is recorded at different sites (e.g., right ventricular apical [RVA], right ventricular outflow tract [RVOT]) and PCLs (e.g., 600, 400 until S2 is refractory).

FIGURE 25.19 Determination of VERP by ventricular extrastimulus delivery. Single ventricular premature extrastimuli are introduced with shortening coupling intervals until the stimulus fails to capture the ventricle. In this example, at PCL 400 ms, a ventricular premature extrastimulus captures the ventricle at a coupling interval of 280 ms but fails to capture the ventricle at 260 ms. The VERP is 260 ms at PCL 400 ms. Ventricular Functional Refractory Period (VFRP). The VFRP is the shortest ventricular coupling interval produced with premature ventricular

stimulation. The VFRP is measured from EGM to EGM and recorded at different sites (e.g., RVA, RVOT) and PCLs (e.g., 600, 400 until S2 is refractory). Induced Arrhythmias. Definitions of ventricular arrhythmias that can be induced with programmed ventricular stimulation include the following: Repetitive ventricular responses—1 to 3 PVCs NSVT—three or more ventricular complexes lasting 30 seconds or requiring earlier termination due to hemodynamic compromise Sustained monomorphic VT—sustained VT of uniform morphology Sustained polymorphic VT—sustained VT of multiform morphology Pleomorphic VT—multiple morphologies of monomorphic VT Ventricular flutter—rapid VT < 220 or 240 ms CL with no isoelectric baseline and a sine wave appearance VF—disorganized chaotic ventricular complexes with loss of organized ventricular contraction. Morphology. Morphology of VT can be described by bundle-branch block morphology and axis using surface ECG leads I, aVF, and V1:

VA Relationship During VT. VA dissociation can be readily recognized using intracardiac atrial and ventricular EGMs (Fig. 25.20), helping to confirm the diagnosis of VT.

FIGURE 25.20 Ventricular stimulation and induction of sustained monomorphic VT with VA dissociation, LB/LSA morphology. VA dissociation is evident during the induction pacing sequence as well as during VT. A, atrial activation.

Supraventricular Tachycardia During EP studies performed for the diagnosis and mapping of SVT, multipolar catheters are generally placed in the HRA or CS, at the His bundle (HBE), and in the right ventricle (RVA or RVOT). SVT mechanisms include atrial arrhythmias (including ectopic atrial tachycardia, macroreentrant atrial tachycardia, atrial flutter, and atrial fibrillation), AV node reentrant tachycardia (AVNRT), and atrioventricular reciprocating tachycardia (AVRT) mediated by an accessory pathway. Stimulation Protocols. Programmed atrial and ventricular stimulation protocols are used in the determination of SVT mechanism and are summarized as follows: Ventricular Pacing. Incremental ventricular pacing at constant rates, but delivered at progressively faster PCLs, is used for assessment of VA conduction. In particular, retrograde atrial activation pattern (via AVN vs.

accessory pathway) is examined to determine the earliest atrial activation site from atrial EGMs recorded on catheters at various atrial sites (Figs. 25.17 and 25.18). The shortest cycle length at which 1:1 VA conduction occurs is recorded and the pattern of VA block at shorter cycle lengths examined. A decremental VA conduction pattern (longer VA times with faster pacing rates) that is concentric (earliest atrial activation in septal leads and later activation in lateral free wall electrodes) suggests retrograde conduction is occurring via the AVN. Retrograde conduction using an accessory pathway may cause an eccentric atrial activation pattern in the CS (earliest atrial activation in the posterior or lateral CS in left-sided accessory pathways, Fig. 25.18) or early activation away from the septum in the RA. In addition, typical accessory pathways do not display significant decremental conduction, so VA conduction times generally are constant. Exceptions occur for septal accessory pathways in which earliest activation will be at septal leads and also for decremental accessory pathways in which VA conduction times may be longer at faster pacing rates. Programmed Ventricular Stimulation. Premature ventricular extrastimuli. Single premature ventricular beats are delivered at one or more drive cycle lengths (e.g., 600, 400 ms) to assess retrograde refractory periods, pattern and change in retrograde atrial activation patterns, site of retrograde VA block, and the presence of dual retrograde AVN pathway physiology. Atrial Pacing. Assessment of anterograde conduction is performed with atrial pacing and programmed atrial stimulation. Baseline AH and HV intervals are assessed, and evidence for decremental AVN conduction is sought. Anterograde conduction via the AVN is characterized by increasing AH intervals with faster atrial pacing rates. The shortest PCL at which 1:1 AV conduction occurs and the pattern of anterograde activation and block at PCL shorter than this are noted. A Wenckebach AV block pattern and a narrow QRS supports conduction occurring anterogradely through the AVN. Anterograde ventricular preexcitation by an accessory pathway may become more manifest by atrial pacing, as faster pacing rates will cause decremental, or slower, conduction through the AVN. Thus, at faster atrial pacing rates, the AVN will conduct slower, leading to later ventricular activation from the AVN–HPS. Since conduction through a typical accessory pathway does not significantly decrement with more rapid pacing rates and ventricular

activation times via the accessory pathway will remain relatively constant, there is less contribution of ventricular activation that occurs via the AVN and more via the accessory pathway (Fig. 25.21). Another potential important function of burst atrial pacing is the induction of SVT for mapping and ablation.

FIGURE 25.21 Left free wall accessory pathway. In sinus rhythm (left panel), there is fusion of ventricular activation occurring via the atrial node and accessory pathway. During atrial pacing and introduction of premature atrial extrastimuli (right panel), preexcitation becomes more manifest as activation via the AVN decrements and becomes later, leaving a larger component of ventricular activation to occur via the accessory pathway. Programmed Atrial Stimulation. Delivery of single or double atrial extrastimuli may serve to study AVN physiology, to determine the presence of an accessory pathway and its refractory period, and to induce SVT. Single premature beats are delivered after fixed drive cycles (e.g., typically after

eight-beat 600, 500, and/or 400 ms PCL atrial drive trains). Normal AVN physiology is characterized by decremental conduction: the faster the stimulation (shorter A1A2 coupling intervals or faster PCLs), the slower the AVN conducts and the longer the AH interval becomes (Fig. 25.22 APD1 and APD2). The following are typical SVT substrates that may be demonstrated:

FIGURE 25.22 Single atrial extrastimuli. Dual AVN physiology and induction of single typical AVN echo beat. Single APD1 and single APD2: decremental AVN conduction with longer AH interval after shorter A1–A2 coupling interval. Decremental AVN conduction is demonstrated with AH 140 and 160 ms with shortening of APD coupling interval (APD1 to APD2). Single APD3: AH jump (>50-ms increase in AH interval for a 10-ms decrease in A1–A2 coupling interval) with single typical AV nodal echo (note atrial activation seen in the CS with a short VA interval). APD, atrial premature depolarization.

AH (jump >50 ms over a decrement of 10 ms in A1S2) ⇒ dual AVN physiology (Fig. 25.22 APD2 and APD3) Induction of AV nodal echo beats or AVNRT by occurrence of block typically in the fast pathway and conduction delay in the slow pathway allowing recovery for retrograde fast pathway conduction and activation of retrograde atrial depolarization (Fig. 25.22, APD3 and Fig. 25.23) Induction of orthodromic AVRT by causing antegrade block in the AP so it is excitable when the impulse returns to conduct retrograde to the atrium

FIGURE 25.23 Initiation of AVNRT single APDs CS 400/250 AH jump, initiation of AVNRT. Refractory Periods. As in the ventricle, refractory periods of the components of the anterograde conduction system can be determined and are defined as follows:

Atrial Effective Refractory Period—Longest atrial coupling interval (A1A2) that fails to capture the atrium, measured from pacing stimulus to pacing stimulus Atrial Functional Refractory Period (AFRP)—Shortest atrial coupling interval during premature atrial stimulation (A1A2), measured from EGM to EGM Fast AVN Pathway ERP—Longest atrial coupling interval that produces an AH jump to conduction via the slow pathway, measured from EGM to EGM during atrial extrastimulus testing Slow AVN Pathway ERP—Longest atrial coupling interval that produces a block in slow pathway conduction (if only two pathways are present and the fast pathway has already blocked, slow AVN pathway ERP = AVN ERP), measured from EGM to EGM during atrial extrastimulus testing Accessory Pathway Anterograde ERP—Longest atrial coupling interval that produces a block in accessory pathway conduction, measured from EGM to EGM during atrial extrastimulus testing Accessory Pathway Retrograde ERP—Longest ventricular coupling interval that produces a block in retrograde accessory pathway conduction, measured from EGM to EGM during ventricular extrastimulus testing Shortest Preexcited R–R during Atrial Fibrillation. Short R–R intervals suggest a short AP ERP and potential increased risk. Activation Patterns. As discussed above, the pattern of atrial and ventricular activation is examined. The anterograde ventricular activation sequence is the sequence of ventricular activation during sinus rhythm, atrial pacing, atrial extrastimuli, or SVT. Eccentric activation of the CS suggests a left-sided accessory pathway (Fig. 25.18, left panel). The atrial activation sequence is the sequence of atrial activation during ventricular pacing, ventricular extrastimuli, or SVT. Eccentric retrograde activation of the CS suggests a left-sided accessory pathway (Figs. 25.18, right panel and 25.24).

FIGURE 25.24 Left-sided accessory pathway. Retrograde atrial activation during ventricular pacing—earliest retrograde atrial activation at CS 3 (arrows). Inducible Supraventricular Tachyarrhythmias. Types of SVTs that may be induced include the following: AV node reentrant tachycardia—AVNRT is usually associated with dual AV nodal pathway physiology (discontinuous AVN conduction curves; an AH “jump”) (Figs. 25.15 and 25.22). In typical AVNRT, antegrade conduction occurs via the slow AVN pathway (long AH) and retrograde conduction via the fast AVN pathway with near-simultaneous atrial and ventricular activation (Figs. 25.22 and 25.23). In a typical AVNRT, antegrade conduction occurs via the fast AVN pathway (with a short PR) and retrograde conduction via the slow AVN pathway (long R–P interval). Atrioventricular reentrant tachycardia—AVRT refers to accessory pathway-mediated reentrant tachycardia. In AVRT, there is 1:1 AV association, as the atria and the ventricles are integral components of the reentrant circuit. In orthodromic AVRT, antegrade conduction occurs via the AVN (with a narrow QRS in the

absence of bundle-branch block/aberration) and retrograde conduction occurs via the accessory pathway (Figs. 25.25 and 25.26). In antidromic AVRT, antegrade conduction occurs via the accessory pathway (with wide QRS) and retrograde conduction via the AVN or another accessory pathway. Atrial flutter—In type I (typical) atrial flutter, right atrial activation proceeds in a counterclockwise activation pattern through the posterior isthmus between the inferior vena cava and tricuspid annulus. There may also be clockwise activation utilizing the isthmus. Type II (atypical) atrial flutter refers to atrial flutter using non–isthmus-dependent flutter circuits. Atrial tachycardia—Atrial tachycardias may be macroreentrant in mechanism, including most incisional or scar-related atrial tachycardias, or due to ectopic (to the sinus node) foci and/or automatic mechanisms. Atrial fibrillation—This most common sustained clinical arrhythmia typically initiates from pulmonary vein ostial or other focal triggering sites or microreentrant circuits. It may sustain with multiple wandering reentrant circuits. Sinus node reentrant tachycardia—This tachycardia is characterized by a similar P-wave morphology to sinus rhythm and may be induced and terminated with premature extrastimuli. Inappropriate sinus tachycardia—Inappropriate sinus tachycardia (IST) is characterized by an inappropriately high resting sinus rate and enhanced sensitivity to adrenergic stimulation.

FIGURE 25.25 Left-sided accessory pathway mediating orthodromic AVRT—earliest retrograde atrial activation occurs via an accessory pathway at CS 2–3 (VA interval 95 ms). Evaluation during tachycardia. Once a tachycardia is induced, various observations and maneuvers can be performed to help determine the SVT mechanism. These include the following: Morphology: Narrow complex, RBBB or LBBB aberrant conduction, or preexcited Atrial activation sequence Ventricular activation sequence HA or VA interval—Short HA interval (100 ms) suggests orthodromic AVRT mediated by an accessory pathway Single ventricular premature extrastimuli during SVT (Fig. 25.27)—If single ventricular premature extrastimuli delivered during His refractoriness advances retrograde atrial activation, then a retrogradely conducting or concealed accessory pathway is present. However, this only demonstrates the presence of an accessory pathway. It does not

prove that the pathway is an integral part of the circuit, as it could be a bystander pathway. Bundle-branch block aberration in SVT (Figs. 25.28 to 25.30)—VA interval prolongation during aberration in SVT indicates a retrogradely conducting accessory pathway ipsilateral to the bundle-branch block. On a surface ECG recording, this may be manifest by a longer cycle length (slower rate) during the wide complex tachycardia/aberration than during narrow complex conduction (Fig. 25.28). The prolongation of the cycle length occurs due to a prolongation of VA conduction times. Bundle-branch block aberration ipsilateral to the accessory pathway results in longer retrograde (VA) activation times due to additional time required for transseptal myocardial conduction (Figs. 25.28 to 25.30). Demonstration of such a change in VA time with aberration demonstrates the presence of the accessory pathway ipsilateral to the bundle-branch blocked and also indicates that the accessory pathway is a component of the reentrant circuit.

FIGURE 25.26 Left free wall accessory pathway mediating orthodromic AVRT—earliest atrial activation occurs in the distal CS at CS 1–2 (arrows).

FIGURE 25.27 Orthodromic AVRT with single VPD introduced during His refractoriness. The single ventricular extrastimulus delivered during His bundle refractoriness advances retrograde atrial activation, suggesting the presence of a retrogradely conducting accessory pathway, in this case located in the right posteroseptal region.

FIGURE 25.28 A:Conversion of wide complex to narrow complex tachycardia with longer RR interval during wide complex tachycardia. This is diagnostic for AVRT with an accessory pathway ipsilateral to the bundle-branch block. B:Orthodromic AVRT with ipsilateral BBB. BBB aberration ipsilateral to the accessory pathway results in longer retrograde (VA) activation times as a result of additional time required for transseptal myocardial conduction.

FIGURE 25.29 Initiation of orthodromic AVRT with initial LBBB aberration. Retrograde VA activation times are longer during LBBB aberration, indicating participation of a left-sided accessory pathway. Local VA time measured nearest the accessory pathway (CS distal 55 ms) is similar, but earliest ventricular to atrial activation is longer with LBBB aberration.

FIGURE 25.30 RBBB aberration during AVRT utilizing a right posteroseptal accessory pathway. Retrograde VA activation times are longer during RBBB aberration, confirming the presence of a right-sided accessory pathway.

MAPPING DURING ABLATION A diagnostic EP study is critical to confirmation and definition of arrhythmia substrate prior to ablation of most SVTs and VTs. Currently, various mapping techniques based on determination of earliest activation sites include the utilization of electrophysiologic recordings and various electroanatomic, contact catheter and noncontact mapping systems that can graphically tag and record activation times in three-dimensional space with computer generation of a display of activation or voltage maps. Although ablation of some arrhythmias is based on anatomic locations (e.g., slow pathway region for AVNRT or pulmonary vein antral isolation for atrial fibrillation ablation), successful ablation of other tachycardias often requires determination of the earliest site of activation, which helps to determine the location of the targeted arrhythmia substrate. An example is shown in Figure 25.31, which demonstrates the fusion of atrial and ventricular EGMs on the ablation catheter at the site of an accessory pathway. Ablation here using radiofrequency energy resulted in prompt ablation of the pathway, loss of ventricular preexcitation, and restoration of normal AV conduction.

FIGURE 25.31 Left-sided accessory pathway. A:Successful ablation site. B:Radiofrequency ablation.

SUMMARY This chapter aims to summarize the components of a comprehensive diagnostic EP study. For users of this book aiming for cardiovascular board

examination review, focus should be paid to the following: Recognition of the His bundle EGM and determination of the sites of AV block (AV nodal vs. infranodal block) Recognition of VA dissociation during wide complex tachycardia using intracardiac EGMs, indicating that the rhythm is most likely VT Recognition of the initiation of AVNRT with demonstration of an “AH jump” and induction of an SVT with near-simultaneous atrial and ventricular activation Recognition of a left free wall accessory pathway with abnormal, eccentric early activation via a more distal CS location (e.g., rather than the normal earliest activation at the septum and later activation in the lateral CS/left atrial or ventricular free wall) Recognition that bundle-branch block that manifests during SVT with a longer cycle length or longer VA time indicates the presence of an accessory pathway ipsilateral to the bundle-branch block

SUGGESTED READINGS Bardy GH, Lee KL, Mark DB, et al. Amiodarone or an implantable cardioverter-defibrillator for congestive heart failure. N Engl J Med. 2005;352:225-237. Blomstrom-Lundqvist C, Scheinman MM, Aliot EM, et al. ACC/AHA/ESC guidelines for the management of patients with supraventricular arrhythmias—executive summary: a report of the American college of cardiology/American heart association task force on practice guidelines and the European society of cardiology committee for practice guidelines (writing committee to develop guidelines for the management of patients with supraventricular arrhythmias) developed in collaboration with NASPE-Heart Rhythm Society. J Am Coll Cardiol. 2003;42:1493-1531. Buxton AE, Lee KL, Fisher JD, et al. A randomized study of the prevention of sudden death in patients with coronary artery disease. Multicenter Unsustained Tachycardia Trial Investigators. N Engl J Med. 1999;341:1882-1890. Epstein AE, DiMarco JP, Ellenborgen KA, et al. ACC/AHA/HRS 2008 Guidelines for device-based therapy of cardiac rhythm abnormalities: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to Revise the ACC/AHA/NASPE 2002 Guideline Update for Implantation of Cardiac Pacemakers and Antiarrhythmia Devices) Developed in Collaboration With the American Association for Thoracic Surgery and Society of Thoracic Surgeons. J Am Coll Cardiol. 2008;51:e1-e62; originally published online May 15, 2008. Kadish A, Dyer A, Daubert JP, et al. Prophylactic defibrillator implantation in patients with nonischemic dilated cardiomyopathy. N Engl J Med. 2004;350:2151-2158.

Knight BP, Ebinger M, Oral H, et al. Diagnostic value of tachycardia features and pacing maneuvers during paroxysmal supraventricular tachycardia. J Am Coll Cardiol. 2000;36:574-582. Knight BP, Zivin A, Souza J, et al. A technique for the rapid diagnosis of atrial tachycardia in the electrophysiology laboratory. J Am Coll Cardiol. 1999;33:775-781. Moss AJ, Hall WJ, Cannom DS, et al. Improved survival with an implanted defibrillator in patients with coronary disease at high risk for ventricular arrhythmia. Multicenter Automatic Defibrillator Implantation Trial Investigators. N Engl J Med. 1996;335:1933-1940. Moss AJ, Zareba W, Hall WJ, et al. Prophylactic implantation of a defibrillator in patients with myocardial infarction and reduced ejection fraction. N Engl J Med. 2002;346:877-883. Tracy CM, Akhtar M, DiMarco JP, et al. American College of Cardiology/American Heart Association clinical competence statement on invasive electrophysiology studies, catheter ablation, and cardioversion. A report of the American College of Cardiology/American Heart Association/American College of Physicians—American Society of Internal Medicine Task Force on clinical competence. J Am Coll Cardiol. 2006;114:1654-1668. Zipes DP, Camm AJ, Borggrefe M, et al. 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. Europace. 2006;8:746-837.

Chapter 25 Review Questions and Answers QUESTIONS 1.

Where is the site of block in Figure 25.32?

FIGURE 25.32 A. . C. D.

AV node (AVN) Infra-His Intra-His AVN and Infra-His

2.

Where is the site of block in Figure 25.33?

FIGURE 25.33 A. . C. D.

AVN Infra-His Intra-His AVN and Infra-His

3.

Where is the site of block in Figure 25.34?

FIGURE 25.34

A. . C. D.

AVN Infra-His Intra-His AVN and Infra-His

4.

What is the diagnosis based on Figure 25.35?

FIGURE 25.35 A. . C. D.

Orthodromic AVRT Left-sided accessory pathway Atrial tachycardia AVN reentrant tachycardia

5.

What is the diagnosis based on Figure 25.36?

FIGURE 25.36 A. . C. D.

Left-sided accessory pathway Right-sided accessory pathway AVN reentrant tachycardia Sinus tachycardia

ANSWERS 1.

Correct Answer: B. Infra-His The tracing (Fig. 25.32) shows atrial pacing with right bundle-branch block (RBBB) and second-degree AV block without prolongation of the PR or AH intervals prior to the blocked beat (third paced beat). On this third paced beat, the His electrode shows an atrial EGM followed by a His deflection but not following ventricular EGM or QRS. Thus, the block occurs below the bundle of His (infra-Hisian block).

2.

Correct Answer: A. AVN

The tracing (Fig. 25.33) shows atrial pacing (S1 drive) with 2:1 AV block. Inspection of the His bundle EGM tracings demonstrates S1 atrial pacing stimuli followed by atrial EGMs. After the first paced beat, there is a His bundle EGM followed by a ventricular EGM and QRS on the surface electrocardiogram (ECG). After the second paced beat, no His bundle EGM follows the atrial EGM. The next paced beats repeat this pattern. The block is at the level of the AVN, because conduction is blocked prior to arrival to the His bundle.

3.

Correct Answer: D. AVN and Infra-His This tracing (Fig. 25.34) shows second-degree AV block during atrial pacing. The His bundle EGM demonstrates the atrial pacing stimuli followed by atrial EGMs. After the first atrial paced beat, there is a long AH interval followed by a His EGM but no ventricular EGM or QRS. This beat blocks below the His bundle. After the second paced beat, there is a slightly longer AH interval followed by a ventricular EGM on the RVA tracing and a corresponding surface QRS. After the third paced beat, the AH is longer still, but there is no conduction after the His EGM to the ventricles. This beat again shows infraHisian block. After the fourth paced beat, there is no His electrogram. This beat blocks in the AVN, and the series shows AVN Wenckebach occurring (gradually prolonging AH interval followed by block in the AVN). The fifth paced beat shows conduction after the block with a shorter AH interval followed by conduction to the ventricles. The sixth paced beat shows a small His deflection with slightly longer AH but infra-Hisian block (no ventricular activation). The seventh paced beat shows a slightly longer AH interval with conduction to the ventricles. Thus, the tracing demonstrates two levels of block—in the AVN (Mobitz I Wenckebach pattern) and infra-Hisian block.

4.

Correct Answer: D. AVN reentrant tachycardia The tracing (Fig. 25.35) shows a narrow QRS complex tachycardia with a cycle length of 350 ms. The coronary sinus (CS) atrial EGMs show a concentric atrial activation pattern (earliest at CS 7 to 8 at the septum and later at more distal CS electrodes) with near-simultaneous

activation of the atrium and ventricle. The earliest atrial activation is likely the small deflection at the onset of the QRS on the HBE tracing, which actually slightly precedes the ventricular activation. This pattern is consistent with AVN reentrant tachycardia.

5.

Correct Answer: A. Left-sided accessory pathway This tracing (Fig. 25.36) shows a narrow complex tachycardia with cycle length of 370 ms. The anterograde activation occurs via the AVN and HPS (AH seen in HBE 1 to 3 with narrow QRS). The earliest atrial activation occurs in the distal CS at CS 1 to 2. This eccentric activation pattern indicates retrograde activation via a left lateral accessory pathway. The tachycardia is consistent with orthodromic AVRT using a retrogradely conducting left-sided accessory pathway.

CHAPTER 26

Sudden Cardiac Death and Ventricular Tachycardia CAMERON T. LAMBERT, DANIEL J. CANTILLON, AND OUSSAMA WAZNI

DEFINITION OF SUDDEN CARDIAC DEATH Sudden cardiac death (SCD) is defined by the 2017 American College of Cardiology/American Heart Association/Heart Rhythm Society (ACC/AHA/HRS) guidelines as the sudden and unexpected death occurring within 1 hour of the onset of symptoms or within 24 hours of a patient being asymptomatic. The definition excludes noncardiac conditions such as pulmonary embolism, intracranial hemorrhage, or airway obstruction. However, it does not exclude nonarrhythmic deaths, as the terminal rhythm is often unknown.

EPIDEMIOLOGY OF SUDDEN CARDIAC DEATH The incidence of SCD is estimated to be 230,000 to 350,000 per year in the United States with some estimates exceeding >450,000 depending on measurement methods. Ninety-seven percent of these deaths are observed in patients over the age of 18. The mortality rate is high, with an overall survival rate of 10%. Of those patients who reach the hospital, 50% die

before discharge. Among those who survive to hospital discharge, the 5 year survival approaches 80%. There is a high recurrence rate of 35% to 50%. More than 75% to 85% of SCDs are associated with ventricular arrhythmias. The most common arrhythmias are ventricular tachycardia (VT) (62%), torsades de pointes (TdP) (13%), primary ventricular fibrillation (VF) (8%), followed by bradycardia (7%). SCD is the first presentation of cardiac disease in 25% of patients. The incidence increases with age at an absolute incidence of 0.1% to 0.2% per year. Men are more commonly affected (3:1) although this discrepancy may be lessening. SCD in patients 35 years old, SCD is most commonly associated with coronary artery disease. Determinants of survival are rapid external defibrillation and bystander cardiopulmonary resuscitation.

RISK FACTORS PATHOPHYSIOLOGY

AND

Risk factors include the following: Prior cardiac arrest: high recurrence rate, up to 35% to 50% at 2 years Syncope in the presence of coexisting cardiac diseases Reduced left ventricular (LV) function and congestive heart failure (CHF) Ventricular premature contractions and nonsustained ventricular tachycardia (NSVT) post myocardial infarction Myocardial ischemia and/or documented scar Conduction system disease The pathophysiology of these arrhythmias requires an underlying substrate conducive to maintaining an arrhythmia and trigger factors that can incite the abnormal rhythm. Examples of these SCD mechanisms include the following: Anatomical reentry around scarred myocardium

Functional reentry using a diseased His–Purkinje system, or areas of nonhomogeneous (anisotropic) conduction Ischemia, electrolyte imbalance, ion channel abnormalities, surges in neurosympathetic tone, pro-arrhythmic effect from antiarrhythmic drugs Rapid and irregular ventricular activation (i.e., atrial fibrillation [AF] with rapid ventricular response in Wolff–Parkinson–White [WPW]) Bradycardic SCD is overall uncommon; however, it remains an important consideration in specific situations (i.e., cardiac transplant recipients).

SUDDEN CARDIAC DEATH CORONARY ARTERY DISEASE

AND

Coronary artery disease is present in 80% of those with SCD. Approximately 75% have a history of prior myocardial infarction (MI). Sudden death can be the first clinical manifestation in up to 25% of patients with coronary artery disease. Approximately 65% have three-vessel obstructive coronary disease at the time of diagnosis. Given this correlation, the most updated SCD guidelines recommend coronary evaluation (CTA or angiography) for patients who were successfully resuscitated from SCD. Risk factors for coronary artery disease–related SCD include depressed LV systolic function and frequent premature ventricular contractions (PVCs). Despite PVCs being a risk factor for SCD, the Cardiac Arrhythmia Suppression Trial (CAST) study demonstrated that suppression with class IC medications resulted in higher mortality. Data from large clinical trials have identified groups of patients with coronary artery disease, depressed LV systolic function, and nonsustained ventricular arrhythmias at increased risk for SCD, as discussed later in this chapter.

NONISCHEMIC CARDIOMYOPATHY Patients with impaired LV systolic function in the absence of coronary artery disease are also at increased risk for ventricular tachyarrhythmias and SCD,

particularly those with symptomatic heart failure. In the heart failure population, total mortality is approximately 25% at 2.5 years, with SCD accounting for 25% to 50% of these deaths. Mortality due to SCD is much higher in New York Heart Association (NYHA) classes II and III than in class IV patients, who have excess mortality due to pump failure. Recent studies have attempted to clarify which patients with NICM may suffer SCD. Noninvasive imaging modalities such as cardiac MRI have demonstrated myocardial late gadolinium enhancement (LGE) to be a reliable marker for heightened risk.

Dilated Cardiomyopathy Fifty percent of deaths in this patient subgroup are arrhythmic. Left ventricular ejection fraction (LVEF) is predictive of sudden death, due to either circulatory failure or fatal arrhythmia. While ventricular ectopy is very common in patients with dilated cardiomyopathy (DCM), it is less predictive of SCD compared to patients with coronary artery disease. Up to 80% of patients may have NSVT on Holter monitor. Inducibility for ventricular tachyarrhythmias at the time of electrophysiologic (EP) study is also less predictive when compared to patients with coronary disease and has almost no role in risk stratification. While some modalities such as abnormal Twave alternans and heart rate variability have been associated with increased risk in this population, only LVEF ≤ 35% and the presence of symptomatic heart failure are recommended by practice guidelines for the purposes of risk stratification, particularly regarding selecting candidates for implantable cardioverter–defibrillator (ICD) implantation.

Hypertrophic Cardiomyopathy HCM is an autosomal dominant disease with incomplete penetrance associated with an increasingly recognized number of genetic mutations. The overall incidence of SCD is 2% to 4% in adults and up to 6% in children. It is the most common cause of SCD in young athletes. Identification of patients at increased risk for SCD is important and requires specific criteria as most of these patients maintain normal left ventricular EF and thus will not meet the traditional indications for ICD therapy. Maron et al. identified factors associated with increased risk

including the presence of NSVT, hypotension with exercise, unexplained syncope, septal thickness >3 cm, and a family history of sudden death in a first-degree relative younger than 50 years old. Among patients with HCM and primary prevention ICDs, appropriate therapy was uncommon among patients with none of the above listed risk factors. Appropriate ICD therapies were delivered in 14% of patients with one risk factor, 11% of patients with two risk factors, and 17% of patients with three or more risk factors. Cardiac magnetic resonance imaging (MRI) has been increasingly utilized for risk stratification in HCM patients (>15% myocardium showing LGE associated with VT). This enhancement is histopathologically associated with scarring and fibrosis and is typically located in the basal septal wall. To help guide clinicians’ decision regarding ICD therapy in HCM, the American Heart Association and European Society of Cardiology provide guidelines to help predict risk for SCD. The AHA guidelines support ICD implant for patients with HCM and additional risk factors for SCD, which include left ventricular outflow tract (LVOT) obstruction (resting gradient ≥ 30 mm Hg), LGE on cardiac MRI, LV apical aneurysm, or high-risk genetic mutations (LAMP2). The 2015 European recommendations add a risk score (HCM Risk-SCD score), which integrates the patient’s age, LV wall thickness, left atrial size, LVOT gradient, family history of SCD, presence of NSVT, and history of unexplained syncope to provide a 5-year SCD risk output.

Arrhythmogenic Right Ventricular Cardiomyopathy Progressive fibrofatty right ventricular tissue replacement is the histopathologic hallmark of arrhythmogenic right ventricular cardiomyopathy (ARVC), although this disease process can affect both ventricles and less commonly even the left ventricle only This pathologic replacement of normal myocardium with fibrofatty tissue is a nidus for ventricular arrhythmia and SCD, although variants of this condition involve only fibrosis without fatty replacement. Given a strong familial inheritance pattern, the 2017 ACC/AHA/HRS guidelines recommend referral for genetic counseling. Globally, it is thought that up to 20% of SCD may be due to ARVC (3% in the United States). MRI is the most useful imaging modality to make the diagnosis. Characteristic epsilon waves may be present on the electrocardiogram (ECG), as shown in Figure 26.1. The frequency and the

severity of ventricular arrhythmias in this disease increase with time making the timing of ICD implantation important. According to the guidelines, a primary prevention ICD should be considered for a patient with ARVC with a marker for increased SCD risk. These risk factors include previous aborted SCD, documented sustained VT, and reduced ventricular function (either RV or LV EF ≤ 35%). Beyond device-based therapy, these patients should avoid intensive exercise and beta-blockers should be prescribed to patients with a history of ventricular arrhythmia.

Figure 26.1 ECG reading in ARVD.

Cardiac Sarcoidosis An increasingly recognized cause of SCD is cardiac sarcoidosis. This condition, pathologically identified by noncaseating granulomas, presents most commonly during the third, fourth, or fifth decades of life. While it traditionally is associated with inducing AV conduction abnormalities sometimes requiring pacemaker implantation, the inflammatory changes to the myocardium can induce ventricular arrhythmias. Common diagnostic modalities include PET scan imaging with FDG avidity present in among granulomas, as well as diagnostic criteria involving cardiac MRI. There is a paucity of epidemiologic data regarding SCD in patients with cardiac sarcoidosis. Inducible ventricular arrhythmias during EP study, unexplained syncope, and poor LV function may be markers of elevated SCD risk. A 2014 consensus statement from the Heart Rhythm Society can assist in the decision-making process relating to ICD therapy in patients with cardiac sarcoidosis.

Myocarditis Myocarditis, or inflammatory changes of the myocardium, often seen in various infections may impact the conduction system leading to abnormal conduction or arrhythmias ranging from AF to more sinister ventricular arrhythmias. Causes include influenza, coxsackie B virus, Chagas disease, HIV, and systemic lupus erythematous. It is imperative that these patients be managed in a hospital equipped to provide mechanical hemodynamic support given these arrhythmias often occurring alongside cardiogenic shock. There should be a high index of suspicion for myocarditis (specifically giant cell myocarditis)-related arrhythmia in a young patient who has suffered SCD. Patients who suffer aborted SCD due to myocarditis can be managed with antiarrhythmics until recovery or mechanical circulatory support can be established (LVAD, transplant).

Noncompaction of the Left Ventricle In this rare congenital condition, there are prominent trabeculations within the LV cavity without other significant structural abnormalities. Diagnosis can be achieved with echocardiography, cardiac CT, or MRI. Ventricular arrhythmias are common and can affect up to 40% of children, although

predictors for SCD are not well established. Specific data regarding the incidence of SCD are not available but given the observed increased rates of SCD, placement of a primary prevention ICD among select patients is considered reasonable.

Catecholaminergic Tachycardia

Polymorphic

Ventricular

SCD in the setting of emotional or physical stress without baseline ECG abnormalities is the hallmark of catecholaminergic polymorphic VT (CPVT). Arrhythmias are typically inducible with exercise stress testing and may display characteristic bidirectional morphology. This is an inherited condition with both autosomal dominant and recessive forms described that can present at any age. Once identified, exercise restriction and beta-blocker therapy are commonly prescribed. An ICD is considered reasonable for selected patients on maximally tolerated beta-blocker therapy with documented VF, hemodynamically intolerant VT, or unexplained syncope. Left-sided cardiac sympathetic denervation is also an option for these patients. Genetic testing plays a prominent role in the diagnosis of this condition.

INHERITED AND CHANNELOPATHIES

ACQUIRED

Long-QT Syndrome Long-QT syndrome consists of the inherited abnormalities that prolong cardiac repolarization as measured by the corrected QT (QTc) interval on surface ECG, which confer an increased risk of SCD by polymorphic ventricular tachycardia (PMVT) or TdP. There are numerous identified mutations involving mostly sodium and potassium ion channels (Table 26.1). Abnormal QTc cutoff values are >470 ms in symptomatic patients and >480 ms in asymptomatic patients, although actual cardiac events occur on a skewed curve and are highest among patients with QTc > 500 ms. The most

common symptoms associated with long QT syndrome are palpitations and unexplained syncope, although associations also exist with seizure disorders. Characteristic clinical triggers for arrhythmia events have been described by genotype including exercise or swimming (LQT1), auditory stimuli, or during the postpartum period (LQT2) and during sleep (LQT3). Features associated with higher risk for SCD include the Jervel and Lange-Nielsen syndrome (congenital deafness), syncope or ventricular arrhythmias while on betablocker therapy, QTc > 500 ms with an LQT1 or LQT2 genotype, female gender, and family history of SCD. Treatment usually includes beta-blocker therapy, except for in the case of LQT3, where a gain-of-function mutation in SCN5A results in voltage-gated sodium channels remaining open that is sometimes treated with mexiletine, a class IB drug. The 5-year sudden death risk in patients on beta-blocker therapy (Long QT Registry) is 30 seconds in duration or requires abortive therapy (i.e., shocks) to return to normal rhythm. This includes patients with acute MI with events occurring beyond 48 hours and not related to immediately reversible causes (i.e., overinjection of contrast dye during angiography of the right coronary artery).

For primary prevention, ICD therapy is recommended in patients 40 days after a medically managed MI (no revascularization performed) with LVEF ≤ 35% on optimal medical therapy and with life expectancy >1 year. For those patients who received successful revascularization, ICD therapy is recommended in patients 90 days after the MI who have LVEF ≤ 35%. Key trials in formulating these primary prevention indications include the MADIT-2 trial (ICD benefit for patients post-MI with LVEF < 30% and NYHA class I symptoms) and SCD-HeFT (ICD benefit for LVEF ≤ 35% and NYHA class II symptoms). In addition, patients may be considered for a primary prevention ICD with prior MI, LVEF < 40%, NSVT detected by ambulatory Holter or telemetry, and inducible VT with programmed stimulation at the time of EP study, largely on the basis of the MADIT-1 trial (LVEF ≤ 35% with NSVT) and MUSST registry (LVEF ≤ 40% with NSVT). Current ICD therapy can terminate up to 90% of all spontaneous VT with antitachycardia pacing (ATP). However, up to one-third of patients will still require antiarrhythmic medications to suppress VT and to minimize shocks and ATP. Catheter ablation of reentrant circuits is indicated for patients with VT that is refractory to medications and requiring multiple ICD shocks.

Dilated Cardiomyopathy More than a quarter of patients with DCM have NSVT on Holter monitoring during a 24-hour period. ICD implantation is recommended for secondary prevention in patients with DCM and prior sustained VT/VF and also as primary prevention for patients with LVEF ≤ 35% with NYHA class II symptoms based on the SCD-HeFT trial. Studies have shown more robust increases in longevity in patients with DCM and appropriate ICD indications when compared to patients with ischemic cardiomyopathy and indications for ICD. The 2012 device therapy guidelines also allow a primary prevention ICD to be offered to patients with DCM, LVEF ≤ 35%, and NYHA class I symptoms, although this is based on weaker evidence. In addition to scar-related VT, patients with DCM are particularly susceptible to bundle branch reentry VT. This is a VT most commonly occurring with left bundle branch bundle (LBBB) morphology. EP testing reveals abnormal conduction in the His–Purkinje system as measured by a

prolonged HV interval in sinus rhythm. Most frequently, the right bundle is used as the antegrade limb and the left bundle as the retrograde limb of the tachycardia, and the right bundle is typically targeted for catheter ablation.

Ventricular Tachycardia and the Structurally Normal Heart Outflow Tract Ventricular Tachycardia VT occurring in patients without structural heart disease most commonly originates from discrete foci in the right and the left ventricular outflow tracts (LVOTs). These arrhythmias are thought to be secondary to enhanced automaticity related to delayed after depolarization (DAD)–mediated triggered activity resulting from increases in intracellular calcium (during phase 4 of the action potential). DAD–mediated outflow tract VT is frequently inducible during an EP study using pacing maneuvers, in addition to provocation by an isoproterenol infusion (typically in the “wash-out” phase of infusion). The right ventricular outflow tract (RVOT) is more common than the LVOT by a ratio of 9:1. However, data by Iwai et al. suggest that these tachycardias share identical EP mechanisms and clinical behavior due to embryologic origin in the maturation of the outflow tract. Outflow tract tachycardias can occur as sustained monomorphic VT, frequent salvos of NSVT, or frequent symptomatic VPDs. The classic ECG pattern for RVOT VT is a LBBB with precordial Rwave transition in V2–V3, and an inferior limb lead axis, with tall R waves in II, III, and aVF. LVOT VT can occur with a RBBB morphology, inferior axis, or a LBBB morphology, inferior axis with earlier precordial R-wave transition by V2 (Fig. 26.3). In the EP lab, outflow tract tachycardia may be induced with programmed stimulation and has a characteristic pharmacologic response of adenosine sensitivity in most cases. Mapping and ablation of the site of earliest origin is highly successful. Left-sided foci are also commonly ablated from left and right coronary cusps either just above or immediately beneath the aortic valve. Outflow tract VTs are not associated with SCD, and catheter ablation is curative. Therefore, ICD therapy is not indicated (class III recommendation by 2012 guidelines).

Figure 26.3 ECG reading in RVOT VT.

Idiopathic Left Ventricular Tachycardia This is a paroxysmal VT that occurs predominantly in men between 15 and 40 years of age. It is also called “fascicular VT” because of the circuit’s typical involvement of the LV anterior and posterior fascicles. It accounts for 10% to 20% of all idiopathic VTs and is characterized by the following triad: (a) inducibility by atrial pacing or premature complexes, (b) RBBB morphology most commonly with left anterior hemiblock pattern, and (c) absence of structural heart disease. This type of VT is highly sensitive to calcium channel blockers like verapamil. Ventricular activation at the earliest site is usually preceded by high-frequency potentials termed Purkinje potentials. Ablation at these sites is highly successful in terminating this arrhythmia (70% success rate). In the absence of concomitant structural heart disease, true fascicular VT is not associated with SCD and thus not recommended for ICD implantation according to the 2012 guidelines.

Papillary Muscle Ventricular Tachycardia Ventricular arrhythmias originating from the papillary muscles (LV more often than RV) have become more recognized over the past 10 years and account for a small fraction of the structurally normal heart ventricular arrhythmias (5% to 12%). They typically affect men and women in their 50s and 60s and are frequently exercise induced. Patients may present with frequent PVCs, NSVT, or SCD (often VT triggered by a PVC). Treatment consists of beta blockade and catheter ablation albeit with a lower success rate (60%) than with other forms of ventricular tachycardia ablation.

ACKNOWLEDGMENTS The authors wish to acknowledge the contributions of J. David Burkhart, MD, to an earlier version of this chapter.

SUGGESTED READINGS Al-Khatib SM, Stevenson WG, Ackerman MJ, et al. ACC/AHA/HRS 2017 guideline for management of patients with ventricular arrhythmias and prevention of sudden cardiac death. J Am Coll Cardiol. 2018;72:e91-e220. Birnie DH, Sauer WH, Bogun F, et al. HRS expert consensus statement on the diagnosis and management of arrhythmias associated with cardiac sarcoidosis. Heart Rhythm. 2014;11:13041323. Dukkipati SR, Choudry S, Koruth JS, et al. Catheter ablation of ventricular tachycardia in structurally normal hearts. J Am Coll Cardiol. 2017;70:2909-2923. Elliot PM, Anastasakis A, Borger MA, et al. 2014 ESC guidelines on diagnosis and management of hypertrophic cardiomyopathy. Eur Heart J. 2014;35:2733-2779. Epstein AE, DiMarco JP, Ellenbogen KA, et al. ACC/AHA/HRS 2008 guidelines for device-based therapy of cardiac rhythm abnormalities. J Am Coll Cardiol. 2008;51:E1-E62. Epstein AE, DiMarco JP, Ellenbogen KA, et al. 2012 ACC/AHA/HRS focused update incorporated into the ACCF/AHA/HRS 2008 guidelines for device-based therapy of cardiac rhythm abnormalities. J Am Coll Cardiol. 2008;61:e6-e75. Gersh BJ, Maron BJ, Bonow RO, et al. 2011 ACCF/AHA guideline for the diagnosis and treatment of hypertrophic cardiomyopathy. Circulation. 2011;124:e783-e831. Haïssaguerre M, Derval N, Sacher F, et al. Sudden cardiac death associated with early repolarization. N Eng J Med. 2008;358(19):2016-2023. Iwai S, Cantillon DJ, Kim RJ, et al. Right and left ventricular outflow tract tachycardias: evidence for a common electrophysiologic mechanism. J Cardiovasc Electrophysiol. 2006;17(10):1052-1058. Nogami A. Idiopathic left ventricular tachycardia: assessment and treatment. Cardiac Electrophysiol Rev. 2002;6:448-457. Samie FH, Jalife J. Mechanisms underlying ventricular tachycardia and its transition to ventricular fibrillation in the structurally normal heart. Cardiovasc Res. 2001;50:242-250. Trivedi A, Knight BP. ICD therapy for primary prevention in hypertrophic cardiomyopathy. Arrhythm Electrophysiol Rev. 2016;5:188-196. Wever EFD, Robles de Medina EO. Sudden death in patients without structural heart disease. J Am Coll Cardiol. 2004;43(7):1137-1144.

Chapter 26 Review Questions and Answers QUESTIONS A 57-year-old male presents to your clinic to discuss primary prevention ICD implant after an ST elevation myocardial infarction 6 weeks prior managed with a single drug eluting stent to the left anterior descending coronary artery. His vital signs include a heart rate of 52 bpm, BP 126/64 mm Hg, respiratory rate of 12, and a pulse oximetry of 99%. He reports dyspnea with moderate exertion. His ECG shows sinus rhythm with QRS duration 100 ms without Q waves. His ejection fraction on the day of the office visit is 30%. Medications include aspirin, ticagrelor, and metoprolol. He has no drug allergies, and lab work reveals normal electrolytes and renal function. What is the most appropriate next course of action? Schedule for single chamber ICD implant Schedule for dual chamber ICD implant Schedule for biventricular ICD implant (CRT-D) Add angiotensin-converting enzyme inhibitor and schedule follow-up appointment

1.

A. . C. D.

A primary prevention implantable cardioverter–defibrillator (ICD) is most strongly indicated in which of following patients? Male patient with syncope, QTc 440 ms, and LQT1 genotype not previously treated with beta-blockers Young patient with syncope, NSVT, and diagnostic criteria for arrhythmogenic right ventricular cardiomyopathy (ARVC), including cardiac magnetic resonance imaging (MRI) Asymptomatic patient with newly diagnosed nonischemic dilated cardiomyopathy (DCM), left ventricular ejection fraction (LVEF) 35% Young patient without structural heart disease and monomorphic ventricular tachycardia (VT) (left bundle branch block [LBBB] morphology, right inferior axis, precordial R-wave transition in V3)

2.

A. . C. D.

Which of the following patients with Wolff–Parkinson–White syndrome should be taken for electrophysiology study and ablation? Asymptomatic 18-year-old male with preexcitation and shortest preexcited R–R interval during induced atrial fibrillation of 350 msec Asymptomatic 24-year-old male with resting intermittent preexcitation that reliably resolves with any level of exertion A 28-year-old male with recurrent lightheadedness episodes and presyncope associated with preexcited tachycardia A and C

3.

A. . C. D.

Bundle branch reentry VT is most commonly associated with A. Enhanced automaticity in the right bundle . Enhanced automaticity in the left bundle C. Supranormal conduction in the His bundle D. Abnormally slow conduction in the His–Purkinje system

4.

5.

The ECG shown in Figure 26.4 is consistent with

Figure 26.4 A. . C. D.

Acute anteroseptal MI Abnormal SCN5A channel Abnormal KCQN1 channel Old anteroseptal MI with an aneurysm

ANSWERS 1.

Correct Answer: D. Add angiotensin-converting enzyme inhibitor and schedule follow-up appointment

The patient is not on guidelines-directed medical therapy and does not have a contraindication to adding an angiotensin-converting enzyme inhibitor to his medical regimen (normotensive, no drug allergies, normal renal function). If the patient returns after 90 days of appropriate guideline-directed medical therapy after a successful revascularization procedure and continues to have a decreased ejection fraction (300 to 400 beats/min (bpm) Mechanical effects: Loss of coordinated atrial contraction

Irregular electrical inputs to the AV node and His–Purkinje system leading to irregular ventricular contraction Surface electrocardiogram: No discrete P waves Irregular fibrillatory waves Irregularly, irregular ventricular response

Atrial Flutter Reentrant Mechanism Cavotricuspid Isthmus–Dependent Atrial Flutter Cavotricuspid isthmus (CTI)-dependent flutters refer to circuits, which involve the isthmus of tissue in the right atrium between the tricuspid annulus and inferior vena cava (IVC) (Fig. 27.1). The circuit can propagate around the isthmus in a clockwise or counterclockwise direction. Counterclockwise atrial flutter is characterized by dominant negative flutter waves in the inferior leads and positive flutter deflection in lead V1. Clockwise atrial flutter is characterized by positive flutter waves in inferior leads and negative flutter waves in lead V1. In contrast to coarse AF, the flutter waves on an ECG will usually have the same morphology, amplitude, and cycle length. Ablation of the CTI is curative.

FIGURE 27.1 Type I counterclockwise right atrial flutter.

Noncavotricuspid Isthmus–Dependent Atrial Flutter Noncavotricuspid isthmus (NCTI)-dependent flutters do not use the CTI. NCTI flutters are often related to atrial scar, which creates a conduction block and a central obstacle that allows for reentry. NCTI can be found in patients with prior cardiac surgery involving the atrium, such as repair of congenital heart disease, mitral valve surgery, or MAZE procedure as well as in patients post pulmonary vein isolation procedures. NCTI-dependent flutters are less common than CTI flutters.

Treatment

Atrial flutter may be difficult to treat medically (it is notoriously difficult to rate control) and may develop with organization of AF reentrant flutter circuits during treatment with antiarrhythmic therapy. Successful ablation is dependent on identifying a critical portion of the reentry circuit where it can be interrupted with catheter ablation.

ATRIAL FIBRILLATION DEFINITIONS Lone: Patients under the age of 60 years with absence of cardiopulmonary or other conditions predisposing to AF New onset: First episode of AF Recurrent: Has two or more paroxysmal or persistent episodes Paroxysmal: Self-terminating or with an intervention (medical or cardioversion) within 7 days Persistent: Sustaining for more than 7 days but less than a year Long-standing persistent: Sustaining for more than a year Permanent: Decision made to rate control only with no further attempts to restore SR

EVALUATION History Precipitating factors and conditions Alcohol, caffeine, sympathomimetics, herbal supplements, or other drug use Duration and frequency of episodes Degree of associated symptoms Manner of AF initiation Prior therapies for AF (past antiarrhythmic drugs that may have failed or past ablation attempts)

Documentation of Atrial Fibrillation and Initiation ECGs, rhythm strips Transtelephonic (remote) event monitoring Evaluation for precipitating bradycardia, paroxysmal supraventricular tachycardia (PSVT), atrial flutter, atrial ectopy, atrial tachycardia

Diagnostic Testing Lab studies—thyroid function, renal, and hepatic tests Echocardiogram—evaluate LV function, valves, atrial size. Functional stress testing or cardiac catheterization—evaluate for CAD in patients with risk factors and evaluate candidacy for 1C agents.

MANAGEMENT FIBRILLATION

OF

ATRIAL

Treatment Strategies Ventricular rate control AV nodal–blocking drugs Atrioventricular node (AVN) modification/ablation and pacing Achievement and maintenance of SR Antiarrhythmic drugs Cardioversions Nonpharmacologic therapies Ablation Surgery—MAZE procedure Anticoagulation

Atrial Fibrillation Follow-Up Investigation of Rhythm Management

The Atrial Fibrillation Follow-Up Investigation of Rhythm Management (AFFIRM) study was a multicenter trial of rate versus rhythm control strategies (Table 27.1). It tested the hypothesis that in patients with AF, total mortality with primary therapy intended to maintain SR is equal to that with primary therapy intended to control heart rate. The study randomized 4,060 patients (>65 years old or with risk factors for stroke), with a primary endpoint of total mortality. No significant difference in total mortality was found among strategies. The study also showed that continued anticoagulation is important even in the rhythm control arm, so this may be the best strategy in relatively asymptomatic older patients with good rate control.

Table 27.1 Rate Control versus Rhythm Control

Control of Ventricular Rate Rapid ventricular rates can cause symptoms and/or ventricular dysfunction. The goal of treatment, a heart rate of 70 to 100 bpm at rest, can be achieved pharmacologically with agents that slow AV nodal conduction, such as digoxin, beta-adrenergic blockers, and calcium channel blockers (Table

27.2). These agents, however, should not be used in patients with ventricular preexcitation due to the risk of very rapid antidromic conduction during AF over the pathway. In patients who are hemodynamically stable with evidence of preexcited AF, amiodarone, ibutilide, procainamide, and disopyramide are acceptable choices.

Table 27.2 Pharmacologic Rate Control for Atrial Arrhythmias

The RACE II trial compared strict rate control (resting heart rate S in V1 (Fig. 28.7). APs on the right free wall will typically have a positive delta wave in leads I and/or aVL (as the wavefront travels from the right toward the leftsided leads), as well as a positive delta wave and R < S in V1, with a precordial R/S transition occurring in V3 or later (Fig. 28.8). Septal APs typically have a negative delta wave in V1.

FIGURE 28.6 Milstein algorithm for localization of APs. LL, left lateral; PS, posteroseptal; RAS, right anteroseptal; RL, right lateral. *LBBB, +QRS LL, rS V1 and V2. (Reprinted from Milstein S, Sharma AD, Guiraudon GM, et al. An algorithm for the electrocardiographic localization of accessory pathways in the Wolff–Parkinson–White syndrome. Pacing Clin Electrophysiol. 1987;10(3 pt 1):555-563, with permission from John Wiley and Sons.)

FIGURE 28.7 ECG showing left free wall accessory pathway.

FIGURE 28.8 ECG showing right free wall accessory pathway.

Mechanism AVRT is a reentrant arrhythmia in which one limb of the reentrant circuit is the AV node/His–Purkinje system and the other limb is the AP. The conduction properties of the AP (speed of conduction and recovery)

determine the likelihood of developing a reentrant circuit arrhythmia. The direction of the circuit differentiates the two types of AVRT: orthodromic and antidromic. Orthodromic reciprocating tachycardia comprises the majority of the reciprocating tachycardias and is diagnosed when the antegrade limb of the reentrant circuit is the AV node and the retrograde limb is the AP. Because the ventricle is activated via the AV node, the QRS complex is narrow. Antidromic reciprocating tachycardia (ART) is less common and uses the AP as the antegrade limb and the AV node as the retrograde limb. Because the ventricle is activated via the AP, the QRS complex is wide (maximal preexcitation).

Electrophysiologic Characteristics and Diagnostic Maneuvers ORT is typically characterized by a short RP and a long PR interval as the circuit is conducting up the AP and down the AV node. Because conduction from the atria to the ventricles is via the AV node, the QRS morphology during tachycardia should be similar (in the absence of aberration) to the QRS morphology during normal sinus rhythm. An interesting and potentially useful phenomenon may be observed if a functional bundle-branch block develops during ORT. As demonstrated in Figure 28.9, if a bundle-branch block ipsilateral to a free wall bypass tract develops during tachycardia, then the retrograde reentrant wavefront is compelled to traverse a greater distance from the His–Purkinje fibers to the AP and the atrium. As a result, the VA conduction time during the tachycardia must increase (usually by at least 35 ms). The tachycardia cycle length may also increase such that the rate of the tachycardia becomes slower. In contrast, if the bundle-branch block is contralateral to a free wall bypass tract, there is no change in the distance the retrograde reentrant wavefront must travel to reach the atrium. Thus, there is no effect on the VA conduction time or tachycardia cycle length. Therefore, an SVT that slows with the development of bundle-branch block should raise suspicion for ORT using an AP located on the free wall ipsilateral to the side of bundle-branch block.

FIGURE 28.9 A:A narrow complex tachycardia utilizing the ipsilateral bundle (left bundle) antegrade and accessory pathway retrograde. Note the cycle length of the tachycardia and compare to (B) where the tachycardia now utilizes the contralateral bundle as the left bundle is blocked. This may result in prolongation of the cycle length of the tachycardia and is diagnostic of the location of the pathway.

Exceptions and Rare Forms of AVRT Occasionally, patients present with an incessant ORT involving retrograde conduction up a decrementally conducting posteroseptal AP; this is called permanent junctional reciprocating tachycardia (PJRT). The slow, decremental conduction of this AP prolongs the time between the R and P, often leading to a “long RP” tachycardia. Because of the incessant nature of

this arrhythmia, it has been associated with tachycardia-induced cardiomyopathy. Antidromic tachycardia is the least common arrhythmia associated with WPW syndrome, occurring in only 5% to 10% of patients. This tachycardia is characterized by a wide QRS complex that is fully preexcited with a regular R–R interval. If the diagnosis of WPW is not recognized, this tachycardia may be mistaken for ventricular tachycardia. Uncommonly, patients may have more than one AP, therefore allowing for multiple potential reentrant arrhythmia circuits. Of such patients, 33% to 60% will present with antidromic tachycardia. Even less common is a tachycardia involving one AP as the antegrade limb and another AP as the retrograde limb of the circuit, without any involvement of the AV node. In these very rare cases, the tachycardia does not terminate with AV node blockade. In patients with more than one pathway, the more likely scenario is ORT or ART involving only one pathway in the circuit, while the other pathways remain as “bystanders.” Occasionally, the presence of multiple APs will become apparent only after the dominant pathway has been ablated. Ebstein anomaly is a congenital heart defect, which is associated multiple right-sided APs; WPW syndrome occurs in 6% to 26% of such patients.

Treatment Treatment of a patient with WPW syndrome may include both drug therapy and catheter ablation. In the acute setting, patients with ORT (conduction down the AV node and thus a narrow QRS complex) can be treated with AV nodal–blocking agents such as adenosine and vagal maneuvers. If adenosine is given for ORT in a patient with a known AP, defibrillation pads should be in place on the patient, as adenosine may trigger AF that, in the setting of adenosine-induced AV block, may conduct rapidly down the AP leading to VF arrest. Chronic treatment may be directed at any essential component of the circuit. Administration of calcium channel antagonists or beta-adrenergic blockers affects the AV node, whereas antiarrhythmic drugs including flecainide, propafenone, quinidine, procainamide, and amiodarone may be chosen to target the AP. Catheter ablation is a class I recommendation for patients with AVRT. With newer electroanatomic mapping technologies, the success rate is >93% with a 250 beats per minute) to the ventricles in a 1:1 manner, inducing a VF arrest (Fig. 28.10). Preexcited AF or AFL should be treated with intravenous procainamide or ibutilide; beta-blockers, calcium channel blockers, and amiodarone are contraindicated. Of course, if the arrhythmia is hemodynamic unstable or refractory to pharmacologic therapy, then electrical cardioversion is the treatment of choice.

FIGURE 28.10 Preexcited atrial fibrillation; note the varying degrees of ventricular preexcitation.

Asymptomatic Accessory Pathways and Sudden Cardiac Death Sudden cardiac death (SCD) has been reported to occur rarely in patients with ventricular preexcitation on ECG, with an incidence of VF of 0.15% in one population-based study. SCD in this circumstance has been associated with a history of symptomatic arrhythmias, multiple APs, and APs with rapid antegrade conduction (shortest preexcited R–R interval 250 ms indicates an AP that is incapable of dangerously rapid antegrade conduction. Finding a shortest preexcited R–R interval 100 beats/min (bpm) and a QRS duration >120 ms on a 12-lead electrocardiogram (ECG). Utilizing the ECG, the correct mechanistic diagnosis of a WCT rhythm is often difficult. Besides being an intellectual exercise, it is very important to establish the correct diagnosis in order to deliver appropriate acute therapy and to plan subsequent long-term patient management. Several criteria and algorithms have been developed to help distinguish among different causes of WCT. When used individually, none of these criteria reaches 100% specificity; however, when properly applied together and in conjunction with the clinical history and presentation, the algorithms serve as a guide to the correct diagnosis in the majority of the cases. WCT can result from either a ventricular or a supraventricular mechanism. Ventricular tachycardia (VT) originates below the level of the His bundle. Supraventricular tachycardia (SVT) originates in or involves structures above the His bundle. SVT may involve atrial tachycardia, atrial fibrillation, atrial flutter, atrioventricular (AV) node reentrant tachycardia (Fig. 29.1), or AV reentrant tachycardia. AV reentrant tachycardia may be either orthodromic reentrant tachycardia or antidromic reentrant tachycardia (Fig. 29.2). Orthodromic reentrant tachycardia occurs when antegrade ventricular conduction occurs via the AV node and retrograde conduction to the atrium is via the accessory pathway. Antidromic reentrant tachycardia

occurs when ventricular antegrade conduction occurs over the accessory pathway and retrograde conduction occurs via the AV node.

FIGURE 29.1 Supraventricular tachycardia.

FIGURE 29.2 AV reentrant tachycardia.

DIFFERENTIAL DIAGNOSIS WCT can occur by three different mechanisms: 1. VT is the most common cause of WCT in the general population, accounting for >80% of all cases. It is even more common in patients with structural heart disease, and it may occur in 98% of patients with a prior history of a myocardial infarction. VT may be either monomorphic or polymorphic. Monomorphic VT occurs when the QRS morphology is stable and uniform, whereas polymorphic VT occurs when the QRS complexes vary in morphology. 2. The second mechanism of WCT occurs when the tachycardia originates above the ventricle and has abnormal ventricular activation, also known as SVT with aberrancy. It accounts for 15% to 20% of all cases of WCT and includes a variety of disorders. The first example is SVT with bundle branch block aberration, which may be either a right bundle branch block (RBBB) or a left bundle branch block (LBBB) morphology (Fig. 29.3). Activation of the

ventricle through the His–Purkinje system (His bundle and both bundle branches) results in a narrow QRS complex. Activation of the ventricle unilaterally via one bundle branch results in a wide QRS complex, because activation of the remainder of the ventricular myocardium is dependent on slow myocardial conduction. Aberration occurs when there are abnormalities of intraventricular conduction in response to changing heart rate, and when the conduction over the His–Purkinje conduction system is delayed or blocked in either the right or left bundle branch. RBBB is more common, occurring in 80% of cases. The aberration may be fixed, occurring in normal sinus rhythm at a slow heart rate, or it may be functional and present only during tachycardia. SVT with antegrade conduction via an accessory pathway, such as in Wolff–Parkinson–White syndrome, accounts for 1% to 5% of all WCT. The accessory pathway is an anomalous AV connection that inserts directly into ventricular myocardium at the base of the ventricle along the mitral or tricuspid valve annulus. Ventricular activation is initiated at this insertion point and is termed ventricular preexcitation. Preexcited tachycardia can occur with SVT with antegrade conduction via the accessory pathway. The accessory pathway is not part of the tachycardia circuit and is not essential for its perpetuation. The other form of preexcited tachycardia can occur with antidromic reciprocating tachycardia, in which the accessory pathway is part of the tachycardia circuit (Fig. 29.4). Another form of WCT is SVT with an intraventricular conduction delay. This can occur in patients with cardiomyopathy, corrected congenital heart disease such as tetralogy of Fallot, or Ebstein anomaly, in which myocardial conduction is further impaired. The conduction abnormality is usually apparent during normal sinus rhythm. Some medications are capable of producing nonspecific widening of the QRS complex during SVT. These include Na+ channel blockers, especially Class IC agents (flecainide, encainide), less so Class IA antiarrhythmics (quinidine, procainamide, disopyramide), and amiodarone. The most common example is a patient with atrial flutter being treated with flecainide. Flecainide can induce flutter rate slowing to permit 1:1 AV nodal conduction and a secondary increase

in the ventricular rate with a wide QRS complex. This is as a result of the slow ventricular conduction in response to the Na+ channel blockade. This can be easily and erroneously interpreted as VT (Fig. 29.5). Electrolyte abnormalities such as hyperkalemia can cause widening of the QRS complex and can be mistakenly interpreted as VT. The morphology is typically LBBB. 3. Ventricular paced rhythms can also mimic WCT (Fig. 29.6). Most pacemakers are dual chamber, with a lead in the right atrium and one in the right ventricle. Pacing of the right ventricle causes an LBBB QRS morphology. The surface ECG representation of the pacing stimulus is less apparent with the use of bipolar pacing modes and a resultant decrease in the energy requirement for reliable ventricular pacing. Therefore, the pacing spike may be overlooked or even absent from ECG tracings. A wide QRS tachycardia can occur in any SVT with atrial tracking, in which the ventricle is paced in response to atrial sensing. In these cases, it is essential to obtain an adequate history and to analyze a previous ECG to evaluate the baseline morphology of the QRS complex. 4. Pacemaker-mediated tachycardia can also produce a WCT. The pacemaker is itself responsible for the tachycardia when ventricular pacing results in retrograde conduction to the atrium. The pacemaker senses the atrial conduction, resulting in ventricular pacing, which in turn is followed by retrograde conduction to the atrium, resulting in “endless loop tachycardia” (Fig. 29.7). 5. Lastly, artifacts from recording equipment problems (such as fastsweep speed recording) or from external repetitive motion (such as brushing teeth) can present as “WCT” (Fig. 29.8).

FIGURE 29.3 SVT with bundle branch block.

FIGURE 29.4 SVT with preexcitation.

FIGURE 29.5 Atrial flutter with 1:1 conduction.

FIGURE 29.6 Ventricular paced tachycardia.

FIGURE 29.7 Ventricular paced tachycardia. A: Atrial tracking. B: Pacemaker-mediated tachycardia.

FIGURE 29.8 Artifact mimicking WCT.

DIAGNOSIS Clinical Presentation

In order to diagnose the etiology of the WCT, it is important to evaluate the clinical presentation. As mentioned before, obtaining an accurate patient history is crucial in formulating an accurate rhythm diagnosis. A prior history of heart disease, myocardial infarction, or congestive heart failure makes the diagnosis of VT highly suggestive as the cause of the WCT. Akhtar et al. have reported that the positive predictive value of a WCT representing VT in a patient with a prior history of myocardial infarction is 98%. Tchou reported that of patients who had a prior myocardial infarction and a first episode of tachycardia occurring after the infarction, 28 of 29 patients presented with VT and were diagnosed correctly. The older the patient is, the more likely that the tachycardia is ventricular; however, there is a significant overlap with SVT patients. It is also helpful to know if there is any presence of congenital heart disease, or if the patient has a pacemaker or defibrillator. Knowing that the patient has an implantable cardioverter–defibrillator (ICD) raises a concern for pacemaker-associated tachycardia, but more important, the presence of the device suggests that the patient has risk factors for VT. A history of a prior similar episode may also be useful. The first occurrence of the arrhythmia after a myocardial infarction is highly suggestive of VT, whereas SVT may be more likely if there is recurrence of the arrhythmia over several years. The presence of other medical conditions can point to a diagnosis of WCT. For example, in a patient with renal failure, the WCT may be attributable to hyperkalemia. In a patient with known peripheral vascular disease, the WCT may be indicative of VT, because such patients are likely to have underlying coronary artery disease. Knowing what medications the patient is taking, especially cardiac medications, is vital when evaluating WCT. It is important to identify medications that prolong the QT interval, such as dofetilide, sotalol, quinidine, and erythromycin, which can all cause torsade de pointes, a form of polymorphic VT. Electrolyte abnormalities caused by certain medications such as diuretics (hypokalemia and hypomagnesemia) or angiotensinconverting enzyme (ACE) inhibitors (hyperkalemia) may predispose to VT. Patients who are on digoxin are more susceptible to an arrhythmia when hypokalemia is present. The most common arrhythmias are monomorphic VT, bidirectional tachycardia, and junctional tachycardia and typically occur when the plasma digoxin concentration is >2.0 ng/mL. As stated earlier, Class IC agents can cause rate-related aberrant conduction during SVT.

Symptoms such as palpitations, lightheadedness, or chest pain are generally not useful in evaluating the etiology of the WCT. One of the priorities in evaluating a patient with WCT is determining if the patient is hemodynamically stable or unstable. The patient’s blood pressure and heart rate are required. In a patient who is unstable, emergency cardioversion is required and the mechanism of the arrhythmia may not necessarily be known. VT can be present when the patient is hemodynamically stable and should not be mistaken for SVT, lest the patient be given inappropriate medical therapy (such as adenosine or verapamil) that can lead to hemodynamic compromise with VT. When the patient is hemodynamically stable, a more detailed physical examination can be performed. Inspection of the chest can point to underlying cardiovascular disease when there is a sternal incision, a pacemaker, or defibrillator. AV dissociation occurs in 60% to 75% of patients with VT and is a result of the atria and ventricles depolarizing independently. It almost never occurs in SVT. This finding is usually identifiable on the surface ECG. However, it is also possible to make this diagnosis on physical examination by assessing the jugular venous pulsation. Cannon A waves are irregular pulsations that are of greater amplitude than the normal jugular venous waves, and occur intermittently when the atrium and ventricle contract simultaneously. When the tachycardia rate is slower, there can be variable intensity of the first heart sound. However, evaluating this may not be practical in an acute situation. Laboratory tests should be performed for patients with WCT to determine potassium and magnesium levels. If the patient is on digoxin, it is also important to obtain the serum digoxin level. If a chest x-ray is available, one can readily identify the presence of a pacemaker, defibrillator, or sternal wires that might point to underlying structural heart disease.

Provocative Maneuvers Certain bedside maneuvers can be performed to distinguish VT from SVT. The Valsalva maneuver or carotid sinus massage enhances vagal tone, which depresses sinus nodal and AV nodal activity. These maneuvers will slow the heart rate during sinus tachycardia, but once they are completed, the heart rate will increase again. If the patient is in SVT, these maneuvers may terminate the rhythm. If the patient is in an atrial tachycardia or flutter, the

rhythm will persist though the ventricular rate may be slower, thus uncovering the background atrial activity. These maneuvers can also elicit VA conduction block, which can induce AV dissociation during VT. Certain medications can be used to diagnose the tachyarrhythmias. For example, adenosine, given in 6- to 12-mg boluses intravenously during WCT, can result in one of the following scenarios: 1. The tachycardia terminates, making it more likely to be supraventricular in etiology, invoking AV node participation. Some atrial tachycardias may also terminate with adenosine. 2. AV block occurs, uncovering the background atrial activity such as atrial tachycardia, flutter, or fibrillation, thus allowing the diagnosis of an atrial tachyarrhythmia. 3. If 1:1 AV association is present and evident during WCT, adenosineinduced AV block results in AV dissociation, thus making the diagnosis VT. Adenosine has a short half-life of about 10 seconds. However, it has to be used with caution, because it may cause hemodynamic compromise in a patient with VT. Some paroxysmal VT in structurally normal hearts may terminate with adenosine. Termination of the rhythm with lidocaine suggests VT as the mechanism. Amiodarone and procainamide, however, will not diagnose the rhythm if the WCT is terminated. Beta-blockers may be given as well. They can terminate SVT or uncover AV dissociation during VT in a manner similar to adenosine. It is important that verapamil not be given if the diagnosis is in question, because it can lead to significant hemodynamic compromise in VT and induce ventricular fibrillation and cardiac arrest.

ECG Criteria The most reliable way to differentiate VT from SVT is by evaluating the ECG. A 12-lead ECG is more helpful than a rhythm strip. A rhythm strip may be additive as a result of analyzing the beginning and termination of the tachycardia. A previous ECG during a normal rhythm will help to identify the baseline QRS morphology and the presence of Q waves that might suggest a

prior myocardial infarction. Ventricular preexcitation may be suggested if there is the presence of delta waves. There are several ECG criteria and different algorithms that may be used to differentiate VT from SVT in WCT: 1. The tachycardia rate has no diagnostic value in determining the mechanism of the WCT. 2. Regularity of the RR intervals is also not a useful criterion, because VT can be irregular in patients on antiarrhythmic medications. 3. QRS complex duration can be useful in differentiating VT from SVT. The WCT is more suggestive of VT when the QRS duration is >140 ms with an RBBB morphology and >160 ms with an LBBB morphology. A study by Wellens showed that all of 70 patients with WCT due to SVT had QRS complex durations 140 ms. Another study, by Akhtar, showed that 15% of patients with VT had QRS complex duration 140 ms with RBBB pattern or >160 ms with LBBB pattern correlates with VT. Wide QRS complex duration can still be seen with preexcitation, ventricular pacing, use of antiarrhythmic drugs, and marked baseline intraventricular conduction delays. VT in structurally normal hearts may have a relatively narrow QRS complex in a case with idiopathic left ventricular VT. 4. The QRS complex axis may also be helpful in diagnosing WCT. A right superior QRS complex axis in the frontal plane is more suggestive of VT. Presence of LBBB and right axis deviation is also almost always due to VT. Presence of Q waves that are also present in normal sinus rhythm suggests prior myocardial infarction, which makes the diagnosis of VT more likely. Pseudo-Q waves can be seen in SVT, which represents retrograde atrial activation. 5. QRS complex concordance in the precordial leads is highly predictive of VT, with a specificity as high as 90% or greater. The sensitivity is low because it is only present in 160 ms RBBB with monophasic R in V1 LBBB with monophasic R in V6

5.

ANSWERS 1.

Correct Answer: D. rSR′ in V1 Options A through C are all part of the Brugada algorithm. The last step of the Brugada algorithm when options A through C are not met is to refer to the morphologic criteria in V1 and V6. A RBBB pattern with an rSR′ is more suggestive of SVT.

2.

Correct Answer: B. Capture; VT

The third beat is a capture beat which is highly suggestive of VT. The second beat is actually a fusion beat which would also be indicative of VT.

3.

Correct Answer: C. Digoxin This strip (Fig. 29.21) shows bidirectional VT and can be caused by digoxin.

4.

Correct Answer: A. VT The rhythm strip (Fig. 29.22) clearly demonstrates AV dissociation which is indicative of VT.

5.

Correct Answer: D. LBBB with monophasic R in V6 The presence of a LBBB pattern throughout the precordial leads with a monophasic R (no q waves) supports the diagnosis of SVT instead.

SUGGESTED READINGS Akhtar M, Shenasa M, Jazayeri M, et al. Wide QRS complex tachycardia: reappraisal of a common clinical problem. Ann Intern Med. 1988;109:905-912. Baerman JM, Morady F, DiCarlo LA, et al. Differentiation of ventricular tachycardia from supraventricular tachycardia with aberration: value of the clinical history. Ann Emerg Med. 1987;16:40-43. Belhassen B, Rotmensch HH, Laniado S. Response of recurrent sustained ventricular tachycardia to verapamil. Br Heart J. 1981;46:679-682. Brugada P, Brugada J, Mont L, et al. A new approach to the differential diagnosis of a regular tachycardia with a wide QRS complex. Circulation. 1991;83:1649-1659. Buxton AE, Marchlinski FE, Doherty JU, et al. Hazards of intravenous verapamil for sustained ventricular tachycardia. Am J Cardiol. 1987;59:1107-1110. Coumel P, Leclercq JF, Attuel P, et al. The QRS morphology in post-myocardial infarction ventricular tachycardia: a study of 100 tracings compared with 70 cases of idiopathic ventricular tachycardia. Eur Heart J. 1984;5:792-805. Curione M, Fuoco U, Borgia C, et al. An electrocardiographic criterion to detect AV dissociation in wide QRS tachyarrhythmias. Clin Cardiol. 1988;11:250-252.

Gelband H, Waldo AL, Kaiser GA, et al. Etiology of right bundle branch block in patients undergoing total repair of tetralogy of Fallot. Circulation. 1971;44:1022-1033. Kindwall KE, Brown J, Josephson ME. Electrocardiographic criteria for ventricular tachycardia in wide complex left bundle branch block morphology tachycardias. Am J Cardiol. 1988;61: 12791283. Miller JM. The many manifestations of ventricular tachycardia. J Cardiovasc Electrophysiol. 1992;3:88-107. Miller JM. Ventricular tachycardia: ECG manifestations. In: Zipes DP, Jalife J, eds. Cardiac Electrophysiology: From Cell to Bedside. 2nd ed. WB Saunders; 1995:990-1008. Miller JM, Marchlinski FE, Buxton AE, et al. Relationship between the 12-lead electrocardiogram during ventricular tachycardia and endocardial site of origin in patients with coronary artery disease. Circulation. 1988;77:759-766. Morady F, Baerman JM, DiCarlo LA, et al. A prevalent misconception regarding wide-complex tachycardias. JAMA. 1985;254:2790-2792. Nathan AW, Hellestrand KJ, Bexton RS, et al. Proarrhythmic effects of the new antiarrhythmic agent flecainide acetate. Am Heart J. 1984;107:222-228. Pick A, Langendorf R. Differentiation of supraventricular and ventricular tachycardias. Prog Cardiovasc Dis. 1960;2: 391-407. Rankin AC, Oldroyd KG, Chong E. Value and limitations of adenosine in the diagnosis and treatment of narrow and broad complex tachycardias. Br Heart J. 1989;62:195-203. Reddy GV, Leghari RU. Standard limb lead QRS concordance during wide QRS tachycardia: a new surface ECG sign of ventricular tachycardia. Chest. 1987;92:763-765. Steinman RT, Herrera C, Schuger CD, et al. Wide QRS tachycardia in the conscious adult: ventricular tachycardia is the most frequent cause. JAMA. 1989;261:1013-1016. Vereckei A, Duray G, Szenasi G, et al. New algorithm using only lead aVR for differential diagnosis of wide QRS complex tachycardia. Heart Rhythm. 2008;5:89-98. Wellens HJJ, Bar FWHM, Lie K. The value of the electrocardiogram in the differential diagnosis of a tachycardia with a widened QRS complex. Am J Med. 1978;64:27-33. Wellens HJJ, Brugada P. Diagnosis of ventricular tachycardia from the 12 lead electrocardiogram. In: Barold SS, ed. 12-Lead Electrocardiography. Cardiology Clinics. Vol. 5, no 3. WB Saunders; 1987:511-525.

Wide Complex Tachycardia: Ventricular Tachycardia (VT) versus supraventricular tachycardia (SVT) Worksheet 1. QRS Complex Duration VT: QRS > 140 ms for right bundle branch block (RBBB), QRS > 160 ms for left bundle branch block (LBBB) 2. QRS Complex Axis VT: right superior

3. Capture and Fusion Complexes 4. QRS Precordial Concordance 5. WCT: Brugada’s Criteria I Step 1.Absence of an RS complex in all precordial leads? Step 2.R-to-S interval >100 ms in one precordial lead? Step 3.AV dissociation? Step 4.Morphology criteria for VT present in both V1 to V2 and V6? RBBB morphology

6. WCT: Brugada’s Criteria II Step 1.Predominantly negative QRS complex in precordial leads V4 to V6? Step 2.Presence of a QR complex in one or more of leads V2 to V6? Step 3.Atrioventricular dissociation? 7. Diagnosis: ECG Criteria Miscellaneous Conditions 1. QRS complex during WCT narrower than during NSR: suggests VT. 2. Contralateral BBB in NSR and WCT: suggests VT. 3. Rapid irregular WCT + beat-to-beat QRS-to-QRS interval variation: atrial fibrillation with WPW. 8. Special Cases 1. Misclassification of SVT for VT: Preexcited tachycardia, paced ventricular rhythm. 2. Misclassification of VT for SVT: BBR-VT (without evidence of AV dissociation). 3. Narrow QRS VT: ILV-VT

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CHAPTER 30

Pacemakers and Defibrillators DIVYANG PATEL, BRUCE L. WILKOFF AND KHALDOUN G. TARAKJI

CARDIAC PACING Cardiac pacing is the only definitive therapy for symptomatic bradycardia. Whether iatrogenic, ischemic, or intrinsic conduction system disease is present, cardiac pacing can be a temporary bridge to recovery, a backup safety therapy, or a permanent therapy, depending on the clinical scenario. What follows is a review of major topics and advances in the field of cardiac pacing.

Indications Indications for cardiac pacing vary with the clinical scenario. The major determinant of need for permanent pacing is the anticipated duration of the pacing indication. For example, symptomatic bradycardia associated with a toxic ingestion of a nodal blocking drug (e.g., digitalis, toluene) or infection (e.g., Lyme carditis) can be anticipated to resolve as the drug/toxin is cleared and/or treated. Temporary pacing may be indicated in the short term, but a permanent device is usually not needed. Alternatively, a transient neurocardiogenic (cardioinhibitory) bradycardic episode may resolve spontaneously, and temporary pacing should not be needed. However, if episodes recur on medical therapy to the point of causing recurrent syncope, a permanent pacemaker is indicated to protect the patient from subsequent syncopal episodes.

Temporary Pacing

In the emergency department setting, transcutaneous pacing can be used as a bridge to a transvenous temporary pacing system in the setting of symptomatic bradycardia of any etiology with hemodynamic compromise. In the critical care setting, temporary pacing can be a life-saving bridge to recovery or, further, to a definitive therapy for the underlying cause of bradycardia. The indications can roughly be divided into those related to ischemia, and all other categories. Acute myocardial infarction can be associated with bradycardia due to either sinus bradycardia, which does not require therapy unless it is causing hemodynamic compromise, or due to AV block or intraventricular block. AV block can be (a) intranodal, which is usually associated with inferoposterior infarcts (right coronary artery [RCA] 90%, left circumflex artery [LCX] 10%), manifests as first degree or Mobitz I pattern, is usually transient with benign prognosis, and rarely requires temporary pacing and almost never requires permanent pacing, or (b) infranodal, which is usually associated with anteroseptal infarcts (left anterior descending artery [LAD]), manifests as Mobitz II or third-degree block, is usually transient but may persist, and carries a poor prognosis as it signifies extensive infarction; it often requires temporary pacing and if it persists permanent pacing. In general, “high-degree” heart block such as Mobitz type II seconddegree heart block and third-degree heart block warrant temporary pacing during the acute phase of anterior (LAD territory) infarcts or inferior (RCA territory) infarcts. Further, new bifascicular block or alternating bundle branch block reflects ischemia within the interventricular septum and warrants temporary pacing as a backup in case of progression to complete heart block. Refractory bradycardia in the setting of an infarct in any territory necessitates temporary pacing. In the absence of an acute myocardial infarction, symptomatic bradycardia with or without AV dissociation and third-degree AV block with ventricular escape warrant temporary pacing. Backup pacing indications include temporary ventricular pacing during right heart catheterization in the setting of preexisting left bundle branch block (LBBB), new bundle branch block or AV block in the setting of endocarditis, and essential pharmacologic therapies that may induce or exacerbate bradycardia. In contrast to patients with ischemia, certain patients with endocarditis, electrolyte/drug abnormalities, or infection may require prolonged temporary pacing until

recovery of intrinsic conduction system and therefore may benefit from an active fixation lead over a passive pacing lead. Temporary pacing systems with temporary epicardial atrial and ventricular wires are routinely used in the setting of open heart surgery. These systems are used to optimize cardiac output coming off cardiopulmonary bypass, and subsequently as a backup system in case AV nodal conduction block occurs postoperatively, especially in the setting of valvular heart surgery.

Permanent Pacing The indications for permanent pacing are listed in detail in the 2018 ACC/AHA/HRS guidelines on the evaluation and management of patients with bradycardia and cardiac conduction delay: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines, and the Heart Rhythm Society. This document is summarized in Table 30.1.

Table 30.1 Indications for Permanent Pacemakers

Class I Symptomatic SND • Symptomatic sinus bradyca rdia seconda ry to required drug thera py fo r medica l conditions such as beta-blockers Acquired second degree t ype 2, high-grade AV bl ock, or t hird-degree AV block that is no t reversible or physio logic even if asympto matic Syncope and bundl e branch block with HV > 70 ms or evidence of infranodal block w ith EP resting Alterna ting bundle branch block Thi rd-degree AV bl ock and advanced second-degree AV b lock after ca theter a blation of the AV junctio n or post cardiac surgery w hen it is not expected to resolve Neuromuscular disease associated with AV block, such as Erb's dystrophy, myotoni c muscular dystrophy, Kea rns- Sayre syndrome, peroneal muscular atro phy with or without sympto ms • Any second-degree AV bl ock with symptomatic bradycardia Asymptomatic patients with persistent third-degree AV block with average awake rates o f 40 bpm or faster if cardiomegaly or left ventricular dysfunction is present or if the site o f block is below the AV node Second or third-degree AV block during exercise in the a bsence o f myoca rdial ischemia Chronic bifascicula r block with advanced second-degree AV b lock or intermittent third-degree AV block, or type II second-degree AV block, o r a lternating bundle branch block After acute phase o f myoca rdial infarction: Persistent second-degree AV block in the His-Purkinje system with alternating bundle bra nch bl ock or third-degree AV block within or below the His-Purkinje system after ST-eleva tion myocardia l infa rction Transient advanced second- o r third-degree infranoda l AV block and associated bundle branch block. (If site of block is uncertain, EPS may be needed ) • Persistent a nd symptomatic second- or third-degree AV block Recurrent syncope with spo ntaneous caro tid sinus stimulatio n and ca ro tid sinus pressure that induces ventricular asysto le of mo re tha n 3 seconds Do cumented pause-dependent VT with or witho ut QT pro longation • Symptomatic bradycardia/chrono tropic incompetence afte r cardiac transplanta tion

Class Ila Sympto matic chronotropic incompetence Tachy-bra dy syndrome with symptoms from bradycardia from drug thera py used to suppress and/or control a tria l arrhythmi as SN D with hea rt rate < 40 bpm when a clea r associati on between severe symptoms o f bradycardia a nd actual presence o f bradycard ia has not been documented Syncope of unexpla ined o rigin a nd SND discovered or provoked in EPS • Asymptomatic second-degree AV block a t intra- o r infra-His level at EPS Fi rst- or second-degree AV block with symptoms simi lar to pacema ker syndrome o r hemo dynamic compromise Bifasc icular block with sy ncope not a ttributable to AV block when other causes excluded , espec ially VT High-risk congenital lo ng QT Recurrent syncope w ith hype rsensitive ca rdioinhibitory response of 3 s o r longer

AV, atrioventricular; MI, myocardial infarction; SND, sinus node dysfunction; VT, ventricular tachycardia; LV, left ventricular; EPS, electrophysiology study; CRT, cardiac resynchronization therapy; NYHA, New York Heart Association; HV, Histo ventricular conduction time; DCM, dilated cardiomyopathy; LVEF, left ventricular ejection fraction; HOCM, hypertrophic obstructive cardiomyopathy. Derived from Kusumoto FM, Schoenfeld MH, Barrett C, et al. 2018 ACC/AHA/HRS guidelines on the evaluation and management of patients with bradycardia and cardiac conduction delay: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines, and the Heart Rhythm Society. Circulation. 2019;140:e382-e482.

Device Features Single-chamber devices that only pace the ventricle or atrium have fallen by the wayside in favor of more sophisticated dual chamber atrioventricular pacing devices that have the ability to track the sinus node rate when appropriate and pace the ventricle after a set delay or pace in the atrium if the intrinsic sinus rate falls below a set lower rate limit. Further, cardiac resynchronization therapy (CRT) with biventricular pacing has a significant beneficial role in patients with symptomatic heart failure (New York Heart Association [NYHA] Class III and ambulatory Class IV) and evidence of left ventricular dysynchrony (EF ≤ 35% and wide QRS duration ≥120 ms). Recent advances in pacing have led to an increased interest of implanting a His pacing lead in the His bundle region to allow for more physiologic

pacing than that produced by right ventricular pacing. Early data suggest that it may be a better alternative than RV pacing and an alternative option for CRT nonresponders or when the implantation of coronary sinus lead fails, though more data are needed on its long-term outcomes and the patient population that would derive the most benefit given its difficult learning curve for implantation. Patients who may not need atrioventricular pacing, biventricular pacing, or patients with difficult transvenous/surgical anatomy or infection history may be candidates for a leadless pacemaker. This is a device the size of a capsule that is implanted into the RV via the femoral vein and paces the patient in VVI mode. Figure 30.1 shows a schematic of pacemaker timing cycles.

FIGURE 30.1 Schematic of important device timing cycles and impulses. PVARP: Post-ventricular atrial refractory period

Rate-Adaptive Pacing A variety of methods have been employed to allow for implantable pacemakers to increase their pacing rate in the setting of metabolic demand for increased cardiac output. The most commonly employed methods include activity sensors (vibration, acceleration), or minute ventilation sensors. Other sensors include peak endocardial oxygen sensors and right ventricle

(RV) impedance-based sensors, which have the advantages of responding to nonexertional stimuli (emotions). These techniques utilize vibration, acceleration, minute ventilation, or other measurements as a surrogate for increased metabolic demand for oxygen delivery. In patients with chronotropic incompetence, or the inability to increase cardiac output in response to exercise, rate-adaptive devices can utilize these surrogates to increase the pacing rate and therefore increase cardiac output. There are advantages and disadvantages to each type of sensor system. Vibration sensors and accelerometers provide an almost immediate rise in rate and therefore cardiac output when they detect activity. However, they can be “fooled” by stimuli external to the patient that mimics patient activity (i.e., turbulence during flight, etc.). The accelerometer tends to respond more specifically to patient activity than does the motion sensor. The advantage of the minute ventilation sensor is that it responds specifically to the patient’s respiratory rate—a parameter that is controlled by the brainstem. Although this parameter perhaps more reliably reflects the degree of patient exertion, it tends to lag behind the initiation of strenuous activity. Dual-sensor systems that utilize data collected from more than one sensor modality may actually be best suited for effective rate-adaptive pacing.

Mode Switching Another feature of dual-chamber cardiac pacemakers that allows the devices to respond to changes in the physiology of the patient is mode switching. Mode switching is the ability of the device to revert to a separate, backup pacing mode in the event that the primary pacing mode no longer best serves the patient’s pacing need. For example, in a patient with AV nodal block, a dual-chamber device may be programmed to sense or track the patient’s intrinsic sinoatrial rate and to pace the ventricle after a set delay within the range of 60 to 120 beats/min (bpm). If the atria begin to fibrillate, the sensed atrial rate would exceed the rate parameter and the device would switch modes to a backup ventricular-only mode with a set rate sufficient to prevent hemodynamic compromise. If the patient reverts to sinus rhythm subsequently, the device would recognize the atrial rate back within the set parameter range and switch back to the primary mode, tracking the atrium and pacing the ventricle. Mode switching allows for the maximum responsiveness to the patient’s intrinsic rhythm. These devices are most

commonly programmed DDDR and revert to DDI, DDIR, or VVIR during periods of high atrial rates.

Other Programmable Features Modern pacemakers now include a myriad of programmable features to better match the patient’s physiologic status. They can be programmed to pace at a lower “sleep” rate during typical sleeping hours, with absence of strenuous activity confirmed by the devices metabolic sensing system. Programmable pulse width and output allow the programmer to optimize the impulse specifications to ensure capture while preserving battery power. Diagnostic information and event data including mode-switching data can be stored and retrieved later to assess for the presence and prevalence of atrial arrhythmias and other events. Atrial and ventricular electrograms can be obtained and stored. Device status data can also be retrieved, including battery usage and projected battery life given current settings.

Leads The pacing leads conduct the electrical pacing impulse to the myocardium and conduct the intrinsic electrical activity of the myocardium to the sense amplifiers within the device. Unipolar leads, which have a single electrode at their tip, exhibited a large pacing artifact on ECG and direct current from their tip to the can of the device through the patient’s tissues, or vice versa. For this reason, problems such as pectoral, intercostal, or diaphragmatic stimulation are more likely to occur, particularly in implants requiring higher outputs to capture the ventricle. Bipolar leads have two electrodes with close proximity at their tip and direct current proximal to distal or distal to proximal over much smaller distances. These leads can achieve capture of the myocardium with lower output energies and thus are more efficient. They are capable of unipolar function as well, but with the same limitations as standard unipolar leads. Furthermore, they are less likely to sense noncardiac signals than unipolar leads. Of note, bipolar leads are by necessity larger and stiffer than unipolar leads and have been historically more prone to mechanical failures than unipolar leads. Coronary sinus leads are small, highly flexible unipolar or bipolar leads. They can be directed from the right atrium via the coronary sinus into a branch cardiac vein for the purpose of pacing the left ventricle in synchrony

with the RV in patients with ventricular dysfunction and delayed intraventricular conduction, usually manifest as a LBBB. Epicardial leads can be placed surgically using minimally invasive techniques or during open heart surgery for another indication such as valve surgery for endocarditis and subsequently utilized instead of transvenous leads for standard pacing or more commonly for CRT (biventricular pacing) in patients without a suitable coronary sinus anatomy. Often two leads are placed at the time of surgery and one of the two is subsequently utilized for biventricular pacing, depending on the thresholds and pacing characteristics of each at the time of device implant. A variety of fixation techniques are utilized to maintain the contact of the lead tip with the myocardium. Active fixation leads employ a fixed extended or retractable screw to engage the myocardium. These systems allow for better localization of the lead tip at the desired site of implantation during deployment of the fixation helix. Passive fixation systems utilize plastic projections near the distal electrode that entrap in the trabeculations of the right ventricle or the right atrial appendage to maintain the position of the lead. As lead implants “mature” over time, pacing thresholds tend first to rise due to inflammation and then improve as healing continues and the inflammation resolves. Most leads have a small amount of steroid impregnated at the lead tip that reduces the size of the fibrotic tissue capsule and reduces the chronic thresholds.

Basic Concepts of Impulses and Timing Following is a review of some basic concepts in pacemaker theory that are central to an understanding of the clinical application of pacing technology. Stimulation threshold: The minimum amount of electrical energy that consistently produces a cardiac depolarization. The energy is a combination of voltage and pulse duration. It can be expressed in terms of amplitude (milliamperes or volts), pulse duration (milliseconds), charge (microcoulombs), or energy (microjoules). Voltage output: The amount of voltage being delivered to the heart every time the pacemaker emits a stimulus. It is expressed in volts (V).

Impedance (R): Resistance of flow of current across the lead. Used to measure lead integrity over time. High or low values can indicate lead fracture. Pulse width (or pulse duration): The length in milliseconds the voltage is delivered to the heart. Strength–duration curve: The hyperbolic relationship between the voltage output and the pulse width that defines the stimulation threshold (Fig. 30.2). Sensing: Sensing occurs when the electrical wave front through the myocardium passes directly underneath the electrode. Atrial sensitivity: A programmed parameter that defines the largest signal that will be ignored by the device and thus determines which signals are detected by the pacemaker or implantable cardioverter/defibrillator (ICD) in the atrial channel. Atrial sensing in the dual-chamber pacing mode, DDD, will inhibit the atrial stimulus which would occur at the end of the atrial escape interval (V-to-A interval), initiate the AV interval, and trigger the ventricular output at the end of the AV interval. Ventricular sensitivity: A programmed parameter that defines the largest signal that will be ignored by the device and thus determines which signals are detected by the pacemaker or ICD in the ventricular channel. Ventricular sensing in the dual-chamber pacing mode, DDD, will inhibit both atrial and ventricular stimuli that were scheduled to be output at the end of the atrial escape interval (atrial) or AV interval (ventricle) and initiate a new atrial escape interval (V-to-A interval). Atrial oversensing: Sensing on the atrial channel that occurs due to signals on the atrial lead either related to signals originating outside the atrium, such as far-field ventricular signals, myopotentials from the pectoralis major muscle or diaphragm, or from noise originating from a dysfunctional lead (insulation or conductor fractures or a loose set screw). Depending on the mode of pacing, atrial oversensing will either inhibit or trigger atrial and/or ventricular stimuli. Ventricular oversensing: Sensing on the ventricular channel that occurs due to signals on the ventricular lead either relating to signals originating outside the ventricle, such as myopotentials from

the pectoralis major muscle in a unipolar lead system or from lead dysfunction secondary to insulation or conductor fracture or loose set screws. Sometimes the ventricular channel will oversense the atrial paced output and inhibit the ventricular output. This is called crosstalk inhibition and is usually prevented by a blanking of the ventricular sensing amplifier during the atrial paced outputs. Chronotropic competence: The ability to match cardiac output to the metabolic needs of the body by appropriate modification of the heart rate. Minimum rate: Also called the escape rate, this is the slowest rate at which the pacemaker will allow the heart to beat. The minimum paced rate is calculated by the ventricular paced or sensed event to atrial paced output interval plus the programmed A–V delay measured in milliseconds and converted to rate by dividing 60,000 by that sum. V–A interval: Also called the atrial escape interval, this is calculated by subtracting the paced AV interval from the minimum rate interval. It is initiated by a paced or sensed ventricular event and concludes with a paced atrial event or is interrupted by either an atrial or ventricular sensed event. A–V delay: This programmed interval is initiated by an atrial sensed or paced event and is terminated with a ventricular paced stimulus unless interrupted by a ventricular sensed event (either a conducted beat through the AV node or a premature ventricular beat). Often AV delays initiated by sensed atrial events are programmed to be shorter than AV delays initiated by atrial paced events. Upper rate limit: The fastest rate at which the ventricular channel can track intrinsic P waves or, in the case of rate-adaptive pacing on the basis of a sensor, the fastest rate at which the ventricular channel can track the sensor rate algorithm. The atrial tracking or upper rate limit is constrained by dividing 60,000 by the sum of the sensed AV delay and the postventricular atrial refractory period (PVARP). PVARP: This is the Post-Ventricular Atrial Refractory Period. The PVARP is the timeframe during which the atrial channel is refractory after either a paced or sensed (R wave) ventricular event.

Its purpose is to prevent atrial sensing and tracking of any V–A (retrograde) conduction of ventricular events to the atrium that would trigger a pacemaker-mediated tachycardia (see later).

FIGURE 30.2 The strength–duration curve.

Programming Device programming has become more complex as dual-chamber pacing systems have become ubiquitous and biventricular pacing is becoming common place. It is important to note that the basic parameters discussed above can usually be derived with caliper measurements of the intervals observed on a 12-lead electrocardiogram (ECG) or rhythm strip. Following is a concise review of programming codes and timing cycles that provide the underpinnings of device programming.

Codes A standard coding system has been adopted to delineate the basic settings of the device as follows: The first designation is the chamber paced, the second designation is the chamber sensed, the third designation is the device

response to a sensed event, and the final designation reflects the rateadaptive status of the device. There is a fifth position in the code that was originally used to indicate the antitachycardia response that the device will provide during a tachycardia, but now indicates whether multisite pacing is present or not. Table 30.2 reviews the mode codes in detail.

Table 30.2 Mode Codes for Cardiac Pacemakers

As an example, a DDIR pacemaker can pace in both the atrium and the ventricle, and sense activity in both the atrium and the ventricle. Further, it will inhibit upon sensing intrinsic activity, and it has rate-adaptive functionality as well. A VOO device will pace the ventricle asynchronously, without sensing intrinsic activity.

Timing Cycles When a dual-chamber device paces the atrium, the ventricular channel is blanked for a period of 20 to 40 ms as a safety feature to prevent inhibition of the ventricular channel by far-field (ventricular) sensing of the atrial paced output. The blanking period prevents “crosstalk inhibition,” which could cause, in patients with complete lack of AV conduction, a string of atrial paced events and ventricular asystole. After the blanking period, the ventricular channel is open to sensed events. Typically, the first 100 ms is the safety alert period. If, during this alert period a sensed event occurs, then the AV interval is abbreviated, usually to 120 ms. This abbreviated AV delay is designed to prevent pacing during the vulnerable period of the ventricle, for instance, when the sensed event is caused by a premature ventricular depolarization. During the remainder of the AV delay (after the blanking and safety alert period), any sensed ventricular event will cause the ventricular

output to be inhibited and reinitiate the atrial escape interval. If by the end of the programmed AV interval no event has been sensed, the device will pace the ventricle. After every paced or sensed ventricular event, a PVARP is initiated. During this period, the atrial channel is refractory to detecting atrial activity. The purpose of the PVARP is to prevent detection of atrial activity produced by retrograde conduction through the AV node. Without making the atrium refractory to retrograde atrial events (V-to-A conducted beats), an endless loop cycle can be set up that continues until the retrograde conduction fails. This endless loop tachycardia is one of several types of pacemaker-mediated tachycardia (see Fig. 30.1 for a schematic of pacemaker timing cycles in comparison to the surface ECG).

Diagnostics Modern pacing devices are capable of storing tremendous amounts of data and reporting data in a variety of usable formats. Following is a brief review of device diagnostics and their applications. Histograms: Histograms are a statistical report of a parameter describing the relative frequency of an event relative to time, heart rate, or another parameter. Histograms do not correlate symptoms to specific events, and from them one can only infer cause and effect (Fig. 30.3). Trends: Trends evaluate the progression of a parameter over time. They are not a statistical representation but instead describe the correlation of an activity over time with symptoms. Trends can document concurrence of patient and rhythm events if interrogated quickly after the event occurs. Trends require extrapolation to connect patient and rhythm events (see Fig. 30.3). Event monitoring: Event monitoring captures an exact record of an event as characterized by electrograms, marker channel, and intervals. These monitored records are not statistical reflections of data but the actual recordings. Therefore, they can capture the relationship of symptoms and objective data. They require neither inference nor extrapolation (see Fig. 30.3).

FIGURE 30.3 Histogram: ventricular hysteresis.

Troubleshooting and Complications While pacemaker implantation is a low-risk procedure, proper device follow-up and troubleshooting must be done to ensure pacemaker integrity. Device troubleshooting most often involves interrogation of the device and adjustment of the pacing mode or timing cycles in order to optimize device function. Further, device interrogation using a programmer can reveal diagnostic information about the integrity of the leads, status of the battery, and performance of the device’s algorithms, including the behavior of the rate-adaptive sensor function. A review of some specific device troubleshooting issues follows. Pacemaker Mediated Tachycardia Endless loop tachycardia is a type of pacemaker-mediated tachycardia specific to dual-chamber devices programmed to the VDD or DDD mode. Endless loop tachycardia is triggered by the atrial channel sensing retrograde conduction of a paced ventricular impulse. In response to the sensed event, the ventricle is paced again after the set AV interval, and retrograde conduction to the atrium recurs. As the atrium senses the retrograde V–A signal, the cycle begins again. The phenomenon is terminated by either applying a magnet to the

device, thus reverting the device to nominal asynchronous pacing, or by reprogramming the device to lengthen the PVARP so that the atrial channel is refractory during the retrograde (V–A) conduction.

Pacemaker Syndrome The so-called pacemaker syndrome is a constellation of physical symptoms and signs associated with loss of AV synchrony, most commonly associated with VVI pacing. Affected patients suffer weakness, dizziness, lightheadedness, dyspnea on exertion, and sometimes even orthopnea and dyspnea at rest, independent of their underlying ventricular function. The symptoms result from ventricular pacing, typically with retrograde atrial conduction, which produces atrial contraction against a closed AV valve. The decrease in efficiency associated with loss of atrial kick as well as the increased back pressure within the pulmonary circuit both contribute to the symptomatology. Similar symptoms and physiology can result from atrial pacing with delayed AV conduction. The result is also related to atrial contraction against a closed AV valve. The treatment for pacemaker syndrome is device upgrade to a dual-chamber device. An atrial tracking ventricular pacemaker eliminates the physiologic underpinnings of pacemaker syndrome and typically alleviates the symptoms.

Pacing-Induced Cardiomyopathy A certain subset of patients who are being paced the majority of time with a single ventricular lead may develop pacing-induced cardiomyopathy, which is likely secondary to deleterious neurohormonal remodeling from RV pacing. Therefore, devices are set to minimize RV pacing. Nevertheless, patients with pacemakers should be interrogated about their heart failure symptoms and echoes should be considered in follow-up in patients with pacemakers who there is a strong suspicion for pacing-induced cardiomyopathy. Patients who have developed pacing-induced cardiomyopathy should be considered for upgrade to a CRT device given that the majority will see an improvement in their LVEF and symptoms. In patients with reduced LVEF who have an indication for pacing and high likelihood for having a significant pacing burden, it is reasonable to consider implanting a BiV device instead of a single ventricular lead pacemaker.

Lead Fracture/Failure Lead fracture is the term used to describe failures in the integrity of the lead wires, insulation, and/or coil. Fractures often occur at the ingress of the lead into the thorax within the subclavian vein as it passes between the clavicle and the first rib, particularly at the suture sleeve, due to tight ligatures or a sharp angulation of the lead in the pacemaker pocket. Crush injuries and chronic abrasion at this site are common etiologies of lead fracture. Disruption of the insulation causes a significant reduction of the pacing impedance and is often manifest by intermittent oversensing and either failure to produce a paced output or failure to capture the heart. Disruption of the lead conductor causes an increase in the pacing impedance and can also be manifest by intermittent oversensing and failure either to produce a paced output or to capture the heart. After the ECG, the chest x-ray is often the first diagnostic modality to reveal a lead fracture. Device interrogation typically suggests the diagnosis (abnormally high or low lead impedance, as noted in the previous section).

Infection/Erosion Device infection occurs most commonly from bacterial contamination at the time of device implantation. Most infections do not present within the first month after implantation but are manifest within the first 2 years after implantation. Some infections can be indolent and persist for years before becoming apparent. The most commonly responsible organisms are Staphylococcus species, with gram-negative organisms occurring predominantly in diabetic patients or those otherwise immunocompromised. Physical findings associated with device infection may range from normal pocket appearance to mildly erythematous overlying tissue, to a swollen, boggy pocket and incision line. Occasionally a device will erode through the skin in the setting of a chronic device infection. When the pocket appears normal, the infection is typically endovascular and is unmasked by the presence of fevers and positive blood cultures along with supportive findings from transesophageal echo or chest CT scan. Less commonly, device infection can occur secondary to bacterial endocarditis or other bloodstream infection. Vegetations can sometimes be observed on the leads, most commonly utilizing transesophageal echocardiography.

The treatment for device infection with or without endocarditis is with antibiotics and device and lead extraction. The replacement device cannot be reimplanted at the time of device and lead extraction but should be delayed for few days or longer until it is deemed appropriate from the infectious disease stand point. Not all patients require immediate reimplant after extraction and the indication should be reinvestigated prior to reimplant. The reimplant is usually performed on the contralateral side.

Extraction The most compelling reason for lead extraction is device–related infection, either localized to the pocket or endovascular with associated bacteremia or endocarditis. Other reasons for extraction may include lead migration, untreatable thrombosis or embolism of the lead or lead fragment, or, compromise of venous flow from multiple leads, risking subclavian or superior vena cava (SVC) occlusion with symptoms, or prevent the addition of leads for upgrade to an ICD or BiV system. Lead extraction can range from simply applying traction to a recently implanted lead, to the use of mechanical, electrosurgical, or excimer laser extraction sheaths to facilitate the removal of fibrosed leads from the endovascular surface. Lead extraction using these devices can be complicated by serious bleeding complications leading to tamponade and even death and are thus best relegated to experienced operators in large volume centers.

IMPLANTABLE DEFIBRILLATORS

CARDIOVERTER–

ICDs initiated a new era in the treatment of ventricular tachyarrhythmias. In contrast to modern devices, the early ICD systems were implanted via thoracotomy with epicardial placement of defibrillating patches and sensing electrodes and abdominal implantation of the device can. The devices themselves had no programmability, no significant diagnostics, and an abbreviated battery life of about 1 year. Patients requiring permanent pacing had to have a separate pacing device implanted. Over time, ICD components have reduced in size, allowing for prepectoral implantation with transvenous

leads, possess bradycardia and antitachycardia pacing (ATP), and hundreds of programmable parameters, diagnostics, and event storage, all while device longevity has expanded to 5 to 7 years. The devices now have full pacing and resynchronization capabilities as well.

Indications Indications for implantation of ICDs have expanded greatly over the past decade, based on data collected from the major ICD trials and are summarized in Table 30.3. It is very important to note that all these indications require a reasonable expectation of survival with an acceptable functional status for at least 1 year. ICDs are not indicated for patients with incessant ventricular tachycardia (VT) or ventricular fibrillation (VF), NYHA Class IV patients with drug refractory heart failure who are not transplant candidates or candidates for a CRT device, patients with significant psychiatric illnesses, when VF or VT is amenable to surgical or catheter ablation (e.g., atrial arrhythmias associated with Wolf–Parkinson– White [WPW] syndrome, right ventricular outflow tract [RVOT] or left ventricular outflow tract [LVOT], idiopathic VT in the absence of structural heart disease), or patients with ventricular arrhythmias due to a completely reversible disorder in the absence of structural heart disease.

Table 30.3 Indications for ICDs

Class I • Survivors o f a cardiac arrest due to VF or hemodynamically unstable su stained VT after exclusio n of a ny reversible causes • Structural heart disease and spon taneous sustained VT • Syncope of undetermined origin and inducible sustained unsta ble VT or VF at EPS • LVEF:::; 35 % due to p rior MI who are a t least 40 days post MI and are NYHA Class II or III • LVEF:::; 30%, due to prior MI who are at least 40 days post MI, and are NYHA class I • LVEF:::; 40 % due to prior MI, with nonsustained VT and inducible VF or sustained VT at EP study • LVEF :::; 35 % in nonischemic DCM and NYHA Class II or III

Class Ila • Unexplained syncope, significant LY dysfunction, and nonischemic DCM • Sustained VT and normal or near-normal ventricular function • H CM with o ne or more major risk factors for SCD • Arrhythmogenic right ventricular dysplasia/cardiom yopathy who have 1 or mo re risk factor for SCD • Long QT syndrome with syncope and/or VT while on beta-blockers • No nhospita lized patients awaiting transpla ntation • Brugada syndrome with syncope or documented VT that has not resulted in cardiac arrest • Catecho laminergic polymorphic VT with syncope and/or documented VT while receiving beta-blockers • Cardiac sarcoidosis, giant cell m yocarditis, o r Chagas di sease

Class llb • LVEF:::; 35 % in nonischemic DCM and NYHA Class I • Long QT syndrome and risk factors for SCD • Syncope with structural heart disease in whom thorough invasive and noninvasive testing have failed to define a cause • Familial cardiomyopathy associa ted with SCD • LY no ncompaction syndrome

VF, ventricular fibrillation; VT, ventricular tachycardia; EPS, electrophysiology study; LVEF, left ventricular ejection fraction; MI, myocardial infarction; NYHA, New York Heart Association; HCM, hypertrophic cardiomyopathy; SCD, sudden cardiac death; DCM, dilated cardiomyopathy.

The Center for Medicare and Medicaid Services (CMS) published updated guidelines in 2005 for reimbursement for ICD implantation, recognizing the data from the primary and secondary prevention trials of ICDs with and without capacity for cardiac resynchronization. The practical (reimbursed) indications for ICD implantation are listed in Table 30.4.

Table 30.4 CMS-Approved (Reimbursed) Indications for ICD Therapy

VF, ventricular fibrillation; VT, ventricular tachycardia; EPS, electrophysiology study; MI, myocardial infarction; HCM, hypertrophic cardiomyopathy; LVEF, left ventricular ejection fraction; NYHA, New York Heart Association; CABG, coronary artery bypass grafting; PCI, percutaneous coronary intervention; DCM, dilated cardiomyopathy. Providers must be able to justify the medical necessity of devices other than single-lead devices.

Devices The current generation of ICDs includes single-chamber VVI devices, dualchamber devices with fully programmable pacing capabilities, and CRT devices capable of biventricular pacing and antitachycardia therapies. As technology has progressed, these devices have become smaller, with better longevity and greater programmability. The diagnostics available allow for extensive troubleshooting and event monitoring.

Lead Systems Typically, single-chamber ICD systems are implanted using active- or passive-fixation multipolar leads with shocking coils that lie in the RV apposed to the endocardium as well as the SVC. With this configuration, the device can deliver energy from the RV (+) coil to the SVC (−) coil or vice versa, or from either coil (+) to the ICD can (−) itself or vice versa. Various investigations have demonstrated that defibrillation thresholds (DFTs) can be reduced using optimal polarity and an “active can” configuration. ICDs can be attached to epicardial leads or patches implanted during surgery. These leads are typically placed using minimally invasive techniques for patients with high DFTs or during open heart surgery performed for other indications. Subcutaneous arrays and even azygous vein leads can be placed. Virtually all ICDs are implanted with transvenous in lieu of surgically placed leads. Dual-chamber devices possess an atrial lead in addition to the ventricular shocking coil lead. The atrial lead is typically a standard bipolar pacing lead without a shocking coil and plays no role in defibrillation. Newer subcutaneous ICDs deliver shocks via left lateral generator and a subcutaneous left parasternal lead. These devices are MRI compatible and preferred in patients who do not need pacing therapy, younger, and/or have had previous transvenous device infections.

Implantation The most common site for device implantation is the left prepectoral space. This site gives access to the left subclavian vein for transvenous lead placement. Especially in “active can” configurations, this site of implantation allows for lower DFTs as the path for energy transmission from can to coil or vice versa traverses the LV myocardium. In the case of prior device infection, scarring, subclavian stenosis, or mastectomy on the left side, the right prepectoral space may be used. Lead implantation technique is much like that used for standard pacing lead implantation; however, there is an impetus to implant the lead tip at the RV apex so that the RV shocking coil rests completely within the right ventricle. The subcutaneous ICD is placed in the 4th to 5th intercostal space in the left axillary region with a subcutaneous parasternal lead tunneled across the rib in a position located just left of the patient’s sternum.

Device Function Detection ICDs have a variety of programmed routines designed to aid in the detection and verification of VT and VF, and to minimize the number of inappropriately delivered therapies. The device must be able to sense low-amplitude highrate signals in VF, while not oversensing far-field atrial activity or ventricular repolarization. Appropriate sensing thresholds must be achieved at the time of implantation, or the device cannot be relied on to appropriately detect and treat malignant ventricular arrhythmias. Detection algorithms utilize counters, and detection criteria are based on signal counts registered faster than the tachycardia threshold criterion programmed into the device. For example, if an ICD is programmed to detect VT at cycle lengths of 10-fold. . Tobacco is one of the leading preventable causes of mortality in the United States. C. Lower annual income, less education, mental illness, LGBT, and HIV were all associated with increased risk for tobacco use. D. The overall prevalence of smokers has steadily increased over the past decade.

3.

Which of the following is not considered a criterion for the metabolic syndrome? Having a fasting blood glucose ≥100 mg/dL Undergoing treatment for hypertension Having a body mass index (BMI) ≥ 30 Triglycerides ≥150 mg/dL

4.

A. . C. D.

5.

Treatment with statins has been shown to reduce the incidence of major cardiovascular events in nonhyperlipidemic patients with which elevated risk biomarker?

A. . C. D.

High-sensitivity C-reactive protein (hsCRP) Lp-PLA2 Lp(a) Homocysteine

ANSWERS 1.

Correct Answer: C. Blacks Black Americans have the highest mortality rate relative to all other races. Additionally, blacks are more likely to suffer from hypertension, diabetes, and obesity.

2.

Correct Answer: C. Alcoholism Tobacco, hyperlipidemia, hypertension, diabetes, and obesity are the five modifiable risk factors that account for half of CVD mortality in the United States. Other risk factors identified by the INTERHEART study that contribute to risk of index MI include sedentary lifestyle, alcoholism, low intake of fruits and vegetables, and psychosocial index.

3.

Correct Answer: D. The overall prevalence of smokers has steadily increased over the past decade. The highest incidence of new smokers is observed in persons 80% of all smokers started smoking when 1 mm resting STsegment depression, and complete left bundle branch block (ACC/AHA Class III recommendation). Certain medications such as digitalis may also produce abnormalities in the resting ECG, which render it uninterpretable for ischemic changes during stress. The diagnostic accuracy of exercise stress ECG has been studied extensively. The mean sensitivity and specificity for detecting significant CAD is 68% and 77%, respectively. Although exercise ECG is less sensitive than stress tests performed with imaging modalities, particularly in women, it remains the primary noninvasive tool for both the diagnosis and risk stratification of patients with suspected CAD and interpretable ECGs. As a diagnostic tool, exercise ECG testing is most useful in patients with stable chest pain syndromes and an intermediate risk of CAD (ACC/AHA Class I recommendation). In the 2012 ACC/AHA guidelines, exercise ECG also carries a Class IIa recommendation in patients with stable chest pain and a low risk of CAD. However, in patients with high risk for CAD, stress testing with advanced imaging (echocardiography or myocardial perfusion imaging [MPI]) is preferred over exercise ECG alone. In addition to the ECG

portion, there are other variables that contribute to the interpretation of the test. The usual definition for a positive exercise ECG test is 1 mm or more of ST-segment elevation or horizontal or downsloping ST-segment depression at point 60 to 80 ms after the QRS complex during exercise or recovery. Additionally, symptoms, exercise capacity, and hemodynamic and rhythm response to exercise should be considered. The most important prognostic variables measured during exercise testing are exercise capacity, typically expressed in metabolic equivalents of task (METs), and exercise-induced ischemic ST-segment changes. The Duke treadmill score (DTS) integrates these two objective variables with the subjective presence or absence of anginal symptoms to generate a risk score that separates patients into high-, moderate-, and low-risk subsets (5%, 1.25%, and 0.25% annual mortality rates, respectively) (Table 38.2). Patients with high-risk DTSs frequently have left main or three-vessel CAD that would benefit from revascularization, and these patients should be referred for coronary angiography. Low-risk patients, on the other hand, have an excellent prognosis that is unlikely to improve with further evaluation or revascularization and thus can be treated safely with medical therapy.

Table 38.2 Duke Treadmill Score

From Mark DB, Shaw L, Harrell FE Jr, et al. Prognostic value of a treadmill exercise score in outpatients with suspected coronary artery disease. N Engl J Med. 1991;325(12):849-853, with permission from the Massachusetts Medical Society.

Echocardiography Most patients undergoing a diagnostic evaluation for stable angina do not require echocardiography. More specifically, in patients with a normal ECG, no history of prior MI, and no clinical signs or symptoms of heart failure, valvular disease, or hypertrophic cardiomyopathy, routine echocardiography is not indicated. An exception is when there is a murmur suspicious for aortic stenosis or hypertrophic cardiomyopathy on physical examination, as these diagnoses may produce symptoms of chronic stable angina in the absence of obstructive CAD.

Stress Testing with Nuclear or Echocardiographic Imaging Although stress imaging modalities have greater diagnostic accuracy than does exercise electrocardiography, the increased cost of these tests precludes their routine use in all patients with suspected CAD. Most commonly, nuclear

(single positron emission computed tomography [SPECT] or positron emission tomography [PET]) or echocardiographic stress imaging is reserved as first-line testing in patients with abnormal baseline ECGs (i.e., preexcitation, resting ST-segment depression ≥1 mm) or with symptoms and history of prior revascularization (percutaneous coronary intervention [PCI] or coronary artery bypass grafting [CABG]) (ACC/AHA Class I recommendation). In general, patients who are able to exercise with at least moderate physical functioning should undergo exercise rather than pharmacologic stress testing regardless of the modality of imaging selected (ECG, echocardiography, MPI, CMR). However, there are certain unique exceptions to this rule. In patients with either paced ventricular rhythms or left bundle branch block, pharmacologic stress testing is preferred over exercise stress testing due to the difficulty with interpreting echocardiographic wall motion or MPI in these conditions (ACC/AHA Class I recommendation). For patients who are unable to exercise, pharmacologic stress MPI and dobutamine stress echocardiography are both valid options (ACC/AHA Class I recommendation). For a summary of the ACC/AHA recommendations, see Table 38.3.

Table 38.3 ACC/AHA Recommendations for Exercise ECG Testing and Stress Imaging Studies in Patients with Suspected Stable CAD

CABG, coronary artery bypass grafting; CAD, coronary artery disease; ECG, electrocardiogram; LBBB, left bundle branch block; LV, left ventricular; MPI, myocardial perfusion imaging; PCI, percutaneous coronary intervention. From Fihn SD, Gardin JM, Abrams J, et al. ACC/AHA 2012 guideline for the diagnosis and management of patients with stable ischemic heart disease: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines, and the American College of Physicians, American Association for Thoracic Surgery, Preventive Cardiovascular Nurses Association, Society for Cardiovascular Angiography and Interventions, and Society of Thoracic Surgeons. J Am Coll Cardiol. 2012;60(24):e44-e164, with permission.

As mentioned, stress MPI has a higher sensitivity for the diagnosis of CAD than exercise ECG in patients with intermediate risk. The data vary depending on the population studied, but generally the sensitivity is accepted to be around 90% for MPI. Similar numbers are seen with exercise stress echocardiography (sensitivity around 85%) and dobutamine echocardiography (sensitivity around 82%). The choice of test depends on both patient characteristics and local expertise in performing the different imaging modalities. There are some special populations or situations in which exercise stress imaging should be considered over exercise ECG. Women have an overall lower prevalence of CAD than men and thus have a lower pretest probability

of disease, making false-positive exercise ECGs more common. The higher sensitivity of stress imaging, therefore, could theoretically improve on the positive predictive value of the exercise ECG. Additionally, elderly patients are oftentimes less able to exercise due to comorbid medical conditions or deconditioning. Therefore, pharmacologic stress imaging may be the test of choice in this population. As with exercise electrocardiography, stress imaging results can also provide prognostic information, separating patients who are appropriate for medical therapy (low risk, ≤1% annual mortality) from those who may benefit from further angiographic evaluation and possible revascularization (intermediate risk, 1% to 3%; high risk, ≥3% annual mortality) (Table 38.4).

Table 38.4 Risk Stratification Based on Findings of Noninvasive Testing

DTS, Duke treadmill score; EF, ejection fraction; HR, heart rate; LV, left ventricular. From Fihn SD, Gardin JM, Abrams J, et al. ACC/AHA 2012 guideline for the diagnosis and management of patients with stable ischemic heart disease: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines, and the American College of Physicians, American Association for Thoracic Surgery, Preventive Cardiovascular Nurses Association, Society for Cardiovascular Angiography and Interventions, and Society of Thoracic Surgeons. J Am Coll Cardiol. 2012;60(24):e44-e164, with permission.

Coronary Angiography Coronary angiography may be performed noninvasively with gated cardiac computed tomography angiography (CTA) or with invasive coronary angiography, which remains the gold standard diagnostic test for CAD. Coronary CTA offers noninvasive anatomic evaluation of patients with stable or unstable chest pain syndromes, and the merit of anatomic versus functional (ischemia-based stress testing modalities) is an area of ongoing investigation. The 2012 ACC AHA guidelines give a class IIa indication for coronary CTA in patients with indeterminate results of functional testing and a class IIb recommendation for coronary CTA as an alternative to invasive angiography in patients with moderate- to high-risk functional testing. The more recent SCOT-HEART trial, published in 2018, was a randomized trial evaluating the role of coronary CTA versus standard care in 4,146 patients. The primary endpoint of coronary death or nonfatal MI at 5 years was significantly reduced in the coronary CTA group (2.3% vs. 3.9%, p = 0.004). The rates of invasive angiography and revascularization were similar between groups, but preventive and medical therapies were employed more commonly in the CTA group. The relative merit of routine anatomic testing with coronary CTA in patients with suspected CAD is an area of ongoing evaluation. Invasive coronary angiography remains the gold standard test for CAD and is able to provide anatomic definition of disease extent and severity as well as prognostic information, identifying those patients who would achieve survival benefits related to surgical revascularization. Specifically, from the early studies of CABG, patients with severe left main trunk stenosis, threevessel disease, and two-vessel disease involving the proximal left anterior descending (LAD) coronary artery are known to derive a survival benefit with bypass surgery over medical therapy. In general, coronary angiography is performed in patients with stable chest pain syndromes when noninvasive tests are inconclusive or cannot be performed, when clinical evaluation or noninvasive testing suggests high-risk features (see Table 39.4), and when symptoms persist despite appropriate medical therapy. Less commonly, diagnostic coronary angiography is recommended for patients in whom coronary artery spasm is suspected, for those with occupations that necessitate a definitive diagnosis (e.g., pilots, police, professional athletes), and for survivors of sudden cardiac death. For

the list of ACC/AHA recommendations related to coronary angiography, see Table 38.5.

Table 38.5 Appropriate Use Criteria for Coronary Angiography in Stable Angina Pectoris

CAD, coronary artery disease; CTA, computed tomography angiogram; ECG, electrocardiogram; LV; left ventricular; MPI, myocardial perfusion imaging; MRI, magnetic resonance imaging; PCI,

percutaneous coronary intervention. From Patel MR, Bailey SR, Bonow RO, et al. ACCF/SCAI/AATS/AHA/ASE/ASNC/HFSA/HRS/SCCM/SCCT/SCMR/STS 2012 appropriate use criteria for diagnostic catheterization. J Am Coll Cardiol. 2012;59(22):1-33.

For patients determined to be at low risk of adverse events, medical therapy alone is usually sufficient and may be superior to an invasive approach. For the moderate- or high-risk subsets, there is older evidence from randomized trials that medical therapy coupled with surgical revascularization improves long-term survival over medical therapy alone. Therefore, the judicious use of noninvasive and invasive studies can help establish the diagnosis of CAD while simultaneously performing the critical risk stratification that is essential in determining the appropriate risk-reducing treatment strategies, from medical therapy alone to medical therapy plus revascularization.

Summary Chest pain is the most common initial presenting symptom for patients diagnosed with CAD. Although coronary angiography provides powerful prognostic information and remains the gold standard for diagnosis, noninvasive tests are often more appropriate initial tools for patients with low or intermediate clinical predictors of CAD. Even for patients with a high pretest probability of CAD, noninvasive testing can be a useful prognostic tool that allows for selection of patients who warrant further invasive evaluation.

MEDICAL TREATMENT FOR STABLE ANGINA There are two primary goals of medical treatment for chronic stable angina: (a) prevent cardiovascular events (MI, death) and (b) improve quality of life by decreasing anginal symptoms and improving functional capacity. However, the process of atherosclerosis cannot be reversed by medications or by revascularization procedures. Lifestyle changes can and do influence the disease course and are most often underutilized in the treatment of

patients with stable CAD. Lifestyle changes are inexpensive, readily available, and very effective but require a motivated patient as well as support and emphasis from the physician. Lifestyle changes should be implemented first-line and should be complementary to medical therapy. PCIs became increasingly more common in the late 1990s and early 2000s due to an overall favorable effect on reducing anginal symptoms in numerous studies of PCI versus medical therapy in CAD. The early metaanalyses of these studies did not show a reduction in mortality or MI incidence compared with medical therapy alone in these patients. As mentioned previously, CABG does have clear-cut long-term survival benefits versus medical therapy alone, but only in a minority of patients with high-risk angiographic features. An initial trial of medical therapy, therefore, remains the mainstay of treatment for the majority of patients with chronic, stable CAD. This is achieved through a combination of therapies that target both ischemic symptoms and modifiable risk factors known to aggravate angina and cardiovascular disease. Medications known to reduce the risk of MI and death receive the highest priority. Medications aimed at improving quality of life by reducing the frequency and severity of anginal episodes serve as important supplementary therapies. Underuse of guideline-directed medical therapy remains an important area for quality improvement in the care of patients with stable CAD. A review of five clinical trials of revascularization versus medical therapy in CAD revealed that overall compliance with medical therapy was low (67% at 1 year, 53% at 5 years) across treatment arms.

Medical Therapy to Reduce Cardiovascular Events Antiplatelet Therapy The benefit of aspirin in a broad spectrum of patients with both stable and unstable atherosclerotic syndromes has been well established for decades. Aspirin exerts its antiplatelet effects by inhibiting cyclooxygenase, thus preventing the release of the prothrombotic platelet-aggregant thromboxane A2. Although it does not improve symptoms, clinical trials of aspirin in patients with chronic stable angina have demonstrated risk reductions for adverse cardiac events that are of a magnitude similar to that seen in patients with ACS. In the Swedish Angina Pectoris Aspirin Trial, the largest

randomized trial of aspirin therapy for chronic stable angina, the addition of 75 mg of aspirin to sotalol resulted in a 34% reduction in the primary composite endpoint of MI and sudden death and a 22% to 32% reduction in the measured secondary vascular endpoints (vascular death, all-cause mortality, and stroke). A similar 33% reduction in adverse cardiovascular events (vascular death, stroke, and MI) was demonstrated among 2,920 patients with stable angina included in a meta-analysis performed by the Antithrombotic Trialists’ Collaboration. Therefore, aspirin, administered at 75 to 162 mg daily, is first-line therapy in all chronic CAD patients (ACC/AHA Class I recommendation). P2Y12 receptor inhibitors are a second class of antiplatelet agents that exert their effects by inhibiting the binding of adenosine diphosphate (ADP) to receptors on the platelet surface, thus preventing platelet activation. Without platelet activation, the glycoprotein IIb/IIIa receptor is unable to undergo a conformational change, which then makes it unable to bind fibrinogen or von Willebrand factor. In this manner, platelet aggregation is inhibited. There are currently five drugs in this class on the market: ticlopidine, clopidogrel, prasugrel, ticagrelor, and cangrelor. Ticlopidine, clopidogrel, and prasugrel are thienopyridines, which are prodrugs that are converted to an active metabolite by the cytochrome P 450 system and irreversibly bind the platelet P2Y12 receptor. Ticagrelor and cangrelor are nonthienopyridines, which are active drugs that reversibly bind the platelet P2Y12 receptor. Ticlopidine, is the oldest drug in this case, and is no longer used due to an unfavorable side effect profile, which included a risk of neutropenia as well as thrombotic thrombocytopenic purpura. Clopidogrel, prasugrel, and ticagrelor are the three oral P2Y12 inhibitors in common use in contemporary practice. In the Clopidogrel versus Aspirin in Patients at Risk for Ischemic Events (CAPRIE) trial, clopidogrel appeared to be more effective than aspirin, with an overall 8.7% reduction in the combined primary endpoint (MI, vascular death, or ischemic stroke), in high-risk CAD patients (i.e., those with recent MI or stroke or with symptomatic peripheral arterial disease). Therefore, in stable CAD without stenting, clopidogrel may serve as an acceptable alternative in patients intolerant of aspirin, (ACC AHA Class 1B recommendation). However, in the CHARISMA trial, the combination of aspirin and clopidogrel was not

more effective than aspirin alone in high-risk primary prevention or secondary prevention patients. A meta-analysis of five randomized controlled trials (including CHARISMA) of aspirin monotherapy versus aspirin and clopidogrel dual antiplatelet therapy (DAPT) in the treatment of CAD revealed that DAPT was associated with a 6% relative risk reduction in all-cause mortality, 18% relative risk reduction in MI, and 18% relative risk reduction in stroke compared with aspirin monotherapy. However, DAPT was associated with a 26% relative increase in the risk of major bleeding. Current ACA AHA guidelines give a class IIb recommendation that DAPT with aspirin and clopidogrel may be reasonable in high-risk patients with stable CAD. In patients with stable CAD treated with coronary stents, clopidogrel is often the P2Y12 inhibitor of choice to be given with concomitant aspirin as DAPT poststenting. Prasugrel and ticagrelor are newer, higher potency P2Y12 inhibitors that are commonly used in ACS patients. These agents have higher bleeding risk profile compared with clopidogrel, and their use is uncommon in stable CAD patients. Cangrelor, a newer intravenous P2Y12 inhibitor, has a role in procedural platelet inhibition during and immediately following PCI but has no role in the long-term management of CAD. The ACC AHA guidelines on DAPT duration were updated in 2016. In the most recent iteration, patients with stable CAD who are not at high risk (no history of MI, PCI, or CABG within 12 months) are not recommended to be treated with DAPT. Those with stable CAD treated with PCI with a bare metal stent are recommended to have 1 month of DAPT (class 1 recommendation) and those treated with a drug-eluting stent (DES) are recommended to have at least 6 months of DAPT (class 1 recommendation) and longer duration >6 months may be reasonable in the absence of high bleeding risk or overt bleeding (class IIb recommendation). In patients treated with DESs who are at high bleeding risk or suffer from overt bleeding, there is a class IIb recommendation that discontinuation of DAPT after 3 months may be reasonable, reflecting the safety of current-generation DESs that have a very low rate of late stent thrombosis. Patients treated with CABG for stable CAD have a class IIb recommendation that DAPT may be reasonable for 1 year.

Lipid-Lowering Therapy

The benefit of LDL-lowering statin therapy in the management of stable CAD is well established. Multiple clinical trials have demonstrated reduction in cardiovascular event rates in statin-treated patients with known vascular disease, and there appears to be a dose-dependent relationship by which more intensive statin therapy is associated with lower event rates. For this reason, use of a moderate- to high-intensity statin in stable CAD has an ACCAHA class 1A indication. In addition to improving outcomes, nuclear studies have demonstrated that statin therapy improves myocardial perfusion and reduces ischemia on ambulatory ECG monitoring in stable angina patients with both high and normal serum cholesterol levels. In patients with medically refractory angina that is not amenable to revascularization, aggressive lipid reduction with 80 mg daily of atorvastatin (LDL goal 80% proximal LAD coronary stenosis, and preserved left ventricular function to medical therapy, CABG using an IMA graft, or PTCA. There was no difference in survival or MI between the treatment arms at 3 years. Angina was improved compared to medical therapy following either form of revascularization, although initial CABG provided greater relief and fewer repeat procedures than initial PTCA. A separate trial out of Lausanne, Switzerland, which did not include a medical treatment arm, reported similar survival and symptomatic benefit at 5-year follow-up among 134 patients with a proximal LAD stenosis randomized to PTCA or bypass surgery with an IMA graft. However, there were more MIs and repeat revascularization procedures in the PTCA group. Lastly, a more recent trial comparing the more contemporary approach of minimally invasive CABG with IMA versus stenting for a proximal LAD stenosis failed to detect a difference in death or MI. There were more often recurrent symptoms and repeat interventions in the PCI group, while the CABG group more often had adverse events (i.e., reoperation for graft occlusion, perioperative MI, stroke, chest wall hernia requiring surgical repair, etc.).

PCI versus CABG in Multivessel CAD Multiple early randomized trials comparing initial PCI, consisting mostly of PTCA, versus CABG in multivessel CAD have shown that, except for the subset of patients with diabetes, the long-term risk of death or MI is

equivalent with both procedures. During the PTCA area, randomized trials of PTCA versus CABG for stable CAD routinely demonstrated that treatment with CABG was associated with improved anginal relief and lower risk of subsequent revascularization procedures compared with PTCA. The early trials of PTCA versus CABG had important limitations however. For the most part, the patient populations were younger and at lower risk. Although stenting was initially introduced for the management of complications related to PTCA and was not used in the early trials, it is now the dominant PCI modality because it significantly reduces restenosis and acute vessel closure compared with PTCA. There were four subsequent trials that evaluated PCI incorporating BMS versus CABG in multivessel CAD. In the meta-analysis of the aggregate data from these four trials of 3,051 patients with multivessel CAD, there was no difference in the combined endpoint of death, MI, or stroke at 1 year between the groups. Once again, CABG was superior in need for repeat revascularization procedures (4.4% vs. 18% in PCI patients); however, for the first time, PCI was better in relieving anginal symptoms, with 82% freedom from angina versus 77% in the CABG group (p = 0.002). Even though the need for repeat revascularization was still higher for percutaneous procedures, this meta-analysis showed that the gap had narrowed considerably with the use of BMS. The Synergy between Percutaneous Coronary Intervention with Taxus and Cardiac Surgery (SYNTAX) trial was the largest trial to evaluate PCI versus CABG for the treatment of multivessel CAD. In this study, 1,800 patients with three-vessel or left main CAD were randomized to CABG or PCI with Taxus first- generation DES. At 1 year, the rates of death and MI were similar between the two groups, while stroke was more likely to occur with CABG (2.2% vs. 0.6% with PCI) and an increased rate of repeat revascularization was more likely with PCI (13.5% vs. 5.9% with CABG). Further, the investigators used an angiographic scoring tool (the SYNTAX score) to objectify the severity of CAD. Stratified by the SYNTAX score, patients with low (≤22) or intermediate (23 to 32) scores had similar rates of major adverse cardiac or cerebrovascular events whether undergoing PCI or CABG. However, in those with high (≥33) SYNTAX scores, the CABG group had lower rates of major adverse cardiac or cerebrovascular events (all-cause mortality, stroke, MI, or repeat revascularization) at 1 year. However at 3 and 5 years, patients with both intermediate and high SYNTAX scores had lower rates of major adverse cardiac and cerebrovascular events

with CABG compared with PCI, while those with low SYNTAX scores continued to have similar outcomes with either strategy. Recently, the 10-year follow-up data of SYNTAX demonstrated no significant difference in mortality between CABG and PCI overall, but CABG was associated with improved survival in patients with three-vessel CAD (21% vs. 28%, HR 1.41 [95% CI 1.10 to 1.80]). In the most recent ACC AHA stable CAD guidelines, patients with complex three-vessel CAD and intermediate or high SYNTAX score receive a class IIa indication for CABG over PCI as the favored treatment based on these data. In 2018, a patient-level meta-analysis of 11 trials (n = 11,518) of CABG versus PCI in multivessel or left main CAD was published, which reported all-cause mortality at 5 years. In that study, treatment with CABG was associated with lower 5-year mortality in patients with multivessel CAD (8.9% vs. 11.5%, p = 0.019) and those with diabetes (10.0% vs. 15.5%, p = 0.0004) but not in nondiabetics (8.0% vs. 8.7%, p = 0.49) or patients with left main trunk stenosis (10.5% vs. 10.7%, p = 0.52) with or without diabetes regardless of SYNTAX score.

PCI versus CABG for Patients with Left Main Trunk Stenosis Patients with left main trunk stenosis constitute a unique subgroup that has been studied in multiple randomized trials. The most contemporary trials evaluating these patients are the SYNTAX trial, NOBLE trial, and EXCEL trial. In the SYNTAX trial, the investigators evaluated the subgroup of patients with left main coronary disease. Patients with left main trunk stenosis and low or intermediate SYNTAX scores had similar rates of major adverse cardiac and cerebrovascular events with CABG or PCI, while those with high SYNTAX scores did better with CABG at 5 years. The NOBLE trial was a prospective open label noninferiority trial that randomized 1,201 patients with left main trunk coronary disease 1:1 to treatment with CABG or PCI with second-generation biolimus-eluting stents. The majority (>80%) of both groups had stable CAD, while the remaining patients had non–ST elevation acute coronary syndromes. The primary composite endpoint included death, MI, stroke, and repeat coronary revascularization. The primary endpoint occurred at 28% in the PCI arm and 18% in the CABG arm at 5 years, which did not meet the criteria for noninferiority, suggesting a

benefit of CABG over PCI for left main trunk stenosis. This difference was driven by increased repeat revascularization and MI in the PCI arm. The EXCEL trial also randomly assigned 1,905 patients with left main trunk coronary disease and SYNTAX score ≤32 to CABG versus PCI with contemporary second-generation everolimus-eluting stents and found differing results. The primary endpoint was a composite of death, MI, or stroke at 3 years. Rate of the primary point was 14.7% in the CABG versus 15.4% in the PCI group at 3 years (p = 0.002 for noninferiority). Additionally, the secondary endpoint of death, MI, or stroke at 30 days was significantly lower in the PCI group (7.9% vs. 4.9%, p < 0.001 noninferiority, p = 0.008 superiority). Notably, repeat revascularization was not considered as part of the primary endpoint in this trial and may account in part for the different results compared with the NOBLE trial. Additionally, peri-procedural MI was not included in the MI endpoint definition for the NOBLE trial, while it was included in the EXCEL trial. This difference also likely contributes to the disparate findings. Controversy surrounded the 5year outcomes of the EXCEL trial, which were published in 2019. Advocates for CABG noted that CABG had a lower rate of overall mortality and non-procedural MI, while advocates for PCI noted the non-inferiority of PCI vs. CABG for the primary endpoint, MI, and cardiovascular mortality. A 2017 trial-level meta-analysis of 4,394 patients across four trials of left main trunk revascularization with CABG versus PCI revealed a similar risk of 5-year death, MI, or stroke (16.9% vs. 18.9%, p < 0.001). The aforementioned 2018 meta-analysis of 11 trials (n = 11,518) revealed that patients treated with left main trunk stenosis treated with CABG versus PCI had similar 5-year mortality (10.5% vs. 10.7%, p = 0.52) with or without diabetes regardless of SYNTAX score. Additionally, the 10-year outcomes of the SYNTAX trial similarly demonstrated no difference in mortality between CABG and PCI for left main trunk stenosis. The ACC AHA guidelines on stable CAD have not been updated since these trial results. At the present time, the guidelines do give a class I indication for CABG to improve survival in patients with left main trunk stenosis, while PCI is considered a reasonable alternative in patients with increased surgical risk and appropriate anatomy (low SYNTAX score and nondistal left main trunk lesions) with a class IIa recommendation.

PCI versus CABG for Patients with Diabetes Mellitus The Bypass Angioplasty Revascularization Investigation 2 Diabetes (BARI2D) trial randomized 2,368 patients with diabetes and stable CAD to medical therapy or prompt revascularization, either by CABG or PCI. The decision of CABG or PCI, however, was at the discretion of the treating physician. At 5 years, there was no difference in mortality between medical therapy and revascularization (survival 88.3% in revascularization group vs. 87.8% in medical therapy group). At baseline, the patients stratified to CABG over PCI had more extensive CAD, with more three-vessel CAD, proximal LAD disease, and chronic total occlusions. In spite of this, there was no difference in mortality between either the CABG or PCI arms and the medical therapy arm. While there was no difference in major cardiovascular events (death, MI, or stroke) in PCI versus medical therapy, there was significant improvement in major cardiovascular events in the CABG group over medical therapy alone. When the interaction between study group assignments was evaluated, there was a statistically significant benefit in prompt revascularization over medical therapy in patients selected for CABG over those stratified to PCI. There are some limitations to conclusions drawn from these data. First, this study was not designed to evaluate PCI versus CABG in diabetic patients; as mentioned previously, the patients stratified for CABG had more extensive CAD. Additionally, the use of DESs was low (around 35%) in the PCI arm, as was the use of antiplatelet agents (around 20%). The subsequent Future REvascularization Evaluation in patients with Diabetes mellitus: Optimal management of Multivessel disease (FREEDOM) trial was the definitive trial evaluating for PCI versus CABG in diabetic patients. This study was an international open-label, prospective trial of 1,900 diabetic patients with multivessel CAD randomized to PCI with DES versus CABG. The majority of patients, 83%, had three-vessel CAD. The primary outcome was a composite of death, MI, or stroke. At 5 years, the primary outcome was significantly reduced in the CABG arm (26.6% vs. 18.7%, p = 0.005), with significant reductions in the rates of MI and allcause death. However, the rate of stroke was higher in the CABG arm at 5 years. At a median follow-up of 7.5 years, there was a consistent mortality benefit with CABG (24.3% vs. 18.3%). Based on these data, patients with diabetes and multivessel CAD who require coronary revascularization

should be evaluated for CABG as the preferred initial treatment strategy over PCI. The 2012 ACC AHA guidelines give a class IIb recommendation that CABG is probably recommended over PCI in patients with diabetes and multivessel CAD. PCI may still be reasonable in diabetic patients deemed to be high or inoperable risk for CABG.

Summary Data from randomized trials and observational registries indicate that the benefits of revascularization in stable CAD are proportional to the patient’s estimated long-term risk while on medical therapy. For low-risk patients with single-vessel CAD, medical therapy remains the initial treatment of choice, with revascularization reserved for symptom relief when medical treatment has failed. Patients with multivessel CAD are more complicated. Long-term outcomes of patients with low syntax score treated with percutaneous or surgical revascularization demonstrate comparable outcomes, while patients with more complex CAD (intermediate/high SYNTAX score) or diabetes benefit from surgical rather than percutaneous revascularization. Management of patients with left main trunk stenosis is an area of ongoing evaluation, but. Current guidelines do recommend bypass surgery with a class I indication.

REFRACTORY ANGINA Considerable progress has been made over the last 25 years in expanding the therapeutic options available in ischemic heart disease, including pharmacologic and revascularization therapies that improve both symptoms and prognosis. However, despite the efficacy of these treatments, there remains a subset of patients with severe symptoms who are refractory to conventional medical therapy and are deemed to be unsuitable for coronary revascularization. As many as 1.7 million patients in the United States are suffering from refractory angina pectoris, with the prevalence increasing as the population ages and patients live longer with their CAD. For these patients with refractory angina, there are adjunctive invasive and

noninvasive therapies available that do not improve prognosis but may serve to alleviate symptoms and improve quality of life.

Enhanced External Counterpulsation Although the mechanisms underlying the benefits observed with enhanced external counterpulsation (EECP) in patients with stable angina pectoris remain unclear, this is an effective noninvasive option in the management of patients with refractory angina pectoris. EECP utilizes three sets of pneumatic cuffs applied to the lower extremities at the calves, lower and upper thighs that inflate sequentially from distal to proximal during diastole to provide diastolic augmentation of coronary flow and increased venous return. The cuffs deflate just before systole, reducing afterload and thereby increasing cardiac output. A standard course of EECP involves 1 hour a day for a total of 35 hours of therapy performed over 7 weeks. Observational studies have demonstrated that EECP is associated with improved anginal class, exercise tolerance, and quality of life and reduced nitroglycerin use and the severity of ischemia measured with MPI. The data from these studies are further supported by a randomized, double-blind, sham-controlled study of EECP that demonstrated a reduction in angina, an increase in time to STsegment depression during exercise, and an improvement in quality of life at 1 year (registry data suggest a benefit up to 2 years). For those whose symptoms do eventually recur, a repeat course of EECP performed after 1 year may also be effective. EECP is FDA approved for the treatment of refractory angina and has a Class IIb indication from the ACC/AHA.

Spinal Cord Stimulation Spinal cord stimulation (SCS) is an invasive procedure that involves the surgical placement of an epidural electrode at the level of C7 through T1 and a pulse generator in the left lower abdomen. Neuromodulation of the dorsal columns several times per day by the device is believed to inhibit the painconducting impulses originating from the spinothalamic tract and lower pain perception. More recent data also show some sympatholytic activity and changes in cerebral blood flow that may explain some of its mechanisms of action. The typical course of treatment consists of three 1-hour stimulations daily. Several small observational studies have demonstrated improvements

in anginal class and time to onset of ST-segment depression in patients treated with SCS. In a single randomized trial comparing SCS to CABG in 104 patients with stable angina, the two treatments provided equivalent symptom relief and an improved long-term quality of life. Mortality was improved at 6 months with SCS and similar between the two treatment arms at 5 years. Based on these results, SCS has an ACC/AHA Class IIb recommendation for patients with refractory angina.

ACKNOWLEDGMENT The authors would like to gratefully acknowledge the contribution of Drs. Christian Simpfendorfer and Kellan E. Ashley to prior editions of this manuscript.

SUGGESTED READINGS Boden WE, O’Rourke RA, Teo KK, et al. Optimal medical therapy with or without PCI for stable coronary disease. N Engl J Med. 2007;356(15):1503-1516. De Bruyne B, Pijls NH, Kalesan B, et al. Fractional flow reserve-guided PCI versus medical therapy in stable coronary disease. N Engl J Med. 2012;367(11):991-1001. Fihn SD, Gardin JM, Abrams J, et al. 2012 ACCF/AHA/ACP/AATS/PCNA/SCAI/STS guideline for the diagnosis and management of patients with stable ischemic heart disease: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines, and the American College of Physicians, American Association for Thoracic Surgery, Preventive Cardiovascular Nurses Association, Society for Cardiovascular Angiography and Interventions, and Society of Thoracic Surgeons. J Am Coll Cardiol. 2012;60(24):e44-e164. Levine GN, Bates ER, Bittl JA, et al. 2016 ACC/AHA guideline focused update on duration of dual antiplatelet therapy in patients with coronary artery disease: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. J Am Coll Cardiol. 2016;68(10):1082-1115. Makikallio T, Holm NR, Lindsay M, et al. Percutaneous coronary angioplasty versus coronary artery bypass grafting in treatment of unprotected left main stenosis (NOBLE): a prospective, randomised, open-label, non-inferiority trial. Lancet. 2016;388(10061):2743-2752. Mark DB, Shaw L, Harrell FE Jr, et al. Prognostic value of a treadmill exercise score in outpatients with suspected coronary artery disease. N Engl J Med. 1991;325(12):849-853. Morh FW, Morice MC, Kappetein AP, et al. Coronary artery bypass graft surgery versus percutaneous coronary intervention in patients with three-vessel disease and left main coronary

disease: 5-year follow-up of the randomised, clinical SYNTAX trial. Lancet. 2013;381(9867):629638. Stone GW, Sabik JF, Serruys PW, et al. Everolimus-eluting stents or bypass surgery for left main coronary artery disease. N Engl J Med. 2016;375(23):2223-2235.

Chapter 38 Review Questions and Answers QUESTIONS

A. . C. D.

An 80-year-old man is referred to the Cardiovascular Medicine clinic due to symptoms consistent with stable angina. He has a history of hypertension that is well controlled on metoprolol succinate 150 mg daily. He has been experiencing stable angina for 3 months. After seeing his internist, he is now also on aspirin 81 mg daily, isosorbide mononitrate 120 mg daily, and simvastatin 40 mg daily. On examination, the heart rate is 62 bpm and the blood pressure is 110/60 mm Hg. The cardiopulmonary examination is unremarkable. Resting electrocardiogram (ECG) is within normal limits. An exercise stress test is performed utilizing the Bruce protocol and is significant for 2mm horizontal ST-segment depression in the inferolateral leads, as well as chest discomfort at 4 minutes that required cessation of exercise. The Duke treadmill score (DTS) for this patient is −8, intermediate risk −8, high risk −14, intermediate risk −14, high risk

A. . C. D.

For the patient mentioned in question 1, the next most appropriate step would be Increase the dose of isosorbide mononitrate. Increase the dose of metoprolol succinate. Add nifedipine sustained release (SR). Coronary angiography

1.

2.

Which of the following statements are not true in regard to medical therapy versus percutaneous coronary intervention (PCI) for chronic stable angina? A. PCI is more effective than medical therapy in reducing cardiovascular mortality in patients with chronic stable angina. . PCI is more effective than medical therapy for symptomatic relief of angina.

3.

C. PCI plus optimal medical therapy in the COURAGE trial was no more effective than optimal medical therapy alone in preventing mortality or myocardial infarction in patients with stable coronary artery disease (CAD). D. As evidenced by the nuclear substudy of the COURAGE trial, PCI plus optimal medical therapy is more effective than optimal medical therapy alone in reduction of ischemia in patients with stable CAD. A 60-year-old man with cirrhosis presents to the Cardiovascular Medicine clinic for evaluation of stable angina. He is already on maximum doses of a long-acting nitrate and a beta-blocker. He continues to have angina and is extremely limited. His heart rate is 55 bpm and his blood pressure is 99/62 mm Hg. His cardiopulmonary examination is normal. Stress testing with myocardial perfusion imaging is performed and reveals an exercise-induced reversible defect in the inferior wall. The left ventricular ejection fraction is normal. Coronary angiography reveals a long occlusion of the mid right coronary artery that fills via collaterals from the left anterior descending coronary artery. There is no other significant disease. You consider the addition of ranolazine given he is already maximized on a beta-blocker and a long-acting nitrate. Which of the following statements regarding ranolazine is correct? There is a significant increase in the risk of lethal arrhythmias with the use of ranolazine. Ranolazine would not be an option for this patient, as it would further decrease the blood pressure and heart rate. Ranolazine would be contraindicated in this patient given his liver disease. There is no benefit in adding ranolazine to the medical regimen of patients already receiving combination therapy with other antianginals.

4.

A. . C. D.

5.

A 65-year-old woman with type 2 diabetes mellitus, hypertension, chronic kidney disease stage 3, and asthma reports several months of chest and jaw pain with climbing stairs. She undergoes an exercise SPECT study that demonstrates fair functional capacity of 5 METs with ST depression at peak exercise and reversible perfusion defects in the inferoseptum, anterolateral, and apical territories suggestive of >20% ischemia. Cardiac catheterization reveals an 80% stenosis in the proximal left anterior descending coronary artery and a 90%

A. . C. D.

stenosis in the mid right coronary artery. Which of the following statements is true regarding the best revascularization strategy in this patient? Revascularization is unlikely to improve this patient’s survival and should only be pursued for symptom control if the patient has angina despite optimal medical therapy. Revascularization should be delayed to allow for testing of myocardial viability. PCI is a superior treatment compared with CABG for this patient if the SYNTAX score is low (≤22). CABG is the preferred revascularization strategy in this patient, as it is associated with lower risk of MI and improved survival compared with PCI.

ANSWERS 1.

Correct Answer: D. −14, high risk This patient with exercise-limiting angina has a DTS of −14, which predicts a high probability of severe angiographic coronary artery disease (CAD). The DTS is calculated as follows:

Patients are classified as low-, moderate-, or high-risk based on their DTS. A low-risk DTS is ≥ +5, and these patients have a low (3%) 5year mortality rate. A high-risk DTS is considered ≤ −11. These patients carry the highest mortality rate (35% at 5 years). A moderaterisk DTS is between −10 and +4 and carries a 10% 5-year mortality rate. Generally, patients with high-risk DTS have high-risk anatomy at cardiac catheterization (left main or three-vessel disease) and would benefit from revascularization. Low-risk patients have an overall excellent prognosis that likely cannot be improved with further evaluation and revascularization.

2.

Correct Answer: D. Coronary angiography

The patient is on maximal medical therapy and is unlikely to derive significant benefit from further titration of his current medications or addition of further antianginals. Stress imaging is not warranted at this time given his high-risk Duke treadmill score and likelihood of deriving benefit from revascularization. Thus, coronary angiography would be indicated.

3.

Correct Answer: A. PCI is more effective than medical therapy in reducing cardiovascular mortality in patients with chronic stable angina. Most of the trials comparing medical therapy with PCI confirm that PCI is more effective in relief of anginal symptoms as measured by severity of angina, the need for antianginal medications, and improved quality of life. However, there is no evidence that PCI is more effective than medical therapy in reducing major cardiac events (cardiac death or myocardial infarction). In one of the largest of the trials of patients with stable CAD, COURAGE randomized over 2,000 patients with moderately severe chronic stable angina to PCI plus optimal medical therapy or optimal medical therapy alone. After more than 4 years of follow-up, there was no difference in the two groups in terms of death or myocardial infarction. However, in the nuclear substudy of COURAGE, 314 patients were enrolled for serial rest/stress single positron emission computed tomography (SPECT) myocardial perfusion scanning before treatment and at 6 to 18 months postrandomization. In this substudy, the PCI plus optimal medical therapy group had more significant reduction in ischemic burden with more patients obtaining this reduction than in the optimal medical therapy alone group. Further, those with reduction in ischemic myocardium had a significant improvement in mortality and rate of subsequent myocardial infarction.

4.

Correct Answer: C. Ranolazine would be contraindicated in this patient given his liver disease. Ranolazine is the first antianginal drug approved by the United States Food and Drug Administration (FDA) in more than 20 years and is

used primarily in those patients refractory to traditional agents. Ranolazine, a piperazine derivative, inhibits late sodium channels by lowering total inward sodium influx and thus the subsequent intracellular calcium overload that is associated with ischemia. Fortunately, at therapeutic levels, ranolazine does not alter fast inward sodium channels; the late inward sodium channels are inhibited in ischemic tissue only. By preventing the intracellular calcium overload, there is myocardial diastolic relaxation and a rebalancing of oxygen demand and supply in the coronary vasculature. Unlike other antianginal drugs, ranolazine has no effect on the heart rate or blood pressure. As evidenced in clinical trials, ranolazine is effective as both monotherapy or in combination with other antianginals for patients with stable angina. Because of its effects on sodium channels, there was some concern about the precipitation of lethal arrhythmias. There is a concentration-dependent prolongation of the QT interval and repolarization; however, in MERLIN-TIMI 36, there was no difference in the rates of documented arrhythmias or sudden death in patients receiving ranolazine compared to placebo. Ranolazine is metabolized in the liver (particularly cytochrome 3A); therefore, it is contraindicated in liver disease. Ranolazine is not currently reflected in the ACC/AHA guidelines for stable coronary artery disease (CAD) as it was not FDA approved at the time of the last update.

5.

Correct Answer: D. CABG is the preferred revascularization strategy in this patient, as it is associated with lower risk of MI and improved survival compared with PCI. This patient with diabetes has a high-risk stress test finding (>20% ischemia), which appropriately should prompt coronary angiography. In the setting of multivessel CAD with high-risk criteria on stress testing, there is a class IIa indication to perform CABG to improve survival. In the setting of typical angina and extensive ischemia by noninvasive testing, there is no recommendation that viability testing is useful for this patient. Viability testing may be warranted in patients with decreased left ventricular function and resting perfusion defects in whom revascularization is considered. The FREEDOM trial

demonstrated that CABG is associated with lower rates of MI and death at 5-year follow-up compared with PCI in diabetic patients with multivessel CAD. Based on these data, there is a class IIa recommendation in favor of CABG over PCI to improve survival in patients with diabetes and multivessel CAD.

CHAPTER 39

Unstable Coronary Syndrome JONATHAN D. HANSEN AND A. MICHAEL LINCOFF

TERMINOLOGY AND OVERVIEW The approach to unstable or acute coronary syndromes (ACSs) categorizes a heterogeneous clinical spectrum that ranges from unstable angina (UA) and non–ST-elevation myocardial infarction (NSTEMI) to ST-elevation myocardial infarction (STEMI). This chapter discusses the epidemiology, clinical presentation, pathophysiology, diagnosis, and management of both UA and NSTEMI. There is a separate dedicated chapter on STEMI. Prior to the exam, it is important to review the 2014 American College of Cardiology/American Heart Association (ACC/AHA) guidelines for Management of Patients with Unstable Angina/NSTEMI (Table 39.1). This chapter will assist you in this high yield topic.

Table 39.1 ACC/AHA Classification for Recommendations

Derived from Amsterdam E, Wenger N, Brindis RG, et al. 2014 ACC/AHA guidelines 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. Developed in collaboration with the Society for Cardiovascular Angiography and Interventions, and the Society of Thoracic Surgeons endorsed by the American Association of Clinical Chemistry. J Am Coll Cardiol. 2014;64(24):2645-2687.

EPIDEMIOLOGY AND PROGNOSIS There has been a remarkable decline in cardiovascular disease mortality over the past 30 years. However, cardiovascular and circulatory disease continues to be the leading cause of mortality worldwide. It is interesting to note that the number of ACS that is classified as NSTEMI is rising while the STEMI cases are decreasing.1 This is likely driven from advances to improve primary prevention measures, aging patients, and more sensitive troponin testing. Given the adoption of high-sensitivity cardiac biomarker

assays, there is potential for future reshaping of the diagnosis of UA as cases are more precisely classified in the emergency department that were previously labeled UA patients.2 Most ACSs occur in older individuals >65 years old, and nearly 50% occur in women and men. Certainly, there is a spectrum of clinical presentations across all demographics. In-hospital mortality and 30-day mortality for UA and NSTEMI patients has improved over the past 30 years with the rise of coronary revascularization and adoption of proven medical therapy such as beta blockers, statins, and antiplatelets. Short-term mortality is less in UA and NSTEMI than in STEMI patients, although because the former are at risk for recurrent events, their long-term risk is equivalent or worse compared to STEMI patients.3

CLINICAL PRESENTATION The first foundational step in the assessment of a patient who presents with chest pain is taking an effective and efficient history. ACS patients will frequently describe substernal chest discomfort as a pressure, tightness, or a heavy sensation. Typical symptoms last 50%; (d) ST depression ≥0.05 mV; (e) patient experienced ≥2 anginal events in the past 24 hours; (f) aspirin use in the last 7 days; and (g) an elevated cardiac biomarker (i.e., elevated CK-MB or troponin). It detects near-term events and helps triage, as evidence suggests, those with a higher TIMI risk score of ≥3 that would benefit early invasive strategy. The presence of six or seven risk factors predicts a 40% incidence of death, MI, or ischemia requiring repeat revascularization by 30 days. This is in contrast to zero or one risk factor, where the 30-day cardiac event rate is 140 is considered high risk and has supported an early invasive strategy in some trials.16 The HEART score was originally developed in a cohort of patients presenting to the emergency room with chest pain. The score incorporates history of patient, ECG, age, risk factors, and initial troponin values. It is not used with ST-elevation patients. HEART score of 0 to 3 points signifies a risk of 1.7% for any endpoint and supports consideration of discharge from the emergency room. A score of 4 to 6 represents a 20.3% risk and recommendation to clinically observe. A score >7 has a risk of 72.7% and supports an early invasive strategy. External validation of the score demonstrated a higher c-statistic of 0.83 compared to TIMI (0.75) and GRACE (0.70).18 In all scoring systems for patients presenting with UA/NSTEMI, there is an incremental benefit for more aggressive therapies as the risk score escalates and therefore justify the use of such stratification to help identify and influence clinical decision-making.

MANAGEMENT Initial Approach The initial management of UA/NSTEMI coronary syndromes includes appropriately ruling out an ST-elevation myocardial infarction by obtaining an ECG and subsequent serial ECGs if clinical changes dictate or pain persists (class I). Simultaneously, while an ECG and vital signs are documented, an appropriate focused history and physical exam are

performed. Concurrently establishing intravenous access with cardiac biomarkers is ideal. Historically, supplemental oxygen was given to all suspected ACS patients; however, recent randomized trial data have demonstrated no difference in 1-year mortality, troponin elevation, or adverse events in patients who did not have hypoxemia (SpO2 < 90%).19 The primary management focus during an ACS, after antithrombotic and anti-ischemic medicines are administered (Table 39.2), is to determine a patient’s suitability for early invasive therapy versus conservative therapy. Fibrinolytic therapy plays an invaluable role in STEMI patients but should not be used for the management of UA/NSTEMI unstable coronary syndromes (class III recommendation) discussed in this specific chapter.

Table 39.2 Class I Anti-Ischemic Recommendations

aIntravenous beta-blockers class IIa. bNondihydropyridine calcium channel blockers may be considered when beta-blockers are not successful, or there is a contraindication to their use. cClopidogrel can be substituted in patients who cannot take aspirin due to hypersensitivity or major gastrointestinal intolerance. dPrasugrel is listed as an option along with clopidogrel and ticagrelor as class I in post-PCI patients treated with coronary stents. e Unfractionated heparin for 48 hours or until PCI is performed. SC enoxaparin for duration of hospitalization or until PCI is performed. Bivalirudin or SC fondaparinux until diagnostic angiography or PCI is performed in patients with early invasive strategy only. Additional anticoagulant with anti-IIa activity if PCI is performed while patient is on fondaparinux.

Derived from Amsterdam E, Wenger N, Brindis RG, et al. 2014 ACC/AHA guidelines 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. Developed in collaboration with the Society for Cardiovascular Angiography and Interventions, and the Society of Thoracic Surgeons endorsed by the American Association of Clinical Chemistry. J Am Coll Cardiol. 2014;64(24):2645-2687.

Invasive Therapy All NSTEMI patients should receive optimal medical therapy as outlined later in this chapter. Invasive therapy is defined as performing a diagnostic coronary angiogram with the intent to revascularize if the anatomy is suitable and appropriate. Invasive therapy is further divided into categories based on when the procedure is performed that is guided by the risk and clinical picture of the patient. The spectrum is outlined in the guidelines as (a) an “immediate” or urgent evaluation for unstable patients, (b) an “early invasive” strategy within 24 hours for high risk patients, or (c) a “delayed invasive” strategy within 25 to 72 hours for intermediate risk patients.20 Regarding an immediate or urgent evaluation, this is pursued when patients are experiencing ongoing angina pain despite appropriate guideline medication, hemodynamic instability, ventricular arrhythmias (sustained VT or VF), or the development of heart failure (class I, LOE A). A very early intervention (140.21 Regarding an early invasive strategy, this is indicated in patients who have a stabilized clinical scenario yet retain an elevated risk for clinical events (class I). Current ACC/AHA guidelines recommend (class I) an early invasive approach to patients with angina in the presence of heart failure symptoms (pulmonary edema, an S3 gallop, or new mitral regurgitation), known left ventricular dysfunction, hemodynamic instability, positive noninvasive stress test (large area of ischemia), sustained ventricular tachycardia, or prior revascularization (prior coronary artery bypass grafting [CABG], or PCI within the last 6 months). This has been further described as

patients with GRACE score >140, a new ST segment depression, or a temporal change in troponin (class I). Early invasive therapy is discouraged in low-likelihood patients who are troponin negative or have extensive comorbidities if risks of revascularization are likely to outweigh benefits (class III recommendation). A more conservative ischemia-guided approach is recommended in these patients. Intermediate-risk patients can initially be treated by either an early invasive or a conservative approach with careful monitoring for the development of high-risk features. High-risk features include refractory pain, angina with dynamic ECG changes, or elevated cardiac biomarkers. Such a change in clinical status should advance therapy to a more invasive approach. Low-risk patients can often be treated as outpatients or screened for MI with serial cardiac enzymes in a chest pain unit with a goal of early discharge. High sensitivity troponin has improved the quick triage of patients presenting to the emergency room. Invasive therapy is discouraged in lowrisk patients. Risk-factor modification is emphasized to all patients regardless of their risk at presentation (see Table 39.3.)

Table 39.3 Factors Associated with Appropriate Selection of Early Invasive Strategy or Ischemia-Guided Strategy in Patients with NSTE-ACS

VT, ventricular tachycardia; VF, ventricular fibrillation; TIMI, thrombolysis in myocardial infarction; GRACE, Global Registry of Acute Coronary Events; Tn, troponin; PCI, percutaneous coronary intervention. Derived from Amsterdam E, Wenger N, Brindis RG, et al. 2014 ACC/AHA guidelines 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. Developed in collaboration with the Society for Cardiovascular Angiography and Interventions, and the Society of Thoracic Surgeons endorsed by the American Association of Clinical Chemistry. J Am Coll Cardiol. 2014;64(24):2645-2687.

Once the decision is made to perform coronary angiography, the patient’s suitability for coronary revascularization is determined. Two options for revascularization are PCI (i.e., percutaneous transluminal coronary angioplasty [PTCA] and intracoronary stents) or CABG. The choice of which revascularization to perform is beyond the scope of this chapter, although several general guidelines exist. Severe left main trunk disease is an indication for CABG, although left main PCI is performed in select cases. Severe three-vessel disease or severe two-vessel disease involving the left anterior descending artery, along with left ventricular dysfunction or diabetes, traditionally favor revascularization with CABG. In conclusion, current ACC/AHA guidelines recommend (class I) an early invasive strategy in unstable patients (recurrent or ongoing angina despite medical therapy, sustained ventricular arrhythmias, or hemodynamic instability). It should be pursued in those with an intermediate or high-risk TIMI and GRACE score (>140), recent PCI, history of left ventricle

dysfunction, dynamic ECG changes, history of CABG, diabetes mellitus, and chronic kidney disease. If an ischemia-guided conservative strategy is pursued, it is valuable to risk stratify the patient on whether a diagnostic coronary angiogram is subsequently needed. All patients with NSTEMI should undergo an assessment of LV function noninvasively (typically by echocardiography) to determine if an invasive strategy is required (class I) based on new wall motion changes. In the low and intermediate-risk patients within the ischemia-guided pathway, a treadmill exercise ECG test is recommended for those with an interpretable baseline ECG. If the patient cannot exercise, a pharmacologic evaluation is performed, albeit with a loss of the prognostic exercise functional data.

Antiplatelet Agents The use of antiplatelet therapy plays a central role in ACS patients and the underlying pathophysiology. There is an ongoing clinical balance between platelet inhibition and bleeding risk.

Aspirin Aspirin is the cornerstone of treatment for all unstable coronary syndromes unless there is a serious contraindication to its use (class I recommendation). Aspirin blocks the conversion of arachidonic acid to thromboxane A2 by irreversibly acetylating cyclooxygenase (Fig. 39.3). Full-dose aspirin exerts maximal antiplatelet effects within 40 minutes of absorption; therefore, an initial nonenteric-coated 325-mg aspirin orally (or by rectal suppository if necessary) is given initially during an ACS (see Table 39.2) to all patients as soon as possible. The plasma half-life of aspirin is approximately 20 minutes; however, due to its irreversible binding, it inhibits the platelet for its entire 10 day lifespan.22

FIGURE 39.3 Schema for platelet aggregation and inhibition of platelet aggregation by GP IIb/IIIa inhibitors. Platelets are activated by adenosine diphosphate, thrombin, epinephrine, collagen, and thromboxane A2. Aspirin blocks the conversion of arachidonic acid to thromboxane A2. Clopidogrel blocks adenosine diphosphate–mediated platelet activation. GP IIb/IIIa inhibitors cause a conformational change in the GP IIb/IIIa receptor that prevents fibrinogen-mediated platelet aggregation. (From Yeghiazarians Y, Braunstein JB, Askari A, Stone PH. Unstable angina pectoris. N Engl J Med. 2000;342:101-114, with permission from the Massachusetts Medical Society.) Optimal dosing of aspirin had previously been debated. The CURRENTOASIS 7 (Clopidogrel and Aspirin Optimal Dose Usage to Reduce Recurrent Events–Seventh Organization to Assess Strategies in Ischemic Syndromes) trial demonstrated no difference in 30-day outcomes between patients treated with low-dose (75 to 100 mg) and high-dose aspirin (300 to 325 mg) in all patients and also in the PCI subgroup.23 There was an increase in minor bleeding events with high-dose aspirin, and, therefore, lower doses

of aspirin are recommended. Laboratory aspirin resistance assessment with COX-1 activity is not currently recommended. Recent studies have investigated the use of primary prevention aspirin in all patients. Ongoing evaluation of appropriate use of aspirin in the primary prevention arena will continue; however, it should be given to all ACS patients unless contraindicated.

Thienopyridines and ADP Inhibitors Despite aspirin’s proven benefit in reducing MI and death, it does not fully block platelet aggregation, especially when aggregation is induced by ADP. Other agents such as ADP inhibitors play a valuable role in the management of UA/NSTEMI patients due to their complementary mechanism of action to aspirin. Modern agents used to inhibit the ADP P2Y12 receptor include clopidogrel, prasugrel, and ticagrelor. These agents act by inhibiting ADP receptor–mediated platelet activation. Thienopyridines are prodrugs that are inactive when absorbed and are subsequently converted to active metabolites by the liver. These agents subsequently bind irreversibly to the P2Y12 ADP receptor and render it inactive. This is in comparison to ticagrelor and cangrelor, which are active agents and are not prodrugs. They block the receptor at its ADP ligand; however, they are reversible (when circulating concentrations fall, the drug will dissociate from the receptor) and leave an active platelet. Ticlopidine is a historical drug and is no longer used given its incidence of neutropenia, thrombocytopenia, and onset of action. P2Y12 inhibitors may be used alone if a patient has a hypersensitivity to aspirin, but they are ideally used adjunctively with aspirin. Clopidogrel loading dose of 300 to 600 mg produces maximal antiplatelet effects in 4 to 6 hours. Loading dose of ticagrelor 180 mg produces maximal antiplatelet effects around 90 minutes. Prasugrel loading dose of 60 mg is given only when coronary anatomy is known in the catheterization laboratory with plans for percutaneous intervention. Maintenance dosing for prasugrel is 10 mg once daily. Prasugrel should not be used in patients with prior history of stroke or transient ischemia attack (class III). Prasugrel is also avoided in patients older than 75 years of age. Dual antiplatelet therapy was evaluated in the CURE trial, which tested protection from ischemic events beyond that of monotherapy aspirin by the

addition of clopidogrel to aspirin and standard medical therapy in patients with ACS.24 This trial randomized over 12,000 non–ST-elevation ACS patients within 24 hours of their onset of chest pain to clopidogrel plus aspirin versus aspirin alone. This was largely a conservatively treated population, as 3 mo before presentation, dementia, or other intracranial pathology not listed as an absolute contraindication Traumatic or prolonged CPR(> 10 min) Use of anticoagulation Recent internal bleeding (within 2-4 wk) Pregnancy Active peptic ulcer disease Vascular punctures at noncompressible sites

Adapted from Antman EM, Anbe DT, Armstrong PW, et al. ACC/AHA guidelines for the management of patients with ST-elevation myocardial infarction–executive summary. A report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to revise the 1999 guidelines for the management of patients with acute myocardial infarction). J Am Coll Cardiol. 2004;44:671-719.

RISK STRATIFICATION Killip Class, TIMI Risk Score, GRACE Score Since all patients with STEMI are initially eligible for reperfusion therapy, risk models are used primarily to determine prognosis and not to direct therapy as in UA/NSTEMI risk models. Initial information for risk stratification comes from the physical examination. Assessing for signs of heart failure is a useful tool for risk stratification. Patients who present with cardiogenic shock have a 30-day mortality rate of approximately 60% (Table 40.4). Cardiac biomarkers (troponin I or T and total CK and CK-MB isoenzyme) supplement the physical examination by gauging infarct size and providing additional prognostic information.

Table 40.4 Killip Class—30-Day Mortality

From Lee KL, Woodlief LH, Topol EJ, et al. Predictors of 30-day mortality in the era of reperfusion for acute myocardial infarction. Results from an international trial of 41,021 patients. GUSTO-I Investigators. Circulation. 1995;91:1659-1668, with permission from Wolters Kluwer Health.

Risk models have been created that provide clinicians with a more accurate prediction of risk. These models combine multiple variables that are most predictive for future adverse cardiac outcomes. The thrombolysis in myocardial infarction (TIMI) risk score is an easily used and validated model that has important prognostic implications. It incorporates eight variables that are readily available from the history, physical examination, and ECG (Fig. 40.5). The strongest variable that predicts an adverse prognosis is advanced age (where age ≥75 years receives 3 points and age 65 to 74 years receives 2 points). Other variables include hypotension, tachycardia, or Killip class II to IV at presentation, history of diabetes or hypertension, low body weight, anterior ST elevation (also complete LBBB), and a time to treatment of >4 hours.

FIGURE 40.5 TIMI risk model for prediction of short-term mortality in STEMI patients. (From Morrow DA, Antman EM, Charlesworth A, et al. TIMI risk score for ST-elevation myocardial infarction: a convenient, bedside, clinical score for risk assessment at presentation: an intravenous nPA for treatment of infarcting myocardium early II trial substudy. Circulation.

2000;102:2031-2037, with permission from Wolters Kluwer Health.) The GRACE score was designed to improve the risk prediction of inhospital mortality in patients with ACS. It can be used in patients with STEMI or NSTEMI. Risk is determined based on Killip class, systolic blood pressure, heart rate, age, creatinine level, presence or absence of cardiac arrest at admission, ST-segment deviation, and presence or absence of cardiac biomarkers. A score of ≤60 is associated with a ≤0.2% probability of in-hospital mortality, whereas a score of ≥250 is associated with a ≥52% probability of in-hospital mortality.

MANAGEMENT Regional STEMI Systems of Care Successful reperfusion is dependent on early recognition of symptoms by the patient with prompt activation of emergency medical services (EMS). As a goal, EMS personnel should arrive at the subject’s location within 10 minutes of system activation. Unfortunately, almost 40% of patients with STEMI fail to activate EMS. EMS-transported patients have significantly shorter delays in both symptom onset to arrival and door to reperfusion time. Initial triage of a patient with AMI should focus on establishing intravenous access providing supplemental oxygen if needed, and rapid performance of a 12-lead ECG. In fact, the 2013 ACC AHA guidelines give a class I indication for performance of a 12-lead ECG by EMS personnel at the time of first medical contact. Regional STEMI systems of care have been developed in the United States over the past two decades to improve the public awareness of AMI symptoms, and detection of AMI by EMS and other medical personnel, and to organize processes at primary PCI facilities to provide rapid prior PCI to a large segment of the US population. These efforts have led to drastic improvements in reperfusion times in United States. The 2013 ACC AHA STEMI guidelines give a class I indication for

communities to create and maintain regional STEMI systems of care including continuous quality assessment and quality improvement activities.

Reperfusion Therapy Time is of paramount importance in reinstituting coronary flow. The greatest improvement in mortality comes from reperfusion within the first hour. Reperfusion therapy can be considered up to 12 hours from the onset of chest pain and even longer in select cases. In order to facilitate rapid coronary reperfusion, a pharmacologic or mechanical approach should be decided on quickly (Fig. 40.6). In contemporary practice, the favored approach to achieve reperfusion in the setting of STEMI is primary PCI rather than fibrinolysis. This information comes from a meta-analysis of 23 trials that randomized nearly 8,000 STEMI patients to fibrinolytic therapy versus primary PCI. This analysis revealed a short-term survival advantage as well as a reduction in recurrent MI and hemorrhagic stroke in those who received primary PCI. Short-term mortality was 7% in the primary PCI group, compared with 9% in the fibrinolytic group (p = 0.0002). Long-term mortality was also significantly reduced with primary PCI (p = 0.0019). Thus, among patients who present within 12 hours of the onset of chest pain to a tertiary care center that is capable of performing primary PCI expeditiously, data support the use of primary PCI over fibrinolysis. Fibrinolysis is also limited by post-lysis TIMI 3 flow of 50% lesions) or to culprit-only PCI. Immediate nonculprit PCI was associated with a reduction in the primary endpoint of cardiac death, nonfatal MI, or refractory angina (hazard ratio 0.35, 95% CI 0.21 to 0.58, p < 0.001) with significant reductions in both nonfatal MI and refractory angina. The CvLPRIT trial was a smaller trial randomizing 296 patients in the United Kingdom to complete revascularization by PCI (either at the time of primary PCI or staged prior to hospital discharge) versus culprit-only PCI in the setting of STEMI. The primary endpoint of any death, recurrent MI, heart failure, and ischemia-driven revascularization within 12 months occurred in 10.0% in the complete revascularization group versus 21.2% in the culpritonly group (p = 0.009). The DANAMI-3-PRIMULTI trial subsequently evaluated the role of FFR-guided complete revascularization in STEMI. In that study of 627 patients randomized to culprit-only PCI versus FFR-guided revascularization before discharge, FFR-guided complete revascularization was associated with a lower rate of the primary endpoint of all-cause death, nonfatal MI, or ischemia-driven revascularization at a median follow-up of 27 months (hazard ratio 0.56, 95% CI 0.38 to 0.83, p = 0.004). Based on multiple positive trials demonstrating the benefit of complete revascularization of nonculprit lesions in STEMI patients, the 2015 focused update of the ACC AHA STEMI guidelines changed the recommendation regarding noninfarct PCI in STEMI from class III (harm) to class IIB, stating that PCI to a noninfarct vessel may be considered in selected patients at the time of primary PCI or as a staged procedure. Since that guideline update, further evidence has supported multivessel PCI in STEMI. The 2019 COMPLETE trial randomized 2016 patients with STEMI to culprit-only or staged multivessel PCI and demonstrated a reduced risk of cardiovascular death or MI (7.8% vs. 10.5%, p = 0.004) and a reduced risk of cardiovascular death, MI, or ischemia-driven revascularization (8.9% vs. 16.7%, p < 0.001) in the multivessel PCI group at 3 years. A secondary analysis of that trial demonstrated that the benefit of

multivessel PCI was consistent regardless of whether staged multivessel PCI was performed during or after the index hospitalization. However, this topic remains somewhat controversial as illustrated by the 2018 CULPRIT-SHOCK randomized trial that compared culprit-lesion–only PCI to immediate multivessel PCI in 706 patients with acute MI, cardiogenic shock, and multivessel CAD. That trial demonstrated a high risk of death or renal replacement therapy at 30 days in the multivessel PCI group (55.4% vs. 45.9%, p = 0.01) and a similar risk of 1-year death and recurrent MI between groups.

Coronary Artery Bypass Graft Surgery Although certain patients with stable CAD and non–ST-elevation ACSs should be preferentially treated with CABG over PCI, there is very little role for CABG in the setting of STEMI given the need for immediate reperfusion. In the setting of STEMI, CABG is typically reserved for patients with AMI mechanical complications (e.g., papillary muscle rupture and ventricular septal rupture), PCI complications, or failed PCI.

Antiplatelet Agents Just as aspirin is the cornerstone of treatment for all UA/NSTEMI patients, it is also a class I recommendation for STEMI patients (see Fig. 40.4). Aspirin is associated with a mortality benefit similar to that achieved by streptokinase. Unless there is a serious contraindication to its use, a loading dose of 162 to 325 mg of nonenteric-coated aspirin is currently recommended for all STEMI patients (class I recommendation). If there is any question as to whether the patient received aspirin prior to arrival in the emergency department, another dose should be given. If the patient is vomiting, aspirin can be given by rectal suppository if necessary (at the same dose). All post-PCI STEMI patients should receive aspirin 81 mg indefinitely. When significant hypersensitivity to aspirin exists, clopidogrel should be given in its place (class I recommendation). A platelet P2Y12 receptor inhibitor should be used routinely in all patients with STEMI regardless of whether or not reperfusion therapy is received and should be continued for at least 1 year (class I recommendation). There are currently three oral P2Y12 inhibitors in

contemporary practice: clopidogrel, prasugrel, and ticagrelor. Clopidogrel and prasugrel are thienopyridines, which are prodrugs that require conversion to an active metabolite in the cytochrome P450 system. Ticagrelor is a nonthienopyridine, which is an active drug. Clopidogrel is metabolized by CYP2C19, and approximately 25% of patients may carry a reduced function CYP2C19 allele leading to lower levels of the circulating active metabolite and higher event rates. However, routine platelet function testing or CYP2C19 genotyping is not recommended as it is not associated with improved outcomes. The recommended loading dose of clopidogrel is 600 mg. In patients treated with oral anticoagulants, clopidogrel is generally favored as it has the lowest bleeding risk profile of the available P2Y12 inhibitors discussed. Prasugrel is a more potent thienopyridine than clopidogrel, and the TRITON-TIMI 38 trial demonstrated that treatment with prasugrel in patients with ACS scheduled for PCI was associated with a reduced risk of MACE but an increase in major and life-threatening bleeding compared with clopidogrel. Prasugrel is considered to be contraindicated in patients with any history of stroke or TIA and relatively contraindicated in patients with other risk factors for bleeding (age >75 years, oral anticoagulation, coagulopathy, or weight 75 years old or who have renal insufficiency (creatinine >2.5 mg/dL for men and >2.0 mg/dL for women), the use of an LMWH is not recommended.

Anti-Ischemic Agents Nitroglycerin and beta-blockers are first-line anti- ischemic agents. Nitroglycerin is initiated by a 0.4-mg sublingual tablet (repeated several times every 5 minutes if symptoms persist and hypotension does not develop), followed by intravenous infusion of 10 to 20 μg/min (titrated up until resolution of symptoms or until hypotension develops). An intravenous dose of 200 μg/min is considered a ceiling, although the dose is occasionally increased to 400 μg/min if needed. Notably, large-scale randomized trials have failed to observe any reduction in mortality with nitroglycerin, and indications for this agent in the setting of STEMI are thus to relieve ischemia, hypertension, or pulmonary congestion. Nitrates should not be utilized in the setting of a suspected right ventricular (RV) infarction as venous pooling can

result in significant hypotension. Sildenafil use within 24 hours of presentation is a class III recommendation against the use of nitroglycerin. Similar caution is applicable to other PDE5 inhibitors. Current American STEMI guidelines do not provide a formal recommendation on the use of nitrates in the context of STEMI. Beta-blockers are administered along with nitroglycerin and help to blunt the reflex tachycardia that may occur from their use. A large body of evidence supports the use of beta-blockers in the setting of acute MI. A pooled analysis from the prefibrinolytic era in >24,000 patients (dominated by the ISIS-1 trial) documented a 14% reduction in 7-day mortality (23% long-term reduction) among patients who received beta-blockade. Interestingly, in the reperfusion era, only the CAPRICORN trial with carvedilol has shown a mortality reduction with a beta-blocker. Based on this trial, oral beta-blockers should be administered in the first 24 hours after STEMI presentation in patients without evidence of significant bradycardia or cardiogenic shock (class I recommendation). The use of beta-blockade with metoprolol in the COMMIT trial was associated with an increased risk of precipitating cardiogenic shock however. Blunting the heart rate in patients with compensatory tachycardia likely resulted in this finding. Current guidelines highlight caution in patients at risk for cardiac shock. Risk factors include age >70, systolic blood pressure 110 or 5 were excluded. Study participants were randomly assigned to eplerenone or placebo. Patients in the eplerenone group had a significant reduction in mortality (14.4% vs. 16.7%), cardiovascular mortality (12.3% vs. 14.6%), and combined cardiovascular mortality or hospitalization for cardiac events (26.7% vs. 30.0%). Currently, the ACC/AHA recommends the use of aldosterone blockade in post-MI patients who have an EF < 40%, are already receiving therapeutic doses of ACE-I and beta-blockade, and have either heart failure or diabetes, assuming the patient does not have significant renal dysfunction or hyperkalemia (class I recommendation).

Lipid Management All patients with STEMI should be treated with high-intensity statin therapy (class I recommendation). The PROVE-IT TIMI 22 trial randomized 4,162 patients with ACS to moderate-intensity statin (pravastatin 40 mg daily) versus high-intensity statin (atorvastatin 80 mg daily) for a mean follow-up of 24 months. High-intensity statin therapy significantly reduced the primary endpoint of death, MI, UA rehospitalization, revascularization, or stroke at 2 years (26.3% vs. 22.4%, p = 0.005). It is reasonable to obtain a fasting lipid profile within 24 hours of presentation in all patients with STEMI (class IIa recommendation).

CARDIOGENIC SHOCK Cardiogenic shock complicates 5-10% of STEMI and is associated with increased in-hospital mortality of 40% to 50%. Left ventricular pump failure is the primary mechanism of cardiogenic shock in acute MI, as mechanical complications of acute MI are rare in the primary PCI era. Regardless, a high index of suspicion for mechanical complications and careful imaging are needed in patients with STEMI complicated by cardiogenic shock as the optimal treatment may differ depending on the underlying etiology.

Intraaortic Balloon Pump Intraaortic balloon pump (IABP) counterpulsation is a useful therapy for select patients with STEMI and cardiogenic shock refractory to medical therapy (class IIa recommendation). However, the routine use of IABP in patients with STEMI is generally discouraged. The IABP-SHOCK II trial randomized 600 patients with acute MI complicated by cardiogenic shock to IABP or no IABP. The primary endpoint of 30-day mortality occurred in 39.7% in the IABP group versus 41.3% in the no IABP group (p = 0.69), suggesting that routine IABP insertion in patients with cardiogenic shock complicating MI is not helpful. IABP may be useful in patients with severe MR or VSR after MI as a temporizing measure as described below. IABP may be considered for unstable ventricular arrhythmias as well.

Percutaneous Left Ventricular Assist Device Other options for mechanical circulatory support in acute MI include the Impella device, tandem-heart device, or extracorporeal membrane oxygenation, which is complete cardiopulmonary bypass. There are limited data to support device versus device comparisons in patients with post-MI cardiogenic shock. Use of these devices is reasonable (class IIb recommendation) and should be guided by local expertise and case-by-case selection based on the needs of the specific patient.

Temporary Right Ventricular Pacing

RV pacing may be indicated in the management of conduction disturbances (class I recommendation for patients with symptomatic bradycardia refractory to medical therapy). Bradyarrhythmias are common in the setting of inferior MIs, especially with RV involvement. If such a patient exists who does not respond to chronotropic agents such as dobutamine or dopamine, temporary RV pacing may be needed until electrical and hemodynamic stability returns. Complete heart block can be seen with anterior MIs that involve a large septal perforator branch.

MECHANICAL COMPLICATIONS Several mechanical complications of acute MI should be considered in the patient with STEMI and persistent symptoms or hemodynamic instability. Patients with delayed presentations of STEMI are at particularly increased risk for mechanical complications, and an increased index of suspicion is prudent when treating late presenters.

Mitral Regurgitation Mitral regurgitation after MI may occur due to either (a) acute papillary muscle rupture that results in hemodynamic and respiratory instability or (b) left ventricular dysfunction resulting in ischemic functional MR related to mitral valve tethering or restriction. Papillary muscle rupture in the setting of acute MI results in mitral valve leaflet flail with acute severe mitral regurgitation (MR). The posteromedial papillary muscle is more commonly involved (75%) than the anterolateral papillary muscle, because the posteromedial papillary muscle has a singlevessel blood supply in the majority of patients, whereas the anterolateral papillary muscle is supplied by two vessels in the majority of patients. Acute MR presents with respiratory failure, pulmonary edema, and cardiogenic shock in some patients. A systolic murmur may or may not be audible, and a high index of suspicion is needed in unstable patients with right coronary or left circumflex infarcts. Patients with papillary muscle rupture should be referred for emergent mitral valve surgery, although acute MR carries a 20% mortality rate even in patients with successful mitral valve replacement.

Ischemic functional MR is fairly common with 20% of patients having some degree of MR and 10% with at least moderate MR after STEMI treated with primary PCI. Treatment of these patients includes guideline-directed medical therapy for LV dysfunction and salt/fluid management including diuretics if needed. Increasing severity of ischemic MR after MI is associated with worse short- and long-term prognosis.

Ventricular Septal Rupture Ventricular septal rupture is a relatively infrequent complication that presents with a systolic murmur and heart failure or shock. This condition is typically fatal unless corrected surgically. There is very limited data on percutaneous closure of post-MI ventricular septal defects. Patients who present with ventricular septal rupture who are initially hemodynamically stable may be temporized with vasodilators and an IABP to minimize left to right shunting. Surgical mortality for this condition is high, and a delayed approach to allow for healing of the infarct zone prior to surgery has been advocated in selected patients who are stable with initial conservative therapy.

Free Wall Rupture LV free wall rupture presents with chest pain and rapid hemodynamic deterioration related to tamponade physiology. The classic risk factors for this condition include advanced age, first MI presentation, anterior MI location, and female sex. Use of corticosteroids or nonsteroidal antiinflammatory drugs is also associated with increased risk of ventricular rupture during MI, and these medicines should be avoided in MI patients. Patients with administration of fibrinolytic therapy >14 hours after symptoms onset are also at increased risk. In some patients, left ventricular free wall rupture may stabilize resulting in a left ventricular pseudoaneurysm. Surgical treatment is the only option to address LV free wall rupture in survivors of this highly fatal condition.

Pericarditis Pericarditis after acute MI is rare in the reperfusion era. Pain that occurs within the first 24 hours of an STEMI is unlikely to be secondary to

pericarditis. Pericardial effusion is common, although frank tamponade is infrequent. Unlike ischemic pain, pericarditic pain is more often sharp, worse with deep inspiration and recumbency. A pericardial friction rub is helpful in making the diagnosis, although it is not always present. The ECG may show diffuse ST elevation with PR depression. Pericarditis that occurs 2 to 3 weeks post-MI may be related to Dressler syndrome, which is known as post-MI syndrome. This is an autoimmune form of pericarditis that may result in chest pain and fever with elevated inflammatory markers. This inflammatory reaction occurs in 1% to 2% of AMI patients. The clinical course is usually benign, although constrictive pericarditis may result. The treatment is generally the same as for acute pericarditis. Aspirin is the favored treatment for pericarditis post-MI (class I recommendation), with acetaminophen, colchicine, and/or narcotics reserved as second-line agent (class IIb recommendation). As noted above, steroids and NSAID should be avoided due to the risk of myocardial rupture (class III recommendation).

Left Ventricular Aneurysm Patients with large anterior wall infarcts are at risk for LV aneurysm formation. LV aneurysm may contribute to increased risk of LV thrombus or ventricular arrhythmias. Oral anticoagulant therapy may be considered in STEMI patients with anterior apical wall motion abnormalities (class IIb recommendation).

IMPLANTABLE CARDIOVERTER– DEFIBRILLATOR IMPLANTATION IN PATIENTS AFTER STEMI Several trials have been performed to evaluate the efficacy of implantable cardioverter–defibrillator (ICD) insertion in patients after MI. The following discussion outlines some of these trials and discusses the current ACC/AHA guidelines.

The DINAMIT trial evaluated the role of prophylactic ICD insertion in patients with an LVEF of ≤35% and a history of MI in the preceding 6 to 40 days. Patients with NYHA class IV heart failure, sustained VT > 48 hours after MI, and who had received CABG or three-vessel PCI as management for their MI were excluded. While the patients who received an ICD had less death due to arrhythmia compared to controls, at a mean follow-up of 30 months, there was no significant difference in all-cause mortality (7.5% vs. 6.9%). The IRIS trial also evaluated the benefit of prophylactic ICD insertion in patients with a recent MI (5 to 31 days). Results again showed no difference in all-cause mortality between patients who did and did not receive an ICD. MADIT II evaluated the benefit of delaying ICD insertion until at least 1 month after MI. The trial enrolled 1,232 patients with a history of MI more than 30 days prior to enrollment (more than 90 days if bypass surgery was performed) and an LVEF ≤ 30%. Patients were randomized to prophylactic ICD implantation or standard medical therapy. At an average follow-up of 20 months, ICD implantation significantly reduced all-cause mortality (14.2% vs. 19.8% for standard therapy). This survival benefit was entirely due to a reduction in SCD (3.8% vs. 10.0% for standard therapy). The SCD-HeFT trial randomized 2,521 patients with ischemic or nonischemic cardiomyopathy, an LVEF ≤ 35%, and NYHA class II or III heart failure to ICD implantation, amiodarone, or placebo. At 5 years, allcause mortality was significantly reduced in patients who received an ICD (29% vs. 36% with placebo). This benefit did not differ based on the etiology of heart failure but was nullified in patients with NYHA class III symptoms. Amiodarone therapy was not beneficial. Based on multiple studies, the current ACC/AHA STEMI guidelines recommend that an ICD should be inserted in any patient with VF or sustained hemodynamically significant VT that occurs 48 hours after acute MI (class I recommendation). This is provided that the arrhythmia is not secondary to recurrent ischemia or MI. The ACC/AHA ICD guidelines were updated in 2017 and provide guidance on the use of primary prevention ICD for patients with ischemic heart disease who have not suffered VT/VF. In patients with LVEF ≤ 35% at least 40 days post-MI and at least 90 days postrevascularization with NYHA class II to III heart failure on guidelinedirected medical therapy, ICD is indicated if expected survival is >1 year

(class I recommendation). In patients with LVEF ≤ 30% at least 40 days post-MI and 90 days postrevascularization with NYHA class I symptoms on guideline-directed medical therapy, ICD is also indicated if expected survival is >1 year (class I recommendation). In those with nonsustained VT due to prior MI, LVEF of ≤40%, and inducible VT/VF on an electrophysiology study, ICD is also indicated if expected survival is >1 year (class I recommendation). Wearable cardioverter–defibrillators have been used in patients who are considered at risk for SCD but do not meet the above criteria, such as patients waiting for reassessment of LVEF after coronary artery revascularization. The VEST trial randomly assigned 2,302 patients with acute MI and LVEF of ≤35% in a 2:1 ratio to a wearable cardioverter– defibrillator plus medical therapy or medical therapy alone and evaluated a primary endpoint of sudden death or death from ventricular arrhythmias at 90 days. There was no difference in the primary endpoint (1.6% device group vs. 2.4% control group, p = 0.18) at 90 days, but there was a significant reduction in death from any cause (3.1% vs. 4.9%, p = 0.04) in the device arm at 90 days. While wearable cardioverter–defibrillators are currently not recognized in the ACC/AHA guidelines, their use in select patients may be reasonable.

PREDISCHARGE STRATIFICATION

RISK

Stress testing is a widely used mechanism for risk stratification after AMI. In STEMI patients who do not receive a left heart catheterization, noninvasive testing for myocardial ischemia should be performed before discharge (class I recommendation). Other reasonable indications for noninvasive ischemia testing prior to discharge include (a) evaluation of functional significance of noninfarct stenosis or (b) to guide postdischarge exercise prescription (both class IIb recommendations). Every patient after an AMI should have an assessment of left ventricular function. Patients with moderate to severe left ventricular dysfunction are at higher risk for adverse events. For these individuals, the use of beta-blockers and ACE inhibitors is especially

important. Additionally, the implantation of an ICD may be indicated, after a period of convalescence from an AMI.

SUMMARY STEMI is a distinctly different clinical entity than UA/NSTEMI, with a higher early mortality. Risk models such as the TIMI and GRACE risk scores are used to determine prognosis, not to guide therapy. In STEMI, there is a limited window of opportunity (generally 75 years) predicts the worst outcome for 30-day mortality and receives 3 points in the risk model. The other variables listed receive 1 to 2 points each. Hypotension (i.e., systolic blood pressure 10 mm Hg upon inspiration). In addition, the right atrial pressure is elevated and the y-descent is extremely blunted (arrow). a, atrial contraction; x, atrial relaxation; v, atrial filling (ventricular systole); y, atrial emptying (ventricular diastole). (Modified from Wu LA, Nishimura RA. Pulsus paradoxus. N Engl J Med. 2003;349(7):666.)

Figure 41.7 A:Subcostal long-axis view demonstrating a large pericardial effusion adjacent to the RA. B:Same view demonstrating right atrial wall inversion (arrow) during systole.

Note that IVC plethora is present in both images. HV, hepatic vein; PE, pericardial effusion; RA, right atrium.

Figure 41.8 A:Parasternal short-axis view demonstrating that the right ventricle, while small and underfilled, remains open during systole (arrow). B:Same view demonstrating RV diastolic collapse (smaller arrow). LV, left ventricle; PE, pericardial effusion.

Treatment Patients with acute or subacute rupture should be supported with intravenous fluids and, if hypotensive, with vasopressors while emergency cardiothoracic surgical consultation is obtained. The ideal repair when anatomy allows is a primary patch repair that covers the defect, though sutureless repair with a patch and glue, or a collagen sponge patch, can be pursued in a subset of patients. Pericardiocentesis should be performed only in the operating room, as decompression of the pericardial space may result in further bleeding. If a patient is hemodynamically unstable despite treatment with fluids and vasopressors, pericardiocentesis can be performed as a last resort because decompression may be the only chance for survival.

Pseudoaneurysm Although it is an infrequent complication of AMI, it is important to recognize a pseudoaneurysm because it is prone to rupture. It occurs when pericardial adhesions and thrombus seal off an area of myocardial rupture. Although this can happen at any location, pseudoaneurysms most commonly occur at the inferior or lateral wall, potentially due to dependent pericardial adhesions developing in the recumbent postinfarct patient. In comparison to a true aneurysm, there is no myocardium between the LV cavity and the pericardial space (Fig. 41.9). Risk factors for the development of postinfarction pseudoaneurysm are similar to those for myocardial free wall rupture.

Figure 41.9 Pseudoaneurysm versus aneurysm. (Modified from Cercek B, Shah PK. Complicated acute myocardial infarction: heart failure, shock, mechanical complications. Cardiol Clin. 1991;9(4):569-593.)

Symptoms and Signs Pseudoaneurysms are often silent and are discovered on follow-up imaging or postmortem. Gradual enlargement of the aneurysmal cavity can lead to progressive heart failure symptoms, although this is rare. Some patients present with ventricular arrhythmias. Others develop arterial embolization after expulsion of thrombus from the aneurysmal cavity. The physical examination can be normal or consistent with CHF. Rarely, a patient will present in CS.

Diagnosis The ECG may show persistent ST elevation or regional pericarditis, although it most often demonstrates nonspecific ST changes. CXR can demonstrate an abnormal bulge around the site of involved myocardium but more frequently shows cardiomegaly. There are several imaging modalities available for diagnosis, including contrast ventriculography, TTE, TEE, magnetic

resonance imaging (MRI), and computed tomography (CT). None of these tests has been 100% accurate, and no adequate comparisons between modalities have been made. Contrast ventriculography is the “gold standard” and has been associated with a high degree of diagnostic accuracy. One will see a narrow orifice leading to a saccular cavity. If concomitant coronary arteriography is performed, there will be a lack of vessels at the site of the pseudoaneurysm. Because this is an invasive modality, TTE with color Doppler is a reasonable test to perform first, although its diagnostic accuracy was found to be 26% for this condition (Fig. 41.10). Although TEE and MRI have shown a higher degree of diagnostic accuracy, only small numbers have been studied and a definitive conclusion regarding superiority cannot be made.

Figure 41.10 A:Apical long-axis view demonstrating a pseudoaneurysm of the posterior LV wall. B:Same view with Doppler demonstrating the rupture site (arrow) with turbulence of blood flow in and surrounding the cavity. LA, left atrium; AML,

anterior mitral leaflet; PML, posterior mitral leaflet; Pan, pseudoaneurysm; Ao, aorta.

Treatment While little is known about the natural history of medically managed LV pseudoaneurysms, traditional thinking supports urgent surgery following diagnosis, due to a high risk of progressive rupture. If the pseudoaneurysm is incidentally diagnosed or the patient is asymptomatic, the patient should be monitored until surgical evaluation has occurred. Successful percutaneous closure of pseudoaneurysms can be considered as part of a “Heart Team” approach.

Left Ventricular Aneurysm A true ventricular aneurysm differs anatomically from a pseudoaneurysm in that myocardium is present in its wall and there is no communication between the ventricular cavity and pericardial space (see Fig. 41.9). Its incidence following AMI has been reported as high as 38%. With the advent of reperfusion therapy, its frequency has decreased to between 8% and 15%. Ventricular aneurysms most commonly complicate transmural anterior wall MIs and are thought to be the result of infarct expansion. In contrast to postMI pseudoaneurysms, true ventricular aneurysms rarely rupture because the walls become fibrotic and calcified with time. True aneurysms have a wide base and are frequently associated with mural thrombus.

Signs and Symptoms Aneurysms place the entire ventricle, including the noninfarcted portion, at a mechanical disadvantage. Contractile energy is expended during passive outward expansion of the aneurysmal wall, and cardiac output decreases. This functional decline is more significant with acute aneurysms because the aneurysmal wall is more compliant and therefore expands to a greater degree during systole. Additionally, the distorted geometry can lead to misalignment of the mitral valve apparatus and result in MR. Patients can present early or several weeks following AMI. They can be asymptomatic or develop CHF, CS, or recurrent ventricular arrhythmias. The

index event is less often systemic embolization. The physical examination may demonstrate signs of CHF and/or CS. In addition, patients may have a diffuse, dyskinetic apical impulse that is shifted leftward. Auscultation may reveal a murmur suggestive of MR or a third heart sound.

Diagnosis In addition to the above physical findings, as with pseudoaneurysms, the CXR may demonstrate cardiomegaly and a bulge representing the aneurysmal area. The ECG will often show evidence of a transmural anterior MI and persistent ST-segment elevation. TTE is the diagnostic test of choice and will show thinning of the myocardium and dyskinetic wall motion at the site of infarction. Thrombus should always be excluded, as it is found in more than half of the surgical and autopsy cases that have been studied. If there is inability to exclude thrombus with a standard surface echocardiogram, contrast can be given simultaneously to improve distinction between the ventricular cavity and endocardial lining. Other imaging modalities such as cardiac MRI or CT scanning can be useful in this regard.

Treatment Diagnosis of a ventricular aneurysm does not change the treatment algorithm for a post-MI patient with comparable degrees of heart failure and/or CGS (see previous section). It is important to note that administration of an ACE-I within 24 hours of infarction is especially crucial in this situation, because of the drug’s inhibitory effect on infarct expansion and beneficial effect on ventricular remodeling. If a patient is stable off mechanical and vasopressor support, an ACE-I should be started. Surgery, which should include an LV aneurysmectomy and concomitant CABG, may be indicated when there are symptoms and signs related to the aneurysm. However, careful evaluation and patient selection are necessary as there was no improvement in long-term outcome when aneurysmectomy was added to CABG alone in a recent RCT. Patients with small or moderatesized, asymptomatic aneurysms should not undergo surgery. They do require medical management for heart failure when it is present. Management of large, asymptomatic aneurysms remains controversial, and decisions to proceed with surgery are often individualized as above.

Anticoagulation for at least 3 months is indicated for all post-STEMI patients who develop a mural thrombus in the acute setting. This applies to diagnoses made within 1 month of the event. Anticoagulation is indicated because systemic embolization can occur in as many as 10% with documented mural thrombi, and the risk of late thromboembolism appears to be decreased with oral anticoagulant therapy. The decision to empirically anticoagulate patients who develop an LV aneurysm but no identifiable thrombus in the acute setting is controversial, especially in the setting of increased risk of bleeding from dual antiplatelet therapy following drug eluting stent placement.

ADDITIONAL COMPLICATIONS Right Ventricular Infarction with Hemodynamic Compromise RV infarction rarely happens in isolation and more commonly occurs during an inferior or inferoposterior LV MI. Patients present with various degrees of RV dysfunction, but only 10% to 15% develop hemodynamically significant RV impairment. This typically occurs when there is an ostial or proximal RCA occlusion prior to takeoff of the RV marginal branches.

Symptoms and Signs If one understands the hemodynamic relationship between the LV, RV, and pericardium, the symptoms and signs of RV infarction become clear. It is important to realize that many of the hemodynamic changes overlap with tamponade, constrictive pericarditis, and restrictive cardiomyopathy. This makes clinical context and echocardiographic examination very important. When RV infarction occurs, the RV filling pressure becomes elevated due to systolic and diastolic dysfunction, which in turn causes elevation of right atrial filling pressures. Simultaneously, a decrease in RV output leads to a reduced LV end-diastolic volume and the PCWP will be low. This is not always the case when there is concomitant LV dysfunction from a previous infarction or the current event. LV preload becomes further reduced when

intrapericardial pressure is increased by abrupt dilation of the RV. Similar to tamponade, the LV and RV become interdependent. This combination of events leads to the triad of hypotension, elevated neck veins, and clear lung fields. Neck vein distention may not be seen if the patient is hypovolemic but may become apparent following aggressive fluid resuscitation, one of the key aspects of treatment.

Diagnosis This diagnosis should be considered in any patient who presents with inferior ST-segment elevation on ECG. ST elevation in lead V4R is specific for RV involvement. RV infarction should also be considered in patients with ST depression in leads V1 and V2, as this may represent acute infarction of the posterior myocardium as opposed to septal, subendocardial ischemia. TTE can confirm the diagnosis by demonstrating hypokinesis and dilatation of the RV. RHC can help confirm the diagnosis, but findings are nonspecific and may overlap with those of tamponade, constriction, and restriction. One will see elevated RV filling pressures that are equal to or greater than LV filling pressures, normal or low pulmonary arterial and PCWP, and a reduced CI. Another clue to significant RV involvement in patients with inferior or posterior MI is hypotension following the administration of preload reducing agents such as diuretics and nitrates.

Treatment Similar to patients with AMI and CS secondary to LV dysfunction, patients with AMI complicated by severe RV dysfunction should undergo emergency diagnostic angiography and revascularization. If shock is present, the first line of therapy is aggressive fluid resuscitation. This is done with isotonic saline until the PCWP is between 15 and 18 mm Hg. If shock remains after this is achieved, an inotropic agent should be added. Dobutamine is the preferred drug in this situation because it causes less hypotension. If vasopressors are required, a pure α-agonist should be avoided, as it will lead to pulmonary arterial vasoconstriction and further decrease forward flow into the left ventricle. Mechanical circulatory support options that primarily support the right ventricle are the Impella RP pump and the Protek Duo device.

It is important to avoid factors that increase RV afterload, such as hypoxemia, α-agonists, and elevations in PCWP. In mechanically ventilated patients, the use of PEEP should be minimized and one should avoid agents that decrease RV preload. This includes medications such as nitrates, morphine, and diuretics but also dysrhythmias that lead to disruption of atrioventricular (AV) synchrony, such as atrial fibrillation and high-degree AV block. Atrial fibrillation must be dealt with emergently in the hemodynamically unstable patient following RV infarction, with immediate direct-current cardioversion (DCCV). If the patient is not hemodynamically compromised, a trial of antiarrhythmic therapy can be attempted; however, if sinus rhythm is not restored promptly, DCCV should be performed. Management of bradycardia in AMI is discussed in a subsequent section. It is important to know that if a patient with RV infarction requires temporary pacing, both atrial and ventricular leads should be placed, in order to maintain AV synchrony.

Dynamic Left Ventricular Outflow Tract Obstruction Although development of dynamic LVOT obstruction is a rare complication of MI, it is important to recognize because many of the traditional therapies used in the treatment of AMI complicated by CS should be avoided. These include nitrates, afterload reduction, diuretics, IABPs, and inotropic agents. Dynamic LVOT obstruction most often occurs in the setting of an anteroapical MI with compensatory basal hyperkinesis. This can result in systolic anterior motion (SAM) of the anterior mitral leaflet against the interventricular septum, which results in LVOT obstruction.

Symptoms and Signs Patients with dynamic LVOT obstruction usually have chest pain and evidence of an anterior or anteroapical STEMI. This complication has also been seen in non–ST-elevation myocardial infarction (NSTEMI), but much less frequently. Symptoms and signs of CHF and CS are often present (see above). Patients can have a holosystolic murmur at the left lateral sternal border that radiates to the apex and represents MR in addition to a harsh

crescendo–decrescendo systolic murmur in the left second intercostal space, representing LVOT obstruction.

Diagnosis The possibility of LVOT obstruction should be considered in patients who have progressive hemodynamic deterioration in the setting of standard medical and mechanical therapies used to treat patients with AMI and CGS. The diagnosis is made by TTE. LVEF may be normal or depressed. Apical hypo or akinesis along with hyperkinesis of the basal segments of the heart will be seen, in addition to SAM and eccentric mitral regurgitation. The LVOT best interrogated with continuous-wave Doppler in the apical fiveand three-chamber views.

Treatment Standard revascularization must be instituted. What is different are the supportive measures used during the peri-infarction period. Beta-blockers and fluid boluses improve dynamic gradients by increasing diastolic filling time and increasing preload, respectively. If shock is present, an α-agonist should be used. All of these therapies decrease the degree of LVOT obstruction. Phenylephrine, the most commonly used α-agonist, is started at 20 to 40 μg/min and titrated upward, until there is clinical improvement or the maximum dose has been reached.

Pericarditis There are two forms of pericarditis that occur in the setting of MI. The first, typically occurring within 24 to 96 hours of transmural MI, is a form of localized inflammation in the pericardial region above the necrotic myocardium, which tends to run a benign course. The second, a form of postcardiac injury syndrome also referred to as Dressler syndrome, can manifest 1 to 8 weeks following MI. Although the exact mechanism is unclear, it is felt to be the result of an autoimmune reaction involving myocardial antigen and antibody complexes. This form of pericarditis tends to be a more systemic inflammatory process, is often refractory to first-line therapies, and frequently recurs.

Symptoms and Signs

Patients with pericarditis often develop positional chest pain. This tends to be sharp, pleuritic, exacerbated by recumbency, and commonly radiates to the trapezius ridge. If the patient has Dressler syndrome, he or she may also complain of arthralgias and myalgias. Dressler syndrome can also be associated with pleuritis and pleural effusions. Although these effusions are typically small, they may enlarge and cause dyspnea. Patients may be febrile in both forms of pericarditis, and those with Dressler syndrome can run fevers as high as 40°C. All patients with pericarditis may have leukocytosis and elevation of inflammatory markers such as the erythrocyte sedimentation rate and C-reactive protein. Physical examination may demonstrate a pericardial friction rub.

Diagnosis Symptoms and the presence of a pericardial friction rub are quite specific for pericarditis. ECG can be helpful but is less sensitive, especially in the acute situation, as the evolutionary changes seen following MI can mask the typical ECG features of pericarditis (Table 41.2). Although TTE is not diagnostic in situations of post-MI pericarditis, it must be obtained to rule out a significant pericardial effusion, seen more commonly in patients with Dressler syndrome. Absence of a pericardial effusion does not exclude the diagnosis. Pericardial enhancement can be confirmed utilizing a contrast MRI.

Table 41.2 ECG Changes in Pericarditis versus STEMI

aIn pericarditis, the evolution of repolarization abnormalities does not always occur simultaneously as they typically do in MI. In addition, the distribution of repolarization abnormalities in myocardial infarction remains constant, whereas in pericarditis, multiple areas on the ECG can demonstrate different repolarization patterns. bIf ST-segment elevation does not resolve by 6 weeks, consider the possibility of ventricular aneurysm or a large area of dyskinetic myocardium.

Treatment Anti-inflammatory agent, aspirin, is the first line of therapy. If patients are refractory to standard doses, as much as 650 mg every 4 to 6 hours may be used. When high doses are needed, it is advisable to place the patient on an acid-suppressive regimen. Some patients will be refractory to or unable to take high-dose aspirin therapy. In these patients, 0.6 mg of colchicine every 12 hours and/or 650 mg of acetaminophen every 4 to 6 hours can be tried. Nonsteroidal anti-inflammatory drugs (NSAIDs) other than aspirin and corticosteroids should be avoided. Corticosteroids and NSAIDs adversely affect myocardial scar formation, which can lead to thinning of the scar and, in some circumstances, infarct expansion. There are reports suggesting that both drug classes put the patient at increased risk for myocardial rupture following AMI.

ARRHYTHMIC COMPLICATIONS Bradyarrhythmias In the setting of AMI, management of bradyarrhythmias is complex because decisions regarding temporary and permanent pacing must be made and require multiple considerations. In the acute setting, if a patient is hemodynamically stable despite a bradyarrhythmia, a decision must be made regarding the need for prophylactic, backup pacing. This requires one to predict which patients are likely to progress to a life-threatening rhythm abnormality such as third-degree AV block. Sinus bradycardia occurs in approximately 30% to 40% of AMIs, most commonly with inferior MI and reperfusion of the RCA. Although multiple

mechanisms can be responsible, the most common is hyperactivity of parasympathetics due to stimulation of vagal afferents. This is termed the Bezold–Jarisch reflex and causes both bradycardia and hypotension. When patients become symptomatic from sinus bradycardia or from sinus pauses >3 seconds in duration, intravenous atropine is the first line of therapy. This should be administered in doses of 0.5 to 1 mg every 3 minutes until the patient is no longer symptomatic or a total dose of 0.4 mg/kg has been reached. If symptomatic bradycardia persists, transcutaneous or transvenous pacing must be initiated. The development of atrioventricular conduction block (AVB), intraventricular conduction delay (IVCD), and/or bundle branch block (BBB) in the setting of AMI is associated with an increased risk of in-hospital mortality. Decisions regarding prophylactic or therapeutic temporary pacing depend on the infarction location, the type of block and its presumed relationship to the AV node, the extent of preexisting conduction system disease, and the presence or absence of symptoms. When dealing with any form of heart block, its relationship to the AV node is an important factor to consider. This is significant because blocks proximal to or within the AV node, often referred to as intranodal block, are generally benign, with prophylactic and eventual permanent pacing typically not required. This is in contradiction to infranodal blocks, which tend to be more dangerous, often require prophylactic and therapeutic temporary pacing, and frequently result in permanent pacemaker insertion prior to hospital discharge. Typical intranodal blocks are first-degree and seconddegree, Mobitz type I AVB. These are usually seen in inferior or inferoposterior AMIs, and the RCA is usually the culprit artery, although the LCx can be involved. If third-degree AVB develops in the intranodal region, the QRS width is typically 120 ms and abnormal late potentials recorded on a signal-averaged ECG after acute MI signifies somewhat higher risk for SCD. However, the signal-averaged ECG suffers from a high false-positive rate, which limits its clinical utility. Depressed heart rate variability is an independent predictor of mortality and arrhythmic complications after acute MI. A depressed baroreflex sensitivity value (3.0 ms/mm Hg) is associated with a threefold increase in the risk of mortality. These tests may provide useful prognostic information, but at present, only assessment of ejection fraction (EF). For those patients without an indication for ICD placement post-MI, studies have shown the lack of benefit of early (days 1 to 40) ICD placement in the setting of LVEF 0.2 mV), or the absence of ECG changes during angina are important predictors of future events (see Fig. 42.1). When clinical variables are also considered, heart rate and the presence of ST depression on admission ECG are the most important multivariable predictors.

Biomarkers The presence and degree of troponin elevation on admission and thereafter can identify patients who are at increased risk of experiencing adverse outcomes. Cardiac troponin-I and troponin-T are particularly useful in

identifying high-risk patients with non–ST-elevation ACS. Other markers of inflammation, such as CRP, CD-40, CD-40 ligand, fibrinogen levels, or brain natriuretic peptide (BNP), can add to the prognostic information in NSTEACS. Adding multiple markers to assess a patient may add important prognostic information, as illustrated in the OPUS-TIMI16 (Oral Glycoprotein Ilb/IIIa Inhibition with Orbofiban in Patients with Unstable Coronary Syndromes) trial and the TACTICS-TIMI 18 (Treat Angina with Aggrastat and Determine Cost of Therapy with an Invasive or Conservative Strategy) analyses (Fig. 42.2). However, at the present time, there is no clear consensus on how to incorporate these markers in patient management. The recent development of high-sensitivity troponin (hsTn) assays has significantly increased the sensitivity to detect myocardial necrosis and new rapid evaluation protocols are being adopted in acute care settings to rule out ACS.

FIGURE 42.2 Relative 30-day mortality risks in OPUS-TIM116 (A) and TACTICS-TIM118 (B) in patients stratified by the number of elevated cardiac biomarkers (Tnl, CRP, and BNP). (From Sabatine MS, Morrow DA, de Lemos JA, et al. Multimarker approach to risk stratification in non-ST elevation acute coronary syndromes. Circulation. 2002;105:1760, with permission from Wolters Kluwer Health.)

Risk Scores

An essential element of risk stratification following an ACS is the quantification of short-term and long-term risk. Although there are many historical, physical exam, ECG, and biomarker variables that are significantly and independently associated with worse short-term outcome, the integration of these into an accurate estimation of risk is complex and has traditionally required the use of sophisticated multivariable modeling (Figs. 42.3 and 42.4). Nevertheless, simplified nomograms and risk scores incorporating the most important variables have been derived from a number of these analyses and allow for a reasonably accurate categorization of patients into low-risk, intermediate-risk, and high-risk groups. In the analysis by Boersma et al., patient age, heart rate, SBP, ST-segment deviation, signs of heart failure, and elevation of cardiac markers were the most important predictors of death or MI at 30 days. In the analysis by Antman et al. (TIMI risk score, see Fig. 43.3), age >65 years, >3 coronary risk factors, prior CAD, ST deviation, >2 angina episodes in last 24 hours, use of aspirin within 7 days, and elevated cardiac markers were important in determining death, reinfarction, or recurrent severe ischemia requiring revascularization (termed TIMI risk score). The Global Registry of Acute Coronary Event (GRACE) risk score utilizes age, heart rate, SBP, creatinine, cardiac arrest at admission, ST-segment deviation, abnormal cardiac biomarkers, and Killip class to risk stratify NSTE-ACS patients with scores ranging from 0 to >285, with a score >140 defined as high risk for adverse clinical events based on the analysis by Elbarouni et al.

FIGURE 42.3 TIMI risk score. (Adapted from Antman EM, Cohen M, Bernink PJLM, et al. The TIMI risk score for unstable

angina/non-ST elevation MI. JAMA. 2000;284:835-842.)

FIGURE 42.4 PURSUIT risk score 30-day outcome after non–STelevation ACS. (From Boersma E, Pieper KS, Steyerberg EW, et al. Predictors of outcome in patients with acute coronary syndromes without persistent ST-segment elevation: results from an International trial of 9461 patients. Circulation. 2000;101:2557-2567, with permission from Wolters Kluwer Health.)

During Hospitalization Stratification

and

Predischarge

Risk

According to current ACC/AHA guidelines, patients with refractory angina, worsening heart failure, hemodynamic instability, or ventricular arrhythmias should undergo very early angiography (within 2 hours). Patients who are stable with a GRACE score 75 years and weight 2.5 mg/dL) or hyperkalemia (serum potassium >5.0 mmol/L) were excluded from this trial. These findings led to the inclusion of aldosterone blocking agents for postMI patients with an EF < 40%, symptomatic heart failure, or diabetes who are already on a therapeutic dose of an ACE inhibitor and beta-blocker into the ACC/AHA guidelines with a class I indication.

Beta-Receptor Blockade Beta-receptor blockade (beta-blockers) has long been considered important in patients with acute MI to reduce myocardial ischemia by decreasing wall stress and in turn reducing oxygen demand. However, long-term beta-blocker therapy in the convalescent phase of MI has also been demonstrated to be beneficial in numerous trials. The postulated mechanism of benefit is similar to that seen with the RAAS, which is modulation of LV remodeling and LV dysfunction post-MI. After MI, the sympathetic nervous system has been found to increase infarct size, activate the RAAS, and promote myocyte injury. Oral beta-blockade should be initiated within the first 24 hours post-MI in the absence of signs of heart failure, a low output state, increased risk for cardiogenic shock (age >70, SBP < 120 mm Hg, heart rate >110 or 240 ms, second- or third-degree heart block, active asthma, or reactive airways disease). Intravenous beta-blocker use is reasonable, but no longer has a class I recommendation level in the guidelines after the COMMIT trial demonstrated an increased risk of cardiogenic shock with IV beta-blocker use in STEMI patients. The BHAT trial (Beta-Blocker Heart Attack Trial), a prethrombolytic study, compared 180 to 240 mg of propranolol daily to placebo in post-MI patients, finding a 26% relative risk reduction for all-cause mortality and a 28% reduction in sudden death. Recent evidence has questioned the optimal duration of betablocker continuation in patients post-MI without LV dysfunction with metaanalyses showing limited to no benefit in long-term follow-up. Mechanistically, it is postulated that the benefit of beta-blockers in short- and long-term mortality seen in the thrombolytic area is likely negated by the blunting of sympathetic activation by revascularization, the underlying mechanism of beta-blocker benefit in this patient population. Current ACC/AHA guidelines recommend continuation of beta-blocker therapy for 3 years post-MI in patients with preserved LV function. Numerous landmark trials have demonstrated the benefit of beta-blockers in patients with reduced LV function, including in the post-MI setting. The MERIT-HF (Metoprolol CR/XL Randomized Intervention Trial in Congestive Heart Failure) trial evaluated the use of metoprolol in chronic CHF with EF < 40% and found a 33% reduction in mortality. This trial included 66% of patients with ischemic cardiomyopathy. The COMET (Carvedilol or Metoprolol European Trial) compared carvedilol, a nonselective beta-blocker with alpha-blocking capability, with metoprolol in patients with chronic CHF, and found a 17% reduction in the risk of death from carvedilol, relative to metoprolol. More recently, the CAPRICORN trial (Carvedilol Postinfarct Survival Control in Left Ventricular Dysfunction) tested carvedilol in post-MI patients with significant LV dysfunction (EF ≤ 0.40). This trial found similar reductions in all-cause mortality and sudden death to the BHAT trial. Current ACC/AHA guidelines support the use of beta-blockers indefinitely in all post-MI patients with depressed LVEF in the absence of contraindications with gradual dose titration in those patients with moderate or severe LV dysfunction.

Lipid Management Pharmacologic lipid management after MI is crucial for secondary prevention of cardiac events. Patients should have a lipid profile checked prior to hospital discharge after MI and should have statin therapy initiated before leaving the hospital. The National Cholesterol Education Program (NCEP) published guidelines in 2001 (ATP III) established a LDL goal of 30 min

Factor V Leiden

Bed rest, prolo nged immo bility; longh aul flights

Prothro mbin gene G2 02 10A mutation

O lder age; o besity; smo king

Prothro mbin gene C2 0209T mutation

Previo us histor y of VTE

Antithrombin deficiency

Cancer

Protein C deficiency

M yelo proliferative di sorders, mo noclo nal gammop athies

Protein S deficiency

Paroxysmal nocturnal hemoglobinuria

Elevated factor VIII level

Pregnancy, estrogen-con taining o ral contracep tives, ho rmone replacement, in vitro fertilizatio n

Dysfibrinogenemia

H yp erho mocysteinemia

H yperho mocysteinemia

H eparin-induced thrombocytopenia

PAI-1 mutations

Autoimmune diseases, such as inflammator y bowel disease, vasculitis, systemic lupus erythematosus, nephrotic syndrome

Elevated factor XI level

Antiphospholipid antibod y syndro me

Elevated facto r IX level

Central venou s catheters; pacemaker/ defibrillator leads

Heterozygous factor V Leiden and prothrombin gene G20210A mutation are the two most common inherited predispositions to VTE. As many as 20% of patients presenting with an unprovoked VTE may have heterozygous factor V Leiden mutation, while 6% may have heterozygous prothrombin G20210A mutation.29

D-DIMER TESTING FOR THROMBOEMBOLISM

VENOUS

-Dimer is a specific fragment resulting from the degradation of cross-linked fibrin. High-sensitivity -dimer assays can be used in emergency department and outpatient settings to rule out VTE because of their high sensitivity and negative predictive value (NPV).30 However, an elevated -dimer is not specific for VTE and can be caused by many conditions (Table 48.2).

Table 48.2 Causes of an Elevated -Dimer

The diagnostic performance varies among different quantitative and qualitative -dimer assays: quantitative enzyme-linked immunosorbent assay (ELISA)-derived assays have higher sensitivity than quantitative latexderived and whole-blood agglutination assays.16,31 Thus, it is important for clinicians to know what -dimer assay is available in their centers of practice. Acute VTE (DVT or PE) can be excluded—and anticoagulation withheld —in outpatients with low/moderate pretest probability of VTE and a negative ELISA -dimer, with a 3-month VTE risk 50%.

w ith simvastatin w as

safe a nd improved survival in patients w ith coro nary a rtery

d isease.

Study Title Endarterectomy fo r asymptomatic carotid a rte ry

Year Published

Number of Patients

1995

1,682

sre nosis . Executi ve

Committee fo r the Asymptomatic Carorid Atherosclerosis Srudy54 (ACAS)

Study Aim

Important Findings

Bottom Line

Patients with asymptoma tic exrracranial carotid a rtery stenosis 2:60% were random ized to CEA+ aspirin versus aspi rin alone to study the risk of TIA in the distribution o f the involved artery or a ny stroke, TIA, or death

The aggregate risk for ipsila tera l stroke over 5 yea rs and any perioperative stroke o r dea th was 5.1 % fo r patients who underwent CEA a nd ·11 % for those treated medica lly w ith a n aggregate RR of 53% (95% CI, 22 %- 72%).

Patients with 2:60% asympromaric extracranial ca rotid a rtery stenosis with 80% srenosis (p < 0.001 ).

CEA may be indicated for patients with a recent TIA o r mildly symptomatic carotid territory ische mic

stroke when t he sympto matic stenosis

is >80%.

Study Title Aspirin and clo pidogrel compared with clo pidogrel alone after recent ischemic stroke

Year Published

Number of Patients

2004

7,599

o r transient

ischemic a track in high-ri sk patients (MATCH): randomized, do uble-bli nd, placebocont rolled trial 34

Preventio n of

2004

3,120

disa bling and fata l strokes by successfu l carotid e ndarterectom y in patients

w itho ut recent neurological sympto ms: randomized contro lled tria l55 (ACST )

Study Aim

The combination of as pirin 75 mg and clopidogre l 75 mg was no more effective than clopidogrel 75 mg alone fo r the

Patients with ;:::60% !CA stenosis o n ultra sound who were asymptoma tic for a t least 6 mo nths

In asympto matic

nonperioperative stroke was

to immediate CEA + ma ximal medica l

3.8% in the immediate CEA gro up versus 11 % in t he deferred CEA group (95% CI, 4.95-9.39; p < 0.0001 ). T he 5-yea r risk of combin ed

indefinite deferra l o f CEA + treatment with maximal

nonperioperative events

to st udy the risk o f perioperative stroke and death as well as the incidence of

included 6 .4% vs. 11.8% fo r a ll strokes (95% CI, 3.0-7.8; p < O.OOOJ ), 3.5% vs. 6.1 % for fata l and disa bling strokes (95 % CI, 0.8-4.3; p = 0·004 ), a nd 2 .1 % vs . 4.2 % for fata l stro kes (95% Cl, 0.6- 3.6; p = 0.006) in the immediate CEA versus deferred CEA groups, respective ly. These benefits were significant for those with > 70% carotid artery stenosis and those 70 years old.

Patients with caroti d

randomized to

rosuvasratin 20 mg versus placebo and followed for the occurrence of first rime vascu lar events including M l, stroke, arteria l revascu larizarion,

hospita lization for unstable angina,

or dea th from ca rdiovascula r causes.

Low risk of ipsil arera l stroke in patients with

2010

101

asymptomatic

ca rotid stenosis on best medical trea tment: a

prospective, population-based study

This popula tion-based study included all patients enrolled in the Oxford Va scular Study who had a T IA o r stroke and ;::50% co ntra la tera l asymptoma tic carotid stenoses. They were treated with maxima l

dL, and a C-reactive

protein of >2 mg/L, ro suvasta tin 20 mg reduced the RR of first ever va scula r

event compared with placebo.

asymptomatic ca rotid

stenosis had a low risk of recurrent T IA o r stroke when trea ted with maximal med ical therapy.

medical treatment to assess the risk of

recurrent TIA or stroke. $ te nting versus

enda rterecromy fo r treatment o f ca rotid-a rtery stenosis (CREST)

2010

2,502

Patients with carotid a rtery srenosis of ;::50% on angiography or ;::70% on ultrasonography, CTA, or MRA were randomized to CAS versus CEA to study the risk of vascula r events including stro ke, Ml, or death periprocedurally and postprocedural ipsil ateral stroke.

arrery srenosis

of ;::50% o n angiography or ;::70 % on ultrasonogra phy, CTA, or MRA who underwent CAS were more likely to have periprocedura l stroke while those who underwent CEA were more likely to have periprocedural Ml. Patients 70, while patients> 70 yea rs o ld who underwent CEA had better outcomes tha n those who underwent CAS.

Study Title Clopidogrel with aspirin in acute minor stroke

Year Published

Number of Patients

e2013

5,170

or tra nsient

ischemic a ttack (CH ANCE)

Long-term

2015

1,713

outcomes afrer

ste nting ve rsus enda rterectomy for rrearmenr

o f symptomatic ca rotid stenosis: the Interna l Carotid Stenting Study (ICSS) rando mized tria l

Randomized tria l o f srent versus surgery for asymptomatic ca rotid srenosis

(ACT 1)

Study Aim

Important Findings

Bottom Line

Patients with high-risk TIA or minor stroke were randomized wi thin 24 hours to either clopidogrel 300 mg load fo llowed by 75 mg da ily fo r 90 da ys + aspirin 75 mg for 21 days versus aspirin 75 mg + placebo for 90 days ro study the ri sk o f recurrent stroke.

Recurrent stroke occurred in 8.2 % of patients in the clopidogrel + aspirin group compa red with 11. 7% of those in the aspirin-only group (H R, 0.68; 95% C l, 0.57-0.81; fJ < 0.001 ). Modera te or severe hemorrhage occurred in 0.3 % of the clopidogrel + aspi rin group and in 0.3 % in t he aspirin-only group (fJ = 0 .73).

In patients with highrisk T IA or minor

Patients with ;?.50% ICA stenosis were randomized to CAS versus CEA to study the rate of fata l or disa bl ing st roke. Functional outcome

6.4% of patients in the CAS group suffered fa tal or d isabling stroke versus 6.5% of tho se in the CEA group (H R, 1.06, 95 % C l 0. 72-1.57, fJ = 0.77). The risk of having any st roke was higher in the CAS group at 15.2 % tha n in t he CEA group at 9.4% over 5 yea rs (HR 1. 71, 95% Cl 1.28- 2.30, fJ < 0·001 ), but t hese were ma inl y nondisa bli ng strokes. A comparison of t he modified Rankin scores between rhe rwo groups ar rhe end o f the follow-up period found a fJ = 0.49 when unadjusted a nd fJ = 0 .24 when adjusted for baseline modified Ranki n scale score.

Long-term functional outcome and risk o f fa tal or disabling

The study was stopped early d ue to slow enro llment. 3.8% of the protected CAS group versus 3.4 % of rhe CEA group

In patients 4 mm, Fig. 56.9), and exaggerated septal motion with inspiration (Fig. 56.10A,B), which may help confirm the diagnosis. There are a number of hemodynamic findings by cardiac catheterization (Table 56.5), including but not limited to elevation and equalization of diastolic pressures, “square root sign,” and the “M” pattern of the RA pressure tracing with prominent Y descent to name a few (Table 56.5). The most specific hemodynamic findings for constrictive pericarditis includes discordance of RV and LV systolic pressure variation with respiration (Fig. 56.11) best shown by decreasing LV systolic and increasing RV systolic pressures on inspiration with the systolic area index ([RV area/LV area on inspiration]/[RV area/LV area on expiration]) ≥1.1. It should be emphasized that no single test or finding is completely sensitive or diagnostic for constrictive pericarditis. Often, a diagnosis is made with the help of multiple tests. In considering the entities that are causing the patient’s symptoms, the typical differential diagnoses that present similarly to constriction are right ventricular failure, severe tricuspid regurgitation, and infiltrative cardiomyopathies (most commonly cardiac amyloidosis). Much attention is paid toward differentiating “constrictive” versus “restrictive”

physiology (Table 56.7). Although many of the hemodynamic findings overlap, in clinical practice, the distinction is made by the clinical context and echocardiographic appearance of the heart. The exception to this rule is in the setting of patients who have had previous chest radiation. For these patients, both constriction (pericardial involvement) and restriction (myocardial involvement) are real diagnostic possibilities. In fact, they may even coexist in a particular patient (“mixed disease”) and discerning the dominant pathology in these cases can be challenging.

FIGURE 56.6 Transthoracic echocardiography, pulsed-wave Doppler at the mitral valve leaflet tips. Significant respiratory variation of the mitral E velocity (43%), which decreases with onset of inspiration (white arrow) and increases with onset of expiration (red arrow). Insp, inspiration; exp, expiration.

FIGURE 56.7 Transthoracic echocardiography, tissue Doppler imaging recorded at the septal (A) and lateral mitral annulus (B). There is supranormal e′ velocity (white arrow), suggesting rapid early diastolic ventricular filling. The septal e′ velocity (15 cm/s)

is greater than the lateral e′ velocity (11 cm/s), a phenomenon known as “annulus reversus.” This is unique to constrictive pericarditis and is thought to be related to tethering of the lateral ventricular wall to the thickened pericardium.

FIGURE 56.8 Cardiac MRI, dark-blood sequence, 4 chamber view. There is thickening of the pericardium (white arrows) and conical deformity of the RV (red arrow).

FIGURE 56.9 Cardiac MRI, dark-blood imaging, short-axis view. The black border (white arrows) surrounding the ventricles represents severe thickening of the pericardium, measuring 6 mm in maximal thickness.

FIGURE 56.10 A,B:Cardiac MRI, cine sequences taken during one respiratory cycle. Ventricular interdependence, a hallmark of constrictive pericarditis, is demonstrated by the changes in morphology of the interventricular septum during the respiratory cycle. At end expiration (10A), the interventricular septum has its usual morphology. During inspiration, there is an increase in venous return to the RV; the confinements of the pericardial space prohibit RV expansion, except for bowing of the interventricular septum toward the LV, causing impairment of LV filling. This is demonstrated by exaggerated interventricular septal flattening (white arrow) during diaphragmatic lowering (red arrow).

FIGURE 56.11 Simultaneous LV and RV pressure tracings. There is discordance in the timing of peak LV (arrows) and RV (arrowheads) pressures, with respect to respiratory variation. This can be quantitatively demonstrated by changes in the areas under the curves (systolic area index) of both LV and RV pressures during respiration. A systolic area index >1.1 is highly accurate for detecting constrictive pericarditis.

Table 56.7 Differential Imaging Characteristics between Restrictive Cardiomyopathy and Constrictive Pericarditis

Adapted from Klein AL, Asher C. Diseases of the pericardium, restrictive cardiomyopathy and diastolic dysfunction. In: Topol EJ, ed. Textbook of Cardiovascular Medicine. 3rd ed. Lippincott Williams & Wilkins; 2007:420-459.

On occasion, patients with acute pericarditis, manifesting with severe pericardial inflammation, may demonstrate constrictive physiology. In this setting, the physiology of constriction is related to pericardial inflammation and tissue edema, rather than pericardial calcification and fibrosis and may be reversible with aggressive anti-inflammatory measures (“transient constrictive pericarditis”). In more chronic cases, patients with constriction will present with established pericardial scarring that is irreversible. A

detailed history, inflammatory biomarkers such as ESR and CRP, and pericardial characterization using cardiac MRI are the best tools we have to identify the presence of active pericardial inflammation. Thus, for patients presenting with acute pericarditis symptoms with signs of inflammation (pericardial-type chest pain, ESR and/or CRP elevation, pericardial effusion, MRI enhancement, and/or MRI evidence of pericardial edema) and constrictive physiology, a trial of anti-inflammatories for 3 to 6 months or longer should be considered prior to surgical therapy. Based on a limited experience, pericardiectomy performed in patients with acute inflammation can result in significant postoperative complications due to adhesions.

EFFUSIVE–CONSTRICTIVE PERICARDITIS Effusive–constrictive pericarditis is another clinical entity that deserves some attention. Patients with this condition demonstrate signs of ventricular interdependence clinically and by cardiac imaging, in the setting of a significant pericardial effusion. As many of the hemodynamic changes can be seen in both tamponade and constriction, it is difficult to determine the relative contribution of the pericardial effusion versus the thickened pericardium to the patient’s clinical presentation. Often, the patient requires pericardiocentesis after which the signs of constriction emerge; either by echocardiography (presence of an early septal bounce, respirophasic motion of the interventricular septum, Doppler respiratory changes) or by hemodynamic tracings (failure of the RA pressure to drop by more than 50% postdrainage). As with pericardial effusions, the various etiologies of constrictive pericarditis are similar to those of acute pericarditis. Since pericardial scarring is a process that usually occurs over a period of time, the history usually reveals an episode of pericarditis that occurred remotely. Classically, the separation between initial insult and presentation of constrictive pericarditis is by years, even decades. This is true for patients with constriction as a result of idiopathic pericarditis and radiation-induced pericarditis. However, on occasion, patients may present as soon as months

out from their initial episode, particularly following cardiac surgery. Common causes of constriction that are seen in practice include idiopathic/viral pericarditis, post–radiation therapy, tuberculous pericarditis, and post–open heart surgery.

Treatment Patients with constrictive pericarditis may manifest along a wide spectrum of disease severity, from the asymptomatic patient with detectable constriction only by imaging tests to the debilitated patient with severe right heart failure symptoms. As stated previously, the patient with the possibility of transient constriction in the setting of acute pericarditis deserves a several-month course of aggressive anti-inflammatory treatment to see if his or her physiology improves. In patients with established pericardial scarring, medical management of constriction revolves around diuretic therapy to relieve congestive symptoms. Lastly, in patients with a specific etiology, treatment of the underlying cause may prevent progression (i.e., tuberculous pericarditis). It is still unclear what the appropriate disease severity threshold should be to recommend surgical pericardiectomy. Most would agree that patients with refractory symptoms, and/or New York Heart Association (NYHA) Class III/IV heart failure, should be considered for surgical referral. However, the appropriate management of patients who are discovered earlier in the natural history of the disease course or who have minimal symptoms remains undetermined. Observational data suggest that patients who are operated on later in their disease course have worse outcomes. Some of the reluctance for surgical referral is due to early surgical series demonstrating high rates of morbidity and mortality following pericardiectomy. However, more contemporary data suggest that surgical risk in a high-volume setting is much lower. A number of predictors of poor overall survival have been identified to determine a patient’s overall surgical risk. These include a history of prior radiation, chronic kidney disease, elevated pulmonary artery systolic pressure, abnormal systolic left ventricular function, a low serum sodium level, chronic liver disease, and older age. Pericardial calcification has no effect on survival.

SUGGESTED READINGS

Adler Y, Charron P, Imazio M, et al. 2015 ESC guidelines for the diagnosis and management of pericardial diseases: The Task Force for the Diagnosis and Management of Pericardial Diseases of the European Society of Cardiology (ESC) Endorsed by: The European Association for CardioThoracic Surg. Eur Heart J. 2015;36:2921-2964. Brucato A, Imazio M, Gattorno M, et al. Effect of Anakinra on recurrent pericarditis among patients with colchicine resistance and corticosteroid dependence: The AIRTRIP Randomized Clinical Trial. JAMA. 2016;316:1906-1912. Chetrit M, Xu B, Kwon DH, et al. Imaging-guided therapies for pericardial diseases. JACC Cardiovasc Imaging [Internet]. 2020;13(6):1422-1437. doi:10/j.jcmg.2019.08.027 Chetrit M, Xu B, Verma BR, Klein AL. Multimodality imaging for the assessment of pericardial diseases. Curr Cardiol Rep. 2019;21:41. Chiabrando JG, Bonaventura A, Vecchié A, et al. Management of acute and recurrent pericarditis. J Am Coll Cardiol [Internet]. 2020;75:76-92. http://www.onlinejacc.org/content/75/1/76 Corey GR, Campbell PT, Van Trigt P, et al. Etiology of large pericardial effusions. Am J Med. 1993;95(2):209-213. Available at: http://www.ncbi.nlm.nih.gov/pubmed/8356985 Cremer PC, Kumar A, Kontzias A, et al. Complicated pericarditis: understanding risk factors and pathophysiology to inform imaging and treatment. J Am Coll Cardiol. 2016;68:2311-2328. Imazio M, Brucato A, Cemin R, et al. A randomized trial of colchicine for acute pericarditis. N Engl J Med. 2013;369:1522-1528. Klein AL, Imazio M, Cremer P, et al. Phase 3 Trial of Interleukin-1 Trap Rilonacept in Recurrent Pericarditis. N Engl J Med. 2021;384:31-41. Klein AL, Xu B. Constrictive pericarditis: differentiating the “Purebred” from the “Mixed Bag”. J Am Coll Cardiol. 2019:3322-3325. Sagristà-Sauleda J, Mercé J, Permanyer-Miralda G, et al. Clinical clues to the causes of large pericardial effusions. Am J Med. 2000;109(2):95-101. Available at: http://www.ncbi.nlm.nih.gov/pubmed/10967149 Talreja DR, Nishimura RA, Oh JK, Holmes DR. Constrictive pericarditis in the modern era: novel criteria for diagnosis in the cardiac catheterization laboratory. J Am Coll Cardiol. 2008;51:315319. Unai S, Johnston DR. Radical pericardiectomy for pericardial diseases. Curr Cardiol Rep. 2019;21:6. Welch TD, Ling LH, Espinosa RE, et al. Echocardiographic diagnosis of constrictive pericarditis: Mayo Clinic criteria. Circ Cardiovasc Imaging. 2014;7:526-534.

Chapter 56 Review Questions and Answers QUESTIONS A 65-year-old man has just undergone primary percutaneous intervention for an acute, ST elevation myocardial infarction. Several hours following the procedure, he complains of new onset chest pain, different from his presenting complaint, worse with inspiration and radiating to his left shoulder. His electrocardiogram demonstrates subtle, diffuse ST elevations in the inferior, lateral, and anterior leads. You perform an echocardiogram that demonstrates a small pericardial effusion, without evidence for a mechanical complication following his myocardial infarction. Which of the following would be the next best step? Initiate ASA 650 mg three times daily and colchicine 0.6 mg po bid. Initiate prednisone 1 mg/kg daily. Initiate aspirin 325 mg once daily. Return to the cardiac catheterization laboratory for repeat coronary angiography.

1.

A. . C. D.

A 77-year-old man with a history of end-stage renal disease presents with fevers and chest pain for 2 weeks after returning from a trip in India. He has been on hemodialysis for more than 5 years and has not missed any recent sessions. He appears uncomfortable and diaphoretic. His vital signs are T 103°F, HR 82 BPM, BP 143/96 mm Hg, and RR 12 BPM. His pulsus paradoxus is 6 mm Hg. His examination is remarkable for a pericardial friction rub. His electrocardiogram demonstrates diffuse ST elevations with PR depression. A complete blood count demonstrates a WBC of 14K with an associated elevated CRP (31 mg/dL). An echocardiogram demonstrates a large pericardial effusion but no signs of tamponade physiology. The next best step in managing this patient is A. Initiate ibuprofen 800 mg three times daily with colchicine 0.6 mg twice daily. . Initiate prednisone 1 mg/kg daily for 4 weeks followed by a tapering regimen over 3 months.

2.

C. Call the referring nephrologist for more intensive hemodialysis. D. Perform a pericardiocentesis for diagnostic and therapeutic measures. A 43-year-old woman presents to your office complaining of lower extremity edema and increased abdominal girth. She had undergone mantle radiation for Hodgkin lymphoma 20 years prior. On examination, you find an elevated jugular venous pressure, severe lower extremity edema, and abdominal ascites. Which of the following echocardiographic findings best supports a diagnosis of constrictive pericarditis? >50% collapse of the IVC on inspiration A lateral Doppler velocity > 11 cm/s E/e′ of 17 Increased hepatic vein flow reversal with expiration

3.

A. . C. D.

Central venous pressure examination in tamponade reveals A. Prominent X descent (rapid ventricular filling during systole) and blunted Y descent (absent diastolic filling) . Prominent X and Y descents C. Prominent Y but blunted X descent D. These waveforms can only be discerned with right heart catheterization.

4.

What is the most common cause of constrictive pericarditis in the United States? Previous cardiac surgery Mantle radiation Tuberculosis Idiopathic or viral

5.

A. . C. D.

ANSWERS 1.

Correct Answer: A. Initiate ASA 650 mg three times daily and colchicine 0.6 mg po bid. Although the incidence of acute pericarditis in the post–myocardial infarction setting has decreased with early revascularization, it is still a commonly encountered scenario. Also, this is not to be confused with Dressler syndrome, which is an autoimmune phenomenon that

occurs several weeks later. In this setting, there is some concern that the use of nonsteroidal anti-inflammatory drugs (NSAIDs) and/or corticosteroids may increase the risk of free wall rupture. As such, using high-dose aspirin is the most appropriate therapy in this situation in conjunction with colchicine. The presenting symptoms and ECG do not support stent thrombosis or a complication of the revascularization procedure, so there is no indication for repeat angiography.

2.

Correct Answer: D. Perform a pericardiocentesis for diagnostic and therapeutic measures. A patient who has been on hemodialysis for a prolonged period of time, particularly if he or she has not missed any hemodialysis sessions, is unlikely to present with uremic pericarditis. In this case, bacterial pericarditis should be considered on the differential diagnosis given recent travel and low-grade fevers. Prior to initiating typical anti-inflammatory therapy, a pericardiocentesis should be performed to rule out bacterial seeding of the pericardial space.

3.

Correct Answer: D. Increased hepatic vein flow reversal with expiration In constrictive pericarditis, the tissue Doppler velocity of the mitral annulus is typically normal or even exaggerated (8 cm/s or greater). This represents normal diastolic function of the myocardium itself; the diastolic abnormalities in pure constrictive pericarditis are related to constraint from the pericardium. Occasionally, pericardial scarring adjacent to the lateral wall of the LV can cause tethering of the mitral annulus to the pericardium; in these cases, the lateral tissue Doppler velocity may be decreased (a phenomenon known as annulus reversus). As such, for constrictive pericarditis, it is more reliable to use the septal measurement of the tissue Doppler velocity. There is an increase in the tissue Doppler annular velocity and the E wave velocity resulting in a preserved E/e’, contrary to myocardial diseases in which the increase in E wave velocity is accompanied by a decrease in e’ velocity (annulus paradoxus). Lastly, because of the

constricting pericardium, there is impaired RA filling and a plethoric IVC. Choice E represents typical echocardiographic findings in patients with constrictive physiology and is a surrogate to the interventricular dependence reflected in the hepatic veins.

4.

Correct Answer: A. Prominent X descent (rapid ventricular filling during systole) and blunted Y descent (absent diastolic filling) Prominent X descent (rapid ventricular filling during systole) and absent Y descent (absent diastolic filling).

5.

Correct Answer: D. Idiopathic or viral Idiopathic or viral pericarditis. In one series (Bertog et al.), the etiology was idiopathic in 46%, previous cardiac surgery in 37%, mantle radiation in 9%, and miscellaneous (including tuberculosis) in 8% of the patients. In some series, the representation of constriction as a result of previous cardiac surgery is even higher.

CHAPTER 57

Effects of Systemic Diseases on the Heart and Cardiovascular System JEFFREY S. HEDLEY AND MICHAEL D. FAULX Many inherited and acquired organ system disorders result in clinically significant changes in the heart and cardiovascular system. These changes often demand specific cardiovascular imaging and therapies in addition to disease-specific treatment. Successfully completing the Cardiovascular Board examination requires an understanding of associated clinical situations. In this chapter, the most commonly tested topics are reviewed, categorized by primary organ system.

INHERITED SYNDROMES

DISORDERS/GENETIC

Marfan Syndrome Marfan syndrome is an autosomal dominant disorder that primarily affects connective tissues as a result of various mutations involving the fibrillin-1 (FBN-1) gene. Mutations in the transforming growth factor (TGF)-beta receptor 2 (TGFBR2) and TGFBR1 genes have been linked to the Marfan phenotype in a minority of cases and a related condition termed Loeys– Dietz syndrome associated with a bifid uvula and cleft palate. The histopathology demonstrates cystic medial necrosis. Mitral valve prolapse and aortic root and aortic annular dilation may be seen, leading to

incompetence of the mitral and aortic valves. Aortic disease is the most common cause for morbidity and mortality among Marfan syndrome patients and includes aneurysm formation, intramural hematoma, dissection, and rupture. This risk increases significantly with pregnancy. The 2010 American College of Cardiology/American Heart Association/American Association for Thoracic Surgery (ACC)/(AHA)/(AATS) guidelines for thoracic aortic disease recommend an echocardiogram at the time of diagnosis and in 6 months to determine the aortic root and ascending aortic diameters and their rate of enlargement. Beta-blockers, and possibly angiotensin receptor blockers, are recommended in all patients with Marfan syndrome and aortic aneurysm to reduce the rate of aortic dilatation. That said, this long-held assertion regarding betablockers has been recently challenged. Elective surgical repair is recommended for patients with an external aortic diameter of 5 cm and in patients with aortic diameter 0.5 cm/y), family history of aortic dissection at a smaller diameter, or progressive aortic insufficiency. In patients with Loeys–Dietz syndrome, aortic dissection has been observed for aortic diameters 4.2 cm). In all conditions, the height of the individual should also be considered in determining the optimal timing of surgery. Thus, an aorta size of 4.8 cm may be more concerning in an individual who is 60 inches tall in comparison to someone who is 75 inches tall. An aortic root area-to-height ratio of ≥10 cm2/m is associated with greater risk and, when added to traditional risk assessments, increases predictive value.

Ehlers–Danlos Syndrome Ehlers–Danlos syndrome is also an autosomal dominant syndrome that affects the connective tissues and thereby results in similar heart abnormalities. Mitral and tricuspid valve prolapse causing mitral and tricuspid regurgitation, aortic root dilation causing aortic regurgitation, and dissection of the aorta and great vessels constitute the most common cardiovascular complications. When aortic surgery is indicated, patients with Marfan, Loeys–Dietz, or Ehlers–Danlos vascular-type syndromes with a normal aortic valve should undergo valve-sparing aortic root surgery with

excision of the sinuses if feasible or replacement with a valve–graft conduit if the valve is abnormal.

Noonan Syndrome Noonan syndrome is an autosomal dominant disorder that includes characteristic facies (widely spaced eyes, low-set ears, deep philtrum, micrognathia, and a neck that is often short and webbed) and cognitive impairment in addition to its cardiovascular abnormalities. These abnormalities include pulmonic valve or infundibular stenosis, atrial septal defect, patent ductus arteriosus, tetralogy of Fallot, and hypertrophic cardiomyopathy. Vascular abnormalities include peripheral pulmonary arterial stenosis.

Williams Syndrome Williams syndrome, the result of spontaneous mutations, is characterized by cognitive impairment, an elf-like facies, hypercalcemia, and dental abnormalities. Cardiovascular manifestations include congenital supravalvular aortic stenosis, atrial septal defect, ventricular septal defect, and peripheral pulmonary arterial stenosis.

Osler–Weber–Rendu Syndrome Also known as hereditary hemorrhagic telangiectasia, Osler–Weber–Rendu syndrome is characterized by mucocutaneous telangiectasias (on the tongue, lips, and fingertips) and arteriovenous malformations (AVMs) in the upper and lower gastrointestinal tracts and pulmonary vasculature. These pulmonary AVMs may result in paradoxical emboli in the presence of venous thrombosis.

NEUROMUSCULAR DISORDERS Muscular Dystrophy

The three most common variations of muscular dystrophy—Duchenne, Becker, and Emery–Dreifuss—are each X-linked disorders associated with significant cardiac abnormalities. Conduction disturbances are common, especially atrioventricular (AV) nodal block and atrial dysrhythmias; atrial paralysis and atrial fibrillation/flutter are particularly common in the Emery– Dreifuss variant. Each muscular dystrophy syndrome may also result in a cardiomyopathy, leading to heart failure. The cardiomyopathy that occurs in Duchenne muscular dystrophy preferentially affects the posterobasal left ventricle, which may exacerbate heart failure by causing posteromedial papillary muscle–mediated mitral regurgitation. Baseline assessment of cardiac function at the time of diagnosis or by the age of 6 years followed by echo or MRI annually or biannually is recommended. Treatment of the conduction disturbances and cardiomyopathy is supportive; permanent pacing may become indicated. Angiotensin-converting enzyme (ACE) inhibitors may slow the development of LV dysfunction, while the use of ACE inhibitors and beta-blockers may lead to reverse remodeling in patients who have developed dilated cardiomyopathy. Cardiac transplant may be an option in Becker patients with severe dilated cardiomyopathy and no evidence of skeletal muscle disease.

Friedrich Ataxia Friedrich ataxia is an autosomal recessive neuromuscular disorder, caused by intramitochondrial iron accumulation, resulting in progressive ataxia, areflexia, upper motor neuron injury, and loss of proprioception. From a cardiovascular perspective, it is associated with a hypertrophic cardiomyopathy. Although fatal ventricular dysrhythmias are rare, the cardiomyopathy itself often causes death, especially in cases that progress to dilated cardiomyopathy.

Myotonic Dystrophy Myotonic dystrophy, also known as Steinert disease, is an autosomal dominant disorder caused by a mutation in the myotonin gene; the resultant phenotype includes myotonia, weakness, frontal balding, cataracts, and gonadal dysfunction in addition to its cardiovascular manifestations. Electrocardiogram changes include pathologic Q waves in the absence of

coronary artery disease or myocardial infarction. It also is associated with conduction disturbances, manifested primarily by AV block and intraventricular conduction delay. Progression of AV conduction abnormalities is unpredictable, and pacing is reasonable in asymptomatic patients with neuromuscular diseases and any degree of AV block.

Kearns–Sayre Syndrome Kearns–Sayre syndrome is a mitochondrial encephalopathy characterized by ophthalmologic abnormalities. AV block is seen, often requiring pacemaker placement.

Myasthenia Gravis Myasthenia gravis is an autoimmune process that reduces the number of acetylcholine receptors present at the neuromuscular junction. Affecting more females than males, it presents as progressive weakness and fatigue that worsens with repetitive muscle use and improves with rest. In addition to the autoimmune effect that it has on the neuromuscular endplate, myasthenia gravis can cause a myocarditis that responds to conventional myasthenia gravis treatment modalities.

Guillain–Barré Syndrome Guillain–Barré syndrome (GBS) is an acute, autoimmune-mediated demyelinating disorder of the peripheral nervous system, characterized by ascending motor weakness, paresthesias, and areflexia. The adverse effects that GBS has on the nervous system include autonomic dysfunction involving the cardiovascular system. Hypertension, orthostatic hypotension, resting sinus tachycardia, and potentially fatal dysrhythmias are all potential complications of GBS. Supportive treatment, including plasmapheresis and intravenous immunoglobulin, is the mainstay of care.

ENDOCRINE DISORDERS

AND

METABOLIC

Acromegaly Acromegaly results from an excess of circulating growth hormone, usually from overproduction in the pituitary gland. The most common cardiovascular manifestation of this excess is hypertension, with premature atherosclerosis and cardiomegaly also commonly seen. The cardiomegaly is out of proportion to the overall organomegaly and results in congestive heart failure and cardiac dysrhythmias, occasionally resulting in sudden cardiac death. Treatment consists of destruction of the growth hormone source (i.e., the pituitary gland), via either transsphenoidal surgical resection or externalbeam radiation. The associated cardiovascular abnormalities generally can be controlled with conventional therapies; hypertensive patients respond favorably to diuretics and sodium restriction.

Cushing Syndrome Cushing syndrome is characterized by excess glucocorticoids and androgens, either primarily from adrenal hyperplasia or secondarily from adrenocorticotropic hormone (ACTH)-producing neoplasms or exogenous administration. Patients with this syndrome are characterized by central obesity with slender extremities and proximal muscle weakness. Associated cardiovascular disorders include hypertension, accelerated atherosclerosis, and dyslipidemia. Cardiac dysrhythmias associated with hypokalemia are seen. Therapy is directed at the specific cause of the hormonal excess. From a cardiovascular standpoint, efforts should be aimed at controlling hypertension, which is often difficult without first reducing cortisol production and maintaining normal potassium levels.

Hyperaldosteronism/Conn Syndrome

Usually caused by an aldosterone-secreting adenoma, hyperaldosteronism features hypertension, hypokalemia, and metabolic alkalosis. The hypertension can be resistant to multiple medications and severe enough to cause renal insufficiency or stroke. Typical electrocardiogram changes associated with hypokalemia can also occur and manifest as flattened T waves and prominent U waves. Surgical resection of the adenoma or medical therapy with aldosterone antagonists (e.g., spironolactone, eplerenone) is the treatment of choice, in addition to appropriate potassium replacement.

Adrenal Insufficiency Adrenal insufficiency can result from (a) primary adrenal cortex failure (Addison disease), (b) hypopituitarism (secondary adrenal insufficiency), (c) selective/isolated hypoaldosteronism (a hyperreninemic state usually caused by a congenital inability to produce aldosterone with preserved glucocorticoid function), or (d) enzymatic deficiency (congenital adrenal hyperplasia). Cardiovascular effects include hypotension with orthostasis and several possible electrocardiogram changes—small/inverted T waves, sinus bradycardia, prolonged QT interval, low-voltage QRS complexes, and first-degree AV block. Treatment consists of replacement with corticosteroids.

Hyperthyroidism Excess circulating thyroid hormone results in a physiologic state that resembles activation of the sympathetic nervous system. Hyperthyroidism has a peak incidence in the third and fourth decades, and women are four to eight times more likely to be affected. Cardiac features include palpitations, dyspnea, tachycardia, and systolic hypertension, consistent with the increased chronotropic and inotropic state expected with increased adrenergic tone. Cardiac dysrhythmias and electrocardiogram changes also occur, including atrial fibrillation and other supraventricular tachyarrhythmias, intraventricular conduction delay, and right bundle branch block. Finally, anginal chest pain and congestive heart failure symptoms can occur, even in a structurally normal heart.

Goals of treatment consist of reversal of the hyperthyroid state and resolution of symptoms. The latter is generally accomplished with βadrenergic-blocking agents; the former can be done medically with targeted antithyroid agents such as methimazole and propylthiouracil, radioactively with 131I ablation of thyroid tissue, or surgically via thyroidectomy. ACC/AHA/European Society of Cardiology (ESC) guidelines consider thyrotoxicosis a risk factor for thromboembolism in atrial fibrillation and when associated with one moderate-risk factor recommend anticoagulation until a euthyroid state is restored.

Hypothyroidism A lack of thyroid hormonal effect will also adversely affect the cardiovascular system. Interstitial myocardial fibrosis can result in gross biventricular dilation. Facial and peripheral edema can progress to brawny, nonpitting myxedema, and myxedematous pericardial effusions can be found in as many as one-third of patients. Electrocardiogram changes may include sinus bradycardia, low-voltage QRS complexes, a prolonged QT interval, and intraventricular conduction delay or right bundle branch block. Hypertension or hypotension may result. Dyslipidemia (hypercholesterolemia and/or hypertriglyceridemia) is common. Thyroid hormone replacement should be instituted at a low initial dose, with small increases in dosage at long intervals, especially in elderly patients or those with known coronary artery disease, as abrupt elevation of thyroid hormone levels can precipitate myocardial ischemia and/or heart failure.

CONNECTIVE TISSUE AND ASSOCIATED VASCULAR DISORDERS Systemic Lupus Erythematosus Systemic lupus erythematosus (SLE) is a well-described autoimmune disorder characterized by antibodies against cellular antigens, resulting in an

inflammatory state that is manifested by effects on multiple organ systems. Most commonly, patients with SLE present with arthritis and dermatitis. The most common cardiovascular complication of SLE is pericarditis, with or without pericardial effusion. The effusion, usually exudative, is characterized by an elevated protein concentration, a low/normal glucose concentration, and low complement. Other cardiac abnormalities seen in SLE patients include early coronary artery disease, caused by both progressive atherosclerosis (with chronic corticosteroid use) and coronary arteritis. Myocardial infarction may occur via embolism of noninfectious (Libman– Sacks) endocarditis vegetations, or via SLE-related antiphospholipid antibody (APLA)-mediated thrombosis. The noninfectious endocarditis tends to cause insufficiency of the aortic and mitral valves more commonly, generally sparing the ventricular surface of each valve. Valvular lesions that can be detected by echocardiography are much more common than clinically significant disease. In those patients with clinically significant disease, the tendency is toward valve repair or replacement with bioprosthetic valves rather than mechanical valves, given the propensity of SLE patients to suffer bleeding complications from associated serositis or cerebritis. In patients with the APLA syndrome, mechanical valves are preferred since anticoagulation is already indicated. Infants born to female patients with SLE (especially those having anti-Ro or anti-La antibodies) may suffer congenital heart block as a result of fibrosis of the conduction system in utero. SLE-related pericarditis and pericardial effusions should be treated with nonsteroidal anti-inflammatory agents (NSAIDs) initially, with a plan to switch to corticosteroids should more aggressive treatment be necessary. Percutaneous or surgical drainage may be necessary should there be evidence of cardiac tamponade physiology or should maximized medical therapy (corticosteroids and cyclophosphamide) fail to result in resorption of the effusion. Coronary artery disease treatment consists of conventional measures, except in cases of arteritis (which demands an intensive course of corticosteroids) or APLA-mediated thrombosis that requires systemic anticoagulation. In cases of endocarditis, serial echocardiography should be used to monitor for progressive valvular incompetence and indications for surgical valve repair or replacement. Women with SLE who become pregnant should undergo intensive gestational screening; intrauterine dexamethasone has been used successfully to slow progression of congenital heart block.

Some common cardiovascular medications can cause a drug-induced lupus-like syndrome including hydralazine, atenolol, procainamide, statins, captopril, and enalapril. This can occur after months or years of use and is associated with positive antinuclear antibodies (ANA) and antihistone antibodies.

Rheumatoid Arthritis Rheumatoid arthritis (RA) is a progressive autoimmune arthritis, resulting in joint destruction, deformation, and immobility. In patients with RA, pericardial disease is the most prominent cardiac complication, ranging in complexity from a chronic asymptomatic effusion to constrictive pericarditis. Early coronary artery disease and myocardial infarction can result from the chronic inflammatory state of RA and the long-term use of corticosteroid therapy. Rarely, secondary amyloidosis will occur, causing an infiltrative cardiomyopathy that may be accompanied by conduction abnormalities. The mainstay of initial treatment is NSAIDs, followed by more intensive immunosuppression if necessary.

Seronegative Spondyloarthropathies The seronegative spondyloarthropathies—ankylosing spondylitis, Reiter syndrome, and the inflammatory bowel disease arthritides (ulcerative colitis and Crohn disease)—appear to be closely related from a clinical standpoint and are associated with the HLA-B27 antigen. Ankylosing spondylitis results in ankylosis, sacroiliitis, peripheral arthritis, iritis, and aortitis. Reiter syndrome includes asymmetric arthritis, conjunctivitis, and genital ulcers. Aside from the well-described gastrointestinal findings in inflammatory bowel disease, they also feature an asymmetric arthritis and enthesitis. In general, this set of connective tissue disorders also shares a similar cadre of cardiac involvement: a thickened/dilated aortic root, leading to aortic regurgitation, and AV conduction abnormalities.

Polymyositis Polymyositis is an idiopathic inflammatory myopathy characterized by proximal muscle weakness and elevation of muscle enzyme serum levels.

Cardiac involvement consists of a myopericarditis that can either be focal or generalized, at times involving the conduction system and resulting in conduction system abnormalities including heart block. Corticosteroids are generally administered if myocarditis is proven on endomyocardial biopsy.

Scleroderma/CREST Syndrome Systemic sclerosis, especially when complicated by the CREST syndrome (calcinosis cutis, Raynaud phenomenon, esophageal dysmotility, sclerodactyly, telangiectasias), can cause pericardial effusions and pericarditis. Patchy myocardial fibrosis may occur as well as conduction system abnormalities at all levels. WHO Groups 1 and 3 pulmonary hypertension can be a prominent feature and is often the driver of mortality. A careful physical examination and echocardiography should be used both to assess for pericardial drainage indications and to monitor pulmonary pressures for significant elevations, possibly requiring the institution of vasodilator therapy. A unique form of hypertensive crisis referred to as scleroderma renal crisis is a life-threatening disorder of severely elevated blood pressure and acute renal injury. Treatment consists of intravenous ACE inhibitors.

Takayasu Arteritis Takayasu arteritis is an idiopathic, granulomatous large-vessel vasculitis that generally occurs in young people, with a 10-fold female preponderance and highest incidence found in Japan. Hypertension and aortic regurgitation secondary to aortic annular and aortic root dilation are its most prominent cardiac complications. There is a panarteritis typically affecting the aorta and its major branches. Involvement of the coronary arteries is exceptionally rare. Clinical classification criteria include age 10 mm Hg between arms, and bruit over the subclavian arteries or the abdominal aorta. Onset is associated with constitutional symptoms such as fever, arthralgias, and weight loss, and vessel inflammation can manifest as pain and tenderness, most commonly

found over the carotid arteries. Angiography is the gold standard for detecting diseased vessels. Corticosteroids with or without further immunosuppression (cyclophosphamide, methotrexate) constitute primary therapy. The differential diagnosis for vascular symptoms arising from Takayasu arteritis includes giant cell/temporal arteritis, Behçet disease, fibromuscular dysplasia (FMD), sarcoid vasculopathy, mechanical thoracic outlet syndromes, and infectious or other inflammatory causes for aortitis. Giant cell arteritis shares many clinical, histopathologic, and radiographic findings seen in Takayasu arteritis except that it typically affects individuals older than 50 years of age. It is also associated with new headaches, visual disturbances, and symptoms of polymyalgia rheumatica. Markers of inflammation such as erythrocyte sedimentation rate (ESR) and/or C-reactive protein may be significantly elevated in either condition, and additional findings include constitutional symptoms and jaw and upper extremity claudication. CT or MR angiography can help to distinguish the etiology by demonstrating multisegment stenoses alternating with areas of normal luminal caliber in inflammatory vasculitis versus single stenosis or vascular cutoff at focal sites of functional or mechanical compression.

Fibromuscular Dysplasia FMD is a noninflammatory, nonatherosclerotic process in which various fibrous lesions in the different layers of the vascular wall lead to arterial stenoses. Any vascular bed can be affected but the most commonly involved vessels are the renal (60% to 75% of cases) and carotid arteries (30% to 60%) followed by mesenteric or brachial arteries and rarely coronary arteries. FMD is more common among females, and the mean age at presentation is 58 years. Renal FMD can manifest as severe or resistant hypertension, while involvement of the extracranial vessels can lead to ischemia, spontaneous dissection and occlusion, rupture of aneurysms, or embolic phenomenon. Acute myocardial infarction in a young woman without traditional risk factors should prompt a dedicated assessment for spontaneous coronary artery dissection (SCAD). Treatment is largely supportive as PCI or bypass has not been shown to improve outcomes and may perpetuate the dissection. Digital subtraction angiography is the gold

standard in diagnosis and shows a classic string-of-beads appearance that differentiates FMD from the inflammatory vasculitides.

Vasculitis Affecting Small to Medium-Sized Vessels Polyarteritis nodosa (PAN) is a rare necrotizing vasculitis associated with weight loss, myalgias, neuropathy, testicular pain, elevated diastolic blood pressure, renal insufficiency without glomerulonephritis, and false-positive serum hepatitis B testing. The vessels affected by PAN include the coronary arteries. Coronary arteritis and coronary artery aneurysms are seen, which can lead to an acute myocardial infarction. Atherosclerosis is also accelerated in PAN as a result of the associated hypertension, steroid therapy, and renal failure. Corticosteroids are primary therapy. Churg–Strauss syndrome is an eosinophilic granulomatous inflammation of the respiratory tract, characterized by a necrotizing vasculitis of small and medium-sized vessels. The eosinophilia results in an association with asthma and other atopic diseases. Eosinophilic myocarditis, causing a restrictive cardiomyopathy, pericarditis with or without an associated effusion, and coronary arteritis characterize the cardiac manifestations. Heart failure secondary to the cardiomyopathy is the most common cause of death. Corticosteroids are primary therapy. Granulomatosis with polyangiitis (formerly known as Wegener granulomatosis) is characterized by systemic granulomatous inflammation of the upper and lower respiratory tract as well as a vasculitis that may result in necrotizing glomerulonephritis. Its cardiac manifestations include pericarditis, myocarditis with left ventricular dysfunction, and an uncommon valvulitis, most often aortic. Serial electrocardiograms and echocardiography to monitor electrophysiologic and ventricular function are warranted, respectively, to guide supportive therapy. Corticosteroids are primary therapy, and cyclophosphamide may be added for progressive disease.

Sarcoidosis Sarcoidosis is an idiopathic noncaseating granulomatous disorder that predominantly affects the lungs and mediastinal lymph nodes, causing a restrictive pulmonary physiology similar to that of interstitial lung diseases.

Sarcoidosis may involve the vascular system, pericardium causing pericarditis, the myocardium causing myocarditis or restrictive cardiomyopathy, and the conduction system causing varying levels of AV and intraventricular block. Ventricular arrhythmias, both benign and malignant, can occur in the presence of myocardial sarcoid infiltration. Endomyocardial biopsy demonstrates granulomatous inflammation but has poor sensitivity. Positron emission tomography in conjunction with CT imaging can anatomically localize intracardiac and extracardiac inflammation through detection of fludeoxyglucose (18-F) uptake. Cardiac MRI can also be used to improve the sensitivity of diagnosis and typically demonstrates myocardial delayed enhancement with gadolinium. Classically, the basal septum is most often involved. In addition to monitoring for permanent pacing and implantable cardioverter–defibrillator indications, corticosteroids are the mainstay of treatment. In cases of drug-refractory ventricular tachycardia, catheter radiofrequency ablation through endocardial and/or epicardial access may be considered. Patients with advanced heart failure or malignant ventricular arrhythmias may also be considered for cardiac transplantation.

Relapsing Polychondritis Relapsing polychondritis is an idiopathic, degenerative, inflammatory disease characterized by destruction of cartilage, which results in damage to organs of special sense (outer/inner ear, eyes, nose) in addition to the musculoskeletal system. Relapsing polychondritis can cause aneurysms of the ascending aorta and subsequent aortic regurgitation (because of its effect on the cartilaginous support structures of the mediastinum) as well as vasculitis of vessels ranging in size from the aorta to postcapillary venules. The vasculitis may result in either thrombosis or thrombotic emboli. Corticosteroids are primary therapy.

Behçet Disease Behçet disease is a chronic inflammatory disease— considered a multisystem vasculitis—characterized by oral aphthous ulcers as well as ulcers of the skin, genitals, and eyes. The vasculitis can result in aneurysms of the arch vessels and the abdominal aorta as well as a proximal aortitis that

may cause aortic regurgitation from dilation of the aortic root. Corticosteroids are primary therapy.

HEMATOLOGIC/ONCOLOGIC DISORDERS Iron Overload Iron overload may result from primary hemochromatosis, multiple transfusions, and intestinal hyperabsorption and from diseases characterized by bone marrow failure. The most common cardiac complication of iron overload is a restrictive cardiomyopathy secondary to myocardial iron deposition. Pericarditis, AV conduction disorders, and angina, despite normal coronary arteries, also occur. Phlebotomy and chelation therapy with deferoxamine can remove excess iron and a new oral iron chelator, deferiprone, is being tested in patients with sickle cell anemia.

Anemia Severe anemia can result in left ventricular dysfunction and ultimately congestive heart failure and is associated with a lower quality of life and an impaired survival. Angina may also occur in severe anemia as a consequence of a marked reduction in oxygen transport capacity. For hemolytic anemias related to prosthetic valves or paravalvular leaks (PVL), transfusion can increase blood viscosity and reduce valve-related hemolysis. However, refractory hemolytic anemia is an indication for surgical intervention or PVL closure for the affected valve. Recent studies of erythropoietin to restore near-normal hemoglobin values in patients with renal failure were associated with increased mortality, hypertension, and thrombosis and in another study did not reduce the composite endpoint of death or a cardiovascular event. In sickle cell disease, myocardial infarction may occur with sickling of cells in coronary arteries, leading to coronary artery thrombosis. Acute mitral regurgitation from papillary muscle involvement can complicate myocardial infarctions in sickle cell disease. Pulmonary infarction may also

occur, from either pulmonary arterial thrombosis or embolization of venous thrombi.

Polycythemia In addition to polycythemia vera, other polycythemic states may result in adverse cardiovascular effects. Like polycythemia vera, thrombocytosis, leukocytosis, plasma cell neoplasms, monoclonal gammopathies such as multiple myeloma, and cryoglobulinemia each may cause a hyperviscosity syndrome, leading to vascular thrombosis. Coronary arterial thrombosis may result in myocardial infarction, deep venous thrombosis can lead to pulmonary embolism, and peripheral arterial thrombosis may cause skeletal muscle or organ-specific infarction. Therapy is focused on reducing the polycythemic load with treatment specific to the involved cell line. Polycythemia vera and thrombocytosis may respond to hydroxyurea. Leukocytoses and plasma cell neoplasms should be treated with appropriate chemotherapeutics, and, in the case of paraproteinemias, plasmapheresis is an important adjunctive therapy.

Neoplastic Disease Tumors originating in the heart and those that commonly metastasize to the myocardium are discussed in the Cardiac Tumors chapter. Pericardial disease may take the form of metastatic infiltration causing a constrictive physiology or it may be effusive, resulting in possible cardiac tamponade. Noninfectious, nonmetastatic, thrombotic endocarditis, also known as marantic endocarditis, may occur. Marantic endocarditis generally does not destroy valve architecture or disrupt valvular function but does predispose to peripheral embolism. Myocardial ischemia is a potential complication of thrombotic emboli or extrinsic compression of epicardial coronary arteries. Dysrhythmias are common with metastases to the myocardium. The superior vena cava (SVC) syndrome, caused by extrinsic compression of the SVC by tumor or enlarged lymph nodes resulting in venous stasis in the head, arms, and upper torso, may also complicate malignancies. Effusive pericardial disease is treated with percutaneous or surgical drainage, whereas infiltrative pericardial disease requires surgical pericardial stripping. The presence of marantic endocarditis requires no

specific therapy, though treating ischemic syndromes that may result or occur concomitantly requires anticoagulation that may precipitate further embolic phenomena. The SVC syndrome requires urgent combination therapy with external-beam radiation and chemotherapy, and endovascular stenting has become a common adjunctive treatment.

External-Beam Radiation Therapy Patients who receive external-beam radiation (XRT) for chest wall or mediastinal tumors often suffer heart-specific side effects referred to as radiation-associated cardiac disease (RACD). Mantle field radiation for Hodgkin lymphoma is a common culprit. Pericardial disease may range from an effusion to calcific constrictive pericarditis. Coronary arteries, classically the ostial RCA, may undergo accelerated atherosclerosis or narrowing, a form of radiation fibrosis. Heart valves may also be damaged, resulting in valvulitis that can cause either stenosis or regurgitation. Calcification of the tissue between the aortic and mitral valve (the aorto-mitral curtain) evidence on 2D echocardiography parasternal views should raise suspicion of prior radiation exposure. XRT may also cause a cardiomyopathy from direct myocardial damage, though this can be difficult to distinguish from a cardiomyopathy caused by simultaneously used chemotherapeutic agents. Pericardial disease is treated with drainage or pericardial stripping though this is associated with high morbidity and mortality compared to other etiologies. Coronary artery disease should be managed with conventional therapies, and valvulitis requires serial echocardiography to determine timing of surgical repair or replacement. XRT-related cardiomyopathy is managed by usual congestive heart failure therapies. Cardiac surgery especially reoperation is associated with poorer than anticipated long-term outcomes in RACD possibly as a result of repeat lung injury and fibrosis. Increasingly, percutaneous approaches to valve disease are being attempted in these patients to limit the need for repeat surgical intervention.

Chemotherapy Anthracycline chemotherapeutics and mitoxantrone (a chemically similar antineoplastic medication) are known to cause a well-described dilated cardiomyopathy that is related to cumulative dose. The cardiomyopathy

should be treated with conventional congestive heart failure therapy. These drugs may also cause an acute toxicity, characterized by electrocardiogram changes that include a prolonged QT interval and nonspecific ST-segment and T-wave changes. Other chemotherapeutics are also identified as cardiotoxins. Ischemic coronary syndromes may be precipitated by 5fluorouracil in patients with preexisting coronary artery disease. Treatment consists of usual coronary artery disease management. Cyclophosphamide and ifosfamide have been shown to cause a cardiomyopathy similar to that observed with the anthracyclines and should be managed similarly. Smallmolecule kinase inhibitors and antibody-based therapies targeting signaling pathways in cancer such as sunitinib, imatinib, trastuzumab, and sorafenib have been associated with drug-induced cardiac injury in a subset of treated individuals.

RENAL FAILURE Although congestive heart failure may lead to renal insufficiency, the reverse may also occur. Uremic cardiomyopathy may result from volume and pressure overload related to insufficient fluid clearance, and circulating uremic toxins have a negative inotropic effect. As with most secondary cardiomyopathies, treatment consists of conventional congestive heart failure management measures. Accelerated atherosclerosis can result from the hyperlipidemia that constitutes a component of the nephrotic syndrome, which should be treated with aggressive medical therapy. Hypertension can also occur as a result of renal failure, especially in cases caused by arterionephrosclerosis, glomerulopathies, or transplant-associated renal failure. Treatment consists of antihypertensive medications and early hemodialysis as the renal failure progresses. Calcification of the heart’s valvular apparatus, coronary arteries, conduction system, and pericardium may develop as the calcium phosphorus product increases with worsening renal failure. Diet modification and phosphate-binding agents are the treatments of choice. Furthermore, pericardial disease in renal failure ranges from constriction to uremic pericarditis with effusion. Percutaneous or surgical drainage may

be required. Effective hemodialysis can reduce the likelihood of developing further effusions. Because of the rapid changes in electrolytes and pH that accompany dialysis and the high prevalence of underlying heart disease among patients with renal failure, dysrhythmias are common, requiring supportive care and close monitoring of electrolytes both pre- and postdialysis.

HIV Among the protean clinical manifestations of HIV, the heart is not spared. Left ventricular dysfunction results as HIV infection progresses to individual cardiac myocytes, causing focal myocarditis. This cardiomyopathy is more common as the CD4+ cell count decreases and tends to occur more frequently in infected children. Treatment consists of usual measures for dilated cardiomyopathy. As HIV progresses, the release of cytokines to fight opportunistic infections and to signal maximal activation of the immune system compromises endothelial integrity at the capillary level. This results in pleural, peritoneal, and pericardial effusions. The presence of a pericardial effusion markedly increases predicted mortality. Screening echocardiography is a reasonable consideration in the later stages of HIV, and percutaneous or surgical drainage may become necessary in the presence of hemodynamic compromise or to examine fluid for treatable opportunistic etiologies (e.g., tuberculosis, malignancy). The chronic inflammatory state present in HIV and lipid-raising tendency of protease inhibitors may result in accelerated atherosclerosis of the coronary arteries. Patients on antiretroviral therapy should receive aggressive lipid-lowering therapy, and a high degree of suspicion should exist in even young HIV-positive patients presenting with possible anginal syndromes. A heart-specific opportunistic infection occurring in the setting of HIV is Salmonella endocarditis, as the transient bacteremia that may occur after ingestion of affected food will not be effectively cleared. Fungal endocarditis is also included on the list of HIV-associated opportunistic infections. Treatment consists of broad-spectrum antibiotic therapy pending isolation of a specific pathogen.

Finally, HIV-associated malignancies may involve the heart as well, most commonly metastatic Kaposi sarcoma and lymphomas, which may be heralded by pericardial effusions. Treatment is specifically directed at the identified malignancy. Antiretroviral therapy is implicated in increasing metabolic and cardiovascular risk. All HIV-infected individuals should be evaluated regularly for lipid abnormalities, hyperglycemia, hypertension, and obesity as part of risk stratification for coronary artery disease. Selection of retroviral medications to minimize metabolic risk without compromising suppression of viral replication must be considered.

SUMMARY Given the spectrum of noncardiac disease that may significantly affect the heart and cardiovascular system, a working knowledge of these interactions is essential for treatment of patients with cardiovascular disease and for success on the Cardiovascular Medicine Board Examination. Effective care for patients with systemic disease demands cooperation with internists as well as medical and surgical subspecialists.

SUGGESTED READINGS Birnie DH, Nery PB, et al. Cardiac sarcoidosis. J Am Coll Cardiol. 2016;68:411-421. Hiratzka LF. 2010 ACCF/AHA/AATS/ACR/ASA/SCA/SCAI/SIR/STS/SVM Guidelines for the diagnosis and management of patients with thoracic aortic disease. Circulation. 2010;121:e266e369. Jabbar A, Pingitore A, et al. Thyroid hormones and cardiovascular disease. Nat Rev Cardiol. 2017;14:39-55. Kaplan RC, Hanna DB, Kizer JR. Recent insights into cardiovascular disease (CVD) risk among HIV‐ infected adults. Curr HIV/AIDS Rep. 2016;13:44-52. Lenneman CG, Sawyer DB. Cardio-oncology: an update on cardiotoxicity of cancer-related treatment. Circ Res. 2016;118:1008-1020. Libby P, Loscalzo J, et al. Inflammation, immunity, and infection in atherothrombosis. J Am Coll Cardiol. 2018;17:2071-2081. McKenna WJ. Inherited syndromes associated with cardiac disease. In: Post TW, ed. UpToDate. UpToDate; 2014.

Mozos I. Mechanisms linking red blood cell disorders and cardiovascular disease. Biomed Res Int. 2015;2015:682054. Sarnak MJ, Amann K, et al. Chronic kidney disease and coronary artery disease. J Am Coll Cardiol. 2019;74:1823-1838. Sondheimer HM, Lorts A. Cardiac involvement in inflammatory disease: systemic lupus erythematosus, rheumatic fever, and Kawasaki disease. Adolesc Med. 2001;12(1):69-78.

Chapter 57 Review Questions and Answers QUESTIONS 1.

The following descriptions are associated with inherited syndromes. Pulmonary valve stenosis, atrial septal defect, hypertrophic cardiomyopathy Mitral valve prolapse, aortic regurgitation, aortic aneurysm/dissection Paradoxical emboli Elfin facies, hypercalcemia, supravalvular aortic stenosis, atrial septal defect, ventricular septal defect

A. . C. D.

Choose the answer with the correct order of association. Marfan, Osler–Weber–Rendu, Noonan Syndrome, Williams Syndrome Williams Syndrome, Noonan Syndrome, Marfan, Osler–Weber–Rendu Osler–Weber–Rendu, Marfan, Williams Syndrome, Noonan Syndrome Noonan Syndrome, Marfan, Osler–Weber–Rendu, Williams Syndrome

A. . C. D.

In a patient with myotonic dystrophy, which of the following is not an associated electrocardiographic abnormality? Intraventricular conduction delay Left ventricular hypertrophy by voltage criteria Pathologic Q waves Atrioventricular (AV) conduction block

2.

A 35-year-old woman with rheumatoid arthritis (RA) presents for evaluation of hypertension and palpitations. Her RA is controlled on 5 mg/day of prednisone. She does not experience chest pain or dyspnea but does note recent feelings of anxiety and diarrhea with some unintended weight loss. Her vital signs include an irregular apical pulse of 120 beats/min (bpm) and a blood pressure of 165/70 mm Hg. Serum electrolytes and a complete blood count are within normal limits. What is the most appropriate initial therapy? A. Increase the steroid dosage. . Discontinue steroid therapy.

3.

Transsphenoidal pituitary resection followed by corticosteroid and T4 C. replacement D. β-Adrenergic blockers and methimazole

A. . C. D.

A 55-year-old man with a history of Hodgkin disease presents with dyspnea. He underwent chemotherapy and external-beam radiation 30 years ago, and his Hodgkin disease has been in clinical remission ever since. Radiation-associated cardiac disease is diagnosed. Which of the following is true regarding this condition? Ventricular tachyarrhythmias are the only rhythm disturbances seen. Coronary artery disease often spares the ostial RCA. Aortic stenosis is unlikely to worsen as the insult is three decades ago. Radiation interstitial lung injury is a common noncardiac cause of dyspnea.

A. . C. D.

Which of the following is not a cardiac complication of HIV infection and antiretroviral therapy? Diffuse coronary artery disease Intraventricular conduction delay Pericardial effusion Dilated cardiomyopathy with regional wall motion abnormalities

4.

5.

6.

A 35-year-old woman of Asian descent presents with subacute onset of fevers, arthralgias, headaches, and jaw claudication and presents to the emergency room for further evaluation and management. Figure 57.1 shows the imaging study performed. The most likely diagnosis is

FIGURE 57.1 A. . C. D.

Fibromuscular dysplasia Takayasu arteritis Sarcoid vasculopathy Giant cell arteritis

A 27-year-old male with myotonic muscular dystrophy is referred to your clinic after his neurologist noted second degree, Mobitz I (Wenckebach) as an incidental finding on ECG during a routine office visit. There were no other apparent conduction abnormalities. The patient is asymptomatic with his routine daily activities. Which of the following is the most appropriate management strategy at this time? Implant permanent pacemaker Electrophysiology (EP) study followed by permanent pacemaker if AV block at intra- or infra-His levels is found Holter monitor and close follow-up to evaluate for more advanced degree of heart block Exercise stress testing to evaluate exercise capacity and dromotropic response

7.

A. . C. D.

C. D.

A 24-year-old woman with Marfan syndrome presents to your office because she would like to explore options regarding pregnancy. She has a history of mild aortic root dilatation to 3.7 cm. She has no family history of acute aortic syndromes. What is the most appropriate recommendation at this time? Recommend against pregnancy due to increased risk of acute aortic syndromes Recommend increased cardiovascular monitoring during pregnancy and into the puerperium Prophylactic repair of the aortic root prior to pregnancy Beta-blocker and reassess progression of aortic dilatation in 6 months

A. . C. D.

A 40-year-old, previously healthy woman, suffers an out-of-hospital cardiac arrest. The rhythm was ventricular fibrillation and the first ECG shows anterior ST elevations. Coronary angiography shows a radiolucent linear defect in the LAD but otherwise normal vessels. Which of the following statements is true? Immediate PCI is indicated. Coronary artery bypass is preferred to PCI. An inflammatory arteritis is the culprit etiology. Angiography of the brain and abdominal vessels is indicated.

8.

A. .

9.

10. A 28-year-old otherwise healthy man presents to cardiology clinic for

A. . C. D.

evaluation of an abnormal electrocardiogram. He denies any cardiovascular symptoms. His only complaints are chronic lower back pain and stiffness and recent blurry vision with eye redness. Physical exam reveals a III/VI early diastolic decrescendo murmur heard best over the left lower sternal border. Review of his electrocardiogram reveals first-degree AB block with a PR interval of 240 ms. Review of the medical chart reveals a prior workup for his lower back complaints. An x-ray showed a loss of lumbar lordosis and the spine was said to have a “bamboo” appearance. Aside from a transthoracic echocardiogram, testing for which of the following is likely to clarify the patient’s systemic disorder? Anticitrullinated protein antibodies Anticollagen type II antibodies Human leukocyte antigen typing Anti–double stranded DNA antibodies

ANSWERS 1.

Correct Answer: D. Noonan Syndrome, Marfan, Osler–Weber– Rendu, Williams Syndrome Answer D correctly pairs the inherited syndromes with their commonly associated cardiac (and noncardiac) anomalies.

2.

Correct Answer: B. Left ventricular hypertrophy by voltage criteria Unlike the muscular dystrophies, myotonic dystrophy is not associated with a hypertrophic cardiomyopathy. It is, however, associated with the electrocardiogram abnormalities above.

3.

Correct Answer: D. β-Adrenergic blockers and methimazole This patient has hyperthyroidism. Her RA increases her risk of other autoimmune disorders; the most common cause of hyperthyroidism is Graves disease, an autoimmune disorder characterized by autoantibodies against the thyrotropin receptor. Her associated

hypertension and atrial fibrillation are best managed initially with βadrenergic–blocking agents and then by antithyroid medications.

4.

Correct Answer: D. Radiation interstitial lung injury is a common noncardiac cause of dyspnea. RACD can cause damage to the conduction system and often result in bradyarrhythmias. CAD associated with this condition classically involves the ostial RCA as it is the most anterior vessel. Cardiac injuries sustained from radiation can continually worsen over time despite the ever more remote origin of the insult. While RACD is a common cause of symptoms, radiation lung injury cannot be overlooked as a common contributor.

5.

Correct Answer: B. Intraventricular conduction delay Although HIV and protease inhibitors may cause diffuse coronary artery disease, pericardial effusion, and focal myocarditis, intraventricular conduction delay is not an associated complication of the infection or therapy.

6.

Correct Answer: B. Takayasu arteritis The question highlights several characteristics that are consistent with Takayasu arteritis including young female, Asian origin, and inflammatory constitutional symptoms, and the imaging study demonstrates serial arterial stenoses alternating with regions of normal arterial diameter representing an inflammatory vasculitis.

7.

Correct Answer: A. Implant permanent pacemaker Guidelines have a Class I recommendation for permanent pacing in neuromuscular diseases with AV block, such as myotonic muscular dystrophy, Kearns–Sayre syndrome, Erb dystrophy, and peroneal muscular atrophy with or without symptoms, because there may be unpredictable progression of AV conduction disease. There is a Class IIb recommendation for permanent pacing in neuromuscular diseases

with any degree of AV block (including first-degree AV block) with or without symptoms.

8.

Correct Answer: B. Recommend increased cardiovascular monitoring during pregnancy and into the puerperium Pregnant patients with Marfan syndrome are at increased risk for aortic dissection if the aortic diameter exceeds 4 cm and it is reasonable to prophylactically replace the aortic root and ascending aorta if the diameter exceeds 4.0 cm. All women with Marfan syndrome warrant frequent cardiovascular monitoring throughout pregnancy and into the puerperium.

9.

Correct Answer: D. Angiography of the brain and abdominal vessels is indicated. Spontaneous coronary artery dissection must be considered in a young female with ST-elevation myocardial infarction without traditional risk factors. The angiographic description is that of coronary dissection. Revascularization, PCI, or CABG is rarely indicated as it has the potential to perpetuate the dissection. SCAD is not an inflammatory vasculitis and recurrence rates are closer to 16%. An underlying diagnosis of fibromuscular dysplasia should be pursued. This is done by imaging the abdominal and cerebral vessels to assess for the classic string-of-beads appearance.

10. Correct Answer: C. Human leukocyte antigen typing This patient has ankylosing spondylitis. The diastolic murmur is owing to aortic regurgitation with probable aortic dilatation. Conduction disturbances (in this case first-degree AV block) are commonly seen and can predate structural changes. Human leukocyte antigen typing would likely reveal HLA-B27, present in many “seronegative spondyloarthropathies.” Anticitrullinated protein antibodies are often found in rheumatoid arthritis. Anticollagen type II antibodies are found in relapsing polychondritis. Anti–double stranded DNA antibodies are often found in SLE and correlate with

disease activity. While each of these disorders is capable of causing aortic valvulopathy, the constellation of classic spinal symptoms and x-ray findings as well as uveitis in a young man is most suggestive of ankylosing spondylitis.

CHAPTER 58

Cardiac Neoplasms EOIN DONNELLAN AND BRIAN P. GRIFFIN Primary cardiac neoplasms are rare with an estimated prevalence of between 0.001% and 0.003%. Metastatic involvement of the heart is significantly more common, occurring in roughly 20% of patients dying from extracardiac malignancies. The vast majority of primary cardiac tumors are of mesenchymal origin and accordingly display a variety of histopathologies. Over 75% of primary tumors are benign. Symptoms, when present, may be related to obstruction, interference with valvular structures resulting in regurgitation, direct invasion of the myocardium with associated impaired contractility, arrhythmia and conduction disorders, pericardial effusion, or embolization.

BENIGN TUMORS See Table 58.1.

Table 58.1 Benign Primary Cardiac Tumors

Myxomas Myxomas represent the most common primary cardiac tumors in adults, accounting for approximately 25% of all cardiac neoplasms and 75% of all benign primary cardiac tumors. While once thought to represent organized thrombus, gene expression and immunohistochemical studies have firmly concluded that they are neoplasms arising from multipotent mesenchymal cells. Myxomas have a bimodal peak onset in the third and sixth decades of life and 65% occur in women. A total of 7% to 10% of myxomas are familial. The autosomal-dominant Carney complex represents the majority of these familial cases and is characterized by cardiac and extracardiac myxomas (breast and skin), lentigines, hyperendocrine states, and nonmyxomatous extracardiac tumors including testicular Sertoli cell tumors, schwannomas, pituitary adenomas, and thyroid tumors. Other familial syndromes associated with myxoma formation include the LAMB (lentigines, atrial myxoma, mucocutaneous myxoma, and blue nevi) and NAME (nevi, atrial myxoma, myxoid neurofibromata, and ephelides) syndromes. In contrast to sporadic cases, familial myxomas have no clear predilection for sex or age, are multicentric, apically located, and more likely to recur following resection (20% of cases in the Carney complex). Over 90% of myxomas are solitary, with 80% located in the left atrium, most commonly attaching to the interatrial septum at the inferior border of the

fossa ovalis, 15% occurring in the right atrium, and the remaining 5% arising from the atrioventricular (AV) valves or the ventricles. Myxomas are pedunculated and their surfaces may be smooth or villous. On gross examination, they have a gelatinous consistency with foci of hemorrhage, calcification, ossification, and often cystic components. Diameter at the time of diagnosis is typically 4 to 8 cm though myxomas as large as 16 cm have been described in the literature. As with all cardiac tumors, symptoms are highly variable and depend largely on tumor size, location, and mobility. The classic triad of symptoms includes obstructive symptoms (syncope, sudden cardiac death, or symptomatic heart failure [HF]), embolic phenomenon, and constitutional symptoms (fever, weight loss, arthralgias, and Raynaud syndrome) thought to be due to the release of interleukin-6. Findings on auscultation include diastolic and systolic murmurs. The characteristic low-pitched “tumor plop” occurring 80 to 120 ms after S2 (i.e., after an opening snap and prior to a third heart sound) and correlating with tumor movement through the mitral valve and contact with the ventricular wall is heard in only a minority of cases. Laboratory abnormalities include elevated erythrocyte sedimentation rates and C-reactive protein, anemia (often hemolytic), polycythemia, and thrombocytopenia. The diagnosis is made by echocardiography, contrastenhanced computed tomography (CT), or cine gradient-echo cardiac MR (CMR) where myxomas appear as heterogeneous spherical or ovoid masses (Fig. 58.1). Thrombus is the primary differential diagnosis with protrusion through the mitral annulus being the most specific finding favoring the diagnosis of myxoma.

FIGURE 58.1 A:Left atrial myxoma. B:Surgical specimen, left atrial myxoma (same as part A). C:Right atrial myxoma. Treatment consists of surgical resection, which is associated with a low operative mortality, and, with the exception of familial cases, a low recurrence rate (0% to 3%). Complete resection of the tumor and avoidance of excessive manipulation is essential to preventing local and distant recurrences. As with all cardiac tumors, this is best achieved with extracorporeal circulatory support via femoral or azygous vein cannulation in order to avoid tumor embolization, facilitate direct visualization, and rule out metasynchronous tumors. As with all resected cardiac tumors, annual noninvasive imaging is recommended for follow-up.

Papillary Fibroelastoma Papillary fibroelastoma represents the second most common benign primary cardiac tumor and the most common to involve the cardiac valves. Eighty percent of fibroelastomas occur in the left cardiac chambers with the aortic

and mitral valves being the most common sites. Fibroelastomas are typically found on the downstream aspect of the valve and appear as frond-like projections of collagen and elastic fibers emanating from a short central stalk (often described as sea anemone like) (Fig. 58.2). Their small size and highly mobile nature make them best suited to visualization with echocardiography. They can be differentiated from Lambl excrescences by their location on noncontact surfaces of the valve. Symptoms when present are due to systemic embolization with stroke and myocardial infarction being the most feared complications. The current therapeutic approach is surgical excision for fibroelastomas that are highly mobile, larger than 1 cm in size or associated with prior embolization. In nonsurgical candidates with prior embolic events, long-term anticoagulation may be considered.

FIGURE 58.2 A,B:Aortic valve papillary fibroelastoma.

Other Benign Primary Cardiac Tumors Lipoma Cardiac lipomas are the third most common benign primary cardiac tumors and, as their name implies, represent well-encapsulated collections of mature adipocytes. They are mainly located subepicardially and subendocardially although intramyocardial locations can also occur. Clinical presentations are largely dictated by location with subepicardial lipomas rarely resulting in symptoms unless very large and associated with pericardial effusion or chamber compression. Subendocardial lesions may result in hemodynamic

obstruction when large and intramyocardial lipomas may occasionally present with conduction disorders or arrhythmia. Because lipomas have a nonspecific echocardiographic appearance, CT has become a favored diagnostic modality demonstrating a well-circumscribed mass with low attenuation similar to subcutaneous fat. Surgical resection is reserved for symptomatic cases. Lipomatous hypertrophy of the interatrial septum (LHAS) is a nonneoplastic excessive accumulation of nonencapsulated fat >2 cm in diameter in the superior and inferior portions of the atrial septum, sparing the fossa ovalis. LHAS is more common in elderly, obese, and male patients. Rhythm disturbances and hemodynamic obstruction necessitating surgical intervention are rare.

Rhabdomyoma Cardiac rhabdomyomas are quite rare in adult populations but represent the most common benign primary cardiac tumors in the pediatric population with more than 80% occurring in patients 1.5:1 is considered significant.

Management

Recommendations for ASD closure can be found in Table 60.3.14

Table 60.3 ACC/AHA Interventions

Recommendations

for

ASD

B-NR, moderate quality from nonrandomized trials; C-LD, limited data.14

In patients who remain asymptomatic without evidence of RA and/or RV enlargement or significant shunt (Qp:Qs > 1.5:1), there is no indication for closure. In ASDs that are associated with symptoms, significant shunt, or enlarging RA and/or RV, closure should be done in a timely manner. Earlier closure of ASDs portends an improved survival and reduced incidence of arrhythmia, heart failure, stroke, pulmonary hypertension, and cardiovascular death. However, for patients with significant pulmonary hypertension, defined as pulmonary artery systemic pressure >2/3 systemic pressure or pulmonary vascular resistance (PVR) > 2/3 of systemic vascular resistance (SVR), closure is contraindicated. Similarly, if there is evidence of right-toleft shunt as in Eisenmenger syndrome, closure is contraindicated. In general, only secundum ASDs are amenable to percutaneous closure. The size of the secundum ASD and comfort of the operator with the device determines which device is selected for closure. Management of other types of ASDs, or of very large secundum defects, is often surgical with use of a suture or a pericardial or Dacron patch. Coronary sinus defects often involve direct suture closure or creation of an intra-atrial baffle. There is also

evolving experience of percutaneous closure of both superior sinus venosus isolated defects and coronary sinus defects.15,17 Atrial arrhythmias are common with ASD and also following ASD closure with AF occurring in up to 20% of patients with ASD.16 AF incidence is much more common in patients older than 40 years at the time of ASD closure.2 For ASD closed in childhood, this risk is minimal, but with each passing decade prior to repair, the risk for atrial arrhythmias increases. Patients should be assessed thoroughly for AF prior to closure as this can make AF ablation much more difficult by precluding transseptal approaches. ASD closure seems to reduce but not eliminate the risk of atrial arrhythmias. To meet criterion for percutaneous closure, the defect must be ≤38 mm in diameter with a rim of tissue around the defect of ≥5 mm to prevent obstruction of the coronary sinus, right pulmonary veins, vena cava, or atrioventricular valves. The most common devices used include the Amplatzer Septal Occluder and the Gore Helex Septal Occluder (Fig. 60.9).

FIGURE 60.9 Amplatzer Septal Occluder (A) and Gore Helex Septal Occluder (B). (A: Amplatzer and SJM Regent are trademarks of Abbott or its related companies. Reproduced with permission of Abbott, © 2021. All rights reserved; B: WL Gore & Associates.)

Outcomes Similar to PFO closure, use of antiplatelet agents is recommended though duration is variable. Periprocedural complications are similar to those seen with PFO. Infective endocarditis prophylaxis is recommended for the 6 months for dental procedures only.4 Device erosion is very rare but can be a life-threatening complication. Symptoms and signs of erosion include chest pain, dyspnea, syncope, pericardial effusion +/− tamponade, and sudden cardiac death.

Follow-up Echocardiography should be performed prior to discharge after ASD closure. Follow-up should continue with evaluation every 1 to 2 years. Ambulatory ECG monitoring should be done in patients to assess for atrial arrhythmias.

REFERENCES 1. Meissner I, Whisnant JP, Khandheria BK, et al. Prevalence of potential risk factors for stroke assessed by transesophageal echocardiography and carotid ultrasonography: the SPARC study. Stroke Prevention Assessment of Risk in a Community. Mayo Clin Proc. 1999;74:862-869. 2. Sachdeva R. Atrial septal defects. In: Moss and Adams Heart Disease in Infants, Children and Adolescents. 9th ed. Wolters Kluwer; 2016:739-802. 3. Hart RG, Diener HC, Coutts SB, Easton JD, et al. Embolic strokes of undetermined source: the case for a new clinical construct. Cryptogenic Stroke/ESUS International Working Group. Lancet Neurol. 2014;13(4):429-438. 4. Collado FM, Poulin MF, Murphy JJ, et al. Patent foramen ovale closure for stroke prevention and other disorders. J Am Heart Assoc. 2018;7(12):e007146. 5. Giblett JP, Abdul-Samad O, Shapiro LM, et al. Patent foramen ovale closure in 2019. Interv Cardiol. 2019;14:34-41. 6. Furlan AJ, et al. ‘‘Closure or medical therapy for cryptogenic stroke with patent foramen ovale’’. N Engl J Med. 2012;366(11):991-999. 7. Carroll JD, et al. ‘‘Closure of patent foramen ovale versus medical therapy after cryptogenic stroke’’. N Engl J Med. 2013;368(12):1092-1100. 8. Sondergaard L, Kasner SE, Rhodes JF, et al. Patent foramen ovale closure or antiplatelet therapy for cryptogenic stroke. N Engl J Med. 2017;377:1033-1042. 9. Mas JL, Derumeaux G, Guillon B, Massardier E, et al. Patent foramen ovale closure or anticoagulation vs. antiplatelets after stroke. N Engl J Med. 2017;377:1011-1021. 10. Lee PH, Song JK, Kim JS, Heo R, et al. Cryptogenic stroke and high-risk patent foramen ovale: the DEFENSE-PFO trial. J Am Coll Cardiol. 2018;71(20):2335-2342.

11. Khairy P, O’Donnell CP, Landzberg MJ. Transcatheter closure versus medical therapy of patent foramen ovale and presumed paradoxical thromboemboli: a systematic review. Ann Intern Med. 2003;139:753-760. 12. Staubach S, Steinberg DH, Zimmermann W, Wawra N, Wilson N, Wunderlich N, Sievert H. New onset atrial fibrillation after patent foramen ovale closure. Catheter Cardiovasc Interv. 2009;74:889-895. 13. Liegeois JR, Rigby ML. Chapter 29. Atrial septal defect (interatrial communication). In: Gatzoulis MA, Webb GD, Daubeney PEF, eds. Diagnosis and Management of Adult Congenital Heart Disease. 3rd ed. Elsevier; 2018. 14. Stout KK, Daniels CJ, Aboulhosn JA, et al. 2018 AHA/ACC guideline for the management of adults with congenital heart disease: a report of the American College of Cardiology/American Heart Association Task Force of Clinical Practice Guidelines. J Am Coll Cardiol. 2019;139(14)e698-e800. 15. Hansen JH, Duong P, Jivanji SGM, et al. Transcatheter correction of superior sinus venosus atrial septal defects as an alternative to surgical treatment. J Am Coll Cardiol. 2020;75(11):1266-1278. 16. Berger F, Vogel M, Kramer A, Alexi-Meskishvili V, et al. Incidence of atrial flutter/fibrillation in adults with atrial septal defect before and after surgery. Ann Thorac Surg. 1999;68(1):75.

SUGGESTED READINGS Meier B, Kalesan B, Mattle HP, et al. Percutaneous close of patent foramen ovale in cryptogenic embolism. N Engl J Med. 2013;368:1083-1091. Santoro G, Gaio G, Russo MG. Transcatheter treatment of unroofed coronary sinus. Catheter Cardiovasc Interv. 2013;81:849-852.

CHAPTER 61

Transcatheter Aortic Valve Replacement GRANT W. REED, SAMIR R. KAPADIA AND AMAR KRISHNASWAMY Transcatheter aortic valve replacement (TAVR) has revolutionized the treatment of aortic stenosis (AS). Several clinical trials have shown that for severe, symptomatic AS, TAVR is at least noninferior (and in many cases superior) to surgical aortic valve replacement (SAVR) in terms of short- and intermediate-term safety and efficacy, leads to a shorter hospital length of stay (LOS), quicker return to quality of life (QOL), and less cost to the health care system across the entire spectrum of surgical risk. This has led to the implementation of TAVR across an expanding population of patients. The goal of this chapter is to review the current indications and evidence supporting the use of TAVR in the United States (US), focusing on key facts relevant to clinical practice and the cardiology boards. Emphasis will be placed on recent advances including the recent US Food and Drug Administration (FDA) approval for TAVR in patients at low surgical risk.

CURRENT INDICATIONS FOR TAVR Current U.S. guidelines recommend the choice for SAVR or TAVR be guided by the patient’s surgical risk. The Society of Thoracic Surgeons (STS) Predicted Risk of Mortality (PROM) at 30-days is the most commonly used criteria for determining surgical risk. An STS PROM < 4% indicates low risk, 4% to 8% intermediate risk, 8% to 12% high risk, and >12% extreme (or inoperable) risk. However, the STS score does not account for other

important factors such as patient frailty and may underestimate actual surgical risk. As such, current U.S. guidelines mandate an evaluation by a surgeon to formally document surgical risk prior to TAVR. The 2017 guidelines for the management of patients with valvular heart disease gives TAVR a Class I recommendation for patients with severe, symptomatic AS who are inoperable (STS PROM > 12%) or high surgical risk (STS PROM 8% to 12%). TAVR currently carries a Class IIa recommendation for those at intermediate risk (STS PROM 4% to 8%)1 (Fig. 61.1). Based on recent clinical trial data that will be discussed in this chapter, in August 2019, the FDA expanded the indication for TAVR to cover patients at low surgical risk (STS PROM < 4%). While not yet incorporated into U.S. guidelines at time this chapter was written, guidelines are expected to be updated to include the latest clinical trials, and expanded FDA indication for low-risk patients.

FIGURE 61.1 Summary of 2017 AHA/ACC guidelines for choice of AVR or TAVR for severe, symptomatic AS. (Reprinted with permission Nishimura RA, Otto CM, Bonow RO, et al. 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. Circulation. 2017;135:e1159-e1195. ©2017 American Heart Association, Inc.)

Based on the June 2019 Center for Medicare and Medicaid Services national coverage decision, each patient must be evaluated by a “Heart Team” consisting of at least one cardiologist and one cardiothoracic surgeon to determine each patient’s candidacy for TAVR.2 Surgical AVR can be performed in most patients eligible for TAVR. For board purposes, TAVR is not indicated for patients with pure aortic regurgitation without stenosis, infective endocarditis, or an anatomic exclusion to TAVR including severe lower extremity peripheral artery disease such as diffuse iliofemoral calcification, which would preclude large-bore vascular access. Patients must have a minimal luminal diameter (MLD) of at least 5.0 mm diameter to accommodate the lowest profile TAVR device. For purposes of the cardiology boards, TAVR should not be recommended in patients with a low coronary artery height in the sinus of Valsalva (5.0 mm in patients without bicuspid AV, >4.5 mm in patients with bicuspid AV).

TAVR DEVICES APPROVED IN THE UNITED STATES

As of June 2021, the landscape of commercially available transcatheter heart valves (THVs) in the United States consists of a balloon expandable valve (Edwards Sapien 3), and a self-expanding valve system (Medtronic Evolut R and Evolut PRO) (Fig. 61.2).

FIGURE 61.2 Key features of commercially approved valves for TAVR in the United States, June 2021. A:Edwards-Sapien 3. (Courtesy of Edwards Lifescience.) LLC, Irvine, CA. Edwards, Edwards Lifesciences, Edwards SAPIEN, SAPIEN, SAPIEN XT, and SAPIEN 3 are trademarks of Edwards Lifesciences Corporation.) B:Evolut R, Pro (CoreValve). (Used with permission of Medtronic, Inc.) The Edwards-Sapien 3 (S3) valve (Edwards Lifesciences) consists of bovine pericardium leaflets attached to a balloon-expandable, cobalt chromium frame (Fig. 61.2A). The S3 valve is a newer generation of the prior Edwards SAPIEN and Sapien XT valves and has a smaller profile, an

outer skirt to minimize paravalvular leak, and refined delivery system. The S3 valve is available in 20, 23, 26, and 29 mm sizes depending on the patient’s annular dimensions. Sizes 20, 23, and 26 mm S3 valves are deliverable through a proprietary 14F “E-sheath,” while the 29 mm S3 goes through a 16F E-sheath. Sizing is based on AV annulus cross-sectional area typically determined by gated cardiac CT with IV contrast, and less often by cardiac MRI or 3D TEE in select patients (typically in patients with renal dysfunction who cannot receive IV contrast). The Evolut-R valve (Medtronic) is a self-expanding porcine valve mounted on a nitinol frame, which expands as it is unsheathed. The Evolut-R valve is a newer iteration of the CoreValve device and currently available in 23, 26, 29, and 34 mm sizes. The device is inserted through an “in-line sheath,” which allows for a slightly smaller iliofemoral MLD compared to the S3 valve (Fig. 61.2B). The 23, 26, and 29 mm Evolut-R valves go through a 14F in-line sheath, while the 34 mm device requires a 16F in-line sheath. The latest generation Evolut-PRO valve has an updated skirt designed to minimize paravalvular leak, is offered in 23, 26, and 29 mm sizes, but requires a 16F sheath and thus slightly larger access MLD than the Evolut-R to pass. Now removed from the U.S. market, the Lotus Edge (Boston Scientific) was a mechanically expanding valve with a braided nitinol frame and bovine pericardial leaflets. The device was approved based on results from the REPRISE III clinical trial, however removed from the U.S. market by the manufacturer given issues with device deliverability.

EVIDENCE SUPPORTING USE OF TAVR We next provide an overview of the evidence supporting the current indications for TAVR. Outcomes have improved dramatically as experience using these valves has increased, and valve technology has improved. For the purposes of the boards, examinees should focus on understanding the relative pros and cons of TAVR in relation to optimal medical therapy (OMT) and SAVR, and specific knowledge of complication rates in recent trials of intermediate and low-risk patients as they reflect contemporary practice moreso than earlier trials.

Inoperable Patients PARTNER 1B The earliest trials of TAVR were unique as instead of being studied in healthier populations, and they evaluated the sickest patients first. PARTNER 1B was a randomized control trial of patients with severe, symptomatic AS considered poor (or “inoperable”) surgical candidates (STS PROM ≥ 10%, coexisting conditions with ≥15% risk of death, or a ≥50% risk of death or a serious irreversible complication within 30 days).4 Patients were randomized 1:1 to either TAVR using the first-generation balloon-expandable SAPIEN valve system versus medical therapy. The study included 358 patients in total, with 179 assigned to TAVR and 179 assigned to medical therapy alone. Key results from PARTNER 1B are shown in Table 61.1.

Table 61.1 1-Year Outcomes for TAVR in Extreme-Risk Patients

No shading denotes TAVR noninferior, blue shading denotes TAVR superior, red shading denotes TAVR inferior to OMT. PARTNER 1B was a RCT of TAVR vs. optimal medical therapy (OMT). The CoreValve Extreme Risk Study was a prospective cohort study without a comparison arm. Bleeding reported as life-threatening or disabling. *Denotes statistically significant (p < 0.05). †At least moderate paravalvular leak. ‡Results for 30 days. PPM, permanent pacemaker; PVL, paravalvular leak.

PARTNER 1B met its primary endpoint, as TAVR lowered all-cause mortality compared with medical therapy alone at 1 year (30.7% vs. 49.7%,

hazard ratio [HR] 0.55, 95% confidence interval [CI] 0.40 to 0.74; p < 0.001; a 20% absolute survival advantage, NNT 5). The prevalence of New York Heart Association (NYHA) class III or IV heart failure was less frequent in patients with TAVR compared to medical therapy at 1 year (25.2% vs. 58.0%, p < 0.001). The long-term 5-year results of PARTNER 1B show that while there is a durable reduction in death with TAVR, longterm mortality rates among patients with inoperable AS are nonetheless high (5-year mortality 71.8% with TAVR vs. 93.6% with standard therapy; HR 0.50, 95% CI 0.39 to 0.65; p < 0.0001).5

CoreValve Extreme Risk Study Similar to PARTNER 1B, the CoreValve Extreme Risk Study enrolled patients with severe, symptomatic AS and prohibitive surgical risk.6 A total of 506 patients were recruited and treated with the early generation CoreValve self-expanding THV. Unlike PARTNER 1, the CoreValve Extreme Risk Study was not a randomized control trial; it was a prospective observational study without a true comparison arm and instead used a prespecified objective performance goal as a benchmark for an expected rate of events in patients managed medically. Outcomes for the CoreValve Extreme Risk Study are shown in Table 61.1. The CoreValve was superior to the OPG for the primary endpoint of all-cause mortality and stroke at 1 year (26% vs. 43%, p < 0.0001). An important distinction is that there was a higher rate of need for permanent pacemaker (21.6%) with the selfexpanding CoreValve compared to what was seen with the balloonexpandable SAPIEN valve in PARTNER 1B (4.5%). This finding has persisted in intermediate- and low-risk trials. The PARTNER 1B and CoreValve Extreme Risk studies demonstrated the safety and 1-year efficacy of the CoreValve among inoperable patients,4,6 results which have remained consistent in long-term follow-up.5,7

High–Surgical-Risk Patients PARTNER 1A Similar to PARTNER 1B, the PARTNER 1A trial used the SAPIEN balloon expandable valve, but instead evaluated patients with severe, symptomatic

AS at high surgical risk, and compared to SAVR. Key inclusion criteria were a STS PROM score ≥10% or coexisting conditions with a ≥15% 30-day post-op risk of death.8 PARTNER 1A randomized 699 patients 1:1, with 348 assigned to SAPIEN and 351 to SAVR. The main results of PARTNER 1A are shown in Table 61.2. TAVR was noninferior to surgical AVR for mortality at 30-days and 1-year. Major vascular complications were higher with TAVR compared to SAVR, but major bleeding was lower with TAVR due to more blood loss during surgery. The need for permanent pacemaker implantation was equivalent between TAVR and SAVR. While there was a trend toward increased stroke with TAVR, this did not reach significance and has further shown to be noninferior in follow-up data out to 5 years.9 While more patients in the TAVR group had improvement of their symptoms to NYHA class II or lower as compared to SAVR at 30 days, NYHA class was similar at 1 year. TAVR patients had a 2day shorter intensive care unit stay and a 4-day shorter hospital LOS. The findings of PARTNER 1A have held up at 2-years and 5-years.

Table 61.2 1-Year Outcomes for TAVR in High-Risk Patients

No shading denotes TAVR noninferior, blue shading denotes TAVR superior, red shading denotes TAVR inferior to OMT. Bleeding reported as life-threatening or disabling bleeding. *Denotes statistically significant (p < 0.05). †At least moderate paravalvular leak. ‡As treated population. PPM, permanent pacemaker; PVL, paravalvular leak.

Moderate or severe aortic paravalvular regurgitation was observed to be higher with TAVR versus SAVR out to 5 years. Even mild paravalvular AI

has been associated with increased risk of mortality, emphasizing the importance of optimal procedural outcomes.8,9 In a pooled analysis of both PARTNER 1A and 1B patients adjusted for patient differences using propensity score matching, transapical access was associated with higher mortality at 6 months than transfemoral access (19% vs. 12%; p = 0.01), more adverse procedural events, longer LOS, and slower recovery.10 Reassuringly, long-term follow-up data from PARTNER 1A and 1B suggest that TAVR with the balloon expandable SAPIEN system has equivalent hemodynamic parameters to SAVR (mean gradient, AVA) at every point in follow-up out to 5 years with no signal of early valve deterioration.10,11

CoreValve High Risk Study The U.S. CoreValve High Risk Study was similar to PARTNER 1A in that it evaluated patients at high surgical risk; however, it used the self-expanding CoreValve system previously described.12 A total of 795 patients were randomized 1:1 to either TAVR with CoreValve or SAVR. Though the patient populations are not directly comparable, since clinicians were already becoming used to TAVR at the time, the “high-risk” designation was made at a lower average STS score for enrollees in this trial (7%) than for the PARTNER 1 trials (12%). The key outcomes at 1 year are shown in Table 61.2. One-year mortality was lower with TAVR using CoreValve compared to SAVR (14.2% vs. 19.1%, p = 0.04), and CoreValve was noninferior for stroke. While CoreValve also caused less major bleeding and less atrial fibrillation than SAVR, there were more major vascular complications and moderate-severe paravalvular leak with CoreValve. However, unlike with the balloon-expandable SAPIEN system, CoreValve associated with a higher rate of complete heart block and need for permanent pacemaker implantation than SAVR (22.3% vs. 11.3%, p < 0.001). Long-term follow-up suggests durable results with CoreValve compared to SAVR, with lower 3-year allcause mortality (32.9% vs. 39.1%; p = 0.068), stroke (12.6% vs. 19.0%, p = 0.034), and composite major adverse cardiac and cerebrovascular events (40.2% vs. 47.9%; p = 0.025). Like in PARTNER 1A and 1B, moderate or

severe residual aortic regurgitation was higher with CoreValve patients (6.8% vs. 0.0% in SAVR; p < 0.001).13

Intermediate Surgical Risk PARTNER 2A PARTNER 2A was the first RCT of patients with severe, symptomatic AS at intermediate surgical risk. Key inclusion criteria were an STS PROM score ≥4% or a 5 years to evaluate valve durability in patients treated with newer generation THV devices, the data that do exist suggest comparable if not

better longevity and durability with TAVR compared to surgical AVR. Indeed, the last decade has witnessed a revolution of how aortic valve disease is treated due to TAVR, and the future remains bright in this area.

REFERENCES 1. Nishimura RA, Otto CM, Bonow RO, et al. 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. Circulation. 2017;135:e1159-e1195. 2. Nishimura RA, O'Gara PT, Bavaria JE, et al. 2019 AATS/ACC/ASE/SCAI/STS Expert Consensus Systems of Care Document: a proposal to optimize care for patients with valvular heart disease: a joint report of the American Association for Thoracic Surgery, American College of Cardiology, American Society of Echocardiography, Society for Cardiovascular Angiography and Interventions, and Society of Thoracic Surgeons. J Am Coll Cardiol. 2019;73:2609-2635. 3. Khan JM, Greenbaum AB, Babaliaros VC, et al. The BASILICA Trial: prospective multicenter investigation of intentional leaflet laceration to prevent TAVR coronary obstruction. JACC Cardiovasc Interv. 2019;12:1240-1252. 4. Leon MB, Smith CR, Mack M, et al. Transcatheter aortic-valve implantation for aortic stenosis in patients who cannot undergo surgery. N Engl J Med. 2010;363:1597-1607. 5. Kapadia SR, Leon MB, Makkar RR, et al. 5-Year outcomes of transcatheter aortic valve replacement compared with standard treatment for patients with inoperable aortic stenosis (PARTNER 1): a randomised controlled trial. Lancet. 2015;385:2485-2491. 6. Popma JJ, Adams DH, Reardon MJ, et al. Transcatheter aortic valve replacement using a selfexpanding bioprosthesis in patients with severe aortic stenosis at extreme risk for surgery. J Am Coll Cardiol. 2014;63:1972-1981. 7. Reardon MJ, Adams DH, Kleiman NS, et al. 2-Year outcomes in patients undergoing surgical or self-expanding transcatheter aortic valve replacement. J Am Coll Cardiol. 2015;66:113-121. 8. Smith CR, Leon MB, Mack MJ, et al. Transcatheter versus surgical aortic-valve replacement in high-risk patients. N Engl J Med. 2011;364:2187-2198. 9. Mack MJ, Leon MB, Smith CR, et al. 5-Year outcomes of transcatheter aortic valve replacement or surgical aortic valve replacement for high surgical risk patients with aortic stenosis (PARTNER 1): a randomised controlled trial. Lancet. 2015;385:2477-2484. 10. Blackstone EH, Suri RM, Rajeswaran J, et al. Propensity-matched comparisons of clinical outcomes after transapical or transfemoral transcatheter aortic valve replacement: a placement of aortic transcatheter valves (PARTNER)-I trial substudy. Circulation. 2015;131:1989-2000. 11. Douglas PS, Leon MB, Mack MJ, et al. Longitudinal hemodynamics of transcatheter and surgical aortic valves in the PARTNER trial. JAMA Cardiol. 2017;2:1197-1206. 12. Adams DH, Popma JJ, Reardon MJ, et al. Transcatheter aortic-valve replacement with a selfexpanding prosthesis. N Engl J Med. 2014;370:1790-1798. 13. Deeb GM, Reardon MJ, Chetcuti S, et al. 3-Year outcomes in high-risk patients who underwent surgical or transcatheter aortic valve replacement. J Am Coll Cardiol. 2016;67:2565-2574.

14. Leon MB, Smith CR, Mack MJ, et al. Transcatheter or surgical aortic-valve replacement in intermediate-risk patients. N Engl J Med. 2016;374:1609-1620. 15. Thourani VH. Five-year outcomes from the PARTNER 2A trial: transcatheter vs. surgical aortic valve replacement in intermediate-risk patients. TCT 2019. San Francisco, CA, 2019. 16. Thourani VH, Kodali S, Makkar RR, et al. Transcatheter aortic valve replacement versus surgical valve replacement in intermediate-risk patients: a propensity score analysis. Lancet. 2016;387:2218-2225. 17. Reardon MJ, Van Mieghem NM, Popma JJ, et al. Surgical or transcatheter aortic-valve replacement in intermediate-risk patients. N Engl J Med. 2017;376:1321-1331. 18. Mack MJ, Leon MB, Thourani VH, et al. Transcatheter aortic-valve replacement with a balloon-expandable valve in low-risk patients. N Engl J Med. 2019;380:1695-1705. 19. Popma JJ, Deeb GM, Yakubov SJ, et al. Transcatheter aortic-valve replacement with a selfexpanding valve in low-risk patients. N Engl J Med. 2019;380:1706-1715. 20. Tuzcu EM, Kapadia SR, Vemulapalli S, et al. Transcatheter aortic valve replacement of failed surgically implanted bioprostheses: the STS/ACC Registry. J Am Coll Cardiol. 2018;72:370382. 21. Shivaraju A, Michel J, Frangieh AH, et al. Transcatheter aortic and mitral valve-in-valve implantation using the Edwards Sapien 3 heart valve. J Am Heart Assoc. 2018;7. 22. Yoon SH, Bleiziffer S, De Backer O, et al. Outcomes in transcatheter aortic valve replacement for bicuspid versus tricuspid aortic valve stenosis. J Am Coll Cardiol. 2017;69:2579-2589. 23. Makkar RR, Yoon SH, Leon MB, et al. Association between transcatheter aortic valve replacement for bicuspid vs tricuspid aortic stenosis and mortality or stroke. JAMA. 2019;321:2193-2202. 24. Yoon SH, Schmidt T, Bleiziffer S, et al. Transcatheter aortic valve replacement in pure native aortic valve regurgitation. J Am Coll Cardiol. 2017;70:2752-2763. 25. Pellikka PA, Sarano ME, Nishimura RA, et al. Outcome of 622 adults with asymptomatic, hemodynamically significant aortic stenosis during prolonged follow-up. Circulation. 2005;111:3290-3295. 26. Campo J, Tsoris A, Kruse J, et al. Prognosis of severe asymptomatic aortic stenosis with and without surgery. Ann Thorac Surg. 2019;108:74-79. 27. Spitzer E, Van Mieghem NM, Pibarot P, et al. Rationale and design of the Transcatheter Aortic Valve Replacement to UNload the Left ventricle in patients with ADvanced heart failure (TAVR UNLOAD) trial. Am Heart J. 2016;182:80-88. 28. Huded CP, Tuzcu EM, Krishnaswamy A, et al. Association between transcatheter aortic valve replacement and early postprocedural stroke. JAMA. 2019;321:2306-2315. 29. Schmidt T, Leon MB, Mehran R, et al. Debris heterogeneity across different valve types captured by a cerebral protection system during transcatheter aortic valve replacement. JACC Cardiovasc Interv. 2018;11:1262-1273. 30. Mohananey D, Sankaramangalam K, Kumar A, et al. Safety and efficacy of cerebral protection devices in transcatheter aortic valve replacement: a clinical end-points meta-analysis. Cardiovasc Revasc Med. 2018;19:785-791. 31. Seeger J, Kapadia SR, Kodali S, et al. Rate of peri-procedural stroke observed with cerebral embolic protection during transcatheter aortic valve replacement: a patient-level propensitymatched analysis. Eur Heart J. 2019;40:1334-1340. 32. Thyregod HGH, Ihlemann N, Jorgensen TH, et al. Five-year clinical and echocardiographic outcomes from the nordic aortic valve intervention (NOTION) randomized clinical trial in lower surgical risk patients. Circulation. 2019;139: 2714-2723.

33. Yanagisawa R, Hayashida K, Yamada Y, et al. Incidence, predictors, and mid-term outcomes of possible leaflet thrombosis after TAVR. JACC Cardiovasc Imaging. 2017;10.

Chapter 61 Review Questions and Answers QUESTIONS Based on the results of the PARTNER 3 and Evolut Low-Risk Trials, which of the following is true regarding the risks of TAVR in patients at low-surgical risk? The risk of major stroke at 30 days is lower with TAVR than SAVR. Patients who receive TAVR are at higher risk of atrial fibrillation than patients treated with SAVR. Patients treated with surgical AVR have higher risk of complete heart block and need for permanent pacemaker. Surgical AVR and TAVR have similar rates of major bleeding.

1.

A. . C. D.

Which of the following is true regarding the current indications for TAVR in the United States? TAVR is indicated in patients regardless of surgical risk and does not require a surgical consultation prior to the procedure. TAVR is indicated in patients regardless of surgical risk and requires a single surgeon to be consulted prior to the procedure. TAVR is indicated in patients regardless of surgical risk and requires 2 surgeons to be consulted prior to the procedure. TAVR is indicated in patients who are inoperable, at high-, and intermediate-surgical risk and requires a single surgeon to be consulted prior to the procedure. TAVR is indicated in patients who are inoperable, at high-, and intermediate-surgical risk and requires 2 surgeons to be consulted prior to the procedure.

2.

A. . C. D. .

A patient undergoes transfemoral TAVR with a 26-mm Evolut R selfexpanding device. In the post-procedure recovery area, they develop slurred speech and confusion. CT head rules out an intracranial hemorrhage; however, subsequently brain MRI confirms a small embolic stroke. Which of the following is true regarding the risk of stroke after TAVR? A. Stroke is more common after TAVR than SAVR, even in the most recent trials of patients at low surgical risk.

3.

. Stroke occurs most commonly 30 to 60 days after TAVR. C. The rate of stroke has been rising over time despite improvement in valve technology. D. The risk of stroke could have been reduced with the use of a cerebral embolic protection device. A patient undergoes TAVR with a 23-mm S3 THV and is seen in follow-up 30 days after the procedure. On echocardiogram, 1 day post-TAVR, AV gradients were Peak 12 mm Hg, mean 5 mm Hg without aortic insufficiency. At 30-day follow-up, AV gradients have risen to Peak 36 mm Hg, mean 22 mm Hg, with mild 1+ aortic insufficiency. The patient is otherwise asymptomatic, with complete resolution of heart failure symptoms after TAVR. What is the likely reason for this, and most appropriate next step? Patient prosthesis mismatch; obtain follow-up echocardiogram in 6 months. Patient prosthesis mismatch; start beta-blockade, obtain follow-up echocardiogram in 3 months. Pannus formation; obtain gated cardiac CTA, consider initiation of empiric steroids. Subacute leaflet thrombosis; obtain gated cardiac CTA, consider initiation of empiric anticoagulation.

4.

A. . C. D.

You are referred a 74-year-old male with symptomatic, severe calcific aortic stenosis due to bicuspid AV, atrial fibrillation, and moderate 2 to 3+ degenerative mitral regurgitation. He has no other major medical comorbidities, aside from single vessel CAD involving a 70% stenosis of the mid LAD. He relates dyspnea on exertion and mild chest discomfort symptoms. He is open to surgery or TAVR but would like to wait as long as he is able. He has an overall STS score of 3.46%. What is the most appropriate strategy for this patient? Surgical AVR + Mitral valve repair + Single vessel CABG with LIMA to LAD + MAZE and LAA ligation TAVR + Single vessel PCI to mid LAD TAVR alone, with medical management of CAD, MR, and atrial fibrillation Continued medical management and serial assessment every 6 months.

5.

A. . C. D.

ANSWERS 1.

Correct Answer: A. The risk of major stroke at 30 days is lower with TAVR and SAVR. The rates of stroke after TAVR have fallen over the course of clinical trials, both with balloon-expandable and self-expanding TAVR systems. Recent data from randomized controlled trials indicate that the rate of stroke is lower with TAVR compared to surgical AVR (0.2% vs. 0.9% for PARTNER 3 and 0.8 vs. 2.4 for the Evolut LowRisk Trial). Patients treated with TAVR are at lower risk of postoperative atrial fibrillation and major bleeding than surgical AVR. The rate of permanent pacemaker was similar between TAVR and surgical AVR in the PARTNER 3 trial using the balloonexplandible S3 valve, but higher with TAVR than surgical AVR in the Evolut Low-Risk trial using the Evolut self-expanding valve.

2.

Correct Answer: B. TAVR is indicated in patients regardless of surgical risk and requires a single surgeon to be consulted prior to the procedure. Based on a recent FDA statement, TAVR is now indicated in patients with severe, symptomatic AS at all levels of surgical risk (extreme/inoperable, high, intermediate, and low). The most recent CMS National Coverage Decision issued in June 2019 reduced the requirements such that only a single surgical consultation is required prior to offering TAVR, as a part of the comprehensive Heart Team evaluation.

3.

Correct Answer: D. The risk of stroke could have been reduced with the use of a cerebral embolic protection device. It is estimated that approximately 2% of patients will experience an embolic stroke after TAVR. While the rates have fallen over the course of clinical trials, and recent data show the risk of stroke may be less with TAVR than SAVR in low-risk patients, a recent study of the STS/ACC TVT registry indicates that the risk of stroke has remained relatively constant in recent years. Though individual

device trials have been largely underpowered for clinical endpoints given low event rates, pooled data from meta-analyses and realworld data consistently show that cerebral embolic protection devices reduce the risk of stroke during TAVR.

4.

Correct Answer: D. Subacute leaflet thrombosis; obtain gated cardiac CTA, consider initiation of empiric anticoagulation. Prosthetic valve dysfunction is not common after TAVR, but the common reasons should be understood. An elevated AV mean gradient >20 mm Hg indicates prosthetic valve dysfunction. An AV gradient of >20 mm Hg measured invasively immediately following TAVR may indicate patent prosthesis mismatch and should be a clue to further dilate the THV at time of procedure. This sometimes is more evident at follow-up given hemodynamic conditions at time of TAVR, typically in patients with large body surface area. Pannus formation may be seen and may be an explanation for gradually rising AV gradients over the first year after TAVR and can be diagnosed with gated cardiac CT. The most common cause of a rise in AV gradients within the first month after TAVR is subacute leaflet thrombosis. This is diagnosed with a gated cardiac CT and treated with anticoagulation over a 3-month period, and typically resolves. There are not clear guidelines on the long-term management of subacute leaflet thrombosis, though most providers will continue anticoagulation for as long as tolerated if there is low bleeding risk, and if stopped follow the patient with echocardiogram every 3 to 6 months to assess valve function.

5.

Correct Answer: A. Surgical AVR + Mitral valve repair + Single vessel CABG with LIMA to LAD + MAZE and LAA ligation This patient has a class I indication for AVR given his severe, symptomatic aortic stenosis. Though his preference may be to wait for as long as possible, the physician should counsel the patient that this is not advisable, as morbidity and mortality of untreated, symptomatic aortic stenosis is high. Given his concomitant need for coronary revascularization and mitral valve repair, surgical AVR + MV repair

+ CABG + MAZE/LAA ligation would be most appropriate in this circumstance and is most supported by current guidelines.

CHAPTER 62

Percutaneous Mitral Interventions VINAYAK NAGARAJA AND SAMIR R. KAPADIA The mitral valve is a complex structure consisting of six scallops and subvalvular apparatus. The mitral annulus is a saddle-shaped structure that is extremely dynamic during the cardiac cycle. Several pathophysiologic states affect the mitral valve, and this ranges from rheumatic mitral stenosis (MS) to mitral annular calcification (MAC) resulting in mixed mitral valve disease. The complexity of the disease and varying pathophysiologic states offers new challenges for percutaneous interventions. This chapter provides an overview of different mitral valve interventions that are currently prevalent in clinical practice.

PERCUTANEOUS TRANSVENOUS MITRAL VALVULOPLASTY Rheumatic MS continues to be the most common valvular heart disease in the 12

developing world and the prevalence rate ranges between 0.6% and 14%. , Percutaneous transvenous mitral valvuloplasty (PTMV) was first described 3

in 1984 by Inoue et al. and was designed to open fused commissures. It is essential to select right patient for PTMV. Transthoracic/transesophageal echocardiography are powerful tools to assess patients with MS. This provides valuable information regarding mitral valve area (MVA), transmitral gradient, mitral regurgitation, pulmonary pressures, and right ventricular function. It is also important to identify subvalvular calcification, leaflet thickening/calcification/pliability, and commissural fusion. The main

advantage of PTMV is that it avoids the need for multiple mitral surgeries and the demerits associated with a mitral prosthesis (anticoagulation, infective endocarditis, mechanical mitral valve) especially in young individuals. The Class I indication for PTMV is severe MS, a MVA of 8-1 0 mm)

Ex tensive b rig htness thro ug ho ut much of th e tissue lea flet

Extensive thickening and sho rtening o f a ll chordal st ructures extending down ro the pa pillary m uscle

move forward in diasto le, mainly from the base 4

No o r m in ima l forwa rd movement of the leaflets in dia stole

Ln erpreta tio n o f resu lt

Score range: 4-J 6. A score >8 s uggests that the MY may not be su ita ble to PMBC a nd is associated with poor s hort- and long -term results

Group assignment according to anatomical characteristics of the MV and the MV apparatus as assessed by 20 echocardiography and fluoroscopy (Cormier Score) Group 1

Group 2

Group 3

An a tomical characterjsrics

Pliable, no ncalcified anterio r mitra l lea flet and mild subva lvular disease, i.e., thin chordate 10% points to a value less than the normal reference value lower limit (2. C is correct due to Qp/Qs of 2.35. A is a correct statement; however, it is not an indication for repair independently. B is a false statement; PVR is not elevated.

2.

Correct Answer: A. Proceed with a surgical referral for aortic valve replacement The patient has severe symptomatic aortic valve stenosis and is overall a low-risk patient based on the information available; hence, surgical replacement is indicated. There is no role for further surveillance at this time.

3.

Correct Answer: C. PAPi The PAPi in this setting is 1.5, which is low and suggestive of possible RV failure after LVAD implantation.

INDEX Page numbers followed by t indicate table, those followed by f indicate figure.

A AAA. See Abdominal aortic aneurysm (AAA) Abciximab (Reopro), 585, 700 Abdominal aortic aneurysm (AAA), 719 Abdominojugular reflex, 8 Ablation, 384–385 atrial flutter, 413 atrioventricular junction, 405 catheter, 413 Absolute risk reduction (ARR), 65 Accelerated AV junctional rhythm, 306 Accelerated idioventricular rhythm (AIVR), 306 ACE. See Angiotensin-converting enzyme Acromegaly, 872 ACS. See Acute coronary syndrome Action to Control Cardiovascular Risk in Diabetes (ACCORD), 790t, 791 ACTION trial, 563 Active fixation leads, 449 Active myocardial relaxation, 240 Acute chest pain, nuclear-based cardiac imaging in, 126 Acute coronary syndrome (ACS), 534, 538, 960. See also Non-ST-elevation acute coronary syndrome (NSTE-ACS) ACC/AHA classification for, 576, 577t angiotensin-converting enzyme inhibitors (ACE-I), 588–589 clinical presentation for, 576–577 discharge planning and noninvasive stress testing, 589

epidemiology and prognosis, 576 management of anti-ischemic agents, 587 antiplatelet agents, 583–586, 584f antithrombin therapy, 587 aspirin for, 583–584, 584f DTIs, 586 glycoprotein IIb/IIa inhibitors for, 578 heparins low molecular weight, 586 unfractionated, 586, 586 initial approach, 581 invasive therapy, 581–583 miscellaneous agents, 588–589 thienopyridines, 584–585 pathophysiology, 577–579 risk stratification biomarkers as, 577 ECG and, 577 TIMI risk score, 580, 581f summary on, 585 terminology and overview, 576 Acute corpulmonale, 312 Acute limb ischemia, 745 Acute mitral regurgitation, 489–490. See also Mitral regurgitation diagnosis for, 619, 619f symptoms and signs of, 618–619 treatment for, 619–620 Acute myocardial infarction (AMI), 20, 849–850 dobutamine for, 624 dopamine for, 615 norepinephrine for, 615 phenylephrine for, 625 Acute pericarditis, 311, 857–860. See also Pericarditis

acute episode, beyond, 860–861 etiology of, 857–858, 859t major and minor predictors for, 859t presentation and diagnosis, 857, 858t, 858f treatment for, 858–859, 860t Acute right to left interatrial shunting (ARLIAS), 901 Acute VTE (DVT/PE), 726 Adalat. See Nifedipine Adenosine pharmacologic stress echocardiography, 107 stress protocols, nuclear perfusion imaging, 117 ADMIRAL trial, 604 Adrenal carcinomas, 784 Adrenal insufficiency, 872–873 Adult congenital heart disease, guidelines for, 947 AFCAPS/TexCAPS. See Air Force/Texas Coronary Atherosclerosis Prevention Study AFFIRM (Atrial Fibrillation Follow-Up Investigation of Rhythm Management), 403, 403t African-American Study of Kidney Disease and Hypertension (AASK), 790t, 791–792 AFRP. See Atrial Functional Refractory Period Afterload, 37–38 AHA. See American Heart Association Air Force/Texas Coronary Atherosclerosis Prevention Study, 810t AIVR. See Accelerated idioventricular rhythm Alagille syndrome, 936t Alcohol septal ablation (ASA), 928 Aldomet. See Methyldopa Aldosterone, 50 antagonists, 168 Aldosterone blockade, 640 ALLHAT (Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial), 641–642, 790t, 791

Alpha-adrenergic agonist, midodrine, 468 Alström syndrome, 937t AltaValve device, 930t American Board of Internal Medicine (ABIM) Certifying Examination, 1 assessment, 1 first-time taker pass rates, 2t initial certification examination fee, 1 late fees and COVID-19 pandemic, 1 Maintenance of Certification (MOC) program, 1 registration dates, 1 score, 2 American Heart Association (AHA), 518–519 AMI. See Acute myocardial infarction Aminoglycosides, 517–518 Aminophylline, stress protocols, nuclear perfusion imaging, 118 Amiodarone, 406t, 408, 840t, 892t–897t Amlodipine, 169, 563t Ampicillin, 516t–517t Amplatzer PFO Occluder, 903, 905f Amplatzer Septal Occluder, 908f Amyl nitrite, 20 Anacrotic pulse, 7 Anemia, 875–876 Angina, 475 classifications, 579 medical treatment antiplatelet therapy, 560–561 lipid-lowering therapy, 561 renin–angiotensin–aldosterone system blockade, 561 pathophysiology of, 555 refractory, 571–572 revascularization in ACC/AHA recommendations, 565t coronary artery bypass grafting versus medical therapy, 566–568

PCI versus CABG for Patients with Diabetes Mellitus, 571 PCI versus CABG for Patients with Left Main Trunk Stenosis, 570–571 PCI versus CABG in Multivessel CAD, 569–570 PCI versus CABG in Single-Vessel CAD, 569 percutaneous coronary intervention versus medical therapy, 568– 569 stable CAD, 559t coronary angiography, 557–558 echocardiography, 556 electrocardiography, 555 exercise ECG testing, 555–556 stress testing with nuclear/echocardiographic imaging, 556–557, 557t symptomatic medical therapies, antianginals beta-blockers, 562–563, 562t calcium channel blockers, 563, 563t combination therapy, 564 nitroglycerin and nitrates, 563–564, 564t ranolazine, 564–565 unstable, 579–580 Angiography, 759 pulmonary, 730 Angiotensin II, 50 Angiotensin-converting enzyme (ACE) for stable angina, 561 for STEMI, 606 Angiotensin-converting enzyme inhibitor (ACEi), 58, 166, 760–761 Angiotensin-II (Ang-II), heart failure, 159 Angiotensin receptor blockers (ARBs), 166–167 for hypertension, 788, 792 in post-MI patients, 640 Angiotensin receptor neprilysin inhibitor (ARNI), 167–168

Anglo-Scandinavian Cardiac Outcomes Trial-Lipid Lowering Arm (ASCOTLLA), 810t–811t Ankle-Brachial Index, 745, 746t, 746f Annuloplasty, TR, 502–504 Anthracyclines, 959 limiting dose, 961 liposomal formulation of, 962 Antianginals, stable angina beta-blockers, 562–563, 562t calcium channel blockers, 563, 563t combination therapy, 564 nitroglycerin and nitrates, 563–564, 564t ranolazine, 564–565 Antiarrhythmic drugs, AF, 403, 892t–893t CHA2DS2-VASC, 410–411 class IA, 406t, 407 class IB, 407 class IC, 407 class III, 406t, 407–408 inpatient vs. outpatient initiation, 410 proarrhyrhmia risks associated with, 409–410 selection, 409–410 Antibiotics, 478 Anticholinergic agents, 468 Anticoagulants, 892t–893t during pregnancy, 839–841, 841t therapy, 760 for valves, 524–528, 525t Anticoagulation, 411, 526, 639 recommendations for, 411 Anti-CTLA-4 blocker ipilimumab, 959–960 Antihyperlipidemic therapy, 761 Antihypertensive therapy, 477, 760–761 Anti-ischemic agents, 587, 606

for ACS, 586 Antiplatelet agents, 747–748 for ACS aspirin, 583–584 glycoprotein IIb/IIIa inhibitors, 578 thienopyridines and ADP inhibitors, 584–585 for STEMI, 603–604 Antiplatelet therapies, 637–639, 699–700, 760, 903 Antiproliferative agents, 190 Antitachycardia pacing (ATP), 457 Antithrombin therapies, 587, 700 Antithrombotic agents, for STEMI, 604–606 Antithrombotic Trialists Collaboration, 560 Aorta, 31, 31f. See also Coarctation of aorta anatomy of, 711 diseases of, pathologic processes for, 711–712 Aortic aneurysm, 137, 717–719, 721 abdominal, 719 thoracic, 717–719, 717f Aortic coarctation (CoA), 269–270 Aortic disease, 141 cardiac MRI aortic aneurysm, 137 aortic dissection, 137 intramural hematoma, 137 Aortic dissection, 137, 480, 712–715, 712f, 721 chronic, 715 classifications of, 712, 713t, 713f clinical presentations of, 712–714 diagnostic testing, 714, 714t iatrogenic, 715, 715f management of, 714–715 type A, 21 in young, 715

Aortic insufficiency anorectic drugs, 480 chest X-ray for, 480 clinical findings on, 480 ECG for, 480 echocardiography for, 480–481 etiology of, 479–480 pathophysiology of, 479 physical exam, 480 radiation heart disease, 480 secondary causes, 480 subaortic stenosis, 480 treatment for, 481–482 valvular causes, 479–480 vasodilators for, 481 Aortic regurgitation (AR), 666 diastolic murmurs, 18 pregnancy and, 833 Aortic root dilatation, 480 Aortic sclerosis, systolic murmurs, 15 Aortic stenosis (AS), 666–667, 836 cardiomediastinal silhouette patterns, 76, 76f classifications of, 477 clinical findings in, 475–477, 476f ECG for, 475 estimation, 476–477 etiologies of, 473–475, 474f invasive assessment of, 477, 477f pathophysiology of, 473 pseudostenosis vs. low gradient, 479 stress echo, 111 subvalvular, 474 supravalvular, 474–475 treatment of, 477–478, 478t

TTE for, 475–477 vasodilators for, 477 Aortic valve(s), 30, 30f anatomy, 473, 474f morphology of, 476 resistance, 664 Aortic valve area (AVA), 476 Aortic valve morphology, 476 Aortic valve replacement, AS, 478–479, 478t Aortic valvular stenosis, systolic murmurs, 14–15, 14f–15f Aortography, 680–683, 682f, 684f Aortopathies, 956 Apixaban, 412 Apresoline. See Hydralazine AR. See Aortic regurgitation ARBS. See Angiotensin-receptor blockers Arixtra. See Fondaparinux ARR. See Absolute risk reduction Arrhythmias, 413, 426–427, 463, 953–955, 960 heart failure (HF) and, 212 Arrhythmic complications bradyarrhythmias, 626, 627t tachyarrhythmias, 626–627 Arrhythmogenic right ventricular cardiomyopathy (ARVC), 221, 953 cardiac MRI, 136, 136t Arrhythmogenic right ventricular dysplasia (ARVD), 392f, 938t Arterial pulse(s). See also Pulse(s) anacrotic pulse, 7 Corrigan, 8 dicrotic pulse, 7 disease states, 4, 5t–6t, 6f double-peaked pulse, 7 Duroziez sign, 8 Hill sign, 7

loud systolic sound, 8 Mayen sign, 8 normal, 6f osler sign, 7 pressure/pulse difference in two arms, 7 principles, 4 pulse deficit, 7 pulsus alternans, 4 pulsus paradoxus, 6–7 pulsus tardus and parvus, 7 radial-to-femoral delay, 7 supravalvular AS and, 7 Traube sign and, 8 water-hammer pulse, 8 ARVC. See Arrhythmogenic right ventricular cardiomyopathy ARVD. See Arrhythmogenic right ventricular dysplasia AS. See Aortic stenosis ASCOT-LLA. See Anglo-Scandinavian Cardiac Outcomes Trial-Lipid Lowering Arm ASD. See Atrial septal defect Aspiration thrombectomy, 602 Aspirin, 411–412, 635, 699–700, 760, 903 for ACS, 583–584 for PCI, 700 for stable angina, 560 for STEMI, 608 ASSENT (Assessment of Safety and Efficacy of a New Thrombolytic) and ASSENT-PLUS studies, 633 ASSENT-3 trial, 605–606 Asymptomatic carotid artery stenosis (ACAS), 757 Asymptomatic Carotid Surgery Trial (ACST), 761–762 Asymptomatic patients, AS, 477 Atheromatous aortic disease, 720–721, 720f Atherosclerosis, 712

Athlete's heart, 948–949 Atorvastatin for NSTEMI, 588 for STEMI, 607 Atrial arrhythmias, 908 ablation of maze procedure, 414 pacemaker therapy, 414 pulmonary vein isolation, 413–414 catheter ablation of, 413 Atrial bradycardia, ectopic, 305 Atrial extrastimulus testing, 375 Atrial fibrillation (AF), 10, 261, 305, 902 antiarrhythmic drugs for class IA, 406t, 407 class IB, 407 class IC, 407 class III, 406t, 407–408 inpatient vs. outpatient initiation of, 410 proarrhythmia risks associated with, 409–410 selection of, 409–410 AV node ablation, 413 catheter ablation, 413 definitions, 402 epidemiology, 400 evaluation, 402–403 factors predisposing, 400 management, 403–404, 403t–404t morbidity and mortality, 400–401 nonpharmacologic rate control, 405 onset of, 489 pathogenesis, 401–402 pharmacologic conversion, 405–406, 406t sinus rhythm

maintenance of, 406, 406t restoration of, 405–406, 406t Atrial flutter, 305 clinical presentation and diagnosis, 426 mechanism, 426–427 nonpharmacologic management, 412–413 reentrant mechanism, 401–402 cavotricuspid isthmus–dependent atrial flutter, 401, 402f noncavotricuspid isthmus-dependent atrial flutter, 401 treatment, 427 Atrial Functional Refractory Period (AFRP), 381 Atrial natriuretic peptide (ANP), 58–59 Atrial oversensing, 449 Atrial pacing EP and, 379–380, 380f incremental, 372 Atrial rhythm, ectopic, 305 Atrial sensitivity, 449 Atrial septal aneurysm/large interatrial shunt, 902–903 Atrial septal defect (ASD), 21, 265–267, 266f, 267t, 833 coronary sinus ASD, 287 primum, 283, 284t, 285f, 312 secundum ASD, 283, 286f, 312 sinus venosus ASD, 283, 287f types of, 283–287, 284f Atrial septal defect closure, 903–908 diagnosis, 906 follow-up, 908 management of, 906–908, 907t outcomes, 908 pathophysiology of, 906 presentation, 906 Atrial systole phase, 240 Atrial tachycardia, 305

clinical presentation and diagnosis, 426 mechanisms, 426 treatment, 426 Atrial-dependent arrhythmias, 426–427, 427f Atrial Flitter, 426–427 atrial tachycardia, 426 Atrioventricular block (AVB) first degree, 307 second degree Mobitz Type I (Wenckebach), 307 Mobitz Type II, 307 third degree (complete heart block), 307 Atrioventricular (AV) dissociation/ventricular tachycardia, 8 Atrioventricular junction ablation, 405 Atrioventricular junctional bradycardia, 306 Atrioventricular junctional rhythm, accelerated, 306 Atrioventricular junctional tachycardia, 306 Atrioventricular nodal reentrant tachycardia (AVNR), 305, 954 Atrioventricular (AV) node, 33, 33f Atrioventricular reentrant tachycardia (AVRT), 305, 954 differential diagnosis, 430–432, 431f Atropine, pharmacologic stress echocardiography, 107 Attributable risk, 65 Atypical antipsychotics, 897t Auscultation, dynamic, 19–20 hemodynamic maneuvers, 19–20 pharmacologic agents, 20 respiration, 19 valsalva, 19, 20f Autonomic dysfunction, primary and secondary causes of, 462t Autonomic nervous system dysfunction, heart failure, 159 Autosomal dominant long QT syndrome (LQTS), genes with mutations definitively associated with, 938t Autosomal/mitochondrial genetic disorders, 936t

A–V delay, 450 AV junctional bradycardia, 306 AV junctional tachycardia, 306 AV nodal reentrant tachycardia (AVNRT), 954 AV nodal refractory periods, 375–376, 376f AV node ablation, 413 AV node-dependent tachycardias (AVNRT) clinical presentation and diagnosis, 420 mechanism, 420–421, 421f treatment, 421 AV reciprocating tachycardia (AVRT).See also Wolff–Parkinson–White (WPW) syndrome accessory pathways, 422, 422f–423f antidromic tachycardia, 423–424 clinical presentation and diagnosis, 421–422 electrophysiologic characteristics and diagnostic maneuvers, 423 mechanism, 422–423 treatment, 424–425 Wolff-Parkinson-White syndrome and sudden cardiac death, 425 AVNRT. See Atrioventricular nodal reentrant tachycardia Avoiding Cardiovascular Events Through Combination Therapy in Patients Living With Systolic Hypertension trial (ACCOMPLISH), 790t, 791 AVRT. See Atrioventricular reentrant tachycardia Azathioprine (Imuran), 190 Azole antifungals, 894t–896t

B β-Adrenergic signaling, 56–57 of cardiac myocyte, 57f subtypes, 56–57 Ball-in-cage valve, 13, 523f–524f Balloon aortic valvuloplasty (BAV), 479 Balloon valvotomy, 505 Balloon valvuloplasty, 479 β-Arrestins, 56–57

Baseline intervals, 366–367, 367f Basiliximab (Simulect), 188 Bayes theorem, 66 BBB. See Bundle branch block Bcr-Abl inhibitors, 959–960 Beam-width artifacts, 92 Behçet disease, 875 Bernoulli principle, 93 Beta-adrenergic blockers, 404 Beta-blockers, 562–563, 562t, 587–588, 606, 749, 840t, 962 for MI, 640–641 for syncope, 468 Beta-receptor blockade (beta-blockers), 640–641 Bevacizumab, 959–960, 960t Bias in biostatistics, 67 observation, 67 recall, 67 selection, 67 verification, 67 Bicuspid aortic valve, 288–289, 290f Bileaflet mechanical valve, 523f–524f Biologic valves, 478 Biomarkers, 581, 635, 961 Biostatistics bias in, 67 causality and validity in, 67 confounding and interaction in, 66–67, 67f data presentation/outcomes reporting in, 65–66, 66f, 67f diagnostic test, 66, 66f exposures, 63 outcomes, 63 statistical tests for, 64 types of clinical studies in

case reports as, 63 case series as, 63 case–control study as, 63, 64f cohort study as, 63, 64f meta-analysis, 64 prospective vs. retrospective, 63 randomized controlled trials as, 63–64 Biphasic waveforms, 455 Bipolar leads, pacing leads, 448 Bivalirudin, 605, 700 Blood cultures, 513 microbiology, 511 Blood flow definition, 93 principles of flow, 93 turbulent flow, 93 velocity of, 93 Blood pressure control, 748–749, 749f BMD. See Bone mineral density BMI. See Body mass index Board certification, 1–2. See also American Board of Internal Medicine (ABIM) Certifying Examination Body mass index (BMI), 198 Bone mineral density (BMD), 194 Bortezomib, 959–960, 960t Bradyarrhythmias, 369, 626, 627t, 840 Brain natriuretic peptide (BNP), 58–59, 580, 635 Braunwald classification of unstable angina, 579–580 BRAVE-2 trial, 601 Brockenbrough response, 256, 257f Brucella, 513, 517–518 Brugada syndrome, 394, 394f, 938t Bruton tyrosine kinase inhibitors, 959–960

Bundle branch block (BBB), 626 Bypass Angioplasty Revascularization Investigation 2 Diabetes (BARI-2D) trial, 571

C CABG. See Coronary artery bypass graft CAD. See Coronary artery disease Cadaveric homografts, 478 CADILLAC trial, 604 Calan. See Verapamil Calcification patterns calcific constrictive pericarditis, 79, 79f calcified post-MI left ventricular true aneurysm, 80, 80f cardiac, 79 coronary artery calcification, 81, 81f left atrial wall calcification, 79, 79f mitral annular calcification, 80, 80f paracardiac, 79 Calcineurin inhibitors, 188–190, 189t Calcium blockers, dihydropyridine, 791 elemental, 194 Calcium channel blockers (CCBs), 403, 563, 563t, 840t for HF, 169 for syncope, 468 Calcium-dependent AP versus tissues with sodium channels, 51, 51f Canadian Cardiovascular Society (CCS), 554, 555t Canadian Cardiovascular Society Angina Pectoris Scale, 693t Cancer, 962–963 and venous thromboembolic disease (VTE), 962–963 prevention of, 962–963 risk assessment, 962 risk factors, 962 treatment and secondary prevention, 964 Cancer therapeutics–related cardiac dysfunction (CTRCD), 959–961

cardiotoxic effects and active cardiac surveillance, 962 clinical presentations of, 960–961 limiting anthracycline dose, 961 patient selection, 961–962 prevention of, 961–962 referral to cardio-oncology programs, 962 type 1, 959 type II, 959 type III–IX, 959–960, 960t Candida, 192 Cangrelor, 604 CAPRICORN (Carvedilol Post-Infarct Survival Control in Left Ventricular Dysfunction) trial, 640–641 Captopril, 787, 787t, 892t–893t CAR. See Coxsackie-adenovirus receptor (CAR) Carbamazepine, 896t Carcinoid heart disease, 888 Carcinomas, 887–888 Cardene. See Nicardipine Cardiac allograft vasculopathy (CAV), 183 Cardiac amyloidosis, 245 cardiac MRI, 135 SPECT imaging in, 127 Cardiac anatomy. See also Heart cardiac chambers left atrium, 28, 28f left ventricle, 28–29, 28f right atrium, 27, 27f right ventricle, 28, 28f cardiac valves aortic valve, 30, 30f mitral valve, 29–30, 30f pulmonic valve, 29, 29f tricuspid valve, 29, 29f

conducting system, 33–34, 33f great vessels aorta, 31, 31f cardiac lymphatic system, 33 cardiac veins, 32–33, 33f coronary arteries, 31–32, 31f–32f pulmonary arteries, 30–31 pulmonary veins, 31 vena cavae, 30 location, 26 pericardium, 26–27, 27f position, 26, 27f shape, 26 size, 26 Cardiac arrhythmias, genetic variants of, 938t Cardiac biochemistry, cardiac contractility and calcium homeostasis, 56 Cardiac calcification patterns, 79. See also Calcification patterns Cardiac catheterization, 256, 257f, 646–657, 647f, 649t, 650f, 651f, 652t– 655t, 652f Cardiac chambers enlargement, 308–309 left atrium, 28, 28f left ventricle, 28–29, 28f right atrium, 27, 27f right ventricle, 28, 28f Cardiac computed tomography angiography, 851 cardiac masses evaluation, 142–143, 143t clinical applications, 139–141 CT physics, 137–139 indications, 137 limitations, 141–142 contrast exposure, 142 image quality, 141, 141t radiation exposure, 141–142, 142t

technical considerations, 137–139 Cardiac diseases, 390. See also specific types Cardiac electrophysiology conduction system anatomy and physiology, 51–53 electrical coupling cells (gap junction), 51 fundamental aspects, 49 membrane action potential calcium-dependent AP versus tissues with sodium channels, 51, 51f Na+ channel activity regulation, 50–51 sodium-dependent cells, 49 Cardiac free wall rupture diagnosis of, 620, 621f signs and symptoms of, 620 treatment for, 620 Cardiac hemangiomas, 886 Cardiac imaging guidelines for, 946–947 cardiovascular computed tomography, 946 echocardiography, 946–947 Cardiac intervals, measurement of, 307 Cardiac lipomas, 884 Cardiac lymphatic system, 33 Cardiac magnetic resonance imaging (CMR) 961 aortic disease aortic aneurysm, 137 aortic dissection, 137 intramural hematoma, 137 basic imaging sequences, 132–134 cardiac masses evaluation, 142–143, 143t clinical applications arrhythmogenic right ventricular cardiomyopathy (ARVC), 136, 136t cardiac amyloidosis, 135

cardiac sarcoidosis, 135–136 coronary artery disease, 134 dilated cardiomyopathy, 134 heart failure, 134 hemochromatosis, 136 hypertrophic cardiomyopathy, 135 myocardial disease, 134 myocardial fibrosis, 135 myocarditis, 135–136 restrictive cardiomyopathy, 135 viability assessment, 134 contraindications, 138t delayed hyperenhancement short-axis image, 133f flow curve, 133f gadolinium-based contrast media agents, 134 indications, 133t limitations of, 137 MRI physics, 132 pulse sequences, 132 Cardiac myocyte, 56 Cardiac output (CO), 660 heart failure, 153–156 measurement, 660–661 Cardiac pacing. See also Implantable cardioverter defibrillators basic concepts of impulses and timing, 449–450 device features, 446–449 indications, 445 permanent pacing, 446, 446t–447t programming, 450–451 summary on, 458 temporary pacing, 445–446 troubleshooting and complications, 451–452 Cardiac papillary fibroelastoma, 883t, 884, 884f Cardiac physical examination

arterial pulse anacrotic pulse, 7 Corrigan, 8 dicrotic pulse, 7 disease states, 4, 5t–6t, 6f double-peaked pulse, 7 Duroziez sign, 8 Hill sign, 7 loud systolic sound, 8 Mayen sign, 8 normal, 6f osler sign, 7 pressure/pulse difference in two arms, 7 principles, 4 pulse deficit, 7 pulsus alternans, 4 pulsus paradoxus, 6–7 pulsus tardus and parvus, 7 radial-to-femoral delay, 7 supravalvular AS and, 7 Traube sign and, 8 water-hammer pulse, 8 dynamic auscultation, 19–20 extra heart sound diastole, 12, 12f opening snap, 12 pacemaker sounds, 13 prosthetic heart sounds, 13 systole, 12–13 findings, 5t–6t first heart sound intensity, 10 principles, 10 splitting, 10

fourth heart sound, 11–12 heart murmurs, 13–14 inspection, 4 jugular venous pulse disease states, 8–9 pressure, 8 principles, 8 waveforms, 8 precordial motion dilation, 9 disease states, 9–10 hypertrophy, 9 principles, 9 principles, 4 second heart sound intensity, 10 principles, 10 single S2, 10 splitting, 10–11, 11f third heart sound, 11 Cardiac power output (CPO), 671 Cardiac radioactive tracers nitrogen-13 ammonia, 114–115 oyxgen-15 water, 115 PET tracers, myocardial metabolism, 115 PET tracers, myocardial perfusion, 114 rubidium-82, 114 SPECT perfusion agents, 114 technetium pyrophosphate (PYP-Tc99m), 115 technetium-99m-labeled agents, 114 thallium-201 chloride, 114 transthyretin (ATTR) amyloid cardiomyopathy, 115 Cardiac resynchronization therapy (CRT) with biventricular pacing, 446–447 Cardiac rhabdomyomas, 883t, 884–885

Cardiac sarcoidosis, 392 cardiac MRI, 135–136 PET imaging, 127–128 Cardiac SPECT imaging, 116–117 Cardiac syncope, 463 Cardiac tamponade, 9, 21, 860–862 Cardiac tumors benign, 882–886, 883t, 883f, 884f, 885f malignant, 886–887, 886t, 887f secondary, 887–888, 887f Cardiac valves aortic valve, 30, 30f mitral valve, 29–30, 30f pulmonic valve, 29, 29f tricuspid valve, 29, 29f Cardiac veins, 32–33, 33f Cardiogenic shock, 607, 632, 690 Cardiomediastinal silhouette patterns aortic stenosis, 76, 76f coarctation, 77, 77f mitral regurgitation, 78, 78f mitral stenosis, 78, 78f normal cardiac silhouette, 74, 74f normal landmarks, 74 pectus excavatum, 75, 75f pericardial cyst, 75, 75f pseudocoarctation, 76, 76f size, 74 valvar pulmonic stenosis, 77, 77f Cardiomyopathies, 836, 952–953. See also Dilated cardiomyopathy; Hypertrophic cardiomyopathy arrhythmogenic right ventricular, 221 classification, 215f, 220t dilated, 219–220

forms of, 220t genetic variants of, 937t idiopathic dilated See (Idiopathic dilated cardiomyopathy (IDCM)) inflammatory, 218t inherited, 59, 60t metabolic, 220 mitochondrial, 221 and pressure–volume loop, 41, 41f primary, 215f Cardio-oncology baseline cardiovascular assessment and monitoring, 961 cancer and venous thromboembolic disease (VTE), 962–963 prevention of, 962–963 risk assessment, 962 risk factors, 962 treatment and secondary prevention, 964 cancer therapeutics–related cardiac dysfunction (CTRCD)., 959–961 cardiotoxic effects and active cardiac surveillance, 962 clinical presentations of, 960–961 limiting anthracycline dose, 961 patient selection, 961–962 prevention of, 961–962 referral to cardio-oncology programs, 962 type 1, 959 type II, 959 type III–IX, 959–960, 960t cardioprotective medical therapy, 962 definition of, 959 radiation-associated cardiac disease (RACD), 963–964 screening guidelines and multimodality imaging in, 964, 964t Cardioprotective medical therapy, 962 CardioValve device, 930t Cardiovascular computed tomography, 946 Cardiovascular diseases (CVDs), 72–73

after pregnancy, 836–839, 838t board exam, 2 breakdown in content of, 2t first-time taker pass rates, 2, 2t format, 2, 2t general information, 2t pitfalls, 3b tips, 2–3 management of athletes with, 951–956, 952t aortopathies, 956 arrhythmias, 953–955 cardiomyopathies, 952–953 coronary anomalies, 955–956 Marfan syndrome, 956 pericarditis, 956 valvular disease, 955 risk factors nonconventional, 551 traditional modifiable, 549–551 diabetes mellitus, 550 hypertension, 550 lipids, 549–550 obesity and metabolic syndrome, 550–551 tobacco, 549–550 in United States age and gender variation of, 545–546, 545f, 546f cost and health care resources utilization, 548–549, 549t prognosis and risks associated with SCD, 547–548 racial and socioeconomic disparities of, 545t, 546–547, 547f silent myocardial ischemia/infarction, 544–545, 545f–546f temporal trends of, 543 unrecognized myocardial ischemia/infarction, 544–545, 545f–546f young people and, 547 Cardiovascular drug interactions

food and natural products drug interactions, 897–898 mechanism of action for, 58t pharmacodynamic drug–drug interactions, 897, 897t pharmacokinetic drug–drug interactions, 891–897, 892t–896t Cardiovascular magnetic resonance imaging, 852 Cardioversion, 457 Cardizem. See Diltiazem CARDS. See Collaborative Atorvastatin Diabetes Study CARE. See Cholesterol and Recurrent Events Carfilzomib, 959–960 Carney complex, 882, 883t Carotid aortic arch anatomy, 757–758, 758f artery stenting, 762–763 clinical presentation, 758, 759t diagnostic testing, 758–759 angiography, 759 carotid intima–media thickness, 758 carotid ultrasound, 758, 759t computed tomography angiography, 759 Doppler criteria, 759t magnetic resonance angiography, 759 endarterectomy, 761–762, 762t–763t, 762f epidemiology, 757 medical treatment, 759–761 anticoagulant therapy, 760 antihyperlipidemic therapy, 761 antihypertensive therapy, 760–761 antiplatelet therapy, 760 pathophysiology of, 757 recommendation, 760 Carotid artery stenting, 762–763 Carotid endarterectomy, 761–762, 762t–763t, 762f Carotid intima–media thickness, 758

Carotid Revascularization Endarterectomy versus Stenting Trial (CREST), 762–763 Carotid sinus hypersensitivity (CSH), 465 Carotid sinus massage (CSM), 465 Carotid sinus syncope, 462 Carotid stenosis, 762t Carotid ultrasound, 758, 759t Carvedilol, 640–641 CASS (Coronary Artery Surgery Study), 566 Catapres. See Clonidine Catecholaminergic polymorphic ventricular tachycardia (CPVT), 393, 938t, 948, 954 Catheter(s), 702–703 ablation of AF, 413 maze, 414 Causality, 67 CAV. See Cardiac allograft vasculopathy CBC. See Complete blood count CCBs. See Calcium channel blockers Cellcept. See Mycophenolate mofetil Center for Medicare and Medicaid Services (CMS), 453 Cephea device, 930t CETP. See Cholesteryl ester transfer protein Chagas heart disease, 219 Channelopathies, 953–954 CHARGE (Coloboma, heart defects, atresia choanae, growth retardation, genital and ear abnormalities) syndromes, 936t CHD. See Congenital heart disease; Coronary heart disease Checkpoint inhibitors, 959–960 Chemotherapy, 876–877 Chest discomfort anomalous coronary artery, 540 atypical syndrome, 534 cardiac biomarkers, 536–537

cardiac magnetic resonance (CMR) imaging, 539 causes of, 537t chest x-ray, 538 computed tomography coronary angiography, 539 coronary angiography, 539 diagnostic testing and triage, 535–539 differential diagnosis, 533, 534t electrocardiogram, 535 family/social/medication history and, 535 history of, 533–535 location of, 533 medical history, 534–535 myocardial infarction with nonobstructive coronary arteries, 539–540 physical examination, 535 plaintive and palliative factors, 533 quality of, 533 radiation of, 533 repeat testing, 540 risk scores, 537–538, 538t severity of, 533–534 special populations, 539–540 stress testing, 538–539 syncope, 540 timing of, 533 transthoracic echocardiogram, 538 typical syndrome, 534 in women, 539–540 Chest radiography (CXR) approach and projections, 71 calcification patterns calcific constrictive pericarditis, 79, 79f calcified post-MI left ventricular true aneurysm, 80, 80f cardiac, 79 coronary artery calcification, 81, 81f

left atrial wall calcification, 79, 79f mitral annular calcification, 80, 80f paracardiac, 79 cardiomediastinal silhouette patterns aortic stenosis, 76, 76f coarctation, 77, 77f mitral regurgitation, 78, 78f mitral stenosis, 78, 78f normal cardiac silhouette, 74, 74f normal landmarks, 74 pectus excavatum, 75, 75f pericardial cyst, 75, 75f pseudocoarctation, 76, 76f size, 74 valvar pulmonic stenosis, 77, 77f pulmonary vascular patterns cardiovascular disease states, 72–73 pulmonary edema patterns, 74 Chest x-ray (CXR), 475, 538 Cholesterol absorption inhibitors for dyslipidemias, 807, 808t embolization syndrome, 720 Cholesterol and Recurrent Events (CARE), 810t Cholesteryl ester transfer protein (CETP), 798–799 Cholestyramine, 808t–809t Chromosomal abnormalities, 936t Chronic kidney disease (CKD), 786, 792 Chronic mitral regurgitation, 490–491, 490f, 491f Chronic renal dysfunction, 193 Chronotropic competence, 450 Churg–Strauss syndrome, 875 Chylomicrons, 798, 799f, 803t, 805 CI. See Confidence interval Cilostazol, 750

Cimetidine, 189t, 894t–896t CIN. See Contrast induced nephropathy Ciprofibrate, 808t Circle of Willis, 269 Circulatory-assist devices, 615–616 CK. See Creatine kinase Clarithromycin, 894t–896t CLARITY-TIMI 28 trial, 604 Classic OH, 463 Clevidipine, 793t Clofibrate, 808t–809t Clonidine (Catapres), 786, 793t, 840t Clopidogrel (Plavix), 584, 603, 760, 903 Closing click (CC), 13 CM. See Cardiomyopathy CO. See Cardiac output COA. See Coarctation of aorta Coagulopathies, 603–604 Coarctation, cardiomediastinal silhouette patterns, 77, 77f Coarctation of aorta (CoA), 269–270, 292, 292f, 294f, 834 hypertension, 789 pregnancy and, 834 Coding system, cardiac pacemakers, 450, 450t Colchicine, 858–859 COlchicine for the Prevention of the Postpericardiotomy Syndrome (COPPS) trial, 858–859 Colesevelam, 808t Colestipol, 808t Collaborative Atorvastatin Diabetes Study (CARDS), 811t Color Doppler vs. continuous wave and pulsed wave Doppler, 90t COMET (Carvedilol or Metoprolol European Trial), 640–641 Complete blood count (CBC), 579 Complete heart block, 8 Complex cyanotic congenital heart disease, 835

Complex lesions Ebstein anomaly, 271–272, 272f Eisenmenger Syndrome, 273–274 Single Ventricle Circulations, 272–273 Tetralogy of Fallot, 271 Transposition of the great arteries (TGA), 270–271 Compliance, pressure–volume loop, 40 Computed tomography angiography, 759 Computed tomography pulmonary angiography (CTPA), 730 Computer tomography (CT), cardiac cardiac masses evaluation, 142–143, 143t clinical applications, 139–141 CT physics, 137–139 indications, 137 limitations, 141–142 contrast exposure, 142 image quality, 141, 141t radiation exposure, 141–142, 142t technical considerations, 137–139 Conduction system, 33–34, 33f anatomy and physiology, 51–53 disease, 964 Confidence interval (CI), 64 Confounding factor, 66, 67f altering study design, 67 Congenital heart disease (CHD) in adult cardiac catheterization, 274–275 complex lesions (acyanotic), 270–274 concepts, 265 diagnostic evaluation, 274 diagnostic imaging, 274, 274t general management strategies, 275–276 shunt lesions, 265–268, 267t

stenotic lesions, 268–270 hereditary and chromosomal defects, 283, 284t operations for, 296–298, 299t Congenital valve disease, 474 Congenitally corrected D-TGA, 293, 295, 298f Conn syndrome, 872 Connective tissue disorders, 873–875 Constrictive pericarditis, 8–9, 21, 668–669, 669f, 861t, 862–865, 863f– 865f, 863f, 864f, 865f, 866t differential clinical characteristics, 861t differential imaging characteristics, 861t, 866t presentation and diagnosis, 862–865 Constrictive physiology, 667–670, 668f, 669f, 670f Continuous wave Doppler low-velocity flow on, 91f vs. pulsed wave and color, 90t Contractility myocardial performance, determinants of, 38 pressure–volume loop, 40 Contrast induced nephropathy (CIN), 700 Contrast materials, 703 Convective acceleration, 93 Corlopam. See Fenoldopam Corneal Arcus, 801f–802f Coronary angiography, 557–558, 824 Coronary anomalies, 955–956 Coronary arteries, 31–32, 31f–32f Coronary artery bypass graft (CABG), 757, 824 PCI vs. for diabetes mellitus patients, 571 for left main trunk stenosis, 570–571 in multivessel CAD, 569–570 in single-vessel CAD, 569 PCI/post, 689

Coronary Artery Bypass Graft Surgery, 603 Coronary artery calcification, 81, 81f Coronary artery disease (CAD), 139–140, 395, 837–838, 849–850 cardiac MRI, 134 in catheterization laboratory, 675 global burden of, 543, 544t risk factors nonconventional, 551 traditional modifiable, 549–551 diabetes mellitus, 550 hypertension, 550 lipids, 549–550 obesity and metabolic syndrome, 550–551 tobacco, 549–550 in United States age and gender variation of, 545–546, 545f, 546f cost and health care resources utilization, 548–549, 549t prognosis and risks associated with SCD, 547–548 racial and socioeconomic disparities of, 545t, 546–547, 547f silent myocardial ischemia/infarction, 544–545, 545f–546f temporal trends of, 543 unrecognized myocardial ischemia/infarction, 544–545, 545f–546f young people and, 547 Coronary calcium scoring, 140–141 Coronary CT angiography (CTA), 139 Coronary heart disease (CHD) morbidity/mortality and, 798 prevention of early lipid-regulating trials for, 809t primary, landmark statin trials, 810t secondary, landmark statin trials, 810t subsequent statin trials for, 811t Coronary intravascular imaging intravascular ultrasound

applications of, 679, 679f atherosclerosis, characterization of, 678 normal coronary artery anatomy, 678, 678f optical coherence tomography, 679–680, 680f Coronary sinus defect, 905, 905f Coronary sinus leads, 449 Coronary stents, 602 Corrigan pulse, 8 Corticosteroids, 191, 859 Counterregulatory systems (natriuretic peptides), heart failure, 160 COURAGE study (Clinical Outcomes Utilizing Revascularization and Aggressive Drug Evaluation), 693–694 CoveValve Extreme Risk Study high–surgical-risk patients, 913–914, 913t inoperable patients, 912–913, 912t Coxiella burnetii, 511, 517–518 Coxsackie-adenovirus receptor (CAR), 214 Creatine kinase (CK), 633 CREDO (Clopidogrel for the Reduction of Events during Observation), 637– 639, 699 CREST syndrome, 874 Critical limb ischemia, 745 Cryptogenic stroke, 902t CsA. See Cyclosporine CTPA. See Computed tomography pulmonary angiography C-type natriuretic peptide (CNP), 58–59 CURE (Clopidogrel in Unstable Angina to Prevent Recurrent Events) study, 584, 637–639 CURRENT-OASIS 7 trial, 583 Cushing syndrome, 785, 872 CVDs. See Cardiovascular diseases CXR. See Chest x-ray Cyclophosphamide, 960t Cyclosporine (CsA), 188

Cystic medial degeneration, 711

D Dabigatran, 412 Daclizumab (Zenapax), 188 Dallas criteria, 212 DCM. See Dilated cardiomyopathy D-Dimer test, 726 Deep vein thrombosis (DVT) clinical presentation and diagnosis, 726–727, 727f D-Dimer, 726 diagnostic testing, 728 duplex ultrasonography, 727–728 venography, 728 Defibrillation, 457 DEFINITE trials, 377 Degenerative mitral regurgitation, 923, 925–927 Delayed/progressive OH, 463 Device infection/erosion, 452 Device programming, 450–451 Dexrazoxane, 962 Dextrocardia, 312 Diabetes mellitus (DM), 845–846 CAD and, 550 occurrence, 534–535 Diastasis (slow filling) phase, 240 Diastole, 12, 12f Diastole, phase of atrial systole phase, 240 diastasis (slow filling) phase, 240 isovolumic relaxation phase, 239 rapid filling phase, 239–240 Diastolic function, 476 Diastolic murmurs, 14, 17f aortic regurgitation, 18

mitral stenosis, 17–18 pulmonic regurgitation, 18 tricuspid stenosis, 18 Dicrotic pulse, 7 Digitalis, 58 effect of, 311 toxicity, 311 Digitalis Investigation Group (DIG) trial, 170 Digoxin (Lanoxin), 403, 840t, 892t–896t Dihydropyridines, calcium blockers, 791 Dilacor. See Diltiazem Dilated cardiomyopathy (DCM), 20, 219–220, 391, 823, 953 cardiac MRI, 134 inherited forms, 220–221 SCD and, 391 VT and, 396 Diltiazem, 257–258, 563t, 786, 892t–896t Dimensionless index (DI), 476 definition, 525 DINAMIT trials, 608 Dipyridamole (DP), 760 pharmacologic stress echocardiography, 107 stress protocols, nuclear perfusion imaging, 117 Direct thrombin inhibitors (DTIs), 586–587, 732 Disability-adjusted life year (DALY), 543 Disopyramide, 406t, 407, 897t Diuretics, 619–620, 892t–893t DM. See Diabetes mellitus Dobutamine, pharmacologic stress echocardiography, 106 Dofetilide, 406t, 408, 840t, 892t–897t Dopamine (Inotropic) for AMI, 615 physiologic effects of, 607 Doppler echocardiography, 89–91

Dose modulation, 142 Double-peaked pulse, 7 Down syndrome, 905, 936t Doxorubicin, 960t Dressler syndrome, 608 Dronedarone, 406t, 408, 892t–897t Droperidol, 897t Drug(s). See also specific drugs antiarrhythmic drugs, AF, 403 class IA, 406t, 407 class IB, 407 class IC, 407 class III, 406t, 407–408 inpatient vs. outpatient initiation, 410 selection, 409–410 cardiovascular pharmacodynamic interactions of, 897, 897t pharmacokinetic interactions of, 891–897, 892t–896t DTIs. See Direct Thrombin Inhibitors Dual antiplatelet therapy (DAT), 760 Duke criteria, 512–513 Duke Treadmill Scores, 555–556, 556t Duplex ultrasonography, 727–728 Duroziez sign, 8 Dutch Lipid Network, 802 DVT. See Deep vein thrombosis Dynamic auscultation hemodynamic maneuvers, 19–20 pharmacologic agents, 20 respiration, 19 valsalva, 19, 20f Dynamic LVOT obstruction, 624–626 diagnosis for, 625 signs/symptoms of, 624–625

treatments for, 625 Dyslipidemias apheresis therapies for, 813–814 classification of, 801–802, 802f diabetes and lipid management, 814 diagnosis of, 800–801, 801f–802f fibrates, 805, 808t, 811 future directions for, 813t, 814–815 lipid lipoproteins and, 798–800, 799f, 800t other, 812t metabolic syndrome (metS), 805, 805t metS and, 805t niacin, 807, 811 pharmacologic therapies for, 807–813, 807t–808t primary, 802–804, 803t, 804f secondary, 804–805 TLC for, 806–807, 806t treatments for, 806–807, 806t, 807f Dystrophin (DMD), 937t

E Early menopause, 848 EBCT. See Electron-beam CT Ebstein anomaly, 271–272, 272f, 293, 296f ECG. See Electrocardiogram ECG interpretation in athletes, 951, 951f Echocardiography, 253–256, 254f, 255f, 556, 946–947, 961.See also Stress Echocardiography; Transthoracic echocardiography monitoring prosthetic valves with, 525–528, 525f stress, 851 valve prostheses, dysfunction and complications, 526–528, 527f ECSS. See European Coronary Surgery Study Ectopic atrial bradycardia, 305 Ectopic atrial rhythm, 305

Edwards-Sapien 3 (S3) valve, 523f–524f, 911 EECP. See Enhanced external counterpulsation Effective refractory period (ERP), 367–369 accessory pathway anterograde/retrograde AVN, 371 fast/slow AVN, 381 Effusive–constrictive pericarditis, 865–867 Ehlers–Danlos syndrome, 870 Eisenmenger syndrome, 273–274, 833–835 Ejection murmurs, 14 Ejection systolic murmurs, 14 Ejection type systolic murmurs, 14–16 Elastance, pressure–volume loop, 40 Electrical coupling cells (gap junction), 51 Electrocardiogram (ECG), 632–633, 632f for AS, 475 for ACSs, 579 board preparation, 303 case history, 314–364, 314f–364f interpretation of assessment of standardization/recorded leads and, 304 atrial/ventricular rates/rhythms in, 304–308 measurement of cardiac intervals in, 307 P-wave/QRS-complex axes in, 306–307 P-wave/QRS-complex/T-wave morphologies in, 310–312 twelve-lead, 303 intracardiac, 366 Electrocardiography, 555, 632–633, 632f Electromagnetic interference (EMI), 457–458 Electron-beam CT (EBCT), 139 Electrophysiology (EP) assessment of atrioventricular nodes and, 375–376, 375f, 376f atrioventricular block and, 372–375, 373f–374f atrioventricular conduction, 371–372 basis of, 365–369, 366f, 367f, 368f, 369f

bradyarrhythmia evaluation by, 369 guidelines for, 945–946 indications for, 365 sinus node function and, 369–371, 370f, 371f summary, 385–386 tachyarrhythmia evaluation by, 377–383, 383f–385f testing, syncope, 467, 467t Elevated cholesterol, 846 ELISA. See Enzyme-linked immunosorbent assay ELITE 1. See Evaluation of Losartan in the Elderly study Embolic protection devices, 757 Embolic stroke, 902t Embryology, 901 Emergency cardiac surgery with concomitant CABG, 617 Enalapril, 873 Enalaprilat, 793t Endless loop tachycardia, 450–451 Endocarditis, 527 Loeffler, 244 prophylaxis, 477 Endomyocardial fibrosis, 245 Endothelin-1 (ET-1), 228 antagonist, 892t–893t Enhanced external counterpulsation (EECP), 572 Enzyme-linked immunosorbent assay (ELISA), 729 Eosinophilic endomyocardial disease, 219 EP. See Electrophysiology EPHESUS trial (Eplerenone Postacute Myocardial Infarction Heart failure Efficacy and Survival Study), 640 Epicardial leads, 449 Epidemiology, clinical bias, 67 causality and validity, 67 data presentation/outcomes reporting, 65–66, 66f, 67f

exposures, 63 outcomes, 63 statistical tests, 64 types of clinical studies in case reports as, 63 case series as, 63 case–control study as, 63, 64f cohort study as, 63, 64f meta-analysis, 64 prospective vs. retrospective, 63 randomized controlled trials as, 63–64 Eptifibatide (Integrilin), 585 ERP. See Effective refractory period Erythromycin, 894t–897t Esmolol, 404t Estrogen Replacement and Atherosclerosis (ERA) trial, 848 Estrogen therapy, 848 European Coronary Surgery Study (ECSS), 566 Evaluation of Losartan in the Elderly study (ELITE), 167 Event monitoring, 451, 451f Everolimus (Certican), 189t, 191 Evolut low-risk trial, 915, 915t Evolut-PRO valve, 911–912, 911f Evolut-R valve (Medtronic), 911–912, 911f EVOQUE device, 930t Exercise electrocardiographic (ECG) stress test, 850–851 advantages of, 98 age and gender estimated functional capacity, 101t beta-blockers, 101 contraindications, 98–100, 100t diagnostic interpretation, 101 essential evidence/current guidelines, 98 indications, 98–100, 99t metabolic gas-exchange analyses, 102

methods of testing, 100, 100t placement of electrodes, 100 primary goal of, 98 prognostic interpretation, 101, 101t safety of, 98 in women, 102 Exercise stress test, 636–637, 637t Exercise-induced syncope, 467 Extended VTE prophylaxis, 736 External validity, 67 External-beam radiation therapy (XRT), 876 Extrastimulus, 367 Ezetimibe, 807, 808t, 809–813

F FA. See Fatty acids Fabry disease, 935t Fallot, tetralogy of, 293, 296f Familial combined hyperlipidemia (FCH), 803t Familial Defective Apolipoprotein B100, 802 Familial hypercholesterolemia (FH), 802, 803t Fatty acids (FAs), 798 FC. See Free cholesterol FCH. See Familial combined hyperlipidemia FDA. See U.S. Food and Drug Administration Felodipine, 563t, 892t–893t Fenofibrate, 808t, 812t Fenoldopam, 793t FFR. See Fractional flow reserve FH. See Familial hypercholesterolemia Fibrates, 805, 808t, 811 Fibrinolysis, 598t, 691–692 Fibrinolytics, 690–692 therapy, for STEMI, 601 Fibrin-specific agents, 601

Fibroelastomas, 884, 884f Fibromas, 883t, 885–886, 885f Fibromuscular dysplasia (FMD), 787, 874 Fick technique, 661–662 Fiedler myocarditis, 219 First heart sound intensity, 10 principles, 10 splitting, 10 First-pass radionuclide angiography (FPRNA), 128 Fixation techniques, 449 Flecainide, 406t, 407, 840t Florinef, 472 Flow, basic principles of jets, 93–94 Fludrocortisone, 468 Fluoroscopy, 680–683, 681f, 682f, 683f, 684f 5-Fluorouracil, 960, 960t and its metabolites, 959–960 Fluvastatin, 807t–808t FMD. See Fibromuscular dysplasia Fondaparinux (Arixtra), 605, 732 Foot care, and ulcer prevention, 747 Force–frequency response, heart failure, 159 Force–tension curves, 39, 39f Fractional flow reserve (FFR), 675–676, 677f Fragile X syndrome, 936t Framingham risk score (FRS), 743–744 Frank–Starling Curves, 39, 39f Free cholesterol (FC), 798 Frequency (f), 85 Friedrich ataxia, 871 FRISC II (Fast Revascularization during Instability in Coronary Artery Disease), 636 Functional mitral regurgitation, 927

diagnosis for, 619, 619f symptoms and signs of, 618–619 treatment for, 619–620 Furosemide, 840t

G Gadolinium-based contrast media agents, cardiac MRI, 134 Gap junction, 51 GBS. See Guillain–Barré syndrome (GBS) Gemfibrozil, 808t, 812t General cardiology, guidelines for, 943–944 Genetics and heart disease autosomal dominant long QT syndrome, genes with mutations definitively associated with, 938t autosomal/mitochondrial genetic disorders with, 936t cardiac arrhythmias, variants of, 938t cardiomyopathy, variants of, 937t chromosomal abnormalities, 936t genotype and genetic compositions, 935t HCM, genes with mutations definitively associated with, 937t hereditary thoracic aortic diseases, 937t principles, 934 storage disorders, 935t Gentamicin, 512, 516t German Epidemiological Trial on Ankle-Brachial Index (GET ABI), 743– 744 Gestational diabetes, 847 Gestational hypertension, 847 Giant cell arteritis, 720 Giant cell myocarditis, 219 GISSI. See Italian Group for the Study of Streptokinase in Myocardial Infarction Global registry of acute coronary events (GRACE) score, 580, 636 Glucocorticoids, 194 Glucose, regulation of, 839

Glycemic control, in diabetic patients with PAD, 749–750, 749t Glycoprotein IIb/IIIa inhibitors for ACS, 578 for PCI, 700 for STEMI, 604 Glycosylation, 50 Gore Helex Septal Occluder, 908f Gore Septal Cardioform Occluder, 903, 905f Gorlin formula, 664 GRACE Score, 598–599 Granulomatous myocarditis, 219 Great vessels aorta, 31, 31f cardiac lymphatic system, 33 cardiac veins, 32–33, 33f coronary arteries, 31–32, 31f–32f pulmonary arteries, 30–31 pulmonary veins, 31 vena cavae, 30 Growth hormones, 872 Guidelines for adult congenital heart disease, 947 cardiac imaging, 946–947 cardiovascular computed tomography, 946 echocardiography, 946–947 for electrophysiology, 945–946 general cardiology, 943–944 for heart disease prevention in women, 848–849, 849f for interventional cardiology, 944–945 Guillain–Barré syndrome (GBS), 871–872 GUSTO (Global Utilization of Streptokinase and TPA for Occluded Arteries) I trial, 601, 631 GUSTO (Global Utilization of Streptokinase and TPA for Occluded Arteries) IIb trial, 579

H HAART. See Highly active antiretroviral therapy HACEK organisms, 516t–517t Hakki formula, 664 Haloperidol, 897t Hamman sign, 13 Harmonic imaging, 107 Hazard ratio, 65 HBE. See His bundle catheter HCM. See Hypertrophic cardiomyopathy HCTZ. See Hydrochlorothiazide HDL. See High-density lipoproteins HDL cholesterol (HDL-C), 798–799, 804 Heart blocks, 307, 372–373 cardiac chambers left atrium, 28, 28f left ventricle, 28–29, 28f right atrium, 27, 27f right ventricle, 28, 28f cardiac valves aortic valve, 30, 30f mitral valve, 29–30, 30f pulmonic valve, 29, 29f tricuspid valve, 29, 29f conducting system, 33–34, 33f diseases carcinoid, 888 radiation, 474 rheumatic, 473–474, 479, 496–497, 504 structural, 409 great vessels aorta, 31, 31f cardiac lymphatic system, 33

cardiac veins, 32–33, 33f coronary arteries, 31–32, 31f–32f pulmonary arteries, 30–31 pulmonary veins, 31 vena cavae, 30 location, 26 murmurs, 13–14 characteristics, 14 diastolic, 14–17 ejection, 14 ejection systolic, 14 intensity of, 13 regurgitant systolic, 14 systolic, 14–17 pericardium, 26–27, 27f position, 26, 27f rate, 403 shape, 26 size, 26 sound continuous, 18–19 extra, 12–13 diastole, 12f, 12 pacemaker sounds, 13 prosthetic heart sounds, 13 systole, 12–13 first intensity, 10 principles, 10 splitting, 10 fourth, 11–12 pacemaker, 13 prosthetic, 13 second

intensity, 10 pathologic splitting, 11f principles, 10 single S2, 10 splitting, 11f, 10–11 third, 11 transplantation complications post, 192–194 donor, 180–181 immunosuppresant agents, 187–188 organ allocation, 180 recipient, 181–182, 181t, 182f, 183t–184t rejection, 182–186, 184t survival after, 194 Heart failure (HF), 960 abnormal cellular/molecular mechanisms, 159–160 ACE for, 165–168 acute medical therapy admission to hospital, 170–171 agents, 173 decongestion, 171–172 inotropes, 172–173 invasive hemodynamic monitoring, 171 nerohormonal blockage, 169–170 vasodilators, 172 adaptive mechanisms, 157–161 angiotensin-II (Ang-II), 159 and arrhythmia development, 212 autonomic nervous system dysfunction, 159 beta-blockers, 165 cardiac MRI, 134 cardiac output, 153–156 chronic medical therapy digitalis glycosides, 169–170

investigational agents, 170 neurohormonal blockade, 165–168, 165t related conditions, treatment of, 170 vasodilators, 169 classification, 154t–155t counterregulatory systems (natriuretic peptides), 160 definition and classification, 153 development of, 212–213 devices for circulatory support implantation, 206 clinical trials, 206–207, 206t components and configurations, 200–201, 200f, 201t–202t, 201f considerations regarding, 198–199, 199t operative risk, assessment of, 205–206 patient selection, 201–205, 202t types of, 199–200 diastolic clinical presentation of, 240 function, 240, 240f heart failure, 243 laboratory examination for, 241–243, 241t, 242f, 243t phases of, 239–240 physiology of, 239 prognosis for, 243, 244f treatment, 243 digitalis for, 169–170 force–frequency response, 159 hemodynamics, 153–156 inflammation and oxidative stress, 160–161 lifestyle measures excerise, 164 fluid restriction, 164 sodium restriction, 164 maladaptive compensatory mechanisms, 155f

medications antiarrhythmic, 173–174 calcium channel blockers, 173 chemotherapy agents, 174 NSAIDs, 173 oral hypoglycemics, 174 monitoring and follow-up, 174 pathophysiologic mechanisms, 153–157, 155f, 156t peripheral vascular and skeletal muscle adaptations, 161 preserved LVEF, 173–174 pressure–volume loop analysis in, 156–157, 157f, 158f prevalence, 153 renin–angiotensin–aldosterone system dysfunction, 159 salt and water, renal retention, 161 ventricular remodeling and reverse remodeling, 160 women and, 852–853 survival, 852–853 treatment, 845 Heart failure with preserved ejection fraction (HFpEF) clinical presentation, 240 diastole, phases of, 239–240 diastole, physiology of, 239 diastolic function, 240, 240f diastolic heart failure, 243 laboratory examination, 241–243, 241t, 242f, 243t physical examination, 241 prognosis, 243, 244f restrictive cardiomyopathies, 244–246, 245f, 246f Heart rate, 38–39, 240 Heart transplantation donor, 180–181 organ allocation, 180 posttransplant complications chronic renal dysfunction, 193

fungal infections, 192 hyperlipidemia, 193–194 hypertension, 193 infection, 192 malignancies, 192–193 osteoporosis, 194 protozoal infections, 192 tricuspid regurgitation, 194 viral infections, 192 posttransplant management issues antiproliferative agents, 189t, 190 calcineurin inhibitors, 188–190, 189t combination regimen, 191 corticosteroids, 191 immunosuppressive strategies, 186–187 individual immunosuppresant agents, 187–188 rejection, 182–186, 184t TOR inhibitors, 190–191 recipient, 181–182, 181t, 182f, 183t–184t survival, 194 HeartMate II, 200 Heberden, William, 554 HeFH. See Heterozygous FH Hemangiomas, cardiac, 883t, 886 Hematologic disorders, 875–877 Hematomas, intramural, 716, 716f, 721 Hemochromatosis, 245–246 cardiac MRI, 136 Hemodynamic criteria, 669–670, 670f, 671f heart failure, 153–156 Hemodynamic maneuvers, 19–20 Heparin. See also Low molecular weight heparin agents, 700 intravenous, 601

low molecular weight, 586 subcutaneous, 524 unfractionated, 586 Hepatic lipase (HL), 798 Hereditary hemochromatosis, 935t Hereditary thoracic aortic diseases, 937t HER-2/neu inhibitors, 959 Hertz (Hz), 85 Heterozygous FH (HeFH), 802 Hibernation, 126 myocardial perfusion images, 119 High defibrillation thresholds, 457–458 High-density lipoproteins (HDL), 798–799 High-sensitivity C-reactive protein (hs-CRP), 551, 580 High-sensitivity cTn (hs-cTn), 537 HighLife device, 930t Highly active antiretroviral therapy (HAART), 800, 804 Hill sign, 7 His bundle, 33–34, 52–53 His bundle catheter (HBE), 366–367 His-Purkinje system (HPS), 371 Histone deacetylase inhibitors, 959–960 HIV (human immunodefi ciency virus), 877 HL. See Hepatic lipase HLAs. See Human leukocyte antigens HOCM. See Hypertrophic Obstructive Cardiomyopathy Hodgkin lymphoma, 964f HoFH. See Homozygous FH Holosystolic and holodiastolic murmur, 18 Holt–Oram syndrome, 936t Homografts, 478 Homozygous FH (HoFH), 802 HOPE (Heart Outcomes Prevention Evaluation) trial, 639–640, 786 Hormone replacement therapy (HRT), 848

Hospitalization, 636–637 HPS. See His-Purkinje system hs-CRP. See High- sensitivity C-reactive protein HTN. See Hypertension Human leukocyte antigens (HLAs), 181 Hunter syndrome (type 2 mucopolysaccharidosis), 935t Hurler syndrome (type 1 mucopolysaccharidosis), 935t Hydralazine (Apresoline), 169, 793t, 840t Hydrochlorothiazide (HCTZ), 777, 840t, 892t–896t 11-β-hydroxysteroid dehydrogenase deficiency (11-β-OHSD), 783–784 Hyperactive precordium, 9 Hyperaldosteronism/Conn syndrome, 872 Hypercalcemia, 312 Hyperkalemia, 311 Hyperlipidemia, 193–194, 544–545, 549 Hypersensitive/eosinophilic myocarditis, 219 Hypertension (HTN), 823, 846, 846f angiotensin II receptor blockers for, 788, 792 CAD and, 550 clinical approaches, 789–792, 790t coarctation of aorta, 789 diastolic/ systolic, pulse pressure and, 778 emergencies, 792–794, 793t evaluation of, 778–780, 779f, 780t genetics of, 777–778 isolated systolic, 778 pathogenesis of, 777 prevalence, 153 refractory, 780, 781t, 781f resistant, 780–782, 781t, 781f secondary, 782–789, 782t in women, 788 Hypertension management post-MI, 641–642 Hypertensive emergency, 961

Hyperthyroidism, 50, 872 Hypertriglyceridemia, 805 Hypertrophic cardiomyopathy (HCM), 312, 391–392, 834, 937t, 952–953 and athletics, 261 atrial fibrillation, 261 cardiac MRI, 135 centers, 261–262 classification, 250, 251f diagnostic testing cardiac catheterization, 256, 257f cardiac magnetic resonance, 256 echocardiography, 253–256, 254f, 255f labs, chest X-ray, and electrocardiogram, 253, 253f–254f genetics, 257 infective endocarditis prophylaxis, 260 medical therapy, 257–258 nonobstructive HCM, 261 pathophysiology and histology, 250, 252f percutaneous alcohol septal ablation, 259, 259f permanent pacemaker implantation, 259 physical examination, 251–252, 252t and pregnancy, 261 prevalence and definition, 250, 251t, 251f screening of family members, 257 septal myectomy, 258–259, 258f vs. alcohol ablation, 259, 259f stress echo, 112 sudden cardiac death, 260, 260t symptoms and clinical course, 251 systolic murmurs, 15–16 Hypertrophic obstructive cardiomyopathy (HOCM), 250, 667, 667f, 668f, 823 Hypertrophy, 308–309 Hypocalcemia, 312

Hypokalemia, 312 Hypotension, 872–873 Hypothermia, 312 Hypothyroidism, 872–873 HYVET study, 790t Hz. See Hertz

I IABP. See Intra-aortic balloon pump Ibrutinib, 959–960, 960t Ibutilide, 405, 897t ICDs. See Implantable cardioverter defibrillators ICE. See Intracardiac echocardiography Idiopathic dilated cardiomyopathy (IDCM) cardiotropic viral infections, 214 etiologies, 212–213 hereditary hemochromatosis (HFE) gene, 221 immune related adverse events (IRAE), 215 pathophysiology, 212–213 prevalence, 212 Idiopathic hypertrophic subaortic stenosis (IHSS), 250 Idiopathic interstitial myocarditis, 219 Idiopathic pericarditis, 858 Idiopathic restrictive cardiomyopathy, 244 Idioventricular rhythm, 306 IDL. See Intermediate-density lipo-proteins IE. See Infective endocarditis IHSS. See Idiopathic hypertrophic subaortic stenosis Imaging. See also specific types of imaging radionuclide, 851–852 Imaging artifacts, 92 range ambiguity, 92 Imatinib, 959–960, 960t Impedance (R), 449 Implantable cardioverter defibrillators (ICDs), 631, 948

cause of failure, ventricular arrhythmias, 458 detection algorithms, 454 detection criteria, 455–457, 456f devices, 453 function of, 454–455, 455f implantation, 454 indications, 453, 453t lead systems, 454 management, surgical procedures and MRI, 458 patient care, 458 polarity, 455 programming, 455 shock evaluation, 457–458 shock waveform, VT and VF, 455 summary on, 458 therapies, 457 troubleshooting, 457–458 VF therapy, 454–455 VT therapy, 454–455 Indicator dilution methods, 662–663 Indomethacin, 858–859 Infarct-related artery (IRA), 601 Infection fungal, 192 protozoa, 192 viral, 192 Infective endocarditis (IE) antibiotic therapy, 516–518, 516t–517t blood cultures/microbiology, 511 cardiac complications, 514–515 CIEDs, infections in patients, 518 clinical features, 511–512 complications with, 514–516 definitions of, 509

diagnosis for, 512–514, 513f early detection, 518–519 echocardiography, 513–514 epidemiology of, 509–510 health care–associated, 509 imaging techniques, 514 incidence, 509 invasive medical interventions, 509 medical therapy, 516–518, 516t–517t neurologic complications, 515 pathogenesis of, 510–511 PET imaging, 128 prophylaxis, 518, 519t risk factors for, 510 surgery indications for, 518 systemic embolization, 515–516 treatment for, 515, 516t TTE for, 513–514 uncommon causes, 517–518 Infective endocarditis prophylaxis in valvular heart disease, 489t Inferior vena cava interruption (IVC Filters), 735–736 Infiltrative cardiomyopathies, 244 Inflammation, heart failure, 160–161 Inflammatory aortitis, 720–721 Inflammatory cardiomyopathy, 218t clinical trials of, 218t Inflammatory disorders, 712 Inherited cardiomyopathies, biochemistry of, 59, 60t Inherited and acquired channelopathies Brugada syndrome, 394, 394f idiopathic ventricular fibrillation, 394 long-QT syndrome, 393–394, 393t short-QT syndrome, 394 Inherited disorders, 870–871

Injection drug use, 510 Innocent murmur, systolic murmurs in children (still murmur), 16 in children to young adults (pulmonary ejection murmur), 16 Inotropic. See Dopamine Inoue technique, 922 In-stent restenosis (ISR), 703 Insulin, 329, 341, 344 Insulin resistance syndrome. See Metabolic syndrome Intentional Percutaneous Laceration of the Anterior Mitral Leaflet to Prevent Outflow Obstruction (LAMPOON), 928 Interatrial septum, embryologic formation of, 902f INTERHEART study, 549 Intermediate-density lipo-proteins (IDL), 798 Internal carotid arteries (ICAs), 758 Internal validity, 67 International Society for Heart and Lung Transplantation (ISHLT), 180–181, 183–184, 184t, 185b, 186b, 188b, 190–191, 191b, 194, 203, 206, 206t Interstitial disorder, 244 Interventional cardiology, guidelines for, 944–945 Intra-aortic balloon pump (IABP), 198, 588, 615–616, 619–620 counterpulsation, 607 Intracardiac echocardiography (ICE), 683–684 Intracardiac pressures, pressure–volume loop, 40 Intracardiac waveforms, 658–664, 659t, 659f Intramural hematoma (IMH) , 137, 716, 716f, 721 Intravascular ultrasound (IVUS) applications of, 679, 679f atherosclerosis, characterization of, 678 normal coronary artery anatomy, 678, 678f Intraventricular conduction delay (IVCD), 626 Intrepid device, 930t Ipilimumab, 960t IRA. See Infarct-related artery

Irbesartan Diabetic Nephropathy Trial (IDNT) study, 790t, 792 Iron overload, 875 ISAR trial, 604 ISAR-COOL trial, 636 ISAR-REACT 2 trial, 585–586 2019 ISAR REACT 5 trial, 604 ISHLT. See International Society for Heart and Lung Transplantation Isoptin. See Verapamil Isosorbide dinitrate, 169 Isotretinoin, 800, 804 Isovolumic relaxation phase, 239 ISR. See In-stent restenosis Isradipine (Dynacirc), 563t Italian Group for the Study of Streptokinase in Myocardial Infarction (GISSI), 615, 850 Itraconazole, 894t–897t Ivabradine, 165 and IF current, 57–58 IVC filters. See Inferior Vena Cava Interruption IVCD. See Intraventricular conduction delay IVUS. See Intravascular ultrasound

J Jacobsen syndrome, 936t Janeway lesions, 509, 510f Jet velocity, 476 Jugular venous pulse disease states, 8–9 pressure, 8 principles, 8 waveforms, 8 Junctional premature complexes, 305–306 JVP. See Jugular venous pulse

K

Kaplan–Meier estimates, 641, 641f KE. See Kinetic energy Kearns–Sayre syndrome, 871 Ketoconazole, 894t–897t Khorana Score, 963t Killip classification, 598–599, 599t, 614, 615t Kinetic energy (KE), 93 Klippel–Feil syndrome, 936t Kussmaul sign, 9

L Labetalol, 785, 788, 793–794, 793t LAFB. See Left anterior fascicular block Lamin A/C, 937t Late gadolinium enhancement (LGE), 953 LBBB. See left bundle branch block LDL-C management, 811t Lead extraction, 452 Lead fracture/failure, 452 Left anterior descending artery calcification, 122f Left anterior fascicular block (LAFB), 307 Left atrial abnormality, 309 Left atrial wall calcification, 79, 79f Left atrium, 28, 28f Left bundle branch block (LBBB), 308, 601 Left posterior fascicular block (LPFB), 308 Left ventricle, 28–29, 28f Left ventricular aneurysm diagnosis for, 623 signs and symptoms of, 623 treatment for, 623 Left ventricular dysfunction, 614–615, 615t Left ventricular ejection fraction (LVEF), 164, 365 Left ventricular end diastolic pressure (LVEDP), 10 Left ventricular function, 633

Left ventricular hypertrophy (LVH), 309 Left ventricular outflow tract (LVOT), 624–626 diagnosis for, 625 obstruction murmur, 15, 15t signs/symptoms of, 624–625 treatments for, 625 Legionella IE, 513, 517–518 Levophed. See Norepinephrine Lidocaine, 435, 840t Likelihood ratio (LR), 66 LIPID. See Long-term Intervention with Pravastatin in Ischemic Disease Lipid(s), 798–800. See also Dyslipidemias lipoproteins and, 798–800, 799f, 800t other, 812t Lipid management, 641 Lipid-lowering therapy, 748 Lipoma, 883t, 884 Lipoprotein lipase (LPL), 798 Lipoproteins, 798–800, 799f. See also specific types of lipoproteins Liposomal formulation of anthracyclines, 962 LMWH. See Low Molecular Weight Heparin Loeffler endocarditis, 244 Loeys–Dietz syndrome/TGF-beta–related aneurysm conditions, 937t Loffler endomyocardial fibrosis, 219 Long-QT syndrome (LQTS), 393–394, 393t, 938t, 948, 953–954 Long-term Intervention with Pravastatin in Ischemic Disease (LIPID), 810t Losartan intervention for endpoint (LIFE), 792 Lotus Edge, 911f, 912 Loud systolic sound, 8 Lovastatin, 807t–808t, 892t–893t, 896–898 Low-gradient aortic stenosis versus pseudostenosis, 479 Low high-density lipoprotein, 805 Low molecular weight heparin (LMWH), 524–525, 605–606, 732 for acs, 586

during pregnancy, 839–841, 841t LPFB. See Left posterior fascicular block LPL. See Lipoprotein lipase LQTS. See Long-QT Syndrome (LQTS) LR. See Likelihood ratio LV noncompaction cardiomyopathy, 937t LVEF. See Left ventricular ejection fraction LVH. See Left ventricular hypertrophy LVOT. See Left ventricular outflow tract LVOT obstruction, 928 Lysosomal storage disease, 59, 60t

M MACE. See Major adverse cardiovascular events Magnesium, 190, 426, 435 Magnetic resonance angiography (MRA), 759, 787 Magnetic resonance direct thrombus imaging (MRDTI), 728 Magnetic resonance imaging (MRI), cardiac aortic disease aortic aneurysm, 137 aortic dissection, 137 intramural hematoma, 137 basic imaging sequences, 132–134 clinical applications arrhythmogenic right ventricular cardiomyopathy (ARVC), 136, 136t cardiac amyloidosis, 135 cardiac sarcoidosis, 135–136 coronary artery disease, 134 dilated cardiomyopathy, 134 heart failure, 134 hemochromatosis, 136 hypertrophic cardiomyopathy, 135 myocardial disease, 134 myocardial fibrosis, 135

myocarditis, 135–136 restrictive cardiomyopathy, 135 viability assessment, 134 contraindications, 138t delayed hyperenhancement short-axis image, 133f flow curve, 133f gadolinium-based contrast media agents, 134 indications, 133t limitations of, 137 MRI physics, 132 prosthetic valves, 525 pulse sequences, 132 Magnetic resonance venography (MRV), 728 Major adverse cardiovascular events (MACE), 561, 762 Make Early Diagnosis and Prevent Early Death (MEDPED) criteria, 802 Malignant tumors, 886–887, 886t, 887f Mammary souffle, 18–19 Mapping, 384–385 Marfan syndrome, 718, 833–834, 870, 937t, 956 MAs. See Mycotic aneurysms MASS. See Medicine, Angioplasty or Surgery Study MAT. See Multifocal atrial tachycardia Mayen sign, 8 Maze procedure, 414 MDCT. See Multidetector Computed Tomography MDPIT trial, 169 Means–Lerman scratch, 13 Mechanical prostheses, 478 Mechanical ventilation, 203, 205 Mediastinal crunch, 13 Mediastinal radiation therapy, 959 Medical Research Council/British Heart Foundation (MRC/ BHF), 810t Medicare, 548–549 Medicine, Angioplasty or Surgery Study (MASS), 569

Medtronic CoreValve, 523f–524f Medtronic Open Pivot valve, 522 MELAS (mitochondrial encephalomyopathy, lactic acidosis, stroke-like episodes) syndrome, 221, 936t MERIT-HF (Metoprolol CR/XL Randomised Intervention Trial in Congestive Heart Failure), 640–641 Metabolic cardiomyopathy, 220 Metabolic syndrome (MetS), 805, 805t Methyldopa (Aldomet), 785–786, 788, 793–794, 840t Metoprolol, 640–641 MetS. See Metabolic syndrome Midodrine, 468 Minimum rate, 450 Mitochondrial cardiomyopathy, 221 MitraClip system, 923, 925–927, 926f, 927t Mitral annular calcification (MAC), 80, 80f, 922 Mitral closure, 10 Mitral regurgitation (MR), 607–608, 665, 665f, 833 acute, 489–490, 617–620 cardiomediastinal silhouette patterns, 78, 78f chronic, 490–491, 490f, 491f functional, 617–620, 619f mechanisms, 492–493, 492f–494f medical management, 495 quantitation of, 494–496, 496f stress echo, 111 systolic murmurs, 16, 16f Mitral stenosis (MS), 665–666, 665f, 835–836 cardiomediastinal silhouette patterns, 78, 78f diastolic murmurs, 17–18 features and history of, 496–501, 498f–499f management of, 500 stress echo, 111–112 Mitral valve(s), 10, 29–30, 30f

anatomy, 488 Mitral valve prolapse (MVP), 12, 833 diagnosis of, 488–489, 489t, 489f signs and symptoms of, 488 Mitral valve repair, 495 Mitral valve replacement (MVR), 495, 497f MMF. See Mycophenolate mofetil Mode codes, cardiac pacemakers, 450, 450t Monophasic waveforms, 455 Morganroth hypothesis, 948–949 Morquio (mucopolysaccharidosis type IV), 935t MPA. See Mycophenolic acid MR. See Mitral regurgitation MRA. See Magnetic resonance angiography MRV. See Magnetic resonance venography MS. See Mitral stenosis MSS. See Muscular subaortic stenosis Multidetector computed tomography (MDCT), 137, 139, 684–685 Multifocal atrial tachycardia (MAT), 305 Multigated acquisition (MUGA) imaging, 961 Multiplanar reformation (MPR) image, 140f Multiple endocrine neoplasia (MEN) syndrome, 785 Muscular dystrophies, 59, 60t, 871 Muscular subaortic stenosis (MSS), 250 MUSTT Trial, 377 MVP. See Mitral valve prolapse Myasthenia gravis, 871 Mycophenolate mofetil (MMF), 188, 189t, 190 Mycophenolic acid (MPA), 190 Mycotic aneurysms (MAs), 721 Myocardial blood flow quantification, PET imaging, 124 Myocardial disease, 963 cardiac MRI, 134 Myocardial fibrosis, cardiac MRI, 135

Myocardial flow reserve (MFR), 124 Myocardial infarction (MI). See also Acute myocardial infarction antiplatelet therapies for, 631, 637–639 beta-blockers, 640–641 calcified post left ventricular aneurysm, 622–623 left ventricular pseudo-aneurysm, 620, 622 complications additional, 624–626 arrhythmic, 626–627, 627t of left ventricular dysfunction, 614–615, 615t mechanical, 616–623, 617f, 618f, 619f, 621f, 622f medical therapies, 619–620 revascularization and, 620, 624 post conclusions on, 642 therapies for, 637–642 risk factor management, 641–642 risks for, 538 statins for, 640 stress test predictors of cardiac death and, 636–637, 638t Myocardial injury after noncardiac surgery (MINS), 825–826 Myocardial injury and infarction, 311 Myocardial metabolism, PET imaging, 115 Myocardial performance components of, 41 determinants of, 39 afterload, 37–38 contractility, 38 heart rate, 38–39 mechanisms of action, 38t preload, 37 graphic illustration of force–tension curves, 39, 39f

pressure–volume loops, 39–40, 40f Starling Law and Frank–Starling Curves, 39, 39f Myocardial perfusion imaging, 821–822 clinical use of, 121–124, 122f interpretation of, 118–121 myocardial scar/myocardial hibernation, 119 PET imaging, 114 reversible defect, 121f segmental perfusion, 119 tomographic reconstruction, 119 Myocardial relaxation, 91 Myocardial viability, PET imaging, 124–126 Myocarditis, 392, 953 acute phase, 212–213 with cardiac dysfunction, 212 cardiac MRI diagnostic criteria, 135–136, 216t causes of, 212–213, 214t chronic phase, 214 classification, 212 clinical presentation, 215 clinical trials of, 218t clinicopathologic classification, 213t coxsackie A9, 214 coxsackie B3, 214 coxsackie-adenovirus receptor (CAR), 214 cytokine expression, 213 Dallas criteria, 212 endothelium injury, 213 evaluation, 216–217 giant cell, 219 human herpesvirus-6, 212–213 hypersensitive/eosinophilic, 219 immune checkpoint inhibitors (ICI), 214–215 incidence, 212

infectious and noninfectious agents, 212–213 inflammatory response, 213, 215f parvovirus B19 (PVB19), 212–213 prevalence, 212 protein decay-accelerating factor, 214 SARS-CoV-2 (coronavirus), 212–213 subacute phase, 213 treatment and prognosis, 217–219 viral, 212–214 World Heart Foundation Marburg Criteria, 212 Myocardium, 124, 126 Myofibril, 56 Myotonic dystrophy, 871 Myxedema, 312 Myxomas, 882–884, 883t, 883f

N Na+. See Sodium Na+ channel activity regulation, 50–51 N-acetyl procainamide (NAPA), 405 Nafcillin, 516t–517t Na+/K+ ATPase, 58 NAME syndrome (nevi, Atrial myxoma, myxoid neurofibromata, and ephelides), 882 NAPA. See N-acetyl procainamide Narula method, 370, 370f National Cholesterol Education Program (NCEP), 641 National Cholesterol Education Program's Adult Treatment Panel III (NCEP ATP III), 805 National Institutes of Health (NIH), 680 National Surgical Quality Improvement Program (NSQIP), 822 Natriuretic peptide system, 58–59 heart failure, 160 Naxos disease, 221

NCEP. See National Cholesterol Education Program NCEP ATP III. See National Cholesterol Education Program's Adult Treatment Panel III Negative predictive value (NPV), 66 Neoplastic disease, 876 Neo-Synephrine. See Phenylephrine Neprilysin inhibitors, 892t–893t Nesiritide, 172 Neurocardiogenic syncope, 461–462 Neurofibromatosis 1, 936t Neurohormonal blockade, 639–641 Neuromuscular disorders, 871–872 New York Heart Association (NYHA), 500, 640 NFAT. See Nuclear factor of activated T cells Niacin, 807, 811 Nicardipine (Cardene), 563t, 793t Nicotinic acid, 808t Nifedipine, 786 Nifedipine (Procardia, Adalat), 563, 563t Nitrates, 840t for ACS, 580 for stable angina, 563–564, 564t Nitric oxide (NO), 59, 229, 230f production of, 229 Nitric oxide synthases (NOS), 229 Nitrogen-13 ammonia, 114–115 Nitroglycerin, 172, 325, 340, 490, 534, 563–564, 564t, 587, 606, 793t Nitroprusside (Nipride), 617, 793t sodium, 619–620 Nivolumab, 959–960, 960t NO. See Nitric oxide Nocardia, 192 Noncardiac surgery, 819 controversy and further research, 826

evaluation of patients undergoing, 822–823, 822f management of other cardiovascular conditions and, 823 myocardial infarction and myocardial injury after, 825–826 myocardial perfusion imaging and, 821–822 perioperative coronary revascularization, 824–825, 825f perioperative medical therapy and, 823–824 preoperative cardiac risk assessment, 820–822, 821t, 821f Noncompaction of left ventricle, 392 Nonculprit CAD, 602–603 Non-high-density lipoprotein cholesterol (non-HDL-C), 798. See also Nonhigh-density lipoprotein cholesterol Nonischemic cardiomyopathy arrhythmogenic right ventricular cardiomyopathy, 392, 392f cardiac sarcoidosis, 392 catecholaminergic polymorphic ventricular tachycardia, 393 dilated cardiomyopathy, 391 hypertrophic cardiomyopathy, 391–392 myocarditis, 392 noncompaction of the left ventricle, 392 Non-ST-elevation acute coronary syndrome (NSTE-ACS), 692 risk stratification, 635 Non-ST-elevation myocardial infarction (NSTEMI), 587, 624–625 clinical presentation, 576–577 epidemiology and prognosis, 576 fibrinolytic therapy for, 581 management of ACE-I for, 588–589 anti-ischemic agents, 587 antiplatelet agents, 583–586 antithrombin therapy, 587 aspirin for, 583–584, 584f atorvastatin for, 588 beta-blockers, 587 glycoprotein IIb/IIa inhibitors for, 585–586

initial approach, 581 invasive therapy, 581–583 mechanical devices for, 588 miscellaneous agents for, 588–589 PCI for, 590 predischarge risk stratification for, 579–581, 589 risk stratification, 579–581, 635–636 summary on, 585, 590 thienopyridines for, 584–585 Nonsteroidal anti- inflammatory drugs (NSAIDs), 858–860 Nonsustained VT (NSVT), 955 Noonan syndrome, 871, 936t Norepinephrine, for AMI, 615 Normal sinus rhythm (NSR), 304 NOS. See Nitric oxide synthases NPV. See Negative predictive value NSR. See Normal sinus rhythm NSTE-ACS. See Non-ST-elevation acute coronary syndrome (NSTE-ACS) NSTEMI. See Non-ST-elevation myocardial infarction Nuclear factor of activated T cells (NFAT), 189 Nuclear-based cardiac imaging in acute chest pain, 126 cardiac radioactive tracers nitrogen-13 ammonia, 114–115 oyxgen-15 water, 115 PET tracers, myocardial metabolism, 115 PET tracers, myocardial perfusion, 114 rubidium-82, 114 SPECT perfusion agents, 114 technetium pyrophosphate (PYP-Tc99m), 115 technetium-99m-labeled agents, 114 thallium-201 chloride, 114 transthyretin (ATTR) amyloid cardiomyopathy, 115 cardiac SPECT imaging, 116–117

gamma camera, 115f in heart failure, 127–128 onventional SPECT myocardial perfusion imaging (MPI) study, 115 overview of, 115–116 perfusion studies, 123 PET imaging, 116f, 117 post-MI and postrevascularization, 126–127 stress protocols, nuclear perfusion imaging, 117–118 Number needed to treat (NNT), 65 Nutritional status, 4

O Obesity CAD and, 642 sedentary lifestyle and, 847 Observation bias, 67 OCP. See Oral contraceptives OCT. See Optical coherence tomography Odds ratio, 65 Ohm's law, 228 OHSD. See 11-β-hydroxysteroid dehydrogenase deficiency Omega-3 FAs, 808t Oncologic disorders, 875–877 Ondansetron, 897t ONTARGET study, 790t On-X valve, 522, 524 Opening click (OC), 13 Opening snap (OS), 12, 497 OPO. See Organ procurement organizations Optical coherence tomography (OCT), 679–680, 680f OPTIMAAL study, 167 OPTIME-HF trial, 173 OPUS-TIMI 16 (Oral Glycoprotein IIb/IIIa Inhibition with Orbofi ban in Patients with Unstable Coronary Syndromes), 635 Oral contraceptives (OCPs), 804

Organ procurement organizations (OPOs), 180 Orthostatic challenge, 466 Orthostatic hypotension (OH), 461–463 Osler nodes, 509, 510f Osler sign, 7 Osler–Weber–Rendu syndrome, 871, 936t Osteoporosis, 194 Ovarian diseases, 546 Oxacillin, 516t–517t Oxidative stress, heart failure, 160–161 Oximetry, 663 Oyxgen-15 water, 115

P PA. See Plasma aldosterone Pacemaker(s) device timing cycles and impulses, 446–447, 448f, 450–451 event monitoring, 451 histogram, ventricular hysteresis, 451, 451f implantation, 468 mode switching, 448 pacing leads, 448–449 permanent, 446, 446t–447t strength–duration curve, 449f temporary, 445–446 therapy, 414 trends, 451 Pacemaker Mediated Tachycardia Endless loop tachycardia, 451 Pacemaker sounds, 13 Pacemaker syndrome, 451–452 Pacing-induced cardiomyopathy, 452 PAD. See Peripheral artery disease PAN. See Polyarteritis nodosa Papillary fibroelastoma, 883t, 884, 884f Papillary muscle ventricular tachycardia, 397

Paracardiac calcification patterns, 79 Parathyroid disorders, 788–789 Paravalvular regurgitation, 526, 527f PARTNER 1A trial, 913, 913t PARTNER 1B trial, 912, 912t PARTNER 2A study, 914, 914t PARTNER 2 S3i (P2 S3i) study, 914, 914t PARTNER 3 trial, 915, 915t Passive fixation systems, 449 Passive pressure–volume relationships, 240, 240f Patent ductus arteriosus (PDA), 19, 268, 284t, 291–292, 291f–292f, 833 Patent foramen ovale diagnosis, 902 follow-up, 903 management of, 902–903, 903f, 904t outcomes, 903 pathophysiology, 901, 902f percutaneous closure, 903, 905f postprocedural care, 903 presentation, 901, 902t PATHWAY-2 trial, 781–782, 790t PCI. See Percutaneous coronary intervention PCSK9 inhibitors, 808t, 813 PCW. See Pulmonary capillary wedge PD-1 inhibitors, 959–960 PDA. See Patent Ductus Arteriosus PDIs. See Phosphodiesterase inhibitors PE. See Pulmonary embolism PEACE. See Prevention of Events with Angiotensin Converting Enzyme inhibition Peak aortic valve jet velocity, 476 Peak transaortic valve gradients, 476 Pectus excavatum, cardiomediastinal silhouette patterns, 75, 75f Pembrolizumab, 959–960, 960t

Penetrating aortic ulcer (PAU), 716, 717f, 721 clinical presentations of, 716 intramural hematoma, 716–717, 717f management of, 716–717 Penicillin, 478, 516t, 517–518 Pentoxifyline, 750 Percutaneous alcohol septal ablation, 259, 259f Percutaneous coronary intervention (PCI), 127 adjunct therapy for, 699–700 antithrombin therapies for, 700 bleeding, 701–702, 701t complications following, 700–702, 701t indications for, 689–699, 690t in NSTE-ACS, 693t periprocedural myocardial infarction, 702 post-CABG, 698–699 for STEMI, 586, 601–603 technical aspects of, 702–703 Percutaneous left ventricular assist device, 607 Percutaneous mitral interventions percutaneous transvenous mitral valvuloplasty, 922–923, 924t–925t, 924f, 926f advantage of, 922 Class I indication for, 922 echocardiographic scoring systems for, 924t–925t Inoue technique for, 922 transcatheter mitral valve repair, 923–927 degenerative MR, 925–927 functional MR, 927 transcatheter mitral valve replacement (TMVR), 928, 929f devices for, 928, 930t LVOT obstruction, 928 valve in MAC (ViMAC), 928 valve in ring (ViR), 928

valve in valve (ViV) TMVR, 928 Percutaneous mitral valve repair, 923 Percutaneous revascularization, 692–693 Percutaneous transluminal coronary angioplasty (PTCA), 568, 689–690 Percutaneous transluminal renal angioplasty (PTRA), 787 Percutaneous transvenous mitral valvuloplasty, 922–923, 924t–925t, 924f, 926f advantage of, 922 Class I indication for, 922 echocardiographic scoring systems for, 924t–925t Inoue technique for, 922 Pericardial cyst, cardiomediastinal silhouette patterns, 75, 75f Pericardial disease, 961, 963 Pericardial effusion, 311, 860–862, 861f, 862t Pericardial knock (PK), 12 Pericardial rubs friction, 13 mimic, 13 Pericardial tamponade, 667–668, 668f, 669f Pericarditis, 956. See also Acute pericarditis diagnosis for, 625–626, 625t STEMI and, 608 symptoms and signs of, 625 treatment for, 626 Pericardium, 26–27, 27f Peripartum cardiomyopathy (PPCM), 831, 836–837 Peripheral artery disease (PAD) Ankle-Brachial Index, 745, 746t, 746f definition, 743 diagnostic testing, 745–747 epidemiology and risk factors, 743, 744t foot care and ulcer prevention, 747 imaging studies for, 745–747, 746t marker of cardiovascular risk, 743–744

natural history, 744 physical examination findings in, 745 prevention of cardiovascular events, 747–750 antiplatelet agents, 747–748 beta-blockers and, 749 blood pressure control, 748–749, 749f cilostazol, 750 education about, 751 glycemic control in diabetic patients with, 749–750, 749t lipid-lowering therapy, 748 pentoxifyline, 750 pharmacotherapy for, 750 rehabilitation for, 750 revascularization of, 750, 751f rivaroxaban, 748 smoking cessation, 747 supervised exercise rehabilitation, 750 warfarin, 748 symptoms and signs of, 744–745, 744f therapies to improve function and quality of life, 750 Peripheral vascular disease (PVD), 800 Peripheral vascular muscle adaptations, heart failure, 161 Peripheral vasculature, 534–535 Pernicious myocarditis, 219 PES. See Programmed electrical stimulation PH. See Pulmonary hypertension Pharmacologic lipid management after MI, 641 Phenobarbital, 894t–896t Phenothiazine antipsychotics, 897t Phentolamine, 793t Phenylephrine, for AMI, 625 Phenytoin, 894t–896t Pheochromocytoma, 785–786 Phosphodiesterase inhibitors (PDIs), 58

Phospholamban, 56 Phosphorylation/dephosphorylation, 50 PIOPED trial, 730 Pistol shot, 8 Plasma aldosterone (PA), 782–783 Platelet P2Y12 receptor inhibitor, 603 PLATO trial, 604 Plavix. See Clopidogrel Pletal. See Cilostazol Pleural rubs, 13 Point of maximum pulsation, 465 Polyarteritis nodosa (PAN), 874–875 Polycystic ovarian disease, 546 Polycystic ovary syndrome (PCOS), 847–848 Polycythemia, 876 Polygenic hypercholesterolemia, 802 Polymerase chain reaction (PCR), 513 Polymorphic ventricular tachycardia, 306 Polymyositis, 874 Pompe disease, 935t Positron emission tomography (PET) imaging cardiac sarcoidosis, 127–128 infective endocarditis, 128 metabolic imaging, myocardial viability, 124–126 myocardial blood flow quantification, 124 scanning, 634 tracers myocardial metabolism, 115 myocardial perfusion, 114 Post thrombotic syndrome (PTS), 725, 734 Post-MI, smoking cessation, 642 Post–myocardial infarction therapy, 637–642 Posttransplant lymphoproliferative disease (PTLD), 187 Postural/OH, 462

Postural orthostatic tachycardia syndrome (POTS), 463 Posture, 4 Post-Ventricular Atrial Refractory Period (PVARP), 450 POTS. See Postural orthostatic tachycardia PPCM. See Peripartum cardiomyopathy PR. See Pulmonic regurgitation PRAISE, 169 PRAMI trial, 602–603 Prasugrel, 603–604 Pravastatin, 807t–808t Precordial motion dilation, 9 disease states, 9–10 hypertrophy, 9 principles, 9 Preeclampsia, 847 Pregnancy anticoagulation during, 839–841, 841t AR and, 833 arrhythmias, 838–839 COA and, 834 coronary artery disease and, 837–838 CVDs after, 836–839 expected “normal” findings during, 21–22 HCM and, 261 hypertension, 837 LMWH during, 839–841, 841t and Marfan syndrome, 718, 870 medications during, 840t physiologic changes during, 829–831, 830t planning for optimal maternal and fetal outcomes, 833–836 pre-existing cardiac diseases and, 831–836, 832t unfractionated hepuin during, 839–840, 841t women and, 524–525

Preload, 37 Pressure measurements, 658, 659f wave artifacts, 660, 661f Pressure/pulse, difference in two arms, 7 Pressure–volume loop analysis, 39–40, 40f cardiomyopathy and, 41, 41f compliance, 40 contractility, 40 elastance, 40 in heart failure, 156–157, 157f, 158f intracardiac pressures, 40 stroke work, 41 valvular heart disease, 41t valvular heart disease and, 41, 41f ventricular volumes, 40 Presyncope, 461 Prevention of Events with Angiotensin Converting Enzyme inhibition (PEACE), 561 Primary aldosteronism, 782–785, 783t, 785t Primary cardiomyopathy, 215f Primary CHD prevention, trials for, 810t Primum ASDs, 905, 905f Proarrhythmia, 406t, 407 Procainamide, 406t, 407, 840t, 897t Prochlorperazine, 894t–896t Programmed electrical stimulation (PES), 367, 368f Propafenone, 406t, 407, 840t Propranolol, 371 Prostacyclin, 229, 232–233 Prosthetic heart sounds, 13 Prosthetic valve endocarditis (PVE), 526–527 Proteasome inhibitors, 959–960 PROVED, 170

PROVE-IT (Pravastatin or Atorvastatin Evaluation and Infection Therapy), 641 PS. See Pulmonic stenosis Pseudoaneurysm diagnosis for, 622, 623f signs/symptoms of, 622 treatment for, 622 Pseudocoarctation, cardiomediastinal silhouette patterns, 76, 76f Pseudomonas aeruginosa, 517–518 Pseudostenosis versus low-gradient aortic stenosis, 479 PTCA. See Percutaneous transluminal coronary angioplasty PTLD. See Posttransplant lymphoproliferative disease PTRA. See Percutaneous transluminal renal angioplasty PTS. See Post thrombotic syndrome Pulmonary angiography, 680, 683f, 730 Pulmonary arterial hypertension, 225–227 Pulmonary arteries, 30–31 Pulmonary artery pulsatility index (PAPi), 670 Pulmonary capillary wedge (PCW), 659–660, 659f Pulmonary edema patterns, 74 Pulmonary embolism (PE) clinical presentation and diagnosis, 728–729, 729f CTPA, 730 echocardiography, 729–730 laboratory biomarkers, 730–731 MRA, 730 objective testing, 729–731 pulmonary angiography, 730 transthoracic echocardiogram, 729–730 ventilation/perfusion scintigraphy, 730 Pulmonary hypertension (PH), 21 chronic thromboembolic pulmonary hypertension, 228 combination therapy, 234 definition and classification, 225–228, 226t

diagnosis and evaluation, 229–232 clinical evaluation, 229–230 echocardiography, 230–231 hemodynamic evaluation, 231–232 left heart disease, 227 lung diseases and/or hypoxia, 228 pathophysiology, 229f endothelin-1 (ET-1), 228 hemodynamic consequences, 229 nitric oxide, 229 prostacyclin and thromboxane A2, 228 serotonin (5-hydroxytryptamine), 229 prognosis, 226t, 232, 232f pulmonary arterial hypertension, 225–227 randomized clinical trials, 234 surgical therapies, 234 treatment endothelin pathway, 233 general measures, 232 nitric oxide pathway, 233 prostacyclin pathway, 232–233 pulmonary vasodilators, 232, 233f with unclear multifactorial mechanisms, 228 Pulmonary insufficiency (PI), 482–483 Pulmonary stenosis (PS), 833 Pulmonary vascular patterns cardiovascular disease states, 72–73 pulmonary edema patterns, 74 Pulmonary vascular resistance (PVR), 204, 231 Pulmonary vasculature, 227 Pulmonary vein assessment, 141 Pulmonary vein flow profiles, 494–495, 496f Pulmonary veins, 31, 265–267, 297f, 680 Pulmonic regurgitation, diastolic murmurs, 18

Pulmonic stenosis, 482 systolic murmurs, 16 Pulmonic stenosis (PS), 268–269, 269f, 293, 295f Pulmonic valve, 29, 29f Pulmonic valve disease, 482–483 Pulse(s). See also Arterial pulse(s) deficit, 7 Pulse width (or pulse duration), 449 Pulsed wave vs. color and continuous wave Doppler, 90t Pulsus alternans, 4 Pulsus paradoxus, 6–7 Pulsus tardus and parvus, 7 Purkinje fibers, 33–34, 33f, 52–53 PURSUIT risk score, 636–637, 637f PVD. See Peripheral vascular disease PVE. See Prosthetic valve endocarditis PVR. See Pulmonary vascular resistance P waves, 304–305

Q QRS complex axes, 306–307 interval, 307 morphologies, 306 QT interval, 308, 894t–897t, 897 QT syndrome, 463. See also Long-QT syndrome long, 393–394, 393t short, 394 Quinidine, 406t, 407, 840t, 892t–893t, 897t Quinolone, 897t Q-waves, 310

R RA. See Rheumatoid arthritis RAD. See Renal artery disease

Radial-to-femoral delay, 7 RADIANCE study, 170 Radiation heart disease, 474 Radiation safety, 655 dose estimation and displays, 648–650, 649t, 650f, 651f ionizing radiation and radiation effects deterministic/nonstochastic risk, 650–651, 652t, 652f stochastic risk, 651–652, 652t management collimation, 654 dose and frame rate settings, 653 fluoroscopy time and number of acquisitions, 653 grid use, 654 magnification modes, 654 minimizing patient radiation exposure, 653, 653t operator radiation management, 654, 654t patient radiation, 653 source and distance, 653 x-ray beam, path length and approach, 653 production, 647f generator, 647 image receptor, 647 operating console, 648 x-ray tube, 646–647 regulatory recommendations, 654–655, 655t Radiation-associated cardiac disease (RACD), 963–964 screening guidelines and multimodality imaging in, 964, 964t Radionuclide imaging, 851–852, 961 Radionuclide ventriculography, 128–129 RALES trial (Randomized Aldactone Evaluation Study), 168t, 640 Rapamycin (Sirolimus), 190–191 Rapid filling phase, 239–240 RAPPORT trials, 604 Rate-adaptive pacing, 447

RBBB. See Right bundle branch block RCT. See Reverse cholesterol transport Recall bias, 67 Receiver operating characteristic (ROC) curve, 66, 67f Reduction of Endpoints in NIDDM with the Angiotensin II Antagonist Losartan (RENAAL) study, 790t, 792 Reflex syncope (neurally mediated), 461–462 atypical forms of, 462 Refractory angina ACC/AHA recommendations, 572 enhanced external counterpulsation (EECP), 572 spinal cord stimulation (SCS), 572 Regent valve, 522 Regurgitant systolic murmurs, 14 Regurgitant type, systolic murmurs, 16–17 Relapsing polychondritis, 875 Relative risk, 65 Relative risk reduction (RRR), 65 Remote telemetry, 466 Renal artery disease (RAD), 787 Renal cell carcinoma, 887–888 Renal failure, 700–701, 877 Renal parenchymal disease, 786–787 Renal retention, salt and water, 161 Renin–angiotensin system (RAS), 58–59, 59f Renin–angiotensin–aldosterone system (RAAS), 639–640 dysfunction, heart failure, 159 inhibitors, 962 Renovascular disease, 787–788, 787t Reopro. See Abciximab Reperfusion therapy, 600 REPLACE-2 trial, 586–587 REPRISE III trial, 913–914 RER. See Respiratory exchange ratio

Resin, 803t, 807, 808t Respiratory exchange ratio (RER), 181–182 Restrictive cardiomyopathy, 9, 21, 866t cardiac MRI, 135 definition, 244 primary restrictive cardiomyopathies, 244–245 secondary restrictive cardiomyopathies, 245–246, 247t working classification, 244, 245f Reteplase, r-PA (Retavase), 601 Revascularization MI complications and, 620 stable angina and ACC/AHA recommendations, 565t coronary artery bypass grafting versus medical therapy, 566–568 PCI versus CABG for diabetes mellitus patients, 571 PCI versus CABG for left main trunk stenosis, 570–571 PCI versus CABG in multivessel CAD, 569–570 PCI versus CABG in single-Vessel CAD, 569 percutaneous coronary intervention versus medical therapy, 568– 569 Reverberation artifacts, 92 Reverse cholesterol transport (RCT), 798–799 Reverse remodeling, heart failure, 160 Revised cardiac risk index (RCRI), 822 Revised Geneva Score for Pretest Probability of Acute PE, 729t Rhabdomyomas, 883t, 884–885 Rheumatic fever, AS, 477–478, 478t Rheumatic heart disease, 473–474, 479, 496–497, 504 Rheumatic mitral stenosis (MS), 922 stages of, 923f Rheumatoid arthritis (RA), 873 Rhythms of ventricular origin, 306 Rifampin, 189t, 517–518, 894t–896t Right atrial abnormality, 309

Right atrium, 27, 27f Right bundle branch block (RBBB), 308 Right ventricle, 28, 28f Right ventricular function, 204 Right ventricular hypertrophy (RVH), 283, 309 Right ventricular infarction diagnosis for, 624 symptoms and signs of, 624 treatment for, 624 Right ventricular pacing, 607 Risk ratio (RR), 65 Ritonavir, 896t Rivaroxaban, 412, 748 Ross procedure, 478–479 Rosuvastatin, 807t–808t r-PA. See Reteplase, r-PA (Retavase) RR. See Risk ratio RRR. See Relative risk reduction Rubidium-82, 114 RV infarction, 20 RVH. See Right ventricular hypertrophy

S SA. See Sinoatrial node SA block. See Sinoatrial block SACT. See Sinoatrial conduction time St. Jude's Masters valve, 522 Salt and water, heart failure and renal retention, 161 Sapien M3 device, 930t Sarcoidosis, 246, 875 Sarcomere, anatomy, 57f Sarcoplasmic reticulum (SR), 56 SAVE. See Survival and Ventricular Enlargement SBP. See Systolic blood pressure Scandinavian Simvastatin Survival Study, 810t

SCD. See Sudden cardiac death SCD-HeFT trials, 471 Scleroderma, 874 SCN5A, 937t SCS. See Spinal cord stimulation sdLDL. See Small dense low-density lipoprotein Secondary cardiac tumors, 887–888, 887f Secondary CHD prevention, trials for, 810t Secundum ASDs, 903, 905f, 906f Selection bias, 67 Sensing, 449 Septal myectomy, 258–259, 258f Seronegative spondyloarthropathies, 873 SHOCK (Should We Emergently Revascularize Occluded Coronary Arteries for Cardiogenic Shock) Trial Registry, 618–619, 633 Short-QT syndrome, 394 Short-term circulatory-assist devices, 615–616 Shunt calculations, 663 left-to-right, 663 lesions atrial septal defect, 265–267, 266f, 267t patent ductus arteriosus, 268 ventricular septal defect, 268, 268f operations for, 296–298, 299t Sick sinus syndrome, 312 Sildenafil, 587–588 SIMA (Stenting v. Internal Mammary Artery study), 566 Simvastatin, 892t–896t, 896–898 Single photon emission computed tomography (SPECT) imaging, 852 in cardiac amyloidosis, 127 perfusion agents, 114 Single ventricle circulations, 272–273 Single-chamber devices, 446–447

Sinoatrial block (SA block), 304 Sinoatrial conduction time (SACT), 370, 370f Sinoatrial (SA) node, 33, 33f Sinus arrest/pause, 304–305 Sinus arrhythmia, 304 Sinus bradycardia, 304 Sinus node dependent, 417, 418f, 419f functions, EP and, 369–371, 370f, 371f recovery time, 370 reentrant rhythm, 305 reentrant tachycardia, 305 refractory period, 367–369 Sinus rhythm, 405–406, 406t. See also Normal sinus rhythm Sinus tachycardia, 304 Sinus venosus ASDs, 905, 907f Sinus-dependent arrhythmias, 427–428 Sirolimus. See Rapamycin Situational syncope, 462 Skeletal muscle adaptations, heart failure, 161 SLE. See Systemic lupus erythematosus Small dense low-density lipoprotein (sdLDL), 798, 805 Small molecule tyrosine kinase inhibitors, 959–960 Smoking, 637, 642 CAD and, 549–550 pregnancy and, 846–847 Smooth muscle dysfunction genes, 937t Sodium (NA+), nitroprusside, 619–620 Sodium glucose co-transporter inhibitors (SGLT2 inhibitors), 168–169 Sodium–calcium exchange (NCX1) pump, 58 Sodium-dependent cells, 49 SOLVD. See Studies of Left Ventricular Dysfunction Sorafenib, 959–960, 960t Sorin Carbomedics valve, 522

Sotalol, 406t, 408, 840t, 897t Sound waves, 85 Speckle tracking techniques, 91 SPECT imaging in cardiac amyloidosis, 127 perfusion agents, 114 Spinal cord stimulation (SCS), 572 Splinter hemorrhages, 509, 510f Splitting first heart sound, 10 fixed, 11 paradoxical, 11 pathologic, 11 persistent, 10–11 reverse, 10 S2 (physiologic), 11f second heart sound, 10–11, 11f Sports cardiology, 948 athlete's heart, 948–949 ECG interpretation in athletes, 951, 951f management of athletes with cardiovascular disease, 951–956, 952t aortopathies, 956 arrhythmias, 953–955 cardiomyopathies, 952–953 coronary anomalies, 955–956 Marfan syndrome, 956 pericarditis, 956 valvular disease, 955 preparticipation screening, 950–951 sports, classification of, 949f sudden cardiac death in athletes, 949–950, 950f Stable angina, 692–698 CCS classification of, 554, 555t definition of, 554

diagnostic testing/risk stratification CAD, 559t coronary angiography, 557–558 echocardiography, 556 electrocardiography, 555 exercise ECG testing, 555–556 stress testing with nuclear/echocardiographic imaging, 556–557, 557t medical treatment antiplatelet therapy, 560–561 lipid-lowering therapy, 561 renin–angiotensin–aldosterone system blockade, 561 pathophysiology of, 555 refractory angina, 571–572 revascularization in ACC/AHA recommendations, 565t coronary artery bypass grafting versus medical therapy, 566–568 PCI versus CABG for Patients with Diabetes Mellitus, 571 PCI versus CABG for Patients with Left Main Trunk Stenosis, 570–571 PCI versus CABG in Multivessel CAD, 569–570 PCI versus CABG in Single-Vessel CAD, 569 percutaneous coronary intervention versus medical therapy, 568– 569 symptomatic medical therapies, antianginals beta-blockers, 562–563, 562t calcium channel blockers, 563, 563t combination therapy, 564 nitroglycerin and nitrates, 563–564, 564t ranolazine, 564–565 STAMINA-HF trial, 170 Staphylococcus aureus, 511–512, 518 bacteremia, 518 prosthetic valve endocarditis, 527

Starling Law, 39f Statin(s), 753, 761, 962 for dyslipidernias, 807, 807t high- risk primary prevention, 810t Intolerance, 813 LDL-C management, 809–811 for MI, 640 primary prevention, 810t secondary prevention, 810t trials for, 810t–811t Statistical tests, 64 confidence interval, 64 error analysis type I errors, 64, 64f type II errors, 64, 64f hypothesis testing, 64 Stature, 4 ST-elevation myocardial infarction (STEMI), 586, 614, 626, 689–692 assessment for risk of sudden cardiac death, 634–635 biomarker assessment, 633 clinical and demographic factors, 631–632 clinical presentations of, 595 diagnosis for, 595–597, 596f–597f electrocardiogram, 632–633 free wall rupture, 608 history and physical examination, 597 during hospitalization, 633–635 imaging, 633 implantable cardioverter–defibrillator implantation, 608–609 inferior ST-elevation AMI, 597f left ventricular aneurysm, 608 LV function assessment, 634 management of anti-ischemic agents for, 606

antiplatelet agents, 603–604 antithrombotic agents for, 604–606 aspirin for, 608 atorvastatin for, 607 fibrinolytic therapy, 601 glycoprotein IIb/IIa inhibitors for, 604 mechanical complications, 607–608 PCI for, 601–603 predischarge risk stratification for, 609 regional systems of care, 599 reperfusion therapy for, 600 secondary prevention, 606–607 mitral regurgitation, 607–608 pericarditis for, 608 physical examination, 632 predischarge assessment, 634 predischarge management, 635 risk stratification, 598–599, 631–637, 632t, 635t, 636f, 637t stress testing, 634 thienopyridines for, 603–604 ventricular septal rupture, 608 STEMI. See ST-elevation myocardial infarction Stenotic lesions, 268–270 aortic coarctation, 269–270 pulmonic stenosis (PS), 268–269, 269f Stenting and Angioplasty with Protection in Patients at High Risk for Endarterectomy (SAPPHIRE) trial, 762 Stenting, coronary, 560–561 Stents, 699, 703 Stickler syndrome, 936t Stimulation threshold, 449 Storage disorders, 244, 246, 247t and associated cardiac manifestations, 935t Strain imaging, 91

Strauss method, 370, 371f Strength–duration curve, 449 Streptokinase, 601 Streptomycin, 517–518 Stress echocardiography (SE), 851 class I indications, 106 diastolic function assessment, 111 DSE role to assess viability, 111 false-positive and false-negative, 110t forms of, 106–107 exercise echocardiography, 106 pharmacologic, 106–107 imaging technique, 107 interpretation of, 108, 109t, 112f diagnosis of CAD, 109–110 ischemic cascade, 107f in nonischemic cardiac conditions, 111–112 prognostic role, 110–111 prognostic significance, 106 responses, 109t uses for, 108–112 Stress imaging technique, 821–822 Stress testing, 465 chest discomfort, 538–539 exercise electrocardiographic (ECG). See electrocardiographic (ECG) stress test Stroke Prevention in Reversible Ischemia Trial (SPIRIT), 760 Stroke work, pressure–volume loop, 41 Strokes, 401 Structural cardiac interventions fluoroscopy, 680–683, 681f, 682f, 683f, 684f intracardiac echocardiography, 683–684 multidetector computed tomography, 684–685 transesophageal echocardiography, 683

Exercise

Structural heart disease, 463 ST-segment depression, 310–311 elevation, 310 Studies of Left Ventricular Dysfunction (SOLVD), 166t Subaortic aortic stenosis, 289–290, 291f Subaortic stenosis, 478 Subclinical hemolysis, 526–527 Subvalvular AS, 474 Sudden cardiac death (SCD), 260, 260t, 948 arrhythmogenic right ventricular cardiomyopathy, 392, 392f assessment for, 634–635 in athletes, 949–950, 950f Brugada syndrome, 394, 394f and coronary artery disease, 391 DCM and, 391 definition, 390 epidemiology, 390 evaluation and management of, 395 HCM and, 391–392 idiopathic ventricular fibrillation, 394 long-QT syndrome, 393–394, 393t nonischemic cardiomyopathy, 391–393 risk factors and pathophysiology, 390–391 short-QT syndrome, 394 survivors of, 395 valvular heart disease, 394–395 Wolff–Parkinson–White syndrome, 394 Sunitinib, 959–960, 960t Superior vena cava (SVC) obstruction, 9 Supervised exercise rehabilitation, 750 Supracristal VSDs, 480 Supravalvular AS, 7, 474–475 Supraventricular tachycardia (SVT), 954–955, 960

algorithm, 418f approach, 417–419, 419f–420f atrial-dependent arrhythmias, 426–427, 427f AV node-dependent, 420–425, 422f–423f sinus-dependent arrhythmias, 427–428 wide-complex tachycardia bundle branch block, 430–431, 432f–434f differential diagnosis, 430–432, 431f with pre-excitation, 431, 432f SURTAVI trial, 914–915, 914t Survival and ventricular enlargement (SAVE), 166t SVC. See Superior vena cava SVT. See Supraventricular tachycardia Swedish Angina Pectoris Aspirin Trial, 560 Syncope acute episodes management, 467 alarming features, 464 beta-blockers, 468 CCBs for, 468 clinical features, 465t clinical history, 464, 464t conservative/nonpharmacologic therapy, 467–468 definition, 461 diagnosis, 463–467 diagnostic workup, 464–467 due to orthostatic hypotension, 462–463 ECG monitoring, 465–466 echocardiography, 467 electrophysiology testing, 467, 467t etiology, 461 follow-up, 468–469 incidence of, 461 neurally mediated, 462 pathophysiology, 461

patient morbidity, 468 pharmacologic treatment, 468 physical examination, 463 prevalence of, 461 prognosis, 468–469 stress testing, 467 treatment for, 467–468 types, 461 vasovagal, 462–463 Syphilitic aortitis, 720 Systemic lupus erythematosus (SLE), 873 Systole ejection murmurs, 15f ejection sounds, 12 aortic, 12 pulmonic, 12 nonejection clicks, 12–13 pericardial friction rubs, 13 Systolic blood pressure (SBP), 6 Systolic Blood Pressure Intervention Trial (SPRINT), 790t, 791 Systolic function, 476 Systolic murmurs aortic sclerosis, 15 aortic valvular stenosis, 14–15, 14f–15f ejection type, 14–16 hypertrophic cardiomyopathy, 15–16 innocent murmur in children (still murmur), 16 in children to young adults (pulmonary ejection murmur), 16 mitral regurgitation, 16, 16f pulmonic stenosis, 16 regurgitant type, 16–17 tricuspid regurgitation, 16–17 ventricular septal defect, 17

T Tachyarrhythmias, 626–627 evaluation of, 377–383– 378f, 386f Tachycardia-induced cardiomyopathy, 401 Tacrolimus (Tac), 190 TACTICS (Treat Angina with Aggrastat and Determine Cost of Therapy with an Invasive or Conservative Strategy) TIMI 18 trial, 635 Takayasu arteritis, 720, 874 Takotsubo cardiomyopathy, 961 Tansthoracic echocardiogram (TTE), 525 Target lesion revascularization, 699, 703 Task Force for the Diagnostic Management Syncope of the European Society of Cardiology, 461 T-cell receptor (TCR), 189 Technetium pyrophosphate (PYP-Tc99m), 115 Technetium-99m-labeled agents, 114 TEE. See Transesophageal echocardiography Temporary right ventricular pacing, 607 Tendyne device, 930t Tenecteplase, weight-based dosing, 601, 601t Tetralogy of Fallot (TOF), 271, 293 TGA. See Transposition of the great arteries TGRLs. See Triglyceride-rich lipoproteins Thallium-201 chloride, 114 Theophylline, stress protocols, nuclear perfusion imaging, 118 Therapeutic lifestyle changes (TLC), 806–807, 806t Thienopyridines, 637–639, 699–700 for NSTEMI, 584 for STEMI, 603–604 Thoracic aortic aneurysm (TAA), 717–719 ascending, 717, 717f descending, 717 familial screening, 718 incidence, 717

Marfan syndrome and pregnancy, 718 medical treatment, 718 noninvasive imaging, 718 surgical treatment, 718–719 Thoracic endovascular aortic repair (TEVAR), 719 Thoratec device, 203 Three-dimensional echocardiography, 89 Thromboembolism, 401, 410 Thrombolytics, 850 Thromboprophylaxis, 736 Thyroid disorders, 788–789 Thyroid-stimulating hormone (TSH), 779, 789 Tiara device, 930t Tilt table test, 466 abnormal hemodynamic patterns, 466, 466t relative contraindications, 466 TIMI risk score, 598–599, 599f TIMI (Thrombolysis in Myocardial Infarction ) study 16, 635 18, 636 22, 641, 641f risk score, 636f–637f Tip-to-base technique, 928 Tissue Doppler techniques, 91 Tissue-type plasminogen activator (t-PA), 742 TLC. See Therapeutic lifestyle changes TMP-SMX. See Trimethoprim-sulfamethoxazole TNT. See Treating to New Targets Tobacco, 549–550 Toxoplasma, 192 t-PA. See Tissue-type plasminogen activator TR. See Tricuspid regurgitation Transaortic valve gradients, 476 Transcatheter aortic valve implantation (TAVI), 479

Transcatheter aortic valve replacement (TAVR), 523 access routes for, 915–916 for aortic regurgitation, 916 approved devices in United States, 911–912, 911f for bicuspid AS, 916 cerebral embolic protection, 917 clinical trials, 910 complications, 917 DAPT duration, 918 EARLY TAVR trial, 917 evidence supporting for, 912–916 high–surgical-risk patients, 913–914, 913t inoperable patients, 912–913, 912t intermediate surgical risk, 914–915, 914t low surgical risk, 915, 915t future directions for, 918 hypoattenuation and leaflet thickening after, 918 indications for, 910–911, 911f outcomes in extreme-risk patients, 912t SBE prophylaxis, 918 UNLOAD trial, 917 valve durability, 917–918 valve-in-valve, 916 Transcatheter heart valves (THVs), 911 Transcatheter mitral valve repair, 923–927 degenerative MR, 925–927 functional MR, 927 Transcatheter mitral valve replacement (TMVR), 928, 929f devices for, 928, 930t LVOT obstruction, 928 valve in MAC (ViMAC), 928 valve in ring (ViR), 928 valve in valve (ViV) TMVR, 928 Transducers, 86–87, 86t

Transesophageal echocardiography (TEE), 683 Transient ischemic attack (TIA), 758 Transposition of the great arteries (TGA), 270–271, 294–296, 297f Transthoracic echocardiography (TTE), 475–477, 624 of HCM, 251f, 253, 256 for MR, 491 Transthyretin (ATTR) amyloid cardiomyopathy, 115 Trastuzumab, 959, 960t Traube sign, 8 Trauma, aortic injury, 712 Treadmill, 555 Treating to New Targets (TNT), 811t Triamterene, 894t–896t Tricuspid regurgitation (TR), 194 etiology of, 501 signs/symptoms of, 501–504, 502f, 503f systolic murmurs, 16–17 treatments for, 502–504 Tricuspid stenosis (TS), 8 diastolic murmurs, 18 Tricuspid valves, 10, 29, 29f Tricuspid valve stenosis (TS), signs/symptoms of, 504–505 Tricyclic antidepressants, 393, 897t Triglyceride-rich lipoproteins (TGRLs), 798, 799f Trimethoprim, 894t–896t Trimethoprim-sulfamethoxazole (TMP-SMX), 192 Triple apical impulse, 9–10 Trisomy 21, 936t TS. See Tricuspid valve stenosis Tuberous sclerosis, 936t Tumor plop (TP), 12 Tumors, cardiac benign, 882–886, 883t, 883f, 884f, 885f malignant, 886–887, 886t, 887f

Turner syndrome, 936t T waves, 311

U U waves, 311 Ulcer and foot care prevention, 747 Ultrafiltration, 172 Ultrasound harmonic imaging, 88–89 imaging modalities, 87–88 principles of, 85 with tissue, interaction of, 85 transducers, 86–87, 86t velocity of sound through different media, 86t Unfractionated heparin (UFH), 525 Unipolar leads, pacing leads, 448 United Network for Organ Sharing (UNOS), 180, 184t United States (U.S), CVDs in, 543–549 age and gender variation of, 545–546, 545f, 546f cost and health care resources utilization, 548–549, 549t prognosis and risks associated with SCD, 547–548 racial and socioeconomic disparities of, 545t, 546–547, 547f silent myocardial ischemia/infarction, 544–545, 545f–546f temporal trends of, 543 unrecognized myocardial ischemia/infarction, 544–545, 545f–546f young people and, 547 United States Preventive Services Task Force (USPSTF), 758 Unroofed coronary sinus, 905, 905f Upper rate limit, 450 U.S. Food and Drug Administration (FDA), 564, 733, 794

V V–A interval, 450 VALIANT trial (Valsartan in Acute Myocardial Infarction), 640 Validity, 67

Valsalva maneuvers, 19, 20f, 252, 435 Valvar pulmonic stenosis, 77, 77f Valve(s) anticoagulation, 524–528, 525t biologic, 478 bioprosthetic, 522, 523f–524f gradients, 476 mechanical, 522, 523f–524f Medtronic Open Pivot, 522 monitoring prosthetic with echocardiography, 525–528, 525f, 527f On-X, 522 replacement options, 478–479 Sorin Carbomedic, 522 St. Jude's Masters, 522 types, selection of, 522–523 Valve in MAC (ViMAC), 928 Valve in ring (ViR), 928 Valve in valve (ViV) TMVR, 928 Valve-in-valve TAVR, 916 Valve orifice area (VOA), 664 Valvular disease, 955, 963–964 Valvular heart disease, 823 and pressure–volume loop, 41, 41t, 41f Valvular pulmonic stenosis, 293, 295f Vancomycin, 516, 516t VANQWISH, 692 Vascular access, PCI, 602 Vascular disease, 964 Vascular Ehlers–Danlos syndrome, 937t Vascular endothelial growth factor (VEGF) inhibitors, 959–960 Vascular resistance, 663–664 Vasoactive intestinal peptide, 229 Vasoconstriction, 228 Vasodilators, 614, 617

for AS, 481 pharmacologic stress echocardiography, 107 Vasopressin, antagonists, 172 Vasopressors, 615 Vasovagal syncope, 462 Velocity time integral (VTI), 476 Vena cavae, 30 Vena contracta, 93 Venography, 728 Venous hum, 18 Venous thromboembolism (VTE) and cancer, 962–963 prevention of, 962–963 risk assessment, 962 risk factors, 962 treatment and secondary prevention, 964 diagnosis of, 728–729 DVT clinical presentation and diagnosis, 726–727, 727f D-Dimer testing, 726 diagnostic testing, 728 duplex ultrasonography, 727–728 venography, 728 essential facts about, 725 risk factors, 726, 726t treatment of anticoagulants, 733, 734t DOACs, 733, 733t DTI, 732 fondaparinux, 732 LMWH, 732 mechanical/pharmacologic, 736 pulmonary embolism clinical presentation and diagnosis, 729f, 728–729

CTPA, 730 echocardiography, 729–730 laboratory biomarkers, 730–731 MRA, 730 objective testing, 729–731 pulmonary angiography, 730 transthoracic echocardiogram, 729–730 ventilation/perfusion scintigraphy, 730 thrombolytic therapy for, 734 thromboprophylaxis, 736 unfractionated heparin, 732 VKA, 732–733 Ventilation/perfusion scans (V/Q), 730 Ventricular activation, 367, 372 Ventricular arrhythmias, 955 Ventricular contraction, 91 Ventricular extrastimulus testing, 376–377 Ventricular fibrillation (VF), 306 Ventricular function, 204 Ventricular oversensing, 449–450 Ventricular pacing, 376–377, 376f–377f, 379, 381 Ventricular parasystole, 306 Ventricular rate, 304–308, 403–404, 404t Ventricular remodeling and reverse remodeling heart failure, 160 Ventricular sensitivity, 449 Ventricular septal defect (VSD), 21, 268, 268f, 287–288, 287f, 616–617, 833 diagnosis for, 616–617, 617f membranous, 268, 287 muscular, 287, 288f–289f signs/symptoms of, 616 supracristal, 287, 289f systolic murmurs, 17

treatment for, 617 types of, 287, 287f Ventricular systole, 10 Ventricular tachycardia (VT), 306. See also Supraventricular tachycardia; Wide-complex tachycardia coronary artery disease, 395 dilated cardiomyopathy, 396 idiopathic left ventricular tachycardia, 396–397 morphology of, 379 outflow tract, 396, 396f papillary muscle, 397 short-QT syndrome, 394 structurally normal heart and, 396–397 Ventricular volumes, pressure–volume loop, 40 Verapamil, 169, 257–258, 404t, 563t, 786, 894t–896t Verification bias, 67 Very low-density lipoprotein (VLDL), 798 Veterans Administration Cooperative Study (VA Study), 566 Veterans Affairs Cooperative Studies Program High-Density Lipoprotein Cholesterol Intervention Trial (VA-HIT), 812t Veterans Affairs Cooperative Study (VACS), 757 V-HeFT II, 169 Viability assessment, cardiac MRI, 134 Viral pericarditis, 858 Vitamin D, 194 Vitamin K antagonists (VKA), 731 VKA. See Vitamin K Antagonists VLDL. See Very low-density lipoprotein VMAC, 172 VOA. See Valve orifice area Voltage output, 449 Vorinostat, 959–960, 960t V/Q. See Ventilation/perfusion scans VSD. See Ventricular Septal Defect

VT. See Ventricular tachycardia VTE. See Venous thromboembolism VTI. See Velocity time integral

W Wandering atrial pacemaker (WAP), 305 WAP. See Wandering atrial pacemaker Warfarin, 411, 524–525, 639, 732–733, 748, 839, 841, 892t–896t Warfarin-Aspirin Symptomatic Intracranial Disease (WASID), 760 Water-hammer pulse, 8 Waveforms, 455, 456f intracardiac, 658–664, 659t, 659f Wavelength (λ), 85 Wegener granulomatosis, 875 West of Scotland Coronary Prevention Study (WOSCOPS), 810t Wide-complex tachycardia (WCT) algorithms, 437–438, 438f, 439f, 440f conclusions on, 439–440 diagnosis clinical presentation, 434–435 ECG criteria, 435–437, 436f–437f provocative maneuvers, 435 differential diagnosis, 430–432, 432f–434f special cases, 438–439, 441f Williams syndrome, 474–475, 871, 936t Wolff–Parkinson–White (WPW) syndrome, 394, 954 and sudden cardiac death, 425 Women AHA/ACC guidelines for, 845, 848 cardiac computed tomography angiography, 851 cardiovascular magnetic resonance imaging, 852 chest discomfort in, 539–540 coronary artery disease, 849–850 epidemiology/problem of, 845, 846f exercise electrocardiograms, 850–851

guidelines for heart disease prevention in, 848–849, 849f heart failure and, 852–853 survival, 852–853 treatment, 845 noninvasive evaluation of, 850 pregnancy, 524–525 prevention of, estrogen therapy for, 848 radionuclide imaging, 851–852 risk factors associated with, 847–848 for coronary artery disease, 845–847 stress echocardiography (ECHO), 851 Women's Health Initiative Observational Study (WHI-OS), 788 World Health Organization (WHO), global burden of disease, 543 WOSCOPS. See West of Scotland Coronary Prevention Study

X Xanthomas, 801f X-ray imaging system, 647f generator, 647 image receptor, 647 operating console, 648 x-ray tube, 646–647 XRT. See External-beam radiation therapy

Z Ziprasidone, 897t Z-scores, 956