Cardiology: An Integrated Approach (Human Organ Systems) (Retail Copy) [1 ed.] 9781260116946, 1260116948, 9781260116939, 126011693X

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Cardiology: An Integrated Approach

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Cardiology: An Integrated Approach ADEL ELMOSELHI, MD, PHD Associate Professor Basic Medical Sciences Department College of Medicine University of Sharjah Sharjah, United Arab Emirates and Adjunct Associate Professor Physiology Department Michigan State University East Lansing, Michigan

New York Chicago San Francisco Athens London Madrid Mexico City Milan New Delhi Singapore Sydney Toronto

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Copyright © 2018 by McGraw-Hill Education. All rights reserved. Except as permitted under the United States Copyright Act of 1976, no part of this publication may be reproduced or distributed in any form or by any means, or stored in a database or retrieval system, without the prior written permission of the publisher. ISBN: 978-1-26-011694-6 MHID: 1-26-011694-8 The material in this eBook also appears in the print version of this title: ISBN: 978-1-26-011693-9, MHID: 1-26-011693-X. eBook conversion by codeMantra Version 1.0 All trademarks are trademarks of their respective owners. Rather than put a trademark symbol after every occurrence of a trademarked name, we use names in an editorial fashion only, and to the benefit of the trademark owner, with no intention of infringement of the trademark. Where such designations appear in this book, they have been printed with initial caps. McGraw-Hill Education eBooks are available at special quantity discounts to use as premiums and sales promotions or for use in corporate training programs. To contact a representative, please visit the Contact Ues page at www.mhprofessional.com. NOTICE Medicine is an ever-changing science. As new research and clinical experience broaden our knowledge, changes in treatment and drug therapy are required. The authors and the publisher of this work have checked with sources believed to be reliable in their efforts to provide information that is complete and generally in accord with the standards accepted at the time of publication. However, in view of the possibility of human error or changes in medical sciences, neither the authors nor the publisher nor any other party who has been involved in the preparation or publication of this work warrants that the information contained herein is in every respect accurate or complete, and they disclaim all responsibility for any errors or omissions or for the results obtained from use of the information contained in this work. Readers are encouraged to confirm the information contained herein with other sources. For example and in particular, readers are advised to check the product information sheet included in the package of each drug they plan to administer to be certain that the information contained in this work is accurate and that changes have not been made in the recommended dose or in the contraindications for administration. This recommendation is of particular importance in connection with new or infrequently used drugs. TERMS OF USE This is a copyrighted work and McGraw-Hill Education and its licensors reserve all rights in and to the work. Use of this work is subject to these terms. Except as permitted under the Copyright Act of 1976 and the right to store and retrieve one copy of the work, you may not decompile, disassemble, reverse engineer, reproduce, modify, create derivative works based upon, transmit, distribute, disseminate, sell, publish or sublicense the work or any part of it without McGraw-Hill Education’s prior consent. You may use the work for your own noncommercial and personal use; any other use of the work is strictly prohibited. Your right to use the work may be terminated if you fail to comply with these terms. THE WORK IS PROVIDED “AS IS.” McGRAW-HILL EDUCATION AND ITS LICENSORS MAKE NO GUARANTEES OR WARRANTIES AS TO THE ACCURACY, ADEQUACY OR COMPLETENESS OF OR RESULTS TO BE OBTAINED FROM USING THE WORK, INCLUDING ANY INFORMATION THAT CAN BE ACCESSED THROUGH THE WORK VIA HYPERLINK OR OTHERWISE, AND EXPRESSLY DISCLAIM ANY WARRANTY, EXPRESS OR IMPLIED, INCLUDING BUT NOT LIMITED TO IMPLIED WARRANTIES OF MERCHANTABILITY OR FITNESS FOR A PARTICULAR PURPOSE. McGraw-Hill Education and its licensors do not warrant or guarantee that the functions contained in the work will meet your requirements or that its operation will be uninterrupted or error free. Neither McGraw-Hill Education nor its licensors shall be liable to you or anyone else for any inaccuracy, error or omission, regardless of cause, in the work or for any damages resulting therefrom. McGraw-Hill Education has no responsibility for the content of any information accessed through the work. Under no circumstances shall McGraw-Hill Education and/or its licensors be liable for any indirect, incidental, special, punitive, consequential or similar damages that result from the use of or inability to use the work, even if any of them has been advised of the possibility of such damages. This limitation of liability shall apply to any claim or cause whatsoever whether such claim or cause arises in contract, tort or otherwise.

To my late parents, for unconditional love that has shaped my life; to my wife, Melody, for her love and support throughout our journey together; and to my children, Sarah and Noah, for bringing joy to my heart and sacrificing our time together while I worked on this book.

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Contents Contributors ix Preface xi Abbreviations xii

MBRYOLOGY AND | EMORPHOLOGY OF THE HEART

SECTION I   

AND VESSELS

 1 Development of the Heart and Blood Vessels / 3 MOHAMED A. ELADL

 2 Anatomical Structure of the Heart  /  19 AKRAM JAFFAR

EART AND VASCULAR | HFUNCTIONS

SECTION II   

 3 Cardiovascular Circuitry and Hemodynamics / 35 ADEL ELMOSELHI

 4 Electrophysiology of the Heart  /  51 ADEL ELMOSELHI AND MOHAMED SEIF

 5 Cardiac Output and the Pressure-Volume Relationship / 71

 9 Arrhythmias and Antiarrhythmic Drugs  /  131 SANDEEP BANGA AND NAGIB T. CHALFOUN

10 Valvular Heart Diseases  /  151 SAQIB AHMED AND GREGORY A. BERNATH

11 Congestive Heart Failure and Management Drugs / 169 MOHSIN K. KHAN AND AMAURY SANCHEZ

12 Congenital Heart Diseases  /  183 HARIKRISHNAN K. N. AND JOSEPH J. VETTUKATTIL

13 Systemic Arterial Hypertension and Antihypertensive Drugs / 201 HUSSAIN IBRAHIM AND PRERANA MANOHAR

14 Myocardial Diseases / 215 SANDEEP BANGA, PREETI BANGA, AND SUDHIR MUNGEE

15 Pericardial Diseases / 227 SHAHEER ZULFIQAR AND MANIVANNAN VEERASAMY

16 Diseases of the Peripheral Vessels  /  239 SANDEEP BANGA, PREETI BANGA, AND SUDHIR MUNGEE

17 Cardiovascular Drugs / 255 MAHA M. SABER-AYAD

KRISTEN MILLADO, MARGARET CHI, AND ADEL ELMOSELHI

 6 The Cardiac Cycle  /  83 KATHRYN LARUSSO AND ADEL ELMOSELHI

Answers to Case Studies  /  283

 7 Regulation of Arterial Blood Pressure and Microcirculation / 93 ADEL ELMOSELHI

ARDIOVASCULAR DISEASE | CPROCESSES: DIAGNOSTIC

SECTION III   

AND MANAGEMENT APPROACHES

 8 Ischemic Heart Disease and Management Drugs / 111 ANTHONY PAGANINI, DEBORAH E. BLUE, AND ADEL ELMOSELHI

vii

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Contributors

Saqib Ahmed, MD, MRCP(UK) Internal Medicine Resident Grand Rapids Medical Education Partners Grand Rapids, Michigan Chapter 10

Preeti Banga, MD(Radiology) CIRA (Central Illinois Radiology Associates) OSF St. Francis Medical Center Peoria, Illinois Chapters 14 and 16

Sandeep Banga, MBBS, MD, DNB Cardiology Research Fellow Division of Electrophysiology–Cardiology Frederik Meijer Heart and Vascular Institute Spectrum Health College of Human Medicine Michigan State University Grand Rapids, Michigan Chapters 9, 14, 16

Gregory A. Bernath, MD Interventional Cardiologist Spectrum Health Medical Group Cardiovascular Services Grand Rapids, Michigan Chapter 10

Deborah E. Blue, MD, MT(ASCP) Technical Director, Microbiology Technical Director, Blood Bank Spectrum Health Regional Laboratory/Michigan Pathology Specialists, PC Grand Rapids, Michigan Chapter 8

Nagib T. Chalfoun, MD Electrophysiologist Division of Electrophysiology–Cardiology Frederik Meijer Heart and Vascular Institute Spectrum Health and

Clinical Assistant Professor of Medicine Michigan State College of Human Medicine Grand Rapids, Michigan Chapter 9

Margaret Chi, MD, MPH Internal Medicine Residency Kaiser Permanente Los Angeles, California Chapter 5

Mohamed A. Eladl, MD, MSC, PhD Assistant Professor Department of Basic Medical Sciences College of Medicine University of Sharjah Sharjah, United Arab Emirates Chapter 1

Adel Elmoselhi, MD, PhD Associate Professor Basic Medical Sciences Department College of Medicine University of Sharjah Sharjah, United Arab Emirates and Adjunct Associate Professor Physiology Department Michigan State University East Lansing, Michigan Chapters 3–8

Harikrishnan K. N., MBBS, MD Cardiology Fellow Congenital Heart Center Helen DeVos Children’s Hospital of Spectrum Health Grand Rapids, Michigan Chapter 12

Hussain Ibrahim, MD Cardiology Fellow University of Texas Medical Branch, Division of Cardiology Galveston, Texas Chapter 13 ix

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x

Contributors

Akram Jaffar, MD, PhD Senior Instructor Department of Medical Neuroscience Dalhousie University Halifax, NS, Canada Chapter 2

Mohsin K. Khan, MD

Maha M. Saber-Ayad, MD(Pharm), MRCP(UK), FRCP(Edin.) Associate Professor of Pharmacology College of Medicine University of Sharjah Sharjah, United Arab Emirates Chapter 17

Clinical Assistant Professor of Medicine Internal Medicine Hospitalist Spectrum Health Medical Group Michigan State University Grand Rapids, Michigan Chapter 11

Amaury Sanchez, MD

Kathryn LaRusso, MD, MPH

Mohamed Seif, MD, FRCP(Edin. UK), CBCCT

General Surgery Resident UT Health Science Center San Antonio San Antonio, Texas Chapter 6

MSc Leadership in Health Profession Education RCSI Head Internal Medicine and Family Medicine Departments and Senior Consultant Cardiologist University Hospital of Sharjah Sharjah, United Arab Emirates Chapter 4

Prerana Manohar, MD, FRCPC Medical Director The Heart and Wellness Institute and Associate Professor College of Human Medicine Michigan State University Grand Rapids, Michigan Chapter 13

Kristen Millado, MD Internal Medicine Residency George Washington University Washington, DC Chapter 5

Sudhir Mungee, MD Director, Cardiology Fellowship Program Division of Cardiology University of Illinois College of Medicine at Peoria Peoria, Illinois Chapters 14 and 16

Anthony Paganini, PhD Associate Professor Director of Professional Educational Affairs Departments of Physiology and Radiology College of Human Medicine Michigan State University East Lansing, Michigan Chapter 8

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Internal Medicine Residency Grand Rapids Medical Education Partners Michigan State University Grand Rapids, Michigan Chapter 11

Manivannan Veerasamy, MD SHMG Hospitalist Core Faculty, Internal Medicine Residency Grand Rapids Medical Education Partners Michigan State University Grand Rapids, Michigan Chapter 15

Joseph J. Vettukattil, MBBS, MD, DNB, CCST, FRCPCH, FRSM, FRCP Pediatric Interventional Cardiologist Congenital Heart Center Helen DeVos Children’s Hospital of Spectrum Health Grand Rapids, Michigan Chapter 12

Shaheer Zulfiqar, MBBS, MD Hospitalist, Internal Medicine Parkview Medical Center Pueblo, Colorado Chapter 15

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Preface

The aim of this work is to integrate the basic and clinical science topics of the cardiovascular system in a deliberately clinically oriented review book. Approximately half of the medical schools in the United States have already implemented an integrated curriculum in their pre-clinical programs, a trend which is growing both nationally and internationally. This trend is due in part to the proven benefits of the evidencebased practice of medicine as well as the increasing number of integrative clinical vignette questions in the medical and healthcare professional license examinations. Thus, this book was created to provide a comprehensive review that includes almost all pre-clinical and clinical subjects of the cardiovascular system in a compact volume, replacing the individual subject-specific books, which are now of limited relevance to current curriculum implementation and clinical practice, and providing an instructional resource that is more closely aligned with an integrative approach to the teaching and practice of medicine. The book consists of three sections and 17 chapters. The first section has 2 chapters that cover the embryological development and anatomical structure of the cardiovascular system; the second section consists of 5 chapters that explore the basic physiological and biochemical functions of the heart and bloods vessels. The last section, which is the most substantial, has 10 chapters that address the most common cardiovascular diseases in terms of their causes, risk factors, pathophysiological processes, clinical manifestations, diagnoses, and treatment. The final chapter focuses on the most commonly used cardiovascular pharmacological drugs, their mechanisms of actions, clinical uses, and adverse effects. Embedded in almost all chapters are Clinical Correlation boxes which highlight valuable practical applications, and each chapter concludes with clinical Case Study questions resembling those found on licensing examinations, along with their answer

keys, annotated with brief explanations. A short list of Suggested Readings is also included at the end of each chapter. As the scope of the material is enormous, the book focuses on the most common medical problems in the cardiovascular system and the high-yield areas directed toward medical programs and residency training programs. This review book is intended to be used as a supplement to university-prepared course materials and can serve as an aggregate study guide, especially for the clinically oriented healthcare professional programs. A particular strength of this book is that it brings together the collective efforts of more than 20 faculty and clinicians from diverse academic specialties. It has been an extraordinary experience collaborating on this project with such an impressive ensemble of colleagues who represent an international range of institutions, from the College of Human Medicine, Michigan State University and other teaching hospitals in Grand Rapids, Michigan; Dalhousie University, Halifax, NS, ­Canada; and the College of Medicine, University of Sharjah and University Hospital in the United Arab Emirates. In an interesting coincidence, on a personal note, I am writing this preface on the campus of the Harvard T.H. Chan School of Public Health, where I am participating in a Global Health Delivery Program and reflecting on the interconnectivity and impact of the global setting on determining best evidence-based practices and veritas (truth) with regard to knowledge and the delivery of healthcare. Certainly, this review volume is a testament to the strength of inclusion of a diverse range of experts in a field of cardiovascular health professionals. May this volume serve to support the education and training of medical students, residents, and all other healthcare professional trainees. Adel Elmoselhi, MD, PhD

xi

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Abbreviations

ABI ankle-brachial index ACC American College of Cardiology ACE angiotensin-converting enzyme (ACE) inhibitors ACh acetylcholine ACTH adrenocorticotropic hormone ADH antidiuretic hormone AFib or AF atrial fibrillation AFl atrial flutter AHA American Heart Association AICD automated implantable cardioverter defibrillator AL amyloidosis ANA antinuclear antibody (ANA) test ANP atrial natriuretic peptide APD action potential duration APTT Activated Partial Thromboplastin Time AR aortic regurgitation ARBs angiotensin II receptor blockers ARP absolute refractory period ART antidromic reentrant tachycardia ARVC arrhythmogenic right ventricular cardiomyopathy ARVD arrhythmogenic right ventricular dysplasia AS aortic stenosis ASDs atrial septal defects AV atrioventricular aVF augmented voltage left foot aVL augmented voltage left arm AVP arginine vasopressin aVR augmented voltage right arm AVR aortic valve replacement AVNRTs atrioventricular nodal reentrant tachycardias AVRTs atrioventricular reentrant tachycardias BAT BNP bpm BSA BVH

baroreflex activation therapy B-type natriuretic peptide beats per minute body surface area biventricular hypertrophy

CABG CADs cAMP

coronary artery bypass graft (CABG) surgery cardiovascular diseases cyclic adenosine monophosphate

xii

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Abbreviations

CARDIA CCBs CCF cGMP CHB CHD CHF CICR CKD CMR CO CoA CPA CPVT CTA CVA CVDs CVI Cx

xiii

Coronary Artery Risk Development in Young Adults calcium channel blockers congestive cardiac failure cyclic guanosine monophosphate complete heart block congenital heart disease congestive heart failure calcium-induced calcium release chronic kidney disease cardiovascular magnetic resonance (CMR) imaging cardiac output coarctation of the aorta conventional peripheral angiography catecholaminergic polymorphic ventricular tachycardia computed tomography angiography cerebrovascular accident chronic venous disorders cavotricuspid isthmus circumflex (branch)

DADs delayed afterdepolarizations DCM dilated cardiomyopathy DESs drug-eluting stents DHPs dihydropyridines DORV double outlet right ventricle DP diastolic pressure DVT deep vein thrombosis ECG electrocardiography/electrocardiogram EDP end-diastolic pressure EDV end-diastolic volume EF ejection fraction ERP effective refractory period ESC European Society of Cardiology ESV end-systolic volume ERP effective refractory period GFR GSV

glomerular filtration rate great saphenous vein

HCM hypertrophic cardiomyopathy HLHS hypoplastic left heart syndrome HR heart rate 5HT 5-hydroxytryptamine HTN hypertension ICD IHD ICS IHD INR

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implantable cardioverter defibrillator ischemic heart disease intercostal space ischemic heart disease international normalized ratio

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xiv

Abbreviations

IVC IVS

inferior vena cava interventricular septum

JET JVD JVP

junctional ectopic tachycardia jugular vein distention jugular venous pressure

LA LAA LAD LAP LBBB LDL LMWHs LTRI LV LVAD LVEDP LVES LVH LVOT

left atrium left atrial appendage left anterior descending (branch) left atrial pressure left bundle branch block low-density lipoprotein low molecular weight heparins lower respiratory tract infection left ventricle left ventricular assist device left ventricular end-diastolic pressure left ventricular end-systolic left ventricular hypertrophy left ventricular outflow tract

MAHA MAP MAT MI MIP MMVD MR MRA MV MVP MYBPC3C MYH7

microangiopathic hemolytic anemia mean arterial pressure multifocal atrial tachycardia myocardial infarction maximum intensity projection mixed mitral valve disease mitral regurgitation magnetic resonance angiogram mitral valve mitral valve prolapse myosin-binding protein C myosin heavy chain 7

NCX sodium-calcium exchanger NDF net driving force NDHPs non-dihydropyridines NPY neuropeptide Y NSAIDs nonsteroidal anti-inflammatory drugs NSTEMI non-ST elevation myocardial infarction ORT

orthodromic reentrant tachycardia

PACs PAH PCI PDA PDE-3 PE PET PETN

premature atrial contractions pulmonary arterial hypertension percutaneous coronary intervention patent ductus arteriosus phosphodiesterase isozyme 3 pulmonary thromboembolism positron emission tomography pentaerythritol tetranitrate

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Abbreviations

PFO PND PRU PS PSV PSVT PTA PTRA PVCs PVE PVR

patent foramen ovale paroxysmal nocturnal dyspnea peripheral resistance unit pulmonary stenosis peak systolic velocity paroxysmal supraventricular tachycardia percutaneous transluminal angioplasty percutaneous transluminal renal angioplasty premature ventricular contractions prosthetic valve endocarditis pulmonary vascular resistance

RA RAAS RCA RCM RFA RHC RPLS RRP RV RVH RVOT

right atrium renin-angiotensin-aldosterone system right coronary artery restrictive cardiomyopathy radiofrequency ablation right heart catheterization reversible posterior leukoencephalopathy syndrome relative refractory period right ventricle right ventricular hypertrophy right ventricular outflow tract

xv

SA sinoatrial SACT sinoatrial conduction time SAM systolic anterior motion SBP systolic blood pressure SCD sudden cardiac death SERCA sarcoplasmic reticulum Ca2+-ATPase SJS Stevens-Johnson syndrome SLE systemic lupus erythematosus SNP supranormal period SNS sympathetic nervous system SOB shortness of breath SP systolic pressure SR sarcoplasmic reticulum STEMI ST segment elevation myocardial infarction SV stroke volume SVC superior vena cava SVR systemic vascular resistance SVTs supraventricular tachycardias TA TAPVC TAPVR/D TAVR TCPC TEE TEN TIMI TnC

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tricuspid atresia total anomalous pulmonary venous connection total anomalous pulmonary venous return/drainage transcatheter aortic valve replacement total cavopulmonary connection transesophageal echocardiogram toxic epidermal necrolysis Thrombolysis in Myocardial Infarction troponin C

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xvi

Abbreviations

TnI troponin I TnT troponin T TNNT2 cardiac troponin T ToF tetralogy of Fallot TPR total peripheral resistance TR tricuspid regurgitation TTE transthoracic echocardiograms TV tricuspid valve TXA2 thromboxane UFH

unfractionated heparin

V1A V2 VFib or VF VSDs VT VTE VVs vWF

vasopressin type 1A (V1A) receptor vasopressin type 2 (V2) receptor ventricular fibrillation ventricular septal defects ventricular tachycardia venous thromboembolism varicose veins von Willebrand factor

WPW

Wolff-Parkinson-White (WPW) syndrome

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SECTION

I

EMBRYOLOGY AND MORPHOLOGY OF THE HEART AND VESSELS

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Chapter Development of the Heart and Blood Vessels MOHAMED A. ELADL

Introduction Unlike most other organ systems, the function of the cardiovascular system is critical for embryonic survival. Thus, development of the heart and vascular system begins very early, originating from both the embryonic and extra embryonic mesoderm of the embryo. The heart is the first organ to form during embryogenesis. Before the age of 3 weeks, the nutrient materials reach the fetus by simple diffusion. After that age, the embryo is no longer able to satisfy its nutritional requirements by diffusion alone, thus the blood vessels begin to develop and nourish the embryo. Blood cells and blood vessels arise from the mesoderm. Blood vessels form in two ways: vasculogenesis, whereby vessels arise from blood islands, and angiogenesis, which entails sprouting from existing vessels (Fig. 1.1).

Development of the Heart Tube The first sign of the development of the heart is the formation of cardiogenic cords. These are canalized to form 2 endocardial tubes (day 19). These tubes develop from condensation of splanchnopleuric mesoderm in the cardiogenic region of the trilaminar germ disc. The cardiogenic region is cranial to the neural plate (Fig. 1.2A). On day 20, lateral and cephalic folding of the trilaminar germ disc over the course of several days brings the endocardial tubes together and tucks them ventrally in the thoracic region at the base of the yolk sac. This process also brings the septum transversum into its adult position inferior to the heart. On day 21, medial migration and midline fusion of the endocardial tubes form the primary heart tube through which blood eventually flows in a cranial direction (Fig. 1.2B and Fig. 1.3A). The mesenchyme surrounding the tube condenses to form the myoepicardial mantle (the future myocardium). Gelatinous connective tissue called cardiac jelly separates this mantle from the endothelial heart tube (the future endocardium). A constriction appears in the heart tube and divides it into the cranial outflow part representing the primitive ventricle,

Learning Objectives

1

By the end of this chapter the student will be able to: • Discuss the development of the heart tube. • Describe heart tube looping, chamber formation, and the series of septation that occur for the development of atria, ventricles, and great vessels. • Recognize the relationship of heart tubes to the pericardial cavity. • Indicate the development of valves and conducting system of the heart. • Distinguish the development of the aortic arches and list its derivatives. • Indicate the major changes that happened in development of the sinus venosus. • List and provide a brief anatomical description of the congenital anomalies of the heart and major blood vessels. • Diagram the fetal circulation and recall the changes that occur after birth.

and a caudal inflow part, which represents the primitive atrium (Fig. 1.3B). Two additional constrictions appear in the cranial outflow part differentiating it into 3 chambers from the caudal to cranial ends; the primitive ventricle, bulbus cordis, and truncus arteriosus, which are distally continuous with the aortic sac (Fig. 1.3C). The caudal inflow part dilates and forms the sinus venosus and the heart tube then divides into 5 chambers: sinus venosus, primitive atrium, primitive ventricle, bulbus cordis, and truncus arteriosus (Fig. 1.3D). With further growth and elongation, the linear heart tube undergoes an asymmetric looping process (days 23-28). The caudal inflow region of the heart tube adopts a more cranial final position due to bending of the heart tube as a U-shaped loop (Fig. 1.3E); and then the poles of the heart converge and the heart now appears as an S-shape; with the first bend in the S between the bulbus cordis and ventricle, and the second bend between the atrium and sinus venosus. The bulbus cordis and truncus arteriosus move ventrally to the atrium to form the outflow tract and the atrium now lies superior to the ventricle. Blood begins to circulate through the embryo by day 24. The looping process brings the primitive areas of the heart into the proper spatial relationship for development of the adult heart (Fig. 1.4). While the heart is growing, it pushes into the dorsal wall of the empty pericardial sac during development and becomes 3

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4

Section I  Embryology and Morphology of the Heart and Vessels

Angioblast

Vasculogenesis

2. Situs inversus: As with dextrocardia, this condition is caused by transposition of the abdominal viscera (Fig. 1.5B). 3. Ectopia cordis: Due to failure of the lateral folds to fuse and failure of the thoracic wall to form, the heart is partly or completely exposed on the surface of the thorax. This condition is marked by widely separated halves of the sternum with an open pericardial sac.

Angiogenesis Mother vessel

Sprouting

Development of the Atrioventricular Canal

Bridging Intussusception

Dorsal and ventral atrioventricular endocardial cushions appear at the dorsal and ventral wall of the atrioventricular canal (Fig. 1.6A). The 2 endocardial cushions grow toward each other and fuse together to form the septum intermedium. This septum divides the atrioventricular canal into right and left halves (Fig. 1.6B, C).

Daughter vessels

FIGURE 1.1  Schematic illustration showing angioblasts in the embryo, which assemble in a primitive network (vasculogenesis) that expands and remodels (angiogenesis). Smooth muscle cells cover the endothelial cells during vascular myogenesis and stabilize vessels during arteriogenesis.

Fate of the Atrioventricular Canal

surrounded to such a degree that 2 layers of the dorsal tissue become opposed. This is referred to as the dorsal mesocardium. The dorsal mesocardium suspends the heart for a time but soon breaks down during looping, leaving the heart suspended at its cranial and caudal surfaces but not at the back. The gap, which persists where the dorsal mesocardium once was, is called the transverse sinus (a point of communication across the pericardial coelom) (Fig. 1.3E). After looping and chamber formation, a series of septation events divide the left and right sides of the heart, separate the atria from the ventricles, and form the aorta and pulmonary artery from the truncus arteriosus. Cardiac valves form between the atria and the ventricles and between the ventricles and the outflow vessels.

1. The upper part of the atrioventricular canals is absorbed into the corresponding atria (right and left). 2. The lower part of the atrioventricular canals is absorbed into the corresponding ventricles (right and left). 3. The septum intermedium shares in the formation of the interatrial septum and the membranous part of the interventricular septum.

Anomalies of the Atrioventricular Canal 1. Persistent atrioventricular canal: A common channel between the 2 atria and 2 ventricles that is formed when the septum intermedium fails to form. 2. Unequal division of the atrioventricular canal: This leads to mitral stenosis and/or tricuspid regurgitation, when deviation of the septum intermedium to the left side or tricuspid stenosis and/or mitral regurgitation, when deviation of the septum intermedium occurs to the right side.

Anomalies in the Position of the Heart 1. Dextrocardia with situs solitus: The heart tube bends to the opposite direction and therefore is displaced to the right and its chambers and its vessels are reversed as in a mirror image (Fig.1.5A). Early heart-forming regions

A

Neural folds

Pericardial coelom

Foregut

Forming heart

B

FIGURE 1.2  Schematic depiction of a transverse section through an early embryo. A. Depicts the bilateral region where early heart tubes form. B. Shows the bilateral heart tubes subsequently migrating to the midline and fusing to form the linear heart tube. (Reproduced, with permission, from Longo DL, Fauci AS, Kasper DL, Hauser SL, Jameson JL, Loscalzo J, eds. Harrison’s Principles of Internal Medicine. 18th ed. New York: McGraw-Hill; 2011.)

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Chapter 1  Development of the Heart and Blood Vessels

5

TA TA

BC

BC PV

TA

PV

PV

PA PA A

PA BC PV

SV

B

C

D

SV

E

FIGURE 1.3  Schematic depiction of changes in an early heart tube in a human. A. The 2 heart tubes fuse to form a single heart tube. B. A constriction appears dividing the heart tube into the primitive ventricle (PV) cranially and the primitive atrium (PA) caudally. C. Two additional constrictions appear in the PV forming the bulbus cordis (BC) and truncus arteriosus (TA). D. The area where the veins enter the heart tube enlarges and forms the sinus venosus (SV). E. Bending of the heart tube as a U-shaped loop, breaking the dorsal mesocardium and forming the transverse sinus (arrow).

3. Mitral atresia: Complete fusion of the cusps of the mitral orifice. 4. Tricuspid atresia: Complete fusion of the cusps of the tricuspid.

Development of the Interatrial Septum The primitive atrium is divided into a right and left atrium due to the following changes: •• A sickle-shaped septum (septum primum) grows from the roof of the primitive atrium toward the septum intermedium. The lower rim of the septum primum is

Arterial pole

OFT

AVC

Venous pole

FIGURE 1.4  The heart appears as an S-shape, with the first bend in the S between the bulbus cordis and ventricle, and the second bend between the atrium and sinus venosus (blue). The atrioventricular canal (AVC) is between the primitive common atrium and the primitive ventricle; and the outflow tract (OFT) is continuous cranially. (Reproduced, with permission, from Pahlm O, Wagner GS, eds. Multimodal Cardiovascular Imaging: Principles and Clinical Applications. New York: McGraw-Hill; 2011.)

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separated from the septum intermedium by an opening called the ostium primum (Fig. 1.7A). •• Before complete closure of the ostium primum, the upper part of the septum primum will break down to form the ostium secundum (between the upper margin of the septum primum and the roof of the primitive atrium), allowing free passage of blood flow from the right to left side (Fig. 1.7B). •• A crescent fold from the cephalic wall of the primitive atrium (septum secundum) grows downward to the right side of the septum primum toward the septum intermedium, but does not with it. Its free concave edge begins to overlap the foramen secundum and the new passage formed between the right and left atria is called the foramen ovale. This foramen is not a simple orifice, but an oblique passage for the blood to pass from the right atrium to the left atrium, between the lower edge of the septum secundum and the septum intermedium, then, in-between the septum primum and foramen secundum (Fig. 1.7C). •• Before birth, the pressure in the right atrium is higher because the lungs are not functioning and more oxygenated blood reaches the right atrium from the placenta via the inferior vena cava. This allows the blood to pass from the right atrium to the left atrium through the foramen ovale. After birth, the pressure inside the left atrium increases and exceeds that of the right atrium because of stoppage of the placental circulation and exposure to cold, which stimulates the respiration and lung functions, therefore more blood reaches the left atrium (from the lungs). •• The difference in the pressure between the 2 atria presses the septum primum against the septum secundum and the 2 septa fuse together, and as a result, the lower edge of the septum secundum will form the a­ nnulus ovalis and the septum primum will form the fossa ovalis (the depression below the annulus ovalis) (Fig. 1.7D).

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Section I  Embryology and Morphology of the Heart and Vessels

A

B

FIGURE 1.5  A. Posteroanterior view of a patient with dextrocardia and situs solitus. Note that the aortic arch and the stomach air bubble are both on the left (situs solitus), and the apex of the ventricles is pointing to the right inferiorly. B. Situs inversus chest x-ray. A 26-year-old female complains of chest pain. Her evaluation was negative except for situs inversus. A chest x-ray (CXR) shows a right-sided cardiac apex, aortic knob, gastric bubble. The angles of the mainstem bronchi suggest situs inversus. (Part A: Reproduced, with permission, from Fuster V, Harrington RA, Narula J, Eapen ZJ, eds. Hurst’s The Heart. 14th ed. New York: McGraw-Hill; 2017. Part B: Reproduced, with permission, from Knoop KJ, Stack LB, Storrow AB, Thurman RJ. The Atlas of Emergency Medicine. 3rd ed. New York: McGraw-Hill; 2010. Photo contributor: Katie Johnson, MD.)

Anomalies of the Interatrial Septum 1. Trilocular heart: This condition is caused by the failure of the interatrial septum (septum primum and septum secundum) to develop and thus the heart consists of only 3 chambers (2 ventricles and 1 atrium). 2. Persistent ostium primum (Fig. 1.8A): This is the most common form of atrial septal defects (ASDs), due to the failure of the septum primum to fuse with the septum intermedium, which prevents the ostium primum from closing. 3. Persistent ostium secundum (Fig. 1.8B): This condition is caused by the failure of the septum secundum to

PA

PA SI

PV

A

SI

PV

B

PV

C

FIGURE 1.6  Schematic depiction of the process of development of the atrioventricular canal. A. Formation of the ventral and dorsal endocardial cushions (arrows). B. The septum intermedium (SI) in the atrioventricular canal between the primitive atrium (PA) and the primitive ventricle (PV). C. The atrioventricular canal is divided into two halves.

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develop or by excessive destruction of the cephalic part of the septum primum. 4. Premature closure of foramen ovale: This leads to intrauterine death of the fetus since the blood does not reach the aorta to be distributed to different tissues of the fetus. 5. Patent foramen ovale (Fig. 1.8C): Failure of fusion between the septum primum and septum secundum causes this condition. There is an orifice between the right and left atria that allows a passage of blood from the right to the left when the pressure inside the right atrium is increased, as it would be during crying and exercise. Therefore, it is potentially cyanotic heart disease. 6. Septal aneurysm (Fig. 1.8D): This is caused by a redundancy in the septum primum, and may move back and forth across the foramen ovale.

Development of the Interventricular Septum Anatomically, the interventricular septum consists of a large muscular part and a small membranous part. The muscular part develops as a crescent ridge and arises from the endocardium of the floor of the primitive ventricle. The ridge increases in depth due to the force of the bloodstream on both of its sides. An interventricular foramen persists at the upper edge of the muscular part. The membranous part develops from the septum intermedium as well as the right and left bulbar ridges. This membranous part will close the interventricular foramen (Figs. 1.9A, B).

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Chapter 1  Development of the Heart and Blood Vessels

SP

SP FO

PV

PV

A

PV

C

B

D

FIGURE 1.7  Schematic depiction of the process of development of the interatrial septum. A. The septum primum (blue) is separated from the septum intermedium by the ostium primum (arrow). B. At the superior edge of the septum primum, clefts begin to form that provide a second opening, the ostium secundum (arrow). The ostium secundum provides an alternate right-to-left shunt, and the ostium primum closes. C. The septum secundum (green), begins to grow down from the roof of the right atrium, just lateral to the septum primum. The septum secundum permits the right-to-left shunt of blood through a space called the foramen ovale (arrow). D. After birth, when pulmonary circulation increases blood pressure in the left atrium, the membranous septum primum is pressed against the septum secundum. The 2 septa eventually fuse and block the right-to-left shunt of blood, and the lower edge of the septum secundum will form the annulus ovalis (green), and the septum primum will form the fossa ovalis (FO) (the depression below the annulus ovalis).

Ostium primum

Septum primum

RA

LA Endocardial cusion

A

Foramen ovale

Ostium secundum

RA

B

Septum secundum

RA

C

LA

Septal aneurysm

LA

RA

LA

D

FIGURE 1.8  The formation of the atrial septum and its abnormalities. A. Migration of the septum primum with the ostium primum in the lead. If the septum primum does not fuse with the endocardial cushions, a primum atrial septal defect (ASD) results. B. Once the septum primum fuses with the endocardial cushions, a hole or fenestration appears in the middle of the septum, the ostium secundum. C. The septum secundum then migrates along the right atrial (RA) side of the septum primum, normally covering the ostium secundum. If the septum secundum does not cover the hole, a secundum ASD results. The septum secundum generally completes its migration to the endocardial cushion, leaving a large ovale hole, the foramen ovale persisting. If the septi do not fuse after birth, a pathway referred to as a patent foramen ovale (PFO) persists between the RA and left atrium (LA). D. In some patients, there is redundancy in the septum primum, and it may move back and forth across the foramen ovale. This is referred to as an atrial septal aneurysm.

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Small cavities appear in the myocardium; they unite together to form larger cavities, separated from each other by ridges variable in size that project into the interior of the ventricle. These ridges will differentiate into trabecullae carnae, papillary muscles, and chorda tendineae.

MS

MS A

B

FIGURE 1.9  Schematic depiction of the process of development of the interventricular septum. A. Muscular interventricular septum (MS) begins to grow superiorly from the ventricular floor between the primitive right and left ventricles. This septum stops short of the atrioventricular canal, leaving a space called the interventricular foramen (white arrow), which permits blood from both ventricles to exit via the bulbus cordis. B. The membranous part (white arrow) develops from septum intermedium as well as the right and left bulbar ridges. The yellow arrows show the appearance of the papillary muscles as a result of the multiple small cavities that develop within the myocardium.

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Section I  Embryology and Morphology of the Heart and Vessels

subarterial), perimembranous (the inlet portion of the membranous septum), and malalignment (found in tetralogy of Fallot [TOF] with an overriding aorta) defects. b. Muscular VSDs, often multiple, may be located in the inlet or outlet regions or within the trabecular portion of the septum.

Supracristal Membranous AV canal type Muscular

FIGURE 1.10  Anatomic location of ventricular septal defects (VSDs).

Anomalies of the Interventricular Septum 1. Complete absence of the interventricular septum: This condition is caused by the failure of both the muscular and membranous part of the interventricular septum to develop. The heart consists of only 3 chambers; 3 atria and 1 ventricle. 2. Ventricular septal defect (VSD) (Fig. 1.10): This is classified anatomically according to the defects of both the membranous and muscular portions of the ventricular septum. a. Membranous VSDs can be subdivided into supracristal (also known as doubly committed

Development of Truncus Arteriosus and Bulbus Cordis (Outflow Tract) Pairs of opposing ridges appear in the region of the truncus arteriosus (truncal swelling) and conus cordis region (bulbar swelling) (Fig. 1.11). Neural crest cells also contribute to form these swellings. Two truncal swellings grow in opposite directions (the right superior one grows distally and to the left, and the left inferior one grows distally and to the right side), creating a spiral septum dividing the truncus arteriosus into aortic and pulmonary channels. Two bulbar swellings (right dorsal and left ventral) meet each other and form the bulbar septum, which divide the bulbus cordis into an outflow tract for the right ventricle (infundibulum) and the left ventricle (vestibule). They are also attached to the spiral septum and the membranous part of the IV septum.

Anomalies of Truncus Arteriosus and Bulbus Cordis 1. Transposition of the Great Arteries Transposition of the great arteries (TGA) occurs when the aortopulmonary septum fails to form a spiral course during partitioning of truncus arteriosus. The aorta arises from the right ventricle and the pulmonary artery originates from the left ventricle (Fig. 1.12). The TGA is divided into dextrolooped (d-TGA) and levo-looped (l-TGA). The looping

Ao

APS

PT

APS

AoS

SLV

TS CTS CC

CS Co

A

B

Myo C

FIGURE 1.11  Schematic diagram of some of the developmental events involved in the septation of the outflow tract. A. The stage at which the endocardial cushion tissues in the outflow tract (conal cushions and truncal swellings) and the aorticopulmonary septum have not yet fused. B. The truncal swellings contribute to the formation of the semilunar valves of the aorta (Ao) and pulmonary trunk (PT), whereas the fusing conal cushions (CCs) form the mesenchymal outlet septum. At this stage, the conal myocardium starts to myocardialize the outlet septum. C. One of the final stages. The aorticopulmonary septum (APS) has now completely separated the Ao and PT above the level of the semilunar valves, whereas below the valves, the outlet septum divides the outlet segment of the heart in a subaortic and subpulmonary outlet. AoS, aortic sac; CS, conal septum; CTS, conotruncal segment; Myo, myocardialization; SLV, semilunar valve; TS, truncal swelling. (Reproduced, with permission, from Fuster V, Walsh RA, Harrington RA, eds. Hurst’s The Heart. 13th ed. New York: McGraw-Hill; 2011.)

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Chapter 1  Development of the Heart and Blood Vessels

Posterior Anterior Aortic valve

Aorta

Pulmonary valve

Pulmonary artery

Left ventricle

9

refers to the right or left looping of the primitive heart tube during fetal development, which determines whether the atria and ventricles are concordant (the right atrium attaches to the right ventricle and the left atrium attaches to the left ventricle), or discordant. L-transposition of the great arteries is associated with atrioventricular discordance (the right atrium attaches to the left ventricle and the left atrium attaches to the right ventricle), and is also termed congenitally corrected TGA. L-transposition of the great arteries is a rare variant of TGA. The d-TGA can be subdivided into d-TGA with an intact ventricular septum (55%-60%) and d-TGA with VSD (40%-45%), one-third of which are hemodynamically insignificant. Pulmonic stenosis, causing significant left ventricular outflow tract obstruction, rarely occurs with an IVS and in approximately 10% of d-TGA/ VSDs.

2. Aortopulmonary Window

Pulmonary artery

Aortopulmonary window (APW) is a rare congenital lesion, occurring in about 0.2% of patients, characterized by incomplete development of the aortopulmonary septum. In the majority of cases, APW occurs as a single defect of minimal length, which begins a few millimeters above the semilunar valves on the left lateral wall of the aorta (Fig. 1.13). Coronary artery anomalies, such as an aberrant origin of the right or left coronary artery from the main primitive atrium (PA), are occasionally present.

Left ventricle

3. Persistent Truncus Arteriosus

Ventricular septum

Patent ductus Septal defect

Right ventricle

Aorta

FIGURE 1.12  Typical transposition of the great arteries. The aorta arises from the morphologic right ventricle and is anterior to and slightly to the right of the pulmonary artery, which originates from the morphologic left ventricle. Inset at the bottom illustrates the independent systemic and pulmonary circulations, which may be connected by a patent ductus arteriosus or atrial septal defect. Inset at the top illustrates a common relationship of the 2 great arteries in typical transposition. (Reproduced, with permission, from Doherty GM, ed. CURRENT: Diagnosis & Treatment: Surgery. 14th ed. New York: McGraw-Hill; 2015.)

A

B

This is a rare anomaly, comprising between 1% and 4% of all cases of congenital heart diseases. It is the result of failed development of the aortopulmonary septum and subpulmonary infundibulum (conal septum). Normal septation leads to the development of both pulmonary and systemic outflow tracts, division of the semilunar valves, and formation of the aorta and pulmonary arteries. Failure of septation results in a VSD (absence of the infundibular septum), a single semilunar valve, and a single arterial trunk. It is characterized by a single great artery that arises from the heart, overrides the ventricular

C

FIGURE 1.13  A-C. Classification of aortopulmonary window.

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Section I  Embryology and Morphology of the Heart and Vessels

Collett and Edwards

I

Van Praagh

A1

A2

III

A3

A4

FIGURE 1.14  There are similarities between the Collett and Edwards and the Van Praagh classifications of truncus arteriosus. Type I is the same as A1. Types II and III are grouped as a single type, A2, because they are not significantly distinct embryologically or therapeutically. Type A3 denotes the unilateral pulmonary artery with collateral supply to the contralateral lung (hemitruncus). Type A4 is the truncus associated with the interrupted aortic arch (13% of all cases of truncus arteriosus).

septum, and supplies the pulmonary, systemic, and coronary circulations. The two major classification systems are those of Van Praagh, described in 1965 and Collett and Edwards, described in 1949 (Fig. 1.14). The Van Praagh system is based on the presence or absence of a VSD, the degree of formation of the aorticopulmonary septum, and the status of the aortic arch; whereas the Collett and Edwards classification mainly focuses on the origin of the pulmonary arteries from the common arterial trunk, as follows: •• Type I: A common arterial trunk gives rise to a main pulmonary artery and the aorta. •• Type II: The right and left pulmonary arteries arise directly from and in close proximity to the posterior wall of the truncus.

Elmoselhi_CH01_p001-018.indd 10

4. Tetralogy of Fallot Tetralogy of Fallot (TOF) is caused by an unequal division of truncus arteriosus due to anterior displacement of the spiral septum (conal septum) toward the pulmonary trunk. This results in pulmonary stenosis with right ventricular hypertrophy, which results in widening of the aorta and originates from both the right and left ventricles and patent interventricular foramen (Fig. 1.15).

II

IV

•• Type III: The right and left pulmonary arteries arise from more widely separated orifices on the posterior truncal wall. •• Type IV: The branch pulmonary arteries are absent. Pulmonary blood flow is derived from aortopulmonary collaterals.

Development of the Conductive System of the Heart The specialized conduction system of the human heart is most likely derived from specialized cardiomyocytes of the primary heart field along the 4 intersegmental zones of the primitive heart tube: the sinoatrial (SA) ring between the sinus venosus and primitive atrium (which gives rise to the sinus node and part of the atrioventricular [AV] node), the AV ring between the primitive atrium and primitive left ventricle (which contributes to the AV node), the primary ring between the primitive left ventricle and the bulbus cordis (which gives rise to the His bundle and bundle branches), and the ventriculoarterial ring between the bulbus cordis and the truncus arteriosus. During cardiac looping, these rings come together at the inner curvature of the heart tube, and portions of these rings lose their specialized character (Fig. 1.16). There are also contributions from neural crest cells to both the venous and arterial poles and from epicardium-derived cells (second heart field), especially for peripheral Purkinje fiber development and annulus fibrosis formation.

Development of the Aortic Arches Aortic arch development involves the sequential development and then involution of 6 arch pairs, which arise from paired dorsal aortae that fuse distally (Fig. 1.17A, B). In mammals, the fifth aortic arch is rudimentary. By the 10-mm embryonic stage, the first 2 aortic arches have regressed; the third, fourth, and sixth are present; and the truncoaortic sac has been divided by the formation of the aorticopulmonary septum, so that the sixth arches are now continuous with the pulmonary trunk (Fig. 1.17C). In the 14-mm embryo, the dorsal aortae, between the third and fourth arches, have disappeared, and the third arches begin to elongate (Fig. 1.17D). The right sixth arch has disappeared, but the left sixth arch persists as the ductus arteriosus (DA). The recurrent laryngeal nerves hook around the sixth aortic arches on their way to the developing larynx and so on the right it hooks around the proximal part of the right subclavian artery (fourth arch) and around

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Chapter 1  Development of the Heart and Blood Vessels

Normal heart

Tetralogy of Fallot

Conal septum

A

B

FIGURE 1.15  Anatomy of tetralogy of Fallot (TOF). Note that in TOF, the conal septum is displaced anteriorly and to the right, resulting in a smaller pulmonary artery orifice and subpulmonic obstruction.

DA formed by the distal part of the sixth aortic arch on the left side. Finally, by the 17-mm embryo stage, the right dorsal aorta has become atrophic between its junction with the left dorsal aorta; the origin of the right seventh intersegmental artery has now become attenuated and later disappears (Fig. 1.17E). The remaining components of the right dorsal aorta and right fourth aortic arch form the proximal subclavian artery. The distal part of the left sixth aortic arch, the ductus arteriosus, normally closes within the first few hours following birth to

form the ligamentum arteriosum. The derivatives of the aortic arches are summarized in (Table 1.1). •• The aortic arch develops from the following: •• The truncoaortic sac, which will form the proximal part of the arch to the origin of the brachiocephalic artery. •• The left horn of the truncoaortic sac, which gives rise to the proximal part of the arch between the origin of brachiocephalic and left common carotid arteries.

SAR

AS PA SV

VAR

AVR

VOS VIS PR

FIGURE 1.16  Development of the specialized conduction system. Left. After initiation of normal rightward (“dextro”) looping of the early heart tube, rings at the transitional zones appear. Middle. During later development and early septation, these rings appear at the putative junctions between chambers—the sinoatrial ring (SAR; teal), atrioventricular ring (AVR; blue), primary ring at the bulboventricular foramen (PR; yellow), and ventriculoarterial ring (VAR; green). Right. Position of the rings in the developed heart. AS, aortic sac; PA, primitive atrium; SV, sinus venosus; VIS, ventricular inlet segment; VOS, ventricular outlet segment. (Adapted with permission from Jongbloed MR, Mahtab EA, Blom NA, et al. Development of the cardiac conduction system and the possible relation to predilection sites of arrhythmogenesis. Scientific World Journal. 2008;8:239-269.)

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Section I  Embryology and Morphology of the Heart and Vessels

III

Rt. aortic arch I

IV

II

VI Primitive pulmonary arteries

III

Rt. aortic arch I

IV VI

Rt. aortic arch II

Primitive pulmonary arteries

Rt. dorsal aorta

Dorsal aortae A

Rt. 7th intersegmental art.

B

Internal carotid arteries External carotid arteries Rt. carotid duct IV

External carotid art.

Common carotid arteries Rt. subclavian artery

Brachiocephalic trunk

Lt. carotid duct

Aortic arch Lt. vertebral art.

III VI Ductus arteriosus

Rt. pulmonary artery

C

Rt. subclavian artery

Ductus arteriosus

Rt. pulmonary art.

Lt. subclavian art. Pulmonary trunk

Lt. 7th intersegmental artery Pulmonary trunk D

Internal carotid arteries

E

F

FIGURE 1.17  Aortic arch development. In the 20-day human embryo (E8 in the mouse), the first pair of pharyngeal arteries (I) have formed and connect the arterial pole of the heart with the paired dorsal aortae (DA). In the 30-day human embryo (~E10 in the mouse), the first arch artery has degenerated, and II, III, and IV are present and connected to the dorsal aortae and to the arterial pole of the heart (not shown) through the aortic sac (AS). The paired dorsal aortae have fused caudally to the heart. By 40 days (~E11 in the mouse), the arteries of the first 2 arches have regressed and those of arches III to VI are present. The pulmonary arteries (PAs) start sprouting out from the VI arch arteries, which are the precursors of the pulmonary trunk. In the 6-week embryo (E12.5 in the mouse), the right VI pharyngeal artery and the right dorsal aorta are in regression, and the left VI pharyngeal artery degenerates. The left VI pharyngeal arch artery splits from the aortic trunk to form the pulmonary trunk, which remains connected as the ductus arteriosus to the left dorsal aorta. By 7 weeks, the definitive aortic arch has formed with derivatives of the pharyngeal artery III forming the left and right common carotids (LCC and RCC) and those of the IV pharyngeal arteries make small contributions to the right subclavian artery and aortic arch. The left and right subclavian arteries (LSA and RSA) have remodeled their position to become connected, respectively, to the aortic arch and the brachycephalic artery (BCA; derived from the aortic sac). The right dorsal aorta has degenerated at this stage. (Reproduced, with permission, from Fuster V, Harrington RA, Narula J, Eapen ZJ, eds. Hurst’s The Heart. 14th ed. New York, NY: McGraw-Hill; 2017.)

•• The left fourth aortic arch, which gives rise to the part of the arch between the origin of left common carotid and left subclavian artery. •• The left dorsal aorta between the fourth and sixth aortic arches, which will give rise to the distal part of the arch of the aorta. •• The brachiocephalic artery develops from the right horn of the truncoaortic sac. •• The right and left internal carotid arteries develop from the distal portion of the third aortic arch and the dorsal aorta cranial to the third aortic arch.

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•• The left subclavian artery develops from the left seventh intersegmental artery and left dorsal aorta opposite the left seventh intersegmental artery. •• The right subclavian artery develops from the right fourth aortic arch, right seventh intersegmental artery, and right dorsal aorta opposite the right seventh intersegmental artery.

Anomalies of the Aortic Arch Arteries Most aortic arch anomalies are secondary to abnormal retention or disappearance of various embryonic vascular segments.

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Chapter 1  Development of the Heart and Blood Vessels

Table 1.1  Derivatives of aortic arch vessels Part

Derivatives

First aortic arch

In both sides: disappear and the remaining part forms the maxillary artery

Second aortic arch

In both sides: disappear and the remaining part forms the stapedial artery

Third aortic arch

In both sides: Proximal part—common carotid artery Distal part—internal carotid artery

Fourth aortic arch

Right artery: right subclavian artery Left artery: arch of the aorta

Fifth aortic arch

In both sides: disappear

Sixth aortic arch

Right artery/Proximal part: right pulmonary artery Distal part: disappear Left artery/Proximal part: left pulmonary artery Distal part: ductus arteriosus

Truncoaortic sac and left horn

Arch of the aorta

Right horn

Brachiocephalic artery

Dorsal aorta

Right: internal carotid artery cranial to the third arch The rest: disappear Left: internal carotid artery cranial to the third arch Arch of aorta between the fourth and sixth arch Descending aorta distal to the sixth arch

1. Patent ductus arteriosus (PDA): This is one of the most frequently seen abnormalities of the great vessels in which there is a patent duct between the left pulmonary artery and the arch of the aorta distal to its branches. It is potentially cyanotic heart disease, more common in females than in males and may be accompanied by other congenital heart disease, such as aortic stenosis, pulmonary stenosis, and Fallot’s tetralogy. An anatomic variant of the PDA is the aortopulmonary window (Fig. 1.18), which is usually a relatively large communication between the ascending aorta and the main pulmonary artery. 2. Double aortic arch: This develops when there is a failure of the distal part of the right dorsal aorta to disappear. A vascular ring around the trachea and esophagus with varying degrees of compression of these structures may occur (Fig. 1.19). The left arch of the aorta will give origin to the brachiocephalic artery, which is continuous as the right common carotid, left common carotid artery, and left subclavian artery. The right arch of the aorta will give origin to the right subclavian artery. 3. Abnormal origin of the right subclavian artery (aberrant right subclavian artery): The right fourth

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aortic arch and the proximal part of the right dorsal aorta have been obliterated. The right subclavian artery is formed from the right seventh intersegmental artery and the distal part of the right dorsal aorta. The branches of the arch of aorta from right to left are the brachiocephalic artery, which is continuous as the right common carotid artery, left common carotid, left subclavian artery, and right subclavian artery.

Patent ductus arteriosus

Type III

Type II Type I

A

B

FIGURE 1.18  Anatomic locations of patent ductus arteriosus (A) and aortopulmonary window (B), with multiple distinct anatomic locations possible.

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Section I  Embryology and Morphology of the Heart and Vessels

FIGURE 1.19  Anterior (left) and posterior (right) views of the double aortic arch constricting the trachea and esophagus. (Reproduced, with permission, from Doherty GM, ed. CURRENT: Diagnosis & Treatment: Surgery. 14th ed. New York: McGraw-Hill; 2015.)

The right subclavian artery crosses the middle line (Fig. 1.20) to reach the right upper limb anterior to the esophagus and trachea, and compresses them. The right recurrent laryngeal nerve does not hook around the right subclavian artery, but passes directly to the larynx and supplies it. A transverse compression band in the esophagram suggests the diagnosis. 4. Interrupted aortic arch (IAA): It is a rare defect, comprising approximately 1% of all cases of congenital heart disease results from obliteration of the fourth aortic arch on both sides. There is absence of luminal continuity between the ascending and descending aortae. It does not occur as an isolated defect in most cases, as a VSD or PDA is usually present. The IAA is classified based on the location of the interruption (Fig. 1.21). 5. Coarctation of the aorta: It is a constriction of the aorta distal to the origin of the left subclavian artery.

Coarctation occurs in about 10% of congenital heart diseases. There are 2 types of coarctation: a. Preductal (Fig. 1.22A): Where the coarctation is proximal to the entrance of ductus arteriosus. The ductus arteriosus is persistently open, if closed, it is incompatible with life. b. Postductal (Fig. 1.22B): Where the coarctation of the aorta is distal to the entrance of the ductus arteriosus. This permits development of collateral circulation during the fetal period and the ductus arteriosus is usually obliterated. 6. Persistent ductus caroticus: The ductus caroticus is the portion of the embryonic dorsal aorta between third and fourth arch arteries that normally disappears early in development. Its persistence results when the internal carotid arteries develop from the distal part of the third aortic arch artery and the dorsal aorta between the third and fourth aortic arch arteries. Thus, the left internal carotid artery originates directly from the arch of aorta and the right internal carotid artery originates from the right subclavian artery. 7. Right arch of the aorta: The entire right dorsal aorta persists and the distal part of the left dorsal aorta involutes. So the right arch of the aorta is developed from the aortic sac, the right horn of the aortic sac, and the right fourth aortic arch artery. The brachiocephalic artery, right common carotid artery, and right subclavian artery are the branches of the right arch of aorta left to right. It may pass anterior to the trachea and esophagus causing dyspnea and dysphagia, respectively.

Development of Veins In the fifth week, 3 systems of veins can be recognized: the umbilical venous system, which disappears after birth; the vitelline system, which develops into the portal system; and the cardinal system, which forms the caval system.

Right common carotid artery

Left common carotid artery

Right vertebral artery

Left vertebral artery

Right subclavian artery

Left subclavian artery Aberrant right subclavian artery

Aorta Trachea

Esophagus

FIGURE. 1.20  Aberrant right subclavian artery. The right subclavian artery arises in the descending aorta, distal to the origin of the left subclavian artery. It crosses the midline either behind the esophagus, between the esophagus and the trachea, or anterior to the trachea.

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Chapter 1  Development of the Heart and Blood Vessels

IA

LC

RPA

Ao

IA

LS

LC

IA

PDA LS

PDA LC LS

LPA MPA

A

C

B

FIGURE 1.21  Anatomic types of an interrupted aortic arch. A. Interruption distal to the left subclavian artery. B. Interruption between the left subclavian and left carotid arteries. C. Interruption between the left carotid and innominate arteries. Ao, aorta; IA, innominate artery; LPA, MPA, RPA, left, main, and right pulmonary arteries; LC, left carotid artery; LS, left subclavian artery; PDA, patent ductus arteriosus. (Reproduced, with permission, from Jonas RA. Interrupted aortic arch. In: Mavroudis C, Backer CL, eds. Pediatric Cardiac Surgery. 2nd ed. St. Louis, MO: Mosby; 1994:184.)

Developmental Changes in the Sinus Venosus Sinus venosus is a dilatation of the primitive atrium, which receives the veins of the body, intestine, and placenta. At an early stage (Fig. 1.23A), the sinus venosus is composed of the body (the central part) and right and left horns. Each horn receives a vitelline vein that carries unoxygenated blood from the yolk sac, the umbilical vein that carries oxygenated blood from the placenta, and the common cardinal vein that is formed by the union of the anterior and posterior cardinal veins and carries unoxygenated blood from the body wall. As a result of development of the liver on the right side and the presence of transverse anastomoses between the left and right cardinal veins, the blood is shifted to the right side and so the blood that reaches the right horn becomes more than that of left horn. This leads to an increase in the size of the right horn, while the left horn becomes reduced in size and the sinoatrial orifice, at first, lies transversely, then becomes vertical and guarded by 2 valves (the right and left venous valves) (Fig. 1.23B).

Preductal coarctation

A

Postductal coarctation

B

FIGURE 1.22  Anatomic features of aortic coarctation. A. Preductal coarctation, in which differential cyanosis may occur. B. Postductal coarctation.

Elmoselhi_CH01_p001-018.indd 15

15

Fate of Sinus Venosus 1. The right horn is enlarged and absorbed into the right atrium to form the smooth posterior part of the right atrium. 2. The left horn is reduced in size to form the oblique vein of left atrium. 3. The body becomes reduced in size to form the coronary sinus. 4. The sinoatrial valves (Fig. 1.23C): a. The upper ends of right and left venous valves unite to form the septum spurium. b. The left sinoatrial venous valve will be absorbed into the interatrial septum. c. The right sinoatrial venous valve derivatives: i. The upper one-third with septum spurium gives rise to crista terminalis. ii. The middle one-third gives rise to the valve of IVC. iii. The lower one-third gives rise to the valve of coronary sinus.

Fetal Circulation (Fig. 1.24) During fetal life, the oxygenated blood coming from the placenta is carried via the left umbilical vein to the left branch of the portal vein. Part of this blood is carried via the ductus venosus to the inferior vena cava while the other part enters the liver by means of the portal vein and leaves it by means of the hepatic veins to the inferior vena cava. The blood passes from the inferior vena cava to the right atrium. The greater part of this blood passes through the foramen ovale, the left atrium, where it is mixed with a small amount of venous blood coming from the lungs through the pulmonary veins. This mixture, still of high oxygen content, passes to the left ventricle and then to the aorta. Most of the blood supplies the heart itself, the head and neck, the brain, and the upper limbs. The smaller portion of the blood reaches the right atrium via the inferior vena cava together with the deoxygenated blood returning from the upper part of the body via the superior vena cava, entering the right ventricle and then into the pulmonary trunk. Since the lungs of the fetus are not functioning, a small amount of this blood enters the pulmonary vascular bed while most of the blood passes through the ductus arteriosus into the descending aorta to join the blood coming to this part of the aorta from the left ventricle. It supplies the lower limbs, the trunk, and the viscera. Most of the blood is returned back to the placenta by means of 2 umbilical arteries.

Changes in Fetal Circulation at Birth The placental circulation stops and as a result, the left umbilical vein becomes obliterated and forms the ligamentum teres of the liver, the ductus venosus becomes obliterated and forms the ligamentum venosum of the liver and the umbilical

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Section I  Embryology and Morphology of the Heart and Vessels

Anterior cardinal vein

Anterior cardinal vein

Right common cardinal vein

S.A.O.

Right horn

Posterior cardinal vein

Left common cardinal vein

Sinus venosus

Left horn

Body

Right vetilline vein

Left vetilline vein

Right umbilical vein

Posterior cardinal vein

Left umbilical vein

A Anterior cardinal vein

Anterior cardinal vein

Right common cardinal vein

Left common cardinal vein

Sinus venous

i

ii

a

b

Right horn

S.A.O. Body

Left horn

c C

Posterior cardinal vein

Right vetilline vein Right umbilical vein

Left vetilline Posterior vein cardinal vein Left umbilical vein

B

FIGURE 1.23  Schematic illustration of the process of development of sinus venosus. A. The sinus venosus is formed of central part (body), right horn and left horns. Each horn receives 2 vitelline veins, 2 umbilical veins, and 2 common cardinal veins which are formed by the union of the anterior and posterior cardinal veins. The sino atrial orifice (SAO) is lying horizontally. B. The enlargement of the right horn at the expense of left horn and central part. The sinoatrial orifice, becomes vertical. C. Derivatives of the valves guarding the sinoatrial orifice. The upper ends of the right and left venous valves unite to form the septum spurium. The left sinoatrial venous valve will be absorbed into the interatrial septum. The upper third of the right sinoatrial venous valve with septum derivatives gives rise to crista terminalis. The middle one-third gives rise to the valve of IVC, and the lower one-third gives rise to valve of the coronary sinus.

arteries become obliterated and form the lateral umbilical ligaments. Pulmonary circulation starts due to the immediate functional closure of the ductus arteriosus and the foramen ovale. Their anatomical closure is usually not complete until

Elmoselhi_CH01_p001-018.indd 16

3 months after birth. As a result, the ductus arteriosus becomes obliterated and forms the ligamentum arteriosum, the foramen ovale becomes obliterated forming the fossa ovalis from the septum primum and the annulus ovalis from the edge of the septum secundum.

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Chapter 1  Development of the Heart and Blood Vessels

Left aterium Superior vena cava

17

Ductus arteriosus

Foramen ovale

Right atrium

Pulmonary artery

Right ventricle

Left ventricle

Ductus venosus

Inferior vena cava Aorta

Portal vein

Umbilical arteries

Umbilical vein From placenta To placenta

FIGURE 1.24  Circulation in the fetus. Most of the oxygenated blood reaching the heart via the umbilical vein and inferior vena cava is diverted through the foramen ovale and pumped out the aorta to the head; while the deoxygenated blood returned via the superior vena cava is mostly pumped through the pulmonary artery and ductus arteriosus to the feet and the umbilical arteries. (Reproduced, with permission, from Barrett KE, Barman SM, Boitano S, Brooks HL. Ganong’s Review of Medical Physiology. 25th ed. New York: McGraw-Hill; 2016.)

Key Points •• Blood vessels are formed in two ways: vasculogenesis and angiogenesis. •• The heart is the first organ to form during embyogenesis. •• The looping process of the developing heart and the internal septation will form the 4-chambered heart.

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•• The human arterial system originates from the aortic arches and the dorsal aortae are initially bilateral and then fuse to form the definitive dorsal aorta. •• The veins of the body are developed from the sinus venosus. •• Congenital heart disease defects are related to cardiovascular system (CVS) embryonic defects.

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Section I  Embryology and Morphology of the Heart and Vessels

CASE STUDIES CASE 1.1  A mother brings her 6-year-old child to the emergency room with the complaint that his lips turn blue after exertion. The mother reveals that the child often assumes a squatting position when his lips are bluish. Investigations reveal a boot-shaped heart, indicative of right ventricular hypertrophy. Which of the following is the most likely congenital defect of this infant? a. Narrowing of the aorta distal to the ductus arteriosus b. Failure of closure of the ductus arteriosus c. Failure of closure of the foramen secundum d. Anterior and superior displacement of the aorticopulmonary septum e. Deviation of the septum intermedium to the left side

CASE 1.2  A 38-year-old male patient suffering from pulmonary hypertension has been diagnosed with ostium secundum atrial septal defect. Abnormal development of which of the following structures is responsible for this developmental defect?

a. Aorticopulmonary septum b. Endocardial cushion c. Interventricular septum d. Septum primum e. Sinus venosus

CASE 1.3  During the first 5 to 7 days of life, the umbilical vein can be catherized and used for central venous pressure monitoring. The umbilical vein leads to which of the following vessels? a. ductus venosus b. inferior vena cava c. descending aorta d. ductus arteriosus e. portal vein

Suggested Readings Moore KL, Persaud TVN, Torchia MG. Before We Are Born: Essentials of Embryology and Birth Defects. 7th ed. ­Philadelphia: Saunders/Elsevier; 2008.

Sadler TW, Langman J. Langman’s Medical Embryology 11th ed. Philadelphia: Wolters Kluwer Lippincott Williams & Wilkins; 2010.

Moore KL, Persaud TVN, Torchia MG. The Developing Human: Clinically Oriented Embryology. 9th ed. Philadelphia: ­Saunders; 2011.

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Chapter Anatomical Structure of the Heart AKRAM JAFFAR

Introduction Knowing the anatomical structure of the heart is essential for understanding its function, performing clinical examination, and interpreting radiological findings. The heart consists of 4 chambers: 2 atria (ie, the right atrium and the left atrium) and 2 ventricles (ie, the right ventricle and the left ventricle). Furthermore, the heart contains 4 valves: 2 atrioventricular valves between each atrium and ventricle (ie, the tricuspid valve in the right side and the mitral valve in the left), as well as the pulmonary and aortic valves that originate from the right and the left ventricles, respectively. The heart is located behind the sternum; however, it normally lies “down” with the apex pointing toward the left side. This chapter provides a succinct overview of the gross anatomy of the heart and its blood vessels as well as some clinical aspects pertinent to its structure.

The Pericardium The pericardium is a fibroserous sac that encloses the heart and the roots of the great vessels (Fig. 2.1A, B).

Layers of the Pericardium Fibrous Pericardium The fibrous pericardium is a strong outer layer that fuses with the walls of the great vessels superiorly and with the central tendon of the diaphragm inferiorly. The pericardium is anteriorly attached to the sternum by weak sternopericardial ligaments.

Serous Pericardium The serous pericardium is enclosed within the fibrous pericardium. Like other serous membranes (eg, pleura, peritoneum), the serous pericardium itself consists of parietal and visceral layers which are continuous with each other. The parietal layer of the serous pericardium lines and is firmly adhered to the fibrous pericardium. There is no space in between the parietal layer and the fibrous layer. However, the parietal layer is folded to become continuous with the visceral layer around the root of the great vessels.

Learning Objectives

2

By the end of this chapter the student will be able to: • Describe the pericardium and its sinuses. • Outline the anatomical basis of clinical examination of the heart. • Examine the internal features of the heart chambers. • Explain the functional anatomy of the heart valves. • Highlight the conducting system of the heart. • Outline the course of the coronary arteries and the cardiac veins. • Map the area of supply of the coronary arteries. • Explain the anatomical basis of referral of cardiac ischemic pain. • Summarize the microscopic anatomy of the heart.

The visceral layer of the pericardium covers and is closely attached to the heart. Thus, it is considered to be the outer layer of the heart and is also called the epicardium.

Pericardial Cavity The pericardial cavity is the potential space between the parietal and visceral layers of the serous pericardium. It contains a thin film of fluid that enables the heart to move and beat in a frictionless environment. Normally, the smooth opposing layers of the serous pericardium make no detectable sound during auscultation; however, in pericarditis an abnormal pericardial friction rub is heard.

Sinuses of the Pericardium The heart first appears, during development, as a tube lying in the pericardial cavity. With the elongation and bending of the heart tube, 2 pericardial sinuses form—the transverse and oblique sinuses. The transverse sinus is located in such a position so that a finger placed in this sinus passes in front of the superior vena cava and behind the aorta and pulmonary trunk. The surgical significance of the transverse pericardial sinus is the position of the transverse sinus, where a ligature can be passed through the transverse sinus to occlude the arterial hilum of the heart (the aorta and the pulmonary trunk) during cardiac operations to stop or divert circulation. 19

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Section I  Embryology and Morphology of the Heart and Vessels

Trachea

Left phrenic n.

Superior vena cava Right phrenic n.

Fibrous layer of the parietal pericardium Serous layer of the parietal pericardium Pericardial space Myocardium Endocardium Diaphragm

Epicardium

Pericardium (cut)

B

A

Superior border

Posterior surface (base) Anterior (sternocostal) surface

Right border

Right border

Left border

C

D Apex

Inferior border

Inferior (diaphragmatic) surface

Inferior border

Atrioventricular groove Anterior interventricular groove E

F Inferior (diaphragmatic) surface

Posterior interventricular groove

Inferior (diaphragmatic) surface

FIGURE 2.1  A. Coronary section through the thorax. B. Layers of the pericardial sac. C. Anterior (sternocostal) surface of the heart. D. Posterior (base) and inferior (diaphragmatic) surface of the heart. E. Coronary grooves (anterior view). F. Coronary grooves (posterior view). (Reproduced, with permission, from Morton DA, Foreman KB, Albertine KH. The Big Picture: Gross Anatomy. New York, NY: McGraw-Hill; 2011.)

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Chapter 2  Anatomical Structure of the Heart

The oblique sinus is located behind the heart. It lies between the right and left pulmonary veins and the inferior vena cava. The anterior wall of the oblique sinus is formed by the posterior wall of the left atrium between the 4 pulmonary veins. The posterior wall is related to the esophagus. The oblique sinus may be entered inferiorly; however, a finger passed into it cannot pass around any of its bordering vessels. In other words, it is a blind-end space (cul-de-sac).

Nerve Supply of the Pericardium In all serous membranes, the parietal layer has a somatic innervation while the visceral layer an autonomic innervation. Thus, the fibrous pericardium and the parietal layer of the serous pericardium are innervated by the phrenic nerve (somatic nerve). Hence, the pericardial sac can be a source of pain as in pericarditis. The visceral layer, considered to be part of the heart, is innervated by the autonomic nervous system. The vagus nerve provides parasympathetic innervations while the sympathetic nerves provide the sympathetic innervations.

▶ ▶  C L I N I C A L C O R R E L A T I O N 2 . 1 •  Pericardial effusion is the accumulation of fluid within the pericardial sac, that is, between the visceral and parietal serous layers of the pericardium. •  Cardiac (pericardial) tamponade is the acute accumulation of fluid, usually blood within the pericardial cavity. Eventually, the increased pressure within the pericardium stops the heart if the tamponade is not relieved by a pericardial puncture. •  Pericardiocentesis (pericardial puncture) is a technique used to obtain fluid from the pericardial cavity, where the needle is inserted just below the xiphisternum in the left costoxiphoid angle. During this procedure, care should be taken to avoid the superior epigastric vessels. The needle can also pass through the fourth and fifth left intercostal spaces close to the sternum, where the heart and pericardium are not covered by pleura.

Orientation, Surfaces, and Borders of the Heart From a physiologist’s point of view, the heart consists of 2 atria on top with the 2 ventricles below them. Anatomically, the heart is oriented so that the “physiologist’s heart” lays on its right side and then rotates in a clockwise direction.

Surfaces of the Heart There are 3 surfaces of the heart: anterior, inferior, and posterior (base) (Fig. 2.1C-E). The anterior surface is also called the sternocostal surface because it lies behind the sternum, costal cartilages, and ribs. The anterior surface is formed by the right

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21

atrium, right ventricle, a narrow strip of the left ventricle, and a small part of the left atrium (the left auricular appendage). The area occupied by the ventricles on the anterior surface is formed of approximately two-thirds of the right ventricle and one-third of the left ventricle. The ventricles are separated by an anterior interventricular groove on the anterior surface. This proportion of the ventricular areas is reversed on the diaphragmatic surface. The inferior surface is related to the diaphragm, thus it is also called the diaphragmatic surface. It is formed by the right atrium receiving the inferior vena cava and both the ventricles. The ventricular area is mainly formed by the left ventricle in contrast to the anterior surface. The ventricles on the diaphragmatic surface are separated by the posterior interventricular groove. The left atrium lies at a higher level than the remaining 3 chambers that form the diaphragmatic surface; thus, the left atrium does not reach this surface or participate in its formation. The posterior surface is also called the base of the heart. The term “base” is derived from the cone shape of the heart in which the base is opposite to the apex. Consequently, the base should not be confused with the diaphragmatic surface. In the anatomical position, the heart rests on its diaphragmatic surface and not on its base. The base of the heart consists almost entirely of the left atrium receiving the 4 pulmonary veins.

Borders of the Heart (Fig. 2.2A) The heart has 4 borders. The right border is formed by the right atrium. The inferior border is formed by the right ventricle and a slight portion of the left ventricle. The left ventricle also forms the apex of the heart. The left border is formed by the left ventricle and a slight portion of the left auricle. The superior border is formed by both the left and right atria.

Normal Variations in the Position of the Heart The position of the heart normally varies with age, sex, body size (physique), respiration, and position of the body. The heart in a child is larger, higher, and more transversely placed than in an adult. During inspiration, the heart is lower, narrower, and longer than in expiration. In the recumbent position, the heart is higher than when standing.

Surface Anatomy of the Heart The outline of the heart (precordium) can be traced using the following guidelines and line indicators or markers (Fig. 2.3): •• The superior border is traced from the inferior margin of the second left costal cartilage (3 cm to the left of the median plane) to the superior border of the third right costal cartilage (2 cm from the median plane). •• The right border can be traced from the last mentioned point to the sixth right costal cartilage (2 cm from the median plane).

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Section I  Embryology and Morphology of the Heart and Vessels

A

Aorta Ligamentum arteriosum

Superior vena cava

Left pulmonary artery Pulmonary trunk

Right atrial appendage

Left atrial appendage

Right atrium Left anterior descending coronary artery in interventricular groove

Right coronary artery in atrioventricular groove (coronary sulcus)

Left ventricle Right ventricle

Apex

B Aorta

Superior vena cava

Right atrial appendage

Right pulmonary artery

Pulmonary trunk

Pulmonary veins Right ventricle Fossa ovalis

Tricuspid valve

Orifice of coronary sinus Inferior vena cava

C

Aorta Pericardial reflection

Superior vena cava

Right atrial appendage Right atrium Parietal band Papillary muscle of the conus Tricuspid valve Inferior vena cava

Pulmonary trunk Left atrial appendage Pulmonary valve Infundibulum Cristal supraventricularis Septal band Left ventricle Moderator band

FIGURE 2.2  Anatomy of the heart. A. Anterior view of the heart. B. View of the right heart with the right atrial wall reflected to show the right atrium. C. Anterior view of the heart with the anterior wall removed to show the right ventricular cavity. (Continued)

Elmoselhi_CH02_p019-032.indd 22

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Chapter 2  Anatomical Structure of the Heart

Aorta

D

Pulmonary trunk Left atrial appendage

Anterolateral papillary muscles Chordae tendineae

Pulmonary veins Mitral valve

Left ventricle

Left atrium Coronary sinus Inferior vena cava

Posteromedial papillary muscles E

Pulmonary trunk Aorta Left atrial appendage Fossa ovalis Aortic valve Pulmonary veins

Left ventricle

Left atrium Inferior vena cava

Trabeculae carneae Coronary sinus

FIGURE 2.2  (Continued)  D. View of the left heart with the left ventricular wall turned back to show the mitral valve. E. View of the left heart from the left side with the left ventricular free wall and mitral valve cut away to reveal the aortic valve. (Reproduced, with permission, from Hammer GD, McPhee SJ. Pathophysiology of Disease: An Introduction to Clinical Medicine. 7th ed. New York, NY: McGraw-Hill; 2014.)

•• The inferior border is traced from the last mentioned point to a point in the fifth intercostal space close to the midclavicular line. •• The left border connects the left end of the lines representing the superior and inferior borders.

▶ ▶  C L I N I C A L C O R R E L A T I O N 2 . 2 •  Surface anatomy of the apex beat: The apex beat is where the heartbeat can be most easily palpated furthest downward and to the left. It is made by the part of the heart that is not covered by the left lung. Therefore, it is medial to the actual apex of the heart. Thus, the apex beat lies in the fifth intercostal space just medial to the midclavicular line or just medial to the nipple. The use of the nipple as a landmark is not a reliable guide to the position of the apex beat, especially in mature females due to the variation in the size and pendulousness of the breast.

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•  Surface anatomy of the heart valves and the auscultatory areas (Fig. 2.3): The heart valves are grouped behind the sternum, but this anatomical location is not of clinical interest. The sounds produced by these valves are best heard (auscultated) on the chest wall at sites other than the anatomical location. When listening to the valves at their anatomical locations, it is not possible to clearly distinguish the sounds produced at the individual valves. The auscultatory areas (Table 2.1) are a wide distance apart and differ from the surface projection of the heart valves. Because blood tends to carry the sound in the direction of its flow, each area is situated superficial to the chamber or vessel through which the blood has passed.

The Inside of the Heart Right Atrium (Fig. 2.2B) The right atrium lies between the superior and inferior venae cavae along the right border of the heart. The lower end is

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Section I  Embryology and Morphology of the Heart and Vessels

terminalis, descends. It is produced, when present, by the projection into the cavity of the right atrium of a vertical ridge of heart muscle called the crista terminalis. The interior of the right atrium is smooth to the right of the crista terminalis; however, the inside of the auricle is rough because of the projection of horizontal ridges called the musculi pectinati. The interatrial septum forms the posterior wall of the right atrium. The foramen ovale of the fetal heart is represented by a depression, the fossa ovalis, on the interatrial septum. The crescentic upper margin of the fossa ovalis is called the annulus ovalis (limbus of fossa ovalis). The opening of the superior vena cava is valveless. The opening of the inferior vena cava is guarded by a small valve that was large prenatally in order to direct blood from the inferior vena cava toward the foramen ovale. The opening of the coronary sinus lies near the septal cusp of the tricuspid valve. It is guarded by a valve that prevents regurgitation into the sinus during atrial contraction. A triangular zone (the triangle of Koch) exists between the base of the tricuspid valve’s septal cusp, the margin of the coronary sinus orifice, and the valve of the inferior vena cava. The triangle is the site of the atrioventricular (AV) node.

Right Ventricle (Fig. 2.2C)

FIGURE 2.3  Trace of the outline of the heart and surface anatomy of the auscultatory areas. A, aortic valve; M, mitral valve; P, pulmonary valve; T, tricuspid valve.

occupied by the orifice for the inferior vena cava, while the upper end is prolonged to the left of the superior vena cava as the auricular appendage. The right auricle overlies the commencement of the aorta and the upper part of the right atrioventricular groove and, with the left auricle, it clasps the infundibulum of the right ventricle. From the angle between the superior vena cava and the right auricular appendage, a shallow groove, the sulcus

Table 2.1  Auscultatory areas of the heart valves Valve

Auscultatory area

Mitral

Left fifth intercostal space just medial to the midclavicular line

Tricuspid

Inferior end of the body of the sternum

Aortic

Right second intercostal space at the edge of the sternum

Pulmonary

Left second intercostal space at the edge of the sternum

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The wall of the right ventricle is thicker than the wall of the atrium, and the inside is made rough by the presence of the trabeculae carneae. The trabeculated walls of the inflow tract within the right ventricle may assist in slowing the entry of blood during early diastole. Also, contraction of the trabeculated walls increases the efficiency of ventricular emptying. The right atrioventricular orifice is guarded by the tricuspid valve which has 3 cusps and admits the tips of 3 fingers. The 3 cusps are arranged to lie against the 3 walls of the ventricle, septal, inferior, and anterior. The cusps of the tricuspid valve receive the attachment of inelastic cords (the chordae tendineae). The chordae tendineae diverge from small conical elevations of muscle (papillary muscles) that project into the cavity from the trabeculae carneae. There are usually 3 papillary muscles in the right ventricle that correspond to the cusps of the tricuspid valve. The papillary muscles contract prior to contraction of the ventricle, resulting in tightening of the chordae tendineae and drawing the cusps of the tricuspid valve together, to prevent ventricular blood from passing back into the right atrium at the time of ventricular contraction. The chordae tendineae thus prevent eversion of the cusps into the atrium as ventricular pressure rises (Table 2.2). The interventricular septum bulges into the cavity of the right ventricle causing the inferior wall to be narrower in comparison to the anterior and septal walls; similarly, the inferior cusp of the tricuspid valve is the narrowest of the 3 cusps. In a cross section, the right ventricle is crescentic, while the left ventricle is circular as a result of this bulging. The trabecula septomarginalis (moderator band) represents a muscular ridge that has broken free and lies in the

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Chapter 2  Anatomical Structure of the Heart

cavity, which is attached by its 2 ends to the interventricular septum and to the anterior wall of the ventricle (the base of the anterior papillary muscle). The trabecula transmits part of the right bundle of the conducting system of the heart. The infundibulum is the funnel-shaped upward narrowing part of the right ventricle as it approaches the pulmonary orifice. The walls of the infundibulum are thin and smooth because of the lack of trabeculae carneae. The smooth walls in the outflow tract increase the velocity of ejection. The supraventricular crest is a thick muscular arch between the tricuspid and pulmonary orifices curving from the interventricular septum to the anterior wall. It separates the ridged muscular wall of the inflow part of the chamber from the smooth wall of the outflow part.

Left Ventricle (Fig. 2.2D) The walls of the left ventricle are 3 times as thick as those of the right ventricle because the blood pressure in the pulmonary circulation is less than in the systemic circulation, 25 mmHg compared to 120 mmHg, respectively. The interventricular septum is equal in thickness to the left ventricle and bulges into the cavity of the right ventricle. The interventricular septum lies almost in the coronal plane so that the right ventricle lies in front of it and the cavity of the left ventricle lies behind it. It is marked on the surface of the heart by the interventricular branches of the right and left coronary arteries. The trabeculae carneae are well developed and their entire length is attached to the ventricular walls; thus, there is no moderator band. There are 2 papillary muscles (­anterior and posterior) projected into the cavity of the ventricle that send the chordae tendineae from their apices to the mitral cusps. The bicuspid (mitral) valve has 2 cusps: a large anterior (septal) cusp and a small posterior cusp. Usually, the attachment of the 2 cusps is continuous around the orifice, but sometimes they fail to meet and a small accessory cusp fills the gap between them. The anterior cusp lies between the mitral and aortic orifices. The mitral cusps are smaller in area and thicker than those of the tricuspid valve, and consequently do not balloon back as much into the atrium during ventricular systole. The septal (anterior) cusp of the mitral valve is thicker and more rigid than the posterior cusp (Table 2.2). The upper end of the septal wall is smooth, thin, and more fibrous constituting the membranous part of the interventricular septum. The aortic vestibule is located between the membranous septum and the anterior cusp of the mitral valve, which leads up into the aortic orifice.

Left Atrium (Fig. 2.2E) The left atrium is located behind the right atrium; its inferior margin lies a little above that of the right atrium; here, the posterior wall receives the coronary sinus. The wall of the left atrium is slightly thicker than that of the right atrium. The left atrium cavity has 2 parts: a larger

Elmoselhi_CH02_p019-032.indd 25

smooth-walled part and a smaller muscular auricular part containing pectinate muscles. Similar to the right atrium, the left atrium has a small auricular appendage that overlaps the left side of the infundibulum. The left atrium receives 2 pairs of pulmonary veins. The left atrioventricular orifice is guarded by the bicuspid (mitral) valve which has 2 cusps and admits 2 fingers.

Aortic and Pulmonary (Semilunar) Valves (Figs. 2.2C, E and Fig. 2.6C) Both the aortic and pulmonary valves are guarded by 3 semilunar cusps. In the “A”orta, one cusp is “A”nterior while in the “P”ulmonary trunk, one cusp is “P”osterior. In addition, the aorta has left posterior and right posterior cusps, while the pulmonary has left anterior and right anterior cusps. The cusps are cup-shaped and project into the artery, close to its walls, as blood leaves the ventricle. Opposite each valve, the wall of the artery dilates slightly to form a sinus. The blood in these sinuses prevents the cusps from sticking to the wall of the artery and failing to shut. Following the relaxation of the ventricle, the elastic wall of the artery forces the blood back toward the heart. This backflow of blood opens up and fills the cusps like pockets and closes the orifice; thus preventing blood from returning to the ventricle. The competence of the semilunar valves is therefore a passive phenomenon. The free edge of each cusp is thickened, forming the lunule. The apex of the angulated free edge contains a central fibrous nodule that assists in closing the central areas of the edges of the cusps (Table 2.2).

Table 2.2  Comparison of the semilunar and the atrioventricular valves Semilunar

Atrioventricular

Number of cusps

Three in both the aortic and pulmonary valves

Three in the tricuspid and 2 in the bicuspid valve

Sinus behind the cusps

Present

Absent

Lunule and nodule

Present

Absent

Competence

Passive: following relaxation of the ventricle, the elastic wall of the artery forces the blood back toward the heart —> cusps open up like pockets and close the orifice to prevent arterial blood from passing back into the ventricle

Active: contraction of the papillary muscles prior to contraction of the ventricle —> tightening the chordae tendineae and drawing the cusps together to prevent ventricular blood from passing back into the atrium

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Section I  Embryology and Morphology of the Heart and Vessels

Superior vena cava

Atrioventricular node Bundle of His

Sinoatrial node

Left atrium

Right atrium Right bundle branch

Left ventricle

Right ventricle Purkinje fibers

FIGURE 2.4  Axial MRI image of the heart. CS, coronary sinus; DAo, descending thoracic aorta; LA, left atrium; LV, left ventricle; RA, right atrium; RCA, right coronary artery; RV, right ventricle; TV, tricuspid valve. (Reproduced, with permission, from Fuster V, Harrington RA, Narula J, Eapen ZJ, eds. Hurst’s The Heart. 14th ed. New York, NY: McGraw-Hill; 2017.)

In the aorta, the anterior and left posterior aortic sinuses give rise to the right and left coronary arteries.

▶ ▶  C L I N I C A L C O R R E L A T I O N 2 . 3 Cross-sectional imaging of the heart: Understanding the anatomical position of the heart and appreciating the actual location of its chambers can help interpret crosssectional images. For example, in Fig. 2.4, note how the right ventricle is anterior and the left atrium is located posteriorly at the base of the cone-shaped heart whose apex is formed by the left ventricle.

Conducting System of the Heart (Fig. 2.5) The conducting system consists of specialized cardiac muscle fibers that initiate the normal heartbeat and coordinate the contractions of the heart chambers. The passage of impulses (ie, the action potential) over the heart can be amplified and recorded in an electrocardiogram (ECG). The sinoatrial (SA) node (the normal pacemaker) possesses a rich supply of autonomic nerve fibers. It is located in the right atrium at the superior end of the crista terminalis in front of the opening of the superior vena cava. From the SA node, the electrical impulse is propagated through the atria by cardiac muscle fibers. The atrioventricular (AV) node lies in the interatrial septum just above the opening of the coronary sinus near the attachment of the septal cusp of the tricuspid valve (the triangle of Koch). From it, the conducting bundle (ie, bundle of His) (atrioventricular bundle) descends along the membranous part of the interventricular septum.

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Inferior vena cava Interventricular septum

Left bundle branch

FIGURE 2.5  Sectional view of the heart. Basic anatomy of the heart is indicated, including chambers, major blood vessels, and conducting system (yellow), including the sinoatrial node, the atrioventricular node, and the Purkinje fibers. (Reproduced, with permission, from Barrett KE, Barman SM, Boitano S, Brooks HL. Ganong’s Review of Medical Physiology. 24th ed. New York, NY: McGraw-Hill; 2012.)

At the upper border of the muscular part of the interventricular septum, the AV bundle divides into right and left bundle branches that descend along the right and left sides of the interventricular septum, respectively. A large part of the right bundle branch is carried across the moderator band to the anterior wall of the right ventricle. The bundle branches then ascend from the apex of the heart to the walls of the ventricles. The fibers of the branches continue into the Purkinje fibers beneath the endocardium.

▶ ▶  C L I N I C A L C O R R E L A T I O N 2 . 4 Location of the AV bundle: When there is an atrial septal defect, the AV bundle usually lies in the margin of the defect; its inadvertent destruction during surgery will cut the only physiological link between the atrial and ventricular musculature.

Skeleton of the Heart The skeleton of the heart is made up of fibrous tissue that forms the central support of the heart. The skeleton of the heart includes 3 parts: •• Fibrous rings surround the atrioventricular valves and the origins of the aorta and the pulmonary trunk. •• Right and left fibrous trigons form connections between the rings. •• Membranous part of the interventricular septum.

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Chapter 2  Anatomical Structure of the Heart

The function of the skeleton of the heart is to keep the orifices of the AV and semilunar valves patent and prevent their overdistension. It also provides an attachment for the leaflets of the cusps of the valves and an attachment for the myocardium. Because it is made up of fibrous tissue, it forms an electrical “insulator” between the atria and ventricles so that these chambers contract independently.

Blood Supply of the Heart The coronary arteries and cardiac veins supply most of the myocardium. They are normally embedded in fat and course just deep to the epicardium. The endocardium and some subendocardial tissue receive oxygen and nutrients by diffusion directly from the chambers of the heart.

Coronary Arteries (Fig. 2.6) The arterial supply of the heart is provided by the right and left coronary arteries. The vessels are called “coronary” (L. corona = crown) because they encircle the ventricles like a crown. There are 2 coronary arteries that arise from 2 of the 3 ­aortic sinuses immediately above the aortic valves. The anterior aortic sinus gives rise to the right coronary artery (RCA). The left posterior aortic sinus gives rise to the left coronary artery (LCA). The remaining right posterior aortic sinus is sometimes called the “non-coronary” since it does not provide any origin for the coronary arteries. Unlike other arterial systems in the body, coronary arterial blood flows during diastole. During systole, the blood is squeezed out of the arterial bed by muscle contractions; therefore, diastole is critical for heart nourishment. The flow is propelled by blood that moves in a retrograde direction in the proximal aorta after a systolic contraction has completed. This retrograde flow of blood, while passively closing the cusps of the aortic valve, finds its way through the aortic sinuses into the coronary arteries.

Right Coronary Artery The right coronary artery runs in the right atrioventricular groove (coronary sulcus) and passes between the right auricle and the pulmonary trunk. It descends vertically to reach the inferior border of the heart. It then continues posteriorly into the AV groove to anastomose with the LCA at the crux. The region of this crux is located at the junction of the AV groove with both the interatrial and interventricular grooves. The first branch of the RCA is the right conus artery that anastomoses with a similar branch from the LCA to form an anastomotic circle around the infundibulum. The RCA near its origin also provides the SA nodal branch in about 60% of cases. It then branches off to both the atrium and the ventricle as it passes vertically (the anterior atrial and ventricular rami diverge from the so-called first segment of the RCA). Both groups diverge widely, approaching a right angle in the case of ventricular arteries. This is in contrast to the more acute

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origins of the left coronary ventricular rami. At the inferior border, it branches off the marginal artery (the right marginal artery) that runs along the acute margin of the heart; hence, it is also called the acute marginal artery. The anterior ventricular branches including the right marginal artery run toward, but do not reach the apex of the heart. From the second segment of the RCA between the right border and the crux, 1 to 3 small right posterior ventricular rami supply the diaphragmatic aspect of the right ventricle. Their size is reciprocal to that of the right marginal artery. At the crux of the heart, the RCA provides the AV nodal branch in about 80% of cases. The posterior interventricular (the posterior descending, PDA) branches off to the posterior interventricular groove to supply septal branches to the interventricular septum. Although clinicians know it better as the “posterior” interventricular artery, this is a misnomer since it is related to the inferior surface of the heart rather than to the posterior surface. The remaining part of the RCA is very small and anastomoses with the termination of the LCA. The areas of supply of the RCA are summarized in Table 2.3.

Left Coronary Artery The left coronary artery emerges between the left auricle and the pulmonary trunk and passes around the left atrioventricular groove. It the divides into the anterior interventricular (also called the left anterior descending, LAD) branch and the circumflex (Cx) branch. The LAD passes downward in the anterior interventricular groove. It anastomoses with the termination of the posterior interventricular artery usually by making a turn around the apex into the posterior interventricular sulcus. The LAD provides septal branches to the anterior two-thirds of the interventricular septum, including the AV bundle. It also provides anterior ventricular branches, mainly to the left ventricle (the diagonal branches). The right anterior ventricular branches are small because the right ventricle is supplied mainly by the RCA. The left anterior interventricular arteries are large and numerous and branch at acute angles from the anterior interventricular to cross diagonally to the left ventricle’s anterior aspect. A small left conus artery leaves the anterior interventricular artery near its origin to anastomose with that of the RCA. The circumflex artery follows the coronary groove around the left border of the heart to the posterior surface. It branches off to the posterior wall of the left ventricle and left atrium and continues on to anastomose with a termination of the right coronary artery ending at the left of the crux in most hearts. It provides a marginal branch (the left marginal branch) that is also called the obtuse marginal branch because it follows the obtuse margin of the heart. In 40% of individuals, the Cx artery branches off the sinoatrial nodal artery that runs up over the posterior surface of the left atrium between the upper left pulmonary vein and the auricular appendage, ending in the auricular appendage of the right atrium at the SA node. The artery of the AV node arises near the crux when the circumflex supplies the posterior interventricular branch.

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Section I  Embryology and Morphology of the Heart and Vessels

Superior vena cava

Pulmonary valve

Superior left pulmonary v. Left auricle

Ascending aorta

Left coronary a. Circumflex a.

Branch to sinoatrial node

Left (obtuse) marginal a.

Right coronary a.

Great cardiac v.

Right atrium

Anterior interventricular (left anterior descending) a.

Small cardiac v. Right marginal a. A

Left ventricle Anterior cardiac a. and v.

Left atrium

Right ventricle

Superior vena cava

Left pulmonary vv.

Cardiac apex

Branch to sinoatrial node Right pulmonary vv.

Circumflex a. Right atrium

Great cardiac v.

Coronary sinus Inferior vena cava

Posterior v. of left ventricle

Right coronary a.

Small cardiac v. Right posterolateral a.

Pulmonary valve Aortic valve

Right ventricle

Right coronary a.

B Left ventricle

Middle cardiac v.

Posterior interventricular a.

Left coronary a. Tricuspid valve

Mitral valve C Coronary sinus

Posterior interventricular branch of right coronary a.

FIGURE 2.6  Anterior (A), posterior (B), and superior (C) views of the coronary arteries and cardiac veins. (Reproduced, with permission, from Morton DA, Foreman KB, Albertine KH. The Big Picture: Gross Anatomy. New York, NY: McGraw-Hill; 2011.)

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Chapter 2  Anatomical Structure of the Heart

Table 2.3  Areas of supply of the coronary arteries Area

LCA

RCA

Atrium

Left atrium

Right atrium

Right ventricle

Part of the right ventricle

Most of the right ventricle

Left ventricle

Most of the left ventricle

Part of the left ventricle

Interventricular septum

Anterior two-thirds including the AV bundle

Posterior one-third

SA node

40% of cases

60% of cases

AV node

20% of cases

80% of cases

The LCA most commonly terminates on the posterior aspect of the heart before reaching the crux by anastomosing with the termination of the RCA. In about one-third of hearts, it continues to supply a branch that runs in or adjacent to the posterior interventricular groove. The areas of supply of the LCA are summarized in Table 2-3.

▶ ▶  C L I N I C A L C O R R E L A T I O N 2 . 5 Coronary imaging (ie, angiography): A long, narrow catheter is passed into the ascending aorta via the femoral artery in the inguinal region. The tip of the catheter is placed just inside the opening of a coronary artery. Radiographs are taken after a small injection of radiopaque contrast material, which shows the lumen of the artery and its branches.

Anastomosis of Coronary Arteries The coronary arteries and their branches do anastomose with each other. The anastomosis is present between the terminations of the RCA and LCA in the coronary sulcus and between the interventricular branches around the apex of the heart. However, the anastomoses are insufficient when a major branch is occluded; therefore, they are functionally end arteries. As coronary narrowing progresses, the collateral channels connecting one coronary artery with the other expand, which may initially permit adequate perfusion of the heart during relative inactivity. The insufficient blood supply results in ischemia (angina pectoris) or infarction (myocardial infarction) as explained in detail in Chapter 8.

Coronary Dominance The term “dominance” refers to “the origin of the posterior interventricular artery from either the RCA or LCA.” A right dominance is present in about two-thirds of cases when the posterior interventricular artery is derived from the RCA. A left dominance is present in about 15% of cases when the posterior interventricular artery is derived from the LCA. In about

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18% of cases, a codominance is present when there is a balanced coronary arterial pattern in which the branches of both the RCA and LCA run in or near the interventricular sulcus.

▶ ▶  C L I N I C A L C O R R E L A T I O N 2 . 6 •  Coronary bypass grafting: A segment of an artery or vein is connected to the ascending aorta or to the proximal part of a coronary artery and then to the coronary artery distal to the stenosis. The arteries used in bypass surgery are the radial and the internal thoracic arteries. The great saphenous vein is commonly used for coronary bypass surgery because: •  It has a diameter that is about equal to that of the coronary arteries. •  Being a superficial vein, it can be easily dissected from the lower limb.

Veins of the Heart (Fig. 2.6) The veins of the heart follow, more or less, the same pattern of the arteries but the names are different. The coronary sinus is the main vein of the heart. It is wide, short, and lies in the posterior part of the atrioventricular (coronary) groove. It drains almost all the venous blood from the heart to the right atrium. The main tributary of the coronary sinus is the great cardiac vein. This vein arises at the apex of the heart and ascends into the anterior interventricular groove. The great cardiac vein accompanies the anterior interventricular artery. At the coronary sulcus, the great cardiac vein enters the left end of the coronary sinus. It drains the area of the heart supplied by the LCA. The middle cardiac vein arises at the apex of the heart and ascends into the posterior interventricular groove. It accompanies the posterior interventricular artery then enters the right side of the coronary sinus. The small cardiac vein accompanies the marginal branch of the RCA. The middle and small cardiac veins drain most of the area of the heart supplied by the RCA. The oblique vein of the left atrium is a small vein that arises over the posterior wall of the left atrium and descends obliquely. It unites with the great cardiac vein to form the coronary sinus. The anterior and smallest cardiac veins drain a small amount of blood that is not carried by the coronary sinus. The anterior cardiac veins are 2 to 4 small veins that cross over the coronary groove on the anterior surface of the right ventricle to open directly into the right atrium. The smallest cardiac veins (venae cordis minimae, Thebesian veins) open directly into different chambers of the heart.

Cardiac Referred Pain The sensory nerve supply of the heart is sympathetic; therefore, the myocardium is insensitive to touch, cutting, cold, or

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Section I  Embryology and Morphology of the Heart and Vessels

heat, but is sensitive to ischemia. The pain of angina pectoris and myocardial infarction is a visceral pain that commonly radiates from the substernal region and left pectoral region to the left shoulder and medial aspect of the left arm. Visceral pain, in general, is referred; that is perceived as occurring in remote cutaneous areas. The cutaneous areas of reference for cardiac pain coincide with the dermatomes of the somatic sensory fibers that enter the same spinal cord segments as the fibers coming from the heart. The afferent visceral pain fibers that arise from the myocardium run centrally in the cervical and the thoracic cardiac branches of the sympathetic trunk to enter the spinal cord segments, T1-T4, especially on the left side. Cardiac pain is therefore referred to the left side of the chest (dermatome T3 and T4) as well as the medial aspect of the left arm (dermatome T1 and T2).

Microscopic Anatomy The wall of the heart consists of 3 layers: the endocardium, myocardium, and epicardium (Fig. 2.1B). The endocardium is the innermost layer and is lined by endothelial cells. There is a subendocardial layer containing Purkinje fibers of the heart’s conducting system that consist of modified cardiac muscle fibers. The myocardium consists of cardiac muscle fibers in spiraling sheets that are thickest in the left ventricle and thinnest in the atria. The epicardium (the visceral pericardium) is a single layer of flat mesothelial cells that secrete lubricating fluid. There is a subepicardial layer of loose connective tissue with fat cells in which blood vessels (coronary), lymphatics, and nerves to the heart are located. Cardiac muscle fibers exhibit cross-striations, but unlike skeletal muscle fibers, the cardiac muscle fibers are branched and separated by densely stained cross-bands (intercalated disks), which represent specialized attachment sites between adjacent fibers. Cardiac muscle fibers have centrally located nuclei and some are binucleated. There is a perinuclear region that is free of myofibrils and contains the cytoplasmic organelles, which are not directly involved in the contractile process. Purkinje fibers are modified cardiac muscle fibers that are located in the subendocardial tissue. They are larger than ordinary cardiac muscle fibers and contain large amounts of glycogen in the perinuclear region that is not preserved in most histological preparations. Thus, the nuclei are surrounded by the lighter-stained cytoplasm (Fig. 2.7). The heart valves consist of a core of fibro-elastic connective tissue that is continuous with the cardiac skeleton (the valve ring). The endocardial layer covers the atrial and ventricular surfaces of the valve cusps. Although these cusps are avascular, they are thin leaflets and are exposed to blood on both sides.

Key Points •• The pericardium consists of a fibrous outer layer that encloses a serous sac of parietal and visceral layers. The

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FIGURE 2.7  Purkinje fibers are modified cardiac muscle fibers that are specialized for the transmission of excitation. They are larger than ordinary muscle fibers. (From Takizawa P. @Yale Histology Lectures and Image Gallery. http://medcell.med.yale.edu/histology/muscle_lab/ purkinje_fibers.php.)

••

••

••

••

pericardial cavity is located between the parietal and visceral layers of the serous pericardium. The heart consists of 2 atria and 2 ventricles. It has 3 surfaces: anterior (sternocostal), inferior (diaphragmatic), and posterior (base). The outline of the heart (precordium) can be traced on the front of the chest using skeletal landmarks. The heart valves are grouped behind the sternum, but the auscultatory areas are wide apart and differ from the surface projection of the heart valves. The right atrium has rough and smooth parts. It receives the openings of the superior and inferior vena cavae and the coronary sinus. The right atrioventricular opening is guarded by the tricuspid valve. The right ventricle has thick muscular walls with projecting papillary muscles whose contraction tightens the chordae tendineae and draws the cusps of the tricuspid valve together during ventricular contraction. The infundibulum leads up into the pulmonary orifice and the pulmonary trunk.

•• The left atrium receives the 2 pairs of pulmonary veins. The left atrioventricular orifice is guarded by the bicuspid (mitral) valve. •• The left ventricle is the thickest of the chambers. It forms the apex of the heart. The aortic vestibule leads up into the aortic orifice. •• The aortic and pulmonary (semilunar) valves are guarded by 3 cup-shaped cusps. Behind the cusps, the anterior and left posterior aortic sinuses give rise to the right and left coronary arteries. •• The conducting system of the heart consists of the sinoatrial node (the pacemaker), the atrioventricular node, the conducting bundle (of His) (the atrioventricular ­bundle), the right and left bundle branches, and the ­Purkinje fibers.

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Chapter 2  Anatomical Structure of the Heart

•• The myocardium is supplied by 2 coronary arteries: right and left. The RCA provides the SA nodal branch (≈60% of cases), the right marginal branch, the AV nodal branch (80% of cases), and the posterior interventricular (the posterior descending, PDA) branch when the coronary circulation is right dominant. The LCA divides into the anterior interventricular (the anterior descending also called left anterior descending, LAD) branch and the ­circumflex branch (Cx). •• Anastomosis of the coronary arteries is present between the terminations of the RCA and the LCA in the coronary sulcus and between the interventricular branches around the apex.

•• The veins of the heart follow, more or less, the pattern of the arteries but the names are different. The coronary sinus drains almost all the venous blood from the heart to the right atrium. •• Ischemic pain is visceral and commonly radiates from the substernal region and the left pectoral region to the left shoulder and medial aspect of left arm. These cutaneous areas of reference for cardiac pain coincide with the dermatomes (T1-T4) of somatic sensory fibers that enter the same spinal cord segments as the sympathetic fibers coming from the heart. •• The wall of the heart consists of 3 layers: endocardium, myocardium, and epicardium.

CASE STUDIES CASE 2.1  A transesophageal echocardiography was performed to assess a 5-year-old patient with atrial septal defect. Which of the following is located between the transducer in the esophagus and the left atrium? a. Coronary sulcus b. Oblique sinus

c. Presence of a lunule and nodule at the free edges of the valve cusps d. Extension of the myocardial tissue into the substance of the valve cusps e. Contraction of the trabeculae carneae which causes narrowing of the fibrous ring of the valve

c. Coronary sinus d. Transverse sinus

CASE 2.2  A diagnosis of acute rheumatic fever was made in a 9-year-old boy. The echocardiogram confirmed severe mitral insufficiency. Which of the following maintains the competence of the mitral valve? a. Buildup of pressure in the left atrium during ventricular systole b. Contraction of papillary muscles which pull on the chordae tendineae

CASE 2.3  A 60-year-old male suffered angina pectoris. Cardiac catheterization revealed a significantly narrowed left coronary artery just distal to the left sinus of the aortic valve. If the patient was left dominant, which of the following arteries would be most likely to still have normal blood flow? a. Diagonal b. Circumflex c. Acute marginal d. Obtuse marginal e. Posterior interventricular

Suggested Readings Faiz O, Blackburn S, Moffat D. Anatomy at a Glance. 3rd ed. West Sussex: Blackwell Publishing; 2011:26. Sinnatamby CS. Last’s Anatomy: Regional and Applied. 12th ed. Edinburgh: Churchill Livingstone Elsevier; 2011:196.

Multimedia Resources

External and internal features of the heart. Human Anatomy Education Channel on YouTube. https://www.youtube.com/ watch?v=eFCK7IoV_sQ&channel=akramjfr. Surface anatomy of the thorax. Human Anatomy Education Channel on YouTube. https://www.youtube.com/ watch?v=Q-kpk0tjTgQ&channel=akramjfr.

Blood supply of the heart. Human Anatomy Education Channel on YouTube. https://www.youtube.com/watch?v=eefHDKGW SR4&channel=akramjfr.

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SECTION

II

HEART AND VASCULAR FUNCTIONS

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Chapter Cardiovascular Circuitry and Hemodynamics ADEL ELMOSELHI

Introduction The main function of the cardiovascular system is to deliver oxygenated blood and nutrients to all the tissues of the body and to remove the deoxygenated blood and waste products from the body. The heart acts as an efficient and durable pump that on average beats 100,000 times per day and ejects over 7000 liters of blood per day without a conscious effort on our part. Also, the blood vessels, measuring approximately 60,000 miles in length, act as pipes that are connected to this pump (ie, the heart) in such a way that allows a constant flow of blood to all parts of the body. The blood flow is highly adjustable according to the tissues’ need and activity. However, in a few organs, such as the kidneys and lungs, the blood flow serves additional functions. The kidney, for example, receives much more blood flow than its metabolic requirements mainly due to its excretory function to eliminate waste products from the body. There are multiple variables that regulate the blood vessels which are critical to maintain their function. The most important ones are blood flow, blood pressure, and vessel resistance. How they are regulated and related to each other are important in hemostasis and survival. In this chapter we will discuss in some detail the overall circuitry of the body and how it is regulated. In addition, how its parameters work separately, and how they are connected and dependent on each other. Furthermore, we will briefly address the effects of the aging process on blood pressure and its variables.

Functions of the Cardiovascular System •• To deliver oxygenated blood and nutrients to the tissues, and remove deoxygenated blood and waste products (the main function) •• To help maintain several homeostatic functions such as: •• Arterial blood pressure •• Body fluid balance •• Body temperature

Learning Objectives

3

By the end of this chapter the student will be able to: • List the main functions and components of the cardiovascular system. • Describe the circuitry of the cardiovascular system. • Construct the physical features of the heart and blood vessels and explain the significance of each in its function. • Determine the approximate percentage of the blood volume found in the cardiovascular system. • Indicate how pressure, blood flow velocity and wall tension differ in the various types of blood vessels. • Describe the relationship between blood flow, pressure, and resistance. • Explain the difference between laminar and turbulent blood flow and their significance. • Compare resistance in series to resistance in parallel and their significance. • Describe the blood pressure profiles throughout the systemic and pulmonary vasculature. • Explain the concept of compliance in the blood vessels and the effects of aging on the compliance and consequently on blood pressure.

•• Adaptation during various stress conditions (eg, hemorrhage, exercise, and changes in posture) •• To transport hormones from the endocrine glands to their target sites •• To protect the body from infection through blood components especially white blood cells

Main Components of the Cardiovascular System and Its Anatomical Features That Are Significant to Its Function To accomplish the functions discussed above, the cardiovascular system consists of the following components: 1. Heart (right and left pumps) 2. Blood vessels (systemic circulation and pulmonary circulation) 3. Blood 35

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Section II  Heart and Vascular Functions

The Heart

•• Heart chambers: There are 4 heart chambers (2 atria and 2 ventricles) known as the right atrium, the left atrium, the right ventricle, and the left ventricle. The left ventricle has the thickest wall because it is responsible for generating the highest pressure in the heart to pump blood to the rest of the body. •• Heart valves: There are 2 atrioventricular (AV) valves and 2 semilunar valves. The tricuspid and mitral valves

The heart is a muscular hollow organ that serves as a pump to create a pressure gradient that is essential for blood to move or flow. The blood flow moves from high pressure to lower pressure areas. The heart is usually thought of as 2 pumps: the left and the right, which are connected in series along with the systemic and the pulmonary circulations with the following features and characteristics as shown in Fig. 3.1.

Pulmonary artery

Lungs 100% Pulmonary vein

Right atrium

Left atrium

Tricuspid valve

Mitral valve

Right ventricle

Left ventricle Pulmonic valve Brain 15%

Vena cava 100%

Heart 5%

Aortic valve Aorta 100%

Spleen 25% Liver GI

Kidneys 20%

Skin 8%

Skeletal muscle 15%

Bone, others 12%

FIGURE 3.1  Overview of the circulatory system in the body and approximate % distribution of the cardiac output at rest.

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Chapter 3  Cardiovascular Circuitry and Hemodynamics

are AV valves and the pulmonary and aortic valves are semilunar valves. The opening and closing of the valve is due to the pressure gradient (ie, the pressure difference) across the valve. The valves help the blood to move in one direction. The cusps of the valve are characterized as very delicate but strong fibrinous materials. The free edges of the valves, especially in the AV valves, are attached to the chordae tendineae and papillary muscles to prevent the opening of the valve in the opposite direction (ie, backward). Any damage of these muscles and/or chordae tendineae will lead to leaking and regurgitation of the blood through the valve with some adverse consequences. •• Types of cardiac muscle: The cardiac muscle fibers are arranged in multiple spiral layers that allow the heart to further “squeeze” the blood out while it is contracting. In general, the cardiac muscle has 2 major types: (1) The contractile cells, which are most of the cardiac muscle cells (~99%) and responsible for contraction and relaxation of the cardiac muscle and pumping the blood. (2) The cells in the cardiac conductive system (eg, the SA node, AV node, bundle of His, etc.), which are responsible for initiating and conducting action potential.

Blood Vessels Arteries carry oxygenated blood from the heart to the tissues, and veins carry deoxygenated blood from tissues back to the heart. Capillaries are the smallest and thinnest part of the blood vessels that serve the most critical function of circulation, which is gas exchange. Blood moves continuously into 2 separate pathways or circulations (ie, systemic and pulmonary circulations) that both originate from and terminate into the heart.

Systemic Circulation Systemic circulation consists of the left side of the heart, the systemic arteries, the capillaries, and the veins (ie, involves all the blood vessels in the body except for pulmonary circulation). Blood flow begins from the aorta and ends in the vena cava (superior and inferior). Systemic vessels collectively are connected in series with the heart as well as the pulmonary vessels. The connection in series maintains the same blood flow at any point of the circulation as well as the equality of the cardiac output and the venous return (Fig. 3.2). Nonetheless, different proportions of blood are distributed to the body organs through parallel branches from the aorta. This parallel arrangement offers an independent adjustment of blood supply to each organ based on its need and activity (Fig. 3.1). Systemic circulation is characterized as a high-pressure and high-resistance system. Blood moves from one point to another because of the pressure difference (ie, the pressure gradient). Therefore, understanding the blood pressure differences inside major parts of the cardiovascular system is important. Its approximate values in an average healthy individual are shown in Table 3.1.

Elmoselhi_CH03_p033-050.indd 37

Pulmonary circulation

Right pump

Venous return at rest = ∼5 L/min

Left pump

Systemic circulation

Cardiac output at rest = ∼5 L/min

FIGURE 3.2  Connection between the right and left heart pumps as well as pulmonary and systemic circulations.

Pulmonary Circulation Pulmonary circulation consists of the right side of the heart and the pulmonary arteries, capillaries, and veins. The blood flow begins in the pulmonary artery and ends in the pulmonary veins. The pulmonary capillaries are the sites of gas exchange between the alveolar air and the pulmonary blood. Note that the bronchial circulation that supplies the bronchial tree and lung tissues with blood is part of the systemic circulation. Pulmonary circulation is characterized as a low pressure and low resistance system. The pressures in various parts of the pulmonary circulation are also shown in Table 3.1.

Blood Blood is a transport media of liquid (ie, plasma) and solid (ie, cells) that mainly serves to transport materials (O2, CO2, nutrients, hormones, electrolytes, and waste) from one part of the body to another. Its properties related to the cardiovascular system will be briefly discussed later and in other chapters.

Table 3.1  Approximate values in mmHg of normal blood pressures in various parts of the cardiovascular system Pressures in various parts of the Cardiovascular System

Approximate values (Systolic/Diastolic)

Arterial (aortic) pressure

120/80 mmHg

Left ventricular pressure

120/0 mmHg

Right atrial pressure

− 4 to + 4 mmHg

Pulmonary artery pressure

25/8 mmHg

Right ventricular pressure

25/0 mmHg

Left atrial pressure

5-10 mmHg

Mean pulmonary pressure

15 mmHg

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Section II  Heart and Vascular Functions

Cardiovascular Circuitry As shown in the schematic diagram in Fig. 3.1, the following steps complete the cycle of blood through the 3 components of the cardiovascular system as follows: •• Venous return to right atrium: Following gas exchange in the tissues, blood contains carbon dioxide (CO2) and other waste products, and is called mixed venous blood or deoxygenated blood. The mixed venous blood flows in the veins toward the heart. The superior and inferior vena cava collect the venous blood from above and below the heart level, respectively, and direct it to the right atrium. The venous return occurs passively and continuously since the pressure in the right atrium is normally lower than the pressure in the vena cava and because there is no valve between the vena cava and the right atrium. •• Blood flow to the right ventricle: The mixed venous blood flows from the right atrium to the right ventricle when the tricuspid valve opens (the AV valve of the right heart). •• Blood ejection to the lung: The right ventricle contracts and ejects the mixed venous blood to the lung through the pulmonary artery when the pulmonic valve (a semilunar valve) opens. The cardiac output ejected from the right ventricle normally equals the cardiac output ejected from the left ventricle. In the pulmonary capillaries, O2 is added to the blood from the alveolar air and CO2 is removed, causing the mixed venous blood to become oxygenated blood. The oxygenated blood flows to the left atrium through the pulmonary veins. •• Blood flow to the left ventricle: The oxygenated blood filling the left atrium flows to the left ventricle once the mitral valve opens (the AV valve of the left side of the heart). •• Blood ejection to the rest of the body: The left ventricle contracts and opens the aortic valve (a semilunar valve) that leads to the ejection of the oxygenated blood to all parts of the body. The cardiac output ejected from the left ventricle is the same as the cardiac output ejected from right ventricle as well as the venous return to both sides of the heart. The average total cardiac output is about 5 liters and is distributed to all the organ systems in different proportions via a set of parallel arteries. The parallel arrangement ensures that each part of the body receives a fresh oxygenated blood supply (ie, so that the same oxygenated blood does not pass from organ to organ). Although each organ system receives a specific percentage of the total cardiac output (Fig. 3.1), this percentage distribution is not fixed. The change of the blood distribution is based on the metabolic activity of various organs. For example, during strenuous exercise, the skeletal muscle receives a much higher percentage of blood, and as a consequence, a smaller percentage of blood goes to the other organs (eg, the gastrointestinal system). The mechanism of the blood redistribution is based on an alteration of the arteriolar resistance and the change

Elmoselhi_CH03_p033-050.indd 38

of cardiac output of the heart. Ultimately, in the tissue capillaries, the O2 and nutrients diffuse into the tissues and the CO2 and other waste products are removed by the blood. The blood now becomes deoxygenated and returns to the right atrium through the veins to start another cycle.

Hemodynamics Hemodynamic literally means “blood movement;” however, it is defined as the study of the principles that govern the blood flow in the heart and blood vessels. Those basic principles include flow, pressure, resistance, and capacitance similar to the principles of physics for any fluid movement. The principles of hemodynamics and their relationship relevant to the cardiovascular system will be discussed below in some detail. First, let us describe the various types of blood vessels and their main structure and functions as shown in Fig. 3.3.

Types of Blood Vessels and Their Main Functions •• Arteries transport blood from the heart to the tissues under high pressure (conduit arteries). •• Arterioles control blood before entering the capillaries, and are considered to have the highest resistance (resistant arteries). •• Capillaries exchange gases, fluid, nutrients, hormones, and so on, between the blood and the interstitial spaces or the blood and the alveolar air in the lungs. •• Venules collect blood from the capillaries before gradually coalescing into larger veins. •• Veins transport the blood from the tissues back to the heart under low pressure; and serve as a major reservoir of blood. Microcirculation refers to the arterioles, capillaries, and venules collectively because they are visible only under the microscope. These vessels are normally located within the ­tissues of the organs.

Factors Regulating Normal Blood Pressure Blood pressure is defined as the force exerted by the blood against the wall of blood vessel. Thus, the blood pressure depends mainly on the blood volume and the compliance or the dispensability of the blood vessels.

Blood Volume and Its Relative ­Distribution in the Body Total blood volume in an average healthy adult (70 kg) is approximately 5.0 to 5.6 liters. In the resting state, the relative distribution of the blood volume in various systemic and pulmonary circulations is shown in Fig. 3.4. Approximately 85% of the total blood volume of the body is in the systemic

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Chapter 3  Cardiovascular Circuitry and Hemodynamics

Aorta

Artery

Arteriole

Precapillary sphincter

Venule

39

Vena cava

Vein

Capillary

Diameter Wall thickness Endothelium

25 mm

4 mm

30 µm

35 µm

7 µm 20 µm

5 mm

30 mm

2 mm

1 mm

20 µm

30 µm

1 µm 2 µm

0.5 mm

1.5 mm

20

400

Elastic tissue Smooth muscle Fibrous tissue Approximate total crosssectional area (cm2)

4.5

4500

4000

40

18

FIGURE 3.3  The structure and cross-sectional area (cm2) in various blood vessels. The values here are approximated mainly for illustration. (Adapted, with permission, from Burton AC. Relation of structure to function of the tissues of the wall of blood vessels. Physiol Rev. 1954;34:619.)

circulation and about 15% is in the heart and the lungs. Of the 85% blood volume in the systemic circulation, about 65% is in the veins, venules, and venous sinus, 7% is in the arterioles and the capillaries, and 13% is in the arteries. Please note that the largest blood volume occurs in the venous system because of its high compliance and capacitance. The venous system, therefore, acts as a reservoir for the blood that can be used in various active or stressful conditions.

Vascular Compliance or ­Distensibility and Capacitance The compliance or distensible property of the blood vessels is critical to accommodate and absorb the pulsatile nature of the cardiac output and its effect on the blood pressure. Thus it maintains a continuous blood flow to the tissues. On average, the veins are about 8 times more compliant than the arteries mainly because walls of the veins are thinner compared to the walls of the arteries. This allows the veins to accommodate a larger volume of blood without a major change in pressure and lets the veins act as a reservoir for the blood. Compliance and capacitance have similar meanings and are sometimes used interchangeably. Capacitance is the ease of adding more volume in a container or a vessel, while compliance means how easily a vessel can stretch to accommodate more volume. Compliance is calculated as shown in the equation below. In general, compliance can be calculated as follows: C = ΔV/ΔP

Sytemic veins (65%) Systemic arteries (10%) Capillaries (5%)

Pulmonary vessels (10%) Heart (5%)

FIGURE 3.4  Relative distribution of the % of the blood volume contained in various parts of the circulatory system.

Elmoselhi_CH03_p033-050.indd 39

where, C = Compliance (capacitance) (mL/mmHg) ΔV = change in volume (mL) ΔP = change in pressure (mmHg) The principle of the capacitance in the arteries and veins is illustrated in the pressure-volume curve (Fig. 3.5). The capacitance of each vessel is represented in the slope of each curve. This means that in the veins, unlike the arteries, a large

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Section II  Heart and Vascular Functions

Volume (ml)

Veins

▶ ▶  C L I N I C A L C O R R E L A T I O N 3 . 1

Normal

Arteries Sympathetic stimulation or aging

Aneurysm: An aneurysm is a dilatation of the blood vessel wall. The aorta, especially the abdominal aorta, has a high risk of developing an aneurysm that could lead to an aortic dissection or rupture as shown in Fig. 3.6. Assuming the pressure in the entire length of the aorta with an aneurysm are the same; however, the wall tension in the area of the aneurysm is higher than the rest of the vessel because it has a greater radius and thus presents a greater chance of bursting.

Pressure (mmHg)

FIGURE 3.5  The capacitance in the arteries and veins is represented in the relationship between the volume and pressure. The slope of the curves represents the capacitance. Both age and sympathetic stimulation (dashed line) decrease the compliance and capacitance of the arteries and veins and lead to increased pressure at each increased volume point compared to normal (solid line).

change of volume will lead to a small change in pressure. This explains why a large volume of blood (eg, one-half liter), given or taken within a few minutes, from a healthy individual will not significantly alter the individual’s blood pressure and the function of the circulation. Other than the vessel wall thickness, the sympathetic nervous system and aging also control the compliance of the blood vessels. For example, sympathetic stimulation reduces the compliance of the veins, and consequently, the vessel size maintains the normal function of the circulation in spite of a large loss of blood (~25% of the total blood volume) during hemorrhage in a healthy individual.

Blood Vessel Wall Tension and Wall Stress Wall tension can be thought of as how much the walls of a vessel are stretched when pressure occurs inside the vessel, or how strong the walls must be in order to resist being stretched. The factors that determine the wall tension are described in the Laplace relationship equation below. Based on this relationship, the aorta has the highest wall tension compared to other blood vessels, and consequently, tends to be more susceptible to aneurysms and rupture. Tension ∝ Pressure × Radius (Laplace relationship) Wall stress considers the blood vessel’s wall thickness as shown in the equation below. The higher the wall tension of the blood vessel, the higher its wall stress. The thicker the wall of the blood vessel, the lower its wall stress since the force is distributed over a larger mass per unit surface area. The same concepts of wall tension and wall stress apply in the heart chambers, especially in the ventricles. Wall stress = Wall tension/Wall thickness

Elmoselhi_CH03_p033-050.indd 40

Blood Flow Blood flow is the volume of blood per unit time (eg, mL/min). The direction of the blood flow is always from high to low pressure. The blood flow is determined by two main factors: (1) pressure difference and (2) resistance, as shown in Fig. 3.7. These two factors are similar to the electric current that is governed by Ohm’s law as shown in the following important classic equation: Q = ΔP/R where, Q = blood flow (mL/min) ΔP = the pressure difference between the 2 ends of a ­vessel (P1 and P2) (mmHg) R = vascular resistance (mmHg/mL/min) According to the above equation, the magnitude of the blood flow is directly proportionate to the pressure difference, which is the driving force of the flow while inversely proportionate to the resistance. Changing the resistance is the main mechanism for changing the blood flow in various conditions, especially in the arterioles. A change in the arteriole diameter has a major effect on the resistance, as will be explained later in the resistance to the blood flow section.

Laminar Flow Normally, in a healthy blood vessel, the fluid molecules flow in layers (or lamina, or streamlines) as shown in Fig. 3.8A. Laminar blood flow is characterized as silent with a high velocity. The maximum velocity occurs in the center, while the minimum velocity occurs in the periphery because of the resistance and adherence of the molecules to the vessel wall (ie, parabolic profile).

Turbulent Flow In the turbulent flow, the blood molecules “bounce around” within the vessel as shown in Fig. 3.8B. This happens under certain conditions that disrupt the streamline of the blood flow. Turbulent flow occurs under both physiological and pathological circumstances. For example, it normally occurs at the site of the bifurcation of the vessels, and pathologically, at a vascular aneurysm or as a result of anemia. Turbulent flow

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Chapter 3  Cardiovascular Circuitry and Hemodynamics

Dissection

Ascending aortic aneurysm Thoracic aortic aneurysm Diaphragm

B

Abdominal aortic aneurysm

A

FIGURE 3.6  Aortic aneurysm is a dilation of the aorta which occurs in various locations in the aorta such as abdominal or thoracic. The former is the most common one and usually they cause no symptoms unless complications occur (A). Rupture of the aneurysm is the most common complication which can leads to internal hemorrhage, shock and death. Also aortic dissection (ie, tears in the aortic wall) can occurs as serious complication of aneurysm with severe pain and eventually aortic rupture (B).

is characterized as noisy, thus it can be heard by placing the stethoscope over the blood vessel. Turbulent blood flow also has a low velocity that can lead to the formation of blood clots.

Velocities of the Bloodstream

Reynolds Number (NR)

The Reynolds number is a dimensionless number that is used to predict the blood flow whether it is laminar or turbulent. It is determined by multiple factors as shown in the following equation: NR =

Velocity × Diameter × Density Vis cos ity

In general, when the NR is more than 2000 it indicates that turbulent flow will usually occur, especially in the large, straight, and smooth vessels. In the small vessels, the NR is never high enough to cause turbulence. Two major factors that

Velocity is the speed of the bloodstream, or more accurately, it is the rate of blood displacement with respect to time. The blood velocity is inversely proportional to the cross-sectional area of the blood vessel and directly proportional to the blood flow as indicated in the equation below: v = Q/A where, v = velocity of the blood flow (cm/sec) Q = blood flow (mL/sec) A = cross-sectional area of the blood vessels (cm2)

Laminar flow

Blood flow P1

Pressure gradient

Turbulent flow

P2

Resistance

FIGURE 3.7  Relationships among pressure, resistance, and blood flow.

Elmoselhi_CH03_p033-050.indd 41

influence the NR are the viscosity of the blood (eg, anemia) and the velocity of the blood.

A

B

FIGURE 3.8  Laminar blood flow (A) versus turbulent blood flow (B).

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Section II  Heart and Vascular Functions

Total area (cm2) rof the vascular bed

Relative cross-sectional area of different vessels of the vascular bed

5000 4000 3000 2000 1000

Velocity of blood flow (cm/s)

0 50 40 30 20 10

cav ae Ven ae

s Vei n

ies Ven ule s

llar

les

Ca pi

Ar t erio

Ar t erie

s

120 100 80 60 40 20 0 Ao r ta

Blood pressure (mmHg)

0

FIGURE 3.9  Normal blood pressures in the different portions of the circulatory system when a person is lying in the horizontal position. Also, the relationship between the cross-sectional areas of different blood vessels and their velocity of the blood flow. (Reproduced, with permission, from Fuster V, Harrington RA, Narula J, Eapen ZJ, eds. Hurst’s the Heart. 14th ed. New York: McGraw-Hill; 2017.)

The collective cross-sectional areas vary among blood vessels as shown in Fig. 3.9 and Table 3.2. Although the aorta is largest in diameter and is considered to be the largest blood vessel, it has the smallest cross-sectional area because it is only one vessel. Thus, the blood velocity is highest in the aorta, based on the above equation, which suits its function as a conduit vessel merely moving blood from one point to the other. Each capillary, on the other hand, has the smallest diameter and is considered to be the smallest vessel; however, collectively capillaries have the largest cross-sectional area. Thus, the blood velocity is the lowest in the capillaries, which perfectly fits the main function of the capillaries by allowing more time for the blood to exchange gases and nutrients. Under resting conditions, the blood velocity in the aorta is approximately equal to 33 cm/s, while in the capillaries it is equal to 0.03 cm/s.

Elmoselhi_CH03_p033-050.indd 42

Table 3.2  Collective cross-section areas of the blood

vessels (cm2)

Blood vessels types/names

Collective cross section areas in cm2

Aorta

4.5 (smallest)

Artery

20

Arterioles

400

Capillaries

4500 (largest)

Venules

4000

veins

40

Venae cavae

18

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Chapter 3  Cardiovascular Circuitry and Hemodynamics

Resistance to Blood Flow The equation of the blood flow, according to Ohm’s law described above, can be rearranged to determine the resistance as shown below. This equation can be used to determine total peripheral resistance (TPR) or the resistance of any single organ, R = ΔP/Q where, R = resistance (mmHg/mL/min) or peripheral resistance unit, PRU (mmHg/mL/sec) ΔP = change in pressure (ie, pressure gradient) (mmHg) Q = blood flow (mL/min) Practical Examples •• Total peripheral resistance (TPR): Calculating the TPR or the resistance of the entire systemic vasculature is conducted by using the above equation and substituting the blood flow with the cardiac output and the ΔP by the pressure difference between the aorta and vena cava as follows: Q = Blood flow = 100 mL/sec ΔP = pressure between aorta and vena cava = 100 mmHg TPR = 100/100 = 1 PRU •• Resistance in a single organ: Calculating the resistance of the lungs (ie, pulmonary circulation), for example, is done by substituting the blood flow with the cardiac output (ie, the blood output from the right ventricle) and the ΔP by the pressure difference between the pulmonary artery and the pulmonary veins as follows: •• Q = Blood flow = 100 mL/sec •• ΔP = 14 mmHg •• Total pulmonary vascular resistance = 0.14 PRU

Factors That Determine the Vascular Resistance There are several factors that regulate the resistance of the blood flow including parameters in the blood vessel as well as the blood properties. The relationship among these factors is described in the Poiseuille equation below. Furthermore, the total resistance of a system, which includes several blood vessels is also regulated according to the arrangement of its blood vessels. The total resistance is completely different if the vessels are arranged in a series (ie, end to end) or arranged in parallel (ie, side by side) as explained below.

Poiseuille’s Equation R=

8η L π r4

Resistance = 8 × Viscosity × Length/π × Radius4

Elmoselhi_CH03_p033-050.indd 43

43

where, R = resistance η = the viscosity of the blood L = the length of the vessel r = the radius of the vessel π = constant (3.14) In the above Poiseuille equation, the resistance is directly proportional to the blood viscosity and the length of the blood vessel. The length of the vessels rarely change; however, the viscosity of the blood can change and cause a change in the resistance. For example, increases in the hematocrit level in the case of polycythemia will result in an increase in the resistance of the blood flow. More importantly, the vascular resistance is very sensitive to a change in the vessel radius. The vascular resistance is inversely proportional to the fourth power of radii of vessels (R ∝ 1/ r4). This is a powerful and critical relationship for determining the vascular resistance. For example, when the radius of a vessel decreases by half, its resistance will increase by 16-fold; or when the radius doubles, the resistance will decrease by 1/16 of its original value.

Parallel Versus Series Arrangement of Blood Vessels (Resistors) Resistances in Series R (total) = R1 + R2 + R3 + ∙ ∙ ∙ The total resistance, when the blood vessels or the resistors are arranged in series, is simply calculated by adding all the individual resistances together (Fig. 3.10A). Thus, the total resistance in this case is always greater than any individual resistance. Adding a resistor in series increases the total resistance of the system. The blood flow is equal at all points throughout the series system. Overall, the vessels are arranged in series around the systemic and pulmonary circulations— arteries, arterioles, capillaries, venules, and veins. Vessels are also arranged in series in some organs, for example, in portal circulation (in the liver and gastrointestinal tract). The blood pressure decreases to overcome the resistance in this series arrangement. Resistances in Parallel 1/R total = 1/R1 + 1/R2 + 1/R3 + ∙ ∙ ∙ The reciprocal of the total resistance, when the blood vessels or the resistors are arranged in parallel, is the sum of the reciprocals of the individual resistances (Fig. 3.10B). Thus, the total resistance is always smaller than any individual resistance. While adding a resistor in parallel decreases the total resistance of the system, increasing the resistance in an individual resistance increases the total resistance. Most vascular beds in different organs in the systemic circulation are arranged in parallel, for example, coronary, cerebral, renal, and so on. An important advantage of the parallel arrangement is that each individual resistance can be adjusted independently as it

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Section II  Heart and Vascular Functions

Series Resistances R1

R2

R4

R5

Venule

Vein

R3 Q

Artery

Arteriole

Capillary

RTotal = R1 + R2 + R3 + R4 + R5

A

Parallel Resistances Cerebral (R1) Coronary (R2) Renal (R3)

Aorta

Vena cava

1. Hematocrit: An increased hematocrit, such as in the case of polycythemia, will lead to increased blood viscosity. Conversely, a decreased hematocrit such as in anemia will decrease blood viscosity. 2. Concentration of plasma proteins: An increase in plasma proteins will lead to an increase in blood viscosity. 3. Abnormalities in the shape of red blood cells (RBCs), such as in cases of spherocytosis or sickle cell disease, will lead to an increased blood viscosity. 4. Velocity of the blood flow: A decreased flow in velocity will lead to an increased blood viscosity. 5. Tube diameter: Very small blood vessels will lead to a decreased viscosity.

Gastrointestinal (R4)

Vessel Length (L)

Skeletal muscle (R5)

An increase in the blood vessel length will lead to increased resistance; and doubling the length of the vessel will double its resistance.

Skin (R6)

B

Main Factors That Affect Blood Viscosity

1 = 1 RTotal R1

+

1 R2

+

1 R3

+

1 R4

+

1 R5

+

1 R6

FIGURE 3.10  A. Vessel resistances arrange in series. Total resistance is greater than each individual resistance. B. Vessel resistances arrange in parallel. Total resistance is smaller than individual resistance. (R = resistance; P = blood pressure; Q = blood flow)

occurs in various organs. Parallel resistances also permit independent control of the blood flow through the various vessels. Furthermore, there is no loss of blood pressure in the parallel resistance arrangement. For example, •• If 4 vessels are connected in parallel, each vessel has a resistance of 2 mmHg/ml/min. The total resistance (RT) of these vessels can be calculated as follows: 1/RT = ½ + ½ + ½ + ½ = 2

Blood Pressure In general, blood pressure is defined as the force exerted by the blood against any unit area of the vessel wall and is usually measured as mmHg. The arterial blood pressure pulsates in each heartbeat or cardiac cycle in the aorta and the large arteries. A typical tracing of the blood pressure pulsation in the aorta is shown in Fig. 3.11. Normally, the highest pressure during a heartbeat is called systolic pressure and it is approximately 120 mmHg, while the lowest point of the pressure is called diastolic pressure and it is approximately 80 mmHg. The difference between these two pressures is called pulse pressure and it is about 40 mmHg. The “blip” following the peak of the pressure in the pulse pressure wave recording is called the incisura or dicrotic notch and is a result of the brief retrograde blood flow caused by the closure of the aortic valve. •• Systolic pressure (SP) is the peak aortic pressure that occurs during the ejection of the blood from the left ­ventricle into the aorta during the contraction of the heart.

RT = ½ mmHg/ml/min

RT = 2 + 2 + 2 + 2 = 8 mmHg/ml/min

Blood Viscosity and Hematocrit Viscosity is described as the internal “stickiness” of the fluid. Viscosity of the blood changes with hematocrit. Blood hematocrit that is equal to 40 means that 40% of the blood volume is made up of cells and the remainder is made of plasma. The average normal hematocrit in man is equal to 42 while in women it is equal to 38.

Elmoselhi_CH03_p033-050.indd 44

Arterial pressure (mm Hg)

•• However, if the same vessels are connected in series, the total resistance can be calculated as:

Incisura (dicrotic notch) 120

Systolic pressure

Pulse pressure Mean pressure

93 80

Diastolic pressure Time (msec)

FIGURE 3.11  Normal arterial blood pressure.

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Chapter 3  Cardiovascular Circuitry and Hemodynamics

•• Regulated factors: The major factors are stroke volume and the compliance of the arteries. A minor factor is the heart rate via a change in the stroke volume. For example, increased systolic can be the result of an increase in the stroke volume and a decrease of the arterial compliance, in addition to a decreased heart rate that will increase stroke volume. •• Diastolic pressure (DP) is the minimum aortic pressure during relaxation of the heart when there is no blood ejection to the aorta. •• Regulated factors: The major factor is the total peripheral resistance (TPR) while other factors also contribute, such as a change in stroke volume and heart rate. For instance, a decrease in diastolic pressure could be the result of decreased TPR as well as a decrease in the stroke volume and a decrease in the heart rate that will allow more time for the run off of the blood to the peripheral vessels. •• Pulse pressure = Systolic pressure – Diastolic pressure •• Regulated factors: Major factors include stroke ­volume, compliance of the arteries, and the TPR. For instance, an increase in the pulse pressure that occurs due to an increase in systolic pressure and a decrease in diastolic pressure. This can be the result of increased stroke volume as in the case of increased contractility of the heart (eg, the positive inotropic effect). Also, a decrease in arterial compliance as in the case of atherosclerosis and a decrease in the TPR as in case of sympathetic overstimulation. Furthermore, pulse pressure is determined approximately by the ratio of the stroke volume to the compliance of the arterial vessels, so any condition that affects either of these parameters will also change the pulse pressure. Pulse ­pressure = Stroke volume / Arterial vessel compliance

Normal Blood Pressure in Various Parts of the Circulation Blood pressures are not the same throughout the cardiovascular system as shown in Fig. 3.9 and Table 3.1. Without these differences in the pressures there would be no blood flow. Thus, the flow of blood, like any other fluid, requires a pressure gradient or pressure difference and moves from high to low pressure. As depicted in Fig. 3.9, the mean pressure, the smooth line, is highest in the aorta (about 100 mmHg) and becomes very low in the veins. The high pressure in the aorta is attributed to the large volume of blood ejected from the left ventricle and the low compliance of the arterial wall. Arterial pressure decreases proportionally based on the resistance that it has to overcome. The greatest decrease in blood pressure occurs in the arterioles because the arterioles contribute to the highest resistance in the circulation. Furthermore, the compliance of the aorta and other arteries dampens the systolic and diastolic pressures, which leads to a reduction of the pulsatile pattern of the blood flow in the smaller vessels. Therefore,

Elmoselhi_CH03_p033-050.indd 45

45

by the time the blood flow reaches the capillaries, there will be no pulsation and the tissue blood flow becomes mainly continuous. ∴ The degree of damping a resistance × compliance Mean arterial pressure (MAP) is the average pressure in each heartbeat or cardiac cycle. MAP is not calculated by taking simple average systolic and diastolic pressures, but rather by using either of the equations below. These equations emphasize the fact that diastole is longer than systole in each heartbeat or cardiac cycle, and consequently, diastole has more weight in calculating the MAP than systole. Mean arterial pressure (MAP) = Diastolic pressure + 1/3 Pulse pressure = 2/3 Diastolic pressure + 1/3 Systolic pressure MAP can also be calculated by arranging the previous equation Q = ΔP/R as follows: MAP = Cardiac output × TPR (total peripheral resistance)

Abnormal Pulse Pressure Contours Some cardiovascular disorders cause characteristic abnormalities in the contours of the pulse pressure wave recording as illustrated in Fig. 3.12. In the case of atherosclerosis, because of the decrease in the arterial compliance, the normal stroke volume will cause increases in systolic pressure, pulse pressure, and MAP. A similar pattern will occur in the elderly because of the stiffness of their blood vessels. In aortic stenosis, the aortic valve narrows and interferes with the ejection of the blood from the ventricle which leads to a reduction of the stroke volume. As a result, the systolic pressure, pulse pressure, and MAP are reduced. In aortic regurgitation, the aortic valve is incompetently or incompletely closed, which causes the blood that had been ejected from the ventricle during systole to return during diastole. Therefore, systolic pressure is increased, diastolic pressure is decreased, and the pulse pressure is increased. In addition, the incisura will be absent because of the lack of closure of the aortic valve.

160 120 80 40 0

Normal

Aortic stenosis Aortic regurgitation

FIGURE 3.12  Pulse pressure contours in aortic stenosis and aortic regurgitation.

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Section II  Heart and Vascular Functions

Methods of Measuring Blood Pressure •• Direct method: The measurement of blood pressure is conducted by inserting a catheter directly into an artery, a method used only in rare, special studies. •• Indirect method (clinical): The auscultatory method is very common in clinical practice and is used to measure systolic and diastolic blood pressure (Fig. 3.13). It uses a stethoscope that is placed over the antecubital artery and a sphygmomanometer (inflatable cuff) that is tightly placed around the upper arm. The cuff is briefly inflated until it closes the brachial artery and no sound can be heard by the stethoscope. Then the cuff is slowly deflated, and once a sound is heard, it marks the systolic pressure. With continuous deflation of the cuff, once the sound disappears, it marks the diastolic pressure. These sounds are called the Korotkoff sounds, named after a Russian physician who described it in 1905. The sounds are caused by the turbulent blood flow and vibration of the blood vessels due to the partly occluded vessel. There will be no sound when the vessel is completely

300

250

150 Sound first heard 100

50

Arm

Systolic, diastolic, and mean arterial blood pressure increases with age due to the changes of the blood pressure control mechanisms (Fig. 3.14). In particular, the kidney, which is normally responsible for the long-term regulation of the blood pressure, decreases in efficiency with age. Additionally, a decrease in the elasticity or “hardening” of the arteries, which is often due to the process of atherosclerosis, eventually leads to an increase in systolic blood pressure and pulse pressure, especially after the age of 60.

Venous System All the blood from the systemic circulation returns to the right atrium via the systemic veins. Hence, the pressure in the right atrium is referred to as the central venous pressure. Normally, the central venous pressure is approximately 0 mmHg,

Cross-section of brachial artery

Pressure cuff

Completely closed No blood flow

Fully inflated above 120 mmHg

Partially open Turbulant flow

Semi-inflated between 120–80 mmHg

Completely open Laminar flow

Not inflated below 80 mmHg

Korotkoff’s sounds

Diastolic pressure (80 mmHg) Pressure cuff

Normal Arterial Pressure and Aging

Starting with a high pressure No sound

200

Systolic pressure (120 mmHg)

closed, or when it is completely open and the flow of the blood is laminar.

Sound disapears No sound

0

Elbow

FIGURE 3.13  Indirect method of measuring blood pressure (clinical): auscultatory method.

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Chapter 3  Cardiovascular Circuitry and Hemodynamics

all the blood coming back into it, the right atrial pressure can increase up to 20 or 30 mmHg. Various parameters of the ­circulatory system that were discussed earlier are summarized in Fig. 3.15.

200

Pressure (mm Hg)

Systolic

Mean

Diastolic

150

100

Gravitational Effect on Vascular Blood Pressure The weight of the blood in the vessels creates pressure due to gravity (gravitational pressure), which is especially significant when the person is in a standing position. Fig. 3.16 shows a profile of the venous pressure throughout the body when standing. The venous pressure at the feet is about +80 mmHg and at the neck veins is about 0 mmHg. The rest of the body’s pressure varies proportionally. The valves in the veins and the contraction of the skeletal muscles surrounding the veins help to pump and return blood toward the heart. It is significant to note that the veins inside the skull, such as the sagittal sinus, have negative pressure up to –10 mmHg, which is critical in head surgery as they may develop air embolisms if the vessel is injured. Similarly, gravity has an impact on arterial pressure as well. In a standing position, the mean arterial pressure at the heart level is approximately 100 mmHg, while at the feet the arterial pressure is about 180 mmHg.

50

0

0

20

40 Age (years)

60

80

FIGURE 3.14  Changes in systolic, diastolic, and mean arterial pressures with age. The shaded areas show the approximate normal ranges.

which equals the atmospheric pressure around the body. The right atrial pressure is regulated by the balance between the ­pumping ability of the right side of the heart to pump blood to the lungs and the amount of the blood flow coming back to the right atrium. Any factor or disease that offsets this balance will change the right atrial pressure. For example, in congestive heart failure, when the heart weakens and fails to pump

Arteries

Arterioles

Capillaries

Venules and veins

500 mm/s

Flow velocity 0.5 mm/s

Blood volume

12%

60% 5%

2%

Systolic Mean 100 mmHg 25 mmHg Diastolic blood pressure

Vascular resistance

FIGURE 3.15  Summary of the various parameters such as flow velocity, blood volume, blood pressure, and vascular resistance in different parts of the vascular system. (Reproduced, with permission, from Mohrman DE, Jane Heller LJ. Cardiovascular Physiology. 8th ed. New York: McGraw-Hill; 2014.)

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Section II  Heart and Vascular Functions

−80 −60 −40

Increment in venous pressure due to gravity (mmHg)

−20 0

0

20

20

40

40

60

60

80

80

Increment or decrement in mean arterial pressure (mmHg)

48

FIGURE 3.16  The effect of gravitational pressure on the arterial pressure (right scale) and on the venous pressure (left scale) throughout the body in a standing person. (Reproduced, with permission, from Barrett KE, Barman SM, Boitano S, Brooks HL. Ganong’s Review of Medical Physiology. 25th ed. New York: McGraw-Hill; 2016.)

Key Points •• The main function of the cardiovascular system is to transport oxygen and nutrients to body tissues and remove carbon dioxide and waste products.

•• The right and left sides of the heart as well as systemic and pulmonary circulation, are connected in series which maintains the balance between the cardiac output and the venous return. •• The left ventricle and arteries have thicker walls than the right ventricle and veins, because the former has a higher blood pressure than the latter. •• Veins have a higher percentage of blood volume ­compared to the arteries due to their higher compliance and capacitance. •• Compared to larger vessels, such as the aorta, the blood velocity of the capillaries is much slower, which allows more time for the exchange of gases and nutrients. •• The relationship between blood flow, pressure, and ­resistance is very critical in maintaining hemostasis and tissue perfusion in various metabolic activities. •• Laminar and turbulent blood flow are important in blood resistance and pressure. •• There are several key factors that regulate the vessels’ resistance, including the series and parallel connection as well as the radius of the vessel. •• The systemic circulation is a high pressure and high resistance system compared to the pulmonary circulation. •• Arterial blood pressure increases with age due to changes in the kidney as well as decreases in vessel compliance.

CASE STUDIES CASE 3.1A  A hypothetical healthy female has 10 organs that are arranged in parallel between the aorta and vena cava. The mean arterial pressure in her aorta is 95 mmHg and the average pressure in her vena cava is 5 mmHg. Also, the resistance for each organ is 10 mmHg/mL/min. Which of the following values approximately represents the blood flow of her circulatory system? a. 25 mL/min b. 50 mL/min c. 90 mL/min

a. Increase b. Decrease c. Stay the same d. Increase and then decrease e. Decrease and then increase

CASE 3.2  In a 21-year-old healthy male college student, which of the following has the lowest velocity of blood flow in his circulatory system?

d. 135 mL/min

a. Veins

e. 150 mL/min

b. Venules

CASE 3.1A  In the above hypothetical case, if one of these organs is a fetus, what would you expect to happen after delivery with regard to the woman’s total peripheral resistance?

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c. Capillaries d. Arteries e. Aorta

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Chapter 3  Cardiovascular Circuitry and Hemodynamics

Suggested Readings James PA, et al. Evidence-based guideline for the management of high blood pressure in adults: report from the panel members appointed to the Eighth Joint National Committee (JNC 8). JAMA. 2014;311(5):507-520.

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Jones DW, Appel LJ, et al. Measuring blood pressure accurately: new and persistent challenges. JAMA. 2003;289:1027. Fuster V, Walsh RA, Harrington RA. Hurst’s The Heart, Part 2. 13th ed. New York: McGraw-Hill; 2011.

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Chapter Electrophysiology of the Heart ADEL ELMOSELHI AND MOHAMED SEIF

Learning Objectives

4

By the end of the chapter the student will be able to: • Draw a typical action potential in a ventricular muscle and a pacemaker cell. • Describe the ionic basis of the phases of the action potential.

Introduction The contraction and relaxation of the cardiac muscle follows a specific synchronized pattern between the atria and the ventricles. This rhythmic contraction and relaxation is preceded by electrical activity called the action potential that is represented in the depolarization and repolarization of the cardiac muscle, respectively. The special origin and sequence of the initiation and propagation of the action potential is essential for maintaining normal heart function. The action potential is created by ions fluxes across the plasma membrane of the cardiac muscle cells via specific channels, transporters, and other proteins. Normally, the action potential originates in the sinoatrial (SA) node known as “the pacemaker of the heart,” which propagates a specific sequence in the atria first and then in the ventricle through specialized conducting tissues as shown in Fig. 4.1. Although the SA node activity sets up the heart rate, the autonomic nervous system modulates this heart rate as well as the electrical conduction and contraction of the heart. Electrical activities of the heart can be precisely measured and monitored via electrocardiography (ECG). Any disturbances of the heart electricity result in various types of arrhythmias as discussed in Chapter 9, which can lead to serious consequences including death. This chapter will briefly explain the major components of the electrical activity of the heart and how it is regulated and measured.

Origin and Pathway of the Action Potential of the Heart There are 3 types of cardiac muscles according to their excitability: (1) the pacemaker cells, (2) the conducting tissues (bundle of His, Purkinje fibers), and (3) the ventricular and atrial muscle fibers. Each of these types has its unique action potential as will be discussed. In general, the action potential originates in the SA node and then spreads to both the atrial nodes via the internodal tracts and the atrial tissues. Then, the action potential passes to the atrioventricular (AV) node and to the ventricle through bundles of His and Purkinje fibers. The conduction of the action potential in the AV node is much

• Explain the significance of the long duration of the cardiac action potential and the resultant long refractory period. • Describe the normal sequence of cardiac activation and conduction and predict the consequence of its abnormalities. • Discuss the significance of “overdrive suppression” in a natural pacemaker and the abnormalities leading to an “ectopic pacemaker.” • Explain the effects of the sympathetic and parasympathetic nervous system on the heart rate, cardiac conduction, and contractility. • Describe the main components of a normal ECG recording, their significance, and abnormalities.

slower than in any other part of the heart. This conduction delay in the AV node is important as it allows the atria to contract before the ventricle, so that the ventricle completely fills with blood before it contracts and ejects the stroke volume. Therefore, any shortening of the AV node conduction can result in less ventricular filling and reduce the stroke volume and the cardiac output. The electrical insulation between the atria and the ventricle is critical for preventing electrical conduction other than through the AV node and the bundle of His. This insulation is achieved by fibrous tissue that surrounds the tricuspid and mitral valves as shown in Fig. 4.2. Once the action potential passes the AV node, it spreads very quickly through a common bundle of the His, then to the right and left bundle branches to the Purkinje fibers, and finally to the ventricle tissues from the endocardium to the epicardium. The action potential normally travels in one direction. The fast travel of the action potential in the His-Purkinje fibers allows the ventricles to function as one unit, known as functional syncytium. This rapid spreading of the action potential across the cardiac tissues is due to a large number of gap junctions in the intercalated discs that is unique to the heart.

51

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Section II  Heart and Vascular Functions

Basic Principles of the Action Potential

Atrioventricular node

Superior vena cava

Bundle of His

Sinoatrial node

Left atrium

Right atrium Right bundle branch

Left ventricle

Right ventricle Purkinje fibers Inferior vena cava Interventricular septum

Left bundle branch

FIGURE 4.1  Sectional view of the heart. The basic anatomy of the heart is indicated, including chambers, major blood vessels, and conducting system (yellow), including the sinoatrial node, atrioventricular node, and Purkinje fibers. (Reproduced, with permission, from Barrett KE, Barman SM, Boitano S, Brooks HL. Ganong’s Review of Medical Physiology. 24th ed. New York: McGraw-Hill; 2012.)

Posterior

FIGURE 4.2  Fibrous tissues encircle the tricuspid and mitral valves as well as the great vessels between the atria and the ventricles and serve as electrical insulator to allow the action potential to travel only through the AV node and the AV bundle and also as a valve support.

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The ion movement across the plasma membrane is the basis for the action potential, especially Na+, K+, and Ca2+. In a normal cardiac cell, the Na+ and Ca2+ concentrations are much higher in the extracellular fluid, while the K+ concentration is higher in the intracellular fluid. Ion transport across cell membranes is governed by the concentration gradient, the transmembrane electrical potential, as well as the permeability of the plasma membrane. The ions move from a high concentration area to a lower concentration area, so the higher the concentration gradient, the higher the rate of the ion flow. At the resting state of the cardiac cells, the Na+ concentration is much higher outside the cell compared to inside the cell, it is about 145 mM vs.15 mM, respectively. Therefore, there is a strong tendency of the Na+ to move inside the cell down to its concentration gradient. Furthermore, the resting transmembrane potential of the cardiac cell is approximately -95 mV with the negative charge inside the cell relative to the outside of the cell. This negative charge inside the cardiac cell attracts the positively charged Na+ ions. These two forces, the concentration gradient, and the electrical potential promote the strong tendency of the Na+ ions to enter the cell during depolarization of the action potential. The third critical factor that determines the ion transport across the plasma membrane is a change in the membrane permeability, or the ion conductance. The phospholipid bilayer membrane is not permeable to ions; instead, special ion channels within the membrane allow the ions to pass across the membrane when it is open. The majority of the ion channels consist of repeating transmembrane domains of glycosylated proteins. The channels are characterized by their selectivity to a specific ion and by their gating properties, which are either opened or closed for certain periods of time. The opening and closing of the channel gate is determined by the voltage or legend depending on the type of the channels. A good example for a voltage-sensitive gating channel is the fast sodium channel, which causes depolarization. The membrane potential of cardiac cells depends on the conductance of the ions and the concentration and electrical gradients of those ions across the cell membrane. When the conductance of a specific ion is high, this ion will flow down to its electrochemical gradient and will drive the membrane potential toward its equilibrium gradient according to the Nernst equation. The ions with low conduction will have almost no effect on the membrane potential. In a cardiac cell, the resting membrane potential is mainly determined by K+ ions because its conductance is very high (via the inward rectifier of the potassium channels) which result in K+ outward movement. As a consequence, the resting membrane potential is close to the equilibrium potential of the K+ ions which is –91 mV according to the following Nernst equation, considering that at rest, K+ concentration in the intracellular fluid is about 150 mM and in the extracellular fluid is 5 mM: Potassium equilibrium potential = –26.7 In ([K+]in / [K+]out) = –91 mV

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Chapter 4  Electrophysiology of the Heart

53

The Na+-K+ ATPase pump mainly maintains the Na+ and K ion concentration potential across the cell membranes, but also plays a minor role in contributing to the membrane potential.

its equilibrium potential, which is about +65 mV; however, at the peak of the upstroke, the membrane depolarizes to only about +20 mV.

The Action Potential of the Cardiac Muscle Cells (Ventricles, Atria, and Purkinje Fibers)

Phase 1 (Partial Repolarization)

+

Phase 1 is a partial repolarization at the peak of the upstroke phase, bringing the membrane potential to about 0 mV. It is caused by the outward flow of the K+ current via the transientactivated K+ channels.

The action potential in all cardiac muscle cells except that the SA and AV nodes share similar characteristics, such as longer duration, plateau, and stable resting membrane potential, as shown in Fig. 4.3. The longest duration is in the Purkinje cells, at about 300 ms, followed by 250 msec in the ventricles, and 150 msec in the atria. In general, those durations are much longer compared to the very short duration of the action potential in the skeletal muscle and the nerve cells, which are about 1 to 2 msec. In contrast to the SA and AV node cells, the resting membrane potential of cardiac cells, if not stimulated, remains stable at –90 mV as indicated in phase 4 below. The ionic basis of each phase of the action potential is described in detail below and illustrated in Fig. 4.4A.

Phase 2 (Plateau Phase) Phase 2 is a long depolarization phase that has a plateau due to the balance between the inward Ca2+ current and the outward K+ current. The K+ channels that cause the K+ efflux are called delayed rectifier potassium channels. The inward Ca2+ current is the result of opening the L-type voltage-gated Ca2+ channels (ie, L refers to long-lasting). The Ca2+ channels open slowly and stay open for a longer period of time compared to the more efficient Na+ channels. Calcium influx during this phase has an important role in cardiac muscle contraction by releasing Ca2+ from the sarcoplasmic reticulum (SR) via a Ca2+-induced Ca2+ release mechanism.

Phase 0 (Depolarization or Upstroke Phase)

Phase 3 (Repolarization Phase)

This phase represents the depolarization phase, or the upstroke phase, similar to that of the skeletal muscle and the nerves. It is caused by the increase of the conductance of the Na+ as a result of opening the fast Na+ channels. Once the channels open, an influx of the Na+ occurs, creating an inward Na+ current, bringing the resting membrane toward

Phase 3 is the repolarization phase as the voltage potential returns back to the resting membrane potential of –90 mV. The repolarization is mainly due to the K+ outward current as a result of the increased permeability to the K+ and the decreased permeability to the Ca2+.

Aorta Action potential

SA node

Superior vena cava

Atrial muscle AV node

Sinoatrial node LAF

Internodal pathways

Common bundle Bundle branches

Atrioventricular node

Purkinje fibers Ventricular muscle

Bundle of His Right bundle branch

ECG Purkinje system Left posterior fascicle

T

P QRS

0.2

0.4 Time (s)

U 0.6

FIGURE 4.3  Conducting system of the heart. Typical transmembrane action potentials for the SA and AV nodes, other parts of the conduction system, and the atrial and ventricular muscles are shown along with the correlation to the extracellularly recorded electrical activity (ie, the electrocardiogram [ECG]). The action potentials and ECG are plotted on the same time axis but with different zero points on the vertical scale. The PR interval is measured from the beginning of the P wave to the beginning of the QRS. LAF, left anterior fascicle. (Reproduced, with permission, from Barrett KE, Barman SM, Boitano S, Brooks HL. Ganong’s Review of Medical Physiology. 24th ed. New York: McGraw-Hill; 2012.)

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Section II  Heart and Vascular Functions

+20

1 2

mV

0

0 3

4

−90 INa

ICa

IK 0

Time (ms)

200

A

Ionic currents

Potential (mV)

Phases of the Action Potential in SA Node and its Ionic Events

0 0

3

4

−65

Outward

IK+ Ii

Inward ICa2+

B

Phase 0 = Upstroke phase Phase 1 & 2 = NOT present Phase 3 = repolarization Phase 4 = spontaneous depolarization or pacemaker potential

FIGURE 4.4  A. Dissection of the cardiac action potential. Top: The action potential of a cardiac muscle fiber can be broken down into several phases: 0, depolarization; 1, initial rapid repolarization; 2, plateau phase; 3, late rapid repolarization; 4, baseline. Bottom: Diagrammatic summary of Na+, Ca2+, and cumulative K+ currents during the action potential. As is the convention, the inward currents are downward, and the outward currents are upward. B. Pacemaker cells in the sinoatrial (SA) node lack the same distinct phases as the atrial and ventricular muscle cells and display prominent spontaneous diastolic depolarization.

Phase 4 (Resting Membrane Potential) This is a stable phase when the action potential is fully repolarized and the inward and outward current are balanced. The outward K+ current is due to the high conductance of the K+ in

Elmoselhi_CH04_p051-070.indd 54

this phase that drives the resting membrane potential toward its equilibrium potential. The inward current is mainly due to the Na+ and Ca2+ influx, which both have a low conductance during this phase.

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55

Unlike the other cardiac cells, the action potential the SA and AV nodes is characterized by automaticity (ie, spontaneous depolarization), unstable resting membrane potential, and the lack of the plateau phase. The SA node is the normal pacemaker of the heart; however, the AV node can take over in case of damage to the SA node. Although the ventricle and atrial cells normally do not exhibit automaticity, in certain diseases they may, as seen in cardiac ischemia. The phases and ionic basis of the SA and AV nodes’ action potential is shown in Fig. 4.4B and described below.

Phase 0 (Upstroke Phase) Phase 0 in a node cell is not as rapid or sharp, and it does not reach a higher amplitude as in the other cardiac cells. It is caused by increased Ca2+ conductance that results in an inward Ca2+ current.

Phases 1 and 2 Unlike ventricular action potential phases 1 and 2 are absent in SA and AV nodes action potential.

150 mV

The Action Potential of the SA and AV Nodes Action potential recorded intracellularly

0.5 g ARP 0

100

RRP

ms

200

Mechanical response 300

FIGURE 4.5  Comparison of the action potentials and the contractile response of a mammalian cardiac muscle fiber in a typical ventricular cell. In the top trace, the intracellular recording of the action potential shows the quick depolarization and extended recovery. In the bottom trace, the mechanical response is matched to the extracellular and intracellular electrical activities. Note that in the absolute refractory period (ARP), the cardiac myocyte cannot be excited, whereas in the relative refractory period (RRP) minimal excitation can occur. (Reproduced, with permission, from Barrett KE, Barman SM, Boitano S, Brooks HL. Ganong’s Review of Medical Physiology. 24th ed. New York: McGraw-Hill; 2012.)

Phase 3 (Repolarization) Similar to other cardiac cells, repolarization is caused by the high conductance of K+ ions that result in the K+ efflux. The large electrochemical gradient of the K+ ions drives this outward K+ current during this phase.

Phase 4 (Pacemaker Potential or Spontaneous Depolarization) Unlike other cardiac cells, phase 4 in the nodal cells exhibits a spontaneous gradual depolarization. This property accounts for the automaticity and the ability to spontaneously generate an action potential. The spontaneous depolarization is based on the opening of special Na+ channels that leads to an inward Na+ current If. The “f” refers to “funny Na+ current” because these Na+ channels are unpredictable and possess unusual properties compared to the fast Na+ channels. They open slowly and are stimulated by the preceding repolarization; the depolarization occurs gradually until it reaches a threshold where the upstroke phase starts as a result of the T-type Ca2+ channels (ie, T refers to Transit). The rate of depolarization in phase 4 sets up the heart rate. If the depolarization in phase 4 reaches its threshold quickly, the SA node will fire more frequently and the heart rate will increase. The opposite is true with decreases in the heart rate as a result of the slower rate of depolarization in phase 4. The autonomic nervous system acts on this mechanism to regulate the heart rate as discussed below.

Refractory Periods The refractory period is when the muscle cannot respond to another stimulation. The cardiac muscle refractory period

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is much longer than in a skeletal muscle because the action potential in the cardiac muscle is longer. This unique property of the cardiac muscle allows the ventricles of the heart enough time to be filled with blood before contractions; it is also the reason that heart muscle never endures sustained contractions (ie, tetany). Fig. 4.5 shows different degrees of the refractory period during the action potential. The number of fast Na+ channels recovered and ready to respond for depolarization determines the degree of refractory periods as follows: •• The absolute refractory period (ARP) refers to the time when the cells are completely incapable of generating an action no matter how strong the stimulus. Most of the Na+ channels are closed and cannot be opened. This includes the periods of the upstroke, plateau, and repolarization until almost –50 mV. •• The effective refractory period (ERP) extends a little more beyond the absolute refractory period where a stimulus can generate a localized action potential that cannot be propagated. •• The relative refractory period (RRP) is a period where a stronger than normal stimulus can generate an action potential. However, the characteristics of the action potential generated in this period are abnormal, with a slower rate of rising and a shorter plateau phase. The reason for this abnormality is that some Na+ channels have still not recovered and the K+ channels are still active. •• During the supranormal period (SNP), the cardiac cell is more excitable, so a weaker than normal stimulus can generate an action potential. This is because the

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Section II  Heart and Vascular Functions

membrane potential of the cell is closer to the threshold level and the majority of the Na+ channels have recovered.

Effect of the Autonomic Nervous System on the Heart Rate and the Conduction Velocity of the Heart The distribution of the sympathetic and parasympathetic innervations of the heart is different. Briefly, the parasympathetic nerves mainly supply the SA and AV nodes and some atrial muscles, but not as much in the ventricle muscles. Sympathetic nerves, on the other hand, are equally distributed in all parts of the heart, especially in the ventricle muscles. Normally, there is a dominant parasympathetic effect on the SA node that sets the heart rate during rest at around 70 beats/min instead of the intrinsic rate of 100 beats/min. In general, the autonomic nervous system modulates the heart rate via its effect on the SA node action potential; this is called the chronotropic effect. Fig. 4.6 illustrates the normal rate of the SA node action potential—the sympathetic stimulation that increases the rate of the SA action potential and the heart rate (ie, a positive chronotropic effect) and the parasympathetic stimulation that decreases the rate of the SA action potential and the heart rate (ie, a negative chronotropic effect). Furthermore, the autonomic nervous system changes the velocity of the action potential’s conduction through the heart and the conductive system; this is called the dromotropic effects. Positive dromotropic effect means an increase in the conduction velocity, which is induced by the sympathetic nervous system. Negative dromotropic effect indicates a decrease in the conduction velocity, which is mediated by the parasympathetic nervous system. The mechanisms of the autonomic nervous system effects on both the heart rate (chronotropic) and the conduction velocity (dromotropic) are explained as follows.

0 mV Sympathetic stimulation

60

0 mV Vagal stimulation

60

FIGURE 4.6  Effect of sympathetic (noradrenergic) and vagal (cholinergic) stimulation on the membrane potential of the SA node. Note the reduced slope of the prepotential after vagal stimulation and the increased spontaneous discharge after sympathetic stimulation. (Reproduced, with permission, from Barrett KE, Barman SM, Boitano S, Brooks HL. Ganong’s Review of Medical Physiology. 24th ed. New York: McGraw-Hill; 2012.)

Elmoselhi_CH04_p051-070.indd 56

Sympathetic Effect on the Heart Rate and the Conduction Velocity Norepinephrine from the sympathetic nerve endings binds to the β1-adrenergic receptors that couple to adenyl cyclase through the Gs membrane proteins. Activation of the β1 receptor in the SA node results in an increase of the Na+ inward current “If” and thus enhances depolarization of phase 4 (the spontaneous depolarization phase). Furthermore, it increases the inward Ca2+ current by opening the Ca2+ channels and reducing the threshold to fire an action potential. Both mechanisms increase the frequency of the firing action potential in the SA node and consequently increase the heart rate. In addition, sympathetic activation increases the conduction velocity, especially in the AV node and the AV bundles. The increased permeability of the Ca2+ and the Na+ makes it easier for the action potential to excite the next cells with shorter effective refractory periods and thus the conduction from the atria to the ventricles is faster.

Parasympathetic Effect on the Heart Rate and the Conduction Velocity Acetylcholine (ACh) is released from the parasympathetic nerve endings and binds to the muscarinic (M2) receptors in the SA node that inhibit adenylyl cyclase by coupling with Gi proteins. This inhibition of the adenylyl cyclase decreases the inward Na+ current “If” and reduces the rate of depolarization of phase 4 (the spontaneous depolarization phase). Activation of the Gi proteins also increases the outward K+ current via the opening K+ channels, called K+-ACh, which hyperpolarize the SA nodal membranes, making it more difficult for spontaneous depolarization. Furthermore, the inward Ca2+ current decreases with fewer Ca2+ channels, which also make difficult for the action potential to reach its threshold during phase 4 or spontaneous depolarization. All 3 of these mechanisms contribute to a decrease in the frequency of the action potential in the SA node and decrease the heart rate with the activation of the parasympathetic nervous system. The parasympathetic activation (ie, vagal stimulation) decreases the conduction velocity, especially in the AV node. The mechanism of this reduction is the hyperpolarization of the cell membranes caused by an increased outward K+ current as well as a decreased inward Ca2+ current. This results in prolonging the effective refractory period. The degree of reduction of the action potential traveling from the atria to the ventricle varies from mild to severe degrees, which can lead to a complete heart block. A complete heart block means that there is no action potential passage from the atria to the ventricle, which can lead to a serious condition that might be fatal.

Normal Electrocardiogram Electrical currents (depolarization and repolarization) generated in the heart can be measured by an electrocardiogram (ECG). The heart’s electrical currents spread through the

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Chapter 4  Electrophysiology of the Heart

tissues surrounding the heart up to the surface of the skin. The ECG uses 2 electrodes that are placed on the skin on opposite sides of the heart. The ECG is a useful clinical diagnostic tool used to measure the electrical activity of the heart in normal and abnormal conditions, especially in: (1) rhythm disturbances (eg, cardiac arrhythmias), (2) changes in electrical conduction (eg, heart blocks), and (3) disruption of blood supply (eg, cardiac ischemia and infarction). The details of a normal ECG and the most common abnormalities will be discussed in this chapter. However, for the full description of an ECG and a complete description of all the abnormalities, it is recommended that the reader refer to one of the ECG textbooks listed at the end of this chapter.

Properties of a Normal ECG Normal ECG tracing of one heartbeat consists of a P wave, QRS complex, and T wave as illustrated in Fig. 4.7. The P wave represents the depolarization of the atrial muscle cells which precede an atrial contraction. After the P wave, the tracing returns to the baseline to represent the conduction of the action potential from the atria to the ventricles. The QRS complex usually, but not always, includes 3 waves, as its name implies—the Q wave, R wave, and S wave. The QRS complex represents the depolarization of the ventricular muscle cells that initiates a ventricular contraction. Following the QRS complex, the tracing returns to the baseline, representing the interval between the depolarization and the repolarization of the ventricle. The T wave represents the repolarization of the ventricular muscle cells. Sometimes, a small deflection called

R

P-R segment

S-T segment T

P

P

T

Q S

PR interval 0.12-0.2 s

QRS 0.08 s

S-T interval

Q-T interval 0.25-0.45 s heart rate dependent

FIGURE 4.7  Nomenclature of the deflections, intervals, and segments of the normal electrocardiogram. (Reproduced, with permission, from Fuster V, Walsh RA, Harrington RA, eds. Hurst’s The Heart. 13th ed. New York: McGraw-Hill; 2011.)

Elmoselhi_CH04_p051-070.indd 57

57

a U wave, follows the T wave that is known as the late phase of ventricular depolarization. Furthermore, normal ECG tracing includes the P-R interval, the ST segment, and the Q-T interval. The P-R interval represents the time between the beginning of the P wave until the beginning of the QRS complex (ie, therefore it is sometimes called the P-Q interval, but the Q wave is often absent). Thus, the P-R interval indicates the duration of atrial depolarization plus the AV nodal delay, which is normally between 0.12 and 0.2 sec. The ST segment represents the isoelectric baseline for ventricular muscle depolarization. An elevation or depression of the normal ST segment indicates an ischemic disorder the heart. The Q-T interval represents the duration of the action potential of the ventricular muscle cells including both depolarization and repolarization. It is measured from the beginning of the QRS complex (it starts from the Q wave, or R wave if the Q wave is absent) to the end of the T wave. Normally, it is about 0.35 sec; however, it ranges between 0.2 to 0.4 sec according to the heart rate. Thus, in a faster than normal heart rate, the Q-T interval will be shortened.

Recording Depolarization and Repolarization Waves in Cardiac Muscle Fibers The action potential in cardiac muscle cells is recorded using voltmeter electrodes that are placed on the surface of the cell as shown in Fig. 4.8A. The various phases of the action potential are recorded as follows. •• At rest, the cardiac muscle cell is at a polarized state with the negative charges inside and the positive charges outside the cell membrane. A flat baseline will be recorded if there is no electrical potential gradient or difference between both the electrodes on the surface of the cell membrane. •• During depolarization, the influx of the cations creates positive charges inside the cell and negative charges outside the cell. In partial depolarization of the cell, when only part of the plasma membrane has negative charges outside the cell due to depolarization, while the rest of the cell membranes are still polarized with positive charges outside the cell, an electrical potential gradient and electrical current are created that can be measured. The direction of the flow of the electrical current is from the negative charged to positive charged. An upward deflection is recorded when the electrical current is directed toward a positive electrode. This deflection will return to baseline when depolarization spreads to the rest of the cell membrane. •• During repolarization, the efflux of the cations brings back the positive charges outside and the negative charges inside. In partial repolarization, similar to depolarization, an electrical potential and electrical current are created, which can be detected and measured. However, in repolarization the current is moving away from the positive

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Section II  Heart and Vascular Functions

I

aVR

aVL

V1

V2 V3

V2

V3

V4

V5

V6

Repolarization

V1

V6

Depolarization

V5

V4

R III

II A

aVF

Q

T

S

B

FIGURE 4.8  A. Normal ECG. Tracings from individual electrodes (positions marked in figure) are shown for a normal ECG. B. Monophasic action potential versus ECG in ventricular muscle. (Part A: Reproduced, with permission, from Goldman MJ. Principles of Clinical Electrocardiography. 12th ed. Originally published by Appleton & Lange. Copyright © 1986 by McGraw-Hill.)

electrode and thus it records as a downward deflection. Once the repolarization spreads to the rest of the plasma membrane the deflection returns to the baseline. ECG recordings measure the electrical currents generated in the heart, but spread and are transmitted to the skin. Thus, the voltage measured directly from the muscle cell as in the monophasic action potential is much higher (~110 mV) than the voltage measured by the ECG (0.1 to 4 mV). A comparison between the monophasic action potential and the ECG tracing is shown in Fig. 4.8B, which illustrates that there is no potential as recorded in the ECG when the ventricular muscle is completely polarized or depolarized.

Elmoselhi_CH04_p051-070.indd 58

Direction of the Electrical Current Flow of the Heart The action potential originating in the pacemaker of the heart spreads into the atria and then through the AV node to the septum and the rest of the ventricles. It spreads from the endocardium to the pericardium of the heart. During partial depolarization, the outside surface of the ventricle is negatively charged while the rest is positively charged while it is still in the polarized state. At the same time, electrical currents are generated and their direction takes on an elliptical shape from the base to the apex of the heart, as shown in Fig. 4.9. This pattern and direction of the electrical currents occurs in almost

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Chapter 4  Electrophysiology of the Heart

0 – –

+ +

B A

++ + ++ + – – –– – ++ ++ – –– + ++ ++ –+ + + +–– + + + + ++ –– +++ + + + + + ++ + + + +++ ++

FIGURE 4.9  The direction of the electrical current flow in the heart.

all of the depolarization phases of the heart, except in the very last part, the current flow reverses from the ventricular apex to the base because the last portion of the heart to be depolarized is the other part of the ventricles near its base.

ECG Leads The signal observed in an ECG recording depends on the leads used. There are 2 types of ECG leads: (1) limb (standard) leads and (2) chest leads (precordial leads). Limb leads include (a) 3 bipolar standard limb leads and (b) 3 augmented unipolar limb leads. Thus, the all of the 12 leads of the ECG allow the recording of the same electrical currents of the heart from 12 different views or angles. The limb leads refer to 6 reference axes that are representative to the body’s frontal plane, while the chest leads demonstrate the transverse plane of the body. A brief description of each lead is provided as follows. •• Three bipolar standard limb leads: In this arrangement, there are 2 electrodes placed on 2 different sides of the heart. One limb electrode is the positive pole and the other single electrode is the negative reference. Normal ECG tracings for the bipolar standard limb leads are shown in Fig. 4.10. •• Lead I: The negative electrode is connected to the right arm and the positive electrode is connected to the left arm. •• Lead II: The negative electrode is connected to the right arm and the positive electrode is connected to the left leg. •• Lead III: The negative electrode is connected to left arm and the positive electrode is connected to the left leg.

Elmoselhi_CH04_p051-070.indd 59

•• Einthoven’s law: If the electrical potentials of any 2 of the 3 bipolar limb ECG leads are known at any given instant, the third one can be calculated by ­summing the first 2 leads as shown in Fig. 4.11. The positive and negative signs of those 2 leads need to be considered during summation. •• Augmented unipolar limb leads: As the name implies, in this arrangement of leads there is only one positive electrode or pole attached to one limb and no single negative pole; the other electrodes attached to the other limbs collectively form the negative pole. Normal ECG tracings for the unipolar limb leads are shown in Fig. 4.12. •• aVR (augmented Voltage Right arm): The positive electrode is attached to the right arm. •• aVL (augmented Voltage Left arm): The positive electrode is attached to the left arm. •• aVF (augmented Voltage left Foot): The positive electrode is attached to left leg. By convention, the axial reference system is established based on the aforementioned 6 limb leads as shown in Fig. 4.13. The direction from the negative electrode to the positive electrode of each of those leads is called the axis. The axis of lead I is from the right arm to the left arm; thus, it lies in a horizontal direction and is considered to be 0°. The rest of the axes run clockwise with an angle measured at 30° between each one; that is, +30°, +60°, +90°, and so forth. The axial system is critical in demonstrating the direction and magnitude of the electrical activity of the heart as explained in a vectorial analysis of the ECG. A vector is an arrow that points in the direction of the electrical potential of the heart generated by the current flow (the arrowhead points to the positive direction). The length of the arrow is proportional to the voltage of the potential. The mean vector is an arrow directed from the base to the apex of the heart, passing through the center of the ventricles: Mean QRS vector = +59°

Chest Leads (Precordial Leads) To obtain a further dimension of the electrical activity of the heart, 6 chest electrodes are placed on the anterior and left lateral aspects of the chest as shown in Fig. 4.14. These are unipolar leads with positive electrodes pointing to the heart in a cross-sectional plane and recorded as V1, V2, V3, V4, V5, and V6 for normal heart tracing. In leads V1 and V2, the QRS are recorded as downward deflections because they are located at the base of the heart where the direction of the ventricular depolarization is traveling away from the positive electrode. However, leads V4, V5, and V6 have an upward deflection because they are located at the apex of the heart where the depolarization waves are traveling toward the positive electrode. There are a few important common principles of ECG interpretation that can be summarized as follows: •• A depolarization wave directed toward a positive electrode results in an upward deflection on the ECG tracing of that specific lead.

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Section II  Heart and Vascular Functions

I

+0.5 mV 0 –

+

–

+ Lead I

– –

+ – II

+

+

–0.2 mV

+0.3 mV

+1.2 mV

+0.7 mV

0 –

III

0 +

–

–

+

+

–

Lead II

+ Lead III

+1.0 mV

FIGURE 4.10  Three bipolar standard limb leads.

•• A depolarization wave directed away from a positive electrode results in a downward deflection of that lead. Lead I – +

+

–

II

Le

+

II

I ad Le

–

LA

ad

RA

•• A repolarization wave directed toward a positive electrode results in a downward deflection of that lead. •• A repolarization wave directed away from a positive electrode results in an upward deflection of that lead. •• A depolarization or repolarization wave directed perpendicular to an electrode axis results in no net deflection of that lead.

Practical Interpretation of an ECG LL

FIGURE 4.11  Einthoven’s triangle.

Elmoselhi_CH04_p051-070.indd 60

An ECG recording appears in a standard special grid, divided in vertical and horizontal lines spaces that are 1 mm apart, as shown in Fig. 4.15. For the vertical axis, each 1 mm equals 0.1 mV, while in the horizontal axis, each 1 mm = 0.04 sec (5 mm = 0.2 sec). To facilitate counting, every 5 mm a darker

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Chapter 4  Electrophysiology of the Heart

(+)

(+)

aVR

aVL

aVF

(+)

Unipolar limb leads

FIGURE 4.12  Augmented unipolar limb leads.

line is drawn, thus dividing the grid into larger boxes and smaller boxes. Each large box has 5 small boxes that run vertically and horizontally. It is highly recommended that a systemic approach be followed when reading any ECG tracing to avoid missing any significant information. The systemic approach includes the following: 1. Calibration: 10 mm vertical = 1 mV 2. Rhythm: The following criteria have to be met in order to qualify the tracing as a sinus rhythm: a. Every P wave is followed by a QRS b. Every QRS is preceded by a P wave c. P waves move upward in leads I, II, and III d. A P wave interval in more than 0.12 sec (>3 small boxes) i. Normal sinus rhythm = Heart rate between 60 and 100 beats/min and meets the above criteria

ii. Sinus bradycardia = Heart rate 100 beats/min and meet the above criteria Abnormal rhythms are called arrhythmias or dysrhythmias as discussed in more detail in Chapter 9. 3. Heart rate: There are different methods for counting the heart rate from ECG tracings as follows (Fig. 4.16): a. Method 1: Count the number of large boxes between the 2 adjacent R waves. Start with an R wave that aligns with a dark line of a large box. Track its next R wave and identify the heart rate using the following sequence of numbers that you need to memorize. This method provides a quick but approximate count of the heart rate. 300 —150—100—75—60—50

Superior Posterior

–

–

aVR +

–

Right

aVL +

– – –

–

–

Left + V6

+ I

–

–

– III Right

+

+ aVF

+V

+ II

+ + V1 V2 Anterior

Left

Inferior A

+ V3

5

+ V4

B

FIGURE 4.13  An axial reference system.

Elmoselhi_CH04_p051-070.indd 61

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Section II  Heart and Vascular Functions

EKG paper (enlarged)

one mm

EKG paper (actual size)

one mm

V1

V6

V2 V3

V4

V5

Midaxillary line Anterior axillary line Midclavicular line .2 sec.

FIGURE 4.14  Chest leads (precordial leads). (Reproduced, with permission, from Gomella LG, Haist SA. Clinician’s Pocket Reference. 11th ed. New York: McGraw-Hill; 2006.)

i. 25 mm/sec is the standard paper speed. ii. This method is useful for counting a fast heart rate. c. Method 3: Count the number of R waves within 3 seconds and multiply it by 20. Or, count the number of R waves within 6 seconds and multiply it by 10. The marker for 3 seconds is 15 large boxes, and for 6 seconds it is 30 large boxes. This method is useful for counting an irregular heart rate. 4. Intervals a. PR intervals: Measure from the beginning of the P wave to the beginning of the QRS complex. Normally, it measures between 0.12 to 0.2 sec (3 to 5 small boxes). It is increased in the first-degree heart block and decreased in preexcitation syndrome and the junctional rhythm. b. QT intervals: Measure from the start of the QRS complex until the end of the T wave. Normally, it depends on the heart rate (the faster the heart rate, the shorter the QT interval). Thus, when it is corrected with the heart rate, the corrected QT ≤0.44 sec is normal, or visually, the QT interval is normal if it is less than half of 2 consecutive QRS complexes. QT interval increases occur in cases of

Elmoselhi_CH04_p051-070.indd 62

Time

1 mm = Small box = 0.04 second 5 mm = Big box = 0.2 second

b. Method 2: Count the number of small boxes between the 2 adjacent R waves and then use the following equation: Heart rate = (25 mm/sec × 60 sec/min) / number of small boxes (mm) between 2 adjacent R waves= 1500 / number of small boxes (mm) between 2 adjacent R waves

.04 sec.

3 mm High Baseline 2 mm Deep 10 mm Vertically = one millivolt (mV)

FIGURE 4.15  ECG standard grid.

myocardial ischemia, hypocalcemia, hypokalemia, hypomagnesemia, congenital long QT, hypothermia, acute myocardial infarction, increased intracranial pressure, and side effects from some drugs such as antiarrhythmic drugs. QT interval decreases occur in tachycardia and hypercalcemia. c. QRS intervals: Measure the duration of the QRS complex that is normally ≤0.1 sec (2.5 small boxes). Increases occur in cases of bundle branch blocks, aberrant conduction, premature ventricular contractions (PVCs) ventricular rhythms, severe hyperkalemia, and side effects from some drugs such as antiarrhythmic drugs. 5. Mean QRS axis/vector: The mean QRS axis is the average of the electrical currents generated during depolarization, which is directed from the base to the apex of the heart. Normally, it ranges between –30° and +90° as shown in Fig. 4.17. If the mean QRS axis is between –30° and –90°, it indicates a left-axis deviation. If the mean QRS axis is between +90° and +180°, it

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Chapter 4  Electrophysiology of the Heart

Method 2

63

The “count-off” method requires memorizing the sequence: 300—150—100—75—60—50 Then use this sequence to count the number of large boxes between two consecutive beats: 300 100 60 75 50

Start here

A The second QRS falls between 75 and 60 bpm; therefore, the heart rate is approximately midway between them ∼67 bpm. Knowing that the heart rate is approximately 60–70 bpm is certainly close enough. Method 1

First, count the number of small boxes (1 mm each) between two adjacent QRS complexes (i.e., between 2 “beats”). Then, since the standard paper speed is 25 mm/sec: Heart Rate (25 mm/sec × 60 sec/min) 1,500 = = (beats/min) Number of mm between beats Number of mm between beats In this example, there are 23 mm between the first 2 beats. 23 mm Between beats

B Therefore, the heart rate =

1,500 = 65 bpm 23

Method 1 is particularly helpful for measuring fast heart rates (> 100 bpm) Method 3

ECG recording paper often indicates 3-sec time markers at the top or bottom of the tracing: Marker

Marker 3 sec

C To calculate the heart rate, count the number of QRS complexes between the 3-sec markers (= 6 beats in this example) and multiply by 20. Thus, the heart rate here is approximately 120 bpm. It’s even easier (and more accurate) to count the number of complexes between the first and third markers on the strip (representing 6 sec of the recording) and then multiply by 10 to determine the heart rate. Method 3 is particularly helpful for measuring irregular heart rates.

FIGURE 4.16  Measuring the heart rate from an ECG tracing (method 1 (A), method 2 (B) and methods 3 (C ) as described in the text).

indicates a right-axis deviation. An extreme right-axis deviation or axis indeterminate (no man’s land) occurs when the mean QRS axis is between –90° and +/–180° as shown in Fig. 4.17. There are several methods that can be used to determine the mean QRS axis. The following are the easiest and most commonly used methods:

Elmoselhi_CH04_p051-070.indd 63

a. Look at the direction of QRS deflection in lead I and an aVF lead: i. Upward deflection in both leads = Normal mean axis ii. Upward deflection in lead I and downward in an aVF = Left-axis deviation

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64

Ex tre me

is

tion via e d –120° –II

Left axi sd –90° –aVF

–60° –III

–150° +aVR

ev iat i

on

ax

Section II  Heart and Vascular Functions

–30° +aVL

180° –I

0° +I

Ri g

+150° –aVL

+30° –aVR

v de

n

ax

is ti o

+60° +II

al

ax ia

+90° +aVF

is

ht +120° +III

No

rm

FIGURE 4.17  The mean QRS axis and its abnormalities. (Reproduced, with permission, from Kasper DL, Fauci AS, Hauser SL, Longo DL, Jameson JL, Loscalzo J, eds. Harrison’s Manual of Medicine. 19th ed. New York: McGraw-Hill; 2015.)

b. c.

d. e.

f.

iii. Downward deflection in lead I and upward in an aVF = Right-axis deviation A downward deflection in lead I and downward in aVF = Extreme right-axis deviation or axis indeterminate. In the 6 limb leads, locate the QRS that is the most isoelectric and the mean axis will be perpendicular to that lead. Then, in that perpendicular lead if the QRS is mainly upward, this indicates that the mean axis is directed to the positive pole; while if it is mainly downward, this indicates that the mean axis is directed to the negative pole of that lead. This is the most commonly used method. Vector analysis: This method is explained in sources referenced in the suggested readings and it is not often used in practice. A left-axis deviation results from several pathological conditions where the left ventricle thickens and hypertrophies, pushing the mean QRS axis further to the left. These conditions include a left bundle branch block and a left anterior fascicular block. Other conditions that lead to left ventricular hypertrophy are systemic hypertension, aortic stenosis, and some ventricular arrhythmias. A right-axis deviation occurs when the mean axis is pushed further to right. This is a normal finding in infants and young adults. However, pathologically it results from right ventricular hypertrophy that occurs due to stress on the right side of the heart such as obstructive lung disease, pulmonary hypertension, and acute pulmonary embolism. Other conditions

Elmoselhi_CH04_p051-070.indd 64

include a right bundle branch block, some ventricular arrhythmias, and some congenital heart diseases. 6. P wave abnormalities: Normally, the P wave represents the depolarization of the right and left atria. In the case of right atrial enlargement, the P waves are tall, especially in leads II, III, and the aVF (P pulmonale). While with left atrial enlargement, the P waves in lead II are broad and notched (P mitrale), and in lead V1 they have deep and wide negative components. A slightly exaggerated wave can be seen, especially in lead II and lead V1. 7. QRS complex abnormalities: A normal QRS lasts for equal or less than 0.1 sec and its voltage in the limb leads ranges from 0.5 to 2.0 mV, which is measured from the bottom of the S wave to the peak of the R wave. An abnormally high voltage occurs in ventricular hypertrophy as a result of an increase in muscle mass that creates more electricity. The increase in voltage differs in different leads according to the site of the hypertrophy. Right ventricular hypertrophy further shifts the mean axis to the right-axis deviation. The decrease in voltage, however, occurs in cardiac myopathies, such as in multiple old myocardial infarctions which reduce the muscle mass and electricity. Also, fluid in the pericardial effusion causes a reduction in the electric transmission because of short-circuitry of the electricity that results in an interruption of the electricity from the heart to the electrodes of the ECG in the skin. A similar mechanism, but to a lesser extent, is the case of pleural effusion. Furthermore, a reduction in the cardiac action potential occurs in pulmonary emphysema due to excessive air in the lungs as well as an enlargement of the thoracic cavity as a result of retention of air that acts as an insulator and reduces the conduction of the action potential from the heart to the skin, which makes it difficult for the ECG leads to detect it. A prolonged QRS complex occurs as result of a delayed or longer conduction of the depolarization of the action potential. In the case of cardiac hypertrophy or dilatation, the depolarization takes longer than normal and the duration of the QRS can increase from 0.08 to 0.12 sec. Blocking the spread of depolarization from the atria to the ventricle through Purkinje fibers will also prolong the QRS complex to 0.14 sec or more, depending on the severity and location of the blockage. The pattern of a prolonged QRS can differentiate between a right bundle branch block and a left bundle branch block, especially in chest leads, as shown in Fig. 4.18. However, a blockage of the divisions of the left bundle branch such as a left anterior fascicular block and a left posterior fascicular block do not prolong the QRS significantly and can be recognized in the limb leads. Furthermore, an abnormal pattern of a QRS complex also occurs due to damage of the cardiac muscle as in the case of myocardial infarction and replacement of the cardiac tissue with fibrous tissues. 8. ST segment and T wave abnormalities: ST segment depression and/or T wave inversion is usually common

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Chapter 4  Electrophysiology of the Heart

65

V1

V2

Widened QRS “Rabbit Ears” Right Bundle Branch Block (RBBB): The QRS morphology is characteristic in RBBB with the wide QRS complex as a unique with virtually diagnostic shape (“Rabbit Ears”) in those leads overlying the right ventricle (V1 and V2).

V1

V4

V1

V2

V5

V2

Broad, deep S waves

Normal

Left Bundle Branch Block (LBBB): The QRS morphology is characteristic in LBBB with a broad QRS complex with deep S waves in those leads opposite the left ventricle (right ventricular leads - V1 and V2).

FIGURE 4.18  QRS complex abnormalities.

in transient myocardial ischemia due to the effect of ischemia/reperfusion on cardiac muscle repolarization. ST segment elevations and T wave abnormalities occur in cases of acute STEMI (ST segment elevation myocardial infarction), and its sequence of appearance as shown in Fig. 4.19, can distinguish the timing of the infarction as follows: •• Initially, in the first few minutes of acute myocardial infarction there is an elevation of the ST segment, sometimes with a peak elevation of the T wave. At this stage, a complete reperfusion and reversible cellular or tissue damage is possible with successful fibrinolytic treatment or percutaneous coronary intervention. In this case, the ST segment will return to baseline, otherwise irreversible tissue damage will occur and the following sequence of changes will appear in the ECG tracing.

Elmoselhi_CH04_p051-070.indd 65

•• During the first few hours, if there is no successful intervention, irreversible damage of the myocardial tissues leads to a reduction in the amplitude of the R wave, the ST segment is still elevated and pathologic Q waves appear in certain leads based on the infarction location. Pathologic Q waves indicate a current or previous occurrence of STEMI and usually appear in groups in various ECG leads based on the anatomic location of the infarction. The pathologic Q wave measures more than 25% of the total QRS complex and width equal to or more than one small box. The pathologic Q wave is occurs because the necrotic tissues do not generate or conduct the action potential. •• On day 1 to day 2, the ST segment remains elevated, the T wave becomes inverted, and the pathologic Q waves deepen.

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Section II  Heart and Vascular Functions

A

V3

B

V3

C

V3

D

V3

1

A

B

C

D

2

3. Determine the intervals such as the PR interval (N = 0.12 – 0.2 sec), the QT interval (N = 0.2 – 0.4 sec or equal to or less than half the R – R interval in the case of a normal heart rate), QRS (equal or less than 0.1 sec). 4. Mean axis (normally between -30° to +90°), beyond –30° indicates a left-axis deviation and beyond +90° indicates a right-axis deviation. 5. P wave: Check for any abnormalities such as a right or left atrial enlargement. 6. QRS complex: Check any abnormalities such as hypertrophy, bundle branch block, and myocardial infarction (a pathologic Q wave). 7. ST segment and/or T wave: Check for any abnormalities such as an ST segment elevation or depression, and a T wave inversion.

Common Cardiac Arrhythmias FIGURE 4.19  ST segment and T wave abnormalities. (Reproduced, with permission, from Fuster V, Walsh RA, Harrington RA, eds. Hurst’s The Heart. 13th ed. New York: McGraw-Hill; 2011.)

•• After several days of the beginning of myocardial infarction, the ST segment returns to the baseline, the T wave remains inverted, and the pathologic Q waves remain the same. •• Weeks and months later, the ST segment remains at the baseline and the T wave returns to normal, but the pathologic Q waves persist marking the location of the old infarction. The above changes in an ECG during myocardial infarction (ie, ST elevation, QRS reduction, and inverted T waves) occur in specific leads that determine its site. In the meantime, reciprocal changes can be observed in the opposite site. The exact mechanism(s) of the changes in the ST segment during the process of myocardial infarction is not clear, however, some theories such as diastolic current and systolic current have been used as an explanation. Furthermore, there are many other causes that result in abnormalities of the ST segment and the T wave. For example, ST depression also occurs in acute non-ST segment myocardial infarction, digoxin therapy, and hypokalemia. For more detailed information on ECGs, the reader is referred to the Suggested Readings section at the end of this chapter. However, in any ECG tracings, the following standard parameters need to be checked as these will provide critical information in assessing an individual’s heart condition: 1. Determine the heart rate: Use any of the 3 methods described earlier. 2. Assess the heart rhythm: Sinus rhythm (ie, every P wave is followed a QRS and every QRS is preceded by a P wave, a PR interval is more than 0.12 sec) or no sinus rhythm = any type of arrhythmias.

Elmoselhi_CH04_p051-070.indd 66

A normal sinus rhythm indicates that (1) the heart rate is between 60 and 100 beats per minute, (2) the heart rate originates from the SA node, and (3) the heart rate is conducted through the normal conductive system in the heart following the normal sequence and timing for the heart’s activation. The ECG tracing should show that each P wave follows a QRS complex, and then a T wave is followed by a P wave again, as shown in Fig. 4.20. Sinus tachycardia indicates that the heart rate is more than 100 beats/min, but have otherwise normal ECG characteristics as shown in Fig. 4.21. Sinus tachycardia occurs in several conditions, such as increased body temperature, increased sympathetic stimulation to the heart, and in thyrotoxicosis and anemia. Sinus bradycardia means that the heart rate is less than 60 beats/min, but has normal ECG characteristics as shown in Fig. 4.22. Sinus bradycardia happens in increased vagal tone for a variety of reasons, for example, normally in young adult athletes or during sleep. Premature atrial contractions (PACs) are the result of an ectopic extra atrial contraction, not from the SA node. The additional P wave usually occurs earlier than the sinus P wave and has an abnormal shape with different PR intervals as shown in Fig. 4.23. PACs sometimes occur in a normal heart or as a result of increased stress, catecholamine, alcohol, caffeine as well as from infections, ischemia, digoxin toxicity, or atrial dilation. PACs feel like a “skipped beat” or palpitation in patients. Atrial fibrillation: Common arrhythmias in clinical practice. Multiple atrial beats originate from ectopic foci discharging rapidly at a rate of 350 to 450 beats/min. In ECG tracings, it looks like either small, very fast P waves or straight lines, due to the opposite direction of the waves that electrically neutralize each other. QRS complexes are normal, but irregular in their timing as shown in Fig. 4.24. These are caused by atrial enlargement due to mitral valve diseases, coronary artery diseases, thyrotoxicosis, cardiomyopathy, and myocarditis.

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Chapter 4  Electrophysiology of the Heart

I

aVR

V1

V4

II

aVL

V2

V5

III

aVF

V3

V6

67

FIGURE 4.20  Normal sinus rhythm.

FIGURE 4.21  Sinus tachycardia.

FIGURE 4.22  Sinus bradycardia.

FIGURE 4.23  Premature atrial contractions.

FIGURE 4.24  Atrial fibrillation.

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Section II  Heart and Vascular Functions

FIGURE 4.25  Atrial flutter. FIGURE 4.28  Ventricular fibrillation (V fib).

Atrial flutter is an atrial ectopic foci discharge at a rate of 250 to 350 beats/min. The ECG rhythm is characterized by flutter waves (a “sawtooth” pattern) as shown in Fig. 4.25. Only some impulses conduct through the AV node to the ventricle. The clinical consequences of atrial fibrillation and flutter occur as a result of blood stagnation, especially in the left atrium, which leads to a predisposition of thrombus formation and consequently to a peripheral embolism and stroke. Thus, most patients will receive anticoagulants such as warfarin or new oral anticoagulants. Furthermore, because of the lack of proper atrial systole, the diastolic filling of the ventricle will be reduced that leads to a reduction of preload, stroke volume, and cardiac output. This will significantly worsen the condition, especially in elderly patients with hypertension, left ventricular dysfunction, or heart failure. Paroxysmal supraventricular tachycardia is characterized by a sudden increase in heartbeat (150 to 250 beats/min) that originate either from the atrial or the AV ectopic foci, and return suddenly to a normal rhythm as shown in Fig. 4.26. The most common is due to abnormal conduction in the AV node or antegrade conduction in the accessory pathway. This occurs in young healthy individuals who grow out of it after adolescence. Paroxysmal ventricular tachycardia originates from the ectopic ventricular foci and is characterized by sudden fast heartbeats at a rate of 150 to 250 beats/min. The QRS complex widened with a bizarre shape, but is regular in rhythm as shown in Fig. 4.27. The P wave is usually absent, buried in the wide QRS complex. It is a serious condition because of the severe drop in cardiac output and blood pressure, so it is most likely a result of considerable ventricular ischemia Sudden onset of SVT

and possibly a life-threatening condition. The cause can be from a variety of conditions, such as acute myocardial infarction, cardiomyopathy, digoxin toxicity, and congenital heart disease. Ventricular fibrillation (V fib) is the most serious of the cardiac arrhythmias; if it is not stopped within 1 to 3 minutes by electrical defibrillation, it can lead to death. Cardiac impulses go “berserk” within the ventricle, which leads to no coordination of ventricular muscle contraction and eventually to no cardiac output and no tissue perfusion as shown in Fig. 4.28. It is the most common cause of sudden cardiac death. V fib is initiated by acute myocardial infarction, drug overdose, anesthesia, cardiomyopathy, and heart trauma. A first-degree AV block is characterized by a delay of the AV bundle conduction from the atria to the ventricle but not an actual blockage of the conduction. In the ECG tracing, there will be a fixed prolonged P-R interval of more than 0.2 sec (N = 0.12 – 0.2) as shown in Fig. 4.29. A second-degree AV block is divided into 2 types: Mobitz type I (Wenckebach) and Mobitz type 2. •• Mobitz type I (Wenckebach) is characterized by a progressive delay at the AV node until the impulse is completely blocked. Possible causes include an insult to the AV node, hypoxemia, a myocardial infarction (MI), digitalis toxicity, ischemia, and increased vagal tone. This conduction does not usually progress to a higher-degree heart block. ECG criteria include an irregular rhythm with progressive lengthening of the PR interval until there is a dropped beat (a long, longer drop). The QRS is usually 0.2 sec (at a rate of 70 bpm), which remains constant from beat to beat •  Second-degree AV block: •  Mobitz type 1: •  The cycle with the dropped beat is less than 2 times the previous cycle •  A shortened PR interval after the dropped beat •  The site of block is usually the AV node (proximal to the bundle of His) •  Mobitz type 2: •  Fixed duration of the PR interval •  A sudden appearance of blocked beats •  The site of the block is infranodal •  Third-degree AV block: •  There is no relationship between the P waves and the QRS complexes; P waves constantly change their relationship to the QRS complexes •  The ventricular rate is usually 50 years and females >60 years; however, females present with atypical presentation more often. There are 2 types of stable angina patients: those with a fixed threshold of angina that is induced by a predictable and constant level of stress, and those with a threshold that varies within any time of day or from day to day. For example, the patient with a variable threshold may experience discomfort early in the morning with minor exertion but be symptom-free at midday even though the patients is experiencing much more stress. The variable threshold is thought to be attributed to the change in the vascular tone rather than the fixed stenosis.

Unstable Angina •• Unstable angina is a chest discomfort similar to stable angina but with at least one of the following features: (1) occurs at rest (or minimal effort) and lasts for >10 minutes, (2) changing patterns of angina discomfort (ie more severe, stays longer in duration, or occurs more frequently), and (3) it does not relieve with rest or medicine. •• Unstable angina and acute myocardial infarction are known as ACS. The mechanism of ACS involves a rupture of atherosclerotic plaque, platelet aggregation, and thrombus formation.

Variant Angina (Prinzmetal Angina) Uncommon ischemic chest discomfort due to a coronary artery spasm with no apparent atherosclerotic lesions. The mechanism is not completely understood; however, it seems to involve a combination of endothelial dysfunction and increased sympathetic activity. The angina usually starts at rest and is alleviated spontaneously or with nitrates.

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Silent Ischemia Silent ischemia represents patients who suffer myocardial ischemia without any experience of discomfort or pain. It is more common in diabetic patients, older patients and women. It is difficult to diagnose these patients; however ambulatory ECG and stress test could be beneficial in making the diagnosis. The mechanism of this silent ischemia is not yet clear.

Myocardial Stunning Myocardial stunning is a reversible myocardial dysfunction following reperfusion of an ischemic insult and after a thrombolytic or mechanical revascularization of acute MI. For example, myocardial stunning usually happens in patients following: (1) cardiopulmonary bypass surgery, (2) exercise with partial coronary occlusion, and (3) angina due to intense coronary spasm (ie, variant angina). It is clinically critical to differentiate between various syndromes of the irreversible dysfunction to manage the case accordingly. Although the ECG and coronary blood flow of these patients is usually normal, their myocardial contractions are abnormal and similar to irreversible ischemia (ie, detected by echocardiography). The necrotic changes are diagnosed with the use of special imaging tests (eg, dobutamine echocardiography and PET [positron emission tomography]). The molecular mechanism of myocardial stunning is not completely understood, but it seems to include intracellular cardiomyocyte Ca2+ overload and the harmful effects of accumulation of the reactive oxygen species following reperfusion on cellular Ca2+-handling proteins.

Hibernation A reversible chronic ventricular dysfunction, hibernation is the result of a prolonged reduction in blood flow from coronary artery disease. Once the blood flow is restored, ventricular function improves. The mechanisms of hibernation include adaptation of

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cellular processes (eg, gene expression and autophagy) to maintain the viability of the hibernating myocardial tissue.

ST V5

Ischemic Preconditioning Ischemic preconditioning (IPC) describes an observation of a protective mechanism from a major ischemic insult following brief episodes of ischemia and reperfusion of the heart. For example, short episodes of ischemia and reperfusion in animal models can lead to a significant reduction in the size of a myocardial infarction. There are immediate and delayed phases of this protection, called the first and second windows. The mechanism for this phenomenon is under investigation. •• Clinically, ischemic heart disease patients are divided into 2 large groups. The first group represents patients with chronic artery disease (CAD), who and commonly present with stable angina. The second group represents patients with ACSs. Acute coronary syndrome includes patients with acute myocardial infarction (both STEMI and NSTEMI based on their ECG features) and unstable angina (UA). This second group is usually categorized as STEMI patients and UA/NSTEMI patients. It seems that the relative incidence of UA/NSTEMI is increasing compared to the STEMI cases. Every year in the United States, more than double the cases of UA/NSTEMI are admitted to the hospital relative to acute STEMI cases. (Note: STEMI: ST elevation myocardial infarction; NSTEMI: non-ST elevation myocardial infarction.)

Pathology and Pathophysiology of Myocardial Infarction •• Severe ischemia, within 1 minute, leads to ATP depletion and loss of contractile function, but with no cell death. The damage is still reversible at this point. Complete deprivation of blood flow for 20 to 30 minutes leads to irreversible myocardial injury. Severe compromise of blood flow for prolonged periods for 2 to 4 hours can also cause irreversible myocardial injury. Necrosis is complete within 6 hours of severe ischemia; however, extensive coronary collateral circulation can lengthen the time to necrosis to greater than 12 hours. •• The distribution of myocardial necrosis depends upon the vessel involved, the presence of collateral perfusion, the location of occlusion within the vessel (ie, proximal or distal from the main branch), and the cause of the diminished perfusion (Spasm = Temporary versus Atherosclerosis = Permanent). Most myocardial infarctions are within the distribution of a single coronary artery and are called transmural, which is a result of atherosclerosis and acute plaque changes with thrombosis, known as ST elevation myocardial infarction (STEMI). Subendocardial myocardial infarctions are limited to the inner 30%

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ST

A

ST V5 ST B

FIGURE 8.2  Type of acute myocardial infarction. A. Subendocardial infarction with an ST vector directed inward toward the injured tissues that results in an ST segment depression in the ECG tracing. B. Transmural infarction with an ST vector directed outward that leads to an ST segment elevation in the ECG tracing. (Reproduced, with permission, from Kasper DL, Fauci AS, Hauser SL, Longo DL, Jameson JL, Loscalzo J, eds. Harrison’s Principles of Internal Medicine. 19th ed. New York, NY: McGraw-Hill; 2015.)

to 50% of the ventricle and may involve an area perfused by greater than 1 coronary artery. This is known as non-ST elevation myocardial infarction (NSTEMI) (Fig. 8.2). •• In a typical left dominant heart, the left anterior descending coronary artery is involved 40% to 50% of the time, resulting in myocardial lesions in the anterior wall of the left ventricle near the apex, the anterior portion of the ventricular septum, or the apex circumferentially. The right coronary artery is involved 30% to 40% of the time and results in myocardial lesions in the inferior, posterior wall of the left ventricle; the posterior portion of the ventricular septum; or the inferior, posterior right ventricular free wall. The left circumflex coronary artery is involved 15% to 20% of the time, which results in lesions in the lateral wall of the left ventricle with the exception of the apex (Table 8.2). •• Reperfusion of injured cells via thrombolytic intervention may restore viability; however, the cells will be poorly contractiled or stunned for 1 to 2 days. The myocardium will grossly appear hemorrhagic as a result of ischemic vascular injury. Irreversibly injured myocytes exhibit contraction band necrosis as a result of calcium overload and hyper-tetanic contraction. As inflammatory cells are recruited to the site of infarction, additional injury and perfusion-induced microvascular injury with capillary occlusion occur.

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Table 8.2  Summary of the locations of myocardial lesions, their frequency of occurrence, and their corresponding affected artery branch Artery branch name

Frequency of occurrence

Myocardial lesion areas

Left anterior descending coronary artery

40%-50%

Anterior wall of the left ventricle near apex Anterior portion of the ventricular septum Apex circumferentially

Right coronary artery

30%-40%

Inferior, posterior wall of the left ventricle Posterior portion of the ventricular septum Interior, posterior right ventricle free wall

Left circumflex coronary artery

15%-20%

Lateral wall of the left ventricle with the exception of the apex

•• The gross and microscopic morphologies of a myocardial infarction vary depending upon the time since occurrence, and the time course is influenced by the size of the infarct. See Table 8.3 and Figs. 8.3 through 8.6. The earliest grossly discernible change in acute

FIGURE 8.3  Acute transmural myocardial infarction at 24 to 36 hours, located in the posterior wall of the heart. (Reproduced, with permission, from Fuster V, Harrington RA, Narula J, Eapen ZJ, eds. Hurst’s The Heart. 14th ed. New York: McGraw-Hill, NY; 2017.)

myocardial infarction (AMI) is myocardial pallor, occurring 12 or more hours after the onset of irreversible ischemia. Gross detection can be enhanced by adding tetrazolium salt solutions to fresh tissue where a colored precipitate forms in normal noninfarcted myocardium due to tissue dehydrogenase-mediated activity, leaving the infarcted region, which is depleted of dehydrogenase activity, pale and unstained. Necrotic myocardium can be detected within 2 to 3 hours postinfarct.

Table 8.3  Characterization of the pathological features of a myocardial infarct according to the time scale (modified from Concise Pathology, 3ed by Parakrama Chandrasoma, et al, McGraw-Hill Publishing Co; 3rd edition, 1997) Elapsed time

Gross or naked eye features (at autopsy)

Light microscopic (LM) and electron microscopic (EM) features

0-1/2 hour

None

Reversible injury: Fibers may be wavy at borders via LM, but mitochondrial swelling, distorted cristae, matrix densities, and relaxation of myofibrils are seen via EM

1-2 hours

None

Irreversible injury EM: Sarcolemmal disruption by mitochondrial amorphous densities

4-12 hours

None

EM: Margination of nuclear chromatin LM: Beginning of coagulation necrosis and neutrophilic infiltrate; edema; hemorrhage

12-24 hours

Softening, irregular pallor

As above, plus LM: Loss of striations, cytoplasmic eosinophilia, nuclear pyknosis, mild edema, occasional neutrophils, marginal contraction band necrosis

1-3 days

Pale infarct surrounded by a red (hyperemic) zone

As above, plus: Total coagulative necrosis with loss of nuclei and striations, nuclear lysis, heavy interstitial neutrophilic infiltrate, inflammatory capillary dilatation

4-7 days

Central pale or yellow-brown softening (caused by liquefaction by neutrophils) and definite red margin/hyperemic border

As above, plus: Liquefaction of muscle fibers and resorption of sarcoplasm by macrophages; neutrophils; macrophages remove debris; ingrowth of granulation tissue from margins (marginal fibrovascular response)

7-14 days

Maximally yellow and soft vascularized margins with progressive replacement of yellow infarct by red-purple, depressed (granulation) tissue

As above, plus: Disappearance of necrotic muscle cells (well-developed necrotic changes by day 10); reduced numbers of neutrophils; macrophages, lymphocytes; beginnings of fibrosis and organization of granulation tissue with prominent fibrovascular reaction in margins

2-6 weeks

Becomes gray-white

As above, plus: Development of fibrous scar Decreasing vascularity Contraction of scar

7 weeks

Scarring complete

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A

E

B

F

C

G

D

H

FIGURE 8.4  Acute transmural myocardial infarction at 1 week old, located in the posterolateral part of the heart. (Reproduced, with permission, from Fuster V, Harrington RA, Narula J, Eapen ZJ, eds. Hurst’s The Heart. 14th ed. New York: McGraw-Hill, NY; 2017.)

Clinical Manifestations and Diagnostic Tests of Cardiac Ischemia •• Clinical diagnosis of myocardial infarction is based upon the presence of clinical features, electrocardiographic changes, and elevation of various cardiac biomarkers. The electrocardiogram (ECG) during an angina episode is a very useful tool and during acute myocardial ischemia, tracings will show a transient horizontal or downsloping ST segment depression and T wave ­flattening or inversion. In more severe transmural myocardial ischemia and intense vasospasm of variant

A

FIGURE 8.5  Histopathological features of a myocardial infarction following a complete occlusion of the coronary at 1 week old, located in the posterolateral part of the heart. (Reproduced with permission from Virmani R, Burke AP, Farb A, et al. Cardiovascular Pathology. 2nd ed. Philadelphia, PA: WB Saunders; 2001.)

B

C

FIGURE 8.6  A: 40x; B: 100x; and C: 400x. Hematoxylin and Eosin stained histopathologic features of acute myocardial infarction 3 days after onset. There is coagulative necrosis with loss of nuclei and striations, nuclear lysis, a heavy neutrophilic interstitial infiltrate and inflammatory capillary dilation.

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V1-V2

LV involvement

Normal (basal)

Seconds

Minutes

1

– +

–

+

2

3

50 Multiples of the acute MI cutoff limit

Time

B.

20 10 5 C.

2

A. Acute MI decision limit

1

Upper reference limit

D. 0 0

Hours 4 Days

Weeks 5 1 Year

FIGURE 8.7  The progression of acute myocardial infarction (MI) in an ECG recording as a result occlusion of the left anterior descending coronary artery. These patterns can be altered by immediate intervention that is currently available. The middle panel shows ECG changes in the V1-V2 leads where the ST segment elevation MI and prominent Q wave. The left ventricular wall in the right panel shows: (1) normal, (2) subendocardial ischemia, (3) transmural ischemia, (4) necrosis surrounded by ischemic tissue zone, and (5) chronic ischemia without ischemic tissue. (Reproduced, with permission, from Fuster V, Harrington RA, Narula J, Eapen ZJ, eds. Hurst’s The Heart. 14th ed. New York: McGraw-Hill, NY; 2017.)

angina, the ST segment elevation may be seen. In contrast, ST elevations in patients with stable angina quickly normalize as the patient’s symptoms resolve, and ECGs performed when the patients are free of ischemia are completely normal in half of them. The remainder may have chronic nondiagnostic ST and T wave deviations. Evidence of previous myocardial infarction demonstrating a presence of underlying coronary disease is manifest by pathologic Q waves (Figs. 8.2 and 8.7). •• Clinically acute cases become apparent when a sufficient number of myocytes have undergone necrosis or have lost function; this disruption of membrane integrity results in a loss of intracellular constituents into the extracellular space in detectable quantities, which is the source of cardiac biomarkers. The initial diagnosis of an acute myocardial infarction depends upon an evaluation of the rise and/or fall of biomarkers that usually requires a time sequence of approximately 6 hours in order to define how much of a change is significant (Fig. 8.8). •• Troponins are preferred to CK-MB due to their greater sensitivity and specificity. Cardiac troponin I (cTnI) and troponin T (cTnT) are cardiac regulatory proteins that

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1

2

3 4 5 Days after onset of acute MI

6

7

8

FIGURE 8.8  The change in the cardiac biomarkers in the blood following the start of the symptoms of acute MI. The peak of curve A shows the early release of myoglobin CK-MB isoform. The peak of curve B shows the significant elevation of cardiac troponin. The peak of curve C shows the elevation of CK-MB after and MI. The peak of curve D shows the increase in cardiac troponin after unstable angina. The dotted line at 1 is set as a relative scale to point out the cutoff concentration for acute MI. (Reprinted, with permission, from the American Association for Clinical Chemistry. From Wu AH, Apple FS, Gibler WB, Jesse RL, Warshaw MM, Valdes R Jr. National Academy of Clinical Biochemistry Standards of Laboratory Practice: recommendations for the use of cardiac markers in coronary artery diseases. Clin Chem. 1999;45:1104.)

control the calcium-mediated interaction of actin and myosin. cTnI is expressed only by the heart and cTnT is expressed by the heart and minimally by the skeletal muscle. Cardiac troponin concentrations usually begin to rise 2 to 3 hours after the onset of acute myocardial infarction (AMI) and may persist for 10 to 14 days. Although these markers are specific for myocardial damage, there are variations in sensitivity and specificity of various immunoassays for other markers that are not cardiac specific. Creatine kinase (CK) isoenzyme activity is distributed in many tissues, including the skeletal muscle, but more of the CK-MB fraction is found in the heart. It begins to rise 4 to 6 hours after the onset of infarction, but is not elevated in all patients until about 12 hours. A 2-fold or greater increase in the CK concentration is required for a diagnosis of cardiac damage, but this rapid-appearing marker as well as myoglobin provides little additional information when used together with a more sensitive assay for troponin. As a general rule, point-of-care tests (easily accessible kits that are rapidly available at the bedside or in an emergency department), are less sensitive than laboratory-based tests, so pursuing lab-based testing is the preferred course to follow.

Immediate General Treatment of Acute Angina Pectoris •• Rest and reassurance: Patients are counseled to eliminate physical and/or mental stress. Anxiolytic medications are used to relieve anxiety if necessary. •• Continuous monitoring of vital signs, ECG tracing, and cardiac biomarkers especially in unstable angina as well

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as treating any precipitating conditions (eg, hypertension, thyrotoxicosis, etc.) should be followed. •• Nitroglycerin is the drug of choice. It is a short-acting organic nitrate (initial effect ~1 minute and lasts for ~30 minutes). It is most commonly administered under the tongue (sublingual), but other forms are also available, such as patches and sprays. •• Mechanism of action: Nitrates relax vascular smooth muscle and consequently relieve ischemia through 2 pathways: 1. Vasodilation of the veins that results in a reduction of the venous return to the heart and decreases left ventricular end-diastolic volume (preload) → decreases wall stress → decreases cardiac O2 consumption → relieves cardiac ischemia. (Note: Male patients should be screened for sildenafil [Viagra] as coadministration with nitrates may lead to hazardous hypotension.) 2. Vasodilation of the coronary arteries which increases coronary blood flow → increases O2 supply. This pathway has a minor contribution in an ischemic heart because the coronary vessels are already maximally dilated due to the accumulation of ischemia-induced local metabolites. However, it has a significant effect in the case of an ischemic heart due to coronary vasospasm. Nitroglycerin can also be used as a preventative measure if the patient takes it in anticipation of stress.

Long-Term Treatment to Prevent a Recurrent Acute Angina Attack The aim of this treatment is to reduce the heart’s workload to reduce O2 demand and to increase the O2 supply to the heart. •• Long-acting organic nitrates, such as isosorbide mononitrate and sorbide dinitrate, have the same mechanism of action as nitroglycerin (see above). It is administered as oral tablets or patches. The main limitation is drug tolerance that occurs in various levels but that can be overcome by providing nitrate-free intervals during the day (usually during rest or sleep periods). However, no research evidence to date has shown that nitrates prevent myocardial infarction or improve survival in chronic artery diseases patients. The main side effects include lightheadedness (dizziness), headache, palpitations, and sinus tachycardia (that can be avoided by combining nitrates with β-blockers). •• β-Blockers such as propranolol, metoprolol, betaxolol, and pindolol act mainly by reducing cardiac O2 demand through blocking β1- and β2-adrenergic receptors. Blocking β1 results in a decrease in the ventricular force of contractions and heart rate, which both reduce the O2 demand and improve cardiac ischemia. In addition,

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lowering the heart rate increases the time of the diastolic phase, which is when the heart replenishes itself. Moreover, β-blockers have been shown to reduce the rate of recurrent infarction and mortality following acute MI. Also, β-blockers have been shown to reduce the incidence of first MI in hypertensive patients. Although β-blockers are well-tolerated medications, there are several side effects and contraindications, including: (1) bronchospasm in patients with asthma (blocking β2-adrenergic receptors), (2) negative inotropic effects (contractility) especially in patients with heart failure due to decompensated LV dysfunction, (3) contraindicated in patients with heart block and bradycardia due to its delaying effect of the electrical conduction in the heart, (4) sexual dysfunction and fatigue, (5) masking sympathetic effects in hypoglycemic patients (eg, tachycardia); thus, it should be prescribed cautiously for insulin-dependent diabetic individuals. •• Calcium channel blockers: There are 2 major groups: Dihydropyridines (eg, nifedipine and amlodipine) and non-dihydropyridines (eg, verapamil and diltiazem). Both groups block voltage-gated L-type calcium channels, but they differ slightly in their mechanisms of action. Dihydropyridines are potent vasodilators that relieve cardiac ischemia through the following mechanisms: (1) reduce wall stress by decreasing the O2 demand via venodilation that reduces venous return and ventricular filling (ie, preload) and also through vasodilating resistance arteries that reduce resistance against ventricular contraction (ie, afterload) and (2) coronary vasodilation, which enhances the O2 supply. On the other hand, non-dihydropyridines have similar vasodilating effects though not as potent as dihydropyridines. In addition, non-dihydropyridines have a negative inotropic effect (ie, reduced contractility) and diminish the heart rate, which consequently reduces the O2 demand in the heart. A major concern has been raised regarding shortacting calcium blockers related to increased mortality and incidence of MI. Therefore, only long-acting agents are recommended as the second line of treatment if β-blockers (along with nitrates) were contraindicated or had adverse effects or did not relieve the symptoms. The 3 anti-anginal medications discussed above can be used separately or in combination. However, caution has to be exercised in combining β-blockers and non-dihydropyridines because of their additive cardiac depressive effects (ie, negative inotropic and bradycardia), which can precipitate or exacerbate heart failure due to LV contractile dysfunction. •• Ranolazine: A recent anti-ischemic drug, ranolazine has shown evidence of a decrease in the rate of anginal attacks and improved exercise capacity in patients with chronic coronary artery diseases. Unlike other antiischemic drugs, it does not affect heart rate and blood pressure. The exact mechanism of action is not fully understood. However, it seems that it inhibits the late

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phase of action potential inward Na+ that is currently in ventricular myocytes. In addition, it has been shown to be effective in reducing angina and is also safe for longterm use. It should be noted that none of the above anti-anginal drugs improve or reverse the atherosclerotic process, increase longevity of patients with chronic stable angina or preserved LV function.

Adjunct Treatment to Prevent Acute Cardiac Ischemic Episodes Antiplatelet Therapy •• Aspirin: Unless there is an obvious contraindication (eg, gastric bleeding or allergy) aspirin should be taken by all patients with coronary artery diseases indefinitely. Aspirin has an antithrombotic effect due to the inhibition of platelet aggregation. It also has anti-inflammatory actions that stabilize atheromatous plaque. •• Clopidogrel: One of the novel antiplatelet agents that blocks the platelet P2Y12 ADP receptor. It can be substituted for aspirin in patients who have a contraindication for aspirin. It has also been shown that a combination of aspirin and clopidogrel is superior to aspirin alone in reducing mortality and ischemic complications in patients with ACSs and those undergoing elective angiography and stenting. In addition, long-term drug combinations prevent subsequent cardiac events in patients with a history of MI compared to aspirin alone.

Lipid-Regulating Therapy: HMG-CoA Reductase Inhibitors (Statins) Statins have been shown to reduce MI and death rates in patients who are diagnosed as high risk for coronary artery diseases. It also stabilizes atherosclerotic plaque because it decreases inflammation in the blood vessels and improves endothelial cell dysfunction.

Angiotensin-Converting Enzyme Inhibitors There is some strong evidence that chronic therapy of angiotensin-converting enzyme (ACE) inhibitors reduce the rate of death, MI, and stroke in stable coronary artery diseases that are not associated with heart failure. Thus, many physicians now include ACE inhibitors as a medical regimen for CAD patients.

Revascularization •• General indications for mechanical revascularization: •• Symptoms of angina that do not respond to antianginal medications •• Intolerable side effects from the anti-anginal medications

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•• An expectation to improve the survival outcomes in high-risk CAD patients •• There are 2 methods used to accomplish mechanical revascularization: 1. Percutaneous coronary intervention (PCI) 2. Coronary artery bypass graft (CABG) surgery •• PCI, also known as percutaneous transluminal coronary angioplasty (PTCA): A procedure in which a balloon-tipped catheter is inserted to dilate the stenotic coronary vessel(s). Currently, the standard procedure is to introduce a metal stent with the balloon-tipped catheter to maintain the dilation of the stenotic vessel (Fig. 8.9). Although the stent significantly reduces the rate of restenosis, the procedure is limited to the larger epicardial arteries. For the smaller arteries, a simple balloon angioplasty can be implemented. Once the stent is inserted, an intense dose of combined oral antiplatelet (ie, aspirin and clopidogrel) must be administered until the stent is covered by an endothelial cell layer that reduces the risk of new thrombus developing. Although the metal stent significantly reduces restenosis compared to conventional angioplasty (ie, without a stent), the neointimal proliferation remains a major drawback of the procedure and results in a recurrence of angina symptoms. Drug-eluding stents (DESs) have developed recently to improve the prognosis of the metal stent and target its proliferation’s downside. These stents are coated with antiproliferative medications such as sirolimus, everolimus, and paclitaxel. This method has been shown to reduce restenosis and the need for repeated revascularization by almost half. However, a delay in the protective endothelial formation signifies a risk of thrombus formation and immediate need for intense antiplatelet therapy following drug-eluding stent angioplasty. It should be noted that although PCI decreases the risk of MI and mortality in the case of ACS, it does not decrease these risks for stable coronary artery diseases. •• CABG: There are 2 surgical graft methods that are used. 1. Vein graft: A section of great (long) saphenous vein (removed from the lower limb) is used to connect the base of the aorta to the coronary artery downstream from the obstructed portion. The vein graft is disadvantaged by accelerated atherosclerosis, with more than 50% becoming occluded within 10 years following surgery. 2. Arterial graft: The most common is directly connecting the internal mammary (also known as the internal thoracic) artery distally to the stenotic portion of the coronary artery. The arterial graft suffers much less from atherosclerosis and has a patency rate of 90% after 10 years. Thus, the arterial graft is used in the more critical part of the coronary circulation, such as the left anterior descending artery.

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FIGURE 8.9  Schematic illustration of the placement and mechanism of balloon angioplasty and stenting.

Lipid-lowering medications are currently recommended following CABG because strong evidence has shown that it improves the patency rate in the long-term prognosis. Recently, newer and less invasive surgical techniques are being tested and used, such as videoscopic robotic assistance and off-pump procedures. However, these new procedures are still under investigation to assess their advantages and disadvantages over the long term.

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Selecting Therapy (Medical versus Revascularization) Patients with chronic stable angina are usually managed by medical therapy unless other newly developed indications appear (eg, intolerable side effects), at which point angioplasty is recommended. Also, patients whose conditions are controlled by medical therapy usually undergo standard assessments to determine their long-term risk and prognosis

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Table 8.4  Comparison between PCI (percutaneous coronary intervention) and CABG (coronary artery bypass graft surgery) PCIs

CABG

•• Less invasive and shorter hospital stay •• More effective than pharmacological treatment •• Higher rate of recurrence of angina pain •• Lower risk of complications from the procedure

•• More invasive and longer hospital stay •• More effective than PCI and pharmacological treatment (complete revascularization) •• Lower rate of recurrence especially in the arterial graft •• Higher risk of complications from the surgery •• Improved survival rate in advanced and critical cases (eg, multiple obstructed vessels with impaired LV function; diabetes and multivessel obstruction; >50% occlusion of the main left vessel)

using noninvasive testing, such as an exercise stress test and echocardiography. Some of these patients are recommended for elective coronary revascularization to enhance their potential improvement in the long-term prognosis. The recommendations are usually based on multiple factors as shown in Table 8.4. PCI is recommended for patients with sustained angina in spite of the medical treatment and for patients who have significant stenosis in 1 to 2 coronary arteries. CABG, however, is recommended for patients with more than 50% stenosis of their left main coronary artery and for patients with multivessel stenosis plus a reduction in left ventricle contractile function. There are rapidly accelerating research advancements in this area that continuously change the selection strategies for therapy and improve the outcomes for these patients.

Immediate Treatment for Acute Coronary Syndrome The first line of management for all ACS patients includes: •• •• •• ••

Admission to the intensive care unit Continuous ECG monitoring for possible arrhythmias Bed rest (to minimize oxygen demand) Oxygen supply by mask or nasal cannula (to improve oxygen supply) •• Morphine or other analgesics (to reduce chest pain and anxiety → reduce oxygen demand) The second line of management (based on ST segment changes in the ECG) is discussed below.

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Non-ST Segment Elevation (NSTEMI) and Unstable Angina: The main goal is to restore the balance between the oxygen supply and demand, and minimize further damage to the myocardial cells following partial coronary occlusion using anti-ischemic and antithrombotic therapies, respectively. •• Anti-ischemic therapy as previously described includes β-blockers, nitrates, and calcium channel antagonists. •• Antithrombotic therapy includes antiplatelets and anticoagulant medications. •• Antiplatelet drugs include aspirin, clopidogrel, and glycoprotein (GP) IIb/IIIa receptor antagonists (in high-risk patients usually at the time of PCI). •• Anticoagulant drugs: 1. Unfractionated heparin (UFH) is administered intravenously and considered the standard anticoagulant in these conditions. It binds to antithrombin and also inhibits coagulation factor Xa. Its effect must be monitored and the doses need to be adjusted accordingly because of its high pharmacodynamic variability. However, it is one of the least expensive anticoagulant drugs. 2. Low molecular weight heparins (LMWHs): Although their mechanism of action is similar to UFH, they have more a predictable pharmacologic response. Therefore, LMWHs are easier to use with no need for monitoring tests and adjusting doses. It is usually administered subcutaneously as 1 or 2 doses per day based on the patient’s weight. 3. Other anticoagulant drugs used include: Fondaparinux (a factor Xa inhibitor) and bivalirudin (a direct thrombin inhibitor). Because of the uncertainty of the outcomes of patients with NSTEMI and unstable angina, there are 2 strategies that have been suggested: 1. An early invasive approach where immediate angiography is performed followed by coronary revascularization. 2. A conservative approach where patients are managed with medications until an ischemic episode occurs or a risk of ischemia appears in a stress test, at which point angiography and revascularization are performed.

Thrombolysis in Myocardial Infarction A scoring system, Thrombolysis in Myocardial Infarction (TIMI) is used to predict a patient’s risk of mortality as well as the risk for recurrent ischemic episodes, and to select an appropriate therapeutic approach according to these results.

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An early invasive approach is recommended if the patient scores 3 points or more in the following criteria: 1. Age ≥65 years old 2. ≥3 risk factors for coronary artery disease 3. Known coronary artery disease with stenosis ≥50% (in prior angiography) 4. ASA (acetylsalicylic acid) use during the past 7 days (indicates a resistance to ASA use) 5. ≥2 anginal episodes (severe angina) within the past 24 hours 6. ≥0.5 mm changes in ST segment 7. Positive cardiac biomarker (elevated serum troponin or CK-MB) The overall risk of the TIMI score for mortality, new or recurrent MI, or severe recurrent ischemia that requires urgent revascularization ranges from 5% to 40% based on the positive score from 1 to 7.

II—ST Segment Elevation in ECG (STEMI) An immediate reperfusion of the artery should be attempted either by fibrinolytic drugs or mechanical revascularization to limit tissue damage. Usually, the affected artery is completely occluded, and thus the more immediate the reperfusion the better the results. The decision of management must be made within minutes based on patient history and the changes in ECG tracing, even before the cardiac biomarkers change. •• Anti-ischemic and antithrombotic drugs need to be administered promptly to prevent further thrombus and restore the balance between the oxygen supply and demand, such as: chewing aspirin (to facilitate absorption), β-blockers, intravenous UFH, and nitrates. •• Fibrinolytic therapy involves lysis of the intracoronary thrombus, which consequently restores the blood flow and reduces the myocardial tissue damage. •• Recombinant tissue-type plasminogen activator (Alteplase, tPA), reteplase (rPA), Tenecteplase (TNK-tPA), and early streptokinase (rarely used now in the United States) are all fibrinolytic drugs that act by stimulating the natural fibrinolytic mechanism. The drugs transform the inactive precursor plasminogen into the active protease plasmin that lyses fibrin clots. •• The most common complication of fibrinolytic drugs is bleeding. Plasmin has poor substrate specificity and thus can degrade other proteins including fibrinogen (fibrin’s precursor). Contraindication includes patients with peptic ulcers, recent stroke, and recent surgery. Approximately 30% of patients are not good candidates for thrombolysis treatment.

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•• Although rPA and TNK-tPA are derivatives of tPA, they have practical clinical advantages over tPA. Both rPA and TNK-tPA are administered as IV bolus, which is more convenient and less prone to error compared to the continuous IV administration required for tPA. •• The start time of fibrinolytic therapy after STEMI is critical. It has been shown that patients who receive fibrinolytic therapy within 2 hours of onset of symptoms have half the death rate than those who receive it 6 hours after the symptoms are detected. Early administration of fibrinolytic drugs restores coronary blood flow in 70% to 80% of the STEMI patients and improves the outcome in terms of the extent of tissue damage, postinfarction complications, and survival rates. •• Reperfusion of STEMI patients results in chest pain relief, ST segment return to baseline, and an earlier peak of serum markers (ie, troponins and CK-MB). Transient arrhythmias are common during reperfusion and usually resolve spontaneously without treatment. However, antithrombotic therapy needs to follow successful fibrinolytic therapy to prevent immediate vessel reocclusion. •• Antithrombotic therapy following fibrinolysis includes aspirin with clopidogrel. Also, intravenous UFH should be administered for 48 hours in patients treated with tPA, rPA, or TNK-tPA. LMWH is used as an alternative to UFH.

Primary Percutaneous Coronary Intervention •• Primary percutaneous coronary intervention (PCI) means performing angioplasty plus stenting immediately following an STEMI instead of administering fibrinolytic therapy. This approach yields more than 95% of reestablished optimal flow in STEMI patients (Fig. 8.10). PCI is the preferred approach for coronary reperfusion and yields a greater rate of survival and lower rate of recurrent MI and bleeding compared to the fibrinolytic approach. PCI is also the preferred approach in patients who have contraindication to fibrinolytic drugs, those who suffer from cardiogenic shock, and patients admitted to the hospital more than 3 hours after the start of the symptoms. •• For patients who do not respond well after the administration of fibrinolytic therapy, a “rescue” PCI is recommended. •• Besides aspirin and heparin, it is recommended that patients undergoing primary PCI are provided with a GP IIb/IIIa receptor antagonist. Furthermore, in the case of stenting, thienopyridines such as clopidogrel or the more potent prasugrel have been shown to decrease ischemic complications and stent thrombosis. Summary of ACS classification and management strategies is shown in Figure 8.11.

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Complications of Myocardial Ischemia There are several consequences associated with myocardial ischemia, coronary reperfusion, and necrotic myocardial tissue. These consequences depend on the severity of the insult and the timing and quality of management. In general, these are categorized as electrical, mechanical, and inflammatory consequences. Unstable angina has a mortality rate of 5% to 10% and a high risk to progress to myocardial infarction of 10% to 20%.

Arrhythmias (Electrical Disturbances) A

B

FIGURE 8.10  Primary PCI for acute MI. A. Initial angiography of a patient presenting with acute anterior STEMI shows an occluded left anterior descending (LAD) coronary artery (arrow). B. Following angioplasty and stenting, patency of the LAD is restored. (Reproduced, with permission, from Crawford MH, ed. Current Diagnosis & Treatment: Cardiology. 5th ed. New York, NY: McGraw-Hill; 2017.)

Adjunctive Therapies •• ACE (angiotensin-converting enzyme) inhibitors: It has been shown that ACE inhibitors reduce STEMI complications such as the incidence of heart failure, ventricular remodeling, and death rate, especially for high-risk patients. •• Statins (HMG-CoA reductase inhibitors): This cholesterollowering drug reduces recurrent cardiovascular events. Early and aggressive statin therapy in ACS patients that lower LDL (low-density lipoprotein) to 120 ms) Bradyarrhythmias are treated by reversing the cause of the bradycardia or implanting a pacemaker. Tachyarrhythmias are also treated by reversing the cause if possible, or by using medications such as antiarrhythmics or ablations.

Normal Heart Rate The normal heartbeat originates from the sinus node, also called the natural pacemaker of the heart. The normal heartbeat rate ranges from 60 to 100 bpm. The initial impulse is generated from the sinus node, and is conducted down to the AV node, which is effectively a “bridge” between the signals from the atrium to the ventricles. The impulse then travels from the AV node to the His-Purkinje system and separates into the left bundle (which activates the left ventricle) and the right bundle (which activates the right ventricle).

Learning Objectives

9

By the end of this chapter the student will be able to: • Classify both bradyarrhythmias and tachyarrhythmias. • Identify the rhythm disorders. • Elicit the mechanisms of dysrhythmias. • Determine the best treatment modality for a specific arrhythmia. • Classify the antiarrhythmic drugs. • Describe the dosage and the mechanism of action of some antiarrhythmic drugs. • Apply the above knowledge in a clinical setting.

Normal Sinus Rhythm The normal heart generates an impulse from the sinus node, which is regular, that is, the time interval between 2 beats (the R-R interval) is constant. Sinus arrhythmia is also a normal impulse from the sinus node but is slightly variable due to the vagal tone. The electrocardiography (ECG) findings in sinus rhythms or sinus arrhythmias consist of P wave morphology, in general, it is upright in leads 2/3 and aVF and biphasic in lead V1.

Sinus Arrhythmia The physiological variation in sinus rhythm in response to phases of the respiratory cycle can be observed in sinus arrhythmia. This variation is seen by changes in the R-R interval during inspiration and expiration. This is commonly seen in children. Sinus arrhythmia occurs due to the changes in the vagal tone that cause an alteration in respiration, which does not require any treatment.

▶ ▶  C L I N I C A L C O R R E L A T I O N 9 . 1 R-R interval increases during inspiration, and decreases during expiration.

Bradyarrhythmias There are 2 main causes of bradyarrhythmias: either there is disease of the main pacemaker cells of the heart (ie, sinus node) or disease of the AV node conduction system that serves as the main communication bridge between the sinoatrial (SA) node and the ventricle. 131

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Table 9.1  Causes of bradycardia Causes of physiological sinus bradycardia 1. High vagal tone (ie, in athletes) 2. Sleep

Table 9.2  Types of sinus node exit blocks (mimics AV block classification) Type

ECG findings

First degree

Normal ECG, EP study shows prolonged SACT (sinoatrial conduction time)

Second degree

Type I: Progressive shortening of P-P intervals until a P wave disappears (Wenckebach pattern)

3. Medications such as β-blockers and calcium channel blockers 4. Hypothyroidism

Causes of pathological sinus bradycardia 1. Degenerative sinus node disease

Type II: Sudden absence of one or more P waves at a regular interval from the prior P wave

2. Infiltrative disorders of the heart (sarcoidosis/amyloidosis) 3. Damage to the sinus node during cardiac surgery, or catheter ablation 4. Ischemic heart disease (IHD)

Diseases of the Sinus Node 1. Sinus bradycardia: Sinus bradycardia occurs when the rate of generation of impulses from the sinus node is reduced to less than 60 bpm. This can be a normal phenomenon and is not necessarily pathologic. It is common in athletes and also occurs in states of low adrenergic tone such as during sleep. Increased vagal tone is a common mechanism of sinus bradycardia. Medications with negative chronotropic effects (such as β-blockers and calcium channel blockers) are also a common cause. Asymptomatic bradycardia does not require any treatment. See Table 9.1. 2. Sick sinus syndrome: Intrinsic disease of the SA node, causes sick sinus node syndrome. Involvement can progress into the SA node itself and into the perinodal area. The following electrocardiographic types can be seen: 1. Symptomatic sinus bradycardia (Fig. 9.1) 2. Sinus pauses and sinus arrest: Sinus pauses are the cessation of the generation of impulses in the SA node (Fig 9.1)

▶ ▶  C L I N I C A L C O R R E L A T I O N 9 . 2 Sinus pauses of more than 3 seconds are an indication for a permanent pacemaker if associated with symptoms.

Third degree or complete

Absent P waves with long pauses leading to a lower pacemaker escape rhythm

For further information, see Vijayaraman P, Ellenbogen KA. Bradyarrhythmias and pacemakers. In: Fuster V, Walsh RA, Harrington RA, eds. Hurst’s The Heart. 13th ed. New York: McGraw-Hill; 2011:chap. 43 [1].

3. Sinus node exit block: This occurs when an impulse generates normally in the sinus node but fails to conduct within the SA node or perinodal tissue (Tables 9.2 and 9.3). 4. Tachy brady syndrome/Sick sinus syndrome: A condition that occurs when tachyarrhythmia and bradycardia alternate with each other. The tachyarrhythmias can be atrial fibrillation, atrial flutter, or atrial tachycardia; the rapid rhythm suppresses the natural pacemaker (the SA node) and as soon as the tachyarrhythmia terminates, the SA node tries to take over. A healthy SA node should be able to quickly resume conduction. A diseased SA node, such as in sick sinus syndrome, may exhibit a long pause after the termination of the rapid rhythm. A slow junctional rhythm or sinus bradycardia may take over after the pause.

▶ ▶  C L I N I C A L C O R R E L A T I O N 9 . 3 Sinus node disease can present with symptoms of confusion, dizziness, fatigue, presyncope, or syncope. Syncope can present in patients with tachy brady syndrome as a result of long pauses following the suppression of tachyarrhythmia, and hence, reduced cardiac output that affects the blood supply to the brain during bradycardia.

FIGURE 9.1  ECG showing sinus bradycardia with sinus pauses.

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Table 9.3  Treatment for different types of sinus node dysfunction Type of sinus node dysfunction

Treatment

Symptomatic sinus bradycardia

Dual-chamber pacemaker

Symptomatic sinus pauses for more than 3 seconds

Dual-chamber pacemaker

Sinus node exit block (third degree)

Dual-chamber pacemaker

Tachy brady syndrome/sick sinus syndrome

Dual-chamber pacemaker with or without antiarrhythmic drugs to treat the tachycardia component

For further information, see Epstein AE, DiMarco JP, Kenneth A, 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:el. [2].

Diseases of the AV Conduction System The AV conduction system is comprised of the AV node, the bundle of His and its left and right bundle branches. There are 3 degrees of AV blocks depending on the extent of impaired conduction. 1. First-degree AV block: Usually, this a benign condition of the AV node. It is characterized by a prolongation in the PR interval of more than 200 msec. The 1:1 conduction of the AV node is well preserved and one P wave corresponding to one QRS complex on the surface ECG is observed. The causes are usually reversible. These include (1) medications (β-blockers and calcium channel blockers) that depress AV node conduction, (2) maneuvers that increase vagal tone (eg, during sleep), (3) transient ischemia such as during angioplasty of the right coronary artery, or (4) metabolic causes such

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as hyperkalemia. The PR interval will normalize as soon as the responsible factors are reversed. The irreversible causes of a first-degree AV block include chronic sclero-degenerative disease of the AV node, myocardial injury during infarction, or trauma during cardiac surgery or ablations. A first-degree AV block, in general, does not require any treatment but should be closely monitored when medications are added that can affect the AV node, thus increasing the first-degree AV block to a higher level of block. 2. Second-degree AV block: The next stage of an AV block when an intermittent conduction occurs. There are 2 types of second-degree AV blocks: a. Mobitz type I is usually a benign condition of the AV node. This is characterized on the ECG by a gradual progression of the PR interval with each beat until a QRS does not follow a P wave for a single beat (ie, a P wave without a conducted QRS). On the beat that follows, the PR interval returns to baseline and the whole cycle starts again. The R-R interval typically gets shorter until the QRS drops (Fig. 9.2). This condition is related to the AV node and the majority of the time does not involve the His bundle. It can occur in subjects with a high vagal tone such as athletes or during high vagal tone states such as sleep. Rarely, patients may experience symptoms of fatigue and dizziness and may require a pacemaker.

▶ ▶  C L I N I C A L C O R R E L A T I O N BOX 9.4 Patients who suffer from myocardial infarction (MI) involving the right coronary artery can sometimes have a Mobitz I block, which is usually reversible.

b. Mobitz type II is characterized on an ECG by a sudden loss of the QRS complex following a P wave without progressive P-R lengthening on prior beats. Typically, most P waves conduct in a 1:1 fashion with similar PR intervals, and one P wave suddenly does not conduct to a QRS. Sometimes 2 sequential P waves are followed by a QRS complex in the case

FIGURE 9.2  ECG showing Mobitz type I AV block with Wenckebach phenomenon.

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FIGURE 9.3  ECG showing Mobitz type II with a 2:1 to 3:1 AV block.

of a 2:1 Mobitz type II AV block and 3 sequential P waves followed by a QRS complex if there is 3:1 Mobitz type II AV block (Fig. 9.3). This condition involves structures below the AV node and the His bundle/Purkinje system. It is usually an irreversible condition, unless it is caused by a metabolic disorder such as hyperkalemia. This can be seen during aging due to sclerodegeneration of the AV node. It is also commonly associated with extensive myocardial injury such as during myocardial infarction, or during cardiac surgery or ablation procedures. If no reversible etiologies are found, a permanent pacemaker is the best treatment even if the patient is asymptomatic as it can progress to a sudden complete heart block. 3. Third-degree AV block: The most severe level of the AV blocks as because there is a lack of conduction across the AV node. Also called a complete heart block (CHB), the atria and ventricles beat independently of one another. Hence, this is a type of AV dissociation. An AV dissociation is characterized on an ECG by the lack of a relationship between the P wave and the QRS complex (Fig. 9.4). P waves are seen marching out with a rate different than the ventricular escape rhythm. Patients usually present with symptoms of lightheadedness, fatigue, shortness of breath, or presyncope and syncope. During a third-degree AV block, the blood supply to the brain can be insufficient, leading to a loss of consciousness.

▶ ▶  C L I N I C A L C O R R E L A T I O N 9 . 5 Adams-Stokes (or Stokes-Adams) attacks are attacks of syncope or presyncope in the setting of a third-degree AV block.

Most conditions that cause a third-degree AV block are usually irreversible. These commonly occur during aging due to sclero-degeneration of the AV node, extensive damage during a MI, and during catheter ablation and cardiac surgery of the valves. Infiltrative diseases of the heart such as sarcoid diseases should also be considered, especially in young patients without any other apparent cause. CHB usually requires a permanent pacemaker, unless a readily reversible cause can be found. The reversible causes are usually metabolic in nature such as hyperkalemia. This condition commonly occurs in renal disease particularly in patients on hemodialysis or patients who are on angiotensin-converting enzyme (ACE) inhibitors. AV nodal blocking drugs including β-blockers, calcium channel blockers, or digoxin can also cause potentially reversible AV block. Like Mobitz type II, if no reversible etiologies are found, a permanent pacemaker is the best treatment even if the patient is asymptomatic as it can progress to sudden death.

▶ ▶  C L I N I C A L C O R R E L A T I O N 9 . 6 Congenital CHB that occurs in young children and teenagers can be asymptomatic. Pacemaker implantation can usually be delayed until patients are older or symptomatic. However, because of the small increased risk of sudden death even in asymptomatic CHB, a pacemaker is usually the ultimate recommendation.

Tachyarrhythmias Tachyarrhythmias can be divided into 2 general categories depending on the site of origin: supraventricular (SVT)/atrial or ventricular (see Table 9.4A). There are many forms of atrial

FIGURE 9.4  ECG showing a third-degree AV block with no association between the P waves and QRS complexes.

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Table 9.4A  Types of tachyarrhythmias (based on site of origin)

1. Atrial tachyarrhythmia/supraventricular tachycardia 2. Ventricular tachycardia

Table 9.4B  Types of atrial tachyarrhythmias 1. Inappropriate sinus tachycardia 2. Sinus tachycardia 3. Paroxysmal supraventricular tachycardia: AVNRT/atrial tachycardia /orthodromic reentrant tachycardia (ORT) 4. Atrial flutter 5. Atrial fibrillation

arrhythmias that often cause symptoms but are usually not life-threatening. On the other hand, ventricular tachycardias not only cause symptoms but are often life-threatening. Atrial tachyarrhythmias usually present with a narrow complex QRS (≤120 ms), whereas ventricular arrhythmias present with a wide complex QRS (>120 ms). However, there are some exceptions when an atrial tachyarrhythmia can have a wide QRS; this is termed supraventricular tachycardia with aberrancy (see Table 9.5). Atrial tachyarrhythmias are the most common types of tachycardias. There are many types of atrial tachyarrhythmias (Table 9.4B). The differential diagnosis includes sinus tachycardia, paroxysmal supraventricular tachycardia (PSVT), atrial fibrillation, atrial flutter, and multifocal atrial tachycardia (MAT). PSVT is commonly divided into 3 categories: (1) AV nodal reentrant tachycardia (AVNRT), (2) orthodromic reentrant tachycardia (ORT), and (3) atrial tachycardia (Tables 9.4B and 9.5). These usually present with a narrow complex QRS. However, atrial tachyarrhythmias can also present with a wide QRS. These include SVT with aberrancy, or SVT using an accessory pathway (antidromic reentrant tachycardia).

Table 9.5  Types of tachyarrhythmias (based on QRS

morphology) 1.

Narrow QRS tachycardias

a. Sinus tachycardia (ST) b. Paroxysmal supraventricular tachycardias (PSVT) c. Atrial flutter(AFl) d. Atrial fibrillation (AFib or AF) e. Junctional ectopic tachycardia (JET)

2.

Wide QRS tachycardias

a. PSVT with aberration b. Antidromic reentrant tachycardia (preexcited) c. Ventricular tachycardia (VT)

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Atrial Tachycardia 1. Focal atrial tachycardia •• Mechanism—Automaticity is usually the mechanism responsible for this type of tachycardia. This means that a focal cell triggers a continuous repetitive impulse. •• ECG findings—These include a P wave with a different morphology than a P wave originating from the sinus node with a heart rate more than 100 beats/min. •• Characteristic features—The tachycardia is usually paroxysmal and resolves spontaneously. However, some can become incessant and may need pharmacologic or electric cardioversion to terminate. They can be asymptomatic and short-lasting in clinical presentation. But if they become symptomatic, treatment is required. Pharmacological treatment includes β-blockers, calcium channel blockers, or antiarrhythmic drugs. Tachycardias can also often be often cured by radiofrequency ablation. 2. Multifocal atrial tachycardia •• Mechanism—Automaticity is the mechanism responsible for this type of tachycardia. As the name denotes, there are multiple foci for the origin of P waves other than the sinus node. •• ECG findings—ECG features include P waves with more than at least 3 P waves with different morphologies. Usually, these P waves have varying PR and R-R intervals. •• Characteristic features—These are usually irreversible conditions and often occur in the setting of significant lung disease. The tachycardia can be controlled using AV nodal blocking agents such β-blockers and calcium channel blockers. This condition can also be seen in digitalis toxicity, which is reversible.

▶ ▶  C L I N I C A L C O R R E L A T I O N 9 . 7 Radiofrequency ablation (RFA) has no role in the treatment of MAT.

Atrial Flutter Atrial flutter is a pathological condition that occurs in normal hearts as well as structural heart disease. •• Mechanism—Reentry is the mechanism responsible for this type of tachycardia. This means that a continuous circuit of impulses is created. This circuit can be entrained during electrophysiology study. •• ECG findings—Characteristic ECG features include fast sequences of P waves in a sawtooth pattern (Fig. 9.5). The atria contract is typically at around 300 bpm, though the range can be as low as 150 and as high as 350 bpm.

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FIGURE 9.5  An atrial flutter with a 4:1 AV block.

Because the AV node has decremental conduction properties, it slows impulse conduction to the ventricle, so typically there is a 2:1, 3:1, or 4:1 block from the atrium to the ventricle, resulting in a ventricular frequency of 150, 100, or 75 bpm, respectively, if the atrial rate is 300 bpm. Often the grade of block changes every couple of beats, resulting in for example, 2:1 or 3:1 blocks and a somewhat irregular ventricular heart rate over a period of ECG monitoring. •• Characteristic features—Atrial flutter is divided into 2 major categories: cavotricuspid isthmus (CVI) dependent flutter (ie, typical flutter) and atypical flutter (ie, non-CVI dependent). (See Table 9.6.)

Cavotricuspid Isthmus-Dependent Flutter—Typical Atrial Flutter This type of flutter usually can occur in structurally normal and abnormal hearts. •• Mechanism—The flutter has a macro-reentrant circuit in the right atrium and the direction of propagation

is usually counterclockwise around the cavotricuspid isthmus. The propagation can also be clockwise, and as long as it is around the cavotricuspid isthmus, it is still considered a typical flutter. The counterclockwise form is seen most often and is most commonly referred as a “typical flutter.” The more precise and preferred classification is CVI dependent or atypical (non-CVI dependent). The tissue propagation is described in Table 9.6. •• ECG findings—It is commonly depicted by a sawtooth pattern of P waves in the inferior leads. The characteristic ECG changes include inverted P waves in the inferior leads and upright P waves in lead V1 in a counterclockwise form. Negative P waves in V1 and upright in the inferior leads are seen in a clockwise form.

Atypical Atrial Flutter This type of flutter by definition does not involve CVI. It usually occurs in structurally abnormal hearts; for example, after cardiac surgery around suture lines or after radiofrequency ablation. It can also occur around scarring in

Table 9.6  Types of atrial flutters Forms of atrial flutters

Circuit

ECG findings

“Typical” atrial flutter:

1. Counterclockwise macro-reentrant circuit (most common)

Inverted P waves in the inferior leads and upright P waves in lead V1

Cavotricuspid isthmus dependent

Wave of tissue activation—Atrial tissue between tricuspid annulus (TA) and coronary sinus opening (CS) → interatrial septum → posterior right atrium (RA) → roof of RA → RA free wall→ isthmus (atrial tissue) between TA and inferior vena cava (IVC) then recycles 2. Clockwise macro-reentrant circuit (common variant)

Upright P waves in the inferior leads and inverted P waves in lead V1

Wave of tissue activation—Atrial tissue between tricuspid annulus (TA) and coronary sinus opening (CS) → isthmus → RA free wall → roof of RA → posterior RA → interatrial septum → recycles “Atypical” atrial flutter: Activation is not around cavotricuspid isthmus

Occurs typically in hearts with scarring as a result of open heart surgery around suture lines or after radiofrequency ablation in left atrium; can occur in normal hearts

P wave morphology variable

For further information, see Prystowsky EN, Padanilam BJ; Waldo AL. Atrial fibrillation, atrial flutter, and atrial tachycardia. In: Fuster V, Walsh RA, Harrington RA, eds. Hurst’s The Heart. 13th ed. New York: McGraw-Hill; 2011:chap. 40 [3].

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cardiomyopathies. Atypical atrial flutter occurs in normal hearts as well, although this is rare.

▶ ▶  C L I N I C A L C O R R E L A T I O N 9 . 8 Both CVI dependent and atypical flutter can be treated by RFA (radiofrequency ablation).

•• Clinical presentations—May be asymptomatic with normal ventricular rates but can become symptomatic when AV conduction increases and the ventricular rate rises. The most common symptoms include palpitations, exertional dyspnea, and easy fatigability. Rarely, a rapid 1:1 flutter can occur and present with syncope as the ventricular rates will effectively be 250 to 300 bpm. An atrial flutter can also present as a cardioembolic stroke. •• Treatment—The aim of treatment is to reduce symptoms with either rate control or a return to sinus rhythm. Since the condition can easily be cured with ablation and the need for long-term anticoagulation for stroke prevention can be avoided, RFA is the preferred treatment strategy in most patients that are good candidates and do not have any other contraindications. There are 3 goals in the treatment of an atrial flutter depending on the clinical scenario at presentation. The initial goal is always rate control, to control the speed of the arrhythmia. This can be achieved with AV nodal blocking agents including β-blockers and calcium channel blockers. Digoxin can also be used but is reserved for patients as a third-line drug or for patients that have borderline hypotension as digoxin will not lower blood pressure. However, digoxin is not as effective in controlling heart rates as the first 2 drug classes of AV nodal blocking agents and has a narrow therapeutic window with a significant amount of toxicity. Urgent direct current (DC) cardioversion should be used as an initial treatment goal if the patient is hemodynamically unstable. In most patients, once the rate control is achieved or attempted, rhythm control is tried. The goal of rhythm control is to convert the patient back to a sinus rhythm. This can be achieved with either pharmacologic drugs and antiarrhythmics (class 1C agents, ibutilide, or amiodarone) or DC cardioversion. RFA is the cure for atrial flutter with success rates approaching 95% for CVI-dependent flutter and is the preferred approach in most patients who are candidates. •• Rhythm control can be achieved if the arrhythmia lasts less than 48 hours without the need for a transesophageal echocardiogram (TEE) to rule out a left atrial appendage (LAA) clot. If more than 48 hours elapse since symptoms started, then TEE should be performed to rule out an LAA clot. Anticoagulants should also be started and continued if the arrhythmia lasts more than 48 hours for at least 1 month after cardioversion. Depending on the patient’s CHA2DS2-VASc score (Table 9.10),

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anticoagulants should be continued indefinitely unless an RFA is performed, which is presumed curative. Patients with a CHA2DS2-VASc score of 1 or more should be considered for anticoagulation. Patients with a score of 2 or more should be on anticoagulants unless contraindications exist. However, if radiofrequency is performed then anticoagulants can usually be discontinued after certain duration based on the success of the ablation and the length of time that the atrial flutter lasted.

Atrial Fibrillation Atrial fibrillation (AFib) is the most common cardiac arrhythmia. This chaotic rhythm disorder results from disorganized atrial impulses from all over the atria. Atrial fibrillation is classified depending on the length of episodes: paroxysmal (7 days), and permanent AFib is sustained but restoration of a normal sinus rhythm has not been possible or is not seemingly possible and will not be attempted again (Table 9.7). •• Mechanism—Multiple reentrant circuits that coexist. There are wavelets, drivers, and rotors that have been proposed [3]. •• ECG findings—Typically include irregular R-R intervals and an absence of discrete P waves, which are replaced by irregular, chaotic F waves. P waves occur at a rate between 350 to 600 bpm (Fig. 9.6). Due to the AV node’s decremental conduction properties, the ventricular rates are much slower than the atrial rates. Heart rates can range anywhere from a slow ventricular response to 250 bpm. Sometimes there are aberrantly conducted beats

Table 9.7  Classification of AFib depending on the duration at the time of presentation Type

Definition

Paroxysmal

Two or more episodes that terminate spontaneously in less than 7 days but more commonly in 24 hours

Persistent

AFib is sustained more than 7 days Or Requires pharmacological or DC cardioversion if less than 7 days of duration

Long persistent

When AFib is sustained for more than a year but restoration of rhythm can still be tried

Permanent

When AF is sustained but restoration of normal sinus rhythm is not seemingly achievable and hence will not be tried

For further information, see Fuster V, Rydén LE, Cannom DS, et al. ACC/ AHA/ESC 2006 Guidelines for the management of patients with atrial fibrillation: 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 Revise the 2001 Guidelines for the Management of Patients with Atrial Fibrillation). Eur Heart J. 2006;27:1979-2030 [4].

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FIGURE 9.6  Atrial fibrillation with a varying ventricular rate.

after long-short R-R cycles termed the Ashman phenomenon. When the heart rate is under 60 bpm, it is called atrial fibrillation with a slow ventricular response. When the rate is greater than 100 bpm, then it is denoted as a fast ventricular response. If the rate is between 60 to 100 bpm, then electrophysiologists refer to it as atrial fibrillation with a controlled ventricular response. •• Clinical presentations—These patients can be asymptomatic, especially with controlled ventricular rates. The most common symptoms associated with this disease are palpitations, exertional dyspnea, and fatigue. Chest pain, dizziness, near syncope, and syncope can also occur. Unfortunately, many patients also present with a cardioembolic stroke (cerebrovascular stroke, CVA) as a first symptom, as AFib is a common cause of CVA. If the atrial fibrillation ventricular rate is left uncontrolled, congestive heart failure can occur. •• Causes—The majority of AFibs are idiopathic, but can also be acquired (Table 9.8). Thyrotoxicosis, pericarditis, myocardial ischemia, electrolyte abnormalities, and alcoholism are other causes that can be reversible. AFib is also very common in postcardiac surgery due to pericarditis and often does not recur after a healing period.

Table 9.8  Causes of atrial fibrillation •• •• •• •• •• •• •• •• •• •• •• •• •• •• •• ••

Age Hypertension Coronary artery disease Cardiomyopathy—both ischemic or nonischemic Pericarditis/pericardial intervention Congenital heart disease Mitral valve disease Prior heart surgery—CABG or valvular surgery Hyperthyroidism Sleep apnea Alcohol abuse Smoking CO poisoning Excessive caffeine consumption Atrial flutter Others: •• Chest infections: pneumonia •• Pulmonary disease including lung cancer, COPD—emphysema or pulmonary embolism

For further information, see Estes NAM, Sacco RL, Al-Khatib SM, et al. American Heart Association Atrial Fibrillation Research Summit: a conference report from the American Heart Association. Circulation. 2011;124(3):363-372 [5].

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▶ ▶  C L I N I C A L C O R R E L A T I O N 9 . 9 Treatment of AFib depends on the type of AFib diagnosed clinically.

▶ ▶  C L I N I C A L C O R R E L A T I O N 9 . 1 0 Always check the thyroid profile in all patients presenting with AFib.

There is a strong association between AFib and other cardiovascular diseases such as heart failure, coronary artery disease, hypertension, and lung disorders. All these diseases lead to an increase in LA load and hence LA pressure thus predisposing to AFib.

Treatment Treatment has 3 goals depending on the clinical scenario at presentation. Initially, it is very similar to the treating and atrial flutter. The first goal is always rate control in order to control the speed of the arrhythmia. This can be achieved with AV nodal blocking agents including β-blockers and calcium channel blockers. Digoxin can also be used but is reserved for patients as a third-line drug or for patients with borderline hypotension as it does not lower blood pressure. However, digoxin is not as effective in controlling heart rates as the first 2 drug classes of the AV nodal blocking agents. Urgent DC cardioversion should be used as an initial treatment goal if the patient is hemodynamically unstable. In most patients, once rate control is achieved or attempted, then rhythm control is attempted, unless the patients are elderly and completely asymptomatic. The goal of rhythm control is to convert the patient back to a sinus rhythm. This can be achieved with either antiarrhythmics (class 1C agents, ibutilide, or amiodarone) or DC cardioversion. AAD drugs used for this arrhythmia for long-term maintenance of sinus rhythm include: class 1C agents, sotalol or dofetilide, or amiodarone (Table 9.9). However, RFA is more successful than antiarrhythmics in maintaining sinus rhythm and is therefore a good option for patients that qualify usually after failing with AADs. Because the success rate of AFib ablation is not as high as that of atrial flutter, it is usually reserved for patients that fail AA drugs and are symptomatic. However, some patients with paroxysmal AFib are also candidates for ablation as a first-line therapy. Those with persistent AFib

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Chapter 9  Arrhythmias and Antiarrhythmic Drugs

Table 9.9  Antiarrhythmic drugs for the treatment of atrial fibrillation Serial no.

Drug

Dosage

1.

Flecainide

50 mg to 150 mg per dose BID

2.

Propafenone

150 to 300 mg per dose TID, SR sustained release also available and dosed BID

3.

4.

Dofetilide

Amiodarone

500 mcg PO BID or 250 mcg BID depending on renal function: requires hospital observation for initiation 150 given IV bolus over 10 to 20 min then drip initiation Orally 400 mg TID or BID loading until approximately 8 grams given then maintenance dose of 200 mg daily

5.

Dronedarone

400 mg BID

6.

Sotalol

80 to 160 mg/dose BID

have lower success rates with RFA, and therefore usually should first fail antiarrhythmic therapy. Note: Similar to atrial flutter, rhythm control can be achieved if the arrhythmia lasts for less than 48 hours without the need for a TEE to rule out a LAA clot. If more than 48 hours elapses since symptoms started, then a TEE should be performed to rule out an LAA clot. Anticoagulation should also be started and continued if the arrhythmia lasts more than 48 hours for at least 1 month after cardioversion regardless of the CHA2DS2-VASc score. Long-term anticoagulation beyond the 1 month should be continued depending on the patient’s CHA2DS2-VASc score (Table 9.10).

More on Ablation of Atrial Fibrillation Ablation can be offered to patients who fail AA therapy and are symptomatic for both paroxysmal and persistent AFib. It is a complex procedure that generally targets the elimination of pulmonary vein potentials in the left atrium at a minimum, with other targets and triggers depending on the etiology of the AFib. It can be performed via radiofrequency ablation or via cryoballoon ablation. The success rates of AFib ablation have a wide range depending on the types AFib and whether the AFib is paroxysmal or persistent.

Stroke Prevention This is an important goal of atrial fibrillation treatment due to the morbidity and mortality. Anticoagulation is guided by the CHA2DS2-VASc score (Table 9.10). This is a risk-stratifying system that assigns points to risk factors for a stroke. Anyone with one or more risk factors is a candidate for anticoagulation for stroke prevention. Patients with a score of zero do

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Table 9.10  Showing the CHA2DS2VASc scoring system (The CHA2DS2VASc score is used to estimate the risk of stroke in patients with nonvalvular AFib) Abbreviation

Factors

Points

C

Congestive heart failure

1

H

Hypertension

1

A2

Age ≥75 years

2

D

Diabetes mellitus

1

S2

Stroke/TIA/thromboembolism

2

V

Vascular disease

1

A

Age ≥65 120 msec, it is defined as a wide QRS tachycardia. If the tachycardia is wide and irregular then

FIGURE 9.8  ECG showing paroxysmal supraventricular tachycardia. (Reproduced, with permission, from Knoop KJ, Stack LB, Storrow AB, Thurman RJ. The Atlas of Emergency Medicine. 3rd ed. New York, NY: McGraw-Hill; 2010.)

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Table 9.13A  Maneuvers for AVNRT reversal to normal sinus rhythm Maneuvers

Table 9.13B  Pharmacological treatments for AVNRT Pharmacological treatment 1. Adenosine—At 6 to 12 mg IV bolus

1. Carotid sinus massage

2. Calcium channel blockers

2. Valsalva maneuver

a. Verapamil b. Diltiazem

3. Coughing

3. β-blockers

4. Head immersion in cold water

a. Esmolol b. Metoaprolol

adenosine is not recommended since the arrhythmia can be AFib conducted down an accessory pathway (see next section on Wolff-Parkinson-White). AV nodal drugs such as calcium channel blockers and β-blockers can suppress the arrhythmias, although they are not very effective. •• Radiofrequency ablation is the treatment of choice in patients with recurrent PSVT. The success rate is greater than 95% for RFA. During RFA, if an AVNRT is confirmed, the slow pathway is ablated.

Atrioventricular Reentrant Tachycardia and Wolff-Parkinson-White Syndrome Atrioventricular reentrant tachycardias (AVRTs) are SVTs that are caused by the presence of an accessory pathway. There are 2 types: ORT and antidromic reentrant tachycardia

c. Bisoprolol d. Carvedilol e. Atenolol Other: Antiarrhythmic drugs such as amiodarone or class 1 agents, but significant side effects can occur For further information Table 9.13A, B, Calkins H. Supraventricular tachycardia: atrioventricular nodal reentry and Wolff-Parkinson-White syndrome. In: Fuster V, Walsh RA, Harrington RA, eds. Hurst’s The Heart. 13th ed. New York: McGraw-Hill; 2011:chap. 41 [8]; Marchlinski F. The tachyarrhythmias. In: Longo DL, Fauci AS, Kasper DL, Hauser SL, Jameson JL, Loscalzo J, eds. Harrison’s Principles of Internal Medicine. 18th ed. New York: McGraw-Hill; 2012:chap. 233 [9].

(ART); see Table 9.15. These accessory pathways are “extra” connections that are present between the atria and the ventricles in addition to the normal conduction system of the heart. These accessory pathways are actually myocytes spanning

Table 9.14  Differentiating mechanisms for different types of SVTs Serial no. 1.

2.

Type of arrhythmia Unifocal atrial tachycardia

AV nodal reentry tachycardia

Mechanism

ECG changes for recognition

Pharmacological/ Ablation treatment

Automaticity

a. Narrow QRS

a. β-blockers

b. Usually regular, but may have some irregularity

b. Calcium channel blockers

c. P wave during tachycardia is different from sinus P wave

c. Adenosine sometimes works

d. Terminates with narrow QRS complex

d. Ablation

a. Narrow QRS

a. Adenosine

b. Regular

b. β-blockers

c. P wave is merged in QRS or just after QRS

c. Calcium channel blockers

d. Pseudo S wave (retrograde P wave) in II, III, aVF, and pseudo R (retrograde P wave) in lead V1

d. Ablation

Reentry

e. Terminates with a retrograde P wave or QRS complex 3.

ORT (orthodromic reentrant tachycardia)

Reentry

a. Narrow QRS during tachycardia

a. β-blockers

b. Regular

b. Calcium channel blockers

c. During sinus rhythm, a short PR interval, delta wave, and wide QRS may be present

c. Adenosine d. Ablation

d. Retrograde P wave is usually farther away from QRS e. QRS alternans can be seen f. Terminates with a retrograde P wave or QRS complex For further information, see Prystowsky EN, Padanilam BJ; Waldo AL. Atrial fibrillation, atrial flutter, and atrial tachycardia. In: Fuster V, Walsh RA, Harrington RA, eds. Hurst’s The Heart. 13th ed. New York: McGraw-Hill; 2011:chap. 40 [3]; Calkins H. Supraventricular tachycardia: atrioventricular nodal reentry and Wolff-Parkinson-White syndrome. In: Fuster V, Walsh RA, Harrington RA, eds. Hurst’s The Heart. 13th ed. New York: McGraw-Hill; 2011:chap. 41 [8].

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Chapter 9  Arrhythmias and Antiarrhythmic Drugs

between the upper and lower chambers of the heart across the AV groove. This tissue is distinct from the normal conduction pathway of the heart. These connections disappear during the normal development of the human heart during fetal life but in some cases, they can persist. Many of these pathways remain benign and can disappear over time while others can be responsible for SVTs. AVRTs are most common in children, accounting for approximately 30% of all SVTs. The prevalence of accessory pathways in the general population is 0.15% [10]. Accessory pathways can conduct antegradely or retrogradely. If they conduct antegradely then they can usually be seen on a baseline ECG and are represented by a delta wave. These are termed as “manifest” preexcitations since the pathway is obvious on the ECG by the presence of the delta waves. On the other hand, a pathway may not be obvious on an ECG and only conduct retrogradely during an SVT. In this case, it is termed as “concealed” since in effect the pathway is hidden on the surface of the ECG. Patients with manifest pathways are also labeled as having Wolff-Parkinson-White (WPW) syndrome or ventricular preexcitation. The ECG manifestation of WPW syndrome includes a short PR interval and a delta wave (Fig. 9.9). The short PR interval occurs because there is early ventricular activation through the accessory pathway. The QRS has a slurred delta upstroke because there is slower ventricular activation from myocyte to myocyte initiated by the accessory pathway, as opposed to the usual rapid conduction of the His-Purkinje system. The widening of the QRS complex is a result of the fusion of the 2 electrical waveforms from the normal conduction system down the AV node and the accessory pathway activation of the ventricle merging together. The presence of the accessory pathway can set up the reentry and therefore SVT. The direction of the flow of the cardiac impulse during SVT through this circuit defines the type of AVRT, of which there are 2 types (Table 9.15). If the initial impulse travels down the AV node and retrogradely

143

Table 9.15  Antidromic versus orthodromic AVRT Orthodromic AVRT

Antidromic AVRT

Most common type

Occurs in 10% of patients with WPW syndrome with tachycardia

Impulses transmit anterogradely down the AV node to the ventricles and then retrogradely to the atria up through the accessory pathway

Impulses transmit anterogradely down the accessory pathway to the ventricles and then retrogradely to the atria up through the AV node

Narrow QRS complexes during tachycardia

Wide QRS complex during tachycardia

up the pathway, then it is termed as “orthodromic reentrant tachycardia” and the resultant ECG shows a narrow QRS (120 msec) since the impulse initially travels down the pathway. Unlike the AV nodal pathways, accessory pathways do not have decremental properties. The AV node has the intrinsic property of slowing down impulses from the atrium to avoid very rapid signals from conducting in a 1:1 fashion to the ventricle. However, accessory pathways, in general, do not have decremental properties and therefore can conduct very rapid impulses from the atria. There are some pathways that do exhibit decremental conduction, but these are in the minority. Rare but life-threatening arrhythmias can occur in patients with WPW syndrome when an atrial flutter or atrial fibrillation is present and the accessory pathway conducts in an anterograde fashion to the ventricles at extremely fast rates

FIGURE 9.9  ECG showing normal sinus rhythm and delta waves (arrow) with a short PR interval in a patient with WPW syndrome. (Reproduced, with permission, from Knoop KJ, Stack LB, Storrow AB, Thurman RJ. The Atlas of Emergency Medicine. 3rd ed. New York, NY: McGraw-Hill; 2010.)

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Table 9.16A  Treatment in patients with WPW syndrome with tachyarrhythmia

Table 9.16B  Pharmacological treatment for WPW

syndrome

Hemodynamic stability

Treatment of choice

Indicated

Contraindicated

STABLE

Class IA drugs, eg, procainamide

1. Class IA, IC, III

1. Calcium channel blockers, β-blockers, and digoxin are contraindicated if the tachycardia is irregular and wide

Class III drugs, eg, ibutilide UNSTABLE

DC cardioversion

due to the short refractory periods of these pathways. These impulses, when conducted to ventricles at over 300 bpm depending on the rate of the atrial flutter or atrial fibrillation, can lead to ventricular fibrillation and sudden death.

Treatment Radiofrequency ablation is the treatment of choice in patients with WPW syndrome, which show evidence of preexcitation and are symptomatic. Patients with symptomatic WPW syndrome have an increased risk of sudden death due to the potential rapid conduction of the accessory pathway during an atrial flutter or AFib as described above, and therefore ablation is recommended as first-line therapy. An asymptomatic patient with WPW syndrome can be observed and treated conservatively unless the patient is in a high-risk profession such as an airline pilot. AV nodal agents should be avoided in WPW syndrome if the tachycardia is irregular as the agents may preferentially allow conduction down the accessory pathway by inhibiting the AV node (due to the presence of an underlying atrial fibrillation). Procainamide can be used acutely versus DC cardioversion in patients presenting with WPW syndrome and SVT (Table 9.16A, B). Patients with SVT and a narrow complex without a manifest pathway can be treated with AV nodal blocking agents or radiofrequency ablation depending on their preference. Ablation can be used as a first-line treatment or reserved until medical therapy fails, depending on the patient’s preference. As opposed to the patients with manifest accessory pathways, patients with a narrow complex SVT who cannot

All these drugs slow the conduction and increase the refractory period in the AV node as well as the accessory pathway 2. Procainamide slows conduction in the accessory pathway more than the AV node

They slow the conduction through the AV node only 2. They can precipitate ventricular fibrillation in a patient who has atrial flutter or atrial fibrillation by blocking the AV node only

Or Ibutilide increases the refractory period in the accessory pathway

conduct anterograde down their accessory pathway are not at an increased risk of sudden death compared to the general population since the maximum rate of conduction to the ventricle anterograde is still limited by the AV node, which has decremental properties.

Ventricular Tachycardia Characteristic Features Ventricular tachycardia (VT) is defined when there is a run of 3 or more ventricular premature beats on an ECG. They are therefore wide complex tachycardias with QRS duration >120 msec (Fig. 9.10). These commonly occur in structurally abnormal hearts and may be life-threatening. However, they can also occur in completely normal hearts and be welltolerated. Common associated diseases include myocardial ischemia or injury (ie, myocardial infarction), cardiomyopathies, congenital heart diseases, valvular heart diseases, long QT syndromes/channelopathies, and postcardiac surgery due to scarring. There are also metabolic causes including hypokalemia, hypomagnesemia, and hypoxia.

FIGURE 9.10  ECG showing ventricular tachycardia. (Used with permission from the Innovation Department of the Spectrum Health Fred and Lena Meijer Heart Center, Grand Rapids, Michigan.)

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Chapter 9  Arrhythmias and Antiarrhythmic Drugs

▶ ▶  C L I N I C A L C O R R E L A T I O N 9 . 1 3 Wide QRS regular tachycardia with a hemodynamic compromise; always suspect VT first.

Ventricular tachycardias are classified based on the uniformity of the morphology of the wide QRS complexes. They can be divided into monomorphic VT and polymorphic VT. Monomorphic VTs have a uniform morphology of the wide QRS complex; often these are regular tachycardias but can be irregular. Polymorphic VTs have multiple morphologies of the QRS complex with a duration of more than 120 msec. Polymorphic VTs are usually irregular. If the axis of the QRS changes during polymorphic VT then it can be termed torsades de pointes. Other features are enumerated in Table 9.17. Ventricular tachycardias can also be classified based on the etiology of the structural heart disease with which they are associated, as either ischemic, nonischemic, or idiopathic. Ischemic VT, as the name implies, is associated with coronary artery disease and usually occurs as a result of scarring from a myocardial infarction that causes a reentrant circuit for the VT. These are usually considered to be monomorphic VTs. Ischemia can also cause polymorphic VT, torsades de pointes, and ventricular fibrillation. Nonischemic VT occurs in patients with structurally abnormal hearts without associated coronary artery disease, such as in patients with severe left ventricular (LV) dysfunction. A monomorphic idiopathic VT occurs in the setting of structurally normal hearts without left LV dysfunction or coronary artery disease. These usually have a good prognosis but in rare instances can be life-threatening (Table 9.18). If an “idiopathic” VT is polymorphic in the setting of an otherwise normal heart then it is usually due to channelopathies such as Brugada syndrome, long QT syndrome, catecholaminergic polymorphic VT (CPVT), or short QT syndrome.

Table 9.17  Differentiating monomorphic from polymorphic VTs

Monomorphic VT

Polymorphic VT

1. Uniform morphology of QRS complexes

1. Multiple morphologies of QRS complexes

2. May be related to ischemia, metabolic causes, or scarring

2. Often associated with ischemia or channelopathies

3. Rate of rhythm is mostly constant

3. Rate varies all through the rhythm

4. Reentry is a common mechanism; triggered activity can occur in normal hearts and idiopathic VT

4. Automaticity or unstable reentry circuits are a common mechanism

5. Structural abnormalities and scarring are common causes, although can occur in completely normal hearts

5. Channelopathies and ischemia are common causes

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Table 9.18  Types of idiopathic VTs Types of idiopathic VTs

ECG findings

1. RVOT VT (right ventricular outflow tract VT)

LBBB with inferior axis

2. LVOT VT (left ventricular outflow tract VT)

Broad R in V1 with early transition

3. Fascicular VT

Narrower QRS usually 120 to 150 msec and with a typical RBBB or LBBB pattern

4. Annular VT

RBBB with left-axis deviation

For further information, see Rho RW, Page RL. Ventricular arrhythmias. In: Fuster V, Walsh RA, Harrington RA, eds. Hurst’s The Heart. 13th ed. New York: McGraw-Hill; 2011:chap 42 [11].

▶ ▶  C L I N I C A L C O R R E L A T I O N 9 . 1 4 Channelopathies leading to polymorphic VT include Brugada syndrome, long QT syndrome, and CPVT (catecholaminergic polymorphic VT).

Last, VT can be further described as sustained (>30 sec) and nonsustained (120 msec) because of an “aberrant” or slow conduction of the ventricular conduction system during a SVT. Differentiating SVT with aberrancy from VT has important clinical treatment implications and prognoses. This is not always an easy task but there are certain ECG observations and clinical features that can be helpful (Table 9.20).

Table 9.19  Differentiating nonsustained VT from sustained VT Features

Nonsustained VT

Sustained VT

Duration

Less than 30 seconds

More than 30 sec

Associated symptoms— including presyncope, syncope, palpitations

Usually transient if any at all

Usually present

Termination

Spontaneous termination

DC cardioversion/ antiarrhythmic drugs/or spontaneous

For further information, see Rho RW, Page RL. Ventricular arrhythmias. In: Fuster V, Walsh RA, Harrington RA, eds. Hurst's The Heart. 13th ed. New York: McGraw-Hill; 2011:chap 42 [11].

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Table 9.20  Differentiating features between SVT with aberrancy and monomorphic VT Features favoring SVT with aberration

Features favoring VT

History of heart disease

Unusual

Common

VA (ventricular/ atrial) dissociation

Absent

Can be present

Morphology of QRS in precordial leads

No concordance

Concordance in V1-V6 (ie, all QRS vectors up or down) can be present

Initial R wave in aVR

Small R wave in aVR favors SVT

Large R wave in aVR common

Fusion/capture beats

Absent

Can be present

Interval from onset of R to nadir of S wave in any precordial lead

Interval 40

4 m/s AVA < 1 cm2 Mean gradient > 40 mmHg Reevaluation

Undergoing CABG or other heart surgery? Yes

No

Symptoms? Equivocal Exercise test

Symptoms ↓BP

Less than 0.50 Yes

Class I

Class I

Class IIb

Class I

Normal

Class IIb

Aortic valve replacement Preoperative coronary angiography

LV ejection fraction Normal

Severe valve calcification, rapid progression, and/or expected delays in surgery No Clinical follow-up, patient education, risk factor modification, annual echo

FIGURE 10.2  Management strategy for patients with severe aortic stenosis. (Reproduced, with permission, from Longo DL, Fauci AS, Kasper DL, Hauser SL, Jameson JL, Loscalzo J, eds. Harrison’s Principles of Internal Medicine. 18th ed. New York, NY: McGraw-Hill; 2011.)

present secondary to diseases afflicting the aortic root, such as Marfan syndrome, aortic dissection (cystic medial necrosis), ankylosing spondylitis, syphilitic aortitis, rheumatoid arthritis, giant cell aortitis, and reactive arthritis.

Pathophysiology Acute AR exposes the normally compliant LV to a sudden increase in blood volume. The LV tries to maintain the cardiac output by increasing the heart rate and contractility, which can prove to be inadequate as the compensatory capacity of the LV is overcome. This leads to a rapid increase in LVEDP and LAP, resulting in pulmonary congestion and circulatory collapse. Chronic AR allows the LV to adapt to the sustained increase in blood volume by dilation, asymmetric hypertrophy and increase in its compliance. These changes allow the cardiac output, LVEDP, and left atrial pressure (LAP) to remain within a manageable range. With the persistent burden of the regurgitant blood volume, these adaptations gradually fail to support the heart’s function. Ventricular dilation progresses to the stage where contractility becomes inefficient and cardiac output decreases along with a rise in LVEDP and LAP. The end results are pulmonary congestion, LVH decreased forward flow of blood, and myocardial ischemia as a result of compromised coronary perfusion.

Clinical Presentation Acute AR patients usually present with circulatory collapse (hypotension) and severe SOB. On the other hand, chronic AR patients’ symptoms depend on whether the patient is in a state of compensation or decompensation. Compensated patients

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are usually asymptomatic or experience fatigue and a decrease in functional capacity. Decompensated patients commonly present with exertional SOB, fatigue, and pulmonary congestion. Angina, syncope, and presyncope might also be present but are infrequent. Orthopnea and paroxysmal nocturnal dyspnea (PND) can also be produced in late stages of the disease. Physical examination findings in acute AR patients include tachypnea and tachycardia upon general examination. A normal pulse is common along with a normal or slightly increased pulse pressure. The murmur may be absent or present for a brief duration. A low amplitude early diastolic murmur is best heard at the third left intercostal space (as the LV is ill-equipped to handle the regurgitant volume, the forward SV is reduced and LV pressure rises drastically). The S1 is diminished as a result of premature closure of the mitral valve during diastole (high LV pressure). Chronic AR patients may present with wide arterial pulse pressure along with: a collapsing pulse (water-hammer or Corrigan pulse); a dicrotic pulse (bisferiens) may be present indicating combined AR and AS; prominent carotid pulsations in the neck (Corrigan sign), pulsations in the nail beds (Quincke sign); head bobbing in sync with the heartbeat (de Musset’s sign); blood pressure (BP) in the legs > arms by more than 20 mmHg (Hill sign); systolic and diastolic murmurs heard over the femoral artery (pistol shot sounds/Duroziez sign); Rosenbach liver pulsations in synchrony with the heartbeat; exaggerated retinal artery pulsations (Becker sign); alternating constriction and dilation of the pupils (Landolfi sign); and pulsatile pseudo-proptosis (Ashrafian sign). The apex beat is displaced and is heaving in nature. A diastolic thrill may be present. A decrescendo-type early, high-pitched, early diastolic murmur is best heard at the third

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Chapter 10  Valvular Heart Diseases

left intercostal space at end-expiration. A systolic flow murmur may be heard, as a result of an increase in the systolic blood flow across the valve. An Austin Flint murmur is a mid-­ diastolic rumbling murmur that is a result of the regurgitant jet which displaces the anterior mitral leaflet. Both soft S1 and S3 can be present with heart failure.

Complications If untreated, aortic regurgitation can be complicated by left ventricular dysfunction, dilated cardiomyopathy (DCM), angina, syncope, pulmonary edema, hypertension, and rarely, cor bovinum (an extra-ordinarily enlarged heart).

Investigative Studies •• Chest radiograph: Cardiomegaly, valvular calcification, pulmonary congestion, and widened mediastinum due to a dilated aortic root •• EKG: LVH, LAE, ST-T changes, new conduction blocks if the conduction system is involved •• Echocardiography: Used to confirm the diagnosis, the cause, the valvular morphology, assess the severity, monitor the disease course, the LV dimensions and function, aortic root size estimation, and the transvalvular gradient •• TEE: Superior to TTE when it comes to detecting a bicuspid aortic valve, prosthetic valves, aortic dissection, and endocarditis with or without a ring abscess (Fig. 10.3) •• Doppler study: Most sensitive and specific method to detect AR •• Spiral computed tomography (CT)/magnetic resonance imaging (MRI): Can be used to accurately define the aortic root dimensions and the severity of regurgitation, especially when an echocardiography is inconsequential or an ascending aortic aneurysm is suspected

155

•• Catheterization: Useful to determine the LV function, aortic root dimensions, and AR severity; primarily indicated for patients at risk for CAD (mostly the elderly), where the severity of the AR is unclear and in those in which noninvasive investigations are discordant with clinical findings •• BNP: Recent studies highlight with greater confidence the role of BNP as an early sign of LV dysfunction; raised BNP is hypothetically seen as a cue to consider surgical intervention in patients with AR

Markers of Severity Clinical presence of a collapsing pulse, wide pulse pressure, longer duration of an AR diastolic murmur, S3, an Austin Flint murmur, and congestive heart failure are signs of severe aortic regurgitation. Echocardiographic Markers of Severity •• Mild AR is characterized by a regurgitant volume of 0.29 cm2, and left ventricular ­end-systolic (LVES) dimensions >5 to 5.5 cm2.

Treatment In the setting of severe acute AR, the usual suspects are infective endocarditis and aortic dissection. Emergent surgery is indicated in both, even with ongoing infection. Vasodilators can act as the bridge to surgery during that time.

FIGURE 10.3  Transesophageal still frame echocardiographic view of a patient with a dilated aorta dissection and severe aortic regurgitation. (Reproduced, with permission, from Longo DL, Fauci AS, Kasper DL, Hauser SL, Jameson JL, Loscalzo J, eds. Harrison’s Principles of Internal Medicine. 18th ed. New York, NY: McGraw-Hill; 2011.)

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Although surgery is the most beneficial intervention to reduce mortality from AR, the use of vasodilators is advocated to reduce or postpone the need for surgery in asymptomatic patients with severe AR. It can also be considered for symptomatic patients that are poor candidates for surgery. Current recommendations are to prescribe vasodilators to decrease the afterload in AR when there is associated systolic hypertension. The commonly used vasodilators include nifedipine, β-blockers, and ACE inhibitors. Marfan syndrome was traditionally treated with β-blockers but now ACE inhibitors have proven to be more beneficial. It is also worth mentioning that long-term therapy with vasodilators is not recommended for patients with decreased LV function as these can cause the already compromised stroke volume to become worse. On the whole, vasodilators improve hemodynamics in AR variably from patient to patient, and the effect is inconsistent at best.

Surgery Indications for Surgery 1. Symptoms of heart failure 2. LV dysfunction (EF 5-5.5 cm), even if asymptomatic 3. Asymptomatic patients with EF >50% but LVESD >50 mm or LVEDD >70 mm 4. Severe AS with concomitant coronary artery disease 5. Patients undergoing other cardiac surgery or aortic root surgery 6. AVR and aortic root surgery is indicated for patients with aortic root disease if the ascending aortic segment diameter is >50 mm in Marfan syndrome 7. In Marfan syndrome, surgery is advised if the aortic root diameter exceeds 45 mm in patients that have additional risk factors; in bicuspid valves, surgery is advised if the diameter exceeds 50 mm; surgery for normal patients is advised if the diameter exceeds 55 mm As with AS, AVR is the preferred mode of therapy in aortic regurgitation and offers the best long-term mortality benefit. The choice of replacement valves is dependent on the patient’s age, risk factors, and potential risk of adverse effects of anticoagulation. Generally, prosthetic valves are used in the young because of their durability. In the elderly, bioprosthetic valves are used as these prevent adverse effects from warfarin. The mortality for aortic valve placement is 3% to 5%.

Prognosis and Follow-Up Asymptomatic patients with no LV dysfunction progress to manifesting symptoms at a rate less than 6% and sudden death 70 mm and left ventricular end-systolic dimensions >50 mm, follow-up every 4 months with serial echocardiograms is recommended.

Mitral Valve Stenosis Mitral stenosis (MS) refers to an occlusion/narrowing at the level of the mitral valve: essentially manifesting itself as an obstruction to the left ventricular inflow during diastole. Consequently, that resistance to blood flow creates a diastolic pressure gradient between the left atrium and the left ventricle.

Etiology Mitral stenosis occurs because of a structural abnormality in the mitral valve apparatus. The causes can be broadly classified as congenital, acquired, and rheumatic. Rheumatic MS usually follows recurrent attacks of rheumatic fever and is common in developing countries. Congenital MS is rare and is usually the result of chordal fusion, papillary muscle malposition/fusion (parachute mitral valve), or functional mitral stenosis (cor triatriatum). Rarely, acquired MS can be associated with systemic lupus erythematosus (SLE), rheumatoid arthritis, malignant carcinoid syndrome, Fabry disease, Whipple disease, drugs like methysergide, mitral annular calcification as seen in elderly patients, and end-stage renal disease.

Epidemiology of Mitral Stenosis The incidence of mitral stenosis (MS) in developed countries is low; around 1 in 100,000, while the incidence in developing countries is much more common, at 35 to 150 in 100,000, and is most commonly to the result o rheumatic heart disease. Two-thirds of the patients are females and the age of onset of symptoms is usually in the third to fourth decade of life. The association of atrial septal defect (ASD) with rheumatic MS is known as Lutembacher syndrome.

Pathophysiology The mitral valve orifice normally has a cross-sectional area of 4 to 6 cm2. The diastolic pressure gradient across the valve increases as the valve area decreases to maintain adequate blood flow, and as a result the left atrial pressure (LAP) increases. Sustained increases in LAP lead to a compensatory left atrial enlargement and remodeling, which accounts for the development of atrial fibrillation, and subsequently, a higher risk for thrombus formation. This can lead to serious thromboemboli to various organs such as the brain as in case of a stroke. Increased LAP also leads to an increase in the pulmonary vascular tone and hence the resistance that results in pulmonary hypertension. Consequently, it increases the afterload on the right ventricle that then increases its pressure and causes compensatory hypertrophy and dilatation, and

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eventually to right-sided heart failure. Only when the valve area is 2 to 2.5 cm2 or less will patients start to experience valve-related symptoms. At this point, moderate exercise or tachycardia may result in exertional dyspnea. When the valve area reaches less than 1 cm2, it indicates as severe mitral stenosis. Certain stressful conditions such as pregnancy, exercise, fever, atrial fibrillation, and hyperthyroidism can initiate or precipitate symptoms at any given valve or valve orifice area.

Clinical Presentation Mild to moderate mitral stenosis is symptomatic (ie, mainly dyspnea) only with rigorous exertion. During exercise, the LA pressure and heart rate increase, while the diastolic filling time and cardiac output decrease. Severe mitral stenosis is characterized by more dyspnea even at rest, fatigue, and other symptoms of pulmonary congestion such as orthopnea and paroxysmal nocturnal dyspnea. With more severe MS and sustained pulmonary hypertension, symptoms of right-sided heart failure develop. Clinical manifestations of right-sided heart failure include ascites, pedal edema, and weight gain. Less frequent symptoms include: palpitations (atrial fibrillation), hemoptysis (rupture of bronchial vessels), hoarseness of voice (Ortner syndrome), persistent cough and systemic embolic episodes presenting as stroke, renal failure, or myocardial infarction. A history of rheumatic fever in childhood can be elicited in most cases.

Examination General physical examination signs of MS include tachypnea, mitral facies (ie, rosy cheeks, while the rest of the face has a bluish tinge), and peripheral cyanosis. Ascites, venous congestion, and peripheral edema indicate right heart failure. The pulse can be normal or reduced in volume, regular or irregularly irregular (atrial fibrillation) in rhythm. Jugular venous pressure can be normal or raised. On palpating the precordium, a tapping apex beat, left parasternal heave, or palpable P2 may be felt. On cardiac auscultation, there can be a loud S1 (if the valve cusps are mobile), or a loud P2 (pulmonary hypertension), an opening snap following S2 that is heard best at the apex with the patient in a left decubitus position. The relation of opening snap with A2 is important and is shorter in severe disease. A mid-diastolic low-pitched rumbling murmur is best heard with the patient in a left lateral position and using the bell of stethoscope. The murmur is accentuated by exercise, while it decreases with rest and Valsalva maneuver. There can be additional presystolic accentuation in the sinus rhythm and an opening snap heard right after the S2. In patients with right ventricular dilatation, a pansystolic murmur of TR and an S3 originating from the right ventricle may be noticeable in the fourth left intercostal space. Complications can be one of the presenting features of mitral stenosis. These include: left atrial enlargement, atrial fibrillation, systemic embolization (usually causing strokes in the cerebral hemispheres), pulmonary hypertension, tricuspid

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regurgitation, tight heart failure, hemoptysis and hoarseness of voice, and infective endocarditis.

Diagnostic Studies A chest x-ray (CXR) usually shows left atrial enlargement, a large right ventricle, and pulmonary artery if pulmonary hypertension (HTN) is present; congested upper lobe veins due to redistribution of pulmonary vasculature to the upper lobes; Kerley A and B lines (horizontal lines in the regions of the costophrenic angles representing interstitial edema), mottling caused by secondary pulmonary hemosiderosis, and calcification in the mitral valve in rheumatic mitral stenosis or in the annulus in calcific mitral stenosis. EKG may reveal broad bifid P waves (P mitrale), tall peaked P waves, right axis deviation, or RVH and atrial fibrillation. An echocardiogram is the most specific and sensitive method for diagnosing and quantifying the severity of mitral stenosis (Fig. 10.4). Observing and quantifying the 4 parameters, that is, mitral leaflet thickening, mitral leaflet mobility, submitral scarring, and commissural calcium; each scoring 1 to 4 has led to the development of a scoring system for the candidacy for valve repair options. An echocardiogram also helps to determine the planimetric calculation of the valve area, the transvalvular gradient, the right heart parameters, and the presence of thrombus. Transesophageal echocardiography is only used when TTE proves inconsequential or in order to assess the severity of MR and the exclusion of left atrial thrombus prior to percutaneous mitral balloon valvuloplasty. Cardiac catheterization is indicated when a diagnostic discrepancy exists or there is a question of coronary artery disease after the decision for surgery has already been made.

Markers of Severity of MS •• Mild MS is usually asymptomatic. The S2-OS gap is >120 ms and the P2 is normal. The valve area is >1.5 cm2, the pulmonary artery systolic pressure is 8 to 10. Patients with bioprosthetic valves do not require anticoagulation as long as they remain in sinus rhythm. However, 20% to 40% of these valves fail within 10 years because of structural deterioration. Mechanical valves are largely used in young patients who do not have any contraindications for anticoagulation, and these valves also have excellent long-term durability. Patients with chronic atrial fibrillation who undergo mitral valve surgery can have simultaneous Cox Maze procedures or pulmonary vein ablations, which are beneficial in maintaining sinus rhythm in up to 80% of the patients during the postoperative period. Symptomatic patients with moderate or severe MS with concomitant moderate or severe MR

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should preferably receive valve replacement unless valvotomy is possible at the time of surgery. Complications of the procedures include thromboembolism, endocarditis, primary valve failure, and from general anesthesia. Severe mitral stenosis during pregnancy carries a poor prognosis. Symptoms are precipitated in the second trimester as the cardiac output and blood volume are at a maximum at this point. Previously diagnosed patients with moderate to severe MS should preferably be treated prior to the pregnancy. Otherwise, the optimal time to manage the patient is in the third trimester with percutaneous mitral balloon valvuloplasty being the modality of choice.

Prognosis Mitral stenosis usually progresses slowly with a long latent period between rheumatic fever and symptoms of MS. Tenyear survival of untreated patients depends on severity of the symptoms at presentation. Asymptomatic patients have an 80% chance of a 10-year survival rate. Patients with significant limiting symptoms have a 10% to 15% chance of a 10-year survival rate. Once severe pulmonary HTN occurs, the mean survival rate is 3 years. Mortality is due to pulmonary and systemic congestion, systemic embolization, pulmonary embolism, and infection.

Follow-Up All patients should be monitored with yearly examinations and echocardiograms. For patients with palpitations, ambulatory ECG monitoring (Holter or event recorder) is indicated to detect paroxysmal atrial fibrillation.

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Mitral Regurgitation Mitral regurgitation (MR) is defined as an abnormal reversal of blood flow from the left ventricle (LV) to the left atrium (LA). It is caused by a disruption in any part of the mitral valve (MV) apparatus such as the mitral annulus, valve leaflets, chordae tendineae, or papillary muscle.

Etiology A defect in the mitral annulus is caused by a calcification process during aging, but there is a higher chance of occurrence in patients with hypertension, diabetes, and end-stage renal disorder. Acute mitral regurgitation usually presents over the period of hours to days and is often the result of acute MI (a rupture of the papillary muscle/chordae tendineae), infective endocarditis, chest trauma, and myxomatous degeneration of mitral valve. On the other hand, chronic mitral regurgitation presents over months to years and is usually caused by a degeneration of the valve apparatus as a primary condition (Barlow disease or fibro-elastic deficiency), but has also been linked to connective tissue disorders including Marfan syndrome, EhlersDanlos syndrome, osteogenesis imperfecta, and so on. Other causes include rheumatic heart disease, which can be pure MR, or more commonly, an MR/MS combination and infective endocarditis. Other rare miscellaneous causes include congenital defects (eg, cleft as in Down syndrome, a parachute, fenestrated mitral valve, or an ostium primum atrial septal defect), SLE (Libman-Sacks lesion), and hypertrophic cardiomyopathy with obstruction.

Pathophysiology It is imperative to define the mechanism of MR (intrinsic or functional) as well as the time course (acute vs chronic), as it will prominently impact the clinical management.

Acute Mitral Regurgitation A sudden volume overload on the LV and LA of normal sizes and compliances leads to an abrupt increase in the LVEDV and LAP. An overwhelmed left ventricle cannot accommodate the sudden increase in volume and pressure, despite an above normal EF as a major portion of that is regurgitated into the low resistance LA. These disturbed hemodynamics lead to pulmonary edema and acute heart failure.

Chronic MR There is sufficient time for the LV to accommodate the regurgitant volume so that compensated chronic MR, LA pressure is often normal or only minimally elevated, which prevents pulmonary congestion. The stroke volume is also maintained, albeit at higher EF values. The progressive compensatory eccentric hypertrophy and dilatation of the LV ultimately leads to annular dilation which exacerbates MR, therefore implying that MR begets MR. This eventually leads to decompensation, ventricular dilation, and contractile dysfunction. Signs of pulmonary congestion are seen late in the course of the disease.

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Clinical Presentation Acute MR Symptoms are dominated by the rapid onset of severe SOB, which frequently deteriorates into pulmonary edema, respiratory failure, and cardiogenic shock. Patients are usually tachypneic and tachycardic. There is an S3 and systolic murmur at the apex. The systolic murmur may not resemble the classic MR murmur or may be absent. The patient may be in cardiogenic shock. Signs of etiology of acute MR can dominate the clinical picture.

Chronic MR Patients can be asymptomatic even till late in the course of the disease. Common presenting symptoms include dyspnea on exertion, palpitations, and fatigue. In general, patients with dilated cardiomyopathy as the etiology tend to be more symptomatic. Patients may have peripheral signs of fluid overload. Atrial fibrillation may be present. The apex can be shifted laterally, secondary to ventricular dilation. There may be a loud P2 and raised JVP secondary to accompanying pulmonary hypertension and tricuspid regurgitation. A loud S3 may be present with systolic dysfunction. There may be a midsystolic click if there is an underlying mitral valve prolapse. The murmur characteristically does not change its character after a premature beat contrary to an aortic stenosis murmur.

Investigative Studies •• Chest x-ray: Usually shows signs of pulmonary congestion, ventricular dilation, and pulmonary hypertension •• EKG: May show atrial fibrillation; signs of LVH and left atrial enlargement; signs of right ventricular hypertrophy may also accompany these signs •• Echocardiogram: The diagnostic test of choice; it demonstrates not only the regurgitation but also provides useful information about the possible etiology, size of left ventricle, left atrium, RV and LV function, and pulmonary pressure •• Doppler measurements: Used to assess the severity •• TEE is helpful in assessment of repaired mitral valve and whenever there is suspicion of infective endocarditis (Fig. 10.5) •• Per 2012 European Society of Cardiology (ESC) guidelines: Coronary angiography is indicated in all men over 40 years of age and menopausal women with cardiac risk factors undergoing valvular heart surgery to determine the presence of CAD •• CT angiography: May be used in younger patients 105 in asymptomatic patients has a higher risk of heart failure development •• Cardiac MRI is sometimes required to detect a specific cause, for example, myocarditis

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Etiology and Pathophysiology

FIGURE 10.5  Transesophageal echocardiographic views of a patient with severe MR. (Reproduced, with permission, from Longo DL, Fauci AS, Kasper DL, Hauser SL, Jameson JL, Loscalzo J, eds. Harrison’s Principles of Internal Medicine. 18th ed. New York, NY: McGraw-Hill; 2011.)

Treatment As a general rule, surgery is indicated when symptoms develop, although early surgery is indicated even in asymptomatic patients as irreversible damage may occur before the symptoms may appear. Current guidelines suggest surgery when the EF is 4.0 cm. In acute nonrheumatic mitral regurgitation, emergency surgery is often required. There are no data to suggest that chronic afterload reduction is effective. Mitral valve repair is preferred over mitral valve replacement in a majority of patients. For patients with functional MR secondary to a dilation of the ventricles, the treatment approach is slightly different. Treatment is directed at improving the functional status and reducing the symptoms. The ventricular reconstructive surgical approaches have met with limited success. Mitral valve repair can be done even in patients with an EF 5 mmHg across the ­tricuspid valve indicates severe stenosis but a gradient of 2 mmHg is considered abnormal

Treatment Initial therapy is usually medical with diuretics being the mainstay of treatment. Torsemide is preferred over other loop diuretics because of its effective absorption through the congestion gut wall. Aldosterone antagonists are useful for ascites and liver congestion. Surgically, the treatment of choice is bioprosthetic tricuspid valve replacement. Mechanical valve replacement is not carried out because of a high risk of thrombosis as a result of low flow across the valve and the mechanical valve cannot be crossed if there is a need for pacemaker implantation or right heart catheterization.

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(seen in 50% of patients with Ebstein anomaly). Signs of systemic congestion, that is, pulsatile hepatomegaly, edema, and ascites usually depict severe tricuspid regurgitation.

Investigative Studies •• Chest radiography: Shows RA enlargement or pleural effusion. •• EKG: May show atrial fibrillation or signs of RV enlargement. There are no specific signs for tricuspid regurgitation. •• Echocardiogram: Usually diagnostic. The severity is judged by the area of regurgitated jet, an area >10 cm2 means severe regurgitation. Paradoxical movement of the interventricular septum may be present as a result of RV volume overload. •• Cardiac catheterization: Rarely required (Fig. 10.7).

Tricuspid Regurgitation

Treatment

Tricuspid regurgitation (TR) is the abnormal blood flow back into the right atrium that usually accompanies RV dilation. The primary pathology is usually in the left heart but right heart pathology, for example, infarction or infiltration and ­pulmonary hypertension can also be responsible.

Mild regurgitation is fairly common and usually accompanies left heart disease. Treatment for left heart disease is all that is required. Diuretics are normally sufficient for management. Torsemide is the drug of choice as it is better absorbed by the congested gut wall than furosemide. Aldosterone antagonists are helpful if there are ascites. Aquapharesis can be helpful for systemic edema. The tricuspid valve can be repaired while mitral valve repair is being performed surgically. Choices are annuloplasty without the insertion of a prosthetic ring (DeVega annuloplasty) as well tricuspid valve replacement. Mechanical valves are never used for replacement so anticoagulation is not required.

Etiology Primary Tricuspid Pathology (Rare) 1. 2. 3. 4.

Rheumatic heart disease Ebstein anomaly Tricuspid valve endocarditis usually associated Pacemaker leads to valvular injury

Secondary or Functional Causes (Common)

Pulmonary Valvular Stenosis

1. 2. 3. 4.

Pulmonary valvular stenosis is usually congenital and is associated with other anomalies. Frequent associations include tetralogy of Fallot, Noonan syndrome, and congenital rubella infection. It may occur rarely in postoperative patients that have undergone the Ross procedure, that is, a homograft replacement of the pulmonary valve and a transfer of the pulmonary valve to the aortic valve because of an immune response against the homograft. Major pathology is either dome shaped or a dysplastic valve. The pulmonary blood flow is preferentially diverted to the left lung.

Left heart failure Pulmonary hypertension Pulmonary valvular regurgitation Right ventricular dilation

Pathophysiology Tricuspid regurgitation is usually caused by RV dilation. Tricuspid regurgitation leads to further RV dilation and vice versa. The regurgitated jet leads to right atrial volume overload and systemic congestion.

Clinical Features

Clinical Features

Signs and symptoms are those of right heart failure. Diagnosis is made by carefully inspecting the JVP that usually shows a prominent V wave. There may be a tricuspid regurgitation murmur audible at the tricuspid area. It is a holosystolic murmur that can be differentiated from an MR murmur by demonstrating accentuation during inspiration (Carvallo sign). A right-sided S3 may accompany the murmur. There can be associated cyanosis if there is associated PFO or ASD

Generally, patients with pulmonic stenosis remain asymptomatic if the lesion is mild although strenuous exercise can lead to dyspnea, chest pain, or syncope. The symptoms can occur at rest if the lesion is moderately severe, particularly in pregnancy. On examination, the patient may exhibit signs of systemic congestion. JVP examination may show giant waves. There may be c-v waves if there is associated TR. The right

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FIGURE 10.7  Continuous Doppler wave of tricuspid regurgitation in a patient with pulmonary hypertension. (Reproduced, with permission, from Longo DL, Fauci AS, Kasper DL, Hauser SL, Jameson JL, Loscalzo J, eds. Harrison’s Principles of Internal Medicine. 18th ed. New York, NY: McGraw-Hill; 2011.)

ventricular parasternal lift may be palpable. A loud, harsh ejection systolic murmur is audible along with a thrill at the left second and third intercostal spaces, which increases on inspiration. A loud ejection systolic click may precede the murmur and decreases on inspiration making it the only rightsided sound to diminish on inspiration.

Investigative Studies •• Chest radiography: May reveal poststenotic dilation of the main and left pulmonary artery. The left lung vascularity is higher than the right, also known as Chen sign. •• EKG: May show a peaked P wave and signs of RVH. There may also be right axis deviation. •• Echocardiogram: The diagnostic study of choice that can differentiate between the doming or dysplastic pathology as well assess the gradient across the valve. An echocardiogram can also quantify the severity on the basis of the gradient across the valve. A peak gradient of >60 mmHg or a mean gradient > 40 mmHg means severe pulmonary stenosis. •• Cardiac catheterization: Is usually performed if the data are unclear.

Treatment Mild pulmonary stenosis does not usually require any intervention as it is associated with a normal life span. Patients with moderate stenosis that remain asymptomatic throughout

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adolescence with the degree of stenosis worsening, which can cause right heart failure during their 20s or 30s, will usually require intervention in all symptomatic patients and those who meet the criteria for severe stenosis regardless of the symptoms. Percutaneous balloon valvuloplasty is the procedure of choice with domed valve pathology. Surgical commissurotomy or pulmonary valve replacement with a bioprosthetic or homograft valve is usually required with dysplastic pathology. Percutaneously implanted pulmonary valve placement is currently under investigation.

Pulmonary Regurgitation Pulmonary regurgitation is divided into primary valvular abnormality, for example, dysplastic valve and annular dilation (common after a patch repair of tetralogy of Fallot), or secondary to pulmonary hypertension. The former is usually a low pressure state and the latter is a high pressure state. As the right ventricle is able to tolerate the volume overload well, the low pressure causes the patient to remain asymptomatic for longer periods.

Clinical Presentation A majority of patients remain asymptomatic. Others present with signs of right heart failure. Clinical examination frequently reveals raised JVP as well as prominent RV pulsation. Right ventricular hypertrophy is evident by a palpable thrill in the pulmonary area and a right ventricular parasternal heave. Auscultation reveals wide splitting of the S2. A harsh pulmonary diastolic murmur is usually heard when high pressure

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causes pulmonary regurgitation (Graham Steell murmur). Systemic signs of congestion may be present. The low pressure regurgitation is difficult to diagnose on clinical exam or echo due to low pressure regurgitation.

Investigative Studies •• EKG: May reveal a right bundle branch block or evidence of RV enlargement but is of little value in diagnosis •• Echocardiogram: Shows evidence or RV volume overload with paradoxical septal motion and an enlarged RV •• Doppler: Is helpful in assessing the size of the pulmonary artery •• Cardiac MRI and CT: Are helpful in ruling in or out, the causes of pulmonary hypertension •• Right heart catheterization: Is occasionally required to confirm the diagnosis, particularly in low pressure states

Treatment Low pressure regurgitation is usually well tolerated so a specific therapy is rarely required. The treatment is usually directed toward the primary cause. In the case of RV dysfunction associated with a repair of Fallot’s tetralogy, pulmonary valve replacement is indicated. A QRS prolongation of >180 ms is associated with an increased risk of sudden cardiac death. In high pressure states, the treatment is directed at reducing or eliminating the primary pathology causing the pulmonary hypertension.

Prosthetic Valves Implantation of prosthetic cardiac valves has become an increasingly common procedure during the last two decades. Almost 60,000 to 95,000 patients per year undergo heart valve replacement in the United States. There are more than 80 models of artificial valves that have been introduced but only a few are used in clinical practice. Prosthetic valves are either made from synthetic material such as mechanical prostheses, or are made from biological tissue such as bioprostheses. The replacement of diseased valves reduces the morbidity and mortality associated with native valvular disease; however, there are associated risks in the short and long run. Longterm anticoagulation is usually required in most mechanical prostheses. Transcatheter valvular replacement is a newer arena in prosthetic valve treatment.

Transcatheter Aortic Valve Replacement Transcatheter aortic valve replacement (TAVR) is a minimally invasive surgical procedure that repairs the valve without removing the old, damaged valve. It delivers a fully collapsible replacement valve to the valve site through a catheter. Once the new valve is expanded, it pushes the old valve

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leaflets out of the way and the tissue in the replacement valve takes over the job of regulating the blood flow.

Function of Prosthetic Valves Normal Prosthetic Heart Valve Sounds There are 3 types of metallic prosthetic valves: tilting discs, bi-leaflets, and the ball and cage variety. Mechanical Valves Tilting disc and bi-leaflet valves have a loud, high-frequency, metallic closing sound. This frequently can be heard without a stethoscope. The absence of this distinct closing sound is abnormal and implies a valve dysfunction. These valves can also have a soft opening sound. Tilting disc valves have a ­single circular occlude controlled by a metal strut. They are made up of a metal ring covered by fabric, into which the suture threads are stitched in order to hold the valve in place. The metal ring holds, by means of two metal supports, a disc that opens and closes as the heart pumps blood through the valve. The disc is usually made from an extremely hard carbon material in order to allow the valve to function for years without wearing out. Caged-ball valves (Starr-Edwards) have low-frequency opening and closing sounds of nearly equal intensity. These types of valves utilize a metal cage that houses a silicone elastomer ball. When the blood pressure in the chamber of the heart exceeds the pressure on the outside of the chamber, the ball is pushed against the cage, which allows the blood to flow. At the completion of the heart’s contraction, the pressure inside the chamber drops and is lower than beyond the valve, so the ball moves back against the base of the valve forming a seal. Tissue Valves The closing sounds of tissue valves are similar to those of native valves. A low-frequency early opening sound may be present in the mitral position. Muffled or absent normal prosthetic heart sounds can be a clue to valve failure or thrombosis.

Prosthetic Heart Valve Murmurs Aortic Prosthetic Valves Because of their smaller orifice size, all aortic valves often produce some degree of outflow obstruction that results in a systolic ejection murmur. Caged-ball and small-porcine valves produce the loudest murmurs. The intensity of the murmur increases with rising cardiac output. Tilting disc valves and bi-leaflet valves do not occlude their outflow tract completely when closed that allows for some backflow, which causes a low-intensity diastolic murmur. Any degree of a diastolic murmur in these patients should be considered pathologic until proven otherwise. Mitral Prosthetic Valves Caged-ball valves can cause a low-grade systolic murmur due to the turbulent flow caused by the cage projecting into the left ventricle. Any holosystolic murmur greater than 2/6 should

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be considered pathologic in a patient with an artificial mitral valve. Short diastolic murmurs can be heard with bioprostheses and, occasionally, with the St. Jude bi-leaflet valve. These are best heard at the apex with the patient in the left lateral decubitus position.

Laboratory Studies of Prosthetic Heart Valves A sudden increase in hemolysis may signal a perivalvular leak. A hematocrit lower than 34% is the most common hematologic finding. Glomerulonephritis and acute renal failure may complicate prosthetic valve endocarditis (PVE). Hematuria is present in 57% of patients with PVE.

Echocardiography in Prosthetic Heart Valves Transesophageal echocardiography (TEE) has emerged as the imaging study of choice in patients with a suspected prosthetic valve complication. Adequately excluding prosthetic valve regurgitation with a transthoracic echocardiogram is difficult. Electrocardiography may show an atrioventricular block that can indicate the presence of a myocardial abscess. A fever and new AV block is considered to be PVE until proven otherwise. Atrial fibrillation is fairly common in mitral valve replacement.

Prosthetic Valve Complications Acute Valvular Failure Patients with acute valvular failure present with cardiogenic shock and severe hypotension. Absence of a normal valve closure sound or the presence of an abnormal regurgitant murmur is an important clue. A less dramatic variety is called subacute failure.

Prosthetic Valve Endocarditis The clinical manifestations of prosthetic valve endocarditis (PVE) are often obscure. Fever and a new or changing murmur are present but the absence of these does not exclude the diagnosis. Valvular dehiscence, stenosis, or perforation can also cause the murmur and are potential sequelae. Signs that are considered classic for native valve endocarditis are often absent in PVE. Systemic emboli are a presenting symptom with fungal etiologies. Ring abscesses can form, leading to valve dehiscence, perivalvular leakage, and myocardial abscesses. Further extension often results in a new atrioventricular block. Valve stenosis and purulent pericarditis occur less frequently. Finally, glomerulonephritis, mycotic aneurysms, systemic embolization, and metastatic abscesses can also complicate PVE. Early PVE occurs within the first year of the valve insertion and is a result of perioperative contamination. Causative organisms include Staphylococcus epidermidis (25%-30%), Staphylococcus aureus (15%-20%) and gram-negative aerobes (20%). Late PVE occurs after the first year and is usually the result of transient bacteremia from dental or genitourinary sources, gastrointestinal (GI) manipulation, or intravenous

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drug abuse. The causative organisms are similar to those that cause native valve endocarditis.

Treatment Administer intravenous antibiotics as soon as two sets of blood cultures are drawn. Vancomycin and gentamicin can be used empirically pending blood cultures and determination of methicillin resistance. Patients taking warfarin who develop PVE should stop until central nervous system (CNS) involvement is ruled out and invasive procedures are determined to be unnecessary. Emergency surgery should be considered in patients with moderate to severe heart failure or in patients with an unstable prosthesis noted on imaging.

Prophylaxis The aim is to provide antibiotic prophylaxis to patients undergoing procedures that may result in bacteremia. The following list, although not exhaustive, includes most inpatient and outpatient procedures performed in the emergency department (ED) that can result in bacteremia and, therefore, may lead to prosthetic valve endocarditis (PVE): •• Dental and oral procedures •• Respiratory procedures, particularly those that involve a disruption to the respiratory mucosal surface, or when a known infection is present; in cases of known or suspected methicillin-resistant Staphylococcus aureus, ­prophylaxis, vancomycin should be administered •• Sclerotherapy of bleeding esophageal varices •• Routine prophylaxis for gastrointestinal or genitourinary procedures is no longer recommended, unless in the presence of a known infection, urethral catheterization in the presence of a suspected urinary tract infection; ­vaginal delivery in the presence of infection •• Incision and drainage of infected tissues •• For dental, oral, or upper respiratory tract procedures, use amoxicillin 2 g PO 30-60 minutes before the procedure; if the patient is unable to take PO medication, use ampicillin 2 g IM/IV OR cefazolin 1 g IM/IV, OR ceftriaxone 1 g IM/IV 30-60 minutes before the procedure; for penicillin-allergic patients, use clindamycin 600 mg PO/IM/IV OR azithromycin 500 mg PO OR clarithromycin 500 mg PO OR cephalexin 2 g PO 30-60 minutes before the procedure •• Further guidelines on the prevention, diagnosis, and treatment of infective endocarditis are available from the American Heart Association and the European Society of Cardiology

Thromboembolic Complications Patients with complications related to embolization present with signs related to the site of embolization. Stroke syndromes are the most common; however, patients may present

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Chapter 10  Valvular Heart Diseases

with MI, sudden death, or visceral or peripheral embolization. Systemic embolization should alert the physician to suspect valve thrombosis or PVE. Long-term anticoagulation also puts the patients at risk for hemorrhagic complications.

Pregnancy Some debate exists concerning the most advantageous method of providing adequate anticoagulation in pregnant patients. The American College of Obstetrics and Gynecology has recommended against using low molecular weight heparin during pregnancy.

Anticoagulation in Prosthetic Heart Valves Warfarin is the drug of choice for long-term anticoagulation in prosthetic valves as newer anticoagulants have not yet been approved. Recommendations vary as to the target INR (international normalized ratio) (Clinical Correlation 10.2) for the prothrombin time ratio. The following is offered as a general guideline, but therapy must be individualized.

▶▶  C L I N I C A L C O R R E L A T I O N 1 0 . 2 : I N R The INR is the ratio of a patient’s prothrombin time to a normal, that is, a control sample.

Bioprosthetic Valves For a 2:3 INR for 3 months following valve implantation; anticoagulation can be discontinued unless the patient has another indication, such as atrial fibrillation or the development of prosthetic valve thrombosis. Although the risk of thromboembolic events is lower in patients with a bioprosthetic valve than in those with a mechanical prosthesis, low-dose aspirin (75-100 mg/d) is indicated in patients without thromboembolic risk factors. Aspirin in a dose of 75 to 325 mg per day is indicated in patients who are unable to take warfarin. Mechanical Valves Aortic valve INR is 2-3, mitral valve INR is 2.5-3.5; patients with atrial fibrillation should be kept at the higher end of this range. For patients with a low hemorrhage risk, low-dose aspirin is recommended in addition to warfarin. Failure of anticoagulation puts patients at risk for systemic thromboembolism and at a higher risk for stroke. The RE-ALIGN trial that evaluated the safety and efficacy of dabigatran in patients with bi-leaflet mechanical prosthetic heart valves was terminated early because of the occurrence of significantly more thromboembolic events and excessive major bleeding with dabigatran compared with warfarin. These data resulted in a revision of the US dabigatran prescribing information to include a contraindication in patients with mechanical prosthetic valves. Historically, in the setting of prosthetic valve thrombosis, surgery was the mainstay of treatment but was associated with a high mortality rate. Thrombolytic therapy can be used to treat select patients with thrombosed prosthetic valves and is

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a standard of care for right-sided prosthetic valves and should be used with cardiovascular surgical consultation. Recombinant factor VIIa or prothrombin complex concentrate should not be used to reverse excessive anticoagulation in patients with prosthetic heart valves.

Primary Valve Failure In patients with acute valvular failure, diagnostic studies must be performed simultaneously with resuscitative efforts. Patients with valvular failure due to breakage or abrupt tearing of the components usually present with acute hemodynamic deterioration and need emergent valve replacement. Adjunctive therapy should be initiated while these arrangements are being made. A less dramatic presentation of valvular failure is seen in patients with valve thrombosis or in those with more gradual deterioration of the bioprosthetic valves. Afterload reduction and inotropic support should be started in order to reduce the impedance to the forward flow and improve peripheral perfusion. If the mean arterial pressure is higher than 70 mmHg, sodium nitroprusside can be used. If the mean arterial pressure is lower than 70 mmHg, dobutamine alone or in combination with inamrinone can be used. Avoid inotropic agents with vasoconstricting properties. Intra-aortic balloon counterpulsation is useful in cases of acute mitral regurgitation when the patient is in extremis and surgical facilities are not immediately available.

Follow-Up Following valve replacement, every patient should undergo a history, physical examination, and appropriate testing at the first postoperative visit (2-4 weeks after hospital discharge). An echocardiographic examination should also be performed at this time. Thereafter, follow-up visits are recommended annually, or earlier (with echocardiography) if new symptoms develop that are attributable to a potential valvular dysfunction. In patients with a bioprosthetic valve, annual echocardiograms can be considered after the first 5 years in the absence of any changes in clinical status. All patients with prosthetic valves should receive antibiotic prophylaxis against infective endocarditis prior to dental procedures.

Key Points •• Heart valve disorders include: stenosis, regurgitation, and atresia. •• Valvular heart disease affects the aortic, mitral, tricuspid, and pulmonary valves, which significantly disrupt normal hemostasis of blood circulation and result in adverse and sometimes fatal consequences. •• The aging population has significantly contributed to a higher incidence of valvular heart disease, especially aortic stenosis.

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•• Understanding of the echocardiographic principles is vital for the understanding of valve diseases. •• Treatment modalities specific for certain valve diseases has dramatically evolved over the last 2 decades.

•• Prosthetic valves are divided into mechanical valves and tissue valves; each has its pros and cons based on the patients’ age and health condition.

CASE STUDIES CASE 10.1  An 80-year-old man presents with worsening shortness of breath for 5 months. He has dyspnea when lying flat that occasionally wakes him from sleep. He has a past medical history of hypertension, type 2 diabetes, and hypercholesterolemia. He is otherwise active and living an independent life. He quit smoking 5 years ago after smoking 1 pack a day for 35 years. On examination, he has mild shortness of breath that is not distressing at rest. His pulses are difficult to palpate. There is no peripheral pitting edema. There is jugular venous distension. The apex beat is displaced laterally. On cardiac auscultation, there is a soft second heart sound. There is a systolic murmur heard at the mitral area that is harsh, but does not radiate to the axilla. 1.  Which of the following types of valvular lesions are you dealing with in this patient?

d. Vasodilators e. Hospice only

CASE 10.2  A 23-year-old woman was seen in a cardiology clinic. She has been diagnosed with recurrent attacks of central chest pain and anxiety. She has been referred to the cardiologist by her primary care physician who discovered a murmur during heart examination. The murmur is systolic and preceded by an ejection click. It accentuates during expiration. Otherwise, the patient’s examination is unremarkable and she does not complain of shortness of breath or leg swelling. 1.  What is an echocardiogram going to reveal in this patient? a. Mitral stenosis

a. Aortic stenosis

b. Aortic sclerosis

b. Aortic regurgitation

c. Mitral valve prolapse

c. Mitral stenosis

d. Normal echo

d. Mitral regurgitation e. Valvular failure

2.  Which of the following is the best plan of management for this patient?

2.  What should you recommend for infective endocarditis prophylaxis in this particular disease? a. Ampicillin 150 mg daily b. Penicillin V once a week

a. Diuretics

c. Erythromycin 250 mg once weekly

b. Surgical consultation

d. Amoxicillin 500 mg once before dental procedure

c. Valvuloplasty

e. None of the above

Suggested Readings Berg D, Worzala K. Atlas of Adult Physical Diagnosis. ­Philadelphia, PA: Lippincott Williams & Wilkins; 2006:85.

study of a random population sample. J Am Coll Cardiol. 1993;21:1220-1225.

Bergler-Klein J. Natriuretic peptides in the management of aortic stenosis. Curr Cardiol Rep. 2009;11(2):85-93.

Otto CM. Surgery for mitral regurgitation: sooner or later? JAMA. 2013;310(6):587-588.

Karchmer AW. Infective endocarditis. Braunwald’s Heart ­Disease: A Textbook of Cardiovascular Medicine. 7th ed. Philadelphia, PA: WB Saunders; 2005:1633-1658.

Tintinalli JE, Kelen GD, Stapczynski JS, eds. Valvular emergencies. Emergency Medicine: A Comprehensive Study Guide. 6th ed. New York, NY: McGraw-Hill; 2004:54.

Karchmer AW. Infective endocarditis. Harrison’s Principles of Internal Medicine. 16th ed. New York, NY: McGraw-Hill; 2005:731-740.

Vahanian A, Alfieri O, Andreotti F, et al. Guidelines on the ­management of valvular heart disease (version 2012): The Joint Task Force on the Management of Valvular Heart Disease of the European Society of Cardiology (ESC) and the European Association for Cardio-Thoracic Surgery (EACTS). Eur Heart J. 2012;33(19):2451-2496.

Lindroos M, Kupari M, Heikkilä J, Tilvis R. Prevalence of ­aortic valve abnormalities in the elderly: an echocardiographic

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Chapter Congestive Heart Failure and Management Drugs

Learning Objectives

11

By the end of this chapter the student will be able to: • Define heart failure. • Identify the causes of heart failure. • Describe the pathophysiology of heart failure.

MOHSIN K. KHAN AND AMAURY SANCHEZ

• Identify the signs and symptoms of heart failure. • Describe the workup for heart failure.

Introduction Congestive heart failure is the most common cause of hospitalization in the United States. The number of patients that carry the primary diagnosis of heart failure account for greater than 3 million visits per year. The burden of this disease and the cost of caring for these patients are staggering. Heart failure is the last destination and most common complication for the majority of heart diseases such as myocardial infarction, hypertension, valvular heart diseases, atherosclerosis, and congenital heart disease. Consequently, there are various types, stages, and pathogeneses of heart failure. Therefore, an understanding of the pathophysiology of this disease is essential in managing these patients.

Definition When the ability of the heart to effectively pump blood to the rest of the body is compromised, this will result in a mismatch between supply and demand of the metabolizing tissues ­during ordinary activity. Congestive heart failure can occur as a result of impaired cardiac contractility, which is known as systolic congestive heart failure. It can also result from increased myocardial stiffness or an inability of the heart to relax in the absence of reduced contractility, often known as heart failure with preserved ejection fraction (HFEF) or diastolic heart failure. High output cardiac failure is another entity characterized by elevated cardiac output in certain medical conditions such as Beriberi, hyperthyroidism, and systemic AV fistulas. Even though the resting cardiac index is elevated, symptoms of heart failure develop because of a failure to compensate for increased requirements. Table 11.1 lists the major causes of heart failure.

Causes of Heart Failure Heart Failure Due to Impaired Cardiac Function •• Myocardial infarction •• Valvular dysfunction

• Explain the mechanism of medications used for the treatment of heart failure.

•• •• •• •• •• •• •• •• •• •• •• ••

Hypertension Toxins Infections, such as sepsis and Chagas disease Arrhythmias Stress-induced cardiomyopathy Muscular dystrophies, such as Duchenne muscular dystrophy Autoimmune etiologies Endocrinopathies such as hyperthyroidism Glycogen storage diseases Alcohol-induced cardiomyopathy Myocarditis Chemotherapy-induced cardiotoxicity

Heart Failure Due to Impaired Relaxation of the Cardiac Muscle Is Also Known as Heart Failure with Preserved Ejection Fraction •• Left ventricular hypertrophy due to underlying hypertension, aortic stenosis •• Hypertrophic cardiomyopathy •• Infiltrative cardiomyopathy, such as sarcoidosis and amyloidosis •• Ischemic fibrosis

High Output Cardiac Failure •• Hyperthyroidism •• Beriberi 169

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Table 11.1  Causes of heart failure Systolic HF

Diastolic HF

High-output HF

Myocardial infarction

Left ventricular hypertrophy

Hyperthyroidism

Valvular dysfunction

Hypertrophic cardiomyopathy

Systemic AV fistulas

Hypertension

Infiltrative cardiomyopathy

Multiple myeloma

Toxins

Beriberi Anemia Paget disease of the bone

Ischemic fibrosis

Infections Arrhythmias

Hepatic hemangioma

Stress-induced cardiomyopathy

Cirrhosis

Muscular dystrophies Autoimmune etiologies Endocrinopathies Glycogen storage diseases Alcohol-induced cardiomyopathy Myocarditis Chemotherapy cardiotoxicity

•• •• •• •• •• ••

of a patient’s illness so that interventions can be applied to prevent progression. The stages are categorized as follows (Fig. 11.1). Stage A includes people who have underlying risk factors for developing heart failure but do not have any structural abnormalities of the heart. These include patients with hypertension, dyslipidemia, diabetes mellitus, obesity, smoking, metabolic syndrome, and exposure to chemotherapy that can be cardiotoxic. Stage B includes people who have structural abnormalities of the heart but have not yet exhibited signs or symptoms of heart failure. These include patients with underlying left ventricular hypertrophy, myocardial infarction, systolic dysfunction, and valvular heart disease. These are detected by electrocardiography (EKG) or echocardiography (ECG). Stage C includes patients who have signs and symptoms of heart failure. This stage also includes patients who are currently asymptomatic but may have had symptoms previously and are currently on medications such as β-blockers and angiotensin-converting enzyme (ACE) inhibitors. Stage D includes patients who continue to have signs and symptoms of heart failure despite optimal medical treatment. These patients have advanced heart failure and are often evaluated for heart transplant, ventricular assist devices, inotropic therapy, and end-of-life care.

New York Heart Association Heart Failure Classification The New York Heart Association (NYHA) classification of heart failure is useful in classifying patients with heart failure according to the symptoms of their disease. These patients already have evidence of structural heart disease and are in stages C and D as described above (Table 11.2).

Systemic AV fistulas Anemia Multiple myeloma Paget disease of the bone Hepatic hemangioma Cirrhosis

Pathophysiology of Heart Failure

Stages of Heart Failure Since heart failure results in significant morbidity and mortality, it is important to recognize the risk factors that potentially lead to the development of heart failure. Determining the stage of heart failure is a means of identifying the severity

Heart failure can be left sided or right sided or, as in a majority of cases, a combination of both. Left-sided heart failure results from left ventricular dysfunction and presents with signs of reduced cardiac output and pulmonary venous congestion. On the other hand, right-sided heart failure results from right ventricular dysfunction and will present with signs of fluid retention. While right heart failure can occur as an

Stages of CHF Stage A

Stage B

Stage C

Pt with underlying risk factors without structural abnormalities of heart eg, hypertension, dyslipidemia, obesity, diabetes mellitus, metabolic syndrome.

Risk factors and structural abnormalities without signs and symptoms of CHF eg, LVH, MI, valvular heart disease.

Risk factors with structural abnormalities and signs and symptoms of CHF. Includes both systolic and diastolic CHF.

Stage D Continued signs and symptoms of CHF despite optimal medical treatment.

FIGURE 11.1  Stages of heart failure.

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Table 11.2  New York Heart Association (NYHA) functional classification I

Able to perform physical activity without any limitations.

Table 11.4  Common terminology used in cardiovascular physiology Systole

Phase in cardiac cycle when the ventricles contract actively to force blood out of the heart

Diastole

Phase in cardiac cycle when the myocardium relaxes allowing for refilling of the ventricles with blood. This is an energy-dependent process

Physical activity is markedly limited.

End-diastolic volume (EDV)

Volume of blood in the ventricle before the bioenergy of systole

No symptoms at rest, but less than ordinary activity results in symptoms of heart failure.

End-systolic volume (ESV)

Volume of blood remaining in the ventricle at the end of systole

Symptoms of heart failure at rest.

Stroke volume (SV)

Volume of blood pumped from each ventricle with each heartbeat

Cardiac output (CO)

Volume of blood pumped from each ventricle per minute CO = SV × Heart rate (HR)

Ejection fraction (EF)

Measure of systolic functioning of the heart calculated as a percentage by dividing SV with EDV (SV/EDV)

Ventricular preload

Amount to which myocytes are stretched prior to contraction

Ventricular afterload

Amount of pressure the heart has to work against to pump the blood out of the ventricles

No symptoms of heart failure on ordinary activity. II

Physical activity is slightly limited. No symptoms at rest, but ordinary physical activity results in symptoms of heart failure.

III

IV

171

isolated phenomenon, the most common cause of right heart failure is left ventricular dysfunction (Table 11.3).

Systolic Heart Failure In order to understand the pathophysiology of systolic heart failure, it is important to review the basics of the cardiac cycle (Table 11.4). Systole is the phase in the cardiac cycle when the mitral and tricuspid valves are closed and the ventricles contract actively, resulting in the release of the blood from the heart into the aorta and pulmonary artery. The amount of blood in the ventricle before the beginning of systole is the end-diastolic volume (EDV). The stroke volume (SV) is defined as the volume of blood pumped from each ventricle with each heartbeat. In a normal heart, an increase in the enddiastolic volume results in an increase in the stroke volume. Exercise or any kind of stress results in an increase in the stroke volume in order to compensate for increased metabolic demands. In heart failure, despite increased end-diastolic volume, there is little increase in systolic function resulting in reduced stroke volume. Systolic functioning of the heart is measured in terms of the ejection fraction (EF). The EF is calculated as a percentage by dividing the stroke volume with the end-diastolic volume (SV/EDV). The EF is calculated during echocardiography. A normal EF is calculated as 50% to 55%.

Table 11.3  Pathophysiology of heart failure: factors affecting cardiac function Cardiac contractility Cytokines Heart rate and rhythm

The functioning of the heart is determined by various factors, which in turn play an important role in the pathogenesis of heart failure.

Cardiac Contractility The right and left coronary arteries are responsible for the blood supply to the heart. They arise from the ascending aorta just above the aortic valve and give branches that supply the myocardium (see Chapter 2 for more details). The cardiac muscle receives most of its blood supply during diastole. An index event, such as a myocardial infarction, results in a disruption of the coronary blood supply which, if not revived promptly, will lead to permanent damage to the area of the cardiac muscle whose blood supply is disrupted. This, in turn, will affect cardiac contractility depending on the area of the myocardium that has been damaged. Cardiac contractility can also be reduced as a result of exposure to cardiotoxic drugs, such as certain chemotherapy agents like doxorubicin. Severe infections, such as a bacteremia can also reduce cardiac contractility. Underlying muscular disorders, such as Duchene muscular dystrophy can also cause systolic dysfunction.

Myocardial relaxation

Myocardial Relaxation

Renin-angiotensin system

During diastole the ventricles relax, and once the atrioventricular (AV) valves open, the blood moves passively from the atria into the ventricle. When the atrial pressure increases during atrial systole, a topping-off of the blood to the ventricle

Sympathetic nervous system Ventricular preload and afterload

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occurs. If the myocardium is thickened, ventricular pressures will be higher due to decreased compliance. As a result, most of the filling of the ventricles occur because of an active atrial contraction rather than the normal passive filling. In the setting of ischemia, myocardial relaxation is often affected, as it is an energy-driven process. This leads to elevated end-­ diastolic pressures that result in left ventricle (LV) remodeling, as described later in the chapter.

Heart Rate and Rhythm The heart rate (HR) and rhythm can also significantly affect cardiac performance. A normal heart rate ranges between 60 and 100 beats per minute (bpm). In conditions of stress, such as exercise, the heart rate can increase to compensate for the elevated metabolic demands of the body. Cardiac output is the volume of blood pumped from each ventricle per minute. It is calculated by multiplying the stroke volume by the heart rate. Since the stroke volume is relatively fixed, the body responds to increased metabolic demands by increasing the heart rate. As will be noted later in the chapter, an elevated HR is also a compensatory mechanism to achieve adequate blood supply to the body under conditions of reduced systolic functioning when the stroke volume is reduced. Chronic tachycardia in conditions of atrial fibrillation or atrial flutter has been associated with tachycardia-mediated cardiomyopathy. This usually results in structural changes such as LV dilation. Most of the blood supply to the myocardium is achieved during diastole. In the setting of tachycardia, the diastolic phase is shortened; this in turn will lead to myocyte ischemia. Profound bradycardia can also impact cardiac performance. Bradycardia is defined as a HR of less than 60 beats per minute. Profound bradycardia that may present with a complete heart block can reduce the cardiac output resulting in hypotension that usually presents as dizziness or near syncope. A normal cardiac conduction is essential to maintaining cardiac output. In the case of heart failure, there is often an interventricular conduction delay, which can result in dysynchronus contractions, further resulting in reduced cardiac performance.

Ventricular Preload Ventricular preload is the amount to which myocytes are stretched prior to contraction. One of the best indexes for preload is the volume of the blood in the ventricle prior to contraction (ie, end-diastolic volume). This is dependent on various factors. Increased preload is one of the mechanisms of maintaining cardiac output in the setting of reduced systolic function. Normally, an increase in the preload results in increased stroke volume by means of the Frank-Starling mechanism. However, over time, an increase in the preload results in LV remodeling (discussed in Chapter 5), which worsens the systolic function and reduces the cardiac output. The preload is increased by increasing the venous return to the heart that in turn results from sympathetic venoconstriction. The preload can also be increased by increasing the atrial contraction that is also caused by sympathetic stimulation.

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Left ventricular dilation in the case of dilated cardiomyopathy increases the preload by increasing LV compliance. Valvular diseases, such as aortic stenosis and mitral regurgitation can also result in increased preload.

Ventricular Afterload This is the amount of pressure that the heart has to work against to pump blood out of the ventricles. In heart failure, the afterload is increased to maintain adequate perfusion pressure. This is achieved by increasing systemic vascular resistance due to sympathetic stimulation. The afterload can also be increased by aortic stenosis, as the ventricles have to work harder to push the blood out of the thickened aortic valve.

Frank-Starling Mechanism In order to understand how preload and afterload affect the stroke volume and cardiac output, an understanding of the Frank-Starling mechanism is essential. The Frank-Starling mechanism describes how changes in the venous return affect the stroke volume. Cardiac contractility and hence the stroke volume is altered by changes in the venous return to the heart. An increase in the preload because of an increase in the venous return results in a stretching of the cardiac myocytes, which causes an increase in the force generated during systole. This results in an increased ability of the heart to pump blood out of the ventricles and hence an increase in the stroke volume. Changes in afterload and cardiac contractility affect the Frank-Starling curve. With increased afterload or decreased cardiac contractility, the Frank-Starling curve is shifted down and to the right. With decreased contractility, an increase in LVEDP does not result in a significant increase in the stroke volume (Fig. 11.2). Pressure-volume curves indicate how the venous return affects the end-systolic and end-diastolic volumes (Fig. 11.3). End-systolic volume is the volume of blood remaining in the ventricle at the end of systole. With an increase in venous return, the end-diastolic volume increases. If the afterload stays the same, the heart will pump the increased venous return and hence result in an increase in the stroke volume. The pressure-volume curve will show an increase in width to account for the increase in the stroke volume. A normal heart responds in this way. With a decrease in systolic function, the ability of the heart to pump all the LVEDV decreases, resulting in an increase in the end-systolic volume, thus reducing the slope of the pressure-volume curve. This results in reduced stroke volume that is characterized by a reduced width of the pressurevolume curve (Fig. 11.4).

Compensatory Mechanisms in Response to Low Cardiac Output Initially after a major event such as an MI, the depressed cardiac contractility results in a variety of compensatory mechanisms to achieve the metabolic demands of the body and bring it back toward normal function.

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173

Force-frequency relation Circulating catecholamines Sympathetic and parasympathetic nerve impulses

Contractile state of myocardium Intrinsic depression

Stroke volume

Digitalis, other inotropic agents Hypoxia Hypercapnia Acidosis

Pharmacologic depressants

Loss of myocardium

Ventricular EDV

FIGURE 11.2  Frank-Starling curve. An increase in ventricular EDV results in an increase in the stroke volume in a normal heart. With decreased cardiac contractility, EDV increases and stroke volume decreases. The curve shifts downward and to the right. The factors that affect cardiac contractility are summarized on the right.

Sympathetic Nervous System Activation Activation of the sympathetic nervous system (SNS) and inhibition of the parasympathetic nervous system plays an important role in the pathogenesis of heart failure. Activation of the SNS has important effects on different organs, including

Pressure (mmHg)

200 Isovolumic pressurevolume curve

Renal Vasoconstriction

b

c 100

d 0

50

a

Diastolic pressurevolume relationship

130 Volume (mL)

FIGURE 11.3  A normal pressure-volume loop of the left ventricle. During diastole, the ventricle fills passively and pressure rises from d to a. This is followed by an isovolumetric contraction and the pressure rises from a to b. The aortic valve opens at b and blood is ejected from the ventricle. The aortic valve closes at c and the pressure falls during isovolumetric relaxation from c to d. (Reproduced, with permission, from Hammer GD, McPhee SJ, eds. Pathophysiology of Disease. 7th ed. New York, NY: McGraw-Hill; 2014.)

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the heart, kidneys, and peripheral vasculature (Fig. 11.5). The effects of SNS are mediated primarily by norepinephrine and epinephrine. Sympathetic stimulation results in an augmentation of cardiac contractility and the heart rate in acute settings, which helps to maintain the cardiac output. Sympathetic stimulation also results in an increase in the ventricular preload and afterload as described above. The compensatory mechanisms are also counterproductive in the long term. Excessive adrenergic stimulation while maintaining the cardiac output also results in harder work for the heart when its function is already compromised. This will in return weaken the heart muscle even more and also result in remodeling changes in the myocardium, such as myocardial hypertrophy, fibrosis, and ventricular dilation.

Renal blood flow is diminished as a result of an initial cardiac event. This can result in decreased glomerular filtration that results in a diminished ability of the kidneys to maintain water and electrolyte balance and remove toxic products from the body. Renal vasoconstriction at the efferent arteriole mediated by the sympathetic nervous system helps maintain glomerular filtration in the acute setting and compensates for the diminished renal blood flow.

Renin-Angiotensin-Aldosterone System (RAAS) The renin-angiotensin system also plays an important role in the compensatory mechanisms (Fig. 11.6). A decrease in renal blood pressure stimulates the release of renin. Renin is an enzyme secreted by the afferent arterioles of the kidney from the specialized cells of the juxtaglomerular apparatus. Renin causes the breakdown of angiotensinogen to angiotensin I. Angiotensin I is converted to angiotensin II by the

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200

c' c

b' b

100

Pressure (mmHg)

Pressure (mmHg)

200

c

c'

d

b'

100

a' d'

b

a

a

a'

d d'

50 A

100

50 B

Volume (mL)

Volume (mL)

200

c'

b' b

c

100

d' 50

d

a'

Pressure (mmHg)

Pressure (mmHg)

200

C

100

c'

c

b

100

a'

a d' d

100 Volume (mL)

b'

50 D

a 100

Volume (mL)

FIGURE 11.4  A. Decrease in systolic function shifts the volume-pressure curve to the right resulting in decreased stroke volume. The ventricles can compensate by an increase in ventricular compliance (B) (dashed line), (C) increasing cardiac contractility, and (D) increasing preload. (Reproduced, with permission, from Hammer GD, McPhee SJ, eds. Pathophysiology of Disease. 7th ed. New York, NY: McGraw-Hill; 2014.)

angiotensin-converting enzyme (ACE) located in the lungs. Angiotensin II is a potent vasoconstrictor, causing renal efferent vasoconstriction along with catecholamines resulting in the maintenance of the glomerular filtration rate. Prolonged angiotensin II release, however, results in peripheral vasoconstriction, which in turn results in increased afterload. Consequently, the heart has to work harder and ultimately this results in worsening of heart failure. Angiotensin II also results in the release of aldosterone, which causes sodium reabsorption and potassium excretion by the kidneys. Sodium retention, in turn, leads to water retention, which results in increased preload. This initially

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improves the cardiac output but over time worsens the cardiac contractility and causes LV dilation and LV remodeling.

Arginine Vasopressin (Also Called an Antidiuretic Hormone) Arginine vasopressin (AVP) is also released in excessive amounts in CHF. It is a neurohormone that is produced by the hypothalamus and is stored in the posterior pituitary gland. It is responsible for regulating the plasma osmolality and volume. Vasopressin affects 2 types of receptors that are important from a cardiovascular standpoint: vasopressin type 1A

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Baroreceptor dysfunction

Stimuli to renin Afferent inhibitory signals

Liver

Kidney Angiotensinogen (453 aa) Renin (enzyme)

Vasomotor center

Sympathetic nervous system activity

Renin secretion

Angiotensin I (10 aa)

Vasopressin secretion

Angiotensin II

Angiotensinconverting enzyme (endothelium)

Angiotensin I

Angiotensin II

Angiotensinconverting enzyme (endothelium)

Angiotensin II (8 aa)

Limb blood flow

Renal blood flow Aldosterone Sodium reabsorption H2O reabsorption

FIGURE 11.5  A decrease in cardiac output results in off-loading of highpressure baroreceptors in the left ventricle, carotid sinus, and aortic arch. This results in a loss of parasympathetic tone and sympathetic nervous system activation as well as the release of arginine vasopressin from the pituitary gland. (From Nohria A, Cusco JA, Creager MA. Neurohormonal, renal, and vascular adjustments. In: Colucci WS, ed. Atlas of Heart Failure: Cardiac Function and Dysfunction. 4th ed. Philadelphia, PA: Current Medicine Group; 2002:104.)

(V1A) receptor and vasopressin type 2 (V2) receptors.V1A receptors are located on the cardiac myocytes and vascular smooth muscles. Stimulation of these receptors results in vasoconstriction and inotropic effects. V2 receptors are located in the renal collecting ducts and their stimulation results in free water reabsorption. Excessive vasopressin secretion in heart failure results in an increase in water retention thus contributing to vascular congestion that is a hallmark of congestive heart failure (CHF). This also results in hyponatremia, which is characteristic of a poor outcome in these patients. V1 receptor stimulation causes an increase in vascular resistance and hence an elevated afterload resulting in LV remodeling and hypertrophy.

Left Ventricle Remodeling After the loss of myocytes due to myocardial infarction, a series of biochemical changes takes place within the rest of

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Cardiovascular system

Adrenal cortex Aldosterone Kidney Salt and H2O retention

Vasoconstriction

Blood pressure

FIGURE 11.6  A summary of the renin-angiotensin-aldosterone system. The effects of angiotensin II and aldosterone are illustrated in this figure. (Reproduced, with permission, from Barrett KE, Barman SM, Boitano S, Brooks HL. Ganong’s Review of Medical Physiology. 25th ed. New York, NY: McGraw-Hill; 2016.)

the noninfarcted myocytes as part of the response to increased loading conditions. These changes result in left ventricular remodeling characterized by changes in the LV shape and size of the cavity. Myocytes undergo hypertrophy to offset increased load and limit progressive dilation of the LV cavity. LV hypertrophy is mediated by neurohormonal activation, renin-angiotensin system activation, and myocardial stretch. Changes in the extracellular matrix also take place with a rearrangement of the collagen fibers and the formation of scar tissue in the area of the infarction. Cytokines are released from

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the injured myocytes, which results in the activation of the macrophages. The activated macrophages trigger various processes of tissue repair and the eventual formation of scar tissue. The factors that trigger LV remodeling, if not addressed, will result in progressive ventricular dilation, and increase in the size of the myocardial scarring, and a decrease in contractile function.

Clinical Findings Symptoms •• Shortness of breath initially presents following physical exertion; however, with worsening heart failure, it also occurs at rest. Orthopnea is characterized by a difficulty in laying flat due to the shortness of breath in the recumbent position. Paroxysmal nocturnal dyspnea (PND) refers to waking up from sleep due to an acute onset of shortness of breath. These symptoms are caused by pulmonary venous congestion due to the flow of the venous blood from the extremities and splanchnic circulation in a recumbent position. •• A chronic nonproductive cough is a nonspecific finding but is often present. •• Palpitations may indicate an underlying arrhythmia such as atrial fibrillation or tachycardia. •• Fatigue, which is due to reduced cardiac output. •• Exercise intolerance results from pulmonary venous congestion, which causes dyspnea. •• Decreased blood flow to the muscles due to low cardiac output also contributes to exercise intolerance. •• Leg edema and abdominal distension, which is due to venous pooling. •• Loss of appetite caused by intestinal edema. •• Diarrhea, weight loss, and visual changes that is seen in hyperthyroidism.

Signs •• Abnormal vital signs include tachycardia, low pulse pressure, irregular pulse, and hypotension •• Crackles or rales on pulmonary examination •• Murmurs which may indicate aortic stenosis or mitral regurgitation •• Cold clammy extremities •• Jugular venous distention due to elevated right-sided pressures (Fig. 11.7) •• Ascites •• Hepatic enlargement •• Positive hepatojugular reflex characterized by a distention of the neck veins by applying firm pressure on the liver •• Pitting edema (Fig. 11.8) •• Parasternal heave

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FIGURE 11.7  Jugular venous distension seen with severe congestive heart failure. (Reproduced, with permission, from Knoop KJ, Stack LB, Storrow AB, Thurman RJ. The Atlas of Emergency Medicine. 3rd ed. New York, NY: McGraw-Hill; 2010.)

•• A third heart sound S3 resulting from the impact of inflowing blood against a distended or noncompliant ventricle in mid-diastole •• A fourth heart sound S4 is a low frequency sound resulting from forceful atrial contraction during presystolic that ejects blood into a ventricle that cannot expand further •• Proptosis and lid lag are seen with hyperthyroidism

Diagnosis and Testing In the setting of appropriate signs and symptoms of heart failure, a further workup is routinely done. •• Routine lab testing that includes a complete blood count, liver function testing, kidney function evaluation, urine analysis, troponin, and pro-BNP. •• Thyroid testing is conducted in appropriate clinical settings. •• Brain natriuretic peptide (BNP) and N-terminal prohormone of brain natriuretic peptide (NT-pro-BNP) have been studied both as prognostic markers as well as guide to the effectiveness of the therapy. They are released ­primarily from the ventricle of the heart in response to an increase in wall tension. (Note: Their names came about because they were initially extracted from the porcine brain.) Although they are sensitive markers for heart failure, they can be elevated with age and renal impairment, and can appear normal or low in obesity. Thus, it is important to use these markers in an appropriate clinical setting. •• An electrocardiogram (EKG) is used to evaluate for myocardial ischemia, rhythm, LVH, and prior Q waves. •• Chest x-rays (CXRs) are routinely ordered on presentation to evaluate cardiac size, pulmonary vasculature, and

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FIGURE 11.9  Chest x-ray demonstrating enlarged cardiac size and distension of the pulmonary vasculature. (Reproduced, with permission, from Tintinalli J, Stapczynski J, Ma O, Cline D, Cydulka R, Meckler G. Tintinalli’s Emergency Medicine: A Comprehensive Study Guide. 8th ed. New York, NY: McGraw-Hill; 2016.)

A

B

FIGURE 11.8  Pitting edema. Compression of the skin (A) results in temporary impressions (B) indicative of fluid overload. (Reproduced, with permission, from Kemp WL, Burns DK, Travis Brown TG. Pathology: The Big Picture. 8th ed. New York, NY: McGraw-Hill; 2008.)

pleural effusion as well as to rule out other causes of dyspnea such as pneumonia. The characteristic findings seen on x-rays in CHF include cardiomegaly (increased cardiothoracic ratio >50%), cephalization (prominent venous marking in the upper zones due to venous dilation), Kerley B lines (interstitial edema), and perihilar bat wing patterns due to alveolar edema (Fig. 11.9). •• Echocardiography is the most useful test to evaluate cardiac functioning, ventricular size, and wall motion abnormalities. It gives an estimate of the ejection fraction to assess the presence of systolic dysfunction. Also, valvular abnormalities are characterized on the basis of echocardiographic findings. Diastolic dysfunction, LV and RV sizes, and right ventricular pressures are valuable information that is provided by echocardiography.

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•• Coronary artery disease assessment: •• In an appropriate clinical setting, if the patient has ongoing symptoms of cardiac ischemia along with EKG changes and cardiac enzyme elevation, diagnostic evaluation for cardiovascular disease (CAD) urgently needs to be done. This includes a coronary angiography to assess whether a cardiac event resulted in heart failure. •• Patients who have a prior history of myocardial infarction (MI) and heart failure but are not presenting with the signs and symptoms of cardiac ischemia may need to be evaluated by noninvasive stress testing, such as stress echocardiography or nuclear perfusion imaging to assess for myocardial viability and underlying ischemia as the cause of worsening heart failure. •• Under appropriate clinical conditions, such as when fulminant myocarditis is suspected, myocardial biopsy may be indicated. In most cases, there is no role of myocardial biopsy unless sarcoidosis or amyloidosis is suspected and biopsy from other sites is nondiagnostic.

Drugs of Congestive Heart Failure Throughout heart failure, there is a multisystem response and adaptation in order to preserve the cardiac output to normal levels so that tissue perfusion is maintained. Initially this response is compensatory and will allow for adequate perfusion for certain physiological needs. As time goes on, the changes produced by these compensatory mechanisms to the anatomy and physiology of the human body become pathological, resulting in a manifestation of signs and symptoms of heart failure. This section will discuss the range of pharmaceutical options used to treat heart failure during an “exacerbation”

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phase as well as medications that help to preserve normal heart function in the face of constant change that occurs from the vicious cycle of heart failure when already in motion.

Angiotensin-Converting Enzyme Inhibitors Angiotensin-converting enzyme (ACE) inhibitors are drugs that work on the renin-angiotensin-aldosterone system (RAAS). They inhibit the angiotensin-converting enzyme in the vascular endothelium of the lungs. ACE converts angiotensin I into angiotensin II. As discussed previously, RAAS plays an important role in the pathogenesis of heart failure. RAAS has proven to augment cardiac output, which then reduces the drive for compensatory neurohormonal stimulation. This will ultimately decrease the levels of circulating norepinephrine (ie, activated adrenergic system). ACE inhibitors are primarily excreted through the kidneys. ACE inhibitors have been shown to improve the survival benefit in patients with heart failure and systolic dysfunction. The mechanism by which this occurs is thought to correlate indirectly with the inhibition of angiotensin II and aldosterone. ACE inhibitors prevent eventual left ventricular remodeling, which can cause a reduction in the cardiac output needed to maintain adequate perfusion. Examples of ACE inhibitors include lisinopril, captopril, and enalapril. Adverse effects of ACE inhibitors can range from mild to very serious. Between 10% and 15% of patients taking ACE inhibitors will experience a dry cough, which is a common side effect of this drug. This results from an excess of bradykinin which would have otherwise been degraded by an angiotensin-converting enzyme. Patients can be switched to angiotensin receptor blockers (ARBs) in the case of a bothersome cough (see the following section Angiotensin Receptor Blockers). A potentially lifethreatening side effect is angioedema. This can occur days to years after ACE inhibitors have begun and present with edema of the face, oral pharynx, larynx, hands, and stridor. In the case of angioedema, ACE inhibitors must be stopped. If the patient is switched to an ARB, angioedema is extremely rare. As with other diuretics, ACE inhibitors can cause hypovolemic hyponatremia. They can also cause hyperkalemia. To monitor for these side effects, it is important to check electrolytes and kidney function a week after starting the patient on ACE inhibitors. Hypotension can occur in patients with severe systolic dysfunction. This can result in symptoms of orthostatic hypertension. ACE inhibitors are teratogenic and are therefore contraindicated in pregnancy.

Angiotensin Receptor Blockers Angiotensin II receptor blockers (ARBs) are competitive antagonists of angiotensin II at the receptor site. Hence, angiotensin II is unable to mediate its effects on aldosterone and the sympathetic nervous system, thus achieving the same end

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result as ACE inhibitors. Examples of ARBs include losartan, valsartan, and olmesartan. The main advantage of ARBs over ACE inhibitors is their use if patients have a cough or angioedema with an ACE inhibitor (a rare occurrence with ARBs). ARBs have similar side effects as ACE inhibitors, including hyponatremia and hyperkalemia. ARBs are teratogenic, hence they are contraindicated in pregnancy. Aliskiren is a renin inhibitor. It binds to and blocks the renin chemoreceptor. Aliskiren is less widely used and fewer studies have been conducted on it compared to ACE inhibitors and ARBs. Theoretically, it should be as effective as ACE inhibitors and ARBs but has not yet been proven to reduce mortality in heart failure with reduced systolic function. Aliskerin should not be given in addition with ACE inhibitors or ARBs. Side effects include hyperkalemia, hyponatremia, and hypotension. Aliskerin is a teratogen as well. However, it does not cause angioedema or cough.

Potassium-Sparing Diuretics Potassium-sparing diuretics are used as antihypertensives. Specifically, 2 potassium-sparing diuretics (spironolactone and eplerenone) act to block aldosterone receptors in the cortical collecting ducts of renal nephrons. In turn, this decreases the reabsorption of sodium and water that results in a decrease in the preload and improves the symptoms of heart failure. Other potassium-sparing diuretics such as triamterene and amiloride are not aldosterone blocking and therefore do not act on the RAAS. They block the sodium channels in the distal convoluted tubule and collecting ducts resulting in a reduction in the reabsorption of sodium from the lumen. Aldosterone receptor blocking potassium-sparing diuretics have a mortality benefit in NYHA class II-IV heart failure with LVEF 120 ms

*ARB if ACE-intolerant.

NYHA I-IV Beta blocker ARB Aldosterone antagonist Hydralazine/isosorbide digoxin

Persistent symptoms or special populations

FIGURE 11.10  Treatment approach to CHF. Once a diagnosis of CHF is confirmed, fluid retention is assessed. A diuretic is prescribed if there is fluid retention. If there is no fluid retention or fluid retention is resolved, patients are started on an ACE inhibitor and β-blocker. If patients continue to remain symptomatic, an ARB or aldosterone antagonist is added. In the African American population with stage II-IV heart failure, a fixed-dose combination of hydralazine/nitrate is added to the ACE inhibitor and β-blocker. Patients with NYHA class II-III on maximal pharmacological therapy that continue to have an EF 120 ms. (Reproduced, with permission, from Longo DL, Fauci AS, Kasper DL, Hauser SL, Jameson JL, Loscalzo J, eds. Harrison’s Principles of Internal Medicine. 18th ed. New York, NY: McGraw-Hill; 2011.)

Key Points •• Heart failure can result in significant morbidity and mortality. •• Sympathetic stimulation, parasympathetic inhibition, renin-angiotensin-aldosterone system, cytokine release, and LV remodeling play an important role in the pathogenesis of heart failure. •• A workup for heart failure involves correlating history and physical findings with appropriate laboratory work

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and imaging in the form of chest x ray; diagnostic testing including EKG and echocardiogram also play an essential role in understanding the etiology of heart failure. •• Medications used in the treatment for heart failure are directed at disrupting the above-mentioned pathophysiologic mechanisms. Diuretics, β-blockers, ACE inhibitors/ARBs, and aldosterone antagonists are considered the mainstay in the treatment of heart failure.

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CASE STUDIES CASE 11.1  A 70-year-old man with a history of hypertension, diabetes mellitus, and dyslipidemia presents with a 10-day history of worsening shortness of breath. The patient has had shortness of breath on exertion, which has been going on for 4 weeks. This has acutely worsened over the next 10 days to the point where he is short of breath at rest. He admits to orthopnea, paroxysmal nocturnal dyspnea, and a 15-lb weight gain in the last 15 days. He denies any chest pain, palpitations, fever chills, and cough. On examination, he is hypoxic on room air (83%). His blood pressure is 145/70 mmHg and his heart rate is 102/min. On examination he has regular cardiac rhythm. An S4 is heard. He has an elevated jugular venous pressure. A pulmonary exam reveals bilateral basilar crackles. He has bilateral pitting edema on exam. He has no history of congestive heart failure. His pro-BNP is elevated at 4250. CA chest x-ray reveals an increase in interstitial edema consistent with heart failure. He was given Lasix in the emergency department and was admitted to the hospital. Which of the following is the most important diagnostic test that needs to be done to evaluate the etiology of heart failure? a. CT of the chest b. 24-hour urine collection c. Transthoracic echocardiogram d. Cardiac catheterization

CASE 11.2  A 65-year-old man was recently admitted for shortness of breath, lower extremity edema, and a left ventricular ejection fraction of 30%. On further evaluation he was found to have ischemic cardiomyopathy by cardiac catheterization. He was started on lisinopril, carvedilol (Coreg), atorvastatin, and Lasix. He calls your office with regard to swelling of his hands, lips, and tongue. He denies any trouble breathing or throat tightness. In addition to managing his acute episode, what will you do next in the management of this patient?

a. Discontinue Coreg b. Increase Coreg and Lasix c. Discontinue atorvastatin d. Discontinue lisinopril e. Discontinue lisinopril and Lasix

CASE 11.3  A 65-year-old woman presents with worsening shortness of breath, PND, orthopnea, and exertional dyspnea. She has a long-standing history of CHF with an LVEF of 40%. She is on an ACE inhibitor, β-blocker, spironolactone, Lasix, and calcium channel blocker. The patient has a past medical history of coronary artery disease, diabetes mellitus on insulin, hyperlipidemia, chronic kidney disease stage 3, and COPD. She comes into the ED with these symptoms as well as burning with urination. The patient has no chest pain, nausea, vomiting, diaphoresis, or abdominal discomfort. Physical examination shows bilateral crackles at the lung bases and 2+ pitting edema in her lower extremities. Labs, ECG, and chest x-ray are performed which show an elevated BNP, an elevated WBC of 12,000, Na of 132, and Cr of 2.2 (baseline of 2.0) with a BUN of 45. The ECG shows normal sinus rhythm and rate and no acute ST-T wave changes. The chest x-ray shows pulmonary vascular congestion, cephalization, increased cardiac silhouette, and bilateral pleural effusions at the lung bases. Urinalysis shows a urine WBC count of 162, large leukocyte esterase, and positive nitrites. She is diagnosed with an acute CHF exacerbation and admitted for further management and treatment. What is the most likely cause of the patient’s exacerbation? a. ACS b. Pneumonia c. UTI d. Medicine nonadherence e. COPD exacerbation

Suggested Readings Braunwald E. Heart failure. JACC Heart Fail. 2013;1(1):1-20. doi: 10.1016/j.jchf.2012.10.002. [Epub 2013 Feb 4] Cuculich PS, Kates AM. Cardiology Subspecialty Consult (The Washington Manual Subspecialty Consult Series). 2nd ed. ­Philadelphia, PA: Lippincott Williams & Wilkins; 2014. Florea VG, Cohn JN. The autonomic nervous system and heart failure. Circ Res. 2014;114(11):1815-1826. doi: 10.1161/ CIRCRESAHA.114.302589.

Longo DL, Fauci AS, Kasper DL, Hauser SL, Jameson JL, Loscalzo J. Harrison’s Principles of Internal Medicine. 18th ed. New York, NY: McGraw-Hill; 2011. Murphy JG, Lloyd MA. Mayo Clinic Cardiology: Concise ­Textbook. 4th ed. New York, NY: Oxford University Press; 2012:chap 11. Opie LH, Gersh BJ. Drugs for the Heart. Philadelphia, PA: Elsevier Saunders; 2013.

Lilly LS. Pathophysiology of Heart Disease: A Collaborative Project of Medical Students and Faculty. 5th ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2011.

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Chapter Congenital Heart Diseases HARIKRISHNAN K.N. AND JOSEPH J. VETTUKATTIL

Learning Objectives

12

By the end of this chapter the student will be able to: • Discuss common clinical associations of congenital heart disease (CHD). • Understand the embryological basis for various CHDs.

Introduction Congenital heart disease (CHD) constitutes the spectrum of diseases characterized by heart defects arising from anomalous development of the cardiovascular system. All CHDs have aberrant cardiac development, though they may not be symptomatic or manifest as a disease at birth. Some may present for the first time in adulthood. Other defects may remain asymptomatic throughout life and then be diagnosed on routine examination or imaging. A detailed description of CHD is beyond the scope of this chapter. However, knowledge regarding recognition of common CHDs and an approach to diagnosing and managing common presentations is absolutely essential for every physician.

Epidemiology The reported CHD prevalence at birth has increased substantially over the last century, reaching a stable estimate of 9 per 1000 live births in the last 15 years. This corresponds to 1.35 million newborns with CHD every year, representing a major global health burden. Significant geographical differences have been found in a recent meta-analysis. The highest reported total CHD birth prevalence was found in Asia (9.3 per 1000 live births) and the lowest in Africa (1.9 per 1000 live births). Europe had the second highest reported total CHD birth prevalence (8.2 per 1000 live births). The incidence of CHDs in the United States is 0.8% of all live births. The major defects include left-to-right shunts, such as ASD, VSD, and cyanotic CHD including ToF and TGA (Fig. 12.1).

Etiology Studies involving large populations with CHD have shown that CHDs are multifactorial in origin. There are consistent associations with other congenital defects and many of these show evidence of genetic mutations. Siblings and offspring of patients with CHD have an increased probability of having CHD. The risk of having another child with CHD when a sibling has a heart defect has been estimated to be 3% to 4%,

• Recognize the basic physiological variations due to CHD. • Classify CHD into acyanotic and cyanotic and further classify cyanotic heart disease based on the degree of pulmonary blood flow. • Distinguish clinical presentations of common acyanotic CHD with logical reasoning for a variation in their presentation and clinically differentiate between atrial septal defect (ASD), ventricular septal defect (VSD), and patent ductus arteriosus (PDA). • Distinguish between common cyanotic CHD: tetralogy of Fallot (ToF) physiology and other cyanotic heart diseases based on clinical presentation using clinical findings and common diagnostic tools such as electrocardiogram (ECG), chest x-ray (CXR), and echocardiography. • Indicate the approach to a cyanotic newborn and management principles. • List the steps in the treatment of CHD with congestive cardiac failure (CCF), and management of a cyanotic spell. • Enumerate the management options and surgical indications for ASD, VSD, PDA, ToF, and transposition of the great arteries (TGA); and provide a rationale and indications for the Fontan procedure.

and the risk if a parent has CHD is 2% to 10%. There are proven viral infections, drug exposures, and maternal illnesses such as diabetes that have a teratogenic effect. It is important to recognize the common syndromes with heart defects and associated etiological factors when working with patients with CHD (Table 12.1). Most of the CHD do not show any sex preponderance. However, infracardiac total anomalous pulmonary venous connection (TAPVC) and TGA display a strong male preponderance with the affected male to female ratio of 3:1. There is a higher prevalence of right heart lesions in women and left heart lesions in men. 183

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Table 12.1  Common associations of CHD and etiological factors

16% 4%

Associations

Heart defects

Etiology

Down syndrome

Atrioventricular septal defect (AVSD)

Trisomy 21

DiGeorge or Velocardiofacial or Shprintzen syndrome

Conotruncal anomalies (truncus arteriosus, arch abnormalities, etc.)

22q11 microdeletion

Williams syndrome

Supravalvular aortic stenosis (AS), Peripheral pulmonary stenosis (PS)

7q

Turner syndrome

Bicuspid aortic valve, Coarctation of the aorta (CoA), Long QT, Aortic root dissection

45 X0

Noonan syndrome

PS

PTPN 11 mutation

Holt-Oram syndrome

ASD

Congenital rubella syndrome

PDA

Maternal rubella infection

Fetal alcohol syndrome

VSD

Maternal alcohol exposure

34%

5% 5% 5% 13%

8% 10%

VSD

ASD

PDA

PS

TGA

CoA

AS

Others

TOF

FIGURE 12.1  Birth prevalence of CHD lesions. The estimated birth prevalence of CHD lesions from a systematic review of 114 publications between the years 1930-2009, compromising of a total population of 24,091,867 live births with CHD identified in 164,396 individuals. (Data from van der Linde D, Konings EE, Slager MA, Witsenburg M, Helbing WA, Takkenberg JJ, Roos-Hesselink JW. Birth prevalence of congenital heart disease worldwide: a systematic review and meta-analysis. J Am Coll Cardiol. 2011;58(21):2241-2247.)

Maternal phenytoin exposure

Embryology It is important to review the embryological aspects of CHD before considering the pathophysiology (Table 12.2). The cardiac tube undergoes modifications in the first trimester to become the 4-chambered heart, which is obvious by 12 weeks of gestation.

Thrombocytopeniaabsent radius (TAR) syndrome

ASD

Rubenstein-Taybi syndrome

VSD

Clinical Aspects of Fetal Circulation

Ellis-van Creveld syndrome

Common atrium, ASD

Phenylketonuria

ToF

Marfan syndrome

AR

Fibrillin gene mutation

Ebstein anomaly

TR, Dilated RA with atrialized small RV

Maternal Lithium exposure

During fetal development, the pulmonary tree plays a very small role in supplying oxygenated blood to vital organs as it is supported by the placenta, which acts as a low resistance vascular bed. The blood from various parts of the body drains via the superior and inferior caval veins (IVC and SVC) into the right atrium (RA). The majority of the blood (70%) from the IVC is directed toward the left atrium by the crista dividens (eustachian valve), and the blood enters the left atrium (LA) via a flap valve mechanism, which when persistent is titled the patent foramen ovale (PFO). This oxygenated blood flows to the left ventricle and is pumped into the aorta and supplies the brain. Since oxygenated blood is required for vital functions in various parts of the body, the blood pumped by the right ventricle (RV) goes through the ductus arteriosus (DA) into the aorta. The RV is the dominant chamber in fetal life contributing 55% to 60% of the cardiac output, and continues to be relatively hypertrophic till around 3 months of life. It is important to understand that the umbilical venous oxygen saturation is only about 65%, which is adequate for fetal growth and function.

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When there is a significant obstruction to the left heart structures, such as hypoplastic left heart syndrome (HLHS), the oxygenated blood returning from the placenta via the IVC does not cross the oval fossa into the left atrium; instead, it mixes with the SVC blood in the right atrium. Obstruction in the left heart causes the pulmonary venous return to preferentially flow from the LA into the RA. The vena caval and pulmonary venous blood along with the coronary sinus flow enters the right ventricle and the pulmonary artery. A wide DA and high pulmonary vascular resistance (PVR) drives most of the blood into the aortic arch. This flow is then distributed to the head and neck vessels, coronary arteries, and to the descending

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Chapter 12  Congenital Heart Diseases

Table 12.2  Embryological basis of common CHD Lesion

Embryological basis

ASD (Secundum)

Failure of formation of septum secundum (infolding from roof of atrium)

VSD

Interruption in the process of fusion of endocardial cushions Malalignment between processes for septal formation

PDA

Failure of closure of the ductus arteriosus (arises from sixth left aortic arch)

ToF

Antero-cephalad deviation of the developing outlet ventricular septum, or its fibrous remnant with hypertrophy of septoparietal trabeculations

TGA

Resorption of subpulmonary conus with persistence and elongation of subaortic conus (conal inversion)

Double outlet right ventricle (DORV)

Persistence of both subaortic and subpulmonary conus

CoA

Hypoplasia of the transverse aortic arch due to interplay between aortic growth and fetal blood flow

Truncus arteriosus

Proximal truncal septum responsible for spiral septation of outflow tracts fails to develop, infundibular septum is deficient or absent

TAPVC

Failure of development of common pulmonary vein or in establishment of connections with splanchnic plexus

AVSD (Primum ASD/AV canal/ Endocardial cushion defect)

Failure of fusion of endocardial cushions Failure of fusion of septum primum with endocardial cushions

aorta. The distribution of the blood into each vascular bed is determined by the relative resistance in each system. In a left heart obstruction, the fetal circulation differs from the normal in the following manner: •• •• •• ••

Larger PDA with higher PO2 Cerebral blood flow with relatively lower PO2 Higher PO2 in the pulmonary arterial blood Retrograde coronary blood flow containing low PO2 via a long curved aortic arch providing blood to the brain and upper body before supplying the coronaries

There is no significant difference in the fetal circulation when there is an obstruction to the right heart structures. During the time of birth, 3 important changes take place: 1. Clamping of the umbilical cord causes a sudden massive increase in systemic vascular resistance, against which the left ventricle has to pump thereby increasing the left atrial (LA) pressure leading to the closure of the foramen ovale.

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185

2. Entry of air into the lungs leads to a fall in the pulmonary vascular resistance and the lungs become the principal oxygenator. 3. Increased oxygen concentration leads to vasoconstriction and closure of the DA, which causes the systemic and pulmonary circulation to run in parallel. The functional closure of the DA occurs by 15 hours after birth, but anatomical closure may be delayed for up to 3 months of life. This is of functional significance in the presentation of congenital heart disease. CHD, which is dependent on the DA for maintenance of the aortic or pulmonary blood flow (termed as duct-dependent lesions), may manifest with severe cyanosis (with reduced pulmonary blood flow) or circulatory collapse and shock when the DA closes. Hence, maintenance of the patency of the DA is of prime importance in such lesions prior to appropriate corrective interventions. The PVR falls progressively to reach adult values by 3 to 4 weeks of life. In shunt lesions like VSD, this conversion may be delayed up to 6 weeks of life. A cardiac lesion with a left-toright shunt may not have a significant flow/shunting of blood until around 4 to 6 weeks because of an elevated PVR. Hence, children with large VSDs may have normal neonatal examination findings at birth and may manifest at 6 weeks of life. As will be reviewed in Chapter 7, there are multiple mechanisms whereby the heart tries to maintain normal homeostasis when confronted by an insult. These mechanisms are effective in a normal heart. However, in a heart that is already compromised due to congenital lesions, infections or anemia may cause a significant decompensation leading to the clinical manifestation of CCF (Fig. 12.2) or cardiogenic shock. In a heart with a communication between the left and right side, a shunt is usually from left-to-right side because of the difference in resistance and compliance between the chambers. A right-to-left shunt occurs only when there is a right-sided outflow obstruction, pulmonary arterial hypertension (PAH), or severe ventricular diastolic dysfunction, leading to an increase in right-sided pressure or a decrease in compliance (the inability of a chamber to distend with an increase in pressure).

Evaluation of Suspected CHD History and Examination Although all CHDs present with aberrant cardiac development, they may not be symptomatic or manifest as a disease at birth and in some patients may present for the first time in adulthood (Table 12.3). A detailed history and a careful examination help clinch the diagnosis when CHD is suspected. From a good history it is possible to identify: •• Whether the disease is congenital or acquired? •• Whether it is cyanotic or acyanotic CHD? •• If cyanotic, are there indications of increased or decreased pulmonary blood flow?

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Shunting of blood

Increased cardiac work Infection Anaemia

Volume overload of ventricle

Fluid restriction diuretics

Sympathetic activation (compensatory) output Vasoconstriction

Poor myocardial contractility

Congestion Tachypnea, rales Hepatomegaly Dependent edema S3 gallop Poor feeding/growth retardation

Treat

Ionotropes

Decreased cardiac Rapid thready pulses cold peripheries Prolonged CFT Hypotension

Vasodilators

FIGURE 12.2  Pathophysiology and management of CCF. The volume overload imposed on the ventricle along with the increased demand as in anemia or infection, leads to poor myocardial contractility. Treatment modalities shown in green boxes are directed at specific symptoms to alleviate CCF.

•• If acyanotic, are there indications of a significant shunt obstruction or cardiomyopathy? •• Whether there is a presence of complications or past history of congestive cardiac failure (CCF), cardiogenic shock, infective endocarditis, arrhythmias, or growth failure? •• Whether any intervention has been performed in the past, the details, and the response to the intervention? Infants usually present with nonspecific symptoms such as lethargy, irritability, and respiratory symptoms (eg, an increased rate and work at breathing), especially during feeding. Forehead or brow sweating during feeding indicates increased sympathetic activity compensating for decreased cardiac output in infants with significant cardiac disease. Feeding is one of the most important “stressors” that an infant can experience. In shunt lesions, the additional flow of blood into the lungs causes the lungs to be heavy to move with breathing, which increases the efforts and the work of breathing. This leads to frequent small feedings and poor weight gain. Characteristically, this occurs between 3 to 6 weeks of life coinciding with the fall in the PVR and the increase in pulmonary blood flow. Poor weight gain is due to decreased caloric intake because of poor feeding and increased metabolic demands imposed by the underlying cardiac disease. When symptomatic, most children receive more than twice the normal pulmonary blood flow. Increased blood flow into the lungs causes congestion and compression of the

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bronchial tree which runs adjacent to the pulmonary arteries and veins. This leads to increased secretions, decreased ciliary function, and increased work at breathing. Thus, children with significantly increased pulmonary blood flow have frequent chest infections that persist longer and are more severe. Patients with ToF may present with an asymptomatic murmur and cyanosis as a result of a progressive right ventricular outflow tract (RVOT) obstruction. An incidental finding of a large heart on a CXR, multiple heart sounds, or tachyarrhythmia may be the first presentation of Ebstein anomaly. Fatigue on exertion or unexplained syncope in teenage girls may be the first presentation of PAH. Symptoms of “asthma” or “exercise-­ induced wheezing” may be a presenting feature of ASD or partial anomalous pulmonary venous drainage. Hypertension or “pregnancy associated hypertension” may be the first presentation of coarctation of the aorta (CoA) in adults. Older children may present with growth retardation or one of the complications of congenital heart disease. They may have a history of progressive respiratory distress or dyspnea with exertion, palpitations, syncope, or dependent edema. They may have a history of prolonged fever with worsening respiratory distress, arthralgias, or rash. Although chest pain is one of the more frequent reasons for referral to a pediatric cardiologist, it is infrequently associated with cardiac disease. Chest pain associated with syncope or palpitations is suggestive of a tachyarrhythmia. A family history of congenital heart disease (CHD) in a sibling or parent increases the risk of CHD. Other cardiac

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Table 12.3  Timeline: Presentation of congenital heart disease Time of presentation

Physiological changes/Pathology

>20 years

Systemic/respiratory infection, anemia, endocarditis

Congestive cardiac failure

Cyanosis

Other complications

ASD

Eisenmenger complex

Brain abscess

Small/moderate VSD

Eisenmenger complex (in large L-R shunts)

Cerebral thrombosis

Fontan circulation

Truncus arteriosus Ebstein anomaly ToF physiology TGA/TAPVC with large shunts TGA Obstructed TAPVC Ductal-dependent pulmonary circulation Pulmonary atresia Tricuspid atresia HLHS Single ventricle/DORV with PS 10-20 years

Hyperkinetic pulmonary hypertension

1 year

Large VSD, partial AVSD Large PDA AVSD CoA Large R-L shunts in premature infants

6 weeks

Fall in PVR in L-R shunts

4 weeks

Fall in PVR

1 week

Closure of PDA

Ductal-dependent systemic circulation Severe obstruction/hypoplasia: HLHS Critical AS, PS, CoA, Interrupted aortic arch

At birth

Principal oxygenator-lung

Obstructed TAPVC

RV—LV dominance

TGA

Closure of PFO

Severe regurgitant lesions: MR, AR Large systemic arteriovenous fistula

diseases that have a genetic predisposition include familial dilated cardiomyopathy, hypertrophic cardiomyopathy, and familial causes of sudden cardiac death (eg, long QT syndrome). A thorough physical examination should be performed. Key components of the examination to determine whether there is significant cardiac disease include the general appearance of the patient, vital signs (heart rate, blood pressure, and

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respiratory rate), a respiratory and cardiovascular examination, and the presence of any obvious congenital anomaly or syndromic features. Extracardiac abnormalities are frequently detected in children with CHD. Congenital skeletal abnormalities, especially those of the hand and arm, are often associated with cardiac malformations. Poor perfusion is manifested by a delayed capillary refill (greater than 3 seconds), cool distal extremities, and decreased

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peripheral pulses. Tachypnea is often present in patients with left-to-right shunts or heart failure as a result of increased pulmonary blood flow or pulmonary venous congestion. Tachypnea and retractions are also seen in patients with severe left heart obstructive abnormalities or cardiomyopathy as a result of elevated left ventricular end-diastolic pressure (EDP). Cardiac disease should be considered in the differential diagnosis of any infant with wheezing without an obvious pulmonary cause. Rales are often heard in children with heart failure and pulmonary congestion. Rarely, stridor may be a manifestation of airway obstruction, which is caused by a congenital vascular anomaly, such as a vascular ring.

Cardiovascular Examination Palpation of all the peripheral pulses and femoral pulses is an important aspect of clinical examination. A weak femoral pulse is the best clinical evidence of coarctation of the aorta (CoA). The presence of cyanosis, anemia, or clubbing should be noted and pulse oximetry must be performed in all patients suspected of CHD. A quiet precordium decreases but does not eliminate the likelihood of cardiac disease. Auscultation is the key component of the cardiac examination and includes an assessment of the first and second heart sounds, and detecting the presence of a gallop, or heart murmur. Findings that are suggestive of significant CHD and warrant a referral to a cardiologist include: •• •• •• •• •• •• •• •• •• ••

Systolic murmur, grade 3 or higher Diastolic murmur Loud or single or abnormal second heart sound Gallop rhythm Friction rub Cyanosis or clubbing Cardiomegaly Abnormal ECG or CXR Elevated blood pressure (BP) Poor femoral pulses

Innocent Murmurs or Functional Murmurs Innocent or functional murmurs are common in children and characterized by a quiet precordium with an intensity less than grade 3 in a crescendo-decrescendo pattern with a normal second heart sound in an asymptomatic child. A pulmonary flow murmur is the most common murmur because of the small size of the branched pulmonary arteries (as the lung receives only 15% of cardiac output during fetal development). In any patient with suspected CHD, a 4-limb blood pressure measurement should be performed. If the systolic blood pressure in the legs is lower than that measured in the arms by 10 mmHg or more, or the lower limb pulses are poor, the patient should be evaluated for CoA. Hepatomegaly due to hepatic congestion can result from any cause of right-sided heart failure. The jugular venous pulse (JVP) is not usually

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elevated in children with CCF as the liver can distend significantly to accommodate the increased venous congestion. The liver edge is typically firm and smooth.

Cyanosis Central cyanosis, a bluish purple discoloration of the tissues (nail beds, tongue, and mucous membranes) is evident when systemic arterial concentration of deoxygenated hemoglobin in the blood exceeds 5 g/dL (3.1 mmol/L), which generally corresponds to an oxygen saturation ≤85%. Peripheral cyanosis, which is usually a result of cold extremities is not a sign of CHD and suggests poor peripheral blood flow or vasoconstriction. Central cyanosis as a presenting sign of CHD is most commonly seen during the first weeks of life in neonates with duct-dependent lesions (Table 12.4). These conditions include critically obstructive right- or left-sided heart structures with or without an admixture of blood in the cardiac chambers. It is

Table 12.4  Management of cyanotic patients •• Stabilize airway, breathing, and circulation •• Oxygen by prongs/non-rebreathing mask •• Continuous monitoring of the heart rate, pulse volume, respiratory rate, saturation, urine output •• Differentiate cardiac vs pulmonary or other causes of cyanosis Hyperoxia test: This test is performed to distinguish between cardiac and pulmonary causes of central cyanosis. After recording the baseline PaO2 and saturation, the patient is exposed to 100% oxygen for 10 minutes by means of a hood or non-rebreathing mask. The PaO2 is rechecked. PaO2 >100-150 indicates that cyanosis is of a pulmonary origin and unlikely due to a cardiac cause. Cyanosis due to a cardiac cause usually does not improve even when alveoli are flooded with oxygen because there is a mixing of blood occurring at the cardiac level. •• Exception: A well-compensated TGA with large VSD or TAPVC with a large shunt can demonstrate an increase in PaO2 following oxygen administration. PaO2 which fails to improve indicates a cardiac cause of cyanosis. When there is a significant intracardiac right-to-left shunt, the arterial PO2 does not exceed 100 mmHg, and the rise is usually not more than 10-30 mmHg. •• Exception: Extra cardiac shunts (eg, a pulmonary AV fistula) with a normal heart will not improve with oxygen. •• Obtain urgent bedside CXR, ECG, Echo

Urgent bedside echo Ductal dependent circulation

Other CHD TGA-Balloon atrial septostomy

Start PGE1 infusion 0.02-1 mcg/ kg/min

Manage CHF

Titrate based on Po2, blood pressure, improvement in pH (Monitor for apnea, fever, and bradycardia)

Optimize nutrition

Plan to shift to an advanced center with surgical expertise

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Table 12.5  Right and left-sided obstructive lesions Right-sided obstructive lesions

Left-sided obstructive lesions

Tricuspid atresia/stenosis Pulmonary atresia/stenosis

Critical aortic stenosis Coarctation of aorta Interrupted aortic arch Hypoplastic left heart syndrome Congenital mitral stenosis Obstructed pulmonary veins

189

Table 12.7  Lesions that need atrial communication for survival TGA Tricuspid atresia Pulmonary atresia intact septum HLHS TAPVC Severe Ebstein anomaly

important to differentiate between obstructed lesions from admixture lesions to effectively manage these patients. The heart obstructions in this group include severe valve stenosis or atresia. A lesion is called critical when there is an obstruction or stenosis that requires blood supply through the PDA for survival. These conditions are tabulated below (Table 12.5 through Table 12.8). CHD is classified into acyanotic and cyanotic CHD. Acyanotic CHD includes shunt lesions like VSD, ASD, PDA, and AVSD; or obstructive lesions like aortic stenosis, pulmonary stenosis, CoA, or primary myocardial disease like cardiomyopathies. Neonates with critical left-sided obstructive lesions (eg, severe CoA and HLHS) will present with both shock and cyanosis with ductal closure. In these patients, as the PDA closes, metabolic acidosis, hypotension, pulmonary edema, and cyanosis will develop. Cyanosis can be a presenting sign of CHD in infants beyond the neonatal period. Cyanosis as a presenting sign of CHD is often accompanied or preceded by signs and symptoms of pulmonary overcirculation (eg, tachypnea, poor feeding, and failure to thrive) in lesions with increased pulmonary blood flow. Clinically, cyanotic CHD can be classified into: •• Decreased pulmonary blood flow •• Increased pulmonary blood flow •• Normal blood flow In general, when the pulmonary blood flow increases, the patient is minimally cyanotic but may develop CCF because of an excessive volume overload placed on the ventricle. In contrast, when the pulmonary blood flow is reduced, the patient is severely cyanotic and does not develop CCF because there is no volume overload.

Table 12.6  Obstruction with intracardiac shuts

A frequently used mnemonic to identify 5 of the more common cyanotic lesions is the “5 Ts” of cyanotic CHD: •• •• •• •• ••

Transposition of the great arteries Tetralogy of Fallot Truncus arteriosus Total anomalous pulmonary venous connection Tricuspid valve abnormalities (TA and Ebstein anomaly)

There are multiple other conditions such as double outlet right ventricle (DORV), pulmonary atresia, variations of a single ventricle, HLHS, complex conditions associated with heterotaxy syndrome, or an anomalous systemic venous ­connection (eg, the left superior vena cava connected to the left atrium).

Decreased Pulmonary Blood Flow Cyanotic lesions with a decrease in pulmonary blood flow include ToF, tricuspid valve anomalies, pulmonary valve atresia (PA), and critical valvar pulmonary stenosis. •• Tetralogy of Fallot: The pathognomonic feature is the antero-cephalad deviation of the outlet septum which leads to a constellation of 4 anatomic defects consisting of an overriding aorta, right ventricular hypertrophy, pulmonary stenosis, and malalignment VSD. •• Tricuspid valve anomalies: Tricuspid valve anomalies include tricuspid atresia (TA), tricuspid stenosis, and Ebstein anomaly. In TA, there is no communication between the right atrium and the right ventricle, which results in a total and obligatory right-to-left atrial shunt.

Table 12.8  Ductal-dependent lesions for survival

Right heart lesions

Left heart lesions

Ductus-dependent systemic circulation

Ductus-dependent pulmonary circulation

Pulmonary atresia with VSD

Taussing-Bing anomaly

Critical aortic stenosis

Pulmonary atresia

TGA/VSD/PS

HLHS

Coarctation of aorta

Critical PS

ToF

Interrupted aortic arch

Complex lesions with severe PS

DORV

Hypoplastic left heart syndrome

Hypoplastic right ventricle

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Other abnormalities may be present, including VSD, pulmonary stenosis, or transposition of the great arteries. The timing of surgical intervention depends on the degree of cyanosis and the level of pulmonary flow. •• Critical valvar pulmonary stenosis (PS): Critical PS is dependent on a PDA for adequate pulmonary perfusion. These lesions are amenable to balloon dilation of the pulmonary valve via cardiac catheterization. •• Tricuspid stenosis is usually seen with hypoplastic RV and ASD. This also results in an atrial level rightto-left shunt. Ebstein anomaly is a malformation of the tricuspid valve. It is caused by dysplasia of the posterior and septal leaflet resulting in atrialization of the right ventricle. The pathognomonic feature is the rotational anomaly of the TV along the axis of the aorta and ­failure of delamination of the leaflets from the RV wall. The variation in clinical severity is related to the extent of the inferior displacement of the tricuspid leaflets from the tricuspid annulus. In the most serious form of this defect, the tricuspid valve is severely deformed, displaced into the right ventricular outflow tract, with a reduction in the right ventricular cavity size and a right ventricular outflow obstruction. Tricuspid regurgitation increases the right atrial (RA) size and the diameter of a PFO. Cyanosis results from right-to-left shunting at the atrial level but typically improves as pulmonary vascular resistance decreases in the neonatal transition period.

Increased Pulmonary Blood Flow CHD that presents with cyanosis and increased pulmonary blood flow includes TGA with VSD, truncus arteriosus, and TAPVC. •• Transposition of the great arteries with VSD is a ventriculoarterial discordant connection in which the aorta is connected to the right ventricle and the pulmonary is connected to the left ventricle. •• Truncus arteriosus is a condition in which a single great vessel arises from the heart. The aorta, pulmonary arteries, and coronary arteries all originate from the ascending portion of this single vessel. There is always an associated VSD. The single semilunar valve contains 3 to 6 cusps and may be regurgitant. The various subtypes of truncus arteriosus relate to the branching pattern of the pulmonary arteries. The aorta receives a combined output from the left and right ventricles resulting in cyanosis, which may be mild if pulmonary vascular resistance is low and pulmonary blood is excessive. •• Total anomalous pulmonary venous connection also referred to as total anomalous pulmonary venous return/ drainage (TAPVR/D), is a cyanotic congenital defect in which all 4 pulmonary veins fail to make their normal connection to the left atrium. This results in drainage

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of all the pulmonary venous return into the systematic venous circulation. The clinical presentation depends on whether the pulmonary venous drainage is obstructed or nonobstructed. Based on the location of the pulmonary venous drainage, TAPVC is classified as supracardiac (drainage into the superior vena cava via an innominate vein), cardiac (through coronary the sinus), and infracardiac (infradiaphragmatic connections to the portal or hepatic vein). The infracardiac variant is always obstructed and presents early with severe cyanosis with the typical ground glass appearance on a CXR with a normal-sized heart. Conditions that present with cyanosis and heart failure include left-sided obstructive lesions such as HLHS, interrupted aortic arch, and critical valvar aortic stenosis. These obstructive left-sided heart lesions depend upon a PDA to supply the systemic flow. As the DA closes, cyanosis, pulmonary edema, metabolic acidosis, and hypotension develop. •• Hypoplastic left heart syndrome consists of a number of defects involving the underdevelopment of the leftsided chambers and valves. Most commonly, there is aortic valve atresia, severe mitral valve stenosis, and marked hypoplasia of the left ventricle. In HLHS, right-to-left shunting via the PDA provides retrograde perfusion of the ascending and transverse portions of the aorta so that the subclavian, carotid, and coronary arteries are supplied. If untreated, 95% of neonates with HLHS die within the first few weeks of life. With the advancement of medical therapy and the introduction of a 3-staged palliative surgical (Norwood) procedure, survival has improved. •• Coarctation of the aorta is a discrete narrowing of the aorta, which typically involves a thoracic preductal location adjacent to the left subclavian artery. Infants with a severe coarctation of the aorta may present with heart failure when the ductus arteriosus closes. •• Interrupted aortic arch is the most extreme form of coarctation. Complete interruption usually occurs between the left carotid and left subclavian arteries but can occur distal to the left subclavian artery or between the innominate artery and left carotid artery, and is usually associated with a large, nonrestrictive VSD. Surgical correction is required for both the arch obstruction and the VSD. •• Critical valvar aortic stenosis is the result of a severe left ventricular outflow tract obstruction due to critical valvar aortic stenosis, which results in cyanosis and heart failure or even cardiogenic shock. By definition, these patients need a PDA with a right-to-left shunt to maintain adequate systemic blood flow. Affected infants may have a soft murmur and minimal gradient by Doppler echocardiography because of severe left ventricular dysfunction and poor cardiac output. The clinical features are summarized in Table 12.9. The intensity of the

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Table 12.9  Differentiating points between left and right heart obstruction Clinical features

Left heart obstruction

Right heart obstruction

Presentation

For example: Critical AS

For example: Critical PS

Distressed, breathless, irritable, increased work at breathing

Not distressed, tachypnea but not recessing, calm Cyanosis, poor feeding

Signs of hypoperfusion or respiratory distress related to pulmonary edema Exertional chest pain, easy fatigability, or syncope may occur in a child Examination:

Systolic thrill: At upper right sternal border

At the upper left sternal border RV tap

S2

S2 split paradoxically in severe AS

Wide split S2, P2 may be diminished

Murmur

Ejection click, harsh, grade 2-4/6, ejection systolic murmur best heard at the second right or left ICS, transmitting to the neck and apex

Ejection-type systolic murmur (grade 2-5/6) best audible at the upper left sternal border, transmitting well to the back

ECG

LVH with strain pattern (severe)

RAD, RVH good correlation with severity

ECG abnormalities do not correlate with severity

Upright T wave in V1 characteristic of significant RVOT obstruction between age of 7 days and 13 years

Dilated ascending aorta or a prominent aortic knob

Prominent main PA segment (poststenotic dilatation)

CXR

Pulmonary venous congestion

murmur may increase after successful intervention by balloon valvuloplasty or surgical repair due to improvement in left ventricular function and increased forward flow across the valve. The next section includes a detailed description of 5 of the common defects with a note on their management.

Atrial Septal Defects Atrial septal defects (ASDs) are classified based on their position and embryological origin as: Ostium secundum ASD (50%-70%), ostium primum ASD or partial AVSD (30%), sinus venosus ASD, and coronary sinus ASD. Children with isolated ASD are usually asymptomatic at birth. They may go undetected even until adulthood. Most patients with a large ASD tend to develop recurrent respiratory tract infections because of the increased pulmonary blood flow which disturbs the function of the normal mucociliary apparatus. Rarely they may fail to thrive because of a state of chronic CCF. In an ASD, the right atrium receives blood from the systemic venous return and an additional fraction of blood from the LA. This leads to volume overload and dilatation of the RA. The RV receives this blood in diastole and consequently dilates. The RV dilatation can lead to prolonged depolarization with the characteristic rsR’ pattern on an ECG. There is an increased amount of blood flowing through the pulmonary vascular bed that can lead to a hyperkinetic PAH. The PAs can handle an increased amount of blood flow for a long time without developing CCF because there is no direct transmission of

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the systemic pressure to the PA. There is an increased amount of blood flowing through the tricuspid and pulmonary valves causing flow turbulence through the normal-sized valves. This leads to the characteristic murmurs of ASD. As the pulmonary valve is smaller compared to the tricuspid valve (TV), a pulmonary flow murmur is present in hemodynamically significant ASDs. When there is a larger shunt, in addition, there will be a mid-diastolic tricuspid inflow murmur characterizing the larger ASD. A pulmonary ejection murmur is usually heard as an early ejection systolic murmur at the pulmonary area. Since the RA is more compliant than the LA it is emptied preferentially into the RA and the LA size remains normal. Since the RV receives blood from both atria, the RV volume is unchanged during respiration hence the ejection time of the RV and pulmonary hangout interval is prolonged leading to a wide split of the second heart sound. The pulmonary vascular bed cannot be further augmented with inspiration and hence the S2 split is fixed, unlike in a normal heart. There, the ASD flow does not cause a murmur because of the low pressure gradient between the two atria. There may be cardiomegaly due to RA (posteroanterior projection) and RV enlargement (lateral view) on a CXR. The pulmonary vascular markings are prominent when there is a significant shunt. Echocardiography shows the position as well as the size of the defect, which can best be seen in the subcostal 4-­chamber view. The increased size of the RA and RV and prominent pulmonary artery indicates a significant shunt. A transesophageal 3-dimensional echocardiogram is of value in a preprocedural evaluation of ASD or PFO with complex morphologies.

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In patients with an ASD less than 3 mm in size diagnosed before 3 months of age, spontaneous closure occurs in 100% of the patients by 1½ years of age. Spontaneous closure occurs more than 80% of the time in patients with defects between 3 and 8 mm before 1½ years of age. An ASD with a diameter greater than 8 mm rarely closes spontaneously. An untreated large ASD can cause CCF and PAH in adults who are in their 20s and 30s. Infective endocarditis is unlikely in an isolated ASD. Adults can develop atrial arrhythmias. The medical management involves treating respiratory infections and management of CCF (Table 12.10). The indications for closure of an ASD include secundum ASD, measuring 5 mm or more in diameter and a significant left-toright shunt with clinical evidence of right ventricular volume overload (ie, pulmonary to systemic flow Qp/Qs ratio of 1.5:1 or greater or RV enlargement). A percutaneous transcatheter approach for closure is mostly considered as the first option. Several closure devices that are delivered through cardiac catheters have been shown to be safe and efficacious for ASD closure. These devices are applicable only to secundum ASD with an adequate septal rim. Many devices are available for clinical use including the Amplatzer Septal Occluder, Gore Helex Septal Occluder, Occlutech device, and so on. Among these, the Amplatzer Septal Occluder appears to have the most widespread use. There must be an adequate rim of septal tissue around the defect for an appropriate placement of the device. The timing of the device closure for secundum ASD is

Table 12.10  Management of congenital heart disease in congestive cardiac failure

•• Stabilize airway, breathing, and circulation •• Humidified oxygen by prongs/non-rebreathing mask •• Continuous monitoring of heart rate, pulse volume, respiratory rate, saturation, and urine output •• Correct anemia, give antibiotic for suspected/obvious infection •• If child is in cardiogenic shock, restrict IV fluids to two-thirds of the maintenance requirement, start inotropic support with dobutamine at 8-10 μg/kg/min and titrate up to 20 μg/kg/min, add dopamine at 3-5 μg/kg/min based on continuous assessment for correction of shock. Once shock is corrected, add furosemide at 1-2 mg/kg/day (preferably as an infusion initially to prevent severe diuresis which can lead to shock) •• If there are signs of congestion but child is not in shock, add furosemide at 1-2 mg/kg/day divided in 2-3 doses. Start angiotensin-converting enzyme (ACE) inhibitors 0.3 mg/kg/dose 3 times daily after a smaller test dose. Increase dose as tolerated by careful blood pressure monitoring. As the myocardial function is well preserved, digoxin is not indicated unless there is evidence of pump failure •• Obtain a CXR, blood screen for infection, and an echo to rule out endocarditis; evaluate the shunt, ejection fraction, and any valvular abnormalities •• Monitor potassium levels. Consider oral supplementation of potassium 1-2 mEq/kg as KCl •• Evaluate growth and nutritional status. Look for evidence of growth retardation (an indication of chronic heart failure, plan surgical intervention) •• Digoxin therapy is not indicated unless there is myocardial dysfunction

Elmoselhi_CH12_p183-200.indd 192

not well established. The potential for device delivery-related issues are minimal if the child is over 5 years of age. Considering the possibility of spontaneous closure, it is wise not to use the device in infancy unless the patient is symptomatic with heart failure. If device closure is not considered appropriate technically (due to an absent or poor inferior rim) or clinically (small infants), and there exists an indication for closure of the defect, surgical closure can be considered. High pulmonary vascular resistance (ie, >0 units/m2, >7 units/m2 with vasodilators) may be a contraindication for complete closure.

Ventricular Septal Effects Ventricular septal defects (VSDs) are a developmental defect of the interventricular septum (IVS) because of a deficient growth or malalignment of endocardial cushions, conotruncal ridges, tissues at the crest of the IVS and the muscular septum. It may be classified based on the location as: •• Perimembranous (70%): The types can be further classified as perimembranous inlet (atrioventricular [AV] canal type), perimembranous trabecular, or perimembranous outlet (tetralogy type) defects based on the extent and location in the septum. •• Muscular (trabecular) (5%-20%): Locations include anterior, posterior, midmuscular, and apical. Muscular VSDs are often multiple. •• Inlet (AV canal) defects (5%-8%): These VSDs are associated with syndromes. •• Outlet (infundibular or conal) defects (5%-7% and up to 30% in the Far East). •• Doubly committed subarterial defects. In a VSD, the left-to-right shunt occurs during left ventricular systole when the right ventricle is actively contracting. Hence, the right ventricle acts as a conduit for the blood flow and there is no significant volume overload. However, hyperkinetic PAH and increased flow of blood into the LA and subsequently into the LV occurs, which leads to a dilatation of the LA and LV. The murmur in a VSD is pansystolic as a pressure gradient exists between the left and right side throughout systole. It is important to note that LA enlargement occurs in a VSD, unlike in an ASD. The clinical features depend on the size of the VSD and PVR, and it is important to note the radiological and ECG features for an appropriate diagnosis and management (Table 12.11). A transthoracic echocardiogram with color Doppler is widely used to diagnose VSDs. The color Doppler can detect VSDs as small as 2 mm. To assess a VSD completely, one must define its site, size, hemodynamic effects, associated lesions, and complications. The management of VSDs depends on the size, site, number of defects, magnitude of the shunt, and also depends on the associated lesions and the complications. Small VSDs need periodic follow-up once in 6 months with monitoring of

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Table 12.11  Clinical manifestations and diagnostic features of VSD according to size Size of VSD

Symptoms

Signs

CXR

ECG

Small

Asymptomatic

Precordial systolic thrill best felt in the left third and fourth ICS at the left LSB, grade 4/6, harsh holosystolic, crescendo-decrescendo murmur

Normal

Normal

Moderate

Mild tachypnea during feeding, recurrent respiratory infections

Apical impulse hyperdynamic LV type, P2 normal/mildly increased in intensity; mid-diastolic flow murmur in the mitral area

Moderate cardiomegaly, prominent pulmonary vascular markings, main PA segment is prominent, LA enlargement

PR interval normal or slightly prolonged, normal axis

Large

CHF in early infancy, feeding difficulties, repeated LRTI, and failure to thrive

Prominent P2, long crescendodecrescendo murmur in LSB

Cardiomegaly, pulmonary plethora, prominent main PA with RV enlargement

RAD, biventricular hypertrophy

Large VSD with high PVR

Mild symptomatic improvement but have exertional dyspnea, cyanosis

Mild cyanosis may be present, RV S3 Decreased intensity of murmur, palpable loud P2, EDM of pulmonary regurgitation (Graham-Steell murmur)

No cardiomegaly, RVH, aneurysmally dilated main PA, LPA, and RPA

Right axis deviation, P pulmonale, RVH

Eisenmenger complex

Easy fatigability, chest pain, syncope, and hemoptysis

Cyanosis, clubbing, loud palpable P2, parasternal heave, short soft systolic murmur in PA

Water jug appearance

Peaked P waves, right axis, tall R in V1

the symptoms, appearance of any new murmur of the AR, and an evaluation of the growth. The therapies available for the management of VSDs include (1) medical, (2) transcatheter, (3) surgical, and (4) hybrid procedures. It is not uncommon to detect VSDs during a routine examination in newborns. It is important to explain and reassure caregivers about VSDs and their the usual. However, a follow-up examination after 2 weeks and less frequently thereafter, is important for detecting any signs of volume overload or growth failure. A failure in medical management and PAH (if the PA systolic pressure is greater than half the systemic systolic pressure or mean PA pressure =>25 mmHg) is an indication for surgical closure. Medical management is directed at the management of CCF and optimizing growth. A lower respiratory tract infection (LRTI) must be treated with antibiotics. If the child is not gaining weight, is having repeated LRTIs, and the pulmonary artery systolic pressure is greater than half of the systemic systolic pressure, the defect should be closed without delay (within 6 months of life). If there is clinical improvement with optimal weight gain and echocardiographic evidence of a reduction in the size of the VSD without evidence of PAH, medical management can be continued for up to 2 years of age. A child greater than 1 year of age should be operated on if the Qp/Qs ratio is more than 2:1. Older children without any symptoms and no evidence of PAH should have the corrective procedure before school age. Other indications include the development of a significant AR due to aortic cusp prolapse (VSD closure with aortic valve repair/replacement), bacterial endocarditis, and significant LV dilatation based on ECG/ echocardiography. Surgical management depends on careful

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Katz-Wachtel phenomenon

assessment of pulmonary vascular resistance and reversibility of the shunt in patients with a pulmonary-to-systemic vascular resistance ratio of >0.5. The closure of VSDs is based on the type of the VSD and the ease of access. Most VSDs can be closed through a trans-atrial approach and all efforts should be made to avoid a ventriculostomy. Surgical closure is done on all large defects, inlet and outlet VSDs, and in small VSDs with a past history of subacute bacterial endocarditis. A hybrid approach, where the surgeon opens the chest and makes a purse-string suture on the RV free wall to provide access for interventional closure is rarely used to close VSDs that are inaccessible for surgery in small infants (10%). If adequate interatrial communication exists and the anatomic diagnosis of TGA is clear by echocardiography examination, the patient can go to surgery without cardiac catheterization or the balloon atrial septostomy. The definitive correction is by the arterial switch operation, which is the procedure of choice. The coronary arteries are transplanted to the PA, and the proximal great arteries are connected to the distal end of the other great artery, resulting in an anatomic correction. This procedure has advantages over the atrial baffle operations (earlier performed Senning or Mustard procedures) because it is an anatomic (not physiologic) correction and long-term complications are infrequent.

Fontan Circulation The Fontan procedure is a palliative surgical procedure that redirects the systemic venous return directly to the pulmonary arteries without passing through a subpulmonary ventricle. It is done on lesions with a functionally single ventricle. A

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Section III  Cardiovascular Disease Processes: Diagnostic and Management Approaches

single ventricle is unable to pump blood into both systemic and pulmonary circulations and hence ultimately fails to do so. If there is a direct connection between the systemic venous return and the pulmonary artery, there is an effective decompression of the blood flow, thus sustaining the univentricular heart with maintenance of good contractility. The original direct connection between the RA and the pulmonary artery has been replaced by hemodynamically superior versions. The total cavopulmonary anastomosis or lateral tunnel Fontan consists of a direct, end-to-side superior cavopulmonary anastomosis (bidirectional Glenn operation) along with an intraatrial baffle connecting the inferior vena cava to the underside of the pulmonary artery. Recently, an extracardiac conduit between the PA and IVC was introduced. This procedure is performed in •• Tricuspid atresia •• Single ventricle (double inlet ventricle)

•• HLHS •• Isomerism of the right atrial appendages Patients with Fontan circulation have persistently elevated central venous pressure (a state of chronic heart failure) with decreased cardiac output. Physical examination reveals an elevated nonpulsatile jugular venous pulse, a quiet apex, a normal S1, and single S2. A heart murmur is usually absent, unless complicated by systemic AV valvular obstruction or subaortic obstruction. The long-term complications include protein losing enteropathy as a result of elevated venous pressure and intestinal lymphangiectasia, arrhythmias, thromboembolic complications, obstruction of the conduit, and progressive ventricular dysfunction and cyanosis. As discussed throughout this chapter, patients with CHD may require interventional and surgical procedures for management of their condition (Table 12.14).

Table 12.14  Common interventional procedures for CHD Lesion

Interventional procedure

Indication

AS

Percutaneous balloon valvuloplasty

Symptomatic patients with catheterization pressure gradient (cath gradient) >40 mmHg; asymptomatic patients (>60 mmHg)

ASD

Transcatheter placement of an occlusion device

Hemodynamically significant ASD with Qp/Qs of >1.5

PS

Percutaneous balloon valvuloplasty

Gradient across the pulmonary valve >30 mmHg

PFO

PFO closure

Recurrent cryptogenic stroke

Coarctation

Stent angioplasty in older children (>9 years especially postsurgical residual or re-coarctation) or balloon angioplasty in younger children

Pull back gradient across the coarctation segment >20 mmHg

TGA

Balloon atrial septostomy (Rashkind procedure)

Before corrective surgery, to improve oxygen saturation at least by 10% (in TGA without intracardiac mixing causing severe cyanosis)

Baffle/Conduit stenosis or obstruction

Dilatation, stenting

RV pressure >50% systemic levels, or RV dilatation or dysfunction/severe pulmonary regurgitation

Pulmonary hypertension

Atrial flow regulator

Severe pulmonary hypertension and right ventricular failure as means for providing a “pop-off” valve to the failing right ventricle

Transcatheter Valvulation

Insertion of a bioprosthetic valve in position using catheter technique. Commonly used for relieving right ventricular outflow tract obstruction. For example, post ToF or pulmonary atresia surgery

Free pulmonary regurgitation or severe RVOT stenosis not amenable to balloon valvuloplasty

Stent angioplasty

Percutaneous insertion of a stent to augment narrowing in arteries or veins (eg, branch pulmonary artery stenosis, vena caval obstruction)

Significant reduction in flow or reduction in luminal size

VSD

Device closure

Muscular VSDs with LV volume overload, pulmonary/ systemic flow >1.5 Qp/Qs