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2nd Edition

HARRISON’S

Cardiovascular Medicine

Derived from Harrison’s Principles of Internal Medicine, 18th Edition

Editors Dan L. Longo, md

Professor of Medicine, Harvard Medical School; Senior Physician, Brigham and Women’s Hospital; Deputy Editor, New England Journal of Medicine, Boston, Massachusetts

Dennis L. Kasper, md

William Ellery Channing Professor of Medicine, Professor of Microbiology and Molecular Genetics, Harvard Medical School; Director, Channing Laboratory, Department of Medicine, Brigham and Women’s Hospital, Boston, Massachusetts

J. Larry Jameson, md, PhD

Robert G. Dunlop Professor of Medicine; Dean, University of Pennsylvania School of Medicine; Executive Vice-President of the University of Pennsylvania for the Health System, Philadelphia, Pennsylvania

Anthony S. Fauci, md

Chief, Laboratory of Immunoregulation; Director, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland

Stephen L. Hauser, md

Robert A. Fishman Distinguished Professor and Chairman, Department of Neurology, University of California, San Francisco, San Francisco, California

Joseph Loscalzo, md, PhD

Hersey Professor of the Theory and Practice of Medicine, Harvard Medical School; Chairman, Department of Medicine; Physician-in-Chief, Brigham and Women’s Hospital, Boston, Massachusetts

2nd Edition

HARRISON’S

Cardiovascular Medicine Editor Joseph Loscalzo, MD, PhD Hersey Professor of the Theory and Practice of Medicine, Harvard Medical School; Chairman, Department of Medicine; Physician-in-Chief, Brigham and Women’s Hospital, Boston, Massachusetts

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Copyright © 2013 by McGraw-Hill Education, LLC. 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: 978-0-07-181499-7 MHID: 0-07-181499-X The material in this eBook also appears in the print version of this title: ISBN: 978-0-07-181498-0, MHID: 0-07-181498-1. 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 e-mail us at [emailprotected]. Dr. Fauci’s work as an editor and author was performed outside the scope of his employment as a U.S. government employee. This work represents his personal and professional views and not necessarily those of the U.S. government. This book was set in Bembo by Cenveo® Publisher Services. The editors were James F. Shanahan and Kim J. Davis. The production supervisor was Catherine H. Saggese. Project management was provided by Tania Andrabi, Cenveo Publisher Services. The cover design was by Thomas DePierro. Cover illustration, the coronary vessels of the heart, © MedicalRF.com/Corbis. TERMS OF USE This is a copyrighted work and McGraw-Hill Education, LLC. 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 circ*mstances 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.

Contents Contributors. . . . . . . . . . . . . . . . . . . . . . . . . . . . . vii Preface . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ix

13 Diagnostic Cardiac Catheterization and Coronary Angiography . . . . . . . . . . . . . . . . . . 117 Jane A. Leopold, David P. Faxon

SECTION I

SECTION III

Introduction to Cardiovascular Disorders

Heart Rhythm Disturbances 14 Principles of Electrophysiology. . . . . . . . . . . . . 128 David D. Spragg, Gordon F. Tomaselli

1 Basic Biology of the Cardiovascular System. . . . . . 2 Joseph Loscalzo, Peter Libby, Jonathan Epstein

15 The Bradyarrhythmias. . . . . . . . . . . . . . . . . . . 137 David D. Spragg, Gordon F. Tomaselli

2 Epidemiology of Cardiovascular Disease. . . . . . . 20 Thomas A. Gaziano, J. Michael Gaziano

16 The Tachyarrhythmias. . . . . . . . . . . . . . . . . . . 151 Francis Marchlinski

3 Approach to the Patient with Possible Cardiovascular Disease. . . . . . . . . . . . . . . . . . . . 28 Joseph Loscalzo

SECTION IV

Disorders of the heart

SECTION II

Diagnosis of Cardiovascular Disorders

17 Heart Failure and Cor Pulmonale. . . . . . . . . . . 182 Douglas L. Mann, Murali Chakinala

4 Chest Discomfort . . . . . . . . . . . . . . . . . . . . . . . 34 Thomas H. Lee

18 Cardiac Transplantation and Prolonged Assisted Circulation. . . . . . . . . . . . . 201 Sharon A. Hunt, Hari R. Mallidi

5 Dyspnea. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 42 Richard M. Schwartzstein

19 Congenital Heart Disease in the Adult . . . . . . . 207 John S. Child, Jamil Aboulhosn

6 Hypoxia and Cyanosis. . . . . . . . . . . . . . . . . . . . 49 Joseph Loscalzo

20 Valvular Heart Disease. . . . . . . . . . . . . . . . . . . 219 Patrick O’Gara, Joseph Loscalzo

7 Edema . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 54 Eugene Braunwald, Joseph Loscalzo

21 Cardiomyopathy and Myocarditis. . . . . . . . . . . 248 Lynne Warner Stevenson, Joseph Loscalzo

8 Palpitations. . . . . . . . . . . . . . . . . . . . . . . . . . . . 61 Joseph Loscalzo

22 Pericardial Disease. . . . . . . . . . . . . . . . . . . . . . 273 Eugene Braunwald

9 Physical Examination of the Cardiovascular System. . . . . . . . . . . . . . . . . 63 Patrick T. O’Gara, Joseph Loscalzo

23 Tumors and Trauma of the Heart. . . . . . . . . . . 284 Eric H. Awtry, Wilson S. Colucci

10 Approach to the Patient with a Heart Murmur. . . 76 Patrick T. O’Gara, Joseph Loscalzo

24 Cardiac Manifestations of Systemic Disease. . . . 289 Eric H. Awtry, Wilson S. Colucci

11 Electrocardiography. . . . . . . . . . . . . . . . . . . . . . 89 Ary L. Goldberger

25 Infective Endocarditis . . . . . . . . . . . . . . . . . . . 294 Adolf W. Karchmer

12 Noninvasive Cardiac Imaging: Echocardiography, Nuclear Cardiology, and MRI/CT Imaging. . . . . . . . . . . . . . . . . . . 101 Rick A. Nishimura, Panithaya Chareonthaitawee, Matthew Martinez

26 Acute Rheumatic Fever. . . . . . . . . . . . . . . . . . 309 Jonathan R. Carapetis 27 Chagas’ Disease. . . . . . . . . . . . . . . . . . . . . . . . 316 Louis V. Kirchhoff, Anis Rassi, Jr.

Contents

28 Cardiogenic Shock and Pulmonary Edema. . . . 320 Judith S. Hochman, David H. Ingbar

38 Diseases of the Aorta. . . . . . . . . . . . . . . . . . . . 467 Mark A. Creager, Joseph Loscalzo

29 Cardiovascular Collapse, Cardiac Arrest, and Sudden Cardiac Death. . . . . . . . . . . . . . . . . . . 328 Robert J. Myerburg, Agustin Castellanos

39 Vascular Diseases of the Extremities. . . . . . . . . 476 Mark A. Creager, Joseph Loscalzo

SECTION V

Disorders of the vasculature 30 The Pathogenesis, Prevention, and Treatment of Atherosclerosis . . . . . . . . . . . . . . 340 Peter Libby 31 Disorders of Lipoprotein Metabolism. . . . . . . . 353 Daniel J. Rader, Helen H. Hobbs 32 The Metabolic Syndrome . . . . . . . . . . . . . . . . 377 Robert H. Eckel 33 Ischemic Heart Disease . . . . . . . . . . . . . . . . . . 385 Elliott M. Antman, Andrew P. Selwyn, Joseph Loscalzo 34 Unstable Angina and Non-ST-Segment Elevation Myocardial Infarction. . . . . . . . . . . . 407 Christopher P. Cannon, Eugene Braunwald

40 Pulmonary Hypertension. . . . . . . . . . . . . . . . . 490 Stuart Rich SECTION VI

Cardiovascular Atlases 41 Atlas of Electrocardiography. . . . . . . . . . . . . . . 500 Ary L. Goldberger 42 Atlas of Noninvasive Cardiac Imaging . . . . . . . 517 Rick A. Nishimura, Panithaya Chareonthaitawee, Matthew Martinez 43 Atlas of Cardiac Arrhythmias. . . . . . . . . . . . . . 526 Ary L. Goldberger 44 Atlas of Percutaneous Revascularization. . . . . . 539 Jane A. Leopold, Deepak L. Bhatt, David P. Faxon

35 ST-Segment Elevation Myocardial Infarction. . . 415 Elliott M. Antman, Joseph Loscalzo

Appendix Laboratory Values of Clinical Importance. . . . . . . . 549 Alexander Kratz, Michael A. Pesce, Robert C. Basner, Andrew J. Einstein

36 Percutaneous Coronary Interventions and Other Interventional Procedures . . . . . . . . . . . 434 David P. Faxon, Deepak L. Bhatt

Review and Self-Assessment. . . . . . . . . . . . . . . 575 Charles Wiener, Cynthia D. Brown, Anna R. Hemnes

37 Hypertensive Vascular Disease. . . . . . . . . . . . . 443 Theodore A. Kotchen

Index. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 615

CONTRIBUTORS Numbers in brackets refer to the chapter(s) written or cowritten by the contributor. UCLA Adult Noninvasive Cardiodiagnostics Laboratory, Ronald Reagan-UCLA Medical Center, Los Angeles, California [19]

Jamil Aboulhosn, MD Assistant Professor, Departments of Medicine and Pediatrics, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, California [19]

Wilson S. Colucci, MD Thomas J. Ryan Professor of Medicine, Boston University School of Medicine; Chief of Cardiovascular Medicine, Boston Medical Center, Boston, Massachusetts [23, 24]

Elliott M. Antman, MD Professor of Medicine, Harvard Medical School; Brigham and Women’s Hospital, Boston, Massachusetts [33, 35]

Mark A. Creager, MD Professor of Medicine, Harvard Medical School; Simon C. Fireman Scholar in Cardiovascular Medicine; Director, Vascular Center, Brigham and Women’s Hospital, Boston, Massachusetts [38, 39]

Eric H. Awtry, MD Assistant Professor of Medicine, Boston University School of Medicine; Inpatient Clinical Director, Section of Cardiology, Boston Medical Center, Boston, Massachusetts [23, 24]

Robert H. Eckel, MD Professor of Medicine, Division of Endocrinology, Metabolism and Diabetes, Division of Cardiology; Professor of Physiology and Biophysics, Charles A. Boettcher, II Chair in Atherosclerosis, University of Colorado School of Medicine, Anschutz Medical Campus, Director Lipid Clinic, University of Colorado Hospital, Aurora, Colorado [32]

Robert C. Basner, MD Professor of Clinical Medicine, Division of Pulmonary, Allergy, and Critical Care Medicine, Columbia University College of Physicians and Surgeons, New York, New York [Appendix] Deepak L. Bhatt, MD, MPH Associate Professor of Medicine, Harvard Medical School; Chief of Cardiology, VA Boston Healthcare System; Director, Integrated Interventional Cardiovascular Program, Brigham and Women’s Hospital and VA Boston Healthcare System; Senior Investigator, TIMI Study Group, Boston, Massachusetts [36, 44]

Andrew J. Einstein, MD, PhD Assistant Professor of Clinical Medicine, Columbia University College of Physicians and Surgeons; Department of Medicine, Division of Cardiology, Department of Radiology, Columbia University Medical Center and New York-Presbyterian Hospital, New York, New York [Appendix]

Eugene Braunwald, MD, MA (Hon), ScD (Hon) FRCP Distinguished Hersey Professor of Medicine, Harvard Medical School; Founding Chairman, TIMI Study Group, Brigham and Women’s Hospital, Boston, Massachusetts [7, 22, 34]

Jonathan A. Epstein, MD, DTMH William Wikoff Smith Professor of Medicine; Chairman, Department of Cell and Developmental Biology; Scientific Director, Cardiovascular Institute, University of Pennsylvania, Philadelphia, Pennsylvania [1]

Cynthia D. Brown, MD Assistant Professor of Medicine, Division of Pulmonary and Critical Care Medicine, University of Virginia, Charlottesville, Virginia [Review and Self-Assessment]

David P. Faxon, MD Senior Lecturer, Harvard Medical School; Vice Chair of Medicine for Strategic Planning, Department of Medicine, Brigham and Women’s Hospital, Boston, Massachusetts [13, 36, 44]

Christopher P. Cannon, MD Associate Professor of Medicine, Harvard Medical School; Senior Investigator, TIMI Study Group, Brigham and Women’s Hospital, Boston, Massachusetts [34]

J. Michael Gaziano, MD, MPH Professor of Medicine, Harvard Medical School; Chief, Division of Aging, Brigham and Women’s Hospital; Director, Massachusetts Veterans Epidemiology Center, Boston VA Healthcare System, Boston, Massachusetts [2]

Jonathan Carapetis, PhD, MBBS, FRACP, FAFPHM Director, Menzies School of Health Research, Charles Darwin University, Darwin, Australia [26] Agustin Castellanos, MD Professor of Medicine, and Director, Clinical Electrophysiology, Division of Cardiology, University of Miami Miller School of Medicine, Miami, Florida [29]

Thomas A. Gaziano, MD, MSc Assistant Professor, Harvard Medical School; Assistant Professor, Health Policy and Management, Center for Health Decision Sciences, Harvard School of Public Health; Associate Physician in Cardiovascular Medicine, Department of Cardiology, Brigham and Women’s Hospital, Boston, Massachusetts [2]

Murali Chakinala, MD Associate Professor of Medicine, Division of Pulmonary and Critical Care Medicine, Washington University School of Medicine, St. Louis, Missouri [17] Panithaya Chareonthaitawee, MD Associate Professor of Medicine, Mayo Clinic College of Medicine, Rochester, Minnesota [12, 42]

Ary L. Goldberger, MD Professor of Medicine, Harvard Medical School; Wyss Institute for Biologically Inspired Engineering, Harvard University; Beth Israel Deaconess Medical Center, Boston, Massachusetts [11, 41, 43]

John S. Child, MD, FACC, FAHA, FASE Streisand Professor of Medicine and Cardiology, Geffen School of Medicine, University of California, Los Angeles (UCLA); Director, Ahmanson-UCLA Adult Congenital Heart Disease Center; Director,

Anna R. Hemnes, MD Assistant Professor, Division of Allergy, Pulmonary, and Critical Care Medicine, Vanderbilt University Medical Center, Nashville, Tennessee [Review and Self-Assessment]

vii

viii

Contributors

Helen H. Hobbs, MD Professor of Internal Medicine and Molecular Genetics, University of Texas Southwestern Medical Center, Dallas, Texas; Investigator, Howard Hughes Medical Institute, Chevy Chase, Maryland [31] Judith S. Hochman, MD Harold Snyder Family Professor of Cardiology; Clinical Chief, Leon Charney Division of Cardiology; Co-Director, NYU-HHC Clinical and Translational Science Institute; Director, Cardiovascular Clinical Research Center, New York University School of Medicine, New York, New York [28] Sharon A. Hunt, MD, FACC Professor, Division of Cardiovascular Medicine, Stanford University, Palo Alto, California [18] David H. Ingbar, MD Professor of Medicine, Pediatrics, and Physiology; Director, Pulmonary Allergy, Critical Care and Sleep Division, University of Minnesota School of Medicine, Minneapolis, Minnesota [28] Adolf W. Karchmer, MD Professor of Medicine, Harvard Medical School; Division of Infectious Diseases, Beth Israel Deaconess Medical Center, Boston, Massachusetts [25] Louis V. Kirchhoff, MD, MPH Professor of Internal Medicine (Infectious Diseases) and Epidemiology, Department of Internal Medicine, The University of Iowa, Iowa City, Iowa [27] Theodore A. Kotchen, MD Professor Emeritus, Department of Medicine; Associate Dean for Clinical Research, Medical College of Wisconsin, Milwaukee, Wisconsin [37] Alexander Kratz, MD, PhD, MPH Associate Professor of Pathology and Cell Biology, Columbia University College of Physicians and Surgeons; Director, Core Laboratory, Columbia University Medical Center, New York, New York [Appendix] Thomas H. Lee, MD, MSc Professor of Medicine, Harvard Medical School; Network President, Partners Healthcare System, Boston, Massachusetts [4] Jane A. Leopold, MD Associate Professor of Medicine, Harvard Medical School; Brigham and Women’s Hospital, Boston, Massachusetts [13, 44] Peter Libby, MD Mallinckrodt Professor of Medicine, Harvard Medical School; Chief, Cardiovascular Medicine, Brigham and Women’s Hospital, Boston, Massachusetts [1, 30] Joseph Loscalzo, MD, PhD Hersey Professor of the Theory and Practice of Medicine, Harvard Medical School; Chairman, Department of Medicine; Physician-in-Chief, Brigham and Women’s Hospital, Boston, Massachusetts [1, 3, 6–10, 20, 21, 33, 35, 38, 39] Hari R. Mallidi, MD Assistant Professor of Cardiothoracic Surgery; Director of Mechanical Circulatory Support, Stanford University Medical Center, Stanford, California [18] Douglas L. Mann, MD Lewin Chair and Chief, Cardiovascular Division; Professor of Medicine, Cell Biology and Physiology, Washington University School of Medicine, St. Louis, Missouri [17]

Francis Marchlinski, MD Professor of Medicine; Director, Cardiac Electrophysiology, University of Pennsylvania Health System, Philadelphia, Pennsylvania [16] Matthew Martinez, MD Lehigh Valley Physician Group, Lehigh Valley Heart Specialists, Allentown, Pennsylvania [12, 42] Robert J. Myerburg, MD Professor, Departments of Medicine and Physiology, Division of Cardiology; AHA Chair in Cardiovascular Research, University of Miami Miller School of Medicine, Miami, Florida [29] Rick A. Nishimura, MD, FACC, FACP Judd and Mary Morris Leighton Professor of Cardiovascular Diseases; Professor of Medicine; Consultant, Division of Cardiovascular Diseases and Internal Medicine, Mayo Clinic College of Medicine, Rochester, Minnesota [12, 42] Patrick T. O’Gara, MD Professor of Medicine, Harvard Medical School; Director, Clinical Cardiology, Brigham and Women’s Hospital, Boston, Massachusetts [9, 10, 20] Michael A. Pesce, PhD Professor Emeritus of Pathology and Cell Biology, Columbia University College of Physicians and Surgeons; Columbia University Medical Center, New York, New York [Appendix] Daniel J. Rader, MD Cooper-McClure Professor of Medicine and Pharmacology, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania [31] Anis Rassi, Jr., MD, PhD, FACC, FACP, FAHA Scientific Director, Anis Rassi Hospital, Goiânia, Brazil [27] Stuart Rich, MD Professor of Medicine, Department of Medicine, Section of Cardiology, University of Chicago, Chicago, Illinois [40] Richard M. Schwartzstein, MD Ellen and Melvin Gordon Professor of Medicine and Medical Education; Associate Chief, Division of Pulmonary, Critical Care, and Sleep Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts [5] Andrew P. Selwyn, MD, MBCHB Professor of Medicine, Harvard Medical School; Brigham and Women’s Hospital, Boston, Massachusetts [33] David D. Spragg, MD Assistant Professor of Medicine, Johns Hopkins University, Baltimore, Maryland [14, 15] Lynne Warner Stevenson, MD Professor of Medicine, Harvard Medical School; Director, Heart Failure Program, Brigham and Women’s Hospital, Boston, Massachusetts [21] Gordon F. Tomaselli, MD Michel Mirowski, MD Professor of Cardiology; Professor of Medicine and Cellular and Molecular Medicine; Chief, Division of Cardiology, Johns Hopkins University, Baltimore, Maryland [14, 15] Charles M. Wiener, MD Dean/CEO Perdana University Graduate School of Medicine, Selangor, Malaysia; Professor of Medicine and Physiology, Johns Hopkins University School of Medicine, Baltimore, Maryland [Review and Self-Assessment]

PREFACE it. As knowledge about these complex systems expands, the opportunity for identifying unique therapeutic targets increases, holding great promise for definitive interventions in the future. Regenerative medicine is another area of cardiovascular medicine that is rapidly achieving translation. Recognition that the adult human heart can repair itself, albeit sparingly with typical injury, and that cardiac precursor (stem) cells reside within the myocardium to do this can be expanded, and can be used to repair if not regenerate a normal heart is an exciting advance in the field. These concepts represent a completely novel paradigm that will revolutionize the future of the subspecialty. In view of the importance of cardiovascular medicine to the field of internal medicine, and the rapidity with which the scientific basis for the discipline is advancing, Harrison’s Cardiovascular Medicine was developed. The purpose of this sectional is to provide the readers with a succinct overview of the field of cardiovascular medicine. To achieve this goal, Harrison’s Cardiovascular Medicine comprises the key cardiovascular chapters contained in the eighteenth edition of Harrison’s Principles of Internal Medicine, contributed by leading experts in the field. This sectional is designed not only for physicians-in-training on cardiology rotations, but also for practicing clinicians, other health care professionals, and medical students who seek to enrich and update their knowledge of this rapidly changing field. The editors trust that this book will increase both the readers’ knowledge of the field, and their appreciation for its importance. The first section of the book, “Introduction to Cardiovascular Disorders,” provides a systems overview, beginning with the basic biology of the cardiovascular system, followed by epidemiology of cardiovascular disease, and approach to the patient. The integration of pathophysiology with clinical management is a hallmark of Harrison’s, and can be found throughout each of the subsequent disease-oriented chapters. The book is divided into six main sections that reflect the scope of cardiovascular medicine: (I) Introduction to the Cardiovascular System; (II) Diagnosis of Cardiovascular Disorders; (III) Heart Rhythm Disturbances; (IV) Disorders of the Heart; (V) Disorders of the Vasculature; and (VI) Cardiovascular Atlases. Our access to information through web-based journals and databases is remarkably efficient. Although these sources of information are invaluable, the daunting body of data creates an even greater need for synthesis by experts in the field. Thus, the preparation of these chapters is a special craft that requires the ability to distill

Harrison’s Principles of Internal Medicine has been a respected information source for more than 60 years. Over time, the traditional textbook has evolved to meet the needs of internists, family physicians, nurses, and other health care providers. The growing list of Harrison’s products now includes Harrison’s for the iPad, Harrison’s Manual of Medicine, and Harrison’s Online. This book, Harrison’s Cardiovascular Medicine, now in its second edition, is a compilation of chapters related to cardiovascular disorders. Our readers consistently note the sophistication of the material in the specialty sections of Harrison’s. Our goal was to bring this information to our audience in a more compact and usable form. Because the topic is more focused, it is possible to enhance the presentation of the material by enlarging the text and the tables. We have also included a Review and Self-Assessment section that includes questions and answers to provoke reflection and to provide additional teaching points. Cardiovascular disease is the leading cause of death in the United States, and is rapidly becoming a major cause of death in the developing world. Advances in the therapy and prevention of cardiovascular diseases have clearly improved the lives of patients with these common, potentially devastating disorders; yet, the disease prevalence and the risk factor burden for disease (especially obesity in the United States and smoking worldwide) continue to increase globally. Cardiovascular medicine is, therefore, of crucial importance to the field of internal medicine. Cardiovascular medicine is a large and growing subspecialty, and comprises a number of specific subfields, including coronary heart disease, congenital heart disease, valvular heart disease, cardiovascular imaging, electrophysiology, and interventional cardiology. Many of these areas involve novel technologies that facilitate diagnosis and therapy. The highly specialized nature of these disciplines within cardiology and the increasing specialization of cardiologists argue for the importance of a broad view of cardiovascular medicine by the internist in helping to guide the patient through illness and the decisions that arise in the course of its treatment. The scientific underpinnings of cardiovascular medicine have also been evolving rapidly. The molecular pathogenesis and genetic basis for many diseases are now known and, with this knowledge, diagnostics and therapeutics are becoming increasingly individualized. Cardiovascular diseases are largely complex phenotypes, and this structural and physiological complexity recapitulates the complex molecular and genetic systems that underlie

Preface

core information from the ever-expanding knowledge base. The editors are, therefore, indebted to our authors, a group of internationally recognized authorities who are masters at providing a comprehensive overview while being able to distill a topic into a concise and interesting chapter. We are indebted to our colleagues at

McGraw-Hill. Jim Shanahan is a champion for Harrison’s and these books were impeccably produced by Kim Davis. We hope you find this book useful in your effort to achieve continuous learning on behalf of your patients. Joseph Loscalzo, MD, PhD

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.

Review and self-assessment questions and answers were taken from Wiener CM, Brown CD, Hemnes AR (eds). Harrison’s Self-Assessment and Board Review, 18th ed. New York, McGraw-Hill, 2012, ISBN 978-0-07-177195-5.

The global icons call greater attention to key epidemiologic and clinical differences in the practice of medicine throughout the world. The genetic icons identify a clinical issue with an explicit genetic relationship.

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SECTION I

Introduction to Cardiovascular Disorders

CHaPter 1

BASIC BIOLOGY OF THE CARDIOVASCULAR SYSTEM Joseph loscalzo

■

Peter libby

■

Jonathan epstein

sandwiched between layers of smooth-muscle cells (Fig. 1-1E ). Larger arteries have a clearly demarcated internal elastic lamina that forms the barrier between the intima and the media. An external elastic lamina demarcates the media of arteries from the surrounding adventitia.

tHe Blood Vessel VaSCulaR ulTRaSTRuCTuRE Blood vessels participate in homeostasis on a momentto-moment basis and contribute to the pathophysiology of diseases of virtually every organ system. Hence, an understanding of the fundamentals of vascular biology furnishes a foundation for understanding the normal function of all organ systems and many diseases. The smallest blood vessels—capillaries—consist of a monolayer of endothelial cells apposed to a basem*nt membrane, adjacent to occasional smooth-muscle-like cells known as pericytes (Fig. 1-1A). Unlike larger vessels, pericytes do not invest the entire microvessel to form a continuous sheath. Veins and arteries typically have a trilaminar structure (Fig. 1-1B–E). The intima consists of a monolayer of endothelial cells continuous with those of the capillaries. The middle layer, or tunica media, consists of layers of smooth-muscle cells; in veins, the media can contain just a few layers of smooth-muscle cells (Fig. 1-1B). The outer layer, the adventitia, consists of looser extracellular matrix with occasional fibroblasts, mast cells, and nerve terminals. Larger arteries have their own vasculature, the vasa vasorum, which nourishes the outer aspects of the tunica media. The adventitia of many veins surpasses the intima in thickness. The tone of muscular arterioles regulates blood pressure and flow through various arterial beds. These smaller arteries have a relatively thick tunica media in relation to the adventitia (Fig. 1-1C). Medium-size muscular arteries similarly contain a prominent tunica media (Fig. 1-1D); atherosclerosis commonly affects this type of muscular artery. The larger elastic arteries have a much more structured tunica media consisting of concentric bands of smooth-muscle cells, interspersed with strata of elastin-rich extracellular matrix

ORIgIN OF VaSCulaR CEllS The intima in human arteries often contains occasional resident smooth-muscle cells beneath the monolayer of vascular endothelial cells. The embryonic origin of smooth-muscle cells in various types of arteries differs. Some upper-body arterial smooth-muscle cells derive from the neural crest, whereas lower-body arteries generally recruit smooth-muscle cells from neighboring mesodermal structures during development. Derivatives of the proepicardial organ, which gives rise to the epicardial layer of the heart, contribute to the vascular smooth-muscle cells of the coronary arteries. Recent evidence suggests that bone marrow may give rise to both vascular endothelial cells and smooth-muscle cells, particularly under conditions of injury repair or vascular lesion formation. Indeed, the ability of bone marrow to repair an injured endothelial monolayer may contribute to maintenance of vascular health, whereas failure to do so may lead to arterial disease. The precise sources of endothelial and mesenchymal progenitor cells or their stem cell precursors remain the subject of active investigation.

VaSCulaR CEll bIOlOgy Endothelial cell The key cell of the vascular intima, the endothelial cell, has manifold functions in health and disease. Most obviously, the endothelium forms the interface between

A. Capillary

B. Vein

C. Small muscular artery

Pericyte

Endothelial cell

Basic Biology of the Cardiovascular System

D. Large muscular artery

E. Large elastic artery

Internal elastic lamina

External elastic lamina

Adventitia

Figure 1-1 Schematics of the structures of various types of blood vessels. A. Capillaries consist of an endothelial tube in contact with a discontinuous population of pericytes. B. Veins typically have thin medias and thicker adventitias. C. A small muscular artery features a prominent tunica media. D. Larger

tissues and the blood compartment. It therefore must regulate the entry of molecules and cells into tissues in a selective manner. The ability of endothelial cells to serve as a selectively permeable barrier fails in many vascular disorders, including atherosclerosis and hypertension. This dysregulation of permeability also occurs in pulmonary edema and other situations of “capillary leak.” The endothelium also participates in the local regulation of blood flow and vascular caliber. Endogenous substances produced by endothelial cells such as prostacyclin, endothelium-derived hyperpolarizing factor, nitric oxide (NO), and hydrogen peroxide (H2O2) provide tonic vasodilatory stimuli under physiologic conditions in vivo (Table 1-1). Impaired production or excess catabolism of NO impairs this endothelium-dependent vasodilator function and may contribute to excessive vasoconstriction in various pathologic situations. By contrast, endothelial cells also produce potent vasoconstrictor substances such as endothelin in a regulated fashion. Excessive production of reactive oxygen species, such as superoxide anion (O2−), by endothelial or smooth-muscle cells under pathologic conditions (e.g., excessive exposure to angiotensin II) can promote local oxidative stress and inactivate NO.

CHAPTER 1

Vascular smooth-muscle cell

muscular arteries have a prominent media with smoothmuscle cells embedded in a complex extracellular matrix. E. Larger elastic arteries have cylindrical layers of elastic tissue alternating with concentric rings of smooth-muscle cells.

The endothelial monolayer contributes critically to inflammatory processes involved in normal host defenses and pathologic states. The normal endothelium resists prolonged contact with blood leukocytes; however, when activated by bacterial products such as endotoxin or proinflammatory cytokines released during infection or injury, endothelial cells express an array of leukocyte adhesion molecules that bind various classes of Table 1-1 Endothelial Functions in Health and Disease Homeostatic Phenotype

Dysfunctional Phenotype

Vasodilation

Impaired dilation, vasoconstriction

Antithrombotic, profibrinolytic

Prothrombotic, antifibrinolytic

Anti-inflammatory

Proinflammatory

Antiproliferative

Proproliferative

Antioxidant

Prooxidant

Permselectivity

Impaired barrier function

SECTION I Introduction to Cardiovascular Disorders

leukocytes. The endothelial cells appear to recruit selectively different classes of leukocytes in different pathologic conditions. The gamut of adhesion molecules and chemokines generated during acute bacterial infection tends to recruit granulocytes. In chronic inflammatory diseases such as tuberculosis and atherosclerosis, endothelial cells express adhesion molecules that favor the recruitment of mononuclear leukocytes that characteristically accumulate in these conditions. The endothelium also dynamically regulates thrombosis and hemostasis. Nitric oxide, in addition to its vasodilatory properties, can limit platelet activation and aggregation. Like NO, prostacyclin produced by endothelial cells under normal conditions not only provides a vasodilatory stimulus but also antagonizes platelet activation and aggregation. Thrombomodulin expressed on the surface of endothelial cells binds thrombin at low concentrations and inhibits coagulation through activation of the protein C pathway, inactivating clotting factors Va and VIIIa and thus combating thrombus formation. The surface of endothelial cells contains heparan sulfate glycosaminoglycans that furnish an endogenous antithrombotic coating to the vasculature. Endothelial cells also participate actively in fibrinolysis and its regulation. They express receptors for plasminogen and plasminogen activators and produce tissue-type plasminogen activators. Through local generation of plasmin, the normal endothelial monolayer can promote the lysis of nascent thrombi. When activated by inflammatory cytokines, bacterial endotoxin, or angiotensin II, for example, endothelial cells can produce substantial quantities of the major inhibitor of fibrinolysis, plasminogen activator inhibitor 1 (PAI-1). Thus, in pathologic circ*mstances, the endothelial cell may promote local thrombus accumulation rather than combat it. Inflammatory stimuli also induce the expression of the potent procoagulant tissue factor, a contributor to disseminated intravascular coagulation in sepsis. Endothelial cells also participate in the pathophysiology of a number of immune-mediated diseases. Lysis of endothelial cells mediated by complement provides an example of immunologically mediated tissue injury. The presentation of foreign histocompatibility complex antigens by endothelial cells in solid-organ allografts can trigger immunologic rejection. In addition, immunemediated endothelial injury may contribute in some patients with thrombotic thrombocytopenic purpura and patients with hemolytic-uremic syndrome. Thus, in addition to contributing to innate immune responses, endothelial cells participate actively in both humoral and cellular limbs of the immune response. Endothelial cells regulate growth of the subjacent smooth-muscle cells as well. Heparan sulfate glycosaminoglycans elaborated by endothelial cells can hold smooth-muscle proliferation in check. In contrast,

when exposed to various injurious stimuli, endothelial cells can elaborate growth factors and chemoattractants, such as platelet-derived growth factor, that can promote the migration and proliferation of vascular smooth-muscle cells. Dysregulated elaboration of these growth-stimulatory molecules may promote smoothmuscle accumulation in atherosclerotic lesions. Clinical assessment of endothelial function Various invasive and noninvasive approaches can be used to evaluate endothelial vasodilator function in humans. Either pharmacologic agonists or increased flow stimulates the endothelium to release acutely molecular effectors that alter underlying smooth-muscle cell tone. Invasively, infusion of the cholinergic agonists acetylcholine and methacholine stimulates the release of NO from normal endothelial cells. Changes in coronary diameter can be quantitatively measured in response to an intracoronary infusion of these shortlived, rapidly acting agents. Noninvasive assessment of endothelial function in the forearm circulation typically involves occlusion of brachial artery blood flow with a blood pressure cuff, which elicits reactive hyperemia after release; the resulting flow increase normally causes endothelium-dependent vasodilation, which is measured as the change in brachial artery blood flow and diameter by ultrasound (Fig. 1-2). This approach depends on shear stress–dependent changes in endothelial release of NO after restoration of blood flow, as well as the effect of adenosine released (transiently) from ischemic tissue in the forearm. Typically, these invasive and noninvasive approaches detect inducible vasodilatory changes in vessel diameter of ∼10%. In individuals with atherosclerosis or its risk factors (especially hypertension, hypercholesterolemia, diabetes mellitus, and smoking), such studies can detect endothelial dysfunction as defined by a smaller change in diameter and, in the extreme case, a so-called paradoxical vasoconstrictor response owing to the direct effect of cholinergic agonists on vascular smooth-muscle cell tone. Vascular smooth-muscle cell The vascular smooth-muscle cell, the major cell type of the media layer of blood vessels, also contributes actively to vascular pathobiology. Contraction and relaxation of smooth-muscle cells at the level of the muscular arteries controls blood pressure, and, hence, regional blood flow and the afterload experienced by the left ventricle (see later). The vasomotor tone of veins, which is governed by smooth-muscle cell tone, regulates the capacitance of the venous tree and influences the preload experienced by both ventricles. Smooth-muscle cells in the adult vessel seldom

Vascular smooth-muscle cells govern vessel tone. Those cells contract when stimulated by a rise in intracellular calcium concentration by calcium influx through the plasma membrane and by calcium release from intracellular stores (Fig. 1-3). In vascular smoothmuscle cells, voltage-dependent L-type calcium channels open with membrane depolarization, which is

Basic Biology of the Cardiovascular System

replicate. This homeostatic quiescence of smoothmuscle cells changes in conditions of arterial injury or inflammatory activation. Proliferation and migration of arterial smooth-muscle cells, which is associated with a change in phenotype characterized by lower content

Vascular smooth-muscle cell function

CHAPTER 1

Figure 1-2 Assessment of endothelial function in vivo using blood pressure cuff-occlusion and release. Upon deflation of the cuff, changes in diameter (A) and blood flow (B) of the brachial artery are monitored with an ultrasound probe (C). (Reproduced with permission of J. Vita, MD.)

of contractile proteins and greater production of extracellular matrix macromolecules, can contribute to the development of arterial stenoses in atherosclerosis, arteriolar remodeling that can sustain and propagate hypertension, and the hyperplastic response of arteries injured by angioplasty or stent deployment. In the pulmonary circulation, smooth-muscle migration and proliferation contribute decisively to the pulmonary vascular disease that gradually occurs in response to sustained high-flow states such as left-to-right shunts. Such pulmonary vascular disease provides a major obstacle to the management of many patients with adult congenital heart disease. Elucidation of the signaling pathways that regulate the reversible transition of the vascular smooth-muscle cell phenotype remains an active focus of investigation. Among other mediators, microRNAs have emerged as powerful regulators of this transition, offering new targets for intervention. The activated, phenotypically modulated smooth-muscle cells secrete the bulk of vascular extracellular matrix. Excessive production of collagen and glycosaminoglycans contributes to the remodeling and altered biology and biomechanics of arteries affected by hypertension or atherosclerosis. In larger elastic arteries, the elastin synthesized by smooth-muscle cells serves to maintain not only normal arterial structure but also hemodynamic function. The ability of the larger arteries, such as the aorta, to store the kinetic energy of systole promotes tissue perfusion during diastole. Arterial stiffness associated with aging or disease, as manifested by a widening pulse pressure, increases left ventricular afterload and portends a poor outcome. Like endothelial cells, vascular smooth-muscle cells do not merely respond to vasomotor or inflammatory stimuli elaborated by other cell types but can themselves serve as a source of such stimuli. For example, when exposed to bacterial endotoxin or other proinflammatory stimuli, smooth-muscle cells can elaborate cytokines and other inflammatory mediators. Like endothelial cells, upon inflammatory activation, arterial smoothmuscle cells can produce prothrombotic mediators such as tissue factor, the antifibrinolytic protein PAI-1, and other molecules that modulate thrombosis and fibrinolysis. Smooth-muscle cells also elaborate autocrine growth factors that can amplify hyperplastic responses to arterial injury.

NE, ET-1, Ang II

SECTION I

VDCC PIP2

PLC

K+ Ch

Na-K ATPase

GTP

AC ATP

RhoA

Introduction to Cardiovascular Disorders

IP3R RyrR

IP3

pGC sGC

DAG

BetaAgonist

ANP

Plb ATPase

cGMP

cAMP

PKG

PKA

Calcium

PKC Rho Kinase

MLCK

Caldesmon Calponin

MLCP

Figure 1-3 Regulation of vascular smooth-muscle cell calcium concentration and actomyosin ATPase-dependent contraction. AC, adenylyl cyclase; Ang II, angiotensin II; ANP, antrial natriuretic peptide; DAG, diacylglycerol; ET-1, endothelin-1; G, G-protein; IP3, inositol 1,4,5-trisphosphate; MLCK, myosin light chain kinase; MLCP, myosin light chain phosphatase; NE, norepinephrine; NO, nitric oxide;

pGC, particular guanylyl cyclase; PIP2, phosphatidylinositol 4,5-bisphosphate; PKA, protein kinase A; PKC, protein kinase C; PKG, protein kinase G; PLC, phospholipase C; sGC, soluble guanylyl cyclase; SR, sarcoplasmic reticulum; VDCC, voltage-dependent calcium channel. (Modified from B Berk, in Vascular Medicine, 3rd ed, p 23. Philadelphia, Saunders, Elsevier, 2006; with permission.)

regulated by energy-dependent ion pumps such as the Na+,K+-ATPase pump and ion channels such as the Ca2+-sensitive K+ channel. Local changes in intracellular calcium concentration, termed calcium sparks, result from the influx of calcium through the voltagedependent calcium channel and are caused by the coordinated activation of a cluster of ryanodine-sensitive calcium release channels in the sarcoplasmic reticulum (see later). Calcium sparks directly augment intracellular calcium concentration and indirectly increase intracellular calcium concentration by activating chloride channels. In addition, calcium sparks reduce smoothmuscle contractility by activating large-conductance calcium-sensitive K+ channels, hyperpolarizing the cell membrane and thereby limiting further voltage-dependent increases in intracellular calcium. Biochemical agonists also increase intracellular calcium concentration, in this case by receptor-dependent activation of phospholipase C with hydrolysis of phosphatidylinositol 4,5-bisphosphate, resulting in generation of

diacylglycerol (DAG) and inositol 1,4,5-trisphosphate (IP3). These membrane lipid derivatives in turn activate protein kinase C and increase intracellular calcium concentration. In addition, IP3 binds to specific receptors on the sarcoplasmic reticulum membrane to increase calcium efflux from this calcium storage pool into the cytoplasm. Vascular smooth-muscle cell contraction is controlled principally by the phosphorylation of myosin light chain, which in the steady state depends on the balance between the actions of myosin light chain kinase and myosin light chain phosphatase. Calcium activates myosin light chain kinase through the formation of a calcium-calmodulin complex. Phosphorylation of myosin light chain by this kinase augments myosin ATPase activity and enhances contraction. Myosin light chain phosphatase dephosphorylates myosin light chain, reducing myosin ATPase activity and contractile force. Phosphorylation of the myosin-binding subunit (thr695) of myosin light chain phosphatase by Rho kinase

The tone of vascular smooth-muscle cells is governed by the autonomic nervous system and by the endothelium in tightly regulated control networks. Autonomic neurons enter the blood vessel medial layer from the adventitia and modulate vascular smooth-muscle cell tone in response to baroreceptors and chemoreceptors within the aortic arch and carotid bodies and in response to thermoreceptors in the skin. These regulatory components include rapidly acting reflex arcs modulated by central inputs that respond to sensory inputs (olfactory, visual, auditory, and tactile) as well as emotional stimuli. Three classes of nerves mediate autonomic regulation of vascular tone: sympathetic, whose principal neurotransmitters are epinephrine and norepinephrine; parasympathetic, whose principal neurotransmitter is acetylcholine; and nonadrenergic/noncholinergic, which include two subgroups—nitrergic, whose principal neurotransmitter is NO, and peptidergic, whose principal neurotransmitters are substance P, vasoactive intestinal peptide, calcitonin gene-related peptide, and ATP.

Basic Biology of the Cardiovascular System

Control of vascular smooth-muscle cell tone

Each of these neurotransmitters acts through spe- 7 cific receptors on the vascular smooth-muscle cell to modulate intracellular calcium and, consequently, contractile tone. Norepinephrine activates α receptors, and epinephrine activates α and β receptors (adrenergic receptors); in most blood vessels, norepinephrine activates postjunctional α1 receptors in large arteries and α2 receptors in small arteries and arterioles, leading to vasoconstriction. Most blood vessels express β2-adrenergic receptors on their vascular smooth-muscle cells and respond to β agonists by cyclic AMP–dependent relaxation. Acetylcholine released from parasympathetic neurons binds to muscarinic receptors (of which there are five subtypes, M1–5) on vascular smooth-muscle cells to yield vasorelaxation. In addition, NO stimulates presynaptic neurons to release acetylcholine, which can stimulate the release of NO from the endothelium. Nitrergic neurons release NO produced by neuronal NO synthase, which causes vascular smooth-muscle cell relaxation via the cyclic GMP–dependent and –independent mechanisms described earlier. The peptidergic neurotransmitters all potently vasodilate, acting either directly or through endothelium-dependent NO release to decrease vascular smooth-muscle cell tone. The endothelium modulates vascular smooth-muscle tone by the direct release of several effectors, including NO, prostacyclin, hydrogen sulfide, and endothelium- derived hyperpolarizing factor, all of which cause vasorelaxation, and endothelin, which causes vasoconstriction. The release of these endothelial effectors of vascular smooth-muscle cell tone is stimulated by mechanical (shear stress, cyclic strain, etc.) and biochemical mediators (purinergic agonists, muscarinic agonists, peptidergic agonists), with the biochemical mediators acting through endothelial receptors specific to each class. In addition to these local paracrine modulators of vascular smooth-muscle cell tone, circulating mediators can affect tone, including norepinephrine and epinephrine, vasopressin, angiotensin II, bradykinin, and the natriuretic peptides (ANP, BNP, CNP, and DNP), as discussed earlier.

CHAPTER 1

inhibits phosphatase activity and induces calcium sensitization of the contractile apparatus. Rho kinase is itself activated by the small GTPase RhoA, which is stimulated by guanosine exchange factors and inhibited by GTPase-activating proteins. Both cyclic AMP and cyclic GMP relax vascular smooth-muscle cells through complex mechanisms. β agonists, acting through their G-protein-coupled receptors activate adenylyl cyclase to convert ATP to cyclic AMP; NO and atrial natriuretic peptide acting directly and via a G-protein-coupled receptor, respectively, activate guanylyl cyclase to convert GTP to cyclic GMP. These agents in turn activate protein kinase A and protein kinase G, respectively, which inactivate myosin light chain kinase and decrease vascular smooth-muscle cell tone. In addition, protein kinase G can interact directly with the myosin-binding substrate subunit of myosin light chain phosphatase, increasing phosphatase activity and decreasing vascular tone. Finally, several mechanisms drive NO-dependent, protein kinase G–mediated reductions in vascular smooth-muscle cell calcium concentration, including phosphorylation-dependent inactivation of RhoA; decreased IP3 formation; phosphorylation of the IP3 receptor–associated cyclic GMP kinase substrate, with subsequent inhibition of IP3 receptor function; phosphorylation of phospholamban, which increases calcium ATPase activity and sequestration of calcium in the sarcoplasmic reticulum; and protein kinase G–dependent stimulation of plasma membrane calcium ATPase activity, perhaps by activation of the Na+,K+-ATPase pump or hyperpolarization of the cell membrane by activation of calcium-dependent K+ channels.

Vascular Regeneration Growth of new blood vessels can occur in response to conditions such as chronic hypoxemia and tissue ischemia. Growth factors, including vascular endothelial growth factor (VEGF) and forms of fibroblast growth factor (FGF), activate a signaling cascade that stimulates endothelial proliferation and tube formation, defined as angiogenesis. The development of collateral vascular networks in the ischemic myocardium reflects this process and can result from selective activation of endothelial progenitor cells, which may reside in the blood vessel wall or home to the ischemic tissue

Table 1-2 Genetic Polymorphisms in Vascular Function and Disease Risk

SECTION I

Gene

Introduction to Cardiovascular Disorders

Polymorphic Allele

Clinical Implications

`1A

Arg492Cys

None

`2B

Glu9/G1712

Increased CHD events

`2C

A2cDcl3232-325

Ethnic differences in risk of hypertension or heart failure

Angiotensin-converting enzyme (ACE)

Insertion/deletion polymorphism in intron 16

D allele or DD genotype-increased response to ACE inhibitors; inconsistent data for increased risk of atherosclerotic heart disease, and hypertension

Ang II type I receptor

1166A → C Ala-Cys

Increased response to Ang II and increased risk of pregnancy- associated hypertension

Ser49Gly

Increased HR and DCM risk

Arg389Gly

Increased heart failure in blacks

Arg16Gly

Familial hypertension, increased obesity risk

Glu27Gln

Hypertension in white type II diabetics

Thr164Ile

Decreased agonist affinity and worse HF outcome

B2-Bradykinin receptor

Cys58Thr, Cys412Gly, Thr21Met

Increased risk of hypertension in some ethnic groups

Endothelial nitric oxide synthase (eNOS)

Nucleotide repeats in introns 4 and 13, Glu298Asp

Increased MI and venous thrombosis

Thr785Cys

Early coronary artery disease

`-Adrenergic Receptors

a-Adrenergic Receptors β1

β2

Abbreviations: CHD, coronary heart disease; HR, heart rate; DCM, dilated cardiomyopathy; HF, heart failure; MI, myocardial infarction. Source: Derived from B Schaefer et al: Heart Dis 5:129, 2003.

subtended by an occluded or severely stenotic vessel from the bone marrow. True arteriogenesis, or the development of a new blood vessel that includes all three cell layers, normally does not occur in the cardiovascular system of adult mammals. The molecular mechanisms and progenitor cells that can recapitulate blood vessel development de novo are under rapidly advancing study.

with differences in vascular response often (but not invariably) relate to functional differences in the activity or expression of the receptor or enzyme of interest. Some of these polymorphisms appear to have different allele frequencies in specific ethnic groups. A summary of recently identified polymorphisms defining these vascular pharmacogenomic differences is provided in Table 1-2.

Vascular Pharmacogenomics The last decade has witnessed considerable progress in efforts to define the genetic differences underlying individual variations in vascular pharmacologic responses. Many investigators have focused on receptors and enzymes associated with neurohumoral modulation of vascular function as well as hepatic enzymes that metabolize drugs that affect vascular tone. The genetic polymorphisms thus far associated

Cellular Basis of Cardiac Contraction Cardiac Ultrastructure About three-fourths of the ventricular mass is composed of cardiomyocytes, normally 60–140 μm in length and 17–25 μm in diameter (Fig. 1-4A). Each cell contains multiple, rodlike cross-banded strands (myofibrils) that

CHAPTER 1

Myofiber A

Myocyte

10 µm

Ca2+ enters Ca2+ Pump Ca2+ “trigger”

Myofibril

Myocy te

T tubule

Ca2+ leaves Free Ca2+

Myofibril Mitochondrion

Contract Relax

Systole Myofibril

Z C

Diastole

Actin

Head

Titin

Myosin M

43 nm

Figure 1-4 A shows the branching myocytes making up the cardiac myofibers. B illustrates the critical role played by the changing [Ca2+] in the myocardial cytosol. Ca2+ ions are schematically shown as entering through the calcium channel that opens in response to the wave of depolarization that travels along the sarcolemma. These Ca2+ ions “trigger” the release of more calcium from the sarcoplasmic reticulum (SR) and thereby initiate a contraction-relaxation cycle. Eventually, the small quantity of Ca2+ that has entered the cell leaves predominantly through an Na+/Ca2+ exchanger, with a lesser role for the sarcolemmal Ca2+ pump. The varying actin-myosin overlap is shown for (B) systole, when [Ca2+] is maximal, and (C) diastole, when [Ca2+] is minimal. D. The myosin heads, attached to the thick filaments, interact with the thin actin filaments. (From LH Opie, HeartPhysiology, reprinted with permission. Copyright LH Opie, 2004.)

run the length of the cell and are composed of serially repeating structures, the sarcomeres. The cytoplasm between the myofibrils contains other cell constituents, including the single centrally located nucleus, numerous mitochondria, and the intracellular membrane system, the sarcoplasmic reticulum. The sarcomere, the structural and functional unit of contraction, lies between adjacent Z lines, which are dark repeating bands that are apparent on transmission electron microscopy. The distance between Z lines varies with the degree of contraction or stretch of the muscle and ranges between 1.6 and 2.2 μm. Within the confines of the sarcomere are alternating light and dark bands, giving the myocardial fibers their striated appearance under the light microscope. At the center of the sarcomere is a dark band of constant length

(1.5 μm), the A band, which is flanked by two lighter bands, the I bands, which are of variable length. The sarcomere of heart muscle, like that of skeletal muscle, consists of two sets of interdigitating myofilaments. Thicker filaments, composed principally of the protein myosin, traverse the A band; they are about 10 nm (100 Å) in diameter, with tapered ends. Thinner filaments, composed primarily of actin, course from the Z lines through the I band into the A band; they are approximately 5 nm (50 Å) in diameter and 1.0 μm in length. Thus, thick and thin filaments overlap only within the (dark) A band, whereas the (light) I band contains only thin filaments. On electron-microscopic examination, bridges may be seen to extend between the thick and thin filaments within the A band; these are myosin heads bound to actin filaments.

Basic Biology of the Cardiovascular System

Na+ Exchange

SECTION I Introduction to Cardiovascular Disorders

molecules are laid down in an orderly, polarized manner, leaving the globular portions projecting outward so that they can interact with actin to generate force and shortening (Fig. 1-4B). Actin has a molecular mass of about 47,000 Da. The thin filament consists of a double helix of two chains of actin molecules wound about each other on a larger molecule, tropomyosin. A group of regulatory proteins—troponins C, I, and T—are spaced at regular intervals on this filament (Fig. 1-5). In contrast to myosin, actin lacks intrinsic enzymatic activity but does combine reversibly with myosin in the presence of ATP and Ca2+. The calcium ion activates the myosin ATPase, which in turn breaks down ATP, the energy source for contraction (Fig. 1-5). The activity of myosin ATPase determines the rate of forming and breaking of the actomyosin cross-bridges and ultimately the velocity of muscle contraction. In relaxed muscle, tropomyosin inhibits this interaction. Titin (Fig. 1-4D) is a large,

The Contractile Process The sliding filament model for muscle contraction rests on the fundamental observation that both the thick and the thin filaments are constant in overall length during both contraction and relaxation. With activation, the actin filaments are propelled farther into the A band. In the process, the A band remains constant in length, whereas the I band shortens and the Z lines move toward one another. The myosin molecule is a complex, asymmetric fibrous protein with a molecular mass of about 500,000 Da; it has a rodlike portion that is about 150 nm (1500 Å) in length with a globular portion (head) at its end. These globular portions of myosin form the bridges between the myosin and actin molecules and are the site of ATPase activity. In forming the thick myofilament, which is composed of ∼300 longitudinally stacked myosin molecules, the rodlike segments of the myosin

ADP

ATP

1. ATP hydrolysis

Relaxed 4. Dissociation of

Relaxed, energized Actin

Actin

actin and myosin

ATP

2. Formation of active complex Pi

ADP

3. Product dissociation Rigor complex

Figure 1-5 Four steps in cardiac muscle contraction and relaxation. In relaxed muscle (upper left), ATP bound to the myosin cross-bridge dissociates the thick and thin filaments. Step 1: Hydrolysis of myosin-bound ATP by the ATPase site on the myosin head transfers the chemical energy of the nucleotide to the activated cross-bridge (upper right). When cytosolic Ca2+ concentration is low, as in relaxed muscle, the reaction cannot proceed because tropomyosin and the troponin complex on the thin filament do not allow the active sites on actin to interact with the cross-bridges. Therefore, even though the cross-bridges are energized, they cannot interact with actin. Step 2: When Ca2+ binding to troponin C has exposed active sites on the thin filament, actin interacts with the myosin cross-bridges to form an active complex (lower right) in which the energy derived from ATP is retained in the actin-bound cross-bridge, whose orientation

Active complex

has not yet shifted. Step 3: The muscle contracts when ADP dissociates from the cross-bridge. This step leads to the formation of the low-energy rigor complex (lower left) in which the chemical energy derived from ATP hydrolysis has been expended to perform mechanical work (the “rowing” motion of the cross-bridge). Step 4: The muscle returns to its resting state, and the cycle ends when a new molecule of ATP binds to the rigor complex and dissociates the cross-bridge from the thin filament. This cycle continues until calcium is dissociated from troponin C in the thin filament, which causes the contractile proteins to return to the resting state with the cross-bridge in the energized state. ATP, adenosine triphosphate; ATPase, adenosine triphosphatase; ADP, adenosine diphosphate. (From AM Katz: Heart failure: Cardiac function and dysfunction, in Atlas of Heart Diseases, 3rd ed, WS Colucci [ed]. Philadelphia, Current Medicine, 2002. Reprinted with permission.)

into the myocardial fiber along the Z lines, i.e., the ends of the sarcomeres.

Cardiac Activation

Basic Biology of the Cardiovascular System

In the inactive state, the cardiac cell is electrically polarized; i.e., the interior has a negative charge relative to the outside of the cell, with a transmembrane potential of −80 to −100 mV (Chap. 14). The sarcolemma, which in the resting state is largely impermeable to Na+, has a Na+- and K+-stimulating pump energized by ATP that extrudes Na+ from the cell; this pump plays a critical role in establishing the resting potential. Thus, intracellular [K+] is relatively high and [Na+] is far lower; conversely, extracellular [Na+] is high and [K+] is low. At the same time, in the resting state, extracellular [Ca2+] greatly exceeds free intracellular [Ca2+]. The action potential has four phases (Fig. 14-1B). During the plateau of the action potential (phase 2), there is a slow inward current through L-type Ca2+ channels in the sarcolemma (Fig. 1-7). The depolarizing current not only extends across the surface of the cell but penetrates deeply into the cell by way of the ramifying T tubular system. The absolute quantity of Ca2+ that crosses the sarcolemma and the T system is relatively small and by itself appears to be insufficient to bring about full activation of the contractile apparatus. However, this Ca2+ current triggers the release of much larger quantities of Ca2+ from the SR, a process termed Ca2+-induced Ca2+ release. The latter is a major determinant of intracytoplasmic [Ca2+] and therefore of myocardial contractility. Ca2+ is released from the SR through a Ca2+ release channel, a cardiac isoform of the ryanodine receptor (RyR2), which controls intracytoplasmic [Ca2+] and, as in vascular smooth-muscle cells, leads to the local changes in intracellular [Ca2+] called calcium sparks. A number of regulatory proteins, including calstabin 2, inhibit RyR2 and thereby the release of Ca2+ from the SR. PKA dissociates calstabin from the RyR2, enhancing Ca2+ release and thereby myocardial contractility. Excessive plasma catecholamine levels and cardiac sympathetic neuronal release of norepinephrine cause hyperphosphorylation of PKA, leading to calstabin 2–depleted RyR2. The latter depletes SR Ca2+ stores and thereby impairs cardiac contraction, leading to heart failure, and also triggers ventricular arrhythmias. The Ca2+ released from the SR then diffuses toward the myofibrils, where, as already described, it combines with troponin C (Fig. 1-6). By repressing this inhibitor of contraction, Ca2+ activates the myofilaments to shorten. During repolarization, the activity of the Ca2+ pump in the SR, the SR Ca2+ ATPase (SERCA2A), reaccumulates Ca2+ against a concentration gradient, and the Ca2+ is stored in the SR by its attachment to a protein, calsequestrin.

CHAPTER 1

flexible, myofibrillar protein that connects myosin to the Z line; its stretching contributes to the elasticity of the heart. Dystrophin is a long cytoskeletal protein that has an amino-terminal actin-binding domain and a carboxy-terminal domain that binds to the dystroglycan complex at adherens junctions on the cell membrane, thus tethering the sarcomere to the cell membrane at regions tightly coupled to adjacent contracting myocytes. Mutations in components of the dystrophin complex lead to muscular dystrophy and associated cardiomyopathy. During activation of the cardiac myocyte, Ca2+ becomes attached to one of three components of the heterotrimer troponin C, which results in a conformational change in the regulatory protein tropomyosin; the latter, in turn, exposes the actin cross-bridge interaction sites (Fig. 1-5). Repetitive interaction between myosin heads and actin filaments is termed cross-bridge cycling, which results in sliding of the actin along the myosin filaments, ultimately causing muscle shortening and/or the development of tension. The splitting of ATP then dissociates the myosin cross-bridge from actin. In the presence of ATP (Fig. 1-5), linkages between actin and myosin filaments are made and broken cyclically as long as sufficient Ca2+ is present; these linkages cease when [Ca2+] falls below a critical level, and the troponin-tropomyosin complex once more prevents interactions between the myosin cross-bridges and actin filaments (Fig. 1-6). Intracytoplasmic Ca2+ is a principal determinant of the inotropic state of the heart. Most agents that stimulate myocardial contractility (positive inotropic stimuli), including the digitalis glycosides and β-adrenergic agonists, increase the [Ca2+] in the vicinity of the myofilaments, which in turn triggers cross-bridge cycling. Increased impulse traffic in the cardiac adrenergic nerves stimulates myocardial contractility as a consequence of the release of norepinephrine from cardiac adrenergic nerve endings. Norepinephrine activates myocardial β receptors and, through the Gs-stimulated guanine nucleotide-binding protein, activates the enzyme adenylyl cyclase, which leads to the formation of the intracellular second messenger cyclic AMP from ATP (Fig. 1-6). Cyclic AMP in turn activates protein kinase A (PKA), which phosphorylates the Ca2+ channel in the myocardial sarcolemma, thereby enhancing the influx of Ca2+ into the myocyte. Other functions of PKA are discussed later. The sarcoplasmic reticulum (SR) (Fig. 1-7), a complex network of anastomosing intracellular channels, invests the myofibrils. Its longitudinally disposed tubules closely invest the surfaces of individual sarcomeres but have no direct continuity with the outside of the cell. However, closely related to the SR, both structurally and functionally, are the transverse tubules, or T system, formed by tubelike invagin*tions of the sarcolemma that extend

Ca2+

β - Adrenergic agonist

SECTION I

β αs

Adenyl cyclase

Ca2+ +

cAMP

Via protein kinase A

Metabolic • glycolysis • lipolysis • citrate cycle

Ca2+ ADP + Pi + ATP

Troponin C + 2

Myosin ATPase +

ADP + Pi

cAMP via Tnl cAMP via PL

Increased 1. rate of contraction 2. peak force 3. rate of relaxation

+ Control

Force

Introduction to Cardiovascular Disorders

GTP

β Receptor

Time

Pattern of contraction

Figure 1-6 Signal systems involved in positive inotropic and lusitropic (enhanced relaxation) effects of a-adrenergic stimulation. When the β-adrenergic agonist interacts with the β receptor, a series of G protein–mediated changes leads to activation of adenylyl cyclase and the formation of cyclic adenosine monophosphate (cAMP). The latter acts via protein kinase A to stimulate metabolism (left) and phosphorylate the Ca2+ channel protein (right). The result is an enhanced opening probability of the Ca2+ channel, thereby increasing the inward movement of Ca2+ ions through the sarcolemma (SL) of the T tubule. These Ca2+ ions release more calcium from the sarcoplasmic reticulum (SR) to increase cytosolic Ca2+ and activate troponin C. Ca2+ ions

also increase the rate of breakdown of adenosine triphosphate (ATP) to adenosine diphosphate (ADP) and inorganic phosphate (Pi). Enhanced myosin ATPase activity explains the increased rate of contraction, with increased activation of troponin C explaining increased peak force development. An increased rate of relaxation is explained by the fact that cAMP also activates the protein phospholamban, situated on the membrane of the SR, that controls the rate of uptake of calcium into the SR. The latter effect explains enhanced relaxation (lusitropic effect). P, phosphorylation; PL, phospholamban; TnI, troponin I. (Modified from LH Opie, Heart Physiology, reprinted with permission. Copyright LH Opie, 2004.)

This reaccumulation of Ca2+ is an energy (ATP)-requiring process that lowers the cytoplasmic [Ca2+] to a level that inhibits the actomyosin interaction responsible for contraction, and in this manner leads to myocardial relaxation. Also, there is an exchange of Ca2+ for Na+ at the sarcolemma (Fig. 1-7), reducing the cytoplasmic [Ca2+]. Cyclic AMP–dependent PKA phosphorylates the SR protein phospholamban; the latter, in turn, permits activation of the Ca2+ pump, thereby increasing the uptake of Ca2+ by the SR, accelerating

the rate of relaxation and providing larger quantities of Ca2+ in the SR for release by subsequent depolarization, thereby stimulating contraction. Thus, the combination of the cell membrane, transverse tubules, and SR, with their ability to transmit the action potential and release and then reaccumulate Ca2+, plays a fundamental role in the rhythmic contraction and relaxation of heart muscle. Genetic or pharmacologic alterations of any component, whatever its etiology, can disturb these functions.

Na+/Ca2+ exchanger B1

Plasma membrane Ca2+ pump B2 Extracellular

T tubule

Plasma membrane Ca2+ channel

Intracellular (cytosol)

Cisterna

Sarcoplasmic reticulum

Ca2+release channel ('foot' protein)

Plasma membrane

G Calsequestrin C

Sarcoplasmic reticulum Ca2+ pump

Mitochondria

D H

The extent of shortening of heart muscle and, therefore, the stroke volume of the ventricle in the intact heart depend on three major influences: (1) the length of the muscle at the onset of contraction, i.e., the preload; (2) the tension that the muscle is called on to develop during contraction, i.e., the afterload; and (3) the contractility of the muscle, i.e., the extent and velocity of shortening at any given preload and afterload. The major determinants of preload, afterload, and contractility are shown in Table 1-3. The role of muscle length (preload)

Z-line

Troponin C

The preload determines the length of the sarcomeres at the onset of contraction. The length of the sarcomeres associated with the most forceful contraction is Thin filament

Thick filament

Contractile proteins

Figure 1-7 The Ca2+ fluxes and key structures involved in cardiac excitation-contraction coupling. The arrows denote the direction of Ca2+ fluxes. The thickness of each arrow indicates the magnitude of the calcium flux. Two Ca2+ cycles regulate excitation-contraction coupling and relaxation. The larger cycle is entirely intracellular and involves Ca2+ fluxes into and out of the sarcoplasmic reticulum, as well as Ca2+ binding to and release from troponin C. The smaller extracellular Ca2+ cycle occurs when this cation moves into and out of the cell. The action potential opens plasma membrane Ca2+ channels to allow passive entry of Ca2+ into the cell from the extracellular fluid (arrow A). Only a small portion of the Ca2+ that enters the cell directly activates the contractile proteins (arrow A1). The extracellular cycle is completed when Ca2+ is actively transported back out to the extracellular fluid by way of two plasma membrane fluxes mediated by the sodium-calcium exchanger (arrow B1) and the plasma membrane calcium pump (arrow B2). In the intracellular Ca2+ cycle, passive Ca2+ release occurs through channels in the cisternae (arrow C) and initiates contraction; active Ca2+ uptake by the Ca2+ pump of the sarcotubular network (arrow D) relaxes the heart. Diffusion of Ca2+ within the sarcoplasmic reticulum (arrow G) returns this activator cation to the cisternae, where it is stored in a complex with calsequestrin and other calcium-binding proteins. Ca2+ released from the sarcoplasmic reticulum initiates systole when it binds to troponin C (arrow E). Lowering of cytosolic [Ca2+] by the sarcoplasmic reticulum (SR) causes this ion to dissociate from troponin (arrow F) and relaxes the heart. Ca2+ also may move between mitochondria and cytoplasm (H). (Adapted from AM Katz: Physiology of the Heart, 4th ed. Philadelphia, Lippincott, Williams & Wilkins, 2005; with permission.)

Table 1-3 Determinants of Stroke Volume I. Ventricular Preload A. Blood volume B. Distribution of blood volume 1. Body position 2. Intrathoracic pressure 3. Intrapericardial pressure 4. Venous tone 5. Pumping action of skeletal muscles C. Atrial contraction II. Ventricular Afterload A. Systemic vascular resistance B. Elasticity of arterial tree C. Arterial blood volume D. Ventricular wall tension 1. Ventricular radius 2. Ventricular wall thickness III. Myocardial Contractilitya A. Intramyocardial [Ca2+] ↑↓ B. Cardiac adrenergic nerve activity ↑↓b C. Circulating catecholamines ↑↓b D. Cardiac rate ↑↓b E. Exogenous inotropic agents↑ F. Myocardial ischemia ↓ G. Myocardial cell death (necrosis, apoptosis, autophagy) ↓ H. Alterations of sarcomeric and cytoskeletal proteins ↓ 1. Genetic 2. Hemodynamic overload I. Myocardial fibrosis ↓ J. Chronic overexpression of neurohormones ↓ K. Ventricular remodeling ↓ L. Chronic and/or excessive myocardial hypertrophy ↓ a

Arrows indicate directional effects of determinants of contractility. Contractility rises initially but later becomes depressed.

Basic Biology of the Cardiovascular System

Sarcotubular network A1

Control of Cardiac Performance and Output

CHAPTER 1

Na+ pump

SECTION I Introduction to Cardiovascular Disorders

∼2.2 μm. This length provides the optimum configuration for the interaction between the two sets of myofilaments. The length of the sarcomere also regulates the extent of activation of the contractile system, i.e., its sensitivity to Ca2+. According to this concept, termed length-dependent activation, myofilament sensitivity to Ca2+ is also maximal at the optimal sarcomere length. The relation between the initial length of the muscle fibers and the developed force has prime importance for the function of heart muscle. This relationship forms the basis of Starling’s law of the heart, which states that within limits, the force of ventricular contraction depends on the end-diastolic length of the cardiac muscle; in the intact heart, the latter relates closely to the ventricular end-diastolic volume. Cardiac performance The ventricular end-diastolic or “filling” pressure sometimes is used as a surrogate for the end-diastolic volume. In isolated heart and heart-lung preparations, the stroke volume varies directly with the end-diastolic fiber length (preload) and inversely with the arterial resistance (afterload), and as the heart fails—i.e., as its contractility declines—it delivers a progressively smaller stroke volume from a normal or even elevated end-diastolic volume. The relation between the ventricular enddiastolic pressure and the stroke work of the ventricle (the ventricular function curve) provides a useful definition of the level of contractility of the heart in the intact organism. An increase in contractility is accompanied by a shift of the ventricular function curve upward and to the left (greater stroke work at any level of ventricular end-diastolic pressure, or lower end-diastolic volume at any level of stroke work), whereas a shift downward and to the right characterizes depression of contractility (Fig. 1-8). Ventricular afterload In the intact heart, as in isolated cardiac muscle, the extent and velocity of shortening of ventricular muscle fibers at any level of preload and of myocardial contractility relate inversely to the afterload, i.e., the load that opposes shortening. In the intact heart, the afterload may be defined as the tension developed in the ventricular wall during ejection. Afterload is determined by the aortic pressure as well as by the volume and thickness of the ventricular cavity. Laplace’s law states that the tension of the myocardial fiber is the product of the intracavitary ventricular pressure and ventricular radius divided by wall thickness. Therefore, at any particular level of aortic pressure, the afterload on a dilated left ventricle exceeds that on a normal-sized ventricle. Conversely, at the same aortic pressure and ventricular diastolic volume, the afterload on a hypertrophied ventricle is lower that of a normal chamber. The aortic

Maximal activity

Normal-exercise

C 1

Ventricular performance

Normal-rest

Contractile state of myocardium Walking B

3 3′

Rest

Exercise Heart failure

A E

Dyspnea

Fatal myocardial depression

Pulmonary edema Ventricular EDV

Stretching of myocardium

Figure 1-8 The interrelations among influences on ventricular enddiastolic volume (EDV) through stretching of the myocardium and the contractile state of the myocardium. Levels of ventricular EDV associated with filling pressures that result in dyspnea and pulmonary edema are shown on the abscissa. Levels of ventricular performance required when the subject is at rest, while walking, and during maximal activity are designated on the ordinate. The broken lines are the descending limbs of the ventricular-performance curves, which are rarely seen during life but show the level of ventricular performance if end-diastolic volume could be elevated to very high levels. For further explanation, see text. (Modified from WS Colucci and E Braunwald: Pathophysiology of heart failure, in Braunwald’s Heart Disease, 7th ed, DP Zipes et al [eds]. Philadelphia: Elsevier, 2005, pp 509–538.)

pressure in turn depends on the peripheral vascular resistance, the physical characteristics of the arterial tree, and the volume of blood it contains at the onset of ejection. Ventricular afterload critically regulates cardiovascular performance (Fig. 1-9). As already noted, elevations in both preload and contractility increase myocardial fiber shortening, whereas increases in afterload reduce it. The extent of myocardial fiber shortening and left ventricular size determine stroke volume. An increase in arterial pressure induced by vasoconstriction, for example, augments afterload, which opposes myocardial fiber shortening, reducing stroke volume. When myocardial contractility becomes impaired and the ventricle dilates, afterload rises (Laplace’s law) and limits cardiac output. Increased afterload also may result from neural and humoral stimuli that occur in response to a fall in cardiac output. This increased afterload may reduce cardiac output further, thereby increasing ventricular volume and initiating a vicious circle, especially in patients with ischemic heart disease and limited myocardial O2 supply. Treatment with vasodilators has the

Venous return

Preload

Stroke volume

Afterload

Heart rate

Cardiac output Peripheral resistance

Carotid and aortic pressoreceptors

Higher nervous centers

Figure 1-9 Interactions in the intact circulation of preload, contractility, and afterload in producing stroke volume. Stroke volume combined with heart rate determines cardiac output, which, when combined with peripheral vascular resistance, determines arterial pressure for tissue perfusion. The characteristics of the arterial system also contribute to afterload, an increase which reduces stroke volume. The interaction of these components with carotid and aortic arch baroreceptors provides a feedback mechanism to higher medullary and vasomotor cardiac centers and to higher levels in the central nervous system to effect a modulating influence on heart rate, peripheral vascular resistance, venous return, and contractility. (From MR Starling: Physiology of myocardial contraction, in Atlas of Heart Failure: Cardiac Function and Dysfunction, 3rd ed, WS Colucci and E Braunwald [eds]. Philadelphia: Current Medicine, 2002, pp 19–35.)

opposite effect; when afterload is reduced, cardiac output rises (Chap. 17). Under normal circ*mstances, the various influences acting on cardiac performance enumerated earlier interact in a complex fashion to maintain cardiac output at a level appropriate to the requirements of the metabolizing tissues (Fig. 1-9); interference with a single mechanism may not influence the cardiac output. For example, a moderate reduction of blood volume or the loss of the atrial contribution to ventricular contraction ordinarily can be sustained without a reduction in the cardiac output at rest. Under these circ*mstances, other factors, such as increases in the frequency of adrenergic nerve impulses to the heart, heart rate, and venous tone, will serve as compensatory mechanisms and sustain cardiac output in a normal individual. Exercise The integrated response to exercise illustrates the interactions among the three determinants of stroke volume:

Assessment of Cardiac Function Several techniques can define impaired cardiac function in clinical practice. The cardiac output and stroke volume may be depressed in the presence of heart failure, but not uncommonly, these variables are within normal limits in this condition. A somewhat more sensitive index of cardiac function is the ejection fraction, i.e., the ratio of stroke volume to enddiastolic volume (normal value = 67 ± 8%), which is frequently depressed in systolic heart failure even when the stroke volume itself is normal. Alternatively, abnormally elevated ventricular end-diastolic volume (normal value = 75 ± 20 mL/m2) or end-systolic volume (normal value = 25 ± 7 mL/m2) signifies impairment of left ventricular systolic function. Noninvasive techniques, particularly echocardiography as well as radionuclide scintigraphy and cardiac magnetic resonance imaging (MRI) (Chap. 12), have great value in the clinical assessment of myocardial function. They provide measurements of end-diastolic and end-systolic volumes, ejection fraction, and systolic shortening rate, and they allow assessment of ventricular filling (see later) as well as regional contraction and relaxation. The latter measurements are particularly important in ischemic heart disease, as myocardial infarction causes regional myocardial damage. A limitation of measurements of cardiac output, ejection fraction, and ventricular volumes in assessing cardiac function is that ventricular loading conditions strongly influence these variables. Thus, a depressed ejection fraction and lowered cardiac output may be observed in patients with normal ventricular function but reduced preload, as occurs in hypovolemia, or with increased afterload, as occurs in acutely elevated arterial pressure.

Basic Biology of the Cardiovascular System

Medullary vasomotor and cardiac centers

Arterial pressure

CHAPTER 1

Contractility

preload, afterload, and contractility (Fig. 1-8). Hyperventilation, the pumping action of the exercising muscles, and venoconstriction during exercise all augment venous return and hence ventricular filling and preload (Table 1-3). Simultaneously, the increase in the adrenergic nerve impulse traffic to the myocardium, the increased concentration of circulating catecholamines, and the tachycardia that occur during exercise combine to augment the contractility of the myocardium (Fig. 1-8, curves 1 and 2) and together elevate stroke volume and stroke work, without a change in or even a reduction of end-diastolic pressure and volume (Fig. 1-8, points A and B). Vasodilation occurs in the exercising muscles, thus tending to limit the increase in arterial pressure that otherwise would occur as cardiac output rises to levels as high as five times greater than basal levels during maximal exercise. This vasodilation ultimately allows the achievement of a greatly elevated cardiac output during exercise at an arterial pressure only moderately higher than in the resting state.

Normal contractility

ESPVR

Introduction to Cardiovascular Disorders

LV volume

2 1 3

LV volume

Figure 1-10 The responses of the left ventricle to increased afterload, increased preload, and increased and reduced contractility are shown in the pressure-volume plane. Left. Effects of increases in preload and afterload on the pressure-volume loop. Since there has been no change in contractility, ESPVR (the end-systolic pressure-volume relation) is unchanged. With an increase in afterload, stroke volume falls (1 → 2); with an increase in preload, stroke volume rises (1 → 3). Right. With increased myocardial contractility and constant LV end-diastolic volume, the ESPVR moves to the left of the normal line (lower end-systolic volume at any end-systolic pressure) and stroke volume rises (1 → 3). With reduced myocardial contractility, the ESPVR moves to the right; endsystolic volume is increased, and stroke volume falls (1 → 2).

The end-systolic left ventricular pressure-volume relationship is a particularly useful index of ventricular performance since it does not depend on preload and afterload (Fig. 1-10). At any level of myocardial contractility, left ventricular end-systolic volume varies inversely with end-systolic pressure; as contractility declines, end-systolic volume (at any level of end-systolic pressure) rises.

Diastolic Function Ventricular filling is influenced by the extent and speed of myocardial relaxation, which in turn depends on the rate of uptake of Ca2+ by the SR; the latter may be enhanced by adrenergic activation and reduced by ischemia, which reduces the ATP available for pumping Ca2+ into the SR (see earlier). The stiffness of the ventricular wall also may impede filling. Ventricular stiffness increases with hypertrophy and conditions that infiltrate the ventricle, such as amyloid, or is caused by an extrinsic constraint (e.g., pericardial compression) (Fig. 1-11). Ventricular filling can be assessed by continuously measuring the velocity of flow across the mitral valve, using Doppler ultrasound. Normally, the velocity of inflow is more rapid in early diastole than during atrial systole; with mild to moderately impaired relaxation, the rate of early diastolic filling declines, whereas the

Left ventricular pressure

LV pressure

SECTION I

preload 2

Pericardial restraint

Increased chamber stiffness

Chamber dilation

Contractility

afterload

Abnormal relaxation

Contractility

Left ventricular volume

Figure 1-11 Mechanisms that cause diastolic dysfunction reflected in the pressure-volume relation. The bottom half of the pressure-volume loop is depicted. Solid lines represent normal subjects; broken lines represent patients with diastolic dysfunction. (From JD Carroll et al: The differential effects of positive inotropic and vasodilator therapy on diastolic properties in patients with congestive cardiomyopathy. Circulation 74:815, 1986; with permission.)

rate of presystolic filling rises. With further impairment of filling, the pattern is “pseudo-normalized,” and early ventricular filling becomes more rapid as left atrial pressure upstream to the stiff left ventricle rises.

Cardiac Metabolism The heart requires a continuous supply of energy (in the form of ATP) not only to perform its mechanical pumping functions, but also to regulate intracellular and transsarcolemmal ionic movements and concentration gradients. Among its pumping functions, the development of tension, the frequency of contraction, and the level of myocardial contractility are the principal determinants of the heart’s substantial energy needs, making its O2 requirements approximately 15% of that of the entire organism. Most ATP production depends on the oxidation of substrate (glucose and free fatty acids [FFAs]). Myocardial FFAs are derived from circulating FFAs, which result principally from lipolysis in adipose tissue, whereas the myocyte’s glucose derives from plasma as well as from the cell’s breakdown of its glycogen stores (glycogenolysis). These two principal sources of acetyl coenzyme A in cardiac muscle vary reciprocally. Glucose is broken down in the cytoplasm into a three-carbon product, pyruvate, which passes into the

The heart is the first organ to form during embryogenesis (Fig. 1-12) and must accomplish the simultaneous challenges of circulating blood, nutrients, and oxygen to the other forming organs while continuing to grow

Basic Biology of the Cardiovascular System

Developmental biology of the cardiovascular system

and undergo complex morphogenetic changes. Early progenitors of the heart arise within very early crescentshaped fields of lateral splanchnic mesoderm under the influence of multiple signals, including those derived from neural ectoderm long before neural tube closure. Early cardiac precursors express regulatory transcription factors that play reiterated roles in cardiac development, such as NKX2-5 and GATA4; these mutations are responsible for some forms of inherited congenital heart disease. Early cardiac precursors form two bilateral heart tubes, each composed of a single cell layer of endocardium surrounded by a single layer of myocardial precursors. Subsequently, a single midline heart tube is formed by the medial migration and midline fusion of these bilateral structures. The caudal, inflow region of the heart tube adopts a more rostral final position and represents the atrial anlagen, whereas the rostral, outflow portion of the tube forms the truncus arteriosus, which divides to produce the aorta and the proximal pulmonary artery. Between these extremes lie the structural precursors of the ventricles. The linear heart tube undergoes an asymmetric looping process (the first gross evidence of left-right asymmetry in the developing embryo), which positions the portion of the heart tube destined to become the left ventricle to the left of the more rostral precursors of the right ventricle and outflow tract. Looping is coordinated with chamber specification and ballooning of various regions of the heart tube to produce the presumptive atria and ventricles. Relatively recent work has demonstrated that significant portions of the right ventricle are formed by cells that are added to the developing heart after looping has occurred. These cells, which are derived from what is called the second heart field, derive from progenitors in the ventral pharynx and express markers that allow for their identification, including islet-1. Different embryologic origins of cells within the right and left ventricles may help explain why some forms of congenital and adult heart diseases affect these regions of the heart to varying degrees. 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. Early in development, the single layer of myocardial cells secretes an extracellular matrix rich in hyaluronic acid. This extracellular matrix, termed “cardiac jelly,” accumulates within the endocardial cushions, precursors of the cardiac valves. Signals from overlying myocardial cells, including members of the transforming growth factor β family, trigger migration, invasion, and phenotypic changes of underlying endocardial cells, which undergo an epithelial-mesenchymal transformation and

CHAPTER 1

mitochondria, where it is metabolized to the two-carbon fragment, acetyl-Co-A, and undergoes oxidation. FFAs are converted to acyl-CoA in the cytoplasm and acetylCoA in the mitochondria. Acetyl-CoA enters the citric acid (Krebs) cycle to produce ATP by oxidative phosphorylation within the mitochondria; ATP then enters the cytoplasm from the mitochondrial compartment. Intracellular ADP, resulting from the breakdown of ATP, enhances mitochondrial ATP production. In the fasted, resting state, circulating FFA concentrations and their myocardial uptake are high, and they furnish most of the heart’s acetyl-CoA (∼70%). In the fed state, with elevations of blood glucose and insulin, glucose oxidation increases and FFA oxidation subsides. Increased cardiac work, the administration of inotropic agents, hypoxia, and mild ischemia all enhance myocardial glucose uptake, glucose production resulting from glycogenolysis, and glucose metabolism to pyruvate (glycolysis). By contrast, β-adrenergic stimulation, as occurs during stress, raises the circulating levels and metabolism of FFAs in favor of glucose. Severe ischemia inhibits the cytoplasmic enzyme pyruvate dehydrogenase, and despite both glycogen and glucose breakdown, glucose is metabolized only to lactic acid (anaerobic glycolysis), which does not enter the citric acid cycle. Anaerobic glycolysis produces much less ATP than does aerobic glucose metabolism, in which glucose is metabolized to pyruvate and subsequently oxidized to CO2. High concentrations of circulating FFAs, which can occur when adrenergic stimulation is superimposed on severe ischemia, reduce oxidative phosphorylation and also cause ATP wastage; the myocardial content of ATP declines and impairs myocardial contraction. In addition, products of FFA breakdown can exert toxic effects on cardiac cell membranes and may be arrhythmogenic. Myocardial energy is stored as creatine phosphate (CP), which is in equilibrium with ATP, the immediate source of energy. In states of reduced energy availability, the CP stores decline first. Cardiac hypertrophy, fibrosis, tachycardia, increased wall tension resulting from ventricular dilation, and increased intracytoplasmic [Ca2+] all contribute to increased myocardial energy needs. When coupled with reduced coronary flow reserve, as occurs with obstruction of coronary arteries or abnormalities of the coronary microcirculation, an imbalance in myocardial ATP production relative to demand may occur, and the resulting ischemia can worsen or cause heart failure.

Early heart-forming regions

Neural folds

Pericardial coelom

Foregut

Forming heart

SECTION I A

Introduction to Cardiovascular Disorders

First heart field

B Second heart field

RV LV

Figure 1-12 A. Schematic depiction of a transverse section through an early embryo depicts the bilateral regions where early heart tubes form. B. The bilateral heart tubes subsequently migrate to the midline and fuse to form the linear heart tube. C. At the early cardiac crescent stage of embryonic development, cardiac precursors include a primary heart field fated to form the linear heart tube and a second heart field fated to add myocardium to the inflow and outflow poles of the

heart. D. Second heart field cells populate the pharyngeal region before subsequently migrating to the maturing heart. E. Large portions of the right ventricle and outflow tract and some cells within the atria derive from the second heart field. F. The aortic arch arteries form as symmetric sets of vessels that then remodel under the influence of the neural crest to form the asymmetric mature vasculature.

invade the cardiac jelly to cellularize the endocardial cushions. Mesenchymal components proliferate and remodel to form the mature valve leaflets. The great vessels form as a series of bilaterally symmetric aortic arch arteries that undergo asymmetric remodeling events to form the mature vasculature. The immigration of neural crest cells that arise in the dorsal neural tube orchestrates this process. These cells are required for aortic arch remodeling and septation of the truncus arteriosus. They develop into smooth-muscle cells within the tunica media of the aortic arch, the ductus arteriosus, and the carotid arteries. Smooth-muscle cells within the descending aorta arise from a different

embryologic source, the lateral plate mesoderm. Neural crest cells are sensitive to both vitamin A and folic acid, and congenital heart disease involving abnormal remodeling of the aortic arch arteries has been associated with maternal deficiencies of these vitamins. Genetic syndromes associated with aortic arch defects can be associated with other abnormalities of neural crest craniofacial derivatives, including the palate. Coronary artery formation requires yet another cell population that initiates extrinsic to the embryonic heart fields. Epicardial cells arise in the proepicardial organ, a derivative of the septum transversum, which also contributes to the fibrous portion of the diaphragm and to

Regenerating Cardiac Tissue Until very recently, adult mammalian myocardial cells were viewed as fully differentiated and without regenerative potential. Evidence currently supports the existence of limited endogenous regenerative potential of mature cardiac myocytes, resident cardiac progenitors, and/or bone marrow–derived stem cells. Considerable current effort is being devoted to evaluating the utility of cells from these sources to enhance the regenerative potential of the heart. The success of such approaches would offer the exciting possibility of reconstructing an infarcted or failing ventricle.

Basic Biology of the Cardiovascular System

characterize unique cell fates and electrical properties of the tissues. Developmental defects in conduction system morphogenesis and lineage determination can lead to various electrophysiologic disorders, including congenital heart block and preexcitation syndromes such as Wolff-Parkinson-White syndrome (Chap. 16). Studies of cardiac stem and progenitor cells suggest that progressive lineage restriction results in the gradual and stepwise determination of mature cell fates within the heart, with early precursors capable of adopting endothelial, smooth-muscle, or cardiac phenotypes, and subsequent further specialization into atrial, ventricular, and specialized conduction cell types.

CHAPTER 1

the liver. Proepicardial cells contribute to the smoothmuscle cells of the coronary arteries and are required for their proper patterning. Other cell types within the heart, including fibroblasts and potentially some myocardial cells, also can arise from the proepicardium. The cardiac conduction system, which functions both to generate and to propagate electrical impulses, develops primarily from multipotential cardiac precursors. The conduction system is composed of slow (proximal) components, such as the sinoatrial (SA) and atrioventricular (AV) nodes, as well as fast (distal) components, including the His bundle, bundle branches, and Purkinje fibers. The AV node primarily serves to delay the electrical impulse between atria and ventricles (manifesting decremental conduction), whereas the distal conduction system rapidly delivers the impulse throughout the ventricles. Significant recent attention has been focused on the embryologic origins of various components of the specialized conduction network. Precursors within the sinus venosus give rise to the SA node, whereas those within the AV canal mature into heterogeneous cell types that compose the AV node. Myocardial cells transdifferentiate into Purkinje fibers to form the distal conduction system. Fast and slow conducting cell types within the nodes and bundles are characterized by expression of distinct gap junction proteins, including connexins, and ion channels that

CHAPTER 2

EPIDEMIOLOGY OF CARDIOVASCULAR DISEASE Thomas A. Gaziano

■

J. Michael Gaziano of public health systems, cleaner water supplies, and improved nutrition combine to drive down deaths from infectious disease and malnutrition. Infant and childhood mortality rates also decline, but deaths due to CVD increase to between 10% and 35% of all deaths. Rheumatic valvular disease, hypertension, coronary heart disease (CHD), and stroke are the predominant forms of CVD. Almost 40% of the world’s population is currently in this stage. The age of degenerative and human-made diseases is distinguished by mortality from noncommunicable diseases—primarily CVD—surpassing mortality from malnutrition and infectious diseases. Caloric intake, particularly from animal fat, increases. Coronary heart disease and stroke are prevalent, and 35–65% of all deaths can be traced to CVD. Typically, the rate of CHD deaths exceeds that of stroke by a ratio of 2:1 to 3:1. During this period, average life expectancy surpasses 50 years. Roughly 35% of the world’s population falls into this category. In the age of delayed degenerative diseases, CVD and cancer remain the major causes of morbidity and mortality, with CVD accounting for 40% of all deaths. However, age-adjusted CVD mortality declines, aided by preventive strategies such as smoking cessation programs and effective blood pressure control, acute hospital management, and technological advances such as the availability of bypass surgery. CHD, stroke, and congestive heart failure are the primary forms of CVD. About 15% of the world’s population is now in the age of delayed degenerative diseases or is exiting this age and moving into the fifth stage of the epidemiologic transition. In the industrialized world, physical activity continues to decline while total caloric intake increases. The resulting epidemic of overweight and obesity may signal the start of the age of inactivity and obesity. Rates of

Cardiovascular disease (CVD) is now the most common cause of death worldwide. Before 1900, infectious diseases and malnutrition were the most common causes and CVD was responsible for less than 10% of all deaths. Today, CVD accounts for approximately 30% of deaths worldwide, including nearly 40% in highincome countries and about 28% in low- and middleincome countries.

THE EPIDEMIOLOGIC TRANSITION The global rise in CVD is the result of an unprecedented transformation in the causes of morbidity and mortality during the twentieth and twenty-first centuries. Known as the epidemiologic transition, this shift is driven by industrialization, urbanization, and associated lifestyle changes and is taking place in every part of the world among all races, ethnic groups, and cultures. The transition is divided into four basic stages: pestilence and famine, receding pandemics, degenerative and human-made diseases, and delayed degenerative diseases. A fifth stage, characterized by an epidemic of inactivity and obesity, may be emerging in some countries (Table 2-1). Malnutrition, infectious diseases, and high infant and child mortality rates that are offset by high fertility mark the age of pestilence and famine. Tuberculosis, dysentery, cholera, and influenza are often fatal, resulting in a mean life expectancy of about 30 years. Cardiovascular disease, which accounts for less than 10% of deaths, takes the form of rheumatic heart disease and cardiomyopathies due to infection and malnutrition. Approximately 10% of the world’s population remains in the age of pestilence and famine. Per capita income and life expectancy increase during the age of receding pandemics as the emergence

Table 2-1

Five Stages of the Epidemiologic Transition Deaths Related to CVD, % Predominant CVD Type

Pestilence and famine

Predominance of malnutrition and infectious diseases as causes of death; high rates of infant and child mortality; low mean life expectancy

50%. This is somewhat unexpected because stroke tends to be a more dominant factor early in the epidemiologic transition. This finding may reflect inaccuracies in cause-specific mortality estimates or possibly an underlying genetic component. It has been suggested that Indians have exaggerated insulin insensitivity in response to the Western lifestyle pattern that may differentially increase rates of CHD over stroke. The South Asia region has the highest overall prevalence of diabetes in the low-income regions, with rates as high as 14% in urban centers. In certain rural areas, the prevalence of CVD and its risk factors is approaching urban rates. Nonetheless, rheumatic heart disease continues to be a major cause of morbidity and mortality. For the most part, Sub-Saharan Africa remains in the first phase of the epidemiologic transition, with CVD rates half those in developed nations. Life expectancy has decreased by an average of 5 years since the early 1990s largely because of HIV/AIDS and other chronic diseases, according to the World Bank; life expectancies are the lowest in the world. Still, CVD accounts for 46% of noncommunicable deaths and is the leading cause of death among adults >age 35. As more HIV/ AIDS patients receive antiretroviral treatment, managing CVD risk factors such as dyslipidemia in this population requires more attention. However, hypertension continues to be the major public health concern and has resulted in stroke being the dominant form of CVD. Rheumatic heart disease is still an important cause of CVD mortality and morbidity.

Global Trends in Cardiovascular Disease In 1990, CVD accounted for 28% of the world’s 50.4 million deaths and 9.7% of the 1.4 billion lost disability-adjusted life years (DALYs), and by 2001, CVD was responsible for 29% of all deaths and 14% of the 1.5 billion lost DALYs. By 2030, when the population is expected to reach 8.2 billion, 33% of all deaths

Table 2-2

By 2010

By 2030

CVD deaths: annual number of all deaths

18.1 million

24.2 million

CVD deaths: percentage of all deaths

30.8%

32.5%

CHD deaths: percentage of all male deaths

13.1%

14.9%

CHD deaths: percentage of all female deaths

13.6%

13.1%

Stroke deaths: percentage of all male deaths

9.2%

10.4%

Stroke deaths: percentage of all female deaths

11.5%

11.8%

Abbreviations: CVD, cardiovascular disease; CHD, coronary heart disease. Source: Adapted from J Mackay, G Mensah: Atlas of Heart Disease and Stroke. Geneva, World Health Organization, 2004.

will be the result of CVD (Table 2-2). Of these, 14.9% of deaths in men and 13.1% of deaths in women will be due to CHD. Stroke will be responsible for 10.4% of all male deaths and 11.8% of all female deaths. In the high-income countries, population growth will be fueled by emigration from the low- and middle-income countries, but the populations of high-income countries will shrink as a proportion of the world’s population. The modest decline in CVD death rates that began in the high-income countries in the latter third of the twentieth century will continue, but the rate of decline appears to be slowing. However, these countries are expected to see an increase in the prevalence of CVD, as well as the absolute number of deaths as the population ages. Significant proportions of the population living in low- and middle-income countries have entered the third phase of the epidemiologic transition, and some are entering the fourth stage. Changing demographics play a significant role in future predictions for CVD throughout the world. For example, between 1990 and 2001, the population of Eastern Europe and Central Asia grew by 1 million people per year, whereas South Asia added 25 million people each year. CVD rates will also have an economic impact. Even assuming no increase in CVD risk factors, most countries, but especially India and South Africa, will see a large number of people between 35 and 64 die of CVD over the next 30 years as well as an increasing level of morbidity among middle-aged people related to heart disease and stroke. In China, it is estimated that there

Regional Trends In Risk Factors As indicated earlier, the global variation in CVD rates is related to temporal and regional variations in known risk behaviors and factors. Ecological analyses of major CVD risk factors and mortality demonstrate high correlations between expected and observed mortality rates for the three main risk factors—smoking, serum cholesterol, and hypertension—and suggest that many of the regional variations are based on differences in conventional risk factors.

Behavioral Risk Factors Tobacco Every year, more than 5.5 trillion cigarettes are produced, enough to provide every person on the planet with 1000 cigarettes. Worldwide, 1.3 billion people smoked in 2003, a number that is projected to increase to 1.6 billion by 2030. Tobacco currently causes about 5 million deaths—9% of all deaths—annually. Approximately 1.6 million are CVD-related. If current smoking patterns continue, by 2030 the global burden of disease attributable to tobacco will reach 10 million deaths annually. A unique feature of the low- and middle-income countries is easy access to smoking during the early stages of the epidemiologic transition due to the availability of relatively inexpensive tobacco products. In South Asia, the prominence of locally produced forms of tobacco other than manufactured cigarettes makes control of consumption more challenging. Diet Total caloric intake per capita increases as countries develop. With regard to cardiovascular disease, a key element of dietary change is an increase in intake of saturated animal fats and hydrogenated vegetable fats, which contain atherogenic trans-fatty acids, along with a decrease in intake of plant-based foods and an increase in simple carbohydrates. Fat contributes less than 20% of calories in rural China and India, less than 30% in Japan, and well above 30% in the United States. Caloric contributions from fat appear to be falling in the highincome countries. In the United States, between 1971 and 2000, the percentage of calories derived from saturated fat decreased from 13% to 11%. Physical inactivity The increased mechanization that accompanies the economic transition leads to a shift from physically demanding agriculture-based work to largely sedentary

Epidemiology of Cardiovascular Disease

Deaths

will be 9 million deaths from CVD in 2030—up from 2.4 million in 2002—with half occurring in individuals between 35 and 64 years old.

CHAPTER 2

Estimated Morbidity Related to Heart Disease: 2010-2030

SECTION I

industry- and office-based work. In the United States, approximately one-quarter of the population does not participate in any leisure-time physical activity and only 22% report engaging in sustained physical activity for at least 30 min on 5 or more days per week (the current recommendation). In contrast, in countries such as China, physical activity is still integral to everyday life. Approximately 90% of the urban population walks or rides a bicycle to work, shopping, or school daily.

Introduction to Cardiovascular Disorders

Metabolic Risk Factors Lipid levels Worldwide, high cholesterol levels are estimated to cause 56% of ischemic heart disease and 18% of strokes, amounting to 4.4 million deaths annually. As countries move through the epidemiologic transition, mean population plasma cholesterol levels tend to rise. Social and individual changes that accompany urbanization clearly play a role because plasma cholesterol levels tend to be higher among urban residents than among rural residents. This shift is driven largely by greater consumption of dietary fats—primarily from animal products and processed vegetable oils—and decreased physical activity. In the high-income countries, in general, mean population cholesterol levels are falling, whereas wide variation is seen in the low- and middle-income countries. Hypertension Elevated blood pressure is an early indicator of the epidemiologic transition. Worldwide, approximately 62% of strokes and 49% of cases of ischemic heart disease are attributable to suboptimal (>115 mmHg systolic) blood pressure, which is believed to account for more than 7 million deaths annually. Remarkably, nearly half of this burden occurs among those with systolic blood pressure 40 kg/m2) more than tripled, increasing from 1.3% to 4.9%. In many of the low- and middle-income countries, obesity appears to coexist with undernutrition and malnutrition. Obesity is increasing throughout the world, particularly in developing countries, where thetrajectories are steeper than those experienced in the developed countries. According to the latest World Health Organization (WHO) data, this is equivalent to about 1.3 billion overweight adults in the world. A survey undertaken in 1998 found that as many as 58% of African women living in South Africa might have been overweight or obese. Diabetes mellitus As a consequence of, or in addition to, increasing body mass index and decreasing levels of physical activity, worldwide rates of diabetes—predominantly type 2 diabetes—are on the rise. In 2003, 194 million adults, or 5% of the world’s population, had diabetes. By 2025, this number is predicted to increase 72 percent to 333 million. By 2025, the number of people with type 2 diabetes is projected to double in three of the six low- and middle-income regions: the Middle East and North Africa, South Asia, and Sub-Saharan Africa. There appear to be clear genetic susceptibilities to diabetes mellitus in various racial and ethnic groups. For example, migration studies suggest that South Asians and Indians tend to be at higher risk than are people of European ancestry.

Summary Although CVD rates are declining in the high-income countries, they are increasing in virtually every other region of the world. The consequences of this preventable epidemic will be substantial on many levels: individual mortality and morbidity rates, family suffering, and staggering economic costs. Three complementary strategies can be used to lessen the impact. First, the overall burden of CVD risk factors can be lowered through population-wide public health measures such as national campaigns against cigarette

Epidemiology of Cardiovascular Disease

mortality and morbidity, as well as the prevalence of the major preventable risk factors. In the meantime, the high-income countries must continue to bear the burden of research and development aimed at prevention and treatment, being mindful of the economic limitations of many countries. The concept of the epidemiologic transition provides insight into methods to alter the course of the CVD epidemic. The efficient transfer of low-cost preventive and therapeutic strategies could alter the natural course of this epidemic and thereby reduce the excess global burden of preventable CVD.

CHAPTER 2

smoking, unhealthy diets, and physical inactivity. Second, it is important to identify higher-risk subgroups of the population that stand to benefit the most from specific, low-cost prevention interventions, including screening for and treatment of hypertension and elevated cholesterol. Simple, low-cost interventions, such as the “polypill,” a regimen of aspirin, a statin, and an anithypertensive agent, also need to be explored. Third, resources should be allocated to acute as well as secondary prevention interventions. For countries with limited resources, a critical first step in developing a comprehensive plan is better assessment of cause-specific

CHaPter 3

APPROACH TO THE PATIENT WITH POSSIBLE CARDIOVASCULAR DISEASE Joseph Loscalzo

diagnostic accuracy in the prediction of epicardial obstruction in women than in men.

tHe MaGnitude of tHe ProBleM Cardiovascular diseases comprise the most prevalent serious disorders in industrialized nations and are a rapidly growing problem in developing nations (Chap. 2). Age-adjusted death rates for coronary heart disease have declined by two-thirds in the last four decades in the United States, reflecting the identification and reduction of risk factors as well as improved treatments and interventions for the management of coronary artery disease, arrhythmias, and heart failure. Nonetheless, cardiovascular diseases remain the most common causes of death, responsible for 35% of all deaths, almost 1 million deaths each year. Approximately one-fourth of these deaths are sudden. In addition, cardiovascular diseases are highly prevalent, diagnosed in 80 million adults, or ∼35% of the adult population. The growing prevalence of obesity, type 2 diabetes mellitus, and metabolic syndrome (Chap. 32), which are important risk factors for atherosclerosis, now threatens to reverse the progress that has been made in the age-adjusted reduction in the mortality rate of coronary heart disease. For many years cardiovascular disease was considered to be more common in men than in women. In fact, the percentage of all deaths secondary to cardiovascular disease is higher among women (43%) than among men (37%). In addition, although the absolute number of deaths secondary to cardiovascular disease has declined over the past decades in men, this number has actually risen in women. Inflammation, obesity, type 2 diabetes mellitus, and the metabolic syndrome appear to play more prominent roles in the development of coronary atherosclerosis in women than in men. Coronary artery disease (CAD) is more frequently associated with dysfunction of the coronary microcirculation in women than in men. Exercise electrocardiography has a lower

CardiaC sYMPtoMs The symptoms caused by heart disease result most commonly from myocardial ischemia, disturbance of the contraction and/or relaxation of the myocardium, obstruction to blood flow, or an abnormal cardiac rhythm or rate. Ischemia, which is caused by an imbalance between the heart’s oxygen supply and demand, is manifest most frequently as chest discomfort (Chap. 4), whereas reduction of the pumping ability of the heart commonly leads to fatigue and elevated intravascular pressure upstream of the failing ventricle. The latter results in abnormal fluid accumulation, with peripheral edema (Chap. 7) or pulmonary congestion and dyspnea (Chap. 5). Obstruction to blood flow, as occurs in valvular stenosis, can cause symptoms resembling those of myocardial failure (Chap. 17). Cardiac arrhythmias often develop suddenly, and the resulting symptoms and signs—palpitations (Chap. 8), dyspnea, hypotension, and syncope—generally occur abruptly and may disappear as rapidly as they develop. Although dyspnea, chest discomfort, edema, and syncope are cardinal manifestations of cardiac disease, they occur in other conditions as well. Thus, dyspnea is observed in disorders as diverse as pulmonary disease, marked obesity, and anxiety (Chap. 5). Similarly, chest discomfort may result from a variety of noncardiac and cardiac causes other than myocardial ischemia (Chap. 4). Edema, an important finding in untreated or inadequately treated heart failure, also may occur with primary renal disease and in hepatic cirrhosis (Chap. 7). Syncope occurs not only with serious cardiac

As outlined by the New York Heart Association (NYHA), the elements of a complete cardiac diagnosis include the systematic consideration of the following: 1. The underlying etiology. Is the disease congenital, hypertensive, ischemic, or inflammatory in origin? 2. The anatomical abnormalities. Which chambers are involved? Are they hypertrophied, dilated, or both? Which valves are affected? Are they regurgitant and/ or stenotic? Is there pericardial involvement? Has there been a myocardial infarction? 3. The physiological disturbances. Is an arrhythmia present? Is there evidence of congestive heart failure or myocardial ischemia? 4. Functional disability. How strenuous is the physical activity required to elicit symptoms? The classification provided by the NYHA has been found to be useful in describing functional disability (Table 3-1).

New York Heart Association Functional Classification Class I No limitation of physical activity No symptoms with ordinary exertion Class II Slight limitation of physical activity Ordinary activity causes symptoms

Class III Marked limitation of physical activity Less than ordinary activity causes symptoms Asymptomatic at rest Class IV Inability to carry out any physical activity without discomfort Symptoms at rest

Source: Modified from The Criteria Committee of the New York Heart Association: Nomenclature and Criteria for Diagnosis, 9th ed. Boston, Little, Brown, 1994.

One example may serve to illustrate the importance of establishing a complete diagnosis. In a patient who presents with exertional chest discomfort, the identification of myocardial ischemia as the etiology is of great clinical importance. However, the simple recognition of ischemia is insufficient to formulate a therapeutic strategy or prognosis until the underlying anatomical abnormalities responsible for the myocardial ischemia, e.g., coronary atherosclerosis or aortic stenosis, are identified and a judgment is made about whether other physiologic disturbances that cause an imbalance between myocardial oxygen supply and demand, such as severe anemia, thyrotoxicosis, or supraventricular tachycardia, play contributory roles. Finally, the severity of the disability should govern the extent and tempo of the workup and strongly influence the therapeutic strategy that is selected. The establishment of a correct and complete cardiac diagnosis usually commences with the history and physical examination (Chap. 9). Indeed, the clinical examination remains the basis for the diagnosis of a wide variety of disorders. The clinical examination may then be supplemented by five types of laboratory tests: (1) ECG (Chap. 11), (2) noninvasive imaging examinations (chest roentgenogram, echocardiogram, radionuclide imaging, computed tomographic imaging, and magnetic resonance imaging (Chap. 12), (3) blood tests to assess risk (e.g., lipid determinations, C-reactive protein [Chap. 30]) or cardiac function (e.g., brain natriuretic peptide [BNP] [Chap. 17]), (4) occasionally specialized invasive examinations (i.e., cardiac catheterization and coronary arteriography [Chap. 13]), and (5) genetic tests to identify monogenic cardiac diseases (e.g., hypertrophic cardiomyopathy [Chap. 21], Marfan syndrome, and abnormalities of cardiac ion channels that lead to prolongation of the QT interval and an increase in the risk of sudden death [Chap. 16]). These tests are becoming more widely available.

Approach to the Patient with Possible Cardiovascular Disease

Diagnosis

Table 3-1

CHAPTER 3

arrhythmias but in a number of neurologic conditions as well. Whether heart disease is responsible for these symptoms frequently can be determined by carrying out a careful clinical examination (Chap. 9), supplemented by noninvasive testing using electrocardiography at rest and during exercise (Chap. 11), echocardiography, roentgenography, and other forms of myocardial imaging (Chap. 12). Myocardial or coronary function that may be adequate at rest may be insufficient during exertion. Thus, dyspnea and/or chest discomfort that appear during activity are characteristic of patients with heart disease, whereas the opposite pattern, i.e., the appearance of these symptoms at rest and their remission during exertion, is rarely observed in such patients. It is important, therefore, to question the patient carefully about the relation of symptoms to exertion. Many patients with cardiovascular disease may be asymptomatic both at rest and during exertion but may present with an abnormal physical finding such as a heart murmur, elevated arterial pressure, or an abnormality of the electrocardiogram (ECG) or the cardiac silhouette on the chest roentgenogram or other imaging test. It is important to assess the global risk of CAD in asymptomatic individuals, using a combination of clinical assessment and measurement of cholesterol and its fractions, as well as other biomarkers, such as C-reactive protein, in some patients (Chap. 30). Since the first clinical manifestation of CAD may be catastrophic—sudden cardiac death, acute myocardial infarction, or stroke in previous asymptomatic persons—it is mandatory to identify those at high risk of such events and institute further testing and preventive measures.

SECTION I Introduction to Cardiovascular Disorders

Family History

Electrocardiogram

In eliciting the history of a patient with known or suspected cardiovascular disease, particular attention should be directed to the family history. Familial clustering is common in many forms of heart disease. Mendelian transmission of single-gene defects may occur, as in hypertrophic cardiomyopathy (Chap. 21), Marfan syndrome, and sudden death associated with a prolonged QT syndrome (Chap. 16). Premature coronary disease and essential hypertension, type 2 diabetes mellitus, and hyperlipidemia (the most important risk factors for coronary artery disease) are usually polygenic disorders. Although familial transmission may be less obvious than in the monogenic disorders, it is helpful in assessing risk and prognosis in polygenic disorders. Familial clustering of cardiovascular diseases not only may occur on a genetic basis but also may be related to familial dietary or behavior patterns such as excessive ingestion of salt or calories and cigarette smoking.

(See also Chap. 11) Although an ECG usually should be recorded in patients with known or suspected heart disease, with the exception of the identification of arrhythmias, conduction abnormalities, ventricular hypertrophy, and acute myocardial infarction, it generally does not establish a specific diagnosis. The range of normal electrocardiographic findings is wide, and the tracing can be affected significantly by many noncardiac factors, such as age, body habitus, and serum electrolyte concentrations. In general, electrocardiographic changes should be interpreted in the context of other abnormal cardiovascular findings.

Assessment of Functional Impairment When an attempt is made to determine the severity of functional impairment in a patient with heart disease, it is helpful to ascertain the level of activity and the rate at which it is performed before symptoms develop. Thus, it is not sufficient to state that the patient complains of dyspnea. The breathlessness that occurs after running up two long flights of stairs denotes far less functional impairment than do similar symptoms that occur after taking a few steps on level ground. Also, the degree of customary physical activity at work and during recreation should be considered. The development of two-flight dyspnea in a well-conditioned marathon runner may be far more significant than the development of one-flight dyspnea in a previously sedentary person. The history should include a detailed consideration of the patient’s therapeutic regimen. For example, the persistence or development of edema, breathlessness, and other manifestations of heart failure in a patient who is receiving optimal doses of diuretics and other therapies for heart failure (Chap. 17) is far graver than are similar manifestations in the absence of treatment. Similarly, the presence of angina pectoris despite treatment with optimal doses of multiple antianginal drugs (Chap. 33) is more serious than it is in a patient on no therapy. In an effort to determine the progression of symptoms, and thus the severity of the underlying illness, it may be useful to ascertain what, if any, specific tasks the patient could have carried out 6 months or 1 year earlier that he or she cannot carry out at present.

Assessment of the Patient with a Heart Murmur (Fig. 3-1) The cause of a heart murmur can often be readily elucidated from a systematic evaluation of its major attributes: timing, duration, intensity, quality, frequency, configuration, location, and radiation when considered in the light of the history, general physical examination, and other features of the cardiac examination, as described in Chap. 9. EVALUATION OF HEART MURMUR PRESENCE OF CARDIAC MURMUR Systolic Murmur

Diastolic or Continuous Murmur

Grade I + II and midsystolic

Grade III or >, holosystolic, or late systolic

Asymptomatic and no associated findings

Other signs or symptoms of cardiac disease Echocardiography

Normal ECG and chest X-ray

No further workup

Abnormal ECG or chest X-ray

Cardiac consult if appropriate

Figure 3-1 An alternative “echocardiography first” approach to the evaluation of a heart murmur that also uses the results of the electrocardiogram (ECG) and chest x-ray in asymptomatic patients with soft midsystolic murmurs and no other physical findings. This algorithm is useful for patients over age 40 years in whom the prevalence of coronary artery disease and aortic stenosis increases as the cause of systolic murmur. (From RA O’Rourke, in Primary Cardiology, 2nd ed, E Braunwald, L Goldman [eds]. Philadelphia, Saunders, 2003.)

Cardiovascular disorders often present acutely, as in a previously asymptomatic person who develops an acute myocardial infarction (Chap. 35), or a previously asymptomatic patient with hypertrophic cardiomyopathy (Chap. 21), or with a prolonged QT interval (Chap. 16) whose first clinical manifestation is syncope or even sudden death. However, the alert physician may recognize the patient at risk for these complications long before they occur and often can take measures to prevent their occurrence. For example, a patient with acute myocardial infarction will often have had risk factors for atherosclerosis for many years. Had these risk factors been recognized, their elimination or reduction might have delayed or even prevented the infarction. Similarly, a patient with hypertrophic cardiomyopathy may have had a heart murmur for years and a family history of this disorder. These findings could have led to an echocardiographic examination, recognition of the condition, and appropriate therapy long before the occurrence of a serious acute manifestation. Patients with valvular heart disease or idiopathic dilated cardiomyopathy, by contrast, may have a prolonged course of gradually increasing dyspnea and other manifestations of chronic heart failure that is punctuated by episodes of acute deterioration only late in the course of the disease. Understanding the natural history of various cardiac disorders is essential for applying appropriate diagnostic and therapeutic measures to each stage of the condition, as well as for providing the patient and family with the likely prognosis.

Pitfalls in Cardiovascular Medicine Increasing subspecialization in internal medicine and the perfection of advanced diagnostic techniques in cardiology can lead to several undesirable consequences. Examples include the following: 1. Failure by the noncardiologist to recognize important cardiac manifestations of systemic illnesses. For example,

Despite the value of invasive tests in certain circ*mstances, they entail some small risk to the patient, involve discomfort and substantial cost, and place a strain on medical facilities. Therefore, they should be carried out only if the results can be expected to modify the patient’s management.

Disease Prevention and Management The prevention of heart disease, especially of CAD, is one of the most important tasks of primary care health givers as well as cardiologists. Prevention begins with risk assessment, followed by attention to lifestyle, such

Approach to the Patient with Possible Cardiovascular Disease

Natural History

the presence of mitral stenosis, patent foramen ovale, and/or transient atrial arrhythmia should be considered in a patient with stroke, or the presence of pulmonary hypertension and cor pulmonale should be considered in a patient with scleroderma or Raynaud’s syndrome. A cardiovascular examination should be carried out to identify and estimate the severity of the cardiovascular involvement that accompanies many noncardiac disorders. 2. Failure by the cardiologist to recognize underlying systemic disorders in patients with heart disease. For example, hyperthyroidism should be considered in an elderly patient with atrial fibrillation and unexplained heart failure, and Lyme disease should be considered in a patient with an unexplained fluctuating atrioventricular block. A cardiovascular abnormality may provide the clue critical to the recognition of some systemic disorders. For instance, an unexplained pericardial effusion may provide an early clue to the diagnosis of tuberculosis or a neoplasm. 3. Overreliance on and overutilization of laboratory tests, particularly invasive techniques, for the evaluation of the cardiovascular system. Cardiac catheterization and coronary arteriography (Chap. 13) provide precise diagnostic information that may be crucial in developing a therapeutic plan in patients with known or suspected CAD. Although a great deal of attention has been directed to these examinations, it is important to recognize that they serve to supplement, not supplant, a careful examination carried out with clinical and noninvasive techniques. A coronary arteriogram should not be performed in lieu of a careful history in patients with chest pain suspected of having ischemic heart disease. Although coronary arteriography may establish whether the coronary arteries are obstructed and to what extent, the results of the procedure by themselves often do not provide a definitive answer to the question of whether a patient’s complaint of chest discomfort is attributable to coronary atherosclerosis and whether or not revascularization is indicated.

CHAPTER 3

The majority of heart murmurs are midsystolic and soft (grades I–II/VI). When such a murmur occurs in an asymptomatic child or young adult without other evidence of heart disease on clinical examination, it is usually benign and echocardiography generally is not required. By contrast, two-dimensional and Doppler echocardiography (Chap. 12) are indicated in patients with loud systolic murmurs (grades ≥III/VI), especially those that are holosystolic or late systolic, and in most patients with diastolic or continuous murmurs.

SECTION I

as achieving optimal weight, physical activity, smoking cessation, and then aggressive treatment of all abnormal risk factors, such as hypertension, hyperlipidemia, and diabetes mellitus. After a complete diagnosis has been established in patients with known heart disease, a number of management options are usually available. Several examples may be used to demonstrate some of the principles of cardiovascular therapeutics:

Introduction to Cardiovascular Disorders

1. In the absence of evidence of heart disease, the patient should be clearly informed of this assessment and not be asked to return at intervals for repeated examinations. If there is no evidence of disease, such continued attention may lead to the patient’s developing inappropriate concern about the possibility of heart disease. 2. If there is no evidence of cardiovascular disease but the patient has one or more risk factors for the development of ischemic heart disease (Chap. 33), a plan for their reduction should be developed and the patient should be retested at intervals to assess compliance and efficacy in risk reduction. 3. Asymptomatic or mildly symptomatic patients with valvular heart disease that is anatomically severe should be evaluated periodically, every 6 to 12 months, by clinical and noninvasive examinations. Early signs of

deterioration of ventricular function may signify the need for surgical treatment before the development of disabling symptoms, irreversible myocardial damage, and excessive risk of surgical treatment (Chap. 20). 4. In patients with CAD (Chap. 33), available practice guidelines should be considered in the decision on the form of treatment (medical, percutaneous coronary intervention, or surgical revascularization). Mechanical revascularization may be employed too frequently in the United States and too infrequently in Eastern Europe and developing nations. The mere presence of angina pectoris and/or the demonstration of critical coronary arterial narrowing at angiography should not reflexively evoke a decision to treat the patient by revascularization. Instead, these interventions should be limited to patients with CAD whose angina has not responded adequately to medical treatment or in whom revascularization has been shown to improve the natural history (e.g., acute coronary syndrome or multivessel CAD with left ventricular dysfunction). Acknowledgment

Dr. Eugene Braunwald authored this chapter for the previous edition of Harrison’s Principles of Internal Medicine. Some of the material from the 17th edition has been carried forward.

SECTION II

Diagnosis of Cardiovascular Disorders

CHAPTER 4

CHEST DISCOMFORT Thomas H. lee Chest discomfort is a common challenge for clinicians in the office or emergency department. The differential diagnosis includes conditions affecting organs throughout the thorax and abdomen, with prognostic implications that vary from benign to life threatening (Table 4-1). Failure to recognize potentially serious conditions such as acute ischemic heart disease, aortic dissection, tension pneumothorax, or pulmonary embolism can lead to serious complications, including death. Conversely, overly conservative management of low-risk patients leads to unnecessary hospital admissions, tests, procedures, and anxiety.

Table 4-1 DIagNOSES aMONg ChEST paIN paTIENTS WIThOuT MyOCarDIal INFarCTION DIagNOSIS

CauSES OF ChEST DISCOMFOrT

pErCENT

Gastroesophageal diseasea Gastroesophageal reflux Esophageal motility disorders Peptic ulcer Gallstones

Ischemic heart disease

Chest wall syndromes

Pericarditis

Pleuritis/pneumonia

Pulmonary embolism

Myocardial ischemia and injury

Lung cancer

Myocardial ischemia occurs when the oxygen supply to the heart is insufficient to meet metabolic needs. This mismatch can result from a decrease in oxygen supply, a rise in demand, or both. The most common underlying cause of myocardial ischemia is obstruction of coronary arteries by atherosclerosis; in the presence of such obstruction, transient ischemic episodes are usually precipitated by an increase in oxygen demand as a result of physical exertion. However, ischemia can also result from psychological stress, fever, or large meals or from compromised oxygen delivery due to anemia, hypoxia, or hypotension. Ventricular hypertrophy due to valvular heart disease, hypertrophic cardiomyopathy, or hypertension can predispose the myocardium to ischemia because of impaired penetration of blood flow from epicardial coronary arteries to the endocardium.

2 1.5

Aortic aneurysm

Aortic stenosis

Herpes zoster

In order of frequency. Source: P Fruergaard et al: Eur Heart J 17:1028, 1996.

“pain” but may admit to dyspnea or a vague sense of anxiety. The word “sharp” is sometimes used by patients to describe intensity rather than quality. The location of angina pectoris is usually retrosternal; most patients do not localize the pain to any small area. The discomfort may radiate to the neck, jaw, teeth, arms, or shoulders, reflecting the common origin in the posterior horn of the spinal cord of sensory neurons supplying the heart and these areas. Some patients present with aching in sites of radiated pain as their only symptoms of ischemia. Occasional patients report epigastric distress with ischemic episodes. Less common is radiation to below the umbilicus or to the back. Stable angina pectoris usually develops gradually with exertion, emotional excitement, or after heavy meals.

angina pectoris

(See also Chap. 33) The chest discomfort of myocardial ischemia is a visceral discomfort that is usually described as a heaviness, pressure, or squeezing (Table 4-2). Other common adjectives for anginal pain are burning and aching. Some patients deny any

Table 4-2

Typical Clinical Features of Major Causes of Acute Chest Discomfort Quality

Location

Associated Features

Angina

More than 2 and less than 10 min

Pressure, tightness, squeezing, heaviness, burning

Retrosternal, often with radiation to or isolated discomfort in neck, jaw, shoulders, or arms— frequently on left

Precipitated by exertion, exposure to cold, psychologic stress S4 gallop or mitral regurgitation murmur during pain

Unstable angina

10–20 min

Similar to angina but often more severe

Similar to angina

Similar to angina, but occurs with low levels of exertion or even at rest

Acute myocardial infarction

Variable; often more than 30 min

Similar to angina but often more severe

Similar to angina

Unrelieved by nitroglycerin May be associated with evidence of heart failure or arrhythmia

Aortic stenosis

Recurrent episodes as described for angina

As described for angina

Late-peaking systolic murmur radiating to carotid arteries

Pericarditis

Hours to days; may be episodic

Sharp

Retrosternal or toward cardiac apex; may radiate to left shoulder

May be relieved by sitting up and leaning forward Pericardial friction rub

Aortic dissection

Abrupt onset of unrelenting pain

Tearing or ripping sensation; knifelike

Anterior chest, often radiating to back, between shoulder blades

Associated with hypertension and/ or underlying connective tissue disorder, e.g., Marfan syndrome Murmur of aortic insufficiency, pericardial rub, pericardial tamponade, or loss of peripheral pulses

Pulmonary embolism

Abrupt onset; several minutes to a few hours

Pleuritic

Often lateral, on the side of the embolism

Dyspnea, tachypnea, tachycardia, and hypotension

Pulmonary hypertension

Variable

Pressure

Substernal

Dyspnea, signs of increased venous pressure including edema and jugular venous distention

Pneumonia or pleuritis

Variable

Pleuritic

Unilateral, often localized

Dyspnea, cough, fever, rales, occasional rub

Spontaneous pneumothorax

Sudden onset; several hours

Pleuritic

Lateral to side of pneumothorax

Dyspnea, decreased breath sounds on side of pneumothorax

Esophageal reflux

10–60 min

Burning

Substernal, epigastric

Worsened by postprandial recumbency Relieved by antacids

Esophageal spasm

2–30 min

Pressure, tightness, burning

Retrosternal

Can closely mimic angina

Peptic ulcer

Prolonged

Burning

Epigastric, substernal

Relieved with food or antacids

Gallbladder disease

Prolonged

Burning, pressure

Epigastric, right upper quadrant, substernal

May follow meal

Musculoskeletal disease

Variable

Aching

Variable

Aggravated by movement May be reproduced by localized pressure on examination

Herpes zoster

Variable

Sharp or burning

Dermatomal distribution

Vesicular rash in area of discomfort

Emotional and psychiatric conditions

Variable; may be fleeting

Variable

Variable; may be retrosternal

Situational factors may precipitate symptoms Anxiety or depression often detectable with careful history

Chest Discomfort

Duration

CHAPTER 4

Condition

SECTION II

Rest or treatment with sublingual nitroglycerin typically leads to relief within several minutes. In contrast, pain that is fleeting (lasting only a few seconds) is rarely ischemic in origin. Similarly, pain that lasts for several hours is unlikely to represent angina, particularly if the patient’s electrocardiogram (ECG) does not show evidence of ischemia. Anginal episodes can be precipitated by any physiologic or psychological stress that induces tachycardia. Most myocardial perfusion occurs during diastole, when there is minimal pressure opposing coronary artery flow from within the left ventricle. Since tachycardia decreases the percentage of the time in which the heart is in diastole, it decreases myocardial perfusion.

Diagnosis of Cardiovascular Disorders

Unstable angina and myocardial infarction

(See also Chaps. 34 and 35) Patients with these acute ischemic syndromes usually complain of symptoms similar in quality to angina pectoris, but more prolonged and severe. The onset of these syndromes may occur with the patient at rest, or awakened from sleep, and sublingual nitroglycerin may lead to transient or no relief. Accompanying symptoms may include diaphoresis, dyspnea, nausea, and light-headedness. The physical examination may be completely normal in patients with chest discomfort due to ischemic heart disease. Careful auscultation during ischemic episodes may reveal a third or fourth heart sound, reflecting myocardial systolic or diastolic dysfunction. A transient murmur of mitral regurgitation suggests ischemic papillary muscle dysfunction. Severe episodes of ischemia can lead to pulmonary congestion and even pulmonary edema. Other cardiac causes

Myocardial ischemia caused by hypertrophic cardiomyopathy or aortic stenosis leads to angina pectoris similar to that caused by coronary atherosclerosis. In such cases, a loud systolic murmur or other findings usually suggest that abnormalities other than coronary atherosclerosis may be contributing to the patient’s symptoms. Some patients with chest pain and normal coronary angiograms have functional abnormalities of the coronary circulation, ranging from coronary spasm visible on coronary angiography to abnormal vasodilator responses and heightened vasoconstrictor responses. The term “cardiac syndrome X” is used to describe patients with angina-like chest pain and ischemic-appearing ST-segment depression during stress despite normal coronary arteriograms. Some data indicate that many such patients have limited changes in coronary flow in response to pacing stress or coronary vasodilators. Pericarditis (See also Chap. 22) The pain in pericarditis is believed to be due to inflammation of the adjacent parietal

pleura, since most of the pericardium is believed to be insensitive to pain. Thus, infectious pericarditis, which usually involves adjoining pleural surfaces, tends to be associated with pain, while conditions that cause only local inflammation (e.g., myocardial infarction or uremia) and cardiac tamponade tend to result in mild or no chest pain. The adjacent parietal pleura receives its sensory supply from several sources, so the pain of pericarditis can be experienced in areas ranging from the shoulder and neck to the abdomen and back. Most typically, the pain is retrosternal and is aggravated by coughing, deep breaths, or changes in position—all of which lead to movements of pleural surfaces. The pain is often worse in the supine position and relieved by sitting upright and leaning forward. Less common is a steady aching discomfort that mimics acute myocardial infarction. Diseases of the aorta (See also Chap. 38) Aortic dissection is a potentially catastrophic condition that is due to spread of a subintimal hematoma within the wall of the aorta. The hematoma may begin with a tear in the intima of the aorta or with rupture of the vasa vasorum within the aortic media. This syndrome can occur with trauma to the aorta, including motor vehicle accidents or medical procedures in which catheters or intraaortic balloon pumps damage the intima of the aorta. Nontraumatic aortic dissections are rare in the absence of hypertension and/ or conditions associated with deterioration of the elastic or muscular components of the media within the aorta’s wall. Cystic medial degeneration is a feature of several inherited connective tissue diseases, including Marfan and Ehlers-Danlos syndromes. About half of all aortic dissections in women under 40 years of age occur during pregnancy. Almost all patients with acute dissections present with severe chest pain, although some patients with chronic dissections are identified without associated symptoms. Unlike the pain of ischemic heart disease, symptoms of aortic dissection tend to reach peak severity immediately, often causing the patient to collapse from its intensity. The classic teaching is that the adjectives used to describe the pain reflect the process occurring within the wall of the aorta—“ripping” and “tearing”—but more recent data suggest that the most common presenting complaint is sudden onset of severe, sharp pain. The location often correlates with the site and extent of the dissection. Thus, dissections that begin in the ascending aorta and extend to the descending aorta tend to cause pain in the front of the chest that extends into the back, between the shoulder blades. Physical findings may also reflect extension of the aortic dissection that compromises flow into arteries branching off the aorta. Thus, loss of a pulse in one or

Chest pain due to pulmonary embolism is believed to be due to distention of the pulmonary artery or infarction of a segment of the lung adjacent to the pleura. Massive pulmonary emboli may lead to substernal pain that is suggestive of acute myocardial infarction. More commonly, smaller emboli lead to focal pulmonary infarctions that cause pain that is lateral and pleuritic. Associated symptoms include dyspnea and, occasionally, hemoptysis. Tachycardia is usually present. Although not always present, certain characteristic ECG changes can support the diagnosis.

Neuromusculoskeletal conditions

Pneumonia or pleuritis

Cervical disk disease can cause chest pain by compression of nerve roots. Pain in a dermatomal distribution can also be caused by intercostal muscle cramps or by herpes zoster. Chest pain symptoms due to herpes zoster may occur before skin lesions are apparent. Costochondral and chondrosternal syndromes are the most common causes of anterior chest musculoskeletal pain. Only occasionally are physical signs of costochondritis such as swelling, redness, and warmth (Tietze’s syndrome) present. The pain of such syndromes is usually fleeting and sharp, but some patients experience a dull ache that lasts for hours. Direct pressure on the chondrosternal and costochondral junctions may reproduce the pain from these and other musculoskeletal syndromes. Arthritis of the shoulder and spine and bursitis may also cause chest pain. Some patients who have these conditions and myocardial ischemia blur and confuse symptoms of these syndromes.

Lung diseases that damage and cause inflammation of the pleura of the lung usually cause a sharp, knifelike pain that is aggravated by inspiration or coughing.

Emotional and psychiatric conditions

Pneumothorax Sudden onset of pleuritic chest pain and respiratory distress should lead to consideration of spontaneous pneumothorax, as well as pulmonary embolism. Such events may occur without a precipitating event in persons without lung disease, or as a consequence of underlying lung disorders.

Gastrointestinal conditions Esophageal pain from acid reflux from the stomach, spasm, obstruction, or injury can be difficult to differentiate from myocardial syndromes. Acid reflux typically causes a deep burning discomfort that may be exacerbated by alcohol, aspirin, or some foods; this discomfort is often relieved by antacid or other acid-reducing therapies. Acid reflux tends to be exacerbated by lying down and may be worse in early morning when the stomach is empty of food that might otherwise absorb gastric acid.

As many as 10% of patients who present to emergency departments with acute chest discomfort have panic disorder or other emotional conditions. The symptoms in these populations are highly variable, but frequently the discomfort is described as visceral tightness or aching that lasts more than 30 min. Some patients offer other atypical descriptions, such as pain that is fleeting, sharp, and/or localized to a small region. The ECG in patients with emotional conditions may be difficult to interpret if hyperventilation causes ST-T-wave abnormalities. A careful history may elicit clues of depression, prior panic attacks, somatization, agoraphobia, or other phobias.

Chest Discomfort

Pulmonary embolism

Esophageal spasm may occur in the presence or absence of acid reflux and leads to a squeezing pain indistinguishable from angina. Prompt relief of esophageal spasm is often provided by antianginal therapies such as sublingual nifedipine, further promoting confusion between these syndromes. Chest pain can also result from injury to the esophagus, such as a MalloryWeiss tear caused by severe vomiting. Chest pain can result from diseases of the gastrointestinal tract below the diaphragm, including peptic ulcer disease, biliary disease, and pancreatitis. These conditions usually cause abdominal pain as well as chest discomfort; symptoms are not likely to be associated with exertion. The pain of ulcer disease typically occurs 60 to 90 min after meals, when postprandial acid production is no longer neutralized by food in the stomach. Cholecystitis usually causes a pain that is described as aching, occurring an hour or more after meals.

CHAPTER 4

both arms, cerebrovascular accident, or paraplegia can all be catastrophic consequences of aortic dissection. Hematomas that extend proximally and undermine the coronary arteries or aortic valve apparatus may lead to acute myocardial infarction or acute aortic insufficiency. Rupture of the hematoma into the pericardial space leads to pericardial tamponade. Another abnormality of the aorta that can cause chest pain is a thoracic aortic aneurysm. Aortic aneurysms are frequently asymptomatic but can cause chest pain and other symptoms by compressing adjacent structures. This pain tends to be steady, deep, and sometimes severe.

APPROACH TO THE

PATIENT

Chest Discomfort

SECTION II Diagnosis of Cardiovascular Disorders

The evaluation of the patient with chest discomfort must accommodate two goals—determining the diagnosis and assessing the safety of the immediate management plan. The latter issue is often dominant when the patient has acute chest discomfort, such as patients seen in the emergency department. In such settings, the clinician must focus first on identifying patients who require aggressive interventions to diagnose or manage potentially life-threatening conditions, including acute ischemic heart disease, acute aortic dissection, pulmonary embolism, and tension pneumothorax. If such conditions are unlikely, the clinician must address questions such as the safety of discharge to home, admission to a noncoronary care unit facility, or immediate exercise testing. Table 4-3 displays a sequence of questions that can be used in the evaluation of the patient with chest discomfort, with the diagnostic entities that are most important for consideration at each stage of the evaluation.

Table 4-3 Considerations in the Assessment of the Patient With Chest Discomfort 1. Could the chest discomfort be due to an acute, potentially life-threatening condition that warrants immediate hospitalization and aggressive evaluation? Acute ischemic heart disease

Pulmonary embolism

Aortic dissection

Spontaneous pneumothorax

2. If not, could the discomfort be due to a chronic condition likely to lead to serious complications? Stable angina Aortic stenosis Pulmonary hypertension 3. If not, could the discomfort be due to an acute condition that warrants specific treatment? Pericarditis Pneumonia/pleuritis Herpes zoster 4. If not, could the discomfort be due to another treatable chronic condition? Esophageal reflux

Cervical disk disease

Esophageal spasm

Arthritis of the shoulderor spine

Peptic ulcer disease

Costochondritis

Gallbladder disease

Other musculoskeletal disorders

Other gastrointestinal conditions

Anxiety state

Acute Chest Discomfort In patients with acute chest discomfort, the clinician must first assess the patient’s respiratory and hemodynamic status. If either is compromised, initial management should focus on stabilizing the patient before the diagnostic evaluation is pursued. If, however, the patient does not require emergent interventions, then a focused history, physical examination, and laboratory evaluation should be performed to assess the patient’s risk of life-threatening conditions. Clinicians who are seeing patients in the office setting should not assume that they do not have acute ischemic heart disease, even if the prevalence may be lower. Malpractice litigation related to myocardial infarctions that were missed during office evaluations is becoming increasingly common, and ECGs were not performed in many such cases. The prevalence of highrisk patients seen in office settings may be increasing due to congestion in emergency departments. In either setting, the history should include questions about the quality and location of the chest discomfort (Table 4-2). The patient should also be asked about the nature of onset of the pain and its duration. Myocardial ischemia is usually associated with a gradual intensification of symptoms over a period of minutes. Pain that is fleeting or that lasts hours without being associated with electrocardiographic changes is not likely to be ischemic in origin. Although the presence of risk factors for coronary artery disease may heighten concern for this diagnosis, the absence of such risk factors does not lower the risk for myocardial ischemia enough to be used to justify a decision to discharge a patient. Wide radiation of chest pain increases probability that pain is due to myocardial infarction. Radiation of chest pain to the left arm is common with acute ischemic heart disease, but radiation to the right arm is also highly consistent with this diagnosis. Figure 4-1 shows estimates derived from several studies of the impact of various clinical features from the history on the probability that a patient has an acute myocardial infarction. Right shoulder pain is also common with acute cholecystitis, but this syndrome is usually accompanied by pain that is located in the abdomen rather than the chest. Chest pain that radiates between the scapulae raises the question of aortic dissection. The physical examination should include evaluation of blood pressure in both arms and of pulses in both legs. Poor perfusion of a limb may be due to an aortic dissection that has compromised flow to an artery branching from the aorta. Chest auscultation may reveal diminished breath sounds; a pleural rub; or evidence of pneumothorax, pulmonary embolism, pneumonia, or pleurisy. Tension pneumothorax may lead to a shift in the trachea from the midline, away from the side of the pneumothorax. The cardiac examination should seek

INCREASED LIKELIHOOD OF AMI Radiation to right arm or shoulder Radiation to both arms or shoulders Associated with exertion Radiation to left arm Associated with diaphoresis Associated with nausea or vomiting Worse than previous angina or similar to previous MI

CHAPTER 4

Described as pressure DECREASED LIKELIHOOD OF AMI Inframammary location Reproducible with palpation Described as sharp

Described as pleuritic 0

0.5

1.5

2.5

3.5

4.5

Likelihood ratio for AMI

Figure 4-1 Impact of chest pain characteristics on odds of acute myocardial infarction (AMI). (Figure prepared from data in CJ Swap, JT Nagurney: JAMA 294:2623, 2005.)

pericardial rubs, systolic and diastolic murmurs, and third or fourth heart sounds. Pressure on the chest wall may reproduce symptoms in patients with musculoskeletal causes of chest pain; it is important that the clinician ask the patient if the chest pain syndrome is being completely reproduced before drawing too much reassurance that more serious underlying conditions are not present. An ECG is an essential test for adults with chest discomfort that is not due to an obvious traumatic cause. In such patients, the presence of electrocardiographic changes consistent with ischemia or infarction (Chap. 11) is associated with high risks of acute myocardial infarction or unstable angina (Table 4-4); such patients should be admitted to a unit with electrocardiographic monitoring and the capacity to respond to a cardiac arrest. The absence of such changes does not exclude acute ischemic heart disease, but the risk of life-threatening complications is low for patients with normal electrocardiograms or only nonspecific ST-T-wave changes. If these patients are not considered appropriate for immediate discharge, they are often candidates for early or immediate exercise testing. Markers of myocardial injury are often obtained in the emergency department evaluation of acute chest discomfort. In recent years, the cardiac troponins (I and T) have superceded creatine kinase (CK) and CK-MB as the markers of choice for detecting myocardial injury. Some data support the use of other markers, such as

Table 4-4 Prevalence of Acute Ischemic Heart Disease Syndromes Among Subsets of Emergency Department Patients With Chest Pain

Finding

Prevalence Myocardial Infarction, Unstable % Angina, %

ST elevation (≥1 mm) or Q waves on ECG not known to be old

Ischemia or strain on ECG not known to be old (ST depression ≥1 mm or ischemic T waves)

None of the preceding ECG changes but a prior history of angina or myocardial infarction (history of heart attack or nitroglycerin use)

None of the preceding ECG changes and no prior history of angina or myocardial infarction (history of heart attack or nitroglycerin use)

Abbreviation: ECG, electrocardiogram. Source: Unpublished data from Brigham and Women’s Hospital Chest Pain Study, 1997–1999.

Chest Discomfort

Described as positional

SECTION II Diagnosis of Cardiovascular Disorders

myeloperoxidase and B-type natriuretic peptide (BNP), but their roles in routine care have not been established. Single values of any of these markers do not have high sensitivity for acute myocardial infarction or for prediction of complications. Hence, decisions to discharge patients home should not be made on the basis of single negative values of these tests, including the cardiac troponins. Provocative tests for coronary artery disease are not appropriate for patients with ongoing chest pain. In such patients, rest myocardial perfusion scans can be considered; a normal scan reduces the likelihood of coronary artery disease and can help avoid admission of low-risk patients to the hospital. Computerized tomographic angiography (CTA) is emerging as an alternative diagnostic strategy for patients in whom the likelihood of coronary disease is not clear. Clinicians frequently employ therapeutic trials with sublingual nitroglycerin or antacids or, in the stable patient seen in the office setting, a proton pump inhibitor. A common error is to assume that a response to any of these interventions clarifies the diagnosis. While such information is often helpful, the patient’s response may be due to the placebo effect. Hence, myocardial ischemia should never be considered excluded solely because of a response to antacid therapy. Similarly, failure of nitroglycerin to relieve pain does not exclude the diagnosis of coronary disease. If the patient’s history or examination is consistent with aortic dissection, imaging studies to evaluate the aorta must be pursued promptly because of the high risk of catastrophic complications with this condition. Appropriate tests include a chest CT scan with contrast, MRI, or transesophageal echocardiography. Current data indicate that elevated d-dimer levels should raise clinicians’ suspicion of aortic dissection. Acute pulmonary embolism should be considered in patients with respiratory symptoms, pleuritic chest pain, hemoptysis, or a history of venous thromboembolism or coagulation abnormalities. Initial tests usually include CT angiography or a lung scan, which are sometimes combined with lower extremity venous ultrasound or d-dimer testing. If patients with acute chest discomfort show no evidence of life-threatening conditions, the clinician should then focus on serious chronic conditions with the potential to cause major complications, the most common of which is stable angina. Early use of exercise electrocardiography, stress echocardiography, or stress perfusion imaging for such patients, whether in the office or the emergency department, is now an accepted management strategy for low-risk patients. Exercise testing is not appropriate, however, for patients who (1) report pain that is believed to be ischemic occurring at rest or (2) have electrocardiographic

changes not known to be old that are consistent with ischemia. Patients with sustained chest discomfort who do not have evidence for life-threatening conditions should be evaluated for evidence of conditions likely to benefit from acute treatment (Table 4-3). Pericarditis may be suggested by the history, physical examination, and ECG (Table 4-2). Clinicians should carefully assess blood pressure patterns and consider echocardiography in such patients to detect evidence of impending pericardial tamponade. Chest x-rays can be used to evaluate the possibility of pulmonary disease.

Guidelines and Critical Pathways for Acute Chest Discomfort Guidelines for the initial evaluation for patients with acute chest pain have been developed by the American College of Cardiology, American Heart Association, and other organizations. These guidelines recommend performance of an ECG for virtually all patients with chest pain who do not have an obvious noncardiac cause of their pain, and performance of a chest x-ray for patients with signs or symptoms consistent with congestive heart failure, valvular heart disease, pericardial disease, or aortic dissection or aneurysm. The American College of Cardiology/American Heart Association guidelines on exercise testing support its use in low-risk patients presenting to the emergency department, as well as in selected intermediaterisk patients. However, these guidelines emphasize that exercise tests should be performed only after patients have been screened for high-risk features or other indicators for hospital admission. Many medical centers have adopted critical pathways and other forms of guidelines to increase efficiency and to expedite the treatment of patients with high-risk acute ischemic heart disease syndromes. These guidelines emphasize the following strategies: • Rapid identification and treatment of patients for whom emergent reperfusion therapy, either via percutaneous coronary interventions or thrombolytic agents, is likely to lead to improved outcomes. • Triage to non-coronary care unit monitored facilities such as intermediate-care units or chest pain units of patients with a low risk for complications, such as patients without new ischemic changes on their ECGs and without ongoing chest pain. Such patients can usually be safely observed in non- coronary care unit settings, undergo early exercise testing, or be discharged home. Risk stratification can be assisted through use of prospectively validated multivariate algorithms that have been published for acute ischemic heart disease and its complications.

• Shortening lengths of stay in the coronary care unit and hospital. Recommendations regarding the minimum length of stay in a monitored bed for a patient who has no further symptoms have decreased in recent years to 12 h or less if exercise testing or other risk stratification technologies are available.

The management of patients who do not require admission to the hospital or who no longer require inpatient

CHAPTER 4

Nonacute chest discomfort

observation should seek to identify the cause of the symptoms and the likelihood of major complications. Noninvasive tests for coronary disease serve both to diagnose this condition and to identify patients with high-risk forms of coronary disease who may benefit from revascularization. Gastrointestinal causes of chest pain can be evaluated via endoscopy or radiology studies, or with trials of medical therapy. Emotional and psychiatric conditions warrant appropriate evaluation and treatment; randomized trial data indicate that cognitive therapy and group interventions lead to decreases in symptoms for such patients.

Chest Discomfort

CHaPTEr 5

DYSPNEA Richard M. Schwartzstein

ALGORITHM FOR THE INPUTS IN DYSPNEA PRODUCTION

dySPnEa

Respiratory centers (Respiratory drive)

he American Thoracic Society defines dyspnea as a T “subjective experience of breathing discomfort that consists of qualitatively distinct sensations that vary in intensity. The experience derives from interactions among multiple physiological, psychological, social, and environmental factors and may induce secondary physiological and behavioral responses.” Dyspnea, a symptom, must be distinguished from the signs of increasedworkofbreathing.

Chemoreceptors Mechanoreceptors Metaboreceptors

Sensory cortex Feedback Feed-forward

Corollary discharge Motor cortex

Error signal Dyspnea intensity and quality

Ventilatory muscles

Figure 5-1 hypothetical model for integration of sensory inputs in the production of dyspnea. Afferent information from the receptors throughout the respiratory system projects directly to the sensory cortex to contribute to primary qualitative sensory experiences and provide feedback on the action of the ventilatory pump. Afferents also project to the areas of the brain responsible for control of ventilation. The motor cortex, responding to input from the control centers, sends neural messages to the ventilatory muscles and a corollary discharge to the sensory cortex (feed-forward with respect to the instructions sent to the muscles). If the feed-forward and feedback messages do not match, an error signal is generated and the intensity of dyspnea increases. (Adapted from MA Gillette, RM Schwartzstein: Mechanisms of dyspnea, in Supportive Care in Respiratory Disease, SH Ahmedzai and MF Muer [eds]. Oxford, UK, Oxford University Press, 2005.)

MechAnisMs of DyspneA espiratory sensations are the consequence of interacR tions between the efferent, or outgoing, motor output fromthebraintotheventilatorymuscles(feed-forward) andtheafferent,orincoming,sensoryinputfromreceptors throughout the body (feedback), as well as the integrative processing of this information that we infer must be occurring in the brain (Fig. 5-1). In contrast to painful sensations, which can often be attributed to thestimulationofasinglenerveending,dyspneasensationsaremorecommonlyviewedasholistic,moreakin to hunger or thirst. A given disease state may lead to dyspnea by one or more mechanisms, some of which maybeoperativeundersomecirc*mstances,e.g.,exercise,butnotothers,e.g.,achangeinposition. Motor efferents

corollary discharge, a neural signal that is sent to the sensory cortex at the same time that motor output is directedtotheventilatorymuscles.

isorders of the ventilatory pump, most commonly D increase airway resistance or stiffness (decreased compliance) of the respiratory system, are associated with increased work of breathing or a sense of an increased effort to breathe. When the muscles are weak or fatigued, greater effort is required, even though the mechanics of the system are normal. The increased neural output from the motor cortex is sensed via a

Sensory afferents hemoreceptors in the carotid bodies and medulla C are activated by hypoxemia, acute hypercapnia, and acidemia. Stimulation of these receptors, as well as

A discrepancy or mismatch between the feed-forward message to the ventilatory muscles and the feedback from receptors that monitor the response of the ventilatory pump increases the intensity of dyspnea. This is particularly important when there is a mechanical derangement of the ventilatory pump, such as in asthma or chronic obstructive pulmonary disease (COPD). Anxiety Acute anxiety may increase the severity of dyspnea either by altering the interpretation of sensory data or by leading to patterns of breathing that heighten physiologic abnormalities in the respiratory system. In patients with expiratory flow limitation, for example, the increased respiratory rate that accompanies acute anxiety leads to hyperinflation, increased work and effort of breathing, and a sense of an unsatisfying breath.

Assessing Dyspnea Quality of sensation As with pain, dyspnea assessment begins with a determination of the quality of the discomfort (Table 5-1). Dyspnea questionnaires, or lists of phrases commonly used by patients, assist those who have difficulty describing their breathing sensations. Sensory intensity A modified Borg scale or visual analogue scale can be utilized to measure dyspnea at rest, immediately following exercise, or on recall of a reproducible physical task, e.g., climbing the stairs at home. An alternative approach is to inquire about the activities a patient can do, i.e., to gain a sense of the patient’s disability. The Baseline Dyspnea Index and the Chronic Respiratory Disease Questionnaire are commonly used tools for this purpose.

Association of Qualitative Descriptors and Pathophysiologic Mechanisms of Shortness of Breath Descriptor

Pathophysiology

Chest tightness or constriction

Bronchoconstriction, interstitial edema (asthma, myocardial ischemia)

Increased work or effort of breathing

Airway obstruction, neuromuscular disease (COPD, moderate to severe asthma, myopathy, kyphoscoliosis)

Air hunger, need to breathe, urge to breathe

Increased drive to breathe (CHF, pulmonary embolism, moderate to severe airflow obstruction)

Cannot get a deep breath, unsatisfying breath

Hyperinflation (asthma, COPD) and restricted tidal volume (pulmonary fibrosis, chest wall restriction)

Heavy breathing, rapid breathing, breathing more

Deconditioning

Abbreviations: CHF, congestive heart failure; COPD, chronic obstructive pulmonary disease. Source: From RM Schwartzstein: The language of dyspnea, in Dyspnea: Mechanisms, Measurement, and Management, DA Mahler and DE O’Donnell (eds). New York, Marcel Dekker, 2005 and RM Schwartzstein, D Feller-Kopman: Shortness of breath, in Primary Cardiology, 2nd ed, E Braunwald and L Goldman (eds). Philadelphia, WB Saunders, 2003.

Affective dimension For a sensation to be reported as a symptom, it must be perceived as unpleasant and interpreted as abnormal. Laboratory studies have demonstrated that air hunger evokes a stronger affective response than does increased effort or work of breathing. Some therapies for dyspnea, such as pulmonary rehabilitation, may reduce breathing discomfort, in part, by altering this dimension.

Differential Diagnosis Dyspnea is the consequence of deviations from normal function in the cardiopulmonary systems. These deviations produce breathlessness as a consequence of increased drive to breathe; increased effort or work of breathing; and/or stimulation of receptors in the heart, lungs, or vascular system. Most diseases of the respiratory system are associated with alterations in the mechanical properties of the lungs and/or chest wall, frequently as a consequence of disease of the airways or lung parenchyma. In contrast, disorders of the cardiovascular system more commonly lead to dyspnea by causing gas exchange abnormalities or stimulating pulmonary and/or vascular receptors (Table 5-2).

Dyspnea

Integration: Efferent-reafferent mismatch

Table 5-1

CHAPTER 5

thers that lead to an increase in ventilation, produce a o sensation of air hunger. Mechanoreceptors in the lungs, when stimulated by bronchospasm, lead to a sensation of chest tightness. J-receptors, sensitive to interstitial edema, and pulmonary vascular receptors, activated by acute changes in pulmonary artery pressure, appear to contribute to air hunger. Hyperinflation is associated with the sensation of increased work of breathing and an inability to get a deep breath or of an unsatisfying breath. Metaboreceptors, located in skeletal muscle, are believed to be activated by changes in the local biochemical milieu of the tissue active during exercise and, when stimulated, contribute to the breathing discomfort.

Table 5-2 Mechanisms of Dyspnea in Common Diseases

Disease

↑ Work of breathing

↑ Drive to breathe

Hypoxemiaa

Acute Hypercapniaa

•

Stimulation of pulmonary receptors

SECTION II

COPD

•

Asthma

•

ILD

•

PVD

•

CPE

•

NCPE

•

Stimulation of vascular receptors

Metaboreceptors

• •

•

Diagnosis of Cardiovascular Disorders

Anemia

•

Decond

•

Hypoxemia and hypercapnia are not always present in these conditions. When hypoxemia is present, dyspnea usually persists, albeit at a reduced intensity, with correction of hypoxemia by the administration of supplemental oxygen. Abbreviations: COPD, chronic obstructive pulmonary disease; CPE, cardiogenic pulmonary edema; Decond, deconditioning; ILD, interstitial lung disease; NCPE, noncardiogenic pulmonary edema; PVD, pulmonary vascular disease.

Respiratory system dyspnea Diseases of the airways

Asthma and COPD, the most common obstructive lung diseases, are characterized by expiratory airflow obstruction, which typically leads to dynamic hyperinflation of the lungs and chest wall. Patients with moderate to severe disease have increased resistive and elastic loads (a term that relates to the stiffness of the system) on the ventilatory muscles and increased work of breathing. Patients with acute bronchoconstriction also complain of a sense of tightness, which can exist even when lung function is still within the normal range. These patients commonly hyperventilate. Both the chest tightness and hyperventilation are probably due to stimulation of pulmonary receptors. Both asthma and COPD may lead to hypoxemia and hypercapnia . from ventilation-perfusion (V/Q) mismatch (and diffusion limitation during exercise with emphysema); hypoxemia is much more common than hypercapnia as a consequence of the different ways in which oxygen and carbon dioxide bind to hemoglobin. Diseases of the chest wall

Conditions that stiffen the chest wall, such as kyphoscoliosis, or that weaken ventilatory muscles, such as myasthenia gravis or the Guillain-Barré syndrome, are also associated with an increased effort to breathe. Large pleural effusions may contribute to dyspnea, both by increasing the work of breathing and by stimulating pulmonary receptors if there is associated atelectasis. Diseases of the lung parenchyma

Interstitial lung diseases, which may arise from infections, occupational exposures, or autoimmune disorders,

are associated with increased stiffness (decreased compliance) of the. lungs and increased work of breathing. In addition, V/Q mismatch, and destruction and/or thickening of the alveolar-capillary interface may lead to hypoxemia and an increased drive to breathe. Stimulation of pulmonary receptors may further enhance the hyperventilation characteristic of mild to moderate interstitial disease. Cardiovascular system dyspnea Diseases of the left heart

Diseases of the myocardium resulting from coronary artery disease and nonischemic cardiomyopathies result in a greater left-ventricular end-diastolic volume and an elevation of the left-ventricular end-diastolic, as well as pulmonary capillary pressures. These elevated pressures lead to interstitial edema and stimulation of pulmonary receptors, thereby causing dyspnea; hypoxemia due to . V/Q mismatch may also contribute to breathlessness. Diastolic dysfunction, characterized by a very stiff left ventricle, may lead to severe dyspnea with relatively mild degrees of physical activity, particularly if it is associated with mitral regurgitation. Diseases of the pulmonary vasculature

Pulmonary thromboembolic disease and primary diseases of the pulmonary circulation (primary pulmonary hypertension, pulmonary vasculitis) cause dyspnea via increased pulmonary-artery pressure and stimulation of pulmonary receptors. Hyperventilation is common, and hypoxemia may be present. However, in most cases, use of supplemental oxygen has minimal effect on the severity of dyspnea and hyperventilation.

Diseases of the pericardium

Constrictive pericarditis and cardiac tamponade are both associated with increased intracardiac and pulmonary vascular pressures, which are the likely cause of dyspnea in these conditions. To the extent that cardiac output is limited, at rest or with exercise, stimulation of metaboreceptors and chemoreceptors (if lactic acidosis develops) contribute as well.

APPROACH TO THE

PATIENT

Dyspnea

(Fig. 5-2) In obtaining a history, the patient should be asked to describe in his/her own words what the discomfort feels like, as well as the effect of position, infections, and environmental stimuli on the dyspnea. Orthopnea is a common indicator of congestive heart failure (CHF), mechanical impairment of the diaphragm associated with obesity, or asthma triggered by esophageal reflux. Nocturnal dyspnea suggests CHF or asthma. Acute, intermittent episodes of dyspnea are more likely to reflect episodes of myocardial ischemia, bronchospasm, or pulmonary embolism, while chronic persistent dyspnea is typical of COPD, interstitial lung disease, and chronic thromboembolic disease. Risk factors for occupational lung disease and for coronary artery disease should be elicited. Left atrial myxoma or hepatopulmonary syndrome should be considered when the patient complains of platypnea, defined as dyspnea in the upright position with relief in the supine position. The physical examination should begin during the interview of the patient. Inability of the patient to speak in full sentences before stopping to get a deep breath suggests a condition that leads to stimulation of the controller or an impairment of the ventilatory pump with reduced vital capacity. Evidence for increased work of breathing (supraclavicular retractions, use of accessory muscles of ventilation, and the tripod position, characterized by sitting with one’s hands braced on the knees) is indicative of increased airway resistance

Dyspnea

Mild to moderate anemia is associated with breathing discomfort during exercise. This is thought to be related to stimulation of metaboreceptors; oxygen saturation is normal in patients with anemia. The breathlessness associated with obesity is probably due to multiple mechanisms, including high cardiac output and impaired ventilatory pump function (decreased compliance of the chest wall). Cardiovascular deconditioning (poor fitness) is characterized by the early development of anaerobic metabolism and the stimulation of chemoreceptors and metaboreceptors.

CHAPTER 5

Dyspnea with normal respiratory and cardiovascular systems

or stiff lungs and chest wall. When measuring the vital signs, one should accurately assess the respiratory rate and measure the pulsus paradoxus (Chap. 22); if it is >10 mmHg, consider the presence of COPD or acute asthma. During the general examination, signs of anemia (pale conjunctivae), cyanosis, and cirrhosis (spider angiomata, gynecomastia) should be sought. Examination of the chest should focus on symmetry of movement; percussion (dullness indicative of pleural effusion, hyperresonance a sign of emphysema); and auscultation (wheezes, rales, rhonchi, prolonged expiratory phase, diminished breath sounds, which are clues to disorders of the airways, and interstitial edema or fibrosis). The cardiac examination should focus on signs of elevated right heart pressures (jugular venous distention, edema, accentuated pulmonic component to the second heart sound); left ventricular dysfunction (S3 and S4 gallops); and valvular disease (murmurs). When examining the abdomen with the patient in the supine position, it should be noted whether there is paradoxical movement of the abdomen (inward motion during inspiration), a sign of diaphragmatic weakness; rounding of the abdomen during exhalation is suggestive of pulmonary edema. Clubbing of the digits may be an indication of interstitial pulmonary fibrosis, and the presence of joint swelling or deformation as well as changes consistent with Raynaud’s disease may be indicative of a collagen-vascular process that can be associated with pulmonary disease. Patients with exertional dyspnea should be asked to walk under observation in order to reproduce the symptoms. The patient should be examined for new findings that were not present at rest and for oxygen saturation. Following the history and physical examination, a chest radiograph should be obtained. The lung volumes should be assessed (hyperinflation indicates obstructive lung disease; low lung volumes suggest interstitial edema or fibrosis, diaphragmatic dysfunction, or impaired chest wall motion). The pulmonary parenchyma should be examined for evidence of interstitial disease and emphysema. Prominent pulmonary vasculature in the upper zones indicates pulmonary venous hypertension, while enlarged central pulmonary arteries suggest pulmonary artery hypertension. An enlarged cardiac silhouette suggests a dilated cardiomyopathy or valvular disease. Bilateral pleural effusions are typical of CHF and some forms of collagen vascular disease. Unilateral effusions raise the specter of carcinoma and pulmonary embolism but may also occur in heart failure. Computed tomography (CT) of the chest is generally reserved for further evaluation of the lung parenchyma (interstitial lung disease) and possible pulmonary embolism. Laboratory studies should include an electrocardiogram to look for evidence of ventricular hypertrophy and prior myocardial infarction. Echocardiography is indicated in patients in

ALGORITHM FOR THE EVALUATION OF THE PATIENT WITH DYSPNEA History Quality of sensation, timing, positional disposition Persistent vs intermittent Physical Exam

SECTION II

General appearance: Speak in full sentences? Accessory muscles? Color? Vital signs: Tachypnea? Pulsus paradoxus? Oximetry-evidence of desaturation? Chest: Wheezes, rales, rhonchi, diminished breath sounds? Hyperinflated? Cardiac exam: JVP elevated? Precordial impulse? Gallop? Murmur? Extremities: Edema? Cyanosis?

At this point, diagnosis may be evident—if not, proceed to further evaluation

Diagnosis of Cardiovascular Disorders

Chest radiograph Assess cardiac size, evidence of CHF Assess for hyperinflation Assess for pneumonia, interstitial lung disease, pleural effusions

Suspect low cardiac output, myocardial ischemia, or pulmonary vascular disease

Suspect respiratory pump or gas exchange abnormality

Suspect high cardiac output

ECG and echocardiogram to assess left ventricular function and pulmonary artery pressure

Pulmonary function testing—if diffusing capacity reduced, consider CT angiogram to assess for interstitial lung disease and pulmonary embolism

Hematocrit, thyroid function tests

If diagnosis still uncertain, obtain cardiopulmonary exercise test

Figure 5-2 An algorithm for the evaluation of the patient with dyspnea. JVP, jugular venous pulse; CHF, congestive heart failure; ECG, electrocardiogram; CT, computed tomography. (Adapted from RM Schwartzstein: The language of dyspnea, in Dyspnea: Mechanisms, Measurement, and Management,

whom systolic dysfunction, pulmonary hypertension, or valvular heart disease is suspected. Bronchoprovocation testing is useful in patients with intermittent symptoms suggestive of asthma but normal physical examination and lung function; up to one-third of patients with the clinical diagnosis of asthma do not have reactive airways disease when formally tested.

DA Mahler and DE O’Donnell [eds]. New York, Marcel Dekker, 2005 and RM Schwartzstein, D Feller-Kopman: Shortness of breath, in Primary Cardiology, 2nd ed, E Braunwald and L Goldman [eds]. Philadelphia, WB Saunders, 2003.)

the problem. Alternatively, if the heart rate is >85% of the predicted maximum, if anaerobic threshold occurs early, if the blood pressure becomes excessively high or decreases during exercise, if the O2 pulse (O2 consumption/heart rate, an indicator of stroke volume) falls, or if there are ischemic changes on the electrocardiogram, an abnormality of the cardiovascular system is likely the explanation for the breathing discomfort.

Distinguishing Cardiovascular From Respiratory System Dyspnea

If a patient has evidence of both pulmonary and cardiac disease, a cardiopulmonary exercise test should be carried out to determine which system is responsible for the exercise limitation. If, at peak exercise, the patient achieves predicted maximal ventilation, demonstrates an increase in dead space or hypoxemia, or develops bronchospasm, the respiratory system is probably the cause of

treatment

Dyspnea

The first goal is to correct the underlying problem responsible for the symptom. If this is not possible, one attempts to lessen the intensity of the symptom and its effect on the patient’s quality of life. Supplemental

Mechanisms of Fluid Accumulation The extent to which fluid accumulates in the interstitium of the lung depends on the balance of hydrostatic and oncotic forces within the pulmonary capillaries and in the surrounding tissue. Hydrostatic pressure favors movement of fluid from the capillary into the interstitium. The oncotic pressure, which is determined by the protein concentration in the blood, favors movement of fluid into the vessel. Albumin, the primary protein in the plasma, may be low in conditions such as cirrhosis and nephrotic syndrome. While hypoalbuminemia favors movement of fluid into the tissue for any given hydrostatic pressure in the capillary, it is usually not sufficient by itself to cause interstitial edema. In a healthy individual, the tight junctions of the capillary endothelium are impermeable to proteins, and the lymphatics in the tissue carry away the small amounts of protein that may leak out; together, these factors result in an oncotic force that maintains fluid in the capillary. Disruption of the endothelial barrier, however, allows protein to escape the capillary bed and enhances the movement of fluid into the tissue of the lung. Cardiogenic pulmonary edema (See also Chap. 28) Cardiac abnormalities that lead to an increase in pulmonary venous pressure shift the balance of forces between the capillary and the interstitium. Hydrostatic pressure is increased and fluid exits the capillary at an increased rate, resulting in interstitial and, in more severe cases, alveolar edema. The development of pleural effusions may further compromise respiratory system function and contribute to breathing discomfort. Early signs of pulmonary edema include exertional dyspnea and orthopnea. Chest radiographs show peribronchial thickening, prominent vascular markings in the upper lung zones, and Kerley B lines. As the pulmonary edema worsens, alveoli fill with fluid; the chest radiograph shows patchy alveolar filling, typically in a

Noncardiogenic pulmonary edema In noncardiogenic pulmonary edema, lung water increases due to damage of the pulmonary capillary lining with leakage of proteins and other macromolecules into the tissue; fluid follows the protein as oncotic forces are shifted from the vessel to the surrounding lung tissue. This process is associated with dysfunction of the surfactant lining the alveoli, increased surface forces, and a propensity for the alveoli to collapse at low lung volumes. Physiologically, noncardiogenic pulmonary edema is characterized by intrapulmonary shunt with hypoxemia and decreased pulmonary compliance. Pathologically, hyaline membranes are evident in the alveoli, and inflammation leading to pulmonary fibrosis may be seen. Clinically, the picture ranges from mild dyspnea to respiratory failure. Auscultation of the lungs may be relatively normal despite chest radiographs that show diffuse alveolar infiltrates. CT scans demonstrate that the distribution of alveolar edema is more heterogeneous than was once thought. Although normal intracardiac pressures are considered by many to be part of the definition of noncardiogenic pulmonary edema, the pathology of the process, as described earlier, is distinctly different, and one can observe a combination of cardiogenic and noncardiogenic pulmonary edema in some patients. It is useful to categorize the causes of noncardiogenic pulmonary edema in terms of whether the injury to the lung is likely to result from direct, indirect, or pulmonary vascular causes (Table 5-3). Direct injuries are mediated via the airways (e.g., aspiration) or as the consequence of blunt chest trauma. Indirect injury is the consequence of mediators that reach the lung via the bloodstream. The third category includes conditions that may be the consequence of acute changes in pulmonary vascular pressures, possibly the result of sudden autonomic discharge in the case of neurogenic and highaltitude pulmonary edema, or sudden swings of pleural pressure, as well as transient damage to the pulmonary capillaries in the case of reexpansion pulmonary edema.

Distinguishing cardiogenic from noncardiogenic pulmonary edema The history is essential for assessing the likelihood of underlying cardiac disease as well as for identification of one of the conditions associated with noncardiogenic pulmonary edema. The physical examination in cardiogenic pulmonary edema is notable for evidence of

Dyspnea

Pulmonary Edema

perihilar distribution, which then progresses to diffuse alveolar infiltrates. Increasing airway edema is associated with rhonchi and wheezes.

CHAPTER 5

O2should be administered if the resting O2 saturation is ≤89% or if the patient’s saturation drops to these levels with activity. For patients with COPD, pulmonary rehabilitation programs have demonstrated positive effects on dyspnea, exercise capacity, and rates of hospitalization. Studies of anxiolytics and antidepressants have not demonstrated consistent benefit. Experimental interventions—e.g., cold air on the face, chest-wall vibration, and inhaled furosemide—to modulate the afferent information from receptors throughout the respiratory system are being studied.

Table 5-3 Common Causes of Noncardiogenic Pulmonary Edema Direct Injury to Lung

SECTION II

Chest trauma, pulmonary contusion Aspiration Smoke inhalation Pneumonia Oxygen toxicity Pulmonary embolism, reperfusion Hematogenous Injury to Lung

Diagnosis of Cardiovascular Disorders

Sepsis Pancreatitis Nonthoracic trauma Leukoagglutination reactions Multiple transfusions Intravenous drug use, e.g., heroin Cardiopulmonary bypass Possible Lung Injury Plus Elevated Hydrostatic Pressures High-altitude pulmonary edema Neurogenic pulmonary edema Reexpansion pulmonary edema

increased intracardiac pressures (S3 gallop, elevated jugular venous pulse, peripheral edema), and rales and/or wheezes on auscultation of the chest. In contrast, the physical examination in noncardiogenic pulmonary edema is dominated by the findings of the precipitating condition; pulmonary findings may be relatively normal in the early stages. The chest radiograph in cardiogenic pulmonary edema typically shows an enlarged cardiac silhouette, vascular redistribution, interstitial thickening, and perihilar alveolar infiltrates; pleural effusions are common. In noncardiogenic pulmonary edema, heart size is normal, alveolar infiltrates are distributed more uniformly throughout the lungs, and pleural effusions are uncommon. Finally, the hypoxemia. of cardiogenic pulmonary edema is due largely to V/Q mismatch and responds to the administration of supplemental oxygen. In contrast, hypoxemia in noncardiogenic pulmonary edema is due primarily to intrapulmonary shunting and typically persists despite high concentrations of inhaled O2.

CHaPTER 6

HYPOXIA AND CYANOSIS Joseph Loscalzo Ca2+ channels raising the cytosolic [Ca2+] and causing smooth-muscle cell contraction. Hypoxia-induced pulmonary arterial constriction shunts blood away from poorly ventilated portions toward better ventilated portions of the lung; however, it also increases pulmonary vascular resistance and right ventricular afterload.

HyPoXia The fundamental purpose of the cardiorespiratory system is to deliver O2 and nutrients to cells and to remove CO2 and other metabolic products from them. Proper maintenance of this function depends not only on intact cardiovascular and respiratory systems but also on an adequate number of red blood cells and hemoglobin and a supply of inspired gas containing adequate O2.

Effects on the central nervous system Changes in the central nervous system (CNS), particularly the higher centers, are especially important consequences of hypoxia. Acute hypoxia causes impaired judgment, motor incoordination, and a clinical picture resembling acute alcohol intoxication. High-altitude illness is characterized by headache secondary to cerebral vasodilation, gastrointestinal symptoms, dizziness, insomnia, fatigue, or somnolence. Pulmonary arterial and sometimes venous constriction cause capillary leakage and high-altitude pulmonary edema (HAPE) (Chap. 5), which intensifies hypoxia, further promoting vasoconstriction. Rarely, high-altitude cerebral edema (HACE) develops, which is manifest by severe headache and papilledema and can cause coma. As hypoxia becomes more severe, the regulatory centers of the brainstem are affected, and death usually results from respiratory failure.

responses to HypoxiA Decreased O2 availability to cells results in an inhibition of oxidative phosphorylation and increased anaerobic glycolysis. This switch from aerobic to anaerobic metabolism, the Pasteur effect, maintains some, albeit reduced, adenosine 5’-triphosphate (ATP) production. In severe hypoxia, when ATP production is inadequate to meet the energy requirements of ionic and osmotic equilibrium, cell membrane depolarization leads to uncontrolled Ca2+ influx and activation of Ca2+-dependent phospholipases and proteases. These events, in turn, cause cell swelling and, ultimately, cell death. The adaptations to hypoxia are mediated, in part, by the upregulation of genes encoding a variety of proteins, including glycolytic enzymes such as phosphoglycerate kinase and phosphofructokinase, as well as the glucose transporters Glut-1 and Glut-2; and by growth factors, such as vascular endothelial growth factor (VEGF) and erythropoietin, which enhance erythrocyte production. The hypoxia-induced increase in expression of these key proteins is governed by the hypoxia-sensitive transcription factor, hypoxia-inducible factor-1 (HIF-1). During hypoxia, systemic arterioles dilate, at least in part, by opening of KATP channels in vascular smoothmuscle cells due to the hypoxia-induced reduction in ATP concentration. By contrast, in pulmonary vascular smooth-muscle cells, inhibition of K+ channels causes depolarization which, in turn, activates voltage-gated

CAuses of HypoxiA Respiratory hypoxia When hypoxia occurs from respiratory failure, Pao2 declines, and when respiratory failure is persistent, the hemoglobin-oxygen (Hb-O2) dissociation curve is displaced to the right, with greater quantities of O2 released at any level of tissue Po2. Arterial hypoxemia, i.e., a reduction of O2 saturation of arterial blood (Sao2), and consequent cyanosis are likely to be more marked when such depression of Pao2 results from pulmonary disease than when the depression occurs as the

Section II Diagnosis of Cardiovascular Disorders

result of a decline in the fraction of oxygen in inspired air (Fio2). In this latter situation, Paco2 falls secondary to anoxia-induced hyperventilation and the Hb-O2 dissociation curve is displaced to the left, limiting the decline in Sao2 at any level of Pao2. The most common cause of respiratory hypoxia is ventilation-perfusion mismatch resulting from perfusion of poorly ventilated alveoli. Respiratory hypoxemia may also be caused by hypoventilation, in which case it is then associated with an elevation of Paco2. These two forms of respiratory hypoxia are usually correctable by inspiring 100% O2 for several minutes. A third cause of respiratory hypoxia is shunting of blood across the lung from the pulmonary arterial to the venous bed (intrapulmonary right-to-left shunting) by perfusion of nonventilated portions of the lung, as in pulmonary atelectasis or through pulmonary arteriovenous connections. The low Pao2 in this situation is only partially corrected by an Fio2 of 100%. Hypoxia secondary to high altitude As one ascends rapidly to 3000 m (∼10,000 ft), the reduction of the O2 content of inspired air (Fio2) leads to a decrease in alveolar Po2 to approximately 60 mmHg, and a condition termed high-altitude illness develops (see earlier). At higher altitudes, arterial saturation declines rapidly and symptoms become more serious; and at 5000 m, unacclimated individuals usually cease to be able to function normally owing to the changes in CNS function described earlier. Hypoxia secondary to right-to-left extrapulmonary shunting From a physiologic viewpoint, this cause of hypoxia resembles intrapulmonary right-to-left shunting but is caused by congenital cardiac malformations, such as tetralogy of Fallot, transposition of the great arteries, and Eisenmenger’s syndrome (Chap. 19). As in pulmonary right-to-left shunting, the Pao2 cannot be restored to normal with inspiration of 100% O2. Anemic hypoxia A reduction in hemoglobin concentration of the blood is accompanied by a corresponding decline in the O2carrying capacity of the blood. Although the Pao2 is normal in anemic hypoxia, the absolute quantity of O2 transported per unit volume of blood is diminished. As the anemic blood passes through the capillaries and the usual quantity of O2 is removed from it, the Po2 and saturation in the venous blood decline to a greater extent than normal.

Carbon monoxide (CO) intoxication Hemoglobin that binds with CO (carboxyhemoglobin, COHb) is unavailable for O2 transport. In addition, the presence of COHb shifts the Hb-O2 dissociation curve to the left so that O2 is unloaded only at lower tensions, contributing further to tissue hypoxia. Circulatory hypoxia As in anemic hypoxia, the Pao2 is usually normal, but venous and tissue Po2 values are reduced as a consequence of reduced tissue perfusion and greater tissue O2 extraction. This pathophysiology leads to an increased arterial-mixed venous O2 difference (a-v-O2 difference), or gradient. Generalized circulatory hypoxia occurs in heart failure (Chap. 17) and in most forms of shock. Specific organ hypoxia Localized circulatory hypoxia may occur as a result of decreased perfusion secondary to arterial obstruction, as in localized atherosclerosis in any vascular bed, or as a consequence of vasoconstriction, as observed in Raynaud’s phenomenon (Chap. 39). Localized hypoxia may also result from venous obstruction and the resultant expansion of interstitial fluid causing arteriolar compression and, thereby, reduction of arterial inflow. Edema, which increases the distance through which O2 must diffuse before it reaches cells, can also cause localized hypoxia. In an attempt to maintain adequate perfusion to more vital organs in patients with reduced cardiac output secondary to heart failure or hypovolemic shock, vasoconstriction may reduce perfusion in the limbs and skin, causing hypoxia of these regions. Increased O2 requirements If the O2 consumption of tissues is elevated without a corresponding increase in perfusion, tissue hypoxia ensues and the Po2 in venous blood declines. Ordinarily, the clinical picture of patients with hypoxia due to an elevated metabolic rate, as in fever or thyrotoxicosis, is quite different from that in other types of hypoxia: the skin is warm and flushed owing to increased cutaneous blood flow that dissipates the excessive heat produced, and cyanosis is usually absent. Exercise is a classic example of increased tissue O2 requirements. These increased demands are normally met by several mechanisms operating simultaneously: (1) increase in the cardiac output and ventilation and, thus, O2 delivery to the tissues; (2) a preferential shift in blood flow to the exercising muscles by changing vascular resistances in the circulatory beds of exercising

tissues, directly and/or reflexly; (3) an increase in O2 extraction from the delivered blood and a widening of the arteriovenous O2 difference; and (4) a reduction in the pH of the tissues and capillary blood, shifting the Hb-O2 curve to the right, and unloading more O2 from hemoglobin. If the capacity of these mechanisms is exceeded, then hypoxia, especially of the exercising muscles, will result.

Adaptation to Hypoxia An important component of the respiratory response to hypoxia originates in special chemosensitive cells in the carotid and aortic bodies and in the respiratory center in the brainstem. The stimulation of these cells by hypoxia increases ventilation, with a loss of CO2, and can lead to respiratory alkalosis. When combined with the metabolic acidosis resulting from the production of lactic acid, the serum bicarbonate level declines. With the reduction of Pao2, cerebrovascular resistance decreases and cerebral blood flow increases in an attempt to maintain O2 delivery to the brain. However, when the reduction of Pao2 is accompanied by hyperventilation and a reduction of Paco2, cerebrovascular resistance rises, cerebral blood flow falls, and tissue hypoxia intensifies. The diffuse, systemic vasodilation that occurs in generalized hypoxia increases the cardiac output. In patients with underlying heart disease, the requirements of peripheral tissues for an increase of cardiac output with hypoxia may precipitate congestive heart failure. In patients with ischemic heart disease, a reduced Pao2 may intensify myocardial ischemia and further impair left ventricular function. One of the important compensatory mechanisms for chronic hypoxia is an increase in the hemoglobin concentration and in the number of red blood cells in the circulating blood, i.e., the development of polycythemia secondary to erythropoietin production. In persons with chronic hypoxemia secondary to prolonged residence at a high altitude (>13,000 ft, 4200 m), a condition termed chronic mountain sickness develops. This disorder is characterized by a blunted respiratory drive, reduced ventilation, erythrocytosis, cyanosis, weakness, right ventricular enlargement secondary to pulmonary hypertension, and even stupor.

Hypoxia and Cyanosis

Cyanide and several other similarly acting poisons cause cellular hypoxia. The tissues are unable to utilize O2, and, as a consequence, the venous blood tends to have a high O2 tension. This condition has been termed histotoxic hypoxia.

Cyanosis refers to a bluish color of the skin and mucous membranes resulting from an increased quantity of reduced hemoglobin (i.e., deoxygenated hemoglobin) or of hemoglobin derivatives (e.g., methemoglobin or sulfhemoglobin) in the small blood vessels of those tissues. It is usually most marked in the lips, nail beds, ears, and malar eminences. Cyanosis, especially if developed recently, is more commonly detected by a family member than the patient. The florid skin characteristic of polycythemia vera must be distinguished from the true cyanosis discussed here. A cherry-colored flush, rather than cyanosis, is caused by COHb. The degree of cyanosis is modified by the color of the cutaneous pigment and the thickness of the skin, as well as by the state of the cutaneous capillaries. The accurate clinical detection of the presence and degree of cyanosis is difficult, as proved by oximetric studies. In some instances, central cyanosis can be detected reliably when the Sao2 has fallen to 85%; in others, particularly in dark-skinned persons, it may not be detected until it has declined to 75%. In the latter case, examination of the mucous membranes in the oral cavity and the conjunctivae rather than examination of the skin is more helpful in the detection of cyanosis. The increase in the quantity of reduced hemoglobin in the mucocutaneous vessels that produces cyanosis may be brought about either by an increase in the quantity of venous blood as a result of dilation of the venules and venous ends of the capillaries or by a reduction in the Sao2 in the capillary blood. In general, cyanosis becomes apparent when the concentration of reduced hemoglobin in capillary blood exceeds 40 g/L (4 g/dL). It is the absolute, rather than the relative, quantity of reduced hemoglobin that is important in producing cyanosis. Thus, in a patient with severe anemia, the relative quantity of reduced hemoglobin in the venous blood may be very large when considered in relation to the total quantity of hemoglobin in the blood. However, since the concentration of the latter is markedly reduced, the absolute quantity of reduced hemoglobin may still be small, and, therefore, patients with severe anemia and even marked arterial desaturation may not display cyanosis. Conversely, the higher the total hemoglobin content, the greater the tendency toward cyanosis; thus, patients with marked polycythemia tend to be cyanotic at higher levels of Sao2 than patients with normal hematocrit values. Likewise, local passive congestion, which causes an increase in the total quantity of reduced hemoglobin in the vessels in a given area, may cause cyanosis. Cyanosis is also observed when nonfunctional hemoglobin, such as methemoglobin or sulfhemoglobin, is present in blood.

CHAPTER 6

Improper oxygen utilization

Cyanosis

Section II

Cyanosis may be subdivided into central and peripheral types. In central cyanosis, the Sao2 is reduced or an abnormal hemoglobin derivative is present, and the mucous membranes and skin are both affected. Peripheral cyanosis is due to a slowing of blood flow and abnormally great extraction of O2 from normally saturated arterial blood; it results from vasoconstriction and diminished peripheral blood flow, such as occurs in cold exposure, shock, congestive failure, and peripheral vascular disease. Often in these conditions, the mucous membranes of the oral cavity or those beneath the tongue may be spared. Clinical differentiation between central and peripheral cyanosis may not always be simple, and in conditions such as cardiogenic shock with pulmonary edema there may be a mixture of both types.

Diagnosis of Cardiovascular Disorders

Differential Diagnosis Central cyanosis (Table 6-1) Decreased Sao2 results from a marked reduction in the Pao2. This reduction may be brought about by a decline in the Fio2 without sufficient compensatory alveolar hyperventilation to maintain alveolar Po2. Cyanosis usually becomes manifest in an ascent to an altitude of 4000 m (13,000 ft). Seriously impaired pulmonary function, through perfusion of unventilated or poorly ventilated areas of the lung or alveolar hypoventilation, is a common cause of central cyanosis. This condition may occur acutely, as in Table 6-1 Causes of Cyanosis Central Cyanosis Decreased arterial oxygen saturation Decreased atmospheric pressure—high altitude Impaired pulmonary function Alveolar hypoventilation Uneven relationships between pulmonary ventilation and perfusion (perfusion of hypoventilated alveoli) Impaired oxygen diffusion Anatomic shunts Certain types of congenital heart disease Pulmonary arteriovenous fistulas Multiple small intrapulmonary shunts Hemoglobin with low affinity for oxygen Hemoglobin abnormalities Methemoglobinemia—hereditary, acquired Sulfhemoglobinema—acquired Carboxyhemoglobinemia (not true cyanosis) Peripheral Cyanosis Reduced cardiac output Cold exposure Redistribution of blood flow from extremities Arterial obstruction Venous obstruction

extensive pneumonia or pulmonary edema, or chronically, with chronic pulmonary diseases (e.g., emphysema). In the latter situation, secondary polycythemia is generally present and clubbing of the fingers (see later) may occur. Another cause of reduced Sao2 is shunting of systemic venous blood into the arterial circuit. Certain forms of congenital heart disease are associated with cyanosis on this basis (see earlier and Chap. 19). Pulmonary arteriovenous fistulae may be congenital or acquired, solitary or multiple, microscopic or massive. The severity of cyanosis produced by these fistulae depends on their size and number. They occur with some frequency in hereditary hemorrhagic telangiectasia. Sao2 reduction and cyanosis may also occur in some patients with cirrhosis, presumably as a consequence of pulmonary arteriovenous fistulae or portal vein–pulmonary vein anastomoses. In patients with cardiac or pulmonary right-to-left shunts, the presence and severity of cyanosis depend on the size of the shunt relative to the systemic flow as well as on the Hb-O2 saturation of the venous blood. With increased extraction of O2 from the blood by the exercising muscles, the venous blood returning to the right side of the heart is more unsaturated than at rest, and shunting of this blood intensifies the cyanosis. Secondary polycythemia occurs frequently in patients in this setting and contributes to the cyanosis. Cyanosis can be caused by small quantities of circulating methemoglobin (Hb Fe3+) and by even smaller quantities of sulfhemoglobin; both of these hemoglobin derivatives are unable to bind oxygen. Although they are uncommon causes of cyanosis, these abnormal hemoglobin species should be sought by spectroscopy when cyanosis is not readily explained by malfunction of the circulatory or respiratory systems. Generally, digital clubbing does not occur with them. Peripheral cyanosis Probably the most common cause of peripheral cyanosis is the normal vasoconstriction resulting from exposure to cold air or water. When cardiac output is reduced, cutaneous vasoconstriction occurs as a compensatory mechanism so that blood is diverted from the skin to more vital areas such as the CNS and heart, and cyanosis of the extremities may result even though the arterial blood is normally saturated. Arterial obstruction to an extremity, as with an embolus, or arteriolar constriction, as in cold-induced vasospasm (Raynaud’s phenomenon) (Chap. 39), generally results in pallor and coldness, and there may be associated cyanosis. Venous obstruction, as in thrombophlebitis or deep venous thrombosis, dilates the subpapillary venous plexuses and thereby intensifies cyanosis.

APPROACH TO THE

PATIENT

Cyanosis

Certain features are important in arriving at the cause of cyanosis:

The selective bulbous enlargement of the distal segments of the fingers and toes due to proliferation of connective tissue, particularly on the dorsal surface, is

Acknowledgment

Dr. Eugene Braunwald authored this chapter in the previous edition of Harrison’s Principles of Internal Medicine. Some of the material from the 17th edition has been carried forward.

Hypoxia and Cyanosis

Clubbing

CHAPTER 6

1. It is important to ascertain the time of onset of cyanosis. Cyanosis present since birth or infancy is usually due to congenital heart disease. 2. Central and peripheral cyanosis must be differentiated. Evidence of disorders of the respiratory or cardiovascular systems are helpful. Massage or gentle warming of a cyanotic extremity will increase peripheral blood flow and abolish peripheral, but not central, cyanosis. 3. The presence or absence of clubbing of the digits (see next section) should be ascertained. The combination of cyanosis and clubbing is frequent in patients with congenital heart disease and right-to-left shunting and is seen occasionally in patients with pulmonary disease, such as lung abscess or pulmonary arteriovenous fistulae. In contrast, peripheral cyanosis or acutely developing central cyanosis is not associated with clubbed digits. 4. Pao2 and Sao2 should be determined, and, in patients with cyanosis in whom the mechanism is obscure, spectroscopic examination of the blood performed to look for abnormal types of hemoglobin (critical in the differential diagnosis of cyanosis).

termed clubbing; there is also increased sponginess of the soft tissue at the base of the clubbed nail. Clubbing may be hereditary, idiopathic, or acquired and associated with a variety of disorders, including cyanotic congenital heart disease (see earlier), infective endocarditis, and a variety of pulmonary conditions (among them primary and metastatic lung cancer, bronchiectasis, asbestosis, sarcoidosis, lung abscess, cystic fibrosis, tuberculosis, and mesothelioma), as well as with some gastrointestinal diseases (including inflammatory bowel disease and hepatic cirrhosis). In some instances, it is occupational, e.g., in jackhammer operators. Clubbing in patients with primary and metastatic lung cancer, mesothelioma, bronchiectasis, or hepatic cirrhosis may be associated with hypertrophic osteoarthropathy. In this condition, the subperiosteal formation of new bone in the distal diaphyses of the long bones of the extremities causes pain and symmetric arthritislike changes in the shoulders, knees, ankles, wrists, and elbows. The diagnosis of hypertrophic osteoarthropathy may be confirmed by bone radiograph or MRI. Although the mechanism of clubbing is unclear, it appears to be secondary to humoral substances that cause dilation of the vessels of the distal digits as well as growth factors released from unfragmented platelet precursors in the digital circulation.

CHaPter 7

EDEMA Eugene Braunwald

■

Edema is defined as a clinically apparent increase in the interstitial fluid volume, which may expand by several liters before the abnormality is evident. Therefore, a weight gain of several kilograms usually precedes overt manifestations of edema, and a similar weight loss from diuresis can be induced in a slightly edematous patient before “dry weight” is achieved. Anasarca refers to gross, generalized edema. Ascites and hydrothorax refer to accumulation of excess fluid in the peritoneal and pleural cavities, respectively, and are considered special forms of edema. Depending on its cause and mechanism, edema may be localized or have a generalized distribution. Edema is recognized in its generalized form by puffiness of the face, which is most readily apparent in the periorbital areas, and by the persistence of an indentation of the skin after pressure; this is known as “pitting” edema. In its more subtle form, edema may be detected by noting that after the stethoscope is removed from the chest wall, the rim of the bell leaves an indentation on the skin of the chest for a few minutes. When the ring on a finger fits more snugly than in the past or when a patient complains of difficulty putting on shoes, particularly in the evening, edema may be present.

Joseph Loscalzo colloid oncotic pressure in the interstitial fluid tend to promote movement of fluid from the vascular to the extravascular space. By contrast, the colloid oncotic pressure contributed by plasma proteins and the hydrostatic pressure within the interstitial fluid promote the movement of fluid into the vascular compartment. As a consequence of these forces, there is movement of water and diffusible solutes from the vascular space at the arteriolar end of the capillaries. Fluid is returned from the interstitial space into the vascular system at the venous end of the capillaries and by way of the lymphatics. Unless these channels are obstructed, lymph flow rises with increases in net movement of fluid from the vascular compartment to the interstitium. These flows are usually balanced so that there is a steady state in the sizes of the intravascular and interstitial compartments, yet a large exchange between them occurs. However, if either the hydrostatic or the oncotic pressure gradient is altered significantly, a further net movement of fluid between the two components of the extracellular space will take place. The development of edema then depends on one or more alterations in the Starling forces so that there is increased flow of fluid from the vascular system into the interstitium or into a body cavity. Edema due to an increase in capillary pressure may result from an elevation of venous pressure caused by obstruction to venous and/or lymphatic drainage. An increase in capillary pressure may be generalized, as occurs in congestive heart failure (see later). The Starling forces also may be imbalanced when the colloid oncotic pressure of the plasma is reduced owing to any factor that may induce hypoalbuminemia, such as severe malnutrition, liver disease, loss of protein into the urine or into the gastrointestinal tract, or a severe catabolic state. Edema may be localized to one extremity when venous pressure is elevated due to unilateral thrombophlebitis (see later).

Pathogenesis About one-third of total-body water is confined to the extracellular space. Approximately 75% of the latter is interstitial fluid, and the remainder is in the plasma compartment. Starling forces The forces that regulate the disposition of fluid between these two components of the extracellular compartment frequently are referred to as the Starling forces. The hydrostatic pressure within the vascular system and the

Capillary damage

In many forms of edema, the effective arterial blood volume, a parameter that represents the filling of the arterial tree, is reduced. Underfilling of the arterial tree may be caused by a reduction of cardiac output and/ or systemic vascular resistance. As a consequence of underfilling, a series of physiologic responses designed to restore the effective arterial volume to normal are set into motion. A key element of these responses is the retention of salt and, therefore, of water, ultimately leading to edema. Renal factors and the renin-angiotensinaldosterone (RAA) system In the final analysis, renal retention of Na+ is central to the development of generalized edema (Fig. 7-1). The diminished renal blood flow characteristic of states in which the effective arterial blood volume is reduced is translated by the renal juxtaglomerular cells (specialized myoepithelial cells surrounding the afferent arteriole) into a signal for increased renin release. Renin is an enzyme with a molecular mass of about 40,000 Da that acts on its substrate, angiotensinogen, an α2-globulin synthesized by the liver, to release angiotensin I, a decapeptide, which in turn is converted to angiotensin II (AII), an octapeptide. AII has generalized vasoconstrictor properties; it is especially active on the renal efferent arterioles. This action reduces the hydrostatic pressure in the peritubular capillaries, whereas the increased filtration fraction raises the colloid osmotic pressure in these vessels, thereby enhancing salt and water reabsorption in the proximal tubule as well as in the ascending limb of the loop of Henle. The renin-angiotensin-aldosterone (RAA) system has long been recognized as a hormonal system; however, it also operates locally. Intrarenally produced AII contributes to glomerular efferent arteriolar constriction, and this “tubuloglomerular feedback” causes salt and water

Arginine vasopressin (AVP) The secretion of AVP occurs in response to increased intracellular osmolar concentration, and, by stimulating V2 receptors, AVP increases the reabsorption of free water in the renal distal tubule and collecting duct, thereby increasing total-body water. Circulating AVP is elevated in many patients with heart failure secondary to a nonosmotic stimulus associated with decreased effective arterial volume. Such patients fail to show the normal reduction of AVP with a reduction of osmolality, contributing to edema formation and hyponatremia.

Edema

Reduction of effective arterial volume

CHAPTER 7

Edema may also result from damage to the capillary endothelium, which increases its permeability and permits the transfer of proteins into the interstitial compartment. Injury to the capillary wall can result from drugs, viral or bacterial agents, and thermal or mechanical trauma. Increased capillary permeability also may be a consequence of a hypersensitivity reaction and is characteristic of immune injury. Damage to the capillary endothelium is presumably responsible for inflammatory edema, which is usually nonpitting, localized, and accompanied by other signs of inflammation—i.e., erythema, heat, and tenderness.

retention and thereby contributes to the formation of edema. AII that enters the systemic circulation stimulates the production of aldosterone by the zona glomerulosa of the adrenal cortex. Aldosterone in turn enhances Na+ reabsorption (and K+ excretion) by the collecting tubule. In patients with heart failure, not only is aldosterone secretion elevated but the biologic half-life of aldosterone is prolonged, which increases further the plasma level of the hormone. A depression of hepatic blood flow, especially during exercise, is responsible for reduced hepatic catabolism of aldosterone. Increased quantities of aldosterone are secreted in heart failure and in other edematous states, and blockade of the action of aldosterone by spironolactone or eplerenone (aldosterone antagonists) or by amiloride (a blocker of epithelial Na+ channels) often induces a moderate diuresis in edematous states. Yet persistently augmented levels of aldosterone (or other mineralocorticoids) alone do not always promote accumulation of edema, as witnessed by the lack of significant fluid retention in most instances of primary aldosteronism. Furthermore, although normal individuals retain some NaCl and water with the administration of potent mineralocorticoids, such as deoxycorticosterone acetate and fludrocortisone, this accumulation is self-limiting despite continued exposure to the steroid, a phenomenon known as mineralocorticoid escape. The failure of normal individuals who receive large doses of mineralocorticoids to accumulate large quantities of extracellular fluid and develop edema is probably a consequence of an increase in glomerular filtration rate (pressure natriuresis) and the action of natriuretic substance(s) (see later). The continued secretion of aldosterone may be more important in the accumulation of fluid in edematous states because patients with edema secondary to heart failure, nephrotic syndrome, and hepatic cirrhosis are generally unable to repair the deficit in effective arterial blood volume. As a consequence, they do not develop pressure natriuresis.

↓ Oncotic pressure and/or ↑ Capillary permeability

Low output cardiac failure, Pericardial tamponade, Constrictive pericarditis

↓ Extracellular fluid volume

↓ CARDIAC OUTPUT

Activation of ventricular and arterial receptors

Section II

Non-osmotic vasopression stimulation

Diagnosis of Cardiovascular Disorders

RENAL WATER RETENTION

Activation of the Renin-angiolensinaldosterone system

Stimulation of sympathetic nervous system ↑ SYSTEMIC AND RENAL ARTERIAL VASCULAR RESISTANCE

RENAL SODIUM RETENTION

MAINTENANCE OF ARTERIAL CIRCULATORY INTEGRITY

High-output cardiac failure

Sepsis

Cirrhosis

Arteriovenous fistula

Pregnancy

Arterial vasodilators

SYSTEMIC ARTERIAL VASODILATION

Activation of arterial baroreceptors Non-osmotic AVP stimulation

↑ CARDIAC OUTPUT

WATER RETENTION

SNS stimulation

Activation of RAAS

↑ SYSTEMIC ARTERIAL VASCULAR AND RENAL RESISTANCE

MAINTENANCE OF ARTERIAL CIRCULATORY INTEGRITY

Endothelin This potent peptide vasoconstrictor is released by endothelial cells. Its concentration is elevated in heart failure and contributes to renal vasoconstriction, Na+ retention, and edema in heart failure. Natriuretic peptides Atrial distention and/or a Na+ load cause release into the circulation of atrial natriuretic peptide (ANP),

SODIUM RETENTION

Figure 7-1 Clinical conditions in which a decrease in cardiac output (A) and systemic arterial vasodilation (B) cause arterial underfilling with resulting neurohumoral activation and renal sodium and water retention. In addition to activating the neurohumoral axis, adrenergic stimulation causes renal vasoconstriction and enhances sodium and fluid transport by the proximal tubule epithelium. SNS, sympathetic nervous system; RAAS, renin-angiotensin aldosterone system. (Reprinted from RW Schrier: Ann Intern Med 113:155, 1990.)

a polypeptide; a high-molecular-weight precursor of ANP is stored in secretory granules within atrial myocytes. Release of ANP causes (1) excretion of sodium and water by augmenting glomerular filtration rate, inhibiting sodium reabsorption in the proximal tubule, and inhibiting release of renin and aldosterone and (2) arteriolar and venous dilation by antagonizing the vasoconstrictor actions of AII, AVP, and sympathetic stimulation. Thus, ANP has the capacity to oppose Na+ retention and arterial pressure elevation in hypervolemic states.

Obstruction of venous (and lymphatic) drainage of a limb In this condition, the hydrostatic pressure in the capillary bed upstream (proximal) to the obstruction increases so that an abnormal quantity of fluid is transferred from the vascular to the interstitial space. Since the alternative route (i.e., the lymphatic channels) also may be obstructed or maximally filled, an increased volume of interstitial fluid in the limb develops (i.e., there is trapping of fluid in the interstitium of the extremity). The displacement of fluid into a limb may occur at the expense of the blood volume in the remainder of the body, thereby reducing effective arterial blood volume and leading to the retention of NaCl and H2O until the deficit in plasma volume has been corrected. Congestive heart failure (See also Chap. 17) In this disorder the impaired systolic emptying of the ventricle(s) and/or the impairment of ventricular relaxation promotes an accumulation of blood in the venous circulation at the expense of the effective arterial volume, and the aforementioned sequence of events (Fig. 7-1) is initiated. In mild heart failure, a small increment of total blood volume may repair the deficit of arterial volume and establish a new steady state. Through the operation of Starling’s law of the heart, an increase in ventricular diastolic volume promotes a more forceful contraction and may thereby maintain the cardiac output. However, if the cardiac disorder is more severe, fluid retention continues, and the increment in blood volume accumulates in the venous circulation, raising venous pressure and causing edema. Incomplete ventricular emptying (systolic heart failure) and/or inadequate ventricular relaxation (diastolic heart failure) both lead to an elevation of ventricular diastolic pressure. If the impairment of cardiac function

Nephrotic syndrome and other hypoalbuminemic states The primary alteration in this disorder is a diminished colloid oncotic pressure due to losses of large quantities of protein into the urine. With severe hypoalbuminemia and the consequent reduced colloid osmotic pressure, the NaCl and H2O that are retained cannot be restrained within the vascular compartment, and total and effective arterial blood volumes decline. This process initiates the edema-forming sequence of events described earlier, including activation of the RAA system. Impaired renal function contributes further to the formation of edema. A similar sequence of events occurs in other conditions that lead to severe hypoalbuminemia, including (1) severe nutritional deficiency states, (2) severe, chronic liver disease (see later), and (3) protein-losing enteropathy. Cirrhosis This condition is characterized in part by hepatic venous outflow blockade, which in turn expands the splanchnic blood volume and increases hepatic lymph formation. Intrahepatic hypertension acts as a stimulus for renal Na+ retention and a reduction of effective arterial blood volume. These alterations frequently are complicated by hypoalbuminemia secondary to reduced hepatic synthesis, as well as systemic vasodilation. These effects reduce the effective arterial blood volume further, leading to activation of the RAA system, renal sympathetic nerves, and other NaCl- and H2O-retaining mechanisms. The concentration of circulating aldosterone often is elevated by the failure of the liver to metabolize this hormone. Initially, the excess interstitial fluid is localized preferentially proximal (upstream) to the congested portal venous system

Edema

Clinical Causes of Edema

primarily involves the right ventricle, pressures in the systemic veins and capillaries rise, augmenting the transudation of fluid into the interstitial space and enhancing the likelihood of peripheral edema. The elevated systemic venous pressure is transmitted to the thoracic duct with consequent reduction of lymph drainage, further increasing the accumulation of edema. If the impairment of cardiac function involves the left ventricle primarily, pulmonary venous and capillary pressures rise. Pulmonary artery pressure rises, and this in turn interferes with the emptying of the right ventricle, leading to an elevation of right ventricular diastolic and central and systemic venous pressures, enhancing the likelihood of the formation of peripheral edema. The elevation of pulmonary capillary pressure may cause pulmonary edema, which impairs gas exchange. The resulting hypoxemia may impair cardiac function further, sometimes causing a vicious circle.

CHAPTER 7

The closely related brain natriuretic peptide (BNP) is stored primarily in ventricular myocardium and is released when ventricular diastolic pressure rises. Its actions are similar to those of ANP, and both BNP and ANP bind to the natriuretic receptor-A, which is found in the myocardium. Yet another natriuretic peptide, C-type (CNP), is of endothelial and renal origin. CNP binds preferentially to the natriuretic peptide receptor-B, which is expressed principally in veins. Circulating levels of ANP and BNP are elevated in congestive heart failure and in cirrhosis with ascites, but obviously not sufficiently to prevent edema formation. In addition, in edematous states there is abnormal resistance to the actions of natriuretic peptides.

Table 7-1 Drugs Associated With Edema Formation

Section II Diagnosis of Cardiovascular Disorders

Nonsteroidal anti-inflammatory drugs Antihypertensive agents Direct arterial/arteriolar vasodilators Hydralazine Clonidine Methyldopa Guanethidine Minoxidil Calcium channel antagonists α-Adrenergic antagonists Thiazolidinediones Steroid hormones Glucocorticoids Anabolic steroids Estrogens Progestins Cyclosporine Growth hormone Immunotherapies Interleukin 2 OKT3 monoclonal antibody Source: From GM Chertow: Approach to the patient with edema, in Primary Cardiology, 2nd ed, E Braunwald, L Goldman (eds). Philadelphia, Saunders 2003.

and obstructed hepatic lymphatics, i.e., in the peritoneal cavity (ascites). In later stages, particularly when there is severe hypoalbuminemia, peripheral edema may develop. The excess production of prostaglandins (PGE2 and PGI2) in cirrhosis attenuates renal Na+ retention. When the synthesis of these substances is inhibited by nonsteroidal anti-inflammatory drugs (NSAIDs), renal function deteriorates and Na+ retention increases. Drug-induced edema A large number of widely used drugs can cause edema (Table 7-1). Mechanisms include renal vasoconstriction (NSAIDs and cyclosporine), arteriolar dilation (vasodilators), augmented renal Na+ reabsorption (steroid hormones), and capillary damage (interleukin 2).

Differential Diagnosis Localized edema (See also Chap. 39) Localized edema due to venous or lymphatic obstruction may be caused by thrombophlebitis, chronic lymphangitis, resection of regional lymph nodes, filariasis, etc. Lymphedema is particularly intractable because restriction of lymphatic flow results in increased protein concentration in the interstitial fluid, a circ*mstance that aggravates retention of fluid.

Generalized Edema The differences among the major causes of generalized edema are shown in Table 7-2. A majority of patients with generalized edema develop cardiac, renal, hepatic, or nutritional disorders. Consequently, the differential diagnosis of generalized edema should be directed toward identifying or excluding these several conditions. Edema of heart failure (See also Chap. 17) The presence of heart disease, as manifested by cardiac enlargement and a gallop rhythm, together with evidence of cardiac failure, such as dyspnea, basilar rales, venous distention, and hepatomegaly, usually indicates that edema results from heart failure. Noninvasive tests such as echocardiography may be helpful in establishing the diagnosis of heart disease. The edema of heart failure typically occurs in the dependent portions of the body. Edema of acute glomerulonephritis and other forms of renal failure The edema that occurs during the acute phases of glomerulonephritis is characteristically associated with hematuria, proteinuria, and hypertension. Although some evidence supports the view that the fluid retention is due to increased capillary permeability, in most instances, the edema results from primary retention of NaCl and H2O by the kidneys owing to renal insufficiency. This state differs from congestive heart failure in that it is characterized by a normal (or sometimes even increased) cardiac output and a normal arterial– mixed venous oxygen difference. Patients with edema due to renal failure commonly have evidence of arterial hypertension as well as pulmonary congestion on chest roentgenogram even without cardiac enlargement, but they may not develop orthopnea. Patients with chronic renal failure may also develop edema due to primary renal retention of NaCl and H2O. Edema of the nephrotic syndrome Marked proteinuria (>3.5 g/d), hypoalbuminemia (4.5 cm at 30° elevation is considered abnormal. However, the actual distance between the mid-right atrium and the angle of Louis varies considerably as a function of both body size and the patient angle at which the assessment is made (30°, 45°, or 60°). The use of the sternal angle as a reference point leads to systematic underestimation of CVP, and this method should be used less for semiquantification than to distinguish a normal from an abnormally elevated CVP. The use of the clavicle may provide an easier reference for standardization. Venous pulsations above this level in the sitting position are clearly abnormal, as the distance between the clavicle and the right atrium is at least 10 cm. The patient should always be placed in the sitting position, with the

Physical Examination of the Cardiovascular System

In some patients with advanced obstructive lung disease, the point of maximal cardiac impulse may be in the epigastrium. The liver is frequently enlarged and tender in patients with chronic heart failure. Systolic pulsations over the liver signify severe tricuspid regurgitation (TR). Splenomegaly may be a feature of infective endocarditis, particularly when symptoms have persisted for weeks or months. Ascites is a nonspecific finding but may be present with advanced chronic right heart failure, constrictive pericarditis, hepatic cirrhosis, or an intraperitoneal malignancy. The finding of an elevated JVP implies a cardiovascular etiology. In nonobese patients, the aorta typically is palpated between the epigastrium and the umbilicus. The sensitivity of palpation for the detection of an abdominal aortic aneurysm (pulsatile and expansile mass) decreases as a function of body size. Because palpation alone is not sufficiently accurate to establish this diagnosis, a screening ultrasound examination is advised. The presence of an arterial bruit over the abdomen suggests high-grade atherosclerotic disease, though precise localization is difficult.

CHAPTER 9

Abdomen

the fingers or toes. Splinter hemorrhages are classically identified as linear petechiae in the midposition of the nail bed and should be distinguished from the more common traumatic petechiae, which are seen closer to the distal edge. Lower extremity or presacral edema in the setting of an elevated JVP defines volume overload and may be a feature of chronic heart failure or constrictive pericarditis. Lower extremity edema in the absence of jugular venous hypertension may be due to lymphatic or venous obstruction or, more commonly, to venous insufficiency, as further suggested by the appearance of varicosities, venous ulcers (typically medial in location), and brownish cutaneous discoloration from hemosiderin deposition (eburnation). Pitting edema can also be seen in patients who use dihydropyridine calcium channel blockers. A Homan’s sign (posterior calf pain on active dorsiflexion of the foot against resistance) is neither specific nor sensitive for deep venous thrombosis. Muscular atrophy or the absence of hair along an extremity is consistent with severe arterial insufficiency or a primary neuromuscular disorder.

Section II Diagnosis of Cardiovascular Disorders

legs dangling below the bedside, when an elevated pressure is suspected in the semisupine position. It should also be noted that bedside estimates of CVP are made in centimeters of water but must be converted to millimeters of mercury to provide correlation with accepted hemodynamic norms (1.36 cmH2O = 1.0 mmHg). The venous waveform sometimes can be difficult to distinguish from the carotid pulse, especially during casual inspection. Nevertheless, the venous waveform has several characteristic features, and its individual components can be appreciated in most patients (Fig. 9-1). In patients in sinus rhythm, the venous waveform is typically biphasic, whereas the carotid upstroke is monophasic. The venous waveform is divided into several distinct peaks. The a wave reflects right atrial presystolic contraction and occurs just after the electrocardiographic P wave, preceding the first heart sound (S1). A prominent a wave is seen in patients with reduced right ventricular compliance; a cannon a wave occurs with atrioventricular (AV) dissociation and right atrial contraction against a closed tricuspid valve. In a patient with a wide complex tachycardia, the appreciation of cannon a waves in the jugular venous waveform identifies the rhythm as ventricular in origin. The a wave is not present with atrial fibrillation. The x descent defines the fall in right atrial pressure after inscription of the a wave. The c wave interrupts this x descent and is followed by a further descent. The v wave represents atrial filling (atrial diastole) and occurs during ventricular systole. The height of the v wave is determined by right atrial compliance as well as the volume of blood returning to the right atrium either antegrade from the cavae or retrograde through an incompetent tricuspid valve. In patients with TR, the v wave is accentuated and the subsequent fall in pressure (y descent) is rapid. With progressive degrees of TR, the v wave merges with the c wave, and the right atrial and jugular vein waveforms become “ventricularized.” The y descent, which follows the peak of the v wave, can become prolonged or blunted with obstruction to right ventricular inflow, as may occur with tricuspid stenosis (TS) or pericardial tamponade. Normally, the venous pressure should fall by at least 3 mmHg with inspiration. Kussmaul’s sign is defined by either a rise or a lack of fall of the JVP with inspiration and is classically associated with constrictive pericarditis, although it has been reported in patients with restrictive cardiomyopathy, massive pulmonary embolism, right ventricular infarction, and advanced left ventricular systolic heart failure. Venous hypertension sometimes can be elicited by performance of the abdominojugular reflex or with passive leg elevation. When these signs are positive, a volume-overloaded state with limited compliance of an overly distended or constricted venous system is present. The abdominojugular reflex is elicited with firm

A V

C X A

IV I

Y II

A Severe V

A C Mild

X A C

Normal Y

X I

II III

ECG

A X

JVP

Figure 9-1 A. Jugular venous pulse wave tracing (top) with heart sounds (bottom). The A wave represents right atrial presystolic contraction and occurs just after the electrocardiographic P wave and just before the first heart sound (I). In this example, the A wave is accentuated and larger than normal due to decreased right ventricular compliance, as also suggested by the right-sided S4 (IV). The C wave may reflect the carotid pulsation in the neck and/or an early systolic increase in right atrial pressure as the right ventricle pushes the closed tricuspid valve into the right atrium. The x descent follows the A wave just as atrial pressure continues to fall. The V wave represents atrial filling during ventricular systole and peaks at the second heart sound (II). The y descent corresponds to the fall in right atrial pressure after tricuspid valve opening. B. Jugular venous waveforms in mild (middle) and severe (top) tricuspid regurgitation, compared with normal, with phonocardiographic representation of the corresponding heart sounds below. With increasing degrees of tricuspid regurgitation, the waveform becomes “ventricularized.” C. ECG (top), jugular venous waveform (middle), and heart sounds (bottom) in pericardial constriction. Note the prominent and rapid y descent, corresponding in timing to the pericardial knock (K). (From J Abrams: Synopsis of Cardiac Physical Diagnosis, 2nd ed. Boston, Butterworth Heinemann, 2001, pp 25–35.)

Measurement of blood pressure usually is delegated to a medical assistant but should be repeated by the clinician. Accurate measurement depends on body position, arm size, time of measurement, place of measurement, device, device size, technique, and examiner. In general, physician-recorded blood pressures are higher than nurse-recorded pressures. Blood pressure is best measured in the seated position with the arm at the level of the heart, using an appropriately sized cuff, after 5–10 min of relaxation. When it is measured in the supine position, the arm should be raised to bring it to the level of the mid-right atrium. The length and width of the blood pressure cuff bladder should be 80% and 40% of the arm’s circumference, respectively. A common source of error in practice is to use an inappropriately small cuff, resulting in marked overestimation of true blood pressure, or an inappropriately large cuff, resulting in underestimation of true blood pressure. The cuff should be inflated to 30 mmHg above the expected systolic pressure and the pressure released at a rate of 2–3 mmHg/s. Systolic and diastolic pressures are defined by the first and fifth Korotkoff sounds, respectively. Very low (even 0 mmHg) diastolic blood pressures may be recorded in patients with chronic, severe AR or a large arteriovenous fistula because of enhanced diastolic “runoff.” In these instances, both the phase IV and phase V Korotkoff sounds should be recorded. Blood pressure is best assessed at the brachial artery level, though it can be measured at the radial, popliteal, or pedal pulse level. In general, systolic pressure increases and diastolic pressure decreases when measured in more distal arteries.

Arterial pulse The carotid artery pulse occurs just after the ascending aortic pulse. The aortic pulse is best appreciated in the epigastrium, just above the level of the umbilicus. Peripheral arterial pulses that should be assessed routinely include the subclavian, brachial, radial, ulnar, femoral, popliteal, dorsalis pedis, and posterior tibial. In patients in whom the diagnosis of either temporal arteritis or polymyalgia rheumatica is suspected, the temporal arteries also should be examined. Although one of the two pedal pulses may not be palpable in up to 10% of normal subjects, the pair should be symmetric. The

Physical Examination of the Cardiovascular System

Assessment of blood pressure

Blood pressure should be measured in both arms, and the difference should be less than 10 mmHg. A blood pressure differential that exceeds this threshold may be associated with atherosclerotic or inflammatory subclavian artery disease, supravalvular aortic stenosis, aortic coarctation, or aortic dissection. Systolic leg pressures are usually as much as 20 mmHg higher than systolic arm pressures. Greater leg–arm pressure differences are seen in patients with chronic severe AR as well as patients with extensive and calcified lower extremity peripheral arterial disease. The ankle-brachial index (lower pressure in the dorsalis pedis or posterior tibial artery divided by the higher of the two brachial artery pressures) is a powerful predictor of long-term cardiovascular mortality. The blood pressure measured in an office or hospital setting may not accurately reflect the pressure in other venues. “White coat hypertension” is defined by at least three separate clinic-based measurements >140/90 mmHg and at least two non-clinic-based measurements 20 mmHg or in diastolic pressure >10 mmHg in response to assumption of the upright posture from a supine position within 3 min. There may also be a lack of a compensatory tachycardia, an abnormal response that suggests autonomic insufficiency, as may be seen in patients with diabetes or Parkinson’s disease. Orthostatic hypotension is a common cause of postural lightheadedness/syncope and should be assessed routinely in patients for whom this diagnosis might pertain. It can be exacerbated by advanced age, dehydration, certain medications, food, deconditioning, and ambient temperature.

CHAPTER 9

and consistent pressure over the upper portion of the abdomen, preferably over the right upper quadrant, for at least 10 s. A positive response is defined by a sustained rise of more than 3 cm in JVP for at least 15 s after release of the hand. Patients must be coached to refrain from breath holding or a Valsalva-like maneuver during the procedure. The abdominojugular reflex is useful in predicting a pulmonary artery wedge pressure in excess of 15 mmHg in patients with heart failure. Although the JVP estimates right ventricular filling pressure, it has a predictable relationship with the pulmonary artery wedge pressure. In a large study of patients with advanced heart failure, the presence of a right atrial pressure >10 mmHg (as predicted on bedside examination) had a positive value of 88% for the prediction of a pulmonary artery wedge pressure of >22 mmHg. In addition, an elevated JVP has prognostic significance in patients with both symptomatic heart failure and asymptomatic left ventricular systolic dysfunction. The presence of an elevated JVP is associated with a higher risk of subsequent hospitalization for heart failure, death from heart failure, or both.

Section II Diagnosis of Cardiovascular Disorders

integrity of the arcuate system of the hand is assessed by Allen’s test, which is performed routinely before instrumentation of the radial artery. The pulses should be examined for their symmetry, volume, timing, contour, amplitude, and duration. If necessary, simultaneous auscultation of the heart can help identify a delay in the arrival of an arterial pulse. Simultaneous palpation of the radial and femoral pulses may reveal a femoral delay in a patient with hypertension and suspected aortic coarctation. The carotid upstrokes should never be examined simultaneously or before listening for a bruit. Light pressure should always be used to avoid precipitation of carotid hypersensitivity syndrome and syncope in a susceptible elderly individual. The arterial pulse usually becomes more rapid and spiking as a function of its distance from the heart, a phenomenon that reflects the muscular status of the more peripheral arteries and the summation of the incident and reflected waves. In general, the character and contour of the arterial pulse depend on the stroke volume, ejection velocity, vascular compliance, and systemic vascular resistance. The pulse examination can be misleading in patients with reduced cardiac output and in those with stiffened arteries from aging, chronic hypertension, or peripheral arterial disease. The character of the pulse is best appreciated at the carotid level (Fig. 9-2). A weak and delayed pulse (pulsus parvus et tardus) defines severe aortic stenosis (AS). Some patients with AS may also have a slow, notched, or interrupted upstroke (anacrotic pulse) with a thrill or shudder. With chronic severe AR, by contrast, the carotid upstroke has a sharp rise and rapid falloff (Corrigan’s or water-hammer pulse). Some patients with advanced AR may have a bifid or bisferiens pulse, in which two systolic peaks can be appreciated. A bifid pulse is also described in patients with hypertrophic obstructive cardiomyopathy (HOCM), with inscription of percussion and tidal waves. A bifid pulse is easily appreciated in patients on intraaortic balloon counterpulsation (IABP), in whom the second pulse is diastolic in timing. Pulsus paradoxus refers to a fall in systolic pressure >10 mmHg with inspiration that is seen in patients with pericardial tamponade but also is described in those with massive pulmonary embolism, hemorrhagic shock, severe obstructive lung disease, and tension pneumothorax. Pulsus paradoxus is measured by noting the difference between the systolic pressure at which the Korotkoff sounds are first heard (during expiration) and the systolic pressure at which the Korotkoff sounds are heard with each heartbeat, independent of the respiratory phase. Between these two pressures, the Korotkoff sounds are heard only intermittently and during expiration. The cuff pressure must be decreased slowly to appreciate the finding. It can be difficult to measure pulsus paradoxus in patients with tachycardia, atrial

S4 S1

Dicrotic notch

S4 S1

P2 A2

Dicrotic notch

S4 S1

P2 A2

Dicrotic notch

S4 S1

P2 A2

Dicrotic notch

P2 A2

Dicrotic notch

Figure 9-2 Schematic diagrams of the configurational changes in carotid pulse and their differential diagnoses. Heart sounds are also illustrated. A. Normal. S4, fourth heart sound; S1, first heart sound; A2 aortic component of second heart sound; P2 pulmonic component of second heart sound. B. Aortic stenosis. Anacrotic pulse with slow upstroke to a reduced peak. C. Bisferiens pulse with two peaks in systole. This pulse is rarely appreciated in patients with severe aortic regurgitation. D. Bisferiens pulse in hypertrophic obstructive cardiomyopathy. There is a rapid upstroke to the first peak (percussion wave) and a slower rise to the second peak (tidal wave). E. Dicrotic pulse with peaks in systole and diastole. This waveform may be seen in patients with sepsis or during intraaortic balloon counterpulsation with inflation just after the dicrotic notch. (From K Chatterjee, W Parmley [eds]: Cardiology: An Illustrated Text/Reference. Philadelphia, JB Lippincott, 1991.)

fibrillation, or tachypnea. A pulsus paradoxus may be palpable at the brachial artery or femoral artery level when the pressure difference exceeds 15 mmHg. This inspiratory fall in systolic pressure is an exaggerated consequence of interventricular dependence. Pulsus alternans, in contrast, is defined by beat-to-beat variability of pulse amplitude. It is present only when every other phase I Korotkoff sound is audible as the cuff pressure is lowered slowly, typically in a patient with a regular heart rhythm and independent of the respiratory cycle. Pulsus alternans is seen in patients with severe left ventricular systolic heart failure and is thought to be due to cyclic changes in intracellular calcium and action potential duration. Interestingly, when

indicator of the degree of carotid artery stenosis; the absence of a bruit does not exclude the presence of significant luminal obstruction. If a bruit extends into diastole or if a thrill is present, the obstruction is generally severe. Other causes of arterial bruits include an arteriovenous fistula with enhanced flow. The likelihood of significant lower extremity peripheral arterial disease increases with typical symptoms of claudication, cool skin, abnormalities on pulse examination, or the presence of a vascular bruit. Abnormal pulse oximetry (a >2% difference between finger and toe oxygen saturation) can be used to detect lower extremity peripheral arterial disease and is comparable in its performance characteristics to the ankle-brachial index.

The left ventricular apex beat may be visible in the midclavicular line at the fifth intercostal space in thinchested adults. Visible pulsations anywhere other than this expected location are abnormal. The left anterior Posterior tibial artery pressure

Anterior superior iliac spine

Posterior tibial a.

Inguinal ligament External iliac a.

Symphysis pubis Doppler

Deep femoral a.

Palpatation of popliteal artery pulse

Blood pressure cuff

Femoral a. Dorsalis pedis artery pressure Popliteal a.

Anterior tibial a.

Popliteal a. Posterior tibial a.

Doppler

Femoral a. Anterior tibial a.

Extensor tendon

Dorsalis pedis a. Dorsalis pedis a.

Major arteries of the lower limb

Measurement of ankle systolic pressure

Figure 9-3 A. Anatomy of the major arteries of the leg. B. Measurement of the ankle systolic pressure. (From NA Khan et al: JAMA 295: 536–546, 2006.)

Physical Examination of the Cardiovascular System

Inspection and palpation of the heart

CHAPTER 9

pulsus alternans is associated with electrocardiographic T-wave alternans, the risk for an arrhythmic event appears to be increased. Ascending aortic aneurysms can rarely be appreciated as a pulsatile mass in the right parasternal. Appreciation of a prominent abdominal aortic pulse should prompt noninvasive imaging for better characterization. Femoral and/or popliteal artery aneurysms should be sought in patients with abdominal aortic aneurysm disease. The level of a claudication-producing arterial obstruction can often be identified on physical examination (Fig. 9-3). For example, in a patient with calf claudication, a decrease in pulse amplitude between the common femoral and popliteal arteries will localize the obstruction to the level of the superficial femoral artery, although inflow obstruction above the level of the common femoral artery may coexist. Auscultation for carotid, subclavian, abdominal aortic, and femoral artery bruits should be routine. However, the correlation between the presence of a bruit and the degree of vascular obstruction is poor. A cervical bruit is a weak

Section II Diagnosis of Cardiovascular Disorders

chest wall may heave in patients with an enlarged or hyperdynamic left or right ventricle. As noted previously, a visible right upper parasternal pulsation may be suggestive of ascending aortic aneurysm disease. In thin, tall patients and patients with advanced obstructive lung disease and flattened diaphragms, the cardiac impulse may be visible in the epigastrium and should be distinguished from a pulsatile liver edge. Palpation of the heart begins with the patient in the supine position at 30° and can be enhanced by placing the patient in the left lateral decubitus position. The normal left ventricular impulse is less than 2 cm in diameter and moves quickly away from the fingers; it is better appreciated at end expiration, with the heart closer to the anterior chest wall. Characteristics such as size, amplitude, and rate of force development should be noted. Enlargement of the left ventricular cavity is manifested by a leftward and downward displacement of an enlarged apex beat. A sustained apex beat is a sign of pressure overload, such as that which may be present in patients with AS or chronic hypertension. A palpable presystolic impulse corresponds to the fourth heart sound (S4) and is indicative of reduced left ventricular compliance and the forceful contribution of atrial contraction to ventricular filling. A palpable third sound (S3), which is indicative of a rapid early filling wave in patients with heart failure, may be present even when the gallop itself is not audible. A large left ventricular aneurysm may sometimes be palpable as an ectopic impulse, discrete from the apex beat. Hypertrophic obstructive cardiomyopathy may very rarely cause a triple cadence beat at the apex with contributions from a palpable S4 and the two components of the bisferiens systolic pulse. Right ventricular pressure or volume overload may create a sternal lift. Signs of either TR (cv waves in the jugular venous pulse) and/or pulmonary arterial hypertension (a loud single or palpable P2) would be confirmatory. The right ventricle can enlarge to the extent that left-sided events cannot be appreciated. A zone of retraction between the right and left ventricular impulses sometimes can be appreciated in patients with right ventricle pressure or volume overload when they are placed in the left lateral decubitus position. Systolic and diastolic thrills signify turbulent and high-velocity blood flow. Their locations help identify the origin of heart murmurs.

Cardiac Auscultation Heart sounds Ventricular systole is defined by the interval between the first (S1) and second (S2) heart sounds (Fig. 9-4). The first heart sound (S1) includes mitral and tricuspid

EXPIRATION A2

A Normal S1

B Atrial septal defect

E Close fixed splitting (pulmonary hypertension)

A2 P 2

P2 A2

A2 P 2

A2 P2

C Expiratory splitting with inspiratory S1 increase (RBBB, idiopathic dilatation PA) D Reversed splitting (LBBB, aortic stenosis)

INSPIRATION

A2 P2

Figure 9-4 Heart sounds. A. Normal. S1, first heart sound; S2, second heart sound; A2, aortic component of the second heart sound; P2, pulmonic component of the second heart sound. B. Atrial septal defect with fixed splitting of S2. C. Physiologic but wide splitting of S2 with right bundle branch block. D. Reversed or paradoxical splitting of S2 with left bundle branch block. E. Narrow splitting of S2 with pulmonary hypertension. (From NO Fowler: Diagnosis of Heart Disease. New York, Springer-Verlag, 1991, p 31.)

valve closure. Normal splitting can be appreciated in young patients and those with right bundle branch block, in whom tricuspid valve closure is relatively delayed. The intensity of S1 is determined by the distance over which the anterior leaflet of the mitral valve must travel to return to its annular plane, leaflet mobility, left ventricular contractility, and the PR interval. S1 is classically loud in the early phases of rheumatic mitral stenosis (MS) and in patients with hyperkinetic circulatory states or short PR intervals. S1 becomes softer in the later stages of MS when the leaflets are rigid and calcified, after exposure to β-adrenergic receptor blockers, with long PR intervals, and with left ventricular contractile dysfunction. The intensity of any heart sound, however, can be reduced by any process that increases the distance between the stethoscope and the responsible cardiac event, including mechanical ventilation, obstructive lung disease, obesity, pneumothorax, and a pericardial effusion. Aortic and pulmonic valve closure constitutes the second heart sound (S2). With normal or physiologic splitting, the A2–P2 interval increases with inspiration and narrows during expiration. This physiologic interval

An ejection sound is a high-pitched early systolic sound that corresponds in timing to the upstroke of the carotid pulse. It usually is associated with congenital bicuspid aortic or pulmonic valve disease; however, ejection sounds are also sometimes audible in patients with isolated aortic or pulmonary root dilation and normal semilunar valves. The ejection sound that accompanies bicuspid aortic valve disease becomes softer and then inaudible as the valve calcifies and becomes more rigid. The ejection sound that accompanies pulmonic stenosis (PS) moves closer to the first heart sound as the severity of the stenosis increases. In addition, the pulmonic ejection sound is the only right-sided acoustic event that decreases in intensity with inspiration. Ejection sounds are often heard more easily at the lower left sternal border than they are at the base. Nonejection sounds (clicks), which occur after the onset of the carotid upstroke, are related to mitral valve prolapse and may be single or multiple. The nonejection click may introduce a murmur. This click-murmur complex will move away from the first heart sound with maneuvers that increase ventricular preload, such as squatting. On standing, the click and murmur move closer to S1. Diastolic sounds The high-pitched opening snap (OS) of MS occurs after a very short interval after the second heart sound. The A2–OS interval is inversely proportional to the height of

Cardiac murmurs Heart murmurs result from audible vibrations that are caused by increased turbulence and are defined by their timing within the cardiac cycle. Not all murmurs are indicative of structural heart disease, and the accurate identification of a benign or functional systolic murmur often can obviate the need for additional testing in healthy subjects. The duration, frequency, configuration, and intensity of a heart murmur are dictated by the magnitude, variability, and duration of the responsible pressure difference between two cardiac chambers, the two ventricles, or the ventricles and their respective great arteries. The intensity of a heart murmur is graded on a scale of 1 to 6; a thrill is present with murmurs of grade 4 or greater intensity. Other attributes of the murmur that aid in its accurate identification include its location, radiation, and response to bedside maneuvers. Although clinicians can detect and correctly identify heart murmurs with only fair reliability, a careful and complete bedside examination usually can identify individuals with valvular heart disease for whom transthoracic echocardiography and clinical follow-up are

Physical Examination of the Cardiovascular System

Systolic sounds

the left atrial–left ventricular diastolic pressure gradient. The intensity of both S1 and the OS of MS decreases with progressive calcification and rigidity of the anterior mitral leaflets. The pericardial knock (PK) is also high pitched and occurs slightly later than the opening snap, corresponding in timing to the abrupt cessation of ventricular expansion after tricuspid valve opening and to an exaggerated y descent seen in the jugular venous waveform in patients with constrictive pericarditis. A tumor plop is a lower-pitched sound that rarely can be heard in patients with atrial myxoma. It may be appreciated only in certain positions and arises from the diastolic prolapse of the tumor across the mitral valve. The third heart sound (S3) occurs during the rapid filling phase of ventricular diastole. It can be a normal finding in children, adolescents, and young adults; however, in older patients it signifies heart failure. A leftsided S3 is a low-pitched sound best heard over the left ventricular (LV) apex. A right-sided S3 is usually better heard over the lower left sternal border and becomes louder with inspiration. A left-sided S3 in patients with chronic heart failure is predictive of cardiovascular morbidity and mortality. Interestingly, an S3 is equally prevalent among heart failure patients with and without LV systolic dysfunction. The fourth heart sound (S4) occurs during the atrial filling phase of ventricular diastole and indicates left ventricular presystolic expansion. An S4 is more common among patients who derive significant benefit from the atrial contribution to ventricular filling, such as those with chronic left ventricular hypertrophy or active myocardial ischemia. An S4 is not present with atrial fibrillation.

CHAPTER 9

will widen with right bundle branch block because of the further delay in pulmonic valve closure and in patients with severe MR because of the premature closure of the aortic valve. An unusually narrowly split or even a singular S2 is a feature of pulmonary arterial hypertension. Fixed splitting of S2, in which the A2–P2 interval is wide and does not change during the respiratory cycle, occurs in patients with a secundum atrial septal defect. Reversed or paradoxical splitting refers to a pathologic delay in aortic valve closure, such as that which occurs in patients with left bundle branch block, right ventricular apical pacing, severe AS, HOCM, and acute myocardial ischemia. With reversed or paradoxical splitting, the individual components of S2 are audible at end expiration, and their interval narrows with inspiration, the opposite of what would be expected under normal physiologic conditions. P2 is considered loud when its intensity exceeds that of A2 at the base, when it can be palpated in the area of the proximal pulmonary artery (second left interspace), or when both components of S2 can be appreciated at the lower left sternal border or apex. The intensity of A2 and P2 decreases with aortic and pulmonic stenosis, respectively. In these conditions, a single S2 may result.

Section II Diagnosis of Cardiovascular Disorders

indicated and exclude subjects for whom no further evaluation is necessary. Systolic murmurs can be early, mid-, late, or holosystolic in timing (Fig. 9-5). Acute severe MR results in a decrescendo early systolic murmur, the characteristics of which are related to the progressive attenuation of the left ventricular to left atrial pressure gradient during systole because of the steep and rapid rise in left atrial pressure in this clinical context. Severe MR associated with posterior leaflet prolapse or flail radiates anteriorly and to the base, where it can be confused with the murmur of aortic stenosis. MR that is due to anterior leaflet involvement radiates posteriorly and to the axilla. With acute TR in patients with normal pulmonary arterty (PA) pressures, an early systolic murmur that may increase in intensity with inspiration may be heard at

ECG

ECG LVP

LVP

AOP

LAP HSM S1

EDM S1

ECG

LVP AOP

LVP LAP

MSM S1

PSM A2

MDM S1

Figure 9-5 A. Top. Graphic representation of the systolic pressure difference (green shaded area) between left ventricle and left atrium with phonocardiographic recording of a holosystolic murmur (HSM) indicative of mitral regurgitation. ECG, electrocardiogram; LVP, left ventricular pressure; LAP, left atrial pressure; S1, first heart sound; S2 second heart sound. Bottom. Graphic representation of the systolic pressure gradient (green shaded area) between left ventricle and aorta in patient with aortic stenosis. A mid-systolic murmur (MSM) with a crescendo-decrescendo configuration is recorded. AOP, aortic pressure. B. Top. Graphic representation of the diastolic pressure difference between the aorta and left ventricle (blue shaded area) in a patient with aortic regurgitation, resulting in a decrescendo, early diastolic murmur (EDM) beginning with A2. Bottom. Graphic representation of the diastolic left atrial–left ventricular gradient (blue areas) in a patient with mitral stenosis with a mid-diastolic murmur (MDM) and late presystolic murmurs (PSM).

the left lower sternal border, with regurgitant cv waves visible in the jugular venous pulse. A midsystolic murmur begins after S1 and ends before S2; it is typically crescendo-decrescendo in configuration. Aortic stenosis is the most common cause of a midsystolic murmur in an adult. It is often difficult to estimate the severity of the valve lesion on the basis of the physical examination findings, especially in older hypertensive patients with stiffened carotid arteries or patients with low cardiac output in whom the intensity of the systolic heart murmur is misleadingly soft. Examination findings consistent with severe AS would include parvus et tardus carotid upstrokes, a late-peaking grade 3 or greater midsystolic murmur, a soft A2, a sustained LV apical impulse, and an S4. It is sometimes difficult to distinguish aortic sclerosis from more advanced degrees of valve stenosis. The former is defined by focal thickening and calcification of the aortic valve leaflets that is not severe enough to result in obstruction. These valve changes are associated with a Doppler jet velocity across the aortic valve of 2.5 m/s or less. Patients with aortic sclerosis can have grade 2 or 3 midsystolic murmurs identical in their acoustic characteristics to the murmurs heard in patients with more advanced degrees of AS. Other causes of a midsystolic heart murmur include pulmonic valve stenosis (with or without an ejection sound), HOCM, increased pulmonary blood flow in patients with a large atrial septal defect and left-to-right shunting, and several states associated with accelerated blood flow in the absence of structural heart disease, such as fever, thyrotoxicosis, pregnancy, anemia, and normal adolescence. The murmur of hypertrophic obstructive cardiomyopathy has features of both obstruction to left ventricular outflow and MR, as would be expected from knowledge of the pathophysiology of this condition. The systolic murmur of HOCM usually can be distinguished from other causes on the basis of its response to bedside maneuvers, including Valsalva, passive leg raising, and standing/ squatting. In general, maneuvers that decrease left ventricular preload (or increase left ventricular contractility) will cause the murmur to intensify, whereas maneuvers that increase left ventricular preload or afterload will cause a decrease in the intensity of the murmur. Accordingly, the systolic murmur of HOCM becomes louder during the strain phase of the Valsalva maneuver and after standing quickly from a squatting position. The murmur becomes softer with passive leg raising and when squatting. The murmur of AS is typically loudest in the second right interspace with radiation into the carotids, whereas the murmur of HOCM is best heard between the lower left sternal border and the apex. The murmur of PS is best heard in the second left interspace. The midsystolic murmur associated with enhanced pulmonic blood flow in the setting of a large atrial septal defect (ASD) is usually loudest at the mid-left sternal border.

The murmur of TR is loudest at the lower left sternal border, increases in intensity with inspiration (Carvallo’s sign), and is accompanied by visible cv waves in the jugular venous waveform and, on occasion, by pulsatile hepatomegaly. Diastolic murmurs

Ao LV Contractility

Volume

Figure 9-6 Behavior of the click (C) and murmur (M) of mitral valve prolapse with changes in loading (volume, impedance) and contractility. S1, first heart sound; S2, second heart sound. With standing (left side of figure), volume and impedance decrease, as a result of which the click and murmur move closer to S1. With squatting (right), the click and murmur move away from S1 owing to the increases in left ventricular volume and impedance (afterload). (Adapted from RA O’Rourke, MH Crawford: Curr Prob Cardiol 1:9, 1976.)

Physical Examination of the Cardiovascular System

In contrast to some systolic murmurs, diastolic heart murmurs always signify structural heart disease (Fig. 9-5). The murmur associated with acute, severe AR is relatively soft and of short duration because of the rapid rise in left ventricular diastolic pressure and the progressive diminution of the aortic-left ventricular diastolic pressure gradient. In contrast, the murmur of chronic severe AR is classically heard as a decrescendo, blowing diastolic murmur along the left sternal border in patients with primary valve pathology and sometimes along the right sternal border in patients with primary aortic root pathology. With chronic AR, the pulse pressure is wide and the arterial pulses are bounding in character. These signs of significant diastolic run-off are absent in the acute phase. The murmur of pulmonic regurgitation (PR) is also heard along the left sternal border. It is most commonly due to pulmonary hypertension and enlargement of the annulus of the pulmonic valve. S2 is single and loud and may be palpable. There is a right

Impedance

CHAPTER 9

A late systolic murmur, heard best at the apex, indicates MVP. As previously noted, the murmur may or may not be introduced by a nonejection click. Differential radiation of the murmur, as previously described, may help identify the specific leaflet involved by the myxomatous process. The click-murmur complex behaves in a manner directionally similar to that demonstrated by the murmur of HOCM during the Valsalva and stand/squat maneuvers (Fig. 9-6). The murmur of MVP can be identified by the accompanying nonejection click. Holosystolic murmurs are plateau in configuration and reflect a continuous and wide pressure gradient between the left ventricle and left atrium with chronic MR, the left ventricle and right ventricle with a ventricular septal defect (VSD), and the right ventricle and right atrium with TR. In contrast to acute MR, in chronic MR the left atrium is enlarged and its compliance is normal or increased to the extent that there is little if any further increase in left atrial pressure from any increase in regurgitant volume. The murmur of MR is best heard over the cardiac apex. The intensity of the murmur increases with maneuvers that increase left ventricular afterload, such as sustained hand grip. The murmur of a VSD (without significant pulmonary hypertension) is holosystolic and loudest at the mid-left sternal border, where a thrill is usually present.

Section II Diagnosis of Cardiovascular Disorders

ventricular/parasternal lift that is indicative of chronic right ventricular pressure overload. A less impressive murmur of PR is present after repair of tetralogy of Fallot or pulmonic valve atresia. In this postoperative setting, the murmur is softer and lower pitched and the severity of the accompanying pulmonic regurgitation can be underestimated significantly. Mitral stenosis is the classic cause of a mid- to late diastolic murmur, which is best heard over the apex in the left lateral decubitus position and is low-pitched or rumbling and is introduced by an OS in the early stages of the rheumatic disease process. Presystolic accentuation refers to an increase in the intensity of the murmur just before the first heart sound and occurs in patients with sinus rhythm. It is absent in patients with atrial fibrillation. The auscultatory findings in patients with rheumatic tricuspid stenosis typically are obscured by left-sided events, though they are similar in nature to those described in patients with MS. “Functional” mitral or tricuspid stenosis refers to the generation of mid-diastolic murmurs that are created by increased and accelerated transvalvular diastolic flow, even in the absence of valvular obstruction, in the setting of severe MR, severe TR, or a large ASD with left-to-right shunting. The Austin Flint murmur of chronic severe AR is a low-pitched mid- to late apical diastolic murmur that sometimes can be confused with MS. The Austin Flint murmur typically decreases in intensity after exposure to vasodilators, whereas the murmur of MS may be accompanied by an opening snap and also may increase in intensity after vasodilators because of the associated increase in cardiac output. Unusual causes of a mid-diastolic murmur include atrial myxoma, complete heart block, and acute rheumatic mitral valvulitis. Continuous murmur A continuous murmur is predicated on a pressure gradient that persists between two cardiac chambers or blood vessels across systole and diastole. The murmurs typically begin in systole, envelop the second heart sound (S2), and continue through some portion of diastole. They can often be difficult to distinguish from individual systolic and diastolic murmurs in patients with mixed valvular heart disease. The classic example of a continuous murmur is that associated with a patent ductus arteriosus, which usually is heard in the second or third interspace at a slight distance from the sternal border. Other causes of a continuous murmur include a ruptured sinus of Valsalva aneurysm with creation of an aortic–right atrial or right ventricular fistula, a coronary or great vessel arteriovenous fistula, and an arteriovenous fistula constructed to provide dialysis access. There are two types of benign continuous murmurs. The cervical venous hum is heard in children or adolescents in the supraclavicular fossa. It can be obliterated with

firm pressure applied to the diaphragm of the stethoscope, especially when the subject turns his or her head toward the examiner. The mammary souffle of pregnancy relates to enhanced arterial blood flow through engorged breasts. The diastolic component of the murmur can be obliterated with firm pressure over the stethoscope. Dynamic auscultation Diagnostic accuracy can be enhanced by the performance of simple bedside maneuvers to identify heart murmurs and characterize their significance (Table 9-1). Except for the pulmonic ejection sound, right-sided events increase in intensity with inspiration and decrease with expiration; left-sided events behave oppositely (100% sensitivity, 88% specificity). As previously noted, the intensity Table 9-1 Effects of Physiologic and Pharmacologic Interventions on the Intensity of Heart Murmurs and Sounds Respiration Right-sided murmurs and sounds generally increase with inspiration, except for the PES. Left-sided murmurs and sounds are usually louder during expiration. Valsalva maneuver Most murmurs decrease in length and intensity. Two exceptions are the systolic murmur of HOCM, which usually becomes much louder, and that of MVP, which becomes longer and often louder. After release of the Valsalva maneuver, right-sided murmurs tend to return to control intensity earlier than do left-sided murmurs. After VPB or AF Murmurs originating at normal or stenotic semilunar valves increase in the cardiac cycle after a VPB or in the cycle after a long-cycle length in AF. By contrast, systolic murmurs due to AV valve regurgitation do not change, diminish (papillary muscle dysfunction), or become shorter (MVP). Positional changes With standing, most murmurs diminish, with two exceptions being the murmur of HOCM, which becomes louder, and that of MVP, which lengthens and often is intensified. With squatting, most murmurs become louder, but those of HOCM and MVP usually soften and may disappear. Passive leg raising usually produces the same results. Exercise Murmurs due to blood flow across normal or obstructed valves (e.g., PS, MS) become louder with both isotonic and submaximal isometric (hand grip) exercise. Murmurs of MR, VSD, and AR also increase with hand grip exercise. However, the murmur of HOCM often decreases with nearly maximum hand grip exercise. Left-sided S4 and S3 sounds are often accentuated by exercise, particularly when due to ischemic heart disease. Abbreviations: AF, atrial fibrillation; AR, aortic regurgitation; HOCM, hypertrophic obstructive cardiomyopathy; MR, mitral regurgitation; MS, mitral stenosis; MVP, mitral valve prolapse; PES, pulmonic ejection sound; PR, pulmonic regurgitation; PS, pulmonic stenosis; TR, tricuspid regurgitation; TS, tricuspid stenosis; VPB, ventricular premature beat; VSD, ventricular septal defect.

The first clue that prosthetic valve dysfunction may contribute to recurrent symptoms is frequently a change in the quality of the heart sounds or the appearance of a new murmur. The heart sounds with a bioprosthetic valve resemble those generated by native valves. A mitral bioprosthesis usually is associated with a grade 2 or 3 mid-systolic murmur along the left sternal border

Pericardial disease A pericardial friction rub is nearly 100% specific for the diagnosis of acute pericarditis, though the sensitivity of this finding is not nearly as high, as the rub may come and go over the course of an acute illness or be very difficult to elicit. The rub is heard as a leathery or scratchy three-component or two-component sound, though it may be monophasic. Classically, the three components are ventricular systole, rapid early diastolic filling, and late presystolic filling after atrial contraction in patients in sinus rhythm. It is necessary to listen to the heart in several positions. Additional clues may be present from the history and 12-lead electrocardiogram. The rub typically disappears as the volume of any pericardial effusion increases. Pericardial tamponade can be diagnosed with a sensitivity of 98%, a specificity of 83%, and a positive likelihood ratio of 5.9 (95% confidence intervals 2.4 to 14) by a pulsus paradoxus that exceeds 12 mmHg in a patient with a large pericardial effusion. The findings on physical examination are integrated with the symptoms previously elicited with a careful history to construct an appropriate differential diagnosis and proceed with indicated imaging and laboratory assessment. The physical examination is an irreplaceable component of the diagnostic algorithm and in selected patients can inform prognosis. Educational efforts to improve clinician competence eventually may result in cost saving, particularly if the indications for imaging can be influenced by the examination findings.

Physical Examination of the Cardiovascular System

Prosthetic heart valves

(created by turbulence across the valve struts as they project into the LV outflow tract) as well as by a soft mid-diastolic murmur that occurs with normal LV filling. This diastolic murmur often can be heard only in the left lateral decubitus position and after exercise. A high-pitched or holosystolic apical murmur is indicative of paravalvular leak or bioprosthetic regurgitation, for which additional imaging is indicated. Clinical deterioration can occur rapidly after the first expression of bioprosthetic failure. A tissue valve in the aortic position is always associated with a grade 2 to 3 mid-systolic murmur at the base or just below the suprasternal notch. A diastolic murmur of AR is abnormal in any circ*mstances. Mechanical valve dysfunction may first be suggested by a decrease in the intensity of either the opening or the closing sound. A high-pitched apical systolic murmur in patients with a mechanical mitral prosthesis and a diastolic decrescendo murmur in patients with a mechanical aortic prosthesis indicate paravalvular regurgitation. Patients with prosthetic valve thrombosis may present clinically with signs of shock, muffled heart sounds, and soft murmurs.

CHAPTER 9

of the murmurs associated with MR, VSD, and AR will increase in response to maneuvers that increase LV afterload, such as hand grip and vasopressors. The intensity of these murmurs will decrease after exposure to vasodilating agents. Squatting is associated with an abrupt increase in LV preload and afterload, whereas rapid standing results in a sudden decrease in preload. In patients with MVP, the click and murmur move away from the first heart sound with squatting because of the delay in onset of leaflet prolapse at higher ventricular volumes. With rapid standing, however, the click and murmur move closer to the first heart sound as prolapse occurs earlier in systole at a smaller chamber dimension. The murmur of HOCM behaves similarly, becoming softer and shorter with squatting (95% sensitivity, 85% specificity) and longer and louder on rapid standing (95% sensitivity, 84% specificity). A change in the intensity of a systolic murmur in the first beat after a premature beat or in the beat after a long cycle length in patients with atrial fibrillation suggests valvular AS rather than MR, particularly in an older patient in whom the murmur of the AS may be well transmitted to the apex (Gallavardin effect). Of note, however, the systolic murmur of HOCM also increases in intensity in the beat after a premature beat. This increase in intensity of any LV outflow murmur in the beat after a premature beat relates to the combined effects of enhanced LV filling (from the longer diastolic period) and postextrasystolic potentiation of LV contractile function. In either instance, forward flow will accelerate, causing an increase in the gradient across the LV outflow tract (dynamic or fixed) and a louder systolic murmur. In contrast, the intensity of the murmur of MR does not change in a postpremature beat, as there is relatively little change in the nearly constant LV to left atrial pressure gradient or further alteration in mitral valve flow. Bedside exercise can sometimes be performed to increase cardiac output and, secondarily, the intensity of both systolic and diastolic heart murmurs. Most left-sided heart murmurs decrease in intensity and duration during the strain phase of the Valsalva maneuver. The murmurs associated with MVP and HOCM are the two notable exceptions. The Valsalva maneuver also can be used to assess the integrity of the heart and vasculature in the setting of advanced heart failure.

CHAPTER 10

APPROACH TO THE PATIENT WITH A HEART MURMUR Patrick T. O’Gara

■

Joseph Loscalzo simultaneous palpation of the carotid upstroke, which should closely follow S1.

introDuction The differential diagnosis of a heart murmur begins with a careful assessment of its major attributes and responses to bedside maneuvers. The history, clinical context, and associated physical examination findings provide additional clues by which the significance of a heart murmur is established. Accurate bedside identification of a heart murmur can inform decisions regarding the indications for noninvasive testing and the need for referral to a cardiovascular specialist. Preliminary discussions can be held with the patient regarding antibiotic or rheumatic fever prophylaxis, the need to restrict various forms of physical activity, and the potential role for family screening. Heart murmurs are caused by audible vibrations that are due to increased turbulence from accelerated blood flow through normal or abnormal orifices, flow through a narrowed or irregular orifice into a dilated vessel or chamber, or backward flow through an incompetent valve, ventricular septal defect, or patent ductus arteriosus. They traditionally are defined in terms of their timing within the cardiac cycle (Fig. 10-1). Systolic murmurs begin with or after the first heart sound (S1) and terminate at or before the component (A2 or P2) of the second heart sound (S2) that corresponds to their site of origin (left or right, respectively). Diastolic murmurs begin with or after the associated component of S2 and end at or before the subsequent S1. Continuous murmurs are not confined to either phase of the cardiac cycle but instead begin in early systole and proceed through S2 into all or part of diastole. The accurate timing of heart murmurs is the first step in their identification. The distinction between S1 and S2 and, therefore, systole and diastole is usually a straightforward process but can be difficult in the setting of a tachyarrhythmia, in which case the heart sounds can be distinguished by

Duration The duration of a heart murmur depends on the length of time over which a pressure difference exists between two cardiac chambers, the left ventricle and the aorta, the right ventricle and the pulmonary artery, or the great vessels. The magnitude and variability of this pressure difference, coupled with the geometry and compliance of the involved chambers or vessels, dictate the velocity of flow; the degree of turbulence; and the resulting frequency, configuration, and intensity of the murmur. The diastolic murmur of chronic aortic regurgitation (AR) is a blowing, high-frequency event, whereas the murmur of mitral stenosis (MS), indicative of the left atrial–left ventricular diastolic pressure gradient, is a low-frequency event, heard as a rumbling sound with the bell of the stethoscope. The frequency components of a heart murmur may vary at different sites of auscultation. The coarse systolic murmur of aortic stenosis (AS) may sound higher pitched and more acoustically pure at the apex, a phenomenon eponymously referred to as the Gallavardin effect. Some murmurs may have a distinct or unusual quality, such as the “honking” sound appreciated in some patients with mitral regurgitation (MR) due to mitral valve prolapse (MVP). The configuration of a heart murmur may be described as crescendo, decrescendo, crescendo-decrescendo, or plateau. The decrescendo configuration of the murmur of chronic AR (Fig. 10-1E) can be understood in terms of the progressive decline in the diastolic pressure gradient between the aorta and the left ventricle. The crescendodecrescendo configuration of the murmur of AS reflects the changes in the systolic pressure gradient between the

Figure 10-1 Diagram depicting principal heart murmurs. A. Presystolic murmur of mitral or tricuspid stenosis. B. Holosystolic (pansystolic) murmur of mitral or tricuspid regurgitation or of ventricular septal defect. C. Aortic ejection murmur beginning with an ejection click and fading before the second heart sound. D. Systolic murmur in pulmonic stenosis spilling through the aortic second sound, pulmonic valve closure being delayed. E. Aortic or pulmonary diastolic murmur. F. Long diastolic murmur of mitral stenosis after the opening snap (OS). G. Short mid-diastolic inflow murmur after a third heart sound. H. Continuous murmur of patent ductus arteriosus. (Adapted from P Wood, Diseases of the Heart and Circulation, London, Eyre & Spottiswood, 1968. Permission granted courtesy of Antony and Julie Wood.)

Location and radiation Recognition of the location and radiation of the murmur helps facilitate its accurate identification (Fig. 10-2). Adventitious sounds, such as a systolic click or diastolic snap, or abnormalities of S1 or S2 may provide additional clues. Careful attention to the characteristics of the murmur and other heart sounds during the respiratory cycle and the performance of simple bedside maneuvers complete the auscultatory examination. These features, along with recommendations for further testing, are discussed later in the context of specific systolic, diastolic, and continuous heart murmurs (Table 10-1).

Pulm

Aortic

left ventricle and the aorta as ejection occurs, whereas the plateau configuration of the murmur of chronic MR (Fig. 10-1B) is consistent with the large and nearly constant pressure difference between the left ventricle and the left atrium. Intensity The intensity of a heart murmur is graded on a scale of 1–6 (or I–VI). A grade 1 murmur is very soft and is heard only with great effort. A grade 2 murmur is easily heard but not particularly loud. A grade 3 murmur is loud but is not accompanied by a palpable thrill over the site of maximal intensity. A grade 4 murmur is very loud and is

VSD

Vibratory HOCM

Figure 10-2 Maximal intensity and radiation of six isolated systolic murmurs. HOCM, hypertrophic obstructive cardiomyopathy; MR, mitral regurgitation; Pulm, pulmonary stenosis; Aortic, aortic stenosis; VSD, ventricular septal defect. (From JB Barlow, Perspectives on the Mitral Valve. Philadelphia, FA Davis, 1987, p 140.)

Approach to the Patient withaHeartMurmur

CHAPTER 10

accompanied by a thrill. A grade 5 murmur is loud enough to be heard with only the edge of the stethoscope touching the chest, whereas a grade 6 murmur is loud enough to be heard with the stethoscope slightly off the chest. Murmurs of grade 3 or greater intensity usually signify important structural heart disease and indicate high blood flow velocity at the site of murmur production. Small ventricular septal defects (VSDs), for example, are accompanied by loud, usually grade 4 or greater, systolic murmurs as blood is ejected at high velocity from the left ventricle to the right ventricle. Low-velocity events, such as left-to-right shunting across an atrial septal defect (ASD), are usually silent. The intensity of a heart murmur also may be diminished by any process that increases the distance between the intracardiac source and the stethoscope on the chest wall, such as obesity, obstructive lung disease, and a large pericardial effusion. The intensity of a murmur also may be misleadingly soft when cardiac output is reduced significantly or when the pressure gradient between the involved cardiac structures is low.

Table 10-1 Principal Causes of Heart Murmurs Systolic Murmurs

SECTION II Diagnosis of Cardiovascular Disorders

Early systolic Mitral Acute MR VSD Muscular Nonrestrictive with pulmonary hypertension Tricuspid TR with normal pulmonary artery pressure Mid-systolic Aortic Obstructive Supravalvular—supravalvular aortic stenosis, coarctation of the aorta Valvular—AS and aortic sclerosis Subvalvular—discrete, tunnel or HOCM Increased flow, hyperkinetic states, AR, complete heart block Dilation of ascending aorta, atheroma, aortitis Pulmonary Obstructive Supravalvular—pulmonary artery stenosis Valvular–pulmonic valve stenosis Subvalvular–infundibular stenosis (dynamic) Increased flow, hyperkinetic states, left-to-right shunt (e.g., ASD) Dilation of pulmonary artery Late systolic Mitral MVP, acute myocardial ischemia Tricuspid TVP Holosystolic Atrioventricular valve regurgitation (MR, TR) Left-to-right shunt at ventricular level (VSD) Early Diastolic Murmurs Aortic regurgitation Valvular: congenital (bicuspid valve), rheumatic deformity, endocarditis, prolapse, trauma, post-valvulotomy Dilation of valve ring: aortic dissection, annulo-aortic ectasia, cystic medial degeneration, hypertension, ankylosing spondylitis Widening of commissures: syphilis Pulmonic regurgitation Valvular: post-valvulotomy, endocarditis, rheumatic fever, carcinoid Dilation of valve ring: pulmonary hypertension; Marfan syndrome Congenital: isolated or associated with tetralogy of Fallot, VSD, pulmonic stenosis Mid-Diastolic Murmurs Mitral Mitral stenosis Carey-Coombs murmur (mid-diastolic apical murmur in acute rheumatic fever) Increased flow across nonstenotic mitral valve (e.g., MR, VSD, PDA, high-output states, and complete heart block) Tricuspid Tricuspid stenosis Increased flow across nonstenotic tricuspid valve (e.g., TR, ASD, and anomalous pulmonary venous return) Left and right atrial tumors (myxoma) Severe AR (Austin Flint murmur) Continuous Murmurs Patent ductus arteriosus Coronary AV fistula Ruptured sinus of Valsalva aneurysm Aortic septal defect Cervical venous hum Anomalous left coronary artery

Proximal coronary artery stenosis Mammary souffle of pregnancy Pulmonary artery branch stenosis Bronchial collateral circulation Small (restrictive) ASD with MS Intercostal AV fistula

Abbreviations: AR, aortic regurgitation; AS, aortic stenosis; ASD, atrial septal defect; AV, arteriovenous; HOCM, hypertrophic obstructive cardiomyopathy; MR, mitral regurgitation; MS, mitral stenosis; MVP, mitral valve prolapse; PDA, patent ductus arteriosus; TR, tricuspid regurgitation; TVP, tricuspid valve prolapse; VSD, ventricular septal defect. Source: E Braunwald, JK Perloff, in D Zipes et al (eds): Braunwald’s Heart Disease, 7th ed. Philadelphia, Elsevier, 2005; PJ Norton, RA O’Rourke, in E Braunwald, L Goldman (eds): Primary Cardiology, 2nd ed. Philadelphia, Elsevier, 2003.

Systolic Heart Murmurs Early systolic murmurs

Mid-systolic murmurs begin at a short interval after S1, end before S2 (Fig. 10-1C), and are usually crescendodecrescendo in configuration. Aortic stenosis is the most common cause of a mid-systolic murmur in an adult. The murmur of AS is usually loudest to the right of the sternum in the second intercostal space (aortic area, Fig. 10-2) and radiates into the carotids. Transmission of the midsystolic murmur to the apex, where it becomes higher pitched, is common (Gallavardin effect; see earlier). Differentiation of this apical systolic murmur from MR can be difficult. The murmur of AS will increase in intensity, or become louder, in the beat after a premature beat, whereas the murmur of MR will have constant intensity from beat to beat. The intensity of the AS murmur also varies directly with the cardiac output. With a normal cardiac output, a systolic thrill and a grade 4 or higher murmur suggest severe AS. The murmur is softer in the setting of heart failure and low cardiac output. Other auscultatory findings of severe AS include a soft or absent A2, paradoxical splitting of S2, an apical S4, and a late-peaking systolic murmur. In children, adolescents, and young adults with congenital valvular AS, an early ejection sound (click) is usually

Approach to the Patient withaHeartMurmur

Mid-systolic murmurs

CHAPTER 10

Early systolic murmurs begin with S1 and extend for a variable period, ending well before S2. Their causes are relatively few in number. Acute, severe MR into a normalsized, relatively noncompliant left atrium results in an early, decrescendo systolic murmur best heard at or just medial to the apical impulse. These characteristics reflect the progressive attenuation of the pressure gradient between the left ventricle and the left atrium during systole owing to the rapid rise in left atrial pressure caused by the sudden volume load into an unprepared chamber and contrast sharply with the auscultatory features of chronic MR. Clinical settings in which acute, severe MR occur include (1) papillary muscle rupture complicating acute myocardial infarction (MI) (Chap. 35), (2) rupture of chordae tendineae in the setting of myxomatous mitral valve disease (MVP, Chap. 20), (3) infective endocarditis (Chap. 25), and (4) blunt chest wall trauma. Acute, severe MR from papillary muscle rupture usually accompanies an inferior, posterior, or lateral MI and occurs 2–7 days after presentation. It often is signaled by chest pain, hypotension, and pulmonary edema, but a murmur may be absent in up to 50% of cases. The posteromedial papillary muscle is involved 6 to 10 times more frequently than the anterolateral papillary muscle. The murmur is to be distinguished from that associated with post-MI ventricular septal rupture, which is accompanied by a systolic thrill at the left sternal border in nearly all patients and is holosystolic in duration. A new heart murmur after an MI is an indication for transthoracic echocardiography (TTE) (Chap. 12), which allows bedside delineation of its etiology and pathophysiologic significance. The distinction between acute MR and ventricular septal rupture also can be achieved with right heart catheterization, sequential determination of oxygen saturations, and analysis of the pressure waveforms (tall v wave in the pulmonary artery wedge pressure in MR). Post-MI mechanical complications of this nature mandate aggressive medical stabilization and prompt referral for surgical repair. Spontaneous chordal rupture can complicate the course of myxomatous mitral valve disease (MVP) and result in new-onset or “acute on chronic” severe MR. MVP may occur as an isolated phenomenon, or the lesion may be part of a more generalized connective tissue disorder as seen, for example, in patients with Marfan syndrome. Acute, severe MR as a consequence of infective endocarditis results from destruction of leaflet tissue, chordal rupture, or both. Blunt chest wall trauma is usually self-evident but may be disarmingly trivial; it can result in papillary muscle contusion and rupture, chordal detachment, or leaflet avulsion. TTE is indicated in all cases of suspected acute, severe MR to define its mechanism and severity, delineate left

ventricular size and systolic function, and provide an assessment of suitability for primary valve repair. A congenital, small muscular VSD (Chap. 19) may be associated with an early systolic murmur. The defect closes progressively during septal contraction, and thus, the murmur is confined to early systole. It is localized to the left sternal border (Fig. 10-2) and is usually of grade 4 or 5 intensity. Signs of pulmonary hypertension or left ventricular volume overload are absent. Anatomically large and uncorrected VSDs, which usually involve the membranous portion of the septum, may lead to pulmonary hypertension. The murmur associated with the left-to-right shunt, which earlier may have been holosystolic, becomes limited to the first portion of systole as the elevated pulmonary vascular resistance leads to an abrupt rise in right ventricular pressure and an attenuation of the interventricular pressure gradient during the remainder of the cardiac cycle. In such instances, signs of pulmonary hypertension (right ventricular lift, loud and single or closely split S2) may predominate. The murmur is best heard along the left sternal border but is softer. Suspicion of a VSD is an indication for TTE. Tricuspid regurgitation (TR) with normal pulmonary artery pressures, as may occur with infective endocarditis, may produce an early systolic murmur. The murmur is soft (grade 1 or 2), is best heard at the lower left sternal border, and may increase in intensity with inspiration (Carvallo’s sign). Regurgitant “c-v” waves may be visible in the jugular venous pulse. TR in this setting is not associated with signs of right heart failure.

SECTION II Diagnosis of Cardiovascular Disorders

audible, more often along the left sternal border than at the base. Its presence signifies a flexible, noncalcified bicuspid valve (or one of its variants) and localizes the left ventricular outflow obstruction to the valvular (rather than sub- or supravalvular) level. Assessment of the volume and rate of rise of the carotid pulse can provide additional information. A small and delayed upstroke (parvus et tardus) is consistent with severe AS. The carotid pulse examination is less discriminatory, however, in older patients with stiffened arteries. The electrocardiogram (ECG) shows signs of left ventricular hypertrophy (LVH) as the severity of the stenosis increases. TTE is indicated to assess the anatomic features of the aortic valve, the severity of the stenosis, left ventricular size, wall thickness and function, and the size and contour of the aortic root and proximal ascending aorta. The obstructive form of hypertrophic cardiomyopathy (HOCM) is associated with a mid-systolic murmur that is usually loudest along the left sternal border or between the left lower sternal border and the apex (Chap. 21, Fig. 10-2). The murmur is produced by both dynamic left ventricular outflow tract obstruction and MR, and thus, its configuration is a hybrid between ejection and regurgitant phenomena. The intensity of the murmur may vary from beat to beat and after provocative maneuvers but usually does not exceed grade 3. The murmur classically will increase in intensity with maneuvers that result in increasing degrees of outflow tract obstruction, such as a reduction in preload or afterload (Valsalva, standing, vasodilators), or with an augmentation of contractility (inotropic stimulation). Maneuvers that increase preload (squatting, passive leg raising, volume administration) or afterload (squatting, vasopressors) or that reduce contractility (β-adrenoreceptor blockers) decrease the intensity of the murmur. In rare patients, there may be reversed splitting of S2. A sustained left ventricular apical impulse and an S4 may be appreciated. In contrast to AS, the carotid upstroke is rapid and of normal volume. Rarely, it is bisferiens or bifid in contour (see Fig. 9-2D) due to mid-systolic closure of the aortic valve. LVH is present on the ECG, and the diagnosis is confirmed by TTE. Although the systolic murmur associated with MVP behaves similarly to that due to HOCM in response to the Valsalva maneuver and to standing/squatting (Fig. 10-3), these two lesions can be distinguished on the basis of their associated findings, such as the presence of LVH in HOCM or a nonejection click in MVP. The mid-systolic, crescendo-decrescendo murmur of congenital pulmonic stenosis (PS, Chap. 19) is best appreciated in the second and third left intercostal spaces (pulmonic area) (Figs. 10-2 and 10-4). The duration of the murmur lengthens and the intensity of P2 diminishes with increasing degrees of valvular stenosis (Fig. 10-1D). An early ejection sound, the

Supine S1

Standing

Squatting S1 C

Figure 10-3 A mid-systolic nonejection sound (C) occurs in mitral valve prolapse and is followed by a late systolic murmur that crescendos to the second heart sound (S2). Standing decreases venous return; the heart becomes smaller; C moves closer to the first heart sound (S1), and the mitral regurgitant murmur has an earlier onset. With prompt squatting, venous return increases; the heart becomes larger; C moves toward S2, and the duration of the murmur shortens. (From JA Shaver, JJ Leonard, DF Leon, Examination of the Heart, Part IV, Auscultation of the Heart. Dallas, American Heart Association, 1990, p 13. Copyright, American Heart Association.)

intensity of which decreases with inspiration, is heard in younger patients. A parasternal lift and ECG evidence of right ventricular hypertrophy indicate severe pressure overload. If obtained, the chest x-ray may show poststenotic dilation of the main pulmonary artery. TTE is recommended for complete characterization. Significant left-to-right intracardiac shunting due to an ASD (Chap. 19) leads to an increase in pulmonary blood flow and a grade 2–3 mid-systolic murmur at the middle to upper left sternal border attributed to increased flow rates across the pulmonic valve with fixed splitting of S2. Ostium secundum ASDs are the most common cause of these shunts in adults. Features suggestive of a primum ASD include the coexistence of MR due to a cleft anterior mitral valve leaflet and left axis deviation of the QRS complex on the ECG. With sinus venosus ASDs, the left-to-right shunt is usually not large enough to result in a systolic murmur, although the ECG may show abnormalities of sinus node function. A grade 2 or 3 mid-systolic murmur

Pulmonic stenosis S1

P.Ej S1

A2 S1

P2 S2

A2 S1

patient is the crescendo-decrescendo murmur of aortic valve sclerosis, heard at the second right interspace (Fig. 10-2). Aortic sclerosis is defined as focal thickening and calcification of the aortic valve to a degree that does not interfere with leaflet opening. The carotid upstrokes are normal, and electrocardiographic LVH is not present. A grade 1 or 2 mid-systolic murmur often can be heard at the left sternal border with pregnancy, hyperthyroidism, or anemia, physiologic states that are associated with accelerated blood flow. Still’s murmur refers to a benign grade 2, vibratory mid-systolic murmur at the lower left sternal border in normal children and adolescents (Fig.10-2).

P.Ej

P.Ej = Pulmonary ejection (valvular)

A.Ej

A.Ej = Aortic ejection (root)

Figure 10-4 Left. In valvular pulmonic stenosis with intact ventricular septum, right ventricular systolic ejection becomes progressively longer, with increasing obstruction to flow. As a result, the murmur becomes longer and louder, enveloping the aortic component of the second heart sound (A2). The pulmonic component (P2) occurs later, and splitting becomes wider but more difficult to hear because A2 is lost in the murmur and P2 becomes progressively fainter and lower pitched. As the pulmonic gradient increases, isometric contraction shortens until the pulmonic valve ejection sound fuses with the first heart sound (S1). In severe pulmonic stenosis with concentric hypertrophy and decreasing right ventricular compliance, a fourth heart sound appears. Right. In tetralogy of Fallot with increasing obstruction at the pulmonic infundibular area, an increasing amount of right ventricular blood is shunted across the silent ventricular septal defect and flow across the obstructed outflow tract decreases. Therefore, with increasing obstruction the murmur becomes shorter, earlier, and fainter. P2 is absent in severe tetralogy of Fallot. A large aortic root receives almost all cardiac output from both ventricular chambers, and the aorta dilates and is accompanied by a root ejection sound that does not vary with respiration. (From JA Shaver, JJ Leonard, DF Leon, Examination of the Heart, Part IV, Auscultation of the Heart. Dallas, American Heart Association, 1990, p 45. Copyright, American Heart Association.)

may also be heard best at the upper left sternal border in patients with idiopathic dilation of the pulmonary artery; a pulmonary ejection sound is also present in these patients. TTE is indicated to evaluate a grade 2or3 mid-systolic murmur when there are other signs of cardiac disease. An isolated grade 1 or 2 mid-systolic murmur, heard in the absence of symptoms or signs of heart disease, is most often a benign finding for which no further evaluation, including TTE, is necessary. The most common example of a murmur of this type in an older adult

A late systolic murmur that is best heard at the left ventricular apex is usually due to MVP (Chap. 20). Often, this murmur is introduced by one or more nonejection clicks. The radiation of the murmur can help identify the specific mitral leaflet involved in the process of prolapse or flail. The term flail refers to the movement made by an unsupported portion of the leaflet after loss of its chordal attachment(s). With posterior leaflet prolapse or flail, the resultant jet of MR is directed anteriorly and medially, as a result of which the murmur radiates to the base of the heart and masquerades as AS. Anterior leaflet prolapse or flail results in a posteriorly directed MR jet that radiates to the axilla or left infrascapular region. Leaflet flail is associated with a murmur of grade 3 or 4 intensity that can be heard throughout the precordium in thin-chested patients. The presence of an S3 or a short, rumbling mid-diastolic murmur due to enhanced flow signifies severe MR. Bedside maneuvers that decrease left ventricular preload, such as standing, will cause the click and murmur of MVP to move closer to the first heart sound, as leaflet prolapse occurs earlier in systole. Standing also causes the murmur to become louder and longer. With squatting, left ventricular preload and afterload are increased abruptly, leading to an increase in left ventricular volume, and the click and murmur move away from the first heart sound as leaflet prolapse is delayed; the murmur becomes softer and shorter in duration (Fig. 10-3). As noted earlier, these responses to standing and squatting are directionally similar to those observed in patients with HOCM. A late, apical systolic murmur indicative of MR may be heard transiently in the setting of acute myocardial ischemia; it is due to apical tethering and malcoaptation of the leaflets in response to structural and functional changes of the ventricle and mitral annulus. The intensity of the murmur varies as a function of left ventricular afterload and will increase in the setting of hypertension. TTE is recommended for assessment of late systolic murmurs.

Approach to the Patient withaHeartMurmur

Late systolic murmurs

CHAPTER 10

P.Ej S1

Tetralogy of Fallot

SECTION II Diagnosis of Cardiovascular Disorders

MR will result in further stretching of the annulus and more MR; thus, “MR begets MR.” Chronic severe MR results in enlargement and leftward displacement of the left ventricular apex beat and, in some patients, a diastolic filling complex, as described previously. The holosystolic murmur of chronic TR is generally softer than that of MR, is loudest at the left lower sternal border, and usually increases in intensity with inspiration (Carvallo’s sign). Associated signs include c-v waves in the jugular venous pulse, an enlarged and pulsatile liver, ascites, and peripheral edema. The abnormal jugular venous waveforms are the predominant finding and are seen very often in the absence of an audible murmur despite Doppler echocardiographic verification of TR. Causes of primary TR include myxomatous disease (prolapse), endocarditis, rheumatic disease, carcinoid, Ebstein’s anomaly, and chordal detachment after the performance of right ventricular endomyocardial biopsy. TR is more commonly a passive process that results secondarily from chronic elevations of pulmonary artery and right ventricular pressures, leading to right ventricular enlargement, annular dilation, papillary muscle displacement, and failure of leaflet coaptation. The holosystolic murmur of a VSD is loudest at the mid- to lower left sternal border (Fig. 10-2) and radiates widely. A thrill is present at the site of maximal intensity in the majority of patients. There is no change in the intensity of the murmur with inspiration.

Holosystolic murmurs (Figs. 10-1B and 10-5) Holosystolic murmurs begin with S1 and continue through systole to S2. They are usually indicative of chronic mitral or tricuspid valve regurgitation or a VSD and warrant TTE for further characterization. The holosystolic murmur of chronic MR is best heard at the left ventricular apex and radiates to the axilla (Fig. 10-2); it is usually high pitched and plateau in configuration because of the wide difference between left ventricular and left atrial pressure throughout systole. In contrast to acute MR, left atrial compliance is normal or even increased in chronic MR. As a result, there is only a small increase in left atrial pressure for any increase in regurgitant volume. Several conditions are associated with chronic MR and an apical holosystolic murmur, including rheumatic scarring of the leaflets, mitral annular calcification, postinfarction left ventricular remodeling, and severe left ventricular chamber enlargement. The circumference of the mitral annulus increases as the left ventricle enlarges and leads to failure of leaflet coaptation with central MR in patients with dilated cardiomyopathy (Chap. 21). The severity of the MR is worsened by any contribution from apical displacement of the papillary muscles and leaflet tethering (remodeling). Because the mitral annulus is contiguous with the left atrial endocardium, gradual enlargement of the left atrium from chronic

HOLOSYSTOLIC MURMUR DIFFERENTIAL DIAGNOSIS Onset with S1 terminates at or beyond S2

Maximum intensity over apex Radiation to axilla or base A 2 not heard over apex Decreased intensity with amyl nitrate

Maximum intensity over left sternal border Radiation to epigastrium and right sternal border Increased intensity during inspiration Prominent c-v wave with sharp y descent in jugular venous pulse

Mitral regurgitation

Tricuspid regurgitation

Hyperdynamic left ventricular impulse Wide splitting of S2

Sustained left ventricular impulse Single S2 or narrow splitting of S2

Primary mitral regurgitation (e.g., rheumatic, ruptured chordae)

Secondary mitral regurgitation (dilated cardiomyopathy; papillary muscle dysfunction, or late stage of primary mitral regurgitation)

Figure 10-5 Differential diagnosis of a holosystolic murmur.

Prominent left parasternal diastolic impulse Normal brief left parasternal systolic impulse Normal P2 Rarely paradoxical S2 Primary

Maximum intensity over lower left third and fourth interspace Widespread radiation, palpable thrill Decreased intensity with amyl nitrate No change in intensity during inspiration Wide splitting of S2

Sustained systolic left parasternal impulse Narrow splitting of S2 with marked increase in intensity of P2

Secondary to pulmonary hypertension

Favors ventricular septal defect; often difficult to differentiate from mitral regurgitant murmur

Diastolic Heart Murmurs Early diastolic murmurs

Diastolic Filling Murmur (Rumble) Mitral Stenosis S1

O.S.

Mild A2

ECG S1

S1 O.S.

S2 O.S.

Severe A2 P2

Figure 10-6 Diastolic filling murmur (rumble) in mitral stenosis. In mild mitral stenosis, the diastolic gradient across the valve is limited to the phases of rapid ventricular filling in early diastole and presystole. The rumble may occur during either or both periods. As the stenotic process becomes severe, a large pressure gradient exists across the valve during the entire diastolic filling period, and the rumble persists throughout diastole. As the left atrial pressure becomes greater, the

A 2 P2

interval between A2 (or P2) and the opening snap (O.S.) shortens. In severe mitral stenosis, secondary pulmonary hypertension develops and results in a loud P2 and the splitting interval usually narrows. ECG, electrocardiogram. (From JA Shaver, JJ Leonard, DF Leon, Examination of the Heart, Part IV, Auscultation of the Heart. Dallas, American Heart Association, 1990, p 55. Copyright, American Heart Association.)

Approach to the Patient withaHeartMurmur

(Fig. 10-1E) Chronic AR results in a high-pitched, blowing, decrescendo, early to mid-diastolic murmur that begins after the aortic component of S2 (A2) and is best heard at the second right interspace (Fig. 10-6). The murmur may be soft and difficult to hear unless auscultation is performed with the patient leaning forward at end expiration. This maneuver brings the aortic root closer to the anterior chest wall. Radiation of the murmur may provide a clue to the cause of the AR. With primary valve disease, such as that due to congenital bicuspid disease, prolapse, or endocarditis, the diastolic murmur tends to radiate along the left sternal border, where it is often louder than appreciated in the second right interspace. When AR is caused by aortic root disease, the diastolic murmur may radiate along the right sternal border. Diseases of the aortic root cause dilation or distortion of the aortic annulus and failure of leaflet coaptation. Causes include Marfan

syndrome with aneurysm formation, annulo-aortic ectasia, ankylosing spondylitis, and aortic dissection. Chronic, severe AR also may produce a lowerpitched mid- to late, grade 1 or 2 diastolic murmur at the apex (Austin Flint murmur), which is thought to reflect turbulence at the mitral inflow area from the admixture of regurgitant (aortic) and forward (mitral) blood flow (Fig. 10-1G). This lower-pitched, apical diastolic murmur can be distinguished from that due to MS by the absence of an opening snap and the response of the murmur to a vasodilator challenge. Lowering afterload with an agent such as amyl nitrite will decrease the duration and magnitude of the aortic–left ventricular diastolic pressure gradient, and thus, the Austin Flint murmur of severe AR will become shorter and softer. The intensity of the diastolic murmur of mitral stenosis (Fig. 10-6) may either remain constant or increase with afterload reduction because of the reflex increase in cardiac output and mitral valve flow. Although AS and AR may coexist, a grade 2 or 3 crescendo-decrescendo mid-systolic murmur frequently is heard at the base of the heart in patients with isolated, severe AR and is due to an increased volume and rate of systolic flow. Accurate bedside identification of coexistent AS can be difficult unless the carotid pulse examination is abnormal or the mid-systolic murmur is of grade 4 or greater intensity. In the absence of heart failure, chronic severe AR is accompanied by several peripheral signs of significant diastolic run-off, including a wide pulse pressure, a “water-hammer” carotid upstroke (Corrigan’s pulse), and Quincke’s pulsations of

CHAPTER 10

The intensity of the murmur varies as a function of the anatomic size of the defect. Small, restrictive VSDs, as exemplified by the maladie de Roger, create a very loud murmur due to the significant and sustained systolic pressure gradient between the left and right ventricles. With large defects, the ventricular pressures tend to equalize, shunt flow is balanced, and a murmur is not appreciated. The distinction between post-MI ventricular septal rupture and MR has been reviewed previously.

SECTION II Diagnosis of Cardiovascular Disorders

the nail beds. The diastolic murmur of acute, severe AR is notably shorter in duration and lower pitched than the murmur of chronic AR. It can be very difficult to appreciate in the presence of a rapid heart rate. These attributes reflect the abrupt rate of rise of diastolic pressure within the unprepared and noncompliant left ventricle and the correspondingly rapid decline in the aortic–left ventricular diastolic pressure gradient. Left ventricular diastolic pressure may increase sufficiently to result in premature closure of the mitral valve and a soft first heart sound. Peripheral signs of significant diastolic run-off are not present. Pulmonic regurgitation (PR) results in a decrescendo, early to mid-diastolic murmur (Graham Steell murmur) that begins after the pulmonic component of S2 (P2), is best heard at the second left interspace, and radiates along the left sternal border. The intensity of the murmur may increase with inspiration. PR is most commonly due to dilation of the valve annulus from chronic elevation of the pulmonary artery pressure. Signs of pulmonary hypertension, including a right ventricular lift and a loud single or narrowly split S2, are present. These features also help distinguish PR from AR as the cause of a decrescendo diastolic murmur heard along the left sternal border. PR in the absence of pulmonary hypertension can occur with endocarditis or a congenitally deformed valve. It is usually present after repair of tetralogy of Fallot in childhood. When pulmonary hypertension is not present, the diastolic murmur is softer and lower pitched than the classic Graham Steell murmur, and the severity of the PR can be difficult to appreciate. TTE is indicated for the further evaluation of a patient with an early to mid-diastolic murmur. Longitudinal assessment of the severity of the valve lesion and ventricular size and systolic function help guide a potential decision for surgical management. TTE also can provide anatomic information regarding the root and proximal ascending aorta, although computed tomographic or magnetic resonance angiography may be indicated for more precise characterization (Chap. 12). Mid-diastolic murmurs (Figs. 10-1G and 10-1H) Mid-diastolic murmurs result from obstruction and/or augmented flow at the level of the mitral or tricuspid valve. Rheumatic fever is the most common cause of MS (Fig. 10-6). In younger patients with pliable valves, S1 is loud and the murmur begins after an opening snap, which is a highpitched sound that occurs shortly after S2. The interval between the pulmonic component of the second heart sound (P2) and the opening snap is inversely related to the magnitude of the left atrial–left ventricular pressure gradient. The murmur of MS is low pitched and thus is best heard with the bell of the stethoscope. It is loudest at the left ventricular apex and often is appreciated only when the patient is turned in the left lateral

decubitus position. It is usually of grade 1 or 2 intensity but may be absent when the cardiac output is severely reduced despite significant obstruction. The intensity of the murmur increases during maneuvers that increase cardiac output and mitral valve flow, such as exercise. The duration of the murmur reflects the length of time over which left atrial pressure exceeds left ventricular diastolic pressure. An increase in the intensity of the murmur just before S1, a phenomenon known as presystolic accentuation (Figs. 10-1A and 10-6), occurs in patients in sinus rhythm and is due to a late increase in transmitral flow with atrial contraction. Presystolic accentuation does not occur in patients with atrial fibrillation. The mid-diastolic murmur associated with tricuspid stenosis is best heard at the lower left sternal border and increases in intensity with inspiration. A prolonged y descent may be visible in the jugular venous waveform. This murmur is very difficult to hear and often is obscured by left-sided acoustical events. There are several other causes of mid-diastolic murmurs. Large left atrial myxomas may prolapse across the mitral valve and cause variable degrees of obstruction to left ventricular inflow (Chap. 23). The murmur associated with an atrial myxoma may change in duration and intensity with changes in body position. An opening snap is not present, and there is no presystolic accentuation. Augmented mitral diastolic flow can occur with isolated severe MR or with a large left-to-right shunt at the ventricular or great vessel level and produce a soft, rapid filling sound (S3) followed by a short, low-pitched mid-diastolic apical murmur. The Austin Flint murmur of severe, chronic AR has already been described. A short, mid-diastolic murmur is rarely heard during an episode of acute rheumatic fever (Carey-Coombs murmur) and probably is due to flow through an edematous mitral valve. An opening snap is not present in the acute phase, and the murmur dissipates with resolution of the acute attack. Complete heart block with dyssynchronous atrial and ventricular activation may be associated with intermittent mid- to late diastolic murmurs if atrial contraction occurs when the mitral valve is partially closed. Mid-diastolic murmurs indicative of increased tricuspid valve flow can occur with severe, isolated TR and with large ASDs and significant leftto-right shunting. Other signs of an ASD are present (Chap. 19), including fixed splitting of S2 and a midsystolic murmur at the mid- to upper left sternal border. TTE is indicated for evaluation of a patient with a mid- to late diastolic murmur. Findings specific to the diseases discussed earlier will help guide management.

Continuous Murmurs (Figs. 10-1H and 10-7) Continuous murmurs begin in systole, peak near the second heart sound, and continue into all or part of diastole. Their presence throughout

Continuous Murmur vs. To-Fro Murmur S1

Continuous murmur

To-fro murmur

Dynamic Auscultation (Tables 10-2 and 9-1) Careful attention to the behavior of heart murmurs during simple maneuvers that alter cardiac hemodynamics can provide important clues to their cause and significance. Respiration Auscultation should be performed during quiet respiration or with a modest increase in inspiratory effort, as more forceful movement of the chest tends to obscure the heart sounds. Left-sided murmurs may be best heard at end expiration, when lung volumes are minimized and the heart and great vessels are brought closer to the chest wall. This phenomenon is characteristic of the murmur of AR. Murmurs of right-sided origin, such as tricuspid or pulmonic regurgitation, increase in intensity during inspiration. The intensity of left-sided murmurs either remains constant or decreases with inspiration. Bedside assessment also should evaluate the behavior of S2 with respiration and the dynamic relationship Table 10-2 Dynamic Auscultation: Bedside Maneuvers That Can Be Used to Change the Intensity of Cardiac Murmurs (See Text) 1. Respiration 2. Isometric exercise (hand grip) 3. Transient arterial occlusion 4. Pharmacologic manipulation of preload and/or afterload 5. Valsalva maneuver 6. Rapid standing/squatting 7. Passive leg raising 8. Post-premature beat

Approach to the Patient withaHeartMurmur

the cardiac cycle implies a pressure gradient between two chambers or vessels during both systole and diastole. The continuous murmur associated with a patent ductus arteriosus is best heard at the upper left sternal border. Large, uncorrected shunts may lead to pulmonary hypertension, attenuation or obliteration of the diastolic component of the murmur, reversal of shunt flow, and differential cyanosis of the lower extremities. A ruptured sinus of Valsalva aneurysm creates a continuous murmur of abrupt onset at the upper right sternal border. Rupture typically occurs into a right heart chamber, and the murmur is indicative of a continuous pressure difference between the aorta and either the right ventricle or the right atrium. A continuous murmur also may be audible along the left sternal border with a coronary arteriovenous fistula and at the site of an arteriovenous fistula used for hemodialysis access. Enhanced flow through enlarged intercostal collateral arteries in patients with aortic coarctation may produce a continuous murmur along the course of one or more ribs. A cervical bruit with both systolic and diastolic components (a to-fro murmur, Fig. 10-7) usually indicates a high-grade carotid artery stenosis. Not all continuous murmurs are pathologic. A continuous venous hum can be heard in healthy children and young adults, especially during pregnancy; it is best appreciated in the right supraclavicular fossa and can be obliterated by pressure over the right internal jugular vein or by having the patient turn his or her head toward the examiner. The continuous mammary souffle of pre gnancy is created by enhanced arterial flow through engorged breasts and usually appears during the late third trimester or early puerperium. The murmur is louder in systole. Firm pressure with the diaphragm of the stethoscope can eliminate the diastolic portion of the murmur.

example of a to-fro murmur is aortic stenosis and regurgitation. A continuous murmur crescendos to around the second heart sound (S2), whereas a to-fro murmur has two components. The mid-systolic ejection component decrescendos and disappears as it approaches S2. (From JA Shaver, JJ Leonard, DF Leon, Examination of the Heart, Part IV, Auscultation of the Heart. Dallas, American Heart Association, 1990, p 55. Copyright, American Heart Association.)

CHAPTER 10

Figure 10-7 Comparison of the continuous murmur and the to-fro murmur. During abnormal communication between highpressure and low-pressure systems, a large pressure gradient exists throughout the cardiac cycle, producing a continuous murmur. A classic example is patent ductus arteriosus. At times, this type of murmur can be confused with a to-fro murmur, which is a combination of systolic ejection murmur and a murmur of semilunar valve incompetence. A classic

SECTION II

between the aortic and pulmonic components (Fig. 10-8). Reversed splitting can be a feature of severe AS, HOCM, left bundle branch block, right ventricular apical pacing, or acute myocardial ischemia. Fixed splitting of S2 in the presence of a grade 2 or 3 mid-systolic murmur at the mid- or upper left sternal border indicates an ASD. Physiologic but wide splitting during the respiratory cycle implies either premature aortic valve closure, as can occur with severe MR, or delayed pulmonic valve closure due to PS or right bundle branch block. Alterations of systemic vascular resistance

Diagnosis of Cardiovascular Disorders

Murmurs can change characteristics after maneuvers that alter systemic vascular resistance and left ventricular afterload. The systolic murmurs of MR and VSD Normal Physiologic Splitting A2

Audible Expiratory Splitting Expiration

Inspiration

A2 P 2

Wide physiologic splitting S1

S2 P2

A2 P 2

S1 A2

S2 P2 A2

Reversed splitting S1

A2 P2

Narrow physiologic splitting (↑P2) S1

Figure 10-8 Top. Normal physiologic splitting. During expiration, the aortic (A2) and pulmonic (P2) components of the second heart sound are separated by 20 mm in women and >28 mm in men). The presence of left atrial abnormality increases the likelihood

Intrinsic impairment of conduction in either the right or the left bundle system (intraventricular conduction disturbances) leads to prolongation of the QRS interval. With complete bundle branch blocks, the QRS interval is ≥120 ms in duration; with incomplete blocks, the QRS interval is between 100 and 120 ms. The QRS vector usually is oriented in the direction of the myocardial region where depolarization is delayed (Fig. 11-10). Thus, with right bundle branch block, the terminal QRS vector is oriented to the right and anteriorly (rSR′ in V1 and qRS in V6, typically). Left bundle branch block alters both early and later phases of ventricular depolarization. The major QRS vector V6

V1 Normal

R′ r RBBB T S

q S

LBBB

Figure 11-10 Comparison of typical QRS-T patterns in right bundle branch block (RBBB) and left bundle branch block (LBBB) with the normal pattern in leads V1 and V6. Note the secondary T-wave inversions (arrows) in leads with an rSR′ complex with RBBB and in leads with a wide R wave with LBBB.

Myocardial Ischemia and Infarction (See also Chap. 35) The ECG is a cornerstone in the diagnosis of acute and chronic ischemic heart disease. The findings depend on several key factors: the nature of the process (reversible [i.e., ischemia] versus irreversible [i.e., infarction]), the duration (acute versus chronic), the extent (transmural versus subendocardial), and localization (anterior versus inferoposterior), as well as the presence of other underlying abnormalities (ventricular hypertrophy, conduction defects). Ischemia exerts complex time-dependent effects on the electrical properties of myocardial cells. Severe, acute ischemia lowers the resting membrane potential and shortens the duration of the action potential. Such changes cause a voltage gradient between normal and ischemic zones. As a consequence, current flows between those regions. These currents of injury are represented on the surface ECG by deviation of the ST segment (Fig. 11-11). When the acute ischemia is transmural, the ST vector usually is shifted in the direction of the outer (epicardial) layers, producing ST elevations and sometimes, in the earliest stages of ischemia, tall, positive so-called hyperacute T waves over the

Electrocardiography

and bundle branch blocks may occur that involve the left and right bundle system. Examples of bifascicular block include right bundle branch block and left posterior fascicular block, right bundle branch block with left anterior fascicular block, and complete left bundle branch block. Chronic bifascicular block in an asymptomatic individual is associated with a relatively low risk of progression to high-degree AV heart block. In contrast, new bifascicular block with acute anterior myocardial infarction carries a much greater risk of complete heart block. Alternation of right and left bundle branch block is a sign of trifascicular disease. However, the presence of a prolonged PR interval and bifascicular block does not necessarily indicate trifascicular involvement, since this combination may arise with AV node disease and bifascicular block. Intraventricular conduction delays also can be caused by extrinsic (toxic) factors that slow ventricular conduction, particularly hyperkalemia or drugs (e.g., class 1 antiarrhythmic agents, tricyclic antidepressants, phenothiazines). Prolongation of QRS duration does not necessarily indicate a conduction delay but may be due to preexcitation of the ventricles via a bypass tract, as in WolffParkinson-White (WPW) patterns (Chap. 16) and related variants. The diagnostic triad of WPW consists of a wide QRS complex associated with a relatively short PR interval and slurring of the initial part of the QRS (delta wave), with the latter effect being due to aberrant activation of ventricular myocardium. The presence of a bypass tract predisposes to reentrant supraventricular tachyarrhythmias.

CHAPTER 11

is directed to the left and posteriorly. In addition, the normal early left-to-right pattern of septal activation is disrupted such that septal depolarization proceeds from right to left as well. As a result, left bundle branch block generates wide, predominantly negative (QS) complexes in lead V1 and entirely positive (R) complexes in lead V6. A pattern identical to that of left bundle branch block, preceded by a sharp spike, is seen in most cases of electronic right ventricular pacing because of the relative delay in left ventricular activation. Bundle branch block may occur in a variety of conditions. In subjects without structural heart disease, right bundle branch block is seen more commonly than left bundle branch block. Right bundle branch block also occurs with heart disease, both congenital (e.g., atrial septal defect) and acquired (e.g., valvular, ischemic). Left bundle branch block is often a marker of one of four underlying conditions associated with increased risk of cardiovascular morbidity and mortality rates: coronary heart disease (frequently with impaired left ventricular function), hypertensive heart disease, aortic valve disease, and cardiomyopathy. Bundle branch blocks may be chronic or intermittent. A bundle branch block may be rate-related; for example, it often occurs when the heart rate exceeds some critical value. Bundle branch blocks and depolarization abnormalities secondary to artificial pacemakers not only affect ventricular depolarization (QRS) but also are characteristically associated with secondary repolarization (ST-T) abnormalities. With bundle branch blocks, the T wave is typically opposite in polarity to the last deflection of the QRS (Fig. 11-10). This discordance of the QRS–T-wave vectors is caused by the altered sequence of repolarization that occurs secondary to altered depolarization. In contrast, primary repolarization abnormalities are independent of QRS changes and are related instead to actual alterations in the electrical properties of the myocardial fibers themselves (e.g., in the resting membrane potential or action potential duration), not just to changes in the sequence of repolarization. Ischemia, electrolyte imbalance, and drugs such as digitalis all cause such primary ST–T-wave changes. Primary and secondary T-wave changes may coexist. For example, T-wave inversions in the right precordial leads with left bundle branch block or in the left precordial leads with right bundle branch block may be important markers of underlying ischemia or other abnormalities. A distinctive abnormality simulating right bundle branch block with ST-segment elevations in the right chest leads is seen with the Brugada pattern (Chap. 16). Partial blocks (fascicular or “hemiblocks”) in the left bundle system (left anterior or posterior fascicular blocks) generally do not prolong the QRS duration substantially but instead are associated with shifts in the frontal plane QRS axis (leftward or rightward, respectively). More complex combinations of fascicular

V5 ST

SECTION II Diagnosis of Cardiovascular Disorders

Figure 11-11 Acute ischemia causes a current of injury. With predominant subendocardial ischemia (A), the resultant ST vector will be directed toward the inner layer of the affected ventricle and the ventricular cavity. Overlying leads therefore will

record ST depression. With ischemia involving the outer ventricular layer (B) (transmural or epicardial injury), the ST vector will be directed outward. Overlying leads will record ST elevation.

ischemic zone. With ischemia confined primarily to the subendocardium, the ST vector typically shifts toward the subendocardium and ventricular cavity, so that overlying (e.g., anterior precordial) leads show ST-segment depression (with ST elevation in lead aVR). Multiple factors affect the amplitude of acute ischemic ST deviations. Profound ST elevation or depression in multiple leads usually indicates very severe ischemia. From a clinical viewpoint, the division of acute myocardial infarction into ST-segment elevation and non-ST elevation types is useful since the efficacy of acute reperfusion therapy is limited to the former group. The ECG leads are usually more helpful in localizing regions of ST elevation than non-ST elevation ischemia. For example, acute transmural anterior (including apical and lateral) wall ischemia is reflected by ST elevations or increased T-wave positivity in one or more of the precordial leads (V1–V6) and leads I and aVL. Inferior wall ischemia produces changes in leads II, III, and aVF. “Posterior” wall ischemia (usually associated with lateral or inferior involvement) may be indirectly recognized by reciprocal ST depressions in leads V1 to V3 (thus constituting an ST elevation “equivalent” acute coronary syndrome). Right ventricular ischemia usually produces ST elevations in right-sided chest leads (Fig. 11-5). When ischemic ST elevations occur as the earliest sign of acute infarction, they typically are followed within a period ranging from hours to days by evolving T-wave inversions and often by Q waves occurring in the same lead distribution. Reversible transmural ischemia, for example, due to coronary

vasospasm (Prinzmetal’s variant angina and probably the Tako-Tsubo “stress” cardiomyopathy syndrome), may cause transient ST-segment elevations without development of Q waves, as may very early reperfusion in acute coronary syndromes. Depending on the severity and duration of ischemia, the ST elevations may resolve completely in minutes or be followed by T-wave inversions that persist for hours or even days. Patients with ischemic chest pain who present with deep T-wave inversions in multiple precordial leads (e.g., V1–V4) with or without cardiac enzyme elevations typically have severe obstruction in the left anterior descending coronary artery system (Fig. 11-12). In contrast, patients whose baseline ECG already shows abnormal T-wave inversions may develop T-wave normalization (pseudonormalization) during episodes of acute transmural ischemia. With infarction, depolarization (QRS) changes often accompany repolarization (ST-T) abnormalities. Necrosis of sufficient myocardial tissue may lead to decreased R-wave amplitude or abnormal Q waves (even in the absence of transmurality) in the anterior or inferior leads (Fig. 11-13). Previously, abnormal Q waves were considered markers of transmural myocardial infarction, whereas subendocardial infarcts were thought not to produce Q waves. However, careful ECG-pathology correlative studies have indicated that transmural infarcts may occur without Q waves and that subendocardial (nontransmural) infarcts sometimes may be associated with Q waves. Therefore, infarcts are more appropriately classified as “Q-wave” or “non-Q-wave.”

Figure 11-12 Severe anterior wall ischemia (with or without infarction) may cause prominent T-wave inversions in the precordial leads. This pattern (sometimes referred to as Wellens

Twaves) is usually associated with a high-grade stenosis of the left anterior descending coronary artery.

ECG sequence with anterior Q-wave infarction I

III

aVR

aVL

aVF

aVL

aVF

Early

Evolving

III

aVR

CHAPTER 11

ECG sequence with inferior Q-wave infarction

Early

Electrocardiography

Evolving

Figure 11-13 Sequence of depolarization and repolarization changes with (A) acute anterior and (B) acute inferior wall Q-wave infarctions. With anterior infarcts, ST elevation in leads I and aVL and the precordial leads may be accompanied by reciprocal ST depressions in leads II, III, and aVF. Conversely,

The major acute ECG changes in syndromes of ischemic heart disease are summarized schematically in Fig. 11-14. Loss of depolarization forces due to posterior or lateral infarction may cause reciprocal increases in R-wave amplitude in leads V1 and V2 without diagnostic Q waves in any of the conventional leads. Atrial infarction may be associated with PR-segment deviations due to an atrial current of injury, changes in P-wave morphology, or atrial arrhythmias. In the weeks and months after infarction, these ECG changes may persist or begin to resolve. Complete normalization of the ECG after Q-wave infarction is uncommon but may occur, particularly with smaller infarcts. In contrast, ST-segment elevations that persist for several weeks or more after a Q-wave infarct usually correlate with a severe underlying wall motion disorder (akinetic or dyskinetic zone), although not necessarily a frank ventricular aneurysm. ECG changes due to ischemia may occur spontaneously or may be provoked by various exercise protocols (stress electrocardiography; Chap. 33). The ECG has important limitations in both sensitivity and specificity in the diagnosis of ischemic heart disease. Although a single normal ECG does not exclude ischemia or even acute infarction, a normal ECG throughout the course of an acute infarct is distinctly uncommon. Prolonged chest pain without diagnostic ECG changes therefore should always prompt a careful search for other noncoronary causes of chest pain (Chap. 4). Furthermore,

acute inferior (or posterolateral) infarcts may be associated with reciprocal ST depressions in leads V1 to V3. (After AL Goldberger: Clinical Electrocardiography: A Simplified Approach, 8th ed. Philadelphia, Elsevier/Saunders, 2013.)

the diagnostic changes of acute or evolving ischemia are often masked by the presence of left bundle branch block, electronic ventricular pacemaker patterns, and WolffParkinson-White preexcitation. However, clinicians Non-Q wave (Non-ST elevation) infarction ST depressions or T wave inversions without Q waves

Noninfarction subendocardial ischemia (classic angina) Transient ST depressions

MYOCARDIAL ISCHEMIA

Noninfarction transmural ischemia Transient ST elevations or paradoxical T wave normalization, sometimes followed by T wave inversions

ST elevation/ Q wave infarction New Q waves preceded by hyperacute T waves/ST elevations and followed by T wave inversions

Figure 11-14 Variability of ECG patterns with acute myocardial ischemia. The ECG also may be normal or nonspecifically abnormal. Furthermore, these categorizations are not mutually exclusive. (After AL Goldberger: Clinical Electrocardiography: A Simplified Approach, 7th ed. St. Louis, Mosby/Elsevier, 2006.)

SECTION II Diagnosis of Cardiovascular Disorders

continue to overdiagnose ischemia or infarction based on the presence of ST-segment elevations or depressions; T-wave inversions; tall, positive T waves; or Q waves not related to ischemic heart disease (pseudoinfarct patterns). For example, ST-segment elevations simulating ischemia may occur with acute pericarditis or myocarditis, as a normal variant (including the typical “early repolarization” pattern), or in a variety of other conditions (Table 11-1). Similarly, tall, positive T waves do not invariably represent hyperacute ischemic changes but may also be caused by normal variants, hyperkalemia, cerebrovascular injury, and left ventricular volume overload due to mitral or aortic regurgitation, among other causes. ST-segment elevations and tall, positive T waves are common findings in leads V1 and V2 in left bundle branch block or left ventricular hypertrophy in the absence of ischemia. The differential diagnosis of Q waves includes physiologic or positional variants, ventricular hypertrophy, acute or chronic noncoronary myocardial injury, hypertrophic cardiomyopathy, and ventricular conduction disorders. Digoxin, ventricular hypertrophy, hypokalemia, and a variety of other factors may cause ST-segment depression mimicking subendocardial ischemia. Prominent T-wave inversion may occur with ventricular hypertrophy, cardiomyopathies, myocarditis, and cerebrovascular injury (particularly intracranial bleeds), among many other conditions.

Metabolic Factors and Drug Effects A variety of metabolic and pharmacologic agents alter the ECG and, in particular, cause changes in repolarization

Table 11-1 Differential Diagnosis of ST-Segment Elevations Ischemia/myocardial infarction Noninfarction, transmural ischemia (Prinzmetal’s angina, and probably Tako-Tsubo syndrome, which may also exactly simulate classical acute infarction) Acute myocardial infarction Postmyocardial infarction (ventricular aneurysm pattern) Acute pericarditis Normal variants (including “early repolarization” patterns) Left ventricular hypertrophy/left bundle branch blocka Other (rarer) Acute pulmonary embolisma Brugada patterns (right bundle branch block–like pattern with ST elevations in right precordial leads)a Class 1C antiarrhythmic drugsa DC cardioversion Hypercalcemiaa Hyperkalemiaa Hypothermia (J [Osborn] waves) Nonischemic myocardial injury Myocarditis Tumor invading left ventricle Trauma to ventricles Usually localized to V1−V2 or V3. Source: Modified from AL Goldberger: Clinical Electrocardiography: A Simplified Approach, 8th ed. Philadelphia, Elsevier/Saunders, 2013.

(ST-T-U) and sometimes QRS prolongation. Certain life-threatening electrolyte disturbances may be diagnosed initially and monitored from the ECG. Hyperkalemia produces a sequence of changes (Fig. 11-15), usually beginning with narrowing and peaking (tenting) of the T waves. Further elevation of extracellular K+ leads to

Hyperkalemia Mild-Moderate V1

Moderate-Severe V1

Very Severe Lead I

Lead II V2

V2 P 1mV

Figure 11-15 The earliest ECG change with hyperkalemia is usually peaking (“tenting”) of the T waves. With further increases in the serum potassium concentration, the QRS complexes widen, the P waves decrease in amplitude and may disappear, and

finally a sine-wave pattern leads to asystole unless emergency therapy is given. (After AL Goldberger: Clinical Electrocardiography: A Simplified Approach, 8th ed. Philadelphia, Elsevier/Saunders, 2013.)

QT 0.48 s QTc 0.52

Electrical Alternans Electrical alternans—a beat-to-beat alternation in one or more components of the ECG signal—is a common type of nonlinear cardiovascular response to a variety of hemodynamic and electrophysiologic perturbations. Total electrical alternans (P-QRS-T) with sinus tachycardia is a relatively specific sign of pericardial effusion, usually with cardiac tamponade. The mechanism relates to a periodic swinging motion of the heart in the effusion at a frequency exactly one-half the heart rate. Amiodarone V4

Tricyclic overdose

Figure 11-16 A variety of metabolic derangements, drug effects, and other factors may prolong ventricular repolarization with QT prolongation or prominent U waves. Prominent repolarization prolongation, particularly if due to hypokalemia, inherited “channelopathies,” or certain pharmacologic agents, indicates increased susceptibility to torsades des pointes–type

QT 0.26 s QTc 0.36

transient nonspecific repolarization changes may also occur after a meal or with postural (orthostatic) change, hyperventilation, or exercise in healthy individuals.

QT 0.36 s QTc 0.41

Figure 11-17 Prolongation of the Q-T interval (ST-segment portion) is typical of hypocalcemia. Hypercalcemia may cause abbreviation of the ST segment and shortening of the QT interval.

Hypothermia

Hypercalcemia

Normal

Subarachnoid hemorrhage III

ventricular tachycardia (Chap. 16). Marked systemic hypothermia is associated with a distinctive convex “hump” at the J point (Osborn wave, arrow) due to altered ventricular action potential characteristics. Note QRS and QT prolongation along with sinus tachycardia in the case of tricyclic antidepressant overdose.

Electrocardiography

Hypokalemia

Hypocalcemia

CHAPTER 11

AV conduction disturbances, diminution in P-wave amplitude, and widening of the QRS interval. Severe hyperkalemia eventually causes cardiac arrest with a slow sinusoidal type of mechanism (“sine-wave” pattern) followed by asystole. Hypokalemia (Fig. 11-16) prolongs ventricular repolarization, often with prominent U waves. Prolongation of the QT interval is also seen with drugs that increase the duration of the ventricular action potential: class 1A antiarrhythmic agents and related drugs (e.g., quinidine, disopyramide, procainamide, tricyclic antidepressants, phenothiazines) and class III agents (e.g., amiodarone [Fig. 11-16], dofetilide, dronedarone, sotalol, ibutilide). Marked QT prolongation, sometimes with deep, wide T-wave inversions, may occur with intracranial bleeds, particularly subarachnoid hemorrhage (“CVA T-wave” pattern) (Fig. 11-16). Systemic hypothermia also prolongs repolarization, usually with a distinctive convex elevation of the J point (Osborn wave). Hypocalcemia typically prolongs the QT interval (ST portion), whereas hypercalcemia shortens it (Fig. 11-17). Digitalis glycosides also shorten the QT interval, often with a characteristic “scooping” of the ST–T-wave complex (digitalis effect). Many other factors are associated with ECG changes, particularly alterations in ventricular repolarization. T-wave flattening, minimal T-wave inversions, or slight ST-segment depression (“nonspecific ST–T-wave changes”) may occur with a variety of electrolyte and acid-base disturbances, a variety of infectious processes, central nervous system disorders, endocrine abnormalities, many drugs, ischemia, hypoxia, and virtually any type of cardiopulmonary abnormality. Although subtle ST–T-wave changes may be markers of ischemia,

100

Repolarization (ST-T or U wave) alternans is a sign of electrical instability and may precede ventricular tachyarrhythmias.

Clinical Interpretation of the ECG

SECTION II Diagnosis of Cardiovascular Disorders

Accurate analysis of ECGs requires thoroughness and care. The patient’s age, gender, and clinical status should always be taken into account. Many mistakes in ECG interpretation are errors of omission. Therefore, a systematic approach is essential. The following 14 points should be analyzed carefully in every ECG: (1) standardization (calibration) and technical features (including lead placement and artifacts), (2) rhythm, (3) heart rate, (4) PR interval/AV conduction, (5) QRS interval, (6) QT/QTc interval, (7) mean QRS electrical axis, (8) P waves, (9) QRS voltages, (10) precordial R-wave progression, (11) abnormal Q waves, (12) ST segments, (13) T waves, and (14) U waves. Only after analyzing all these points should the interpretation be formulated. Where appropriate, important clinical correlates or inferences should be mentioned.

For example, sinus tachycardia with QRS and QT-(U) prolongation, especially in the context of changes in mental status, suggests tricyclic antidepressant overdose (Fig. 11-16). The triad of peaked T waves (hyperkalemia), a long QT due to ST-segment lengthening (hypocalcemia), and left ventricular hypertrophy (systemic hypertension) suggests chronic renal failure. Comparison with any previous ECGs is invaluable. The diagnosis and management of specific cardiac arrhythmias and conduction disturbances are discussed in Chaps. 15 and 16.

Computerized Electrocardiography Computerized ECG systems are widely used for immediate retrieval of thousands of ECG records. Computer interpretation of ECGs still has major limitations. Incomplete or inaccurate readings are most likely with arrhythmias and complex abnormalities. Therefore, computerized interpretation (including measurements of basic ECG intervals) should not be accepted without careful clinician review.

cHaPTer 12

NONINVASIVE CARDIAC IMAGING: ECHOCARDIOGRAPHY, NUCLEAR CARDIOLOGY, AND MRI/CT IMAGING Rick A. Nishimura

■

Panithaya Chareonthaitawee

Cardiovascular imaging plays an essential role in the practice of cardiology. Two-dimensional (2D) echocardiography is able to visualize the heart directly in real time using ultrasound, providing instantaneous assessment of the myocardium, cardiac chambers, valves, pericardium, and great vessels. Doppler echocardiography measures the velocity of moving red blood cells and has become a noninvasive alternative to cardiac catheterization for assessment of hemodynamics. Transesophageal echocardiography (TEE) provides a unique window for high-resolution imaging of posterior structures of the heart, particularly the left atrium, mitral valve, and aorta. Nuclear cardiology uses radioactive tracers to provide assessment of myocardial perfusion and metabolism, along with ventricular function, and is applied primarily to the evaluation of patients with ischemic heart disease. Cardiac MRI and CT can delineate cardiac structure and function with high resolution. They are particularly useful in the examination of cardiac masses, the pericardium, the great vessels, and ventricular function and perfusion. Gadolinium enhancement during cardiac MRI adds information on myocardial perfusion. Detection of coronary calcification by CT as well as direct visualization of coronary arteries by CT angiography (CTA) may be useful in selected patients with suspected coronary artery disease (CAD). This chapter provides an overview of the basic concepts of these cardiac imaging modalities as well as the clinical indications for each procedure.

■

Matthew Martinez

the heart (Table 12-1). For a transthoracic echocardiogram (TTE), the imaging is performed with a handheld transducer placed directly on the chest wall. In selected patients, a TEE may be performed, in which an ultrasound transducer is mounted on the tip of an endoscope placed in the esophagus and directed toward the cardiac structures. Current echocardiographic machines are portable and can be wheeled directly to the patient’s bedside. Thus, a major advantage of echocardiography over other imaging modalities is the ability to obtain instantaneous images of the cardiac structures for immediate Table 12-1 clinical uSeS of echocarDiography Two-Dimensional echocardiography Cardiac chambers Chamber size Left ventricular hypertrophy Regional wall motion abnormalities Valve Morphology and motion Pericardium Effusion Tamponade Masses Great vessels Stress echocardiography Two-dimensional Myocardial ischemia Viable myocardium Doppler Valve disease

ecHocardiograPHy Two-DiMenSional echocarDiography Basic principles 2D echocardiography uses the principle of ultrasound reflection off cardiac structures to produce images of

101

Doppler echocardiography Valve stenosis Gradient Valve area Valve regurgitation Semiquantitation Intracardiac pressures Volumetric flow Diastolic filling Intracardiac shunts Transesophageal echocardiography Inadequate transthoracic images Aortic disease Infective endocarditis Source of embolism Valve prosthesis Intraoperative

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SECTION II

interpretation. Thus, echocardiography has become an ideal imaging modality for cardiac emergencies. A limitation of TTE is the inability to obtain high-quality images in all patients, especially those with a thick chest wall or severe lung disease, as ultrasound waves are poorly transmitted through lung parenchyma. Technology such as harmonic imaging and IV contrast agents (which traverse the pulmonary circulation) can be used to enhance endocardial borders in patients with poor acoustic windows. Chamber size and function

Diagnosis of Cardiovascular Disorders

2D echocardiography is an ideal imaging modality for assessing left ventricular (LV) size and function (Fig. 12-1). A qualitative assessment of the ventricular cavity and systolic function can be made directly from the 2D image by experienced observers. 2D echocardiography is useful in the diagnosis of LV hypertrophy and is the imaging modality of choice for the diagnosis of hypertrophic cardiomyopathy. Other chamber sizes are assessed by visual analysis, including the left atrium and right-sided chambers.

Valve abnormalities 2D echocardiography is the “gold standard” for imaging valve morphology and motion. Leaflet thickness and mobility, valve calcification, and the appearance of subvalvular and supravalvular structures can be assessed. Valve stenosis is reliably diagnosed by the thickening and decreased mobility of the valve. 2D echocardiography is also the gold standard for the diagnosis of mitral stenosis, which produces typical tethering and diastolic doming, and the severity of the stenosis can be ascertained from a direct planimetry measurement of the mitral valve orifice. The presence and often the etiology of stenosis of the semilunar valves can be made by 2D echocardiography (Fig. 12-2), but evaluation of the severity of the stenosis requires Doppler echocardiography (discussed later). The diagnosis of valvular regurgitation must be made by Doppler echocardiography, but 2D echocardiography is valuable for determining the etiology of the regurgitation, as well as its effects on ventricular dimensions, shape, and function. Pericardial disease 2D echocardiography is the imaging modality of choice for the detection of pericardial effusion, which is easily visualized as a black echolucent ovoid structure surrounding the heart (Fig. 12-3). In the hemodynamically unstable patient with pericardial tamponade, typical echo findings include a dilated inferior vena cava, right atrial collapse, and then right ventricular collapse. Echocardiographically guided pericardiocentesis has now become a standard of care.

Figure 12-1 Two-dimensional echocardiographic still-frame images from a normal patient with a normal heart. Upper: Parasternal long-axis view during systole and diastole (left) and systole (right). During systole, there is thickening of the myocardium and reduction in the size of the left ventricle (LV). The valve leaflets are thin and open widely. Lower: Parasternal short-axis view during diastole (left) and systole (right) demonstrating a decrease in the left ventricular cavity size during systole as well as an increase in wall thickening. LA, left atrium; RV, right ventricle; Ao, aorta.

Figure 12-2 Two-dimensional echocardiographic still-frame images from a patient with aortic stenosis. Parasternal long-axis view shows a heavily calcified aortic valve. RV, right ventricle; LV, left ventricle; Ao, aorta; LA, left atrium.

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Intracardiac masses Intracardiac masses can be visualized on 2D echocardiography, provided that image quality is adequate. Solid masses appear as echo-dense structures, which can be located inside the cardiac chambers or infiltrating into the myocardium or pericardium. LV thrombus appears as an echo-dense structure, usually in the apical region associated with regional wall motion abnormalities. The appearance and mobility of the thrombus are predictive of embolic events. Vegetations appear as mobile linear echo densities attached to valve leaflets. Atrial myxoma can be diagnosed by the appearance of a

Figure 12-5 Transesophageal still-frame echocardiographic view of a patient with a dilated aorta, aortic dissection, and severe aortic regurgitation. The arrow points to the intimal flap that is seen in the dilated ascending aorta. Left: The long-axis

well-circ*mscribed mobile mass with attachments to the atrial septum (Fig. 12-4). The high-resolution images provided by TEE may be required for further delineation of myocardial masses, especially those 30 s) monomorphic ventricular tachycardia

SECTION II

Nonsustained (15 mmHg, pulmonary artery pressure >60 mmHg, or a pulmonary artery wedge pressure >25 mmHg after exercise is also considered significant and may warrant intervention. The modified Hakki formula has also been used to estimate aortic valve area. This formula calculates the valve area as the cardiac output (L/min) divided by the square root of the pressure gradient. Aortic valve area calculations based on the Gorlin formula are flow-dependent and, therefore, for patients with low cardiac outputs, it is imperative to determine if a decreased valve area actually reflects a fixed stenosis or is overestimated by a low cardiac output and stroke volume that is insufficient to open the valve leaflets fully. In these instances, cautious hemodynamic manipulation using dobutamine to increase the cardiac output and recalculation of the aortic valve area may be necessary. Intracardiac shunts In patients with congenital heart disease, detection, localization, and quantification of the intracardiac shunt should be evaluated. A shunt should be suspected when there is unexplained arterial desaturation or increased oxygen saturation of venous blood. A “step up” or increase in oxygen DIASTOLE

content indicates the presence of a left-to-right shunt while a “step down” indicates a right-to-left shunt. The shunt is localized by detecting a difference in oxygen saturation levels of 5–7% between adjacent cardiac chambers. The severity of the shunt is determined by the ratio of pulmonary blood flow (Qp) to the systemic blood flow (Qs), or Qp/Qs = ([systemic arterial oxygen content − mixed venous oxygen content]/pulmonary vein oxygen content − pulmonary artery oxygen content). For an atrial septal defect, a shunt ratio of 1.5 is considered significant and factored with other clinical variables to determine the need for intervention. When a congenital ventricular septal defect is present, a shunt ratio of ≥2.0 with evidence of left ventricular volume overload is a class I indication for surgical correction.

Ventriculography and Aortography Ventriculography to assess left ventricular function may be performed during cardiac catheterization. A pigtail catheter is advanced retrograde across the aortic valve into the left ventricle and 30–45 mL of contrast is power-injected to visualize the left ventricular chamber during the cardiac cycle. The ventriculogram is usually performed in the right anterior oblique projection to examine wall motion and mitral valve function. Normal wall motion is observed as symmetric contraction of all segments; hypokinetic segments have decreased contraction, akinetic segments do not contract, and dyskinetic segments appear to bulge paradoxically during systole (Fig. 13-3). Ventriculography may also reveal SYSTOLE

Figure 13-3 Left ventriculogram at end diastole (left) and end systole (right). In patients with normal left ventricular function, the ventriculogram reveals symmetric contraction of all walls (top). Patients with coronary artery disease may have wall motion abnormalities on ventriculography as seen in this 60-year-old male following a large anterior myocardial infarction. In systole, the anterior, apical, and inferior walls are akinetic (white arrows) (bottom).

Selective coronary angiography is almost always performed during cardiac catheterization and is used to define the coronary anatomy and determine the extent of epicardial coronary artery and coronary artery bypass graft disease. Specially shaped coronary catheters are used to engage the left and right coronary ostia. Hand

LAD

D LM

LCx

RCA

LAD

PDA

Figure 13-4 Normal coronary artery anatomy. A. Coronary angiogram showing the left circumflex (LCx) artery and its obtuse marginal (OM) branches. The left anterior descending artery (LAD) is also seen but may be foreshortened in this view. B. The LAD and its diagonal (D) branches are best seen in

C cranial views. In this angiogram, the left main (LM) coronary artery is also seen. C. The right coronary artery gives off the posterior descending artery (PDA) so this is a right-dominant circulation.

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Diagnostic Cardiac Catheterization and Coronary Angiography

Coronary Angiography

injection of radiopaque contrast agents create a coronary “luminogram” that is recorded on a radiographic images (cine angiography). Because the coronary arteries are three-dimensional objects that are in motion with the cardiac cycle, angiograms of the vessels using several different orthogonal projections are taken to best visualize the vessels without overlap or foreshortening. The normal coronary anatomy is highly variable between individuals, but, in general, there are two coronary ostia and three major coronary vessels—the left anterior descending, the left circumflex, and the right coronary arteries with the left anterior descending and left circumflex arteries arising from the left main coronary artery (Fig. 13-4). When the right coronary artery is the origin of the A-V nodal branch, the posterior descending artery, and the posterior lateral vessels, the circulation is defined as right dominant; this is found in ∼85% of individuals. When these branches arise from the left circumflex artery as occurs in ∼5% of individuals, the circulation is defined as left dominant. The remaining ∼10% of patients have a codominant circulation with vessels arising from both the right and left coronary circulation. In some patients, a ramus intermedius branch arises directly from the left main coronary artery; this finding is a normal variant. Coronary artery anomalies occur in 1–2% of patients, with separate ostia for the left anterior descending and left circumflex arteries being the most common (0.41%). Coronary angiography visualizes coronary artery stenoses as luminal narrowings on the cine angiogram. The degree of narrowing is referred to as the percent stenosis and is determined visually by comparing the most severely diseased segment with a proximal or distal

CHAPTER 13

a left ventricular aneurysm, pseudoaneurysm, or diverticulum and can be used to assess mitral valve prolapse and the severity of mitral regurgitation. The degree of mitral regurgitation is estimated by comparing the density of contrast opacification of the left atrium with that of the left ventricle. Minimal contrast reflux into the left atrium is considered 1+ mitral regurgitation while contrast density in the left atrium that is greater than that in the left ventricle with reflux of contrast into the pulmonary veins within three beats defines 4+ mitral regurgitation. Aortography in the cardiac catheterization laboratory visualizes abnormalities of the ascending aorta, including aneurysmal dilation and involvement of the great vessels, as well as dissection with compression of the true lumen by an intimal flap that separates the true and false lumina. Aortography can also be used to identify patent saphenous vein grafts that elude selective cannulation, identify shunts that involve the aorta such as a patent ductus arteriosus, and provide a qualitative assessment of aortic regurgitation using a 1+ – 4+ scale similar to that used for mitral regurgitation.

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SECTION II Diagnosis of Cardiovascular Disorders

“normal segment” mg; a stenosis >50% is considered significant (Fig. 13-5). Online quantitative coronary angiography can provide a more accurate assessment of the percent stenosis and lessen the tendency to overestimate lesion severity visually. The presence of a myocardial bridge, which most commonly involves the left anterior descending artery, may be mistaken for a significant stenosis; this occurs when a portion of the vessel dips below the epicardial surface into the myocardium and is subject to compressive forces during ventricular systole. The key to differentiating a myocardial bridge from a fixed stenosis is that the “stenosed” part of the vessel returns to normal during diastole. Coronary calcification is also seen during angiography prior to the injection of contrast agents. Collateral blood vessels may be seen traversing from one vessel to the distal vasculature of a severely stenosed or totally occluded vessel. Thrombolysis in myocardial infarction (TIMI) flow grade, a measure of the relative duration of time that it takes for contrast to opacify the coronary artery fully, may provide an additional clue to the degree of lesion severity, and the presence of TIMI grade 1 or 2 flow suggests that a significant coronary artery stenosis is present.

A B

C D

Intravascular Ultrasound, Fractional Flow Reserve, and Coronary Flow Reserve During coronary angiography, intermediate stenoses (40–70%), indeterminate findings, or anatomic findings that are incongruous with the patient’s symptoms may require further interrogation. In these cases, intravascular ultrasound provides a more accurate anatomic assessment of the coronary artery and the degree of coronary atherosclerosis (Fig. 13-5). Intravascular ultrasound is performed using a small flexible catheter with a 40-mHz transducer at its tip that is advanced into the coronary artery over a guidewire. Data from intravascular ultrasound studies may be used to image atherosclerotic plaque precisely, determine luminal cross-sectional area, and measure vessel size; it is also used during or following percutaneous coronary intervention to assess the stenosis and determine the adequacy of stent placement. Measurement of the fractional flow reserve provides a functional assessment of the stenosis. The fractional flow reserve is the ratio of the pressure in the coronary artery distal to the stenosis divided by the pressure in the artery proximal to the stenosis at maximal vasodilation. Fractional flow reserve is measured using a coronary pressure–sensor guidewire at rest and at maximal hyperemia following the injection of adenosine. A fractional flow reserve of 120 beats/min. Normal automaticity may be affected by a number other factors associated with heart disease. Hypokalemia and ischemia may reduce the activity of Na, K-ATPase, thereby reducing the background repolarizing current and enhancing phase 4 diastolic depolarization. The end result would be an increase in the spontaneous firing rate of pacemaking cells. Modest increases in extracellular potassium may render the maximum diastolic potential more positive, thereby also increasing the firing rate of pacemaking cells. A more significant increase in [K+]o, however, renders the heart inexcitable by depolarizing the membrane potential. Normal or enhanced automaticity of subsidiary latent pacemakers produces escape rhythms in the setting of failure of more dominant pacemakers. Suppression of a pacemaker cell by a faster rhythm leads to an increased intracellular Na+ load ([Na+]i), and extrusion of Na+ from the cell by Na, K-ATPase produces an increased background repolarizing current that slows phase 4 diastolic depolarization. At slower rates, [Na+]i is decreased, as is the activity of the Na, K-ATPase, resulting in

progressively more rapid diastolic depolarization and warm-up of the tachycardia rate. Overdrive suppression and warm-up are characteristic of, but may not be observed in, all automatic tachycardias. Abnormal conduction into tissue with enhanced automaticity (entrance block) may blunt or eliminate the phenomena of overdrive suppression and warm-up of automatic tissue. Abnormal automaticity may underlie atrial tachycardia, accelerated idioventricular rhythms, and ventricular tachycardia, particularly that associated with ischemia and reperfusion. It has also been suggested that injury currents at the borders of ischemic myocardium may depolarize adjacent nonischemic tissue, predisposing to automatic ventricular tachycardia. Afterdepolarizations and triggered automaticity Triggered automaticity or activity refers to impulse initiation that is dependent on afterdepolarizations (Fig. 14-3). Afterdepolarizations are membrane voltage oscillations that occur during (early afterdepolarizations, EADs) or after (delayed afterdepolarizations, DADs) an action potential. The cellular feature common to the induction of DADs is the presence of an increased Ca2+ load in the cytosol and sarcoplasmic reticulum. Digitalis glycoside toxicity, catecholamines, and ischemia all can enhance Ca2+ loading sufficiently to produce DADs. Accumulation of lysophospholipids in ischemic myocardium with consequent Na+ and Ca2+ overload has been suggested as a mechanism

Principles of Electrophysiology

Abbreviations: AP, action potential; AV, atrioventricular; DADs, delayed afterdepolarizations; EADs, early afterdepolarizations; HF, heart failure; LVH, left ventricular hypertrophy; VF, ventricular fibrillation; VT, ventricular tachyarrhythmia.

CHAPTER 14

Multicellular

132 0 mV

EAD

50 mV

Reactivation of L-type Ca current

DAD Intracellular Ca2+ overload

0.5 s

SECTION III

Figure 14-3 Schematic action potentials with early afterdepolarizations (EADs) and delayed afterdepolarizations (DADs). Afterdepolarizations are spontaneous depolarizations in cardiac myocytes. EADs occur before the end of the action potential (phases 2 and 3), interrupting repolarization. DADs occur during phase 4 of the action potential after completion of repolarization. The cellular mechanisms of EADs and DADs differ (see text).

Heart Rhythm Disturbances

for DADs and triggered automaticity. Cells from damaged areas or cells that survive a myocardial infarction may display spontaneous release of calcium from the sarcoplasmic reticulum, and this may generate “waves” of intracellular calcium elevation and arrhythmias. EADs occur during the action potential and interrupt the orderly repolarization of the myocyte. Traditionally, EADs have been thought to arise from action potential prolongation and reactivation of depolarizing currents, but more recent experimental evidence suggests a previously unappreciated interrelationship between intracellular calcium loading and EADs. Cytosolic calcium may increase when action potentials are prolonged. This, in turn, appears to enhance L-type Ca current, further prolonging action potential duration as well as providing the inward current driving EADs. Intracellular calcium loading by action potential prolongation may also enhance the likelihood of DADs. The interrelationship among intracellular [Ca2+], EADs, and DADs may be one explanation for the susceptibility of hearts that are calcium loaded (e.g., in ischemia or congestive heart failure) to develop arrhythmias, particularly on exposure to action potential–prolonging drugs. EAD-triggered arrhythmias exhibit rate dependence. In general, the amplitude of an EAD is augmented at slow rates when action potentials are longer. Indeed, a fundamental condition that underlies the development of EADs is action potential and QT prolongation. Hypokalemia, hypomagnesemia, bradycardia, and, most commonly, drugs can predispose to the generation of EADs, invariably in the context of prolonging the action potential. Antiarrhythmics with class IA and III action (see later) produce action potential and QT prolongation intended to be therapeutic but frequently causing arrhythmias.

Noncardiac drugs such as phenothiazines, nonsedating antihistamines, and some antibiotics can also prolong the action potential duration and predispose to EAD-mediated triggered arrhythmias. Decreased [K+]o paradoxically may decrease membrane potassium currents (particularly the delayed rectifier current, IKr) in the ventricular myocyte, explaining why hypokalemia causes action potential prolongation and EADs. In fact, potassium infusions in patients with the congenital long QT syndrome (LQTS) and in those with drug-induced acquired QT prolongation shorten the QT interval. EAD-mediated triggered activity probably underlies initiation of the characteristic polymorphic ventricular tachycardia, torsades des pointes, seen in patients with congenital and acquired forms of LQTS. Structural heart disease such as cardiac hypertrophy and failure may also delay ventricular repolarization (so-called electrical remodeling) and predispose to arrhythmias related to abnormalities of repolarization. The abnormalities of repolarization in hypertrophy and heart failure are often magnified by concomitant drug therapy or electrolyte disturbances. Abnormal impulse conduction: Reentry The most common arrhythmia mechanism is reentry. Fundamentally, reentry is defined as circulation of an activation wave around an inexcitable obstacle. Thus, the requirements for reentry are two electrophysiologically dissimilar pathways for impulse propagation around an inexcitable region such that unidirectional block occurs in one of the pathways and a region of excitable tissue exists at the head of the propagating wavefront (Fig. 14-4). Structural and electrophysiologic properties

slow

C block

Reentrant circuit

Initiation of reentry

gap

Sustained reentry

Termination of reentry

Figure 14-4 Schematic diagram of reentry. A. The circuit contains two limbs, one with slow conduction. B. A premature impulse blocks in the fast pathway and conducts over the slow pathway, allowing the fast pathway to recover so that the activation wave can reenter the fast pathway from the retrograde direction. C. During sustained reentry utilizing such a circuit, a gap (excitable gap) exists between the activating head of the wave and the recovering tail. D. One mechanism of termination of reentry occurs when the conduction and recovery characteristics of the circuit change and the activating head of the wave collides with the tail, extinguishing the tachycardia.

Approach to the

Patient

Cardiac Arrhythmias

Principles of Electrophysiology

The evaluation of patients with suspected cardiac arrhythmias is highly individualized; however, two key features—the history and ECG—are pivotal in directing the diagnostic workup and therapy. Patients with cardiac arrhythmias exhibit a wide spectrum of clinical presentations that range from asymptomatic ECG abnormalities to survival from cardiac arrest. In general, the more severe the presenting symptoms are, the more aggressive the evaluation and treatment are. Loss of consciousness that is believed to be of cardiac origin typically mandates an exhaustive search for the etiology and often requires invasive, device-based therapy. The presence of structural heart disease and prior myocardial infarction dictates a change in the approach to the management of syncope or ventricular arrhythmias. The presence of a family history of serious ventricular arrhythmias or premature sudden death will influence the evaluation of presumed heritable arrhythmias. The physical examination is focused on determining whether there is cardiopulmonary disease that is associated with specific cardiac arrhythmias. The absence of significant cardiopulmonary disease often, but not always, suggests benignity of the rhythm disturbance. In contrast, palpitations, syncope, or near syncope in the setting of significant heart or lung disease have more ominous implications. In addition, the physical examination may reveal the presence of a persistent arrhythmia such as atrial fibrillation. The judicious use of noninvasive diagnostic tests is an important element in the evaluation of patients with arrhythmias, and there is no test more important than the ECG, particularly if recorded at the time of symptoms. Uncommon but diagnostically important signatures of electrophysiologic disturbances may be unearthed on the resting ECG, such as delta waves in Wolff-Parkinson-White (WPW) syndrome, prolongation or shortening of the QT interval, right precordial ST-segment abnormalities in Brugada syndrome, and epsilon waves in arrhythmogenic right ventricular dysplasia. Variants of body surface ECG recording can provide important information about arrhythmia substrates and triggers. Holter monitoring and event recording, either continuous or intermittent, record the body surface ECG over longer periods, enhancing the possibility of observing the cardiac rhythm during symptoms. Implantable long-term monitors and commercial ambulatory ECG monitoring services permit prolonged telemetric monitoring both for diagnosis and to assess the efficacy of therapy. Long-term recordings permit the assessment of the time-varying behavior of the heart rhythm. Heart rate variability (HRV) and QT interval variability (QTV) provide noninvasive methods to assess autonomic nervous

133

CHAPTER 14

of the heart may contribute to the development of the inexcitable obstacle and that of unidirectional block. The complex geometry of muscle bundles in the heart and spatial heterogeneity of cellular coupling or other active membrane properties (i.e., ionic currents) appear to be critical. A key feature in classifying reentrant arrhythmias, particularly for therapy, is the presence and size of an excitable gap. An excitable gap exists when the tachycardia circuit is longer than the tachycardia wavelength (λ = conduction velocity × refractory period, representing the size of the circuit that can sustain reentry), allowing appropriately timed stimuli to reset propagation in the circuit. Reentrant arrhythmias may exist in the heart in the absence of an excitable gap and with a tachycardia wavelength nearly the same size as the path length. In this case, the wavefront propagates through partially refractory tissue with no anatomic obstacle and no fully excitable gap; this is referred to as leading circle reentry, a form of functional reentry (reentry that depends on functional properties of the tissue). Unlike excitable gap reentry, there is no fixed anatomic circuit in leading circle reentry, and it may therefore not be possible to disrupt the tachycardia with pacing or destruction of a part of the circuit. Furthermore, the circuit in leading circle reentry tends to be less stable than that in excitable gap reentrant arrhythmias, with large variations in cycle length and a predilection to termination. Anatomically determined, excitable gap reentry can explain several clinically important tachycardias, such as AV reentry, atrial flutter, bundle branch reentry ventricular tachycardia, and ventricular tachycardia in scarred myocardium. There is strong evidence to suggest that other, less organized arrhythmias, such as atrial and ventricular fibrillation, are associated with more complex activation of the heart and are due to functional reentry. Structural heart disease is associated with changes in conduction and refractoriness that increase the risk of reentrant arrhythmias. Chronically ischemic myocardium exhibits a downregulation of the gap junction channel protein (connexin 43) that carries intercellular ionic current. The border zones of infarcted and failing ventricular myocardium exhibit not only functional alterations of ionic currents but also remodeling of tissue and altered distribution of gap junctions. The changes in gap junction channel expression and distribution, in combination with macroscopic tissue alterations, support a role for slowed conduction in reentrant arrhythmias that complicate chronic coronary artery disease (CAD). Aged human atrial myocardium exhibits altered conduction, manifest as highly fractionated atrial electrograms, producing an ideal substrate for the reentry that may underlie the very common development of atrial fibrillation in the elderly.

134

SECTION III Heart Rhythm Disturbances

system influence on the heart. A decrease in HRV has been associated with increased sympathetic nervous system tone and increased mortality rates in patients after myocardial infarction. Signal-averaged electrocardiography (SAECG) uses signal-averaging techniques to amplify small potentials in the body surface ECG that are associated with slow conduction in the myocardium. The presence of these small potentials, referred to as late potentials because of their timing with respect to the QRS complex, and prolongation of the filtered (or averaged) QRS duration are indicative of slowed conduction in the ventricle and have been associated with an increased risk of ventricular arrhythmias after myocardial infarction. Exercise electrocardiography is important in determining the presence of myocardial demand ischemia; more recently, analysis of the morphology of the QT interval with exercise has been used to assess the risk of serious ventricular arrhythmias. Microscopic alterations in the T wave (T wave alternans, TWA) at low heart rates may identify patients at risk for ventricular arrhythmias. Cardiac imaging plays an important role in the detection and characterization of myocardial structural abnormalities that may render the heart more susceptible to arrhythmia. Ventricular tachyarrhythmias, for instance, occur more frequently in patients with ventricular systolic dysfunction and chamber dilation, in hypertrophic cardiomyopathy, and in the setting of infiltrative diseases such as sarcoidosis. Supraventricular arrhythmias may be associated with particular congenital conditions, including AV reentry in the setting of Ebstein’s anomaly. Echocardiography is a frequently employed imaging technique to screen for disorders of cardiac structure and function. Increasingly, magnetic resonance (MR) imaging of the myocardium is being used to screen for scar burden, fibrofatty infiltration of the myocardium as seen in arrhythmogenic right ventricular cardiomyopathy, and other structural changes that affect arrhythmia susceptibility. Head-up tilt (HUT) testing is useful in the evaluation of some patients with syncope. The physiologic response to HUT is incompletely understood; however, redistribution of blood volume and increased ventricular contractility occur consistently. Exaggerated activation of a central reflex in response to HUT produces a stereotypic response of an initial increase in heart rate, then a drop in blood pressure followed by a reduction in heart rate characteristic of neurally mediated hypotension. Other responses to HUT may be observed in patients with orthostatic hypotension and autonomic insufficiency. HUT is used most often in patients with recurrent syncope, although it may be useful in patients with single syncopal episodes with associated injury, particularly in the absence of structural heart disease. In patients with structural heart disease, HUT may be indicated in those with syncope, in whom other causes

(e.g., asystole, ventricular tachyarrhythmias) have been excluded. HUT has been suggested as a useful tool in the diagnosis of and therapy for recurrent idiopathic vertigo, chronic fatigue syndrome, recurrent transient ischemic attacks, and repeated falls of unknown etiology in the elderly. Importantly, HUT is relatively contraindicated in the presence of severe CAD with proximal coronary stenoses, known severe cerebrovascular disease, severe mitral stenosis, and obstruction to left ventricular outflow (e.g., aortic stenosis). The method of HUT is variable, but the angle of tilt and the duration of upright posture are central to the diagnostic utility of the test. Pharmacologic provocation of orthostatic stress with isoproterenol, nitrates, adenosine, and edrophonium has been used to shorten the test and enhance specificity. Electrophysiologic testing is central to the understanding and treatment of many cardiac arrhythmias. Indeed, most frequently, electrophysiologic testing is interventional, providing both diagnosis and therapy. The components of the electrophysiologic test are baseline measurements of conduction under resting and stressed (rate or pharmacologic) conditions and maneuvers, both pacing and pharmacologic, to induce arrhythmias. A number of sophisticated electrical mapping and catheter-guidance techniques have been developed to facilitate catheter-based therapeutics in the electrophysiology laboratory.

Treatment

Cardiac Arrhythmias

Antiarrhythmic Drug Therapy The interaction

of antiarrhythmic drugs with cardiac tissues and the resulting electrophysiologic changes are complex. An incomplete understanding of the effects of these drugs has produced serious missteps that have had adverse effects on patient outcomes and the development of newer pharmacologic agents. Currently, antiarrhythmic drugs have been relegated to an ancillary role in the treatment of most cardiac arrhythmias. There are several explanations for the complexity of antiarrhythmic drug action: the structural similarity of target ion channels; regional differences in the levels of expression of channels and transporters, which change with disease; time and voltage dependence of drug action; and the effect of these drugs on targets other than ion channels. Because of the limitations of any scheme to classify antiarrhythmic agents, a shorthand that is useful in describing the major mechanisms of action is of some utility. Such a classification scheme was proposed in 1970 by Vaughan-Williams and later modified by Singh and Harrison. The classes of antiarrhythmic action are class I, local anesthetic effect due to blockade of Na+ current; class II, interference with

the action of catecholamines at the β-adrenergic receptor; class III, delay of repolarization due to inhibition of K+ current or activation of depolarizing current; class IV, interference with calcium conductance (Table 14-2). The limitations of the Vaughan-Williams classification scheme include multiple actions of most drugs, overwhelming consideration of antagonism as a mechanism of action, and the fact that several agents have none of the four classes of action in the scheme.

Device Therapy Bradyarrhythmias due either to primary sinus node dysfunction or to atrioventricular conduction defects are readily treated through implantation

Table 14-2 Antiarrhythmic Drug Actions Class Actions Drug

III

Miscellaneous Action

α-Adrenergic blockade

Procainamide

Ganglionic blockade

Flecainide

+++

Propafenone

Quinidine

+ ++

Sotalol

+++

Dofetilide Amiodarone Ibutilide

+++

+++ +++

α-Adrenergic blockade Na+ channel activator

Principles of Electrophysiology

Catheter Ablation The use of catheter ablation is based on the principle that there is a critical anatomic region of impulse generation or propagation that is required for the initiation and maintenance of cardiac arrhythmias. Destruction of such a critical region results in the elimination of the arrhythmia. The use of radio frequency (RF) energy in clinical medicine is nearly a century old. The first catheter ablation using a DC energy source was performed in the early 1980s by Scheinman and colleagues. By the early 1990s, RF had been adapted for use in catheter-based ablation in the heart (Fig. 14-5). The RF frequency band (300–30,000 kHz) is used to generate energy for several biomedical applications, including coagulation and cauterization of tissues. Energy of this frequency will not stimulate skeletal muscle or the heart and heats tissue by a resistive

135

CHAPTER 14

mechanism, with the intensity of heating and tissue destruction being proportional to the delivered power. Alternative, less frequently used energy sources for catheter ablation of cardiac arrhythmias include microwaves (915 MHz or 2450 MHz), lasers, ultrasound, and freezing (cryoablation). Of these alternative ablation techniques, cryoablation is being used clinically with the most frequency, especially ablation in the region of the AV node. At temperatures just below 32°C, membrane ion transport is disrupted, producing depolarization of cells, decreased action potential amplitude and duration, and slowed conduction velocity (resulting in local conduction block)—all of which are reversible if the tissue is rewarmed in a timely fashion. Tissue cooling can be used for mapping and ablation. Cryomapping can be used to confirm the location of a desired ablation target, such as an accessory pathway in WPW syndrome, or can be used to determine the safety of ablation around the AV node by monitoring AV conduction during cooling. Another advantage of cryoablation is that once the catheter tip cools below freezing, it adheres to the tissue, increasing catheter stability independent of the rhythm or pacing.

136

SECTION III

Heart Rhythm Disturbances

Figure 14-5 Catheter ablation of cardiac arrhythmias. A. A schematic of the catheter system and generator in a patient undergoing radio frequency catheter ablation (RFCA); the circuit involves the catheter in the heart and a dispersive patch placed on the body surface (usually the back). The inset shows a diagram of the heart with a catheter located at the AV valve ring for ablation of an accessory pathway. B. A right anterior oblique fluoroscopic image of the catheter position for ablation of a left-sided accessory pathway. A catheter is placed in the atrial side of the mitral valve ring (abl) via a transseptal puncture. Other catheters are placed in the coronary sinus,

in the right atrium (RA), and in the right ventricular (RV) apex to record local electrical activation. C. Body surface ECG recordings (I, II, V1) and endocardial electrograms (HRA, high right atrium; HISp, proximal His bundle electrogram; CS 7,8, recordings from poles 7 and 8 of a decapolar catheter placed in the coronary sinus) during RFCA of a left-sided accessory pathway in a patient with Wolff-Parkinson-White syndrome. The QRS narrows at the fourth complex; the arrow shows the His bundle electrogram, which becomes apparent with elimination of ventricular preexcitation over the accessory pathway.

of a permanent pacemaker. Clinical indications for pace maker implantation often depend on the presence either of symptomatic bradycardia or of an unreliable endog enous escape rhythm and are more fully reviewed in Chap. 15. Ventricular tachyarrhythmias, particularly those occur ring in the context of progressive structural heart diseases such as ischemic cardiomyopathy or arrhythmogenic right ventricular cardiomyopathy, may recur despite therapy with antiarrhythmic drugs or catheter ablation.

In appropriate candidates, implantation of an internal cardioverter-defibrillator (ICD) may reduce mortality rates from sudden cardiac death. In a subset of patients with congestive heart failure (CHF) and ventricular mechani cal dyssynchrony, ICD or pacemaker platforms can be used to provide cardiac resynchronization therapy, typi cally through implantation of a left ventricular pacing lead. In patients with dyssynchronous CHF, such therapy has been shown to improve both morbidity and mortality rates.

CHAPTER 15

THE BRADYARRHYTHMIAS David D. Spragg

■

Gordon F. Tomaselli

Electrical activation of the heart normally originates in the sinoatrial (SA) node, the predominant pacemaker. Other subsidiary pacemakers in the atrioventricular (AV) node, specialized conducting system, and muscle may initiate electrical activation if the SA node is dysfunctional or suppressed. Typically, subsidiary pacemakers discharge at a slower rate and, in the absence of an appropriate increase in stroke volume, may result in tissue hypoperfusion. Spontaneous activation and contraction of the heart are a consequence of the specialized pacemaking tissue in these anatomic locales. As described in Chap. 14, action potentials in the heart are regionally heterogeneous. The action potentials in cells isolated from nodal tissue are distinct from those recorded from atrial and ventricular myocytes (Fig. 15-1). The complement of ionic currents present in nodal cells results in a less negative resting membrane potential compared with atrial or ventricular myocytes. Electrical diastole in nodal cells is characterized by slow diastolic depolarization (phase 4), which generates an action potential as the membrane voltage reaches threshold. The action potential upstrokes (phase 0) are slow compared with atrial or ventricular myocytes, being mediated by calcium rather than sodium current. Cells with properties of SA and AV nodal tissue are electrically connected to the remainder of the myocardium by cells with an electrophysiologic phenotype between that of nodal cells and that of atrial or ventricular myocytes. Cells in the SA node exhibit the most rapid phase 4 depolarization and thus are the dominant pacemakers in a normal heart. Bradycardia results from a failure of either impulse initiation or impulse conduction. Failure of impulse initiation may be caused by depressed automaticity resulting from a slowing or failure of phase 4 diastolic depolarization (Fig. 15-2), which may result from disease or exposure to drugs. Prominently, the autonomic nervous system modulates the rate of phase 4 diastolic depolarization and thus the firing rate of both primary

(SA node) and subsidiary pacemakers. Failure of conduction of an impulse from nodal tissue to atrial or ventricular myocardium may produce bradycardia as a result of exit block. Conditions that alter the activation and connectivity of cells (e.g., fibrosis) in the heart may result in failure of impulse conduction. SA node dysfunction and AV conduction block are the most common causes of pathologic bradycardia. SA node dysfunction may be difficult to distinguish from physiologic sinus bradycardia, particularly in the young. SA node dysfunction increases in frequency between the fifth and sixth decades of life and should be considered in patients with fatigue, exercise intolerance, or syncope and sinus bradycardia. Transient AV block is common in the young and probably is a result of the high vagal tone found in up to 10% of young adults. Acquired and persistent failure of AV conduction is decidedly rare in healthy adult populations, with an estimated incidence of ∼200/million population per year. Permanent pacemaking is the only reliable therapy for symptomatic bradycardia in the absence of extrinsic and reversible etiologies such as increased vagal tone, hypoxia, hypothermia, and drugs (Table 15-1). Approximately 50% of the 150,000 permanent pacemakers implanted in the United States and 20–30% of the 150,000 of those in Europe were implanted for SA node disease.

sA NodE disEAsE Structure and physiology of the SA node The SA node is composed of a cluster of small fusiform cells in the sulcus terminalis on the epicardial surface of the heart at the right atrial–superior vena caval junction, where they envelop the SA nodal artery. The SA node is structurally heterogeneous, but the central prototypic nodal cells have fewer distinct myofibrils than does the surrounding atrial myocardium, no intercalated

137

138

Voltage, mV

120

–100

ECa + 120 mV ENa + 70 mV 0 mV ECI -30 mV EK -90 mV

0 3 4 Ventricular

Figure 15-1 Action potential profiles recorded in cells isolated from sinoatrial or atrioventricular nodal tissue compared with those of cells from atrial or ventricular myocardium. Nodal

SECTION III Heart Rhythm Disturbances

disks visible on light microscopy, a poorly developed sarcoplasmic reticulum, and no T-tubules. Cells in the peripheral regions of the SA node are transitional in both structure and function. The SA nodal artery arises from the right coronary artery in 55–60% and the left circumflex artery in 40–45% of persons. The SA node is richly innervated by sympathetic and parasympathetic nerves and ganglia. Irregular and slow propagation of impulses from the SA node can be explained by the electrophysiology of nodal cells and the structure of the SA node itself. The action potentials of SA nodal cells are characterized by a relatively depolarized membrane potential (Fig. 15-1) of −40 to −60 mV, slow phase 0 upstroke, and relatively rapid phase 4 diastolic depolarization compared with the action potentials recorded in cardiac muscle

Acetylcholine

Control 0 mV

Phase 4 –50 mV

Depolarizing currents

ΙCa-T, Ι F,

Repolarizing currents

ΙK , Ι K1, Ι K ACh

ΙCa-L

Figure 15-2 Schematics of nodal action potentials and the currents that contribute to phase 4 depolarization. Relative increases in depolarizing L- (ICa-L) and T- (ICa-T) type calcium and pacemaker currents (If) along with a reduction in repolarizing inward rectifier (IK1) and delayed rectifier (IK) potassium currents result in depolarization. Activation of ACh-gated (IKACh) potassium current and beta blockade slow the rate of phase 4 and decrease the pacing rate. (Modified from J Jalife et al: Basic Cardiac Electrophysiology for the Clinician, Blackwell Publishing, 1999.)

Atrial

Nodal

200 ms

cell action potentials exhibit more depolarized resting membrane potentials, slower phase 0 upstrokes, and phase 4 diastolic depolarization.

cells. The relative absence of inward rectifier potassium current (IK1) accounts for the depolarized membrane Table 15-1 Etiologies of SA Node Dysfunction Extrinsic

Intrinsic

Autonomic Carotid sinus hypersensitivity Vasovagal (cardioinhibitory) stimulation Drugs Beta blockers Calcium channel blockers Digoxin Antiarrhythmics (class I and III) Adenosine Clonidine (other sympatholytics) Lithium carbonate Cimetidine Amitriptyline Phenothiazines Narcotics (methadone) Pentamidine Hypothyroidism Sleep apnea Hypoxia Endotracheal suctioning (vagal maneuvers) Hypothermia Increased intracranial pressure

Sick-sinus syndrome (SSS) Coronary artery disease (chronic and acute MI) Inflammatory Pericarditis Myocarditis (including viral) Rheumatic heart disease Collagen vascular diseases Lyme disease Senile amyloidosis Congenital heart disease TGA/Mustard and Fontan repairs Iatrogenic Radiation therapy Postsurgical Chest trauma Familial AD SSS, OMIM #163800 (15q24-25) AR SSS, OMIM #608567 (3p21) SA node disease with myopia, OMIM 182190 Kearns-Sayre syndrome, OMIM #530000 Myotonic dystrophy Type 1, OMIM #160900 (19q13.2-13.3) Type 2, OMIM #602668 (3q13.3-q24) Friedreich’s ataxia, OMIM #229300 (9q13, 9p23-p11)

Abbreviations: AD, autosomal dominant; AR, autosomal recessive; MI, myocardial infarction; OMIM, Online Mendelian Inheritance in Man (database); TGA, transposition of the great arteries.

SA nodal dysfunction has been classified as intrinsic or extrinsic. The distinction is important because extrinsic dysfunction is often reversible and generally should be corrected before pacemaker therapy is considered (Table 15-1). The most common causes of extrinsic SA node dysfunction are drugs and autonomic nervous system influences that suppress automaticity and/ or compromise conduction. Other extrinsic causes include hypothyroidism, sleep apnea, and conditions likely to occur in critically ill patients such as hypothermia, hypoxia, increased intracranial pressure (Cushing’s response), and endotracheal suctioning via activation of the vagus nerve. Intrinsic sinus node dysfunction is degenerative and often is characterized pathologically by fibrous replacement of the SA node or its connections to the atrium. Acute and chronic coronary artery disease (CAD) may be associated with SA node dysfunction, although in the setting of acute myocardial infarction (MI; typically inferior), the vabnormalities are transient. Inflammatory processes may alter SA node function, ultimately producing replacement fibrosis. Pericarditis, myocarditis, and rheumatic heart disease have been associated with SA nodal disease with sinus bradycardia, sinus arrest, and exit block. Carditis associated with systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), and mixed connective tissue disorders (MCTDs) may also affect SA node structure and function. Senile amyloidosis is an infiltrative disorder in patients typically in the ninth decade of life; deposition of amyloid protein

Clinical features of SA node disease SA node dysfunction may be completely asymptomatic and manifest as an ECG anomaly such as sinus bradycardia; sinus arrest and exit block; or alternating supraventricular tachycardia, usually atrial fibrillation, and bradycardia. Symptoms associated with SA node dysfunction, in particular tachycardia-bradycardia syndrome, may be related to both slow and fast heart rates. For example, tachycardia may be associated with palpitations, angina pectoris, and heart failure, and bradycardia may be associated with hypotension, syncope, presyncope, fatigue, and weakness. In the setting of SSS, overdrive suppression of the SA node may result in prolonged pauses and syncope upon termination of the tachycardia. In many cases, symptoms associated with SA node dysfunction result from concomitant cardiovascular disease. A significant minority of patients with SSS develop signs and symptoms of heart failure that may be related to slow or fast heart rates. One-third to one-half of patients with SA node dysfunction develop supraventricular tachycardia, usually atrial fibrillation or atrial flutter. The incidence of persistent atrial fibrillation in patients with SA node dysfunction increases with advanced age, hypertension, diabetes mellitus, left ventricular dilation, valvular heart disease, and ventricular pacing. Remarkably, some symptomatic patients may experience an improvement

139

The Bradyarrhythmias

Etiology of SA nodal disease

in the atrial myocardium can impair SA node function. Some SA node disease is iatrogenic and results from direct injury to the SA node during cardiothoracic surgery. Rare heritable forms of sinus node disease have been described, and several have been characterized genetically. Autosomal dominant sinus node dysfunction in conjunction with supraventricular tachycardia (i.e., tachycardia-bradycardia variant of sick-sinus syndrome [SSS]) has been linked to mutations in the pacemaker current (If) subunit gene HCN4 on chromosome 15. An autosomal recessive form of SSS with the prominent feature of atrial inexcitability and absence of P waves on the electrocardiogram (ECG) is caused by mutations in the cardiac sodium channel gene, SCN5A, on chromosome 3. SSS associated with myopia has been described but not genetically characterized. There are several neuromuscular diseases, including Kearns-Sayre syndrome (ophthalmoplegia, pigmentary degeneration of the retina, and cardiomyopathy) and myotonic dystrophy, that have a predilection for the conducting system and SA node. SSS in both the young and the elderly is associated with an increase in fibrous tissue in the SA node. The onset of SSS may be hastened by coexisting disease, such as CAD, diabetes mellitus, hypertension, and valvular diseases and cardiomyopathies.

CHAPTER 15

potential; the slow upstroke of phase 0 results from the absence of available fast sodium current (INa) and is mediated by L-type calcium current (ICa-L); and phase 4 depolarization is a result of the aggregate activity of a number of ionic currents. Prominently, both L- and T-type (ICa-T) calcium currents, the pacemaker current (so-called funny current, or If) formed by the tetramerization of hyperpolarization-activated cyclic nucleotide-gated channels, and the electrogenic sodiumcalcium exchanger provide depolarizing current that is antagonized by delayed rectifier (IKr) and acetylcholine-gated (IKACh) potassium currents. ICa-L, ICa-T, and If are modulated by β-adrenergic stimulation and IKACh by vagal stimulation, explaining the exquisite sensitivity of diastolic depolarization to autonomic nervous system activity. The slow conduction within the SA node is explained by the absence of INa and poor electrical coupling of cells in the node, resulting from sizable amounts of interstitial tissue and a low abundance of gap junctions. The poor coupling allows for graded electrophysiologic properties within the node, with the peripheral transitional cells being silenced by electrotonic coupling to atrial myocardium.

140 II

Figure 15-3 Sinus slowing and pauses on the ECG. The ECG is recorded during sleep in a young patient without heart disease. The heart rate before the pause is slow, and the PR interval is prolonged, consistent with an increase in vagal tone. The P waves have a morphology consistent with sinus

SECTION III Heart Rhythm Disturbances

in symptoms with the development of atrial fibrillation, presumably from an increase in their average heart rate. Patients with the tachycardia-bradycardia variant of SSS, similar to patients with atrial fibrillation, are at risk for thromboembolism, and those at greatest risk, including patients ≥65 years and patients with a prior history of stroke, valvular heart disease, left ventricular dysfunction, or atrial enlargement, should be treated with anticoagulants. Up to one-quarter of patients with SA node disease will have concurrent AV conduction disease, although only a minority will require specific therapy for high-grade AV block. The natural history of SA node dysfunction is one of varying intensity of symptoms even in patients who present with syncope. Symptoms related to SA node dysfunction may be significant, but overall mortality usually is not compromised in the absence of other significant comorbid conditions. These features of the natural history need to be taken into account in considering therapy for these patients. Electrocardiography of SA node disease The electrocardiographic manifestations of SA node dysfunction include sinus bradycardia, sinus pauses, sinus arrest, sinus exit block, tachycardia (in SSS), and chronotropic incompetence. It is often difficult to distinguish pathologic from physiologic sinus bradycardia.

rhythm. The recording is from a two-lead telemetry system in which the tracing labeled II mimics frontal lead II and V represents Modified Central Lead 1, which mimics lead V1 of the standard 12-lead ECG.

By definition, sinus bradycardia is a rhythm driven by the SA node with a rate of 5.0 cm). Chronic anticoagulation with warfarin targeted to achieve an international normalized ratio (INR) between 2.0 and 3.0 is recommended in patients with persistent or frequent and long-lived paroxysmal AF and risk factors. If patients have not been adequately anticoagulated and the AF is more than 24–48 h in duration, a transesophageal echocardiogram (TEE) can be performed to exclude the presence of a left atrial thrombus that might dislodge with the attempted restoration of sinus rhythm with either nonpharmacologic or pharmacologic therapy. Anticoagulation must be instituted coincident with the TEE and maintained for at least

ACUTE

1 month after restoration of sinus rhythm if the duration of AF has been prolonged or is unknown. Heparin is maintained routinely until the INR is 1.8 with the administration of warfarin after the TEE. For patients who do not warrant early cardioversion of AF, anticoagulation should be maintained for at least 3 weeks with the INR confirmed to be >1.8 on at least two separate occasions before attempts at cardioversion. Termination of AF acutely may be warranted on the basis of clinical parameters and/or hemodynamic status. Confirmation of appropriate anticoagulation status as described earlier in the chapter must be documented unless symptoms and clinical status warrant emergent intervention. Direct current transthoracic cardioversion during short-acting anesthesia is a reliable way to terminate AF. Conversion rates using a 200-J biphasic shock delivered synchronously with the QRS complex typically are >90%. Pharmacologic therapy to terminate AF is less reliable. Oral and/or IV administration of amiodarone or procainamide has only modest success. The acute IV administration of ibutilide appears to be somewhat more effective and may be used in selected patients to facilitate termination with direct current (DC) cardioversion (Tables 16-2 and 16-3). Pharmacologic therapy to maintain sinus rhythm can be instituted once sinus rhythm has been established or in anticipation of cardioversion to attempt to maintain sinus rhythm (Table 16-3). A single episode of AF may not warrant any intervention or only a short course of beta blocker therapy. To prevent recurrent AF unresponsive to beta blockade, a trial of antiarrhythmic therapy may be warranted, particularly if the AF is associated with rapid rates and/or significant symptoms. The selection of antiarrhythmic agents should be dictated primarily by the presence or absence of CAD, depressed LV function not attributable to a reversible tachycardia-induced cardiomyopathy, and/or severe hypertension with evidence of marked LV hypertrophy. The presence of any significant structural heart disease typically narrows treatment to the use of sotalol, amiodarone, dofetilide, or dronedarone. Severely depressed LV function with heart failure symptoms precludes the use of dronedarone and may limit sotalol therapy. Owing to the risk of QT prolongation and polymorphic VT, sotalol and dofetilide have to be initiated in the hospital in most cases. In patients without evidence of structural heart disease or hypertensive heart disease without evidence of severe hypertrophy, the use of the class IC antiarrhythmic agents flecainide or propafenone appears to be well tolerated and does not have significant proarrhythmia risk. It is important to recognize that no drug is uniformly effective, and arrhythmia recurrence should be anticipated in over one-half of the patients during

158

Table 16-2 Commonly Used Antiarrhythmic Agents—Intravenous Dose Range/Primary Indication

SECTION III

Drug

Maintenance

Primary Indication

Classa

Adenosine

6–18 mg (rapid bolus)

N/A

Terminate reentrant SVT involving AV node

—

Amiodarone

15 mg/min for 10 min, 1 mg/ min for 6 h

0.5–1 mg/min

AF, AFL, SVT, VT/VF

III

Digoxin

0.25 mg q2h until 1 mg total

0.125–0.25 mg/d

AF/AFL rate control

—

Diltiazem

0.25 mg/kg over 3–5 min (max 20 mg)

5–15 mg/h

SVT, AF/AFL rate control

Esmolol

500 μg/kg over 1 min

50 μg/kg per min

AF/AFL rate control

Ibutilide

1 mg over 10 min if over 60 kg

N/A

Terminate AF/AFL

III

Lidocaine

1–3 mg/kg at 20–50 mg/min

1–4 mg/min

Metoprolol

5 mg over 3–5 min × 3 doses

1.25–5 mg q6h

SVT, AF rate control; exercise-induced VT; long QT

Procainamide

15 mg/kg over 60 min

1–4 mg/min

Convert/prevent AF/VT

Quinidine

6–10 mg/kg at 0.3–0.5 mg/kg per min

N/A

Convert/prevent AF/VT

Verapamil

5–10 mg over 3–5 min

2.5–10 mg/h

SVT, AF rate control

Heart Rhythm Disturbances

Classification of antiarrhythmic drugs: Class I—agents that primarily block inward sodium current; class IA agents also prolong action potential duration; class II—antisympathetic agents; class III—agents that primarily prolong action potential duration; class IV—calcium channel-blocking agents. Abbreviations: AF, atrial fibrillation; AFL, atrial flutter; AV, atrioventricular; SVT, supraventricular tachycardia; VF, ventricular fibrillation; VT, ventricular tachycardia.

long-term follow-up regardless of the type and number of agents tried. It is also important to recognize that although the maintenance of sinus rhythm has been associated with improved long-term survival, the survival outcome of patients randomized to the pharmacologic maintenance of sinus rhythm was not superior to that of patients treated with rate control and anticoagulation in the AFFIRM and RACE trials. The AFFIRM and RACE trials compared outcome with respect to survival and thromboembolic events in patients with AF and risk factors for stroke using the two treatment strategies. It is believed that the poor outcome related to pharmacologic therapy used to maintain sinus rhythm was primarily due to the common inefficacy of such drug therapy and an increased incidence of asymptomatic AF. Many of the drugs used for rhythm control, including sotalol, amiodarone, propafenone, dronedarone, and flecainide, enhance slowing of AV nodal conduction. The absence of symptoms frequently leads to stopping anticoagulant therapy, and asymptomatic AF without anticoagulation increases stroke risk. Any consideration for stopping anticoagulation therefore must be accompanied by a prolonged period of ECG monitoring to document asymptomatic AF. It is also recommended that patients participate in monitoring by learning to take their pulse on a twice-daily basis and reliably identify its regularity if discontinuing anticoagulant therapy is contemplated seriously.

It is clear that to reduce the risk of drug-induced complications in treating AF, a thorough understanding of the drug planned to be used is critical—its dosing, metabolism, and common side effects and important drug-drug interactions. This information has been summarized in Tables 16-2, 16-3, 16-4, and 16-5 and serves as a starting point for a more complete review. In using antiarrhythmic agents that slow atrial conduction, strong consideration should be given to adding a beta blocker or a calcium channel blocker (verapamil or diltiazem) to the treatment regimen. This should help avoid a rapid ventricular response if AF is converted to “slow” AFL with the drug therapy (Fig. 16-5). Chronic Rate Control This is an option

in patients who are asymptomatic or symptomatic due to the resulting tachycardia. Rate control is frequently difficult to achieve in patients who have paroxysmal AF. In patients with more persistent forms of AF, rate control with beta blockers, the calcium channel blockers diltiazem and verapamil, and/or digoxin frequently can be achieved. Using the drugs in combination may avoid some of the common side effects seen with highdose monotherapy. An effort should be made to document the adequacy of rate control to reduce the risk of a tachycardia-induced cardiomyopathy. Heart rates >80 beats/min at rest or 100 beats/min with very modest physical activity are indications that rate control may

Table 16-3

159

Commonly Used Antiarrhythmic Agents: Chronic Oral Dosing/Primary Indications Drug

Dosing Oral, mg, Maintenance

Half-Life, h

Primary Route(s) of Metabolism/Elimination

Most Common Indication

Acebutolol

200–400 q12h

6–7

Renal/hepatic

AF rate control/SVT Long QT/RVOT VT

Amiodarone

100–400 qd

40–55 d

Hepatic

AF/VT prevention

IIIb

Atenolol

25–100 per d

6–9

Renal

AF rate control/SVT Long QT/RVOT VT

Digoxin

0.125–0.5 qd

38–48

Renal

AF rate control

—

Diltiazem

30–60 q6h

3–4.5

Hepatic

AF rate control/SVT

Disopyramide

100–300 q6–8h

4–10

Renal 50%/hepatic

AF/SVT prevention

Dofetilide

0.125–0.5 q12h

Renal

AF prevention

III

Dronedarone

400 q12 hr

13–19

Hepatic

AF prevention

IIIb

Flecainide

50–200 q12h

7–22

Hepatic 75%/renal

AF/SVT/VT prevention

Metoprolol

25–100 q6h

3–8

Hepatic

AF rate control/SVT Long QT/RVOT VT

Mexiletine

150–300 q8–12h

10–14

Hepatic

VT prevention

Moricizine

100–400 q8h

3–13

Hepatic 60%/renal

AF prevention

Nadolol

40–240 per d

10–24

Renal

Same as metoprolol

Procainamide

250–500 q3–6h

3–5

Hepatic/renal

AF/SVT/VT prevention

Propafenone

150–300 q8h

2–8

Hepatic

AF/SVT/VT prevention

Quinidine

300–600 q6h

6–8

Hepatic 75%/renal

AF/SVT/VT prevention

Sotalol

80–160 q12h

Renal

AF/VT prevention

III

Verapamil

80–120 q6–8h

4.5–12

Hepatic/renal

AF rate control/RVOT VT Idiopathic LV VT

Classa

be inadequate in persistent AF. Extended periods of ECG monitoring and assessment of heart rate with exercise should be considered. In patients with symptoms resulting from inadequate rate control with pharmacologic therapy or worsening LV function due to the persistent tachycardia, ablative therapy to attempt to eliminate atrial fibrillation, or an AV junction ablation can be performed. The AV junction ablation must be coupled with the implantation of an activity sensor pacemaker to maintain a physiologic range of heart rates. Recent evidence that RV pacing can occasionally modestly depress LV function should be taken into consideration in identifying which patients are appropriate candidates for the “ablate and pace” treatment strategy. Occasionally, biventricular pacing may be used to minimize the degree of dyssynchronization that can occur with RV apical pacing alone. Rate control treatment options must be coupled with chronic anticoagulation therapy in all cases. Trials evaluating the

elimination of embolic risk by elimination or isolation of the left atrial appendage or by endovascular insertion of a left atrial appendage-occluding device may provide other treatment options that can eliminate the need for chronic anticoagulation. Catheter and Surgical Ablative Therapy to Prevent Recurrent AF

Although the optimum ablation strategy has not been defined, most ablation strategies incorporate techniques that isolate the atrial muscle sleeves entering the pulmonary veins; these muscle sleeves have been identified as the source of the majority of triggers responsible for the initiation of AF. Ablation therapy is currently considered an alternative to additional pharmacologic therapy trials in patients with recurrent symptomatic AF or AF associated with poor rate control who have failed an initial attempt at rhythm control with pharmacologic management. Ablative therapy appears superior to additional

The Tachyarrhythmias

Classification of antiarrhythmic drugs: Class I—agents that primarily block inward sodium current; class II—antisympathetic agents; class III— agents that primarily prolong action potential duration; class IV—calcium channel-blocking agents. b Amiodarone and dronedarone both are grouped in class III, but both also have class I, II, and IV properties. Abbreviations: AF, atrial fibrillation; LV, left ventricular; RVOT, right ventricular outflow tract; SVT, supraventricular tachycardia; VT, ventricular tachycardia.

CHAPTER 16

160

Table 16-5

Table 16-4

SECTION III Heart Rhythm Disturbances

Common Nonarrhythmic Toxicity of Most Frequently Used Antiarrhythmic Agents

Proarrhythmic Manifestations of Most Frequently Used Antiarrhythmic Agents

Drug

Common Nonarrhythmic Toxicity

Drug

Common Proarrhythmic Toxicity

Amiodarone

Tremor, peripheral neuropathy, pulmonary inflammation, hypo- and hyperthyroidism, photosensitivity

Amiodarone

Adenosine

Cough, flushing

Digoxin

Anorexia, nausea, vomiting, visual changes

Sinus bradycardia, AV block, increase in defibrillation threshold Rare: long QT and torsades des pointes, 1:1 ventricular conduction with atrial flutter

Adenosine

Disopyramide

Anticholinergic effects, decreased myocardial contractility

All arrhythmias potentiated by profound pauses, atrial fibrillation

Digoxin

Dofetilide

Nausea

High-grade AV block, fascicular tachycardia, accelerated junctional rhythm, atrial tachycardia

Dronedarone

Gastrointestinal intolerance, exacerbation of heart failure

Disopyramide

Flecainide

Dizziness, nausea, headache, decreased myocardial contractility

Ibutilide

Nausea

Long QT and torsades des pointes, 1:1 ventricular response to atrial flutter; increased risk of some ventricular tachycardias in patients with structural heart disease

Lidocaine

Dizziness, confusion, delirium, seizures, coma

Dofetilide

Long QT and torsades des pointes

Dronedarone

Mexiletine

Ataxia, tremor, gait disturbances, rash, nausea

Bradyarrhythmias and AV block, long QT and torsades des pointes

Flecainide

Moricizine

Mood changes, tremor, loss of mental clarity, nausea

Procainamide

Lupus erythematosus-like syndrome (more common in slow acetylators), anorexia, nausea, neutropenia

1:1 Ventricular response to atrial flutter; increased risk of some ventricular tachycardias in patients with structural heart disease; sinus bradycardia

Ibutilide

Long QT and torsades des pointes

Procainamide

Long QT and torsades des pointes, 1:1 ventricular response to atrial flutter; increased risk of some ventricular tachycardias in patients with structural heart disease

Propafenone

1:1 Ventricular response to atrial flutter; increased risk of some ventricular tachycardias in patients with structural heart disease; sinus bradycardia

Quinidine

Long QT and torsades des pointes, 1:1 ventricular response to atrial flutter; increased risk of some ventricular tachycardias in patients with structural heart disease

Sotalol

Long QT and torsades des pointes, sinus bradycardia

Propafenone

Taste disturbance, dyspepsia, nausea, vomiting

Quinidine

Diarrhea, nausea, vomiting, cinchonism, thrombocytopenia

Sotalol

Hypotension, bronchospasm

pharmacologic treatment aimed at rhythm control in this setting. Elimination of AF in 50–80% of patients with a catheter-based ablation procedure should be anticipated, depending on the chronicity of the AF, with additional patients becoming responsive to previously ineffective medications. Catheter ablative therapy also holds promise in patients with more persistent forms of AF and even those with severe atrial dilation. Its confirmed efficacy suggests an important alternative to His bundle ablation and pacemaker insertion in many patients. Serious risks related to the left atrial ablation procedure, albeit low (overall 2–4%), include pulmonary vein stenosis, atrioesophageal fistula, systemic embolic events, perforation/tamponade, and phrenic nerve injury. Surgical ablation of AF is typically performed at the time of other cardiac valve or coronary artery surgery and, less commonly, as a stand-alone procedure.

Abbreviation: AV, atrioventricular.

The surgical Cox-Maze procedure is designed to interrupt all macroreentrant circuits that might potentially develop in the atria, thereby precluding the ability of the atria to fibrillate. In an attempt to simplify the operation, the multiple incisions of the traditional Cox-Maze procedure have been replaced with linear lines of ablation and pulmonary vein isolation using a variety of energy sources. Severity of AF symptoms and difficulties in rate and/or rhythm control with pharmacologic therapy

frequently dictate the optimum AF treatment strategy. Similar to the approach with pharmacologic rhythm control, a cautious approach to eliminating anticoagulant therapy is recommended after catheter or surgical ablation. Careful ECG monitoring for asymptomatic AF, particularly in patients with multiple risk factors for stroke, should be considered until guidelines are firmly established. If the left atrial appendage has been removed surgically, the threshold for stopping anticoagulation may be lowered. Antiarrhythmic therapy typically can be discontinued after catheter or surgical ablation of AF. However, in selected patients, satisfactory AF control may require maintenance of previously ineffective drug therapy after the ablation intervention.

161 VI A

VI B

Figure 16-5 Atrial fibrillation. A. Transitions to “slow” atrial flutter during antiarrhythmic drug therapy. B. A rapid ventricular response with 1:1 atrioventricular conduction occurred with exercise, leading to C. symptoms of dizziness.

likely to demonstrate slower rates that overlap with those identified with focal atrial tachycardias. Because lead V1 is frequently monitored in a hospitalized patient, coarse AF may be misdiagnosed as AFL. This occurs because in both typical right AFL and coarse AF the crista terminalis in the right atrium may serve as an effective anatomic barrier. The free wall of the right atrium, whose electrical depolarization is best reflected on the body surface by lead V1, may demonstrate a uniform wave front of atrial activation in both conditions. The timing of atrial activation is much more rapid in AF and always demonstrates variable atrial intervals with some intervals between defined P waves 5 cm left atrial diameter with a high risk of AF, and/or a history of coincident paroxysmal AF. Most focal ATs are readily amenable to catheter ablative therapy. In patients who fail to respond to medical therapy or who are reluctant to take chronic drug therapy, this option should be considered, with an anticipated 90% cure rate. A parahisian location for the AT and/or a focus that is located in the left atrium may modestly increase the risk related to the procedure, and for this reason, every effort should be made to determine the likely origin of the AT based on an analysis of the P-wave morphology on 12-lead ECG before the procedure.

AV Nodal Tachycardias AV nodal reentrant tachycardia Atrioventricular nodal reentrant tachycardia is the most common paroxysmal regular SVT. It is more commonly observed in women than in men and is typically manifest in the second to fourth decades of life. In general, because AVNRT tends to occur in the absence of structural heart disease, it is usually well tolerated. Neck pulsations are usually felt because of the simultaneous atrial and ventricular contraction, and a “frog sign” can be identified on physical examination during the

arrhythmia. In the presence of hypertension or other forms of structural heart disease that limit ventricular filling, hypotension or syncope may occur. Atrioventricular nodal reentrant tachycardia develops because of the presence of two electrophysiologically distinct pathways for conduction in the complex syncytium of muscle fibers that make up the AV node. The fast pathway in the more superior part of the node has a longer refractory period, whereas the pathway lower in the AV node region conducts more slowly but has a shorter refractory period. As a result of the inhom*ogeneities of conduction and refractoriness, a reentrant circuit can develop in response to premature stimulation. Although conduction occurs over both pathways during sinus rhythm, only the conduction over the fast pathway is manifest, and as a result, the PR interval is normal. APCs occurring at a critical coupling interval are blocked in the fast pathway because of the longer refractory period and are conducted slowly over the slow pathway. When sufficient conduction slowing occurs, the blocked fast pathway can recover excitability and atrial activation can occur over the fast pathway to complete the circuit. Repetitive activation down the slow and up the fast pathway results in typical AV nodal reentrant tachycardia (Fig. 16-7). ECG Findings in AVNRT

The APC initiating AVNRT is characteristically followed by a long PR interval consistent with conduction via the slow pathway. AVNRT is manifest typically as a narrow QRS complex tachycardia at rates that range from 120 to 250 beats/min. The QRS-P wave pattern associated with typical AVNRT is quite characteristic, with simultaneous activation of the atria and ventricles from the reentrant AV nodal circuit. The P wave frequently is buried inside the QRS complex and either will not be visible or will distort the initial or terminal portion of the QRS complex (Fig. 16-7). Because atrial activation originates in the region of the AV node, a negative deflection will be generated by retrograde atrial depolarization when recording ECG leads II, III, or aVF. Occasionally, AVNRT occurs with activation in the reverse direction, conducting down the fast pathway and returning up the slow pathway. This form of AVNRT occurs much less commonly and produces a prolonged RP interval during the tachycardia with a negative P wave in leads II, III, and aVF. This atypical form of AVNRT is more easily precipitated by ventricular stimulation.

Treatment

Atrioventricular Nodal Reentrant Tachycardia

Acute Treatment Treatment is directed at altering conduction within the AV node. Vagal stimulation, such as that which occurs with the Valsalva maneuver

or carotid sinus massage, can slow conduction in the AV node sufficiently to terminate AVNRT. In patients in whom physical maneuvers do not terminate the tachyarrhythmia, the administration of adenosine, 6–12 mg IV, frequently does so. Intravenous beta blockade or calcium channel therapy should be considered as second-line treatment. If hemodynamic compromise is present, R-wave synchronous DC cardioversion using 100–200 J can terminate the tachyarrhythmia.

These can also occur in the setting of enhanced normal automaticity, abnormal automaticity, or triggered activity. These tachycardias may or may not be associated with retrograde conduction to the atria, and the P waves may appear dissociated or produce intermittent conduction and early activation of the junction. These arrhythmias may occur as a manifestation of increased adrenergic tone or drug effect in patients with sinus node dysfunction or after surgical or catheter ablation. The arrhythmia may also be a manifestation of digoxin toxicity. The most common manifestation of digoxin intoxication is the sudden regularization of the response to AF. A junctional tachycardia due to digoxin toxicity typically does not manifest retrograde conduction. Sinus activity may appear dissociated or result in intermittent capture beats with a long PR interval. If the rate is >50 beats per minute and 200 beats/min and patients reluctant to take chronic drug therapy should be considered for ablative therapy. Catheter ablation can cure AV nodal reentry in >95% of patients with a single procedure. The risk of AV block requiring a permanent pacemaker is ∼1% with the ablation procedure.

Treatment

166

SECTION III

Heart Rhythm Disturbances

Figure 16-8 A. Sinus rhythm tracing of leads V1–V3 showing evidence of Wolff-Parkinson-White syndrome with short PR interval and delta wave. B. During atrial fibrillation, rapid conduction to the ventricles is observed producing a wide QRS complex tachycardia with marked irregularity of the ventricular response and morphology of the QRS complex.

insertion at a site distant from the AV groove in the fascicles. These pathways conduct more slowly and are referred to as atriofascicular accessory pathways. Atriofascicular APs are unique in their tendency to demonstrate decremental antegrade conduction. Other accessory pathway connections from the AV node to the fascicles may exist. These pathways are referred to as Mahaim fibers and typically manifest a normal PR interval with a delta wave. Patients with manifest preexcitation and WPW syndrome are typically subject to both macroreentrant tachycardias and a rapid response to AF (Fig. 16-8). The most common macroreentrant tachycardia associated with WPW syndrome is referred to as orthodromic AV reentry. Ventricular activation occurs via the AV node and the His-Purkinje system. Conduction then returns or reenters the atria via retrograde conduction over the AP. The reentrant circuit develops because of the inhom*ogeneity in conduction and refractoriness in the AP and the normal AV node. Characteristically, the AP has more rapid conduction but a longer refractory period than that of the AV node. Typical APs do not show evidence of antegrade decremental conduction. An APC can block in the AP and conduct sufficiently slowly or with decrement via the AV node to allow for retrograde recovery of activation of the AP and, in turn, of the atria (Fig. 16-7). This retrograde activation of the atria via the AP is referred

to as an echo beat. If the pattern repeats itself, a tachycardia develops. Uncommonly, the reentrant circuit can be reversed so that the impulse reaches the ventricle via the AP and conducts retrogradely through to the atria via the His-Purkinje system and the AV node; this is referred to as antidromic AV reentry and/or preexcitation macroreentry, with the entire activation of the ventricle originating from the site of insertion of the AP. Although it is uncommon, it is important to recognize antidromic SVT. The ECG pattern during the tachycardia mimics VT originating from the site of ventricular insertion of the AP. The presence of manifest preexcitation in sinus rhythm provides a valuable clue to the diagnosis. The second most common and potentially more serious arrhythmia associated with WPW syndrome is rapidly conducting AF. Nearly 50% of patients with evidence of APs are predisposed to episodes of AF. In patients who have rapid antegrade conduction from the atria to the ventricles over the AP, the AP can conduct rapidly in response to AF, resulting in a faster ventricular rate than would occur normally via the AV node. The rapid ventricular rates can result in hemodynamic compromise and even precipitate VF. The QRS pattern during AF in patients with manifest preexcitation can appear quite bizarre and change on a beat-to-beat basis due to the variability in the degree of fusion from activation over the AV node (Fig. 16-8). Concealed APs In ∼50% of patients with APs, there is no antegrade conduction over the AP; however, retrograde conduction is preserved. As a result, the AP is not manifest in sinus rhythm and is manifest only during the sustained tachycardia. The presence of a concealed AP is suggested by the timing and pattern of atrial activation during the tachycardia: the P wave typically follows ventricular activation with a short RP wave interval (Fig. 16-7). Because many APs connect the left ventricle to the left atrium, the pattern of atrial activation during the tachycardia frequently produces negative P waves in leads I and aVL. The tachycardia circuit and therefore its ECG manifestation during orthodromic tachycardia are identical both in patients with overt preexcitation in sinus rhythm and in those with concealed APs. Patients with concealed APs, although prone to episodes of AF, are not at risk for developing a rapid ventricular response to the AF. Occasionally, APs conduct extremely slowly in a retrograde fashion, resulting in longer retrograde conduction and the development of a long RP interval during the tachycardia (long RP tachycardia). Because of the presence of this dramatically slowed conduction, additional conduction slowing created by premature atrial complexes is not required for tachycardia to ensue.

These patients are more prone to frequent episodes of tachycardia and can present with “incessant” tachycardias and tachycardia-induced LV cardiomyopathy. The correct diagnosis of a long RP tachycardia may be suggested by the pattern of initiation and the P-wave morphology. Frequently, however, an electrophysiologic evaluation is required to establish the diagnosis.

Treatment

Accessory Pathway–Mediated Tachycardias

Ventricular Premature Complexes The origin of premature beats in the ventricle at sites remote from the Purkinje network produces slow ventricular activation and a wide QRS complex that is typically >140 ms in duration. Ventricular premature complexes are common and increase with age and the presence of structural heart disease. VPCs can occur with a certain degree of periodicity that has become incorporated into the lexicon of electrocardiography. Ventricular premature complexes may occur in patterns of bigeminy, in which every sinus beat is followed by a VPC, or trigeminy, in which two sinus beats are followed by a VPC. VPCs may have different morphologies and are thus referred to as multiformed. Two successive VPCs are termed pairs or couplets. Three or more consecutive VPCs are termed VT when the rate is >100 beats per minute. If the repetitive VPCs terminate spontaneously and are more than three beats in duration, the arrhythmia is referred to as nonsustained VT. APCs with aberrant ventricular conduction may also create a wide and early QRS complex. The premature P wave can occasionally be difficult to discern when it falls on the preceding T wave, and other clues must be used to make the diagnosis. The QRS pattern for a VPC does not appear to follow a typical right or left bundle branch block pattern as the QRS morphology

The Tachyarrhythmias

Ventricular Tachyarrhythmias

167

CHAPTER 16

Acute treatment of AP-mediated macroreentrant orthodromic tachycardias is similar to that for AV nodal reentry and is directed at altering conduction in the AV node. Vagal stimulation with the Valsalva maneuver and carotid sinus pressure may create sufficient AV nodal slowing to terminate the AVRT. Intravenous administration of adenosine, 6–12 mg, is first-line pharmacologic therapy; IV, the calcium channel blockers verapamil and diltiazem or beta blockers may also be effective. In patients who manifest preexcitation and AF, therapy should be aimed at preventing a rapid ventricular response. In life-threatening situations, DC cardioversion should be used to terminate the AF. In nonlife-threatening situations, procainamide at a dose of 15 mg/kg administered IV over 20–30 min will slow the ventricular response and may organize and terminate AF. Ibutilide can also be used to facilitate termination of AF. During AF there may be rapid conduction over the AV node as well as the AP. Caution should be used in attempting to slow AV nodal conduction with the use of digoxin or verapamil; when administered IV, these drugs may actually result in an acute increase in rate over the AP, placing the patient at risk for development of VF. Digoxin appears to shorten the refractory period of the AP directly and thus increases the ventricular rate. Verapamil appears to shorten the refractory period indirectly by causing vasodilation and a reflex increase in sympathetic tone. Chronic oral administration of beta blockers and/or verapamil or diltiazem may be used to prevent recurrent supraventricular reentrant tachycardias associated with APs. In patients with evidence of AF and a rapid ventricular response and in those with recurrences of SVT on AV nodal blocking drugs, strong consideration should be given to the administration of a class IA or IC antiarrhythmic drug such as quinidine, flecainide, or propafenone because these drugs slow conduction and increase refractoriness in the AP. Patients with a history of recurrent symptomatic SVT episodes, incessant SVT, and heart rates >200 beats/ min with SVT should be given strong consideration for undergoing catheter ablation. Patients who have demonstrated rapid antegrade conduction over their AP or the potential for rapid conduction should also be

considered for catheter ablation. Catheter ablation therapy has been demonstrated to be successful in >95% of patients with documented WPW syndrome and appears effective regardless of age. The risk of catheter ablative therapy is low and is dictated primarily by the location of the AP. Ablation of parahisian APs is associated with a risk of heart block, and ablation in the left atrium is associated with a small but definite risk of thromboembolic phenomenon. These risks must be weighed against the potential serious complications associated with hemodynamic compromise, the risk of VF, and the severity of the patient’s symptoms with AP-mediated tachycardias. Patients who demonstrate evidence of ventricular preexcitation in the absence of any prior arrhythmia history merit special consideration. The first arrhythmia manifestation can be a rapid SVT or, albeit of low risk (40 beats per minute and 100 beats per minute; most VT patients have rates >120 beats per minute. Sustained VT at rates 250 beats per minute. A rapid rate coupled with the sine wave nature of the arrhythmia makes it impossible to identify a discrete QRS morphology. When antiarrhythmic drugs are being administered, a sine wave appearance of the QRS complex can be observed, even at rates as low as 200 beats per minute. VF is characterized by completely disorganized ventricular activation on the surface ECG. Polymorphic

170

aVR

aVL

III

aVF

SECTION III

Heart Rhythm Disturbances

Figure 16-10 Ventricular tachycardia. ECG showing AV dissociation (arrows mark P waves), wide QRS >200 ms, superior frontal plane axis,

Treatment

Ventricular Tachycardia/Fibrillation

Sustained polymorphic VT, ventricular flutter, and VF all lead to immediate hemodynamic collapse. Emergency asynchronous defibrillation is therefore required, with at least 200-J monophasic or 100-J biphasic shock. The shock should be delivered asynchronously to avoid delays related to sensing of the QRS complex. If the arrhythmia persists, repeated shocks with the maximum energy output of the defibrillator are essential to optimize the chance of

slurring of the initial portion of the QRS, and large S wave in V6—all clues to the diagnosis of ventricular tachycardia.

successful resuscitation. Intravenous lidocaine and/or amiodarone should be administered but should not delay repeated attempts at defibrillation. For any monomorphic wide complex rhythm that results in hemodynamic compromise, a prompt R-wave synchronous shock is required. Conscious sedation should be provided if the hemodynamic status permits. For patients with a well-tolerated wide complex tachycardia, the appropriate diagnosis should be established on the basis of strict ECG criteria (Table 16-6). Pharmacologic treatment to terminate monomorphic VT is not

Table 16-6 ECG Clues Supporting the Diagnosis of Ventricular Tachycardia AV dissociation (atrial capture, fusion beats) QRS duration >140 ms for RBBB type V1 morphology; V1 >160 ms for LBBB type V1 morphology Frontal plane axis −90° to 180° Delayed activation during initial phase of the QRS complex LBBB pattern—R wave in V1, V2 >40 ms RBBB pattern—onset of R wave to nadir of S >100 ms Bizarre QRS pattern that does not mimic typical RBBB or LBBB QRS complex Concordance of QRS complex in all precordial leads RS or dominant S in V6 for RBBB VT Q wave in V6 with LBBB QRS pattern Monophasic R or biphasic qR or R/S in V1 with RBBB pattern Abbreviations: AV, atrioventricular; RBBB/LBBB, right/left bundle branch block.

171

Chart speed 25.0 mm/sec

Atria

Ventricle AF

Pacing

which might not normally be used in patients with structural heart disease because of the risk of proarrhythmia, may be considered in patients with an ICD and recurrent VT. Catheter ablative therapy for VT in patients without structural heart disease results in cure rates >90%. In patients with structural heart disease, catheter ablation that includes a strategy for eliminating unmappable/rapid VT and one that incorporates endocardial as well as epicardial mapping and ablation should be employed. In most patients, catheter ablation can reduce or eliminate the requirement for toxic drug therapy and should be considered in any patient with recurrent VT. The utilization of ablative therapy to reduce the incidence of ICD shocks for VT in patients who receive the ICD as part of primary prevention for VT is being actively investigated. Management of VT Storm Repeated VT

episodes requiring external cardioversion/defibrillation or repeated appropriate ICD shock therapy are referred to as VT storm. Although a definition of more than two episodes in 24 h is used, most patients with VT storm will experience many more episodes. In the extreme form of VT storm, the tachycardia becomes incessant and the baseline rhythm cannot be restored for any extended period. In patients with recurrent polymorphic VT in the absence of the long QT interval, one should have a high suspicion of active ischemic disease or fulminant myocarditis. Intravenous lidocaine or amiodarone administration should be coupled with prompt assessment of the status of the coronary anatomy. Endomyocardial biopsy, if indicated by clinical

The Tachyarrhythmias

typically successful (50% of patients with a history of VT and an ICD may need to be treated with adjunctive antiarrhythmic drug therapy to prevent VT recurrences or to manage atrial arrhythmias. Because of the presence of an ICD, there is more flexibility with respect to the selection of antiarrhythmic drug therapy. The use of sotalol or amiodarone represents first-line therapy for patients with a history of structural heart disease and life-threatening monomorphic or polymorphic VT not due to long QT syndrome. Importantly, sotalol has been associated with a decrease in the defibrillation threshold, which reflects the amount of energy necessary to terminate VF. Amiodarone may be better tolerated in patients with a more marginal hemodynamic status and systolic blood pressure. The risk of end-organ toxicity from amiodarone must be weighed against the ease of use and general efficacy. Antiarrhythmic drug therapy with agents such as quinidine, procainamide, and propafenone,

beginning of the tracing. The ventricular electrogram suddenly changes in morphology (*) and becomes regular, consistent with the diagnosis of VT. Pacing transiently accelerates the rate and interrupts the rapid VT. The patient was unaware of the life-threatening event.

CHAPTER 16

Figure 16-11 Ventricular tachycardia (VT) (*) during atrial fibrillation stopped by pacing (#) from an implantable cardioverter defibrillator (ICD) from recording stored by ICD. The atrial electrogram shows characteristic fibrillatory waves through the tracing. The ventricular electrogram shows an irregularly irregular response consistent with atrial fibrillation at the

172

SECTION III Heart Rhythm Disturbances

circ*mstances, may be used to confirm the diagnosis of myocarditis, although the diagnostic yield is low. In patients who demonstrate QT prolongation and recurrent pause-dependent polymorphic VT (TDP), removal of an offending QT-prolonging drug, correction of potassium or magnesium deficiencies, and emergency pacing to prevent pauses should be considered. Intravenous beta blockade therapy should be considered for polymorphic VT storm. A targeted treatment strategy should be employed if the diagnosis of the polymorphic VT syndrome can be established. For example, quinidine or isoproterenol can be used in the treatment of Brugada syndrome. Intraaortic balloon counterpulsation or acute coronary angioplasty may be needed to stop recurrent polymorphic VT precipitated by acute ischemia. In selected patients with a repeating VPC trigger for their polymorphic VT, the VPC can be targeted for ablation to prevent recurrent VT. In patients with recurrent monomorphic VT, acute IV administration of lidocaine, procainamide, or amiodarone can prevent recurrences. The use of such therapy is empirical, and a clinical response is not certain. Procainamide and amiodarone are more likely to slow the tachycardia and make it hemodynamically tolerated. Unfortunately, antiarrhythmic drugs, especially those that slow conduction (e.g., amiodarone, procainamide), can also facilitate recurrent VT or even result in incessant VT. VT catheter ablation can eliminate frequent recurrent or incessant VT and frequent ICD shocks. Such therapy should be deployed earlier in the course of arrhythmia events to prevent adverse consequences of recurrent VT episodes and adverse effects from antiarrhythmic drugs.

Unique VT Syndromes Although most ventricular arrhythmias occur in the setting of CAD with prior MI, a significant number of patients develop VT in other settings. A brief discussion of each unique VT syndrome is warranted. Information that illustrates a unique pathogenesis and enhances the ability to make the correct diagnosis and institute appropriate therapy will be highlighted. Idiopathic outflow tract VT VT in the absence of structural heart disease is referred to as idiopathic VT. There are two major varieties of these VTs. Outflow tachycardias originate in the RV and LV outflow tract regions. Approximately 80% of outflow tract VTs originate in the RV and ∼20% in the LV outflow tract regions. Outflow tract VTs appear to originate from anatomic sites that form an arc that begins just above the tricuspid valve and extends along the roof of the outflow tract region to include the free wall and septal aspect of the right

ventricle just beneath the pulmonic valve, the aortic valve region, and then the anterior/superior margin of the mitral valve annulus. These arrhythmias appear more commonly in women. Importantly, these ventricular arrhythmias are rarely associated with SCD unless manifest by very short coupled premature complexes that trigger VF. Patients manifest symptoms of palpitations with exercise, stress, and caffeine ingestion. In women, the arrhythmia is more commonly associated with hormonal triggers and can frequently be timed to the premenstrual period, gestation, and menopause. Uncommonly, the VPCs and VTs can be of sufficient frequency and duration to cause a tachycardia-induced cardiomyopathy. The pathogenesis of outflow tract VT remains unknown, and there is no definite anatomic abnormality identified with these VTs. Vagal maneuvers, adenosine, and beta blockers tend to terminate the VTs, whereas catecholamine infusion, exercise, and stress tend to potentiate the outflow tract VTs. Based on these observations, the mechanism of the arrhythmia is most likely calcium-dependent triggered activity. Preliminary data suggest that at least in some patients, a somatic mutation of the inhibitory G protein (Gαi2) may serve as the genetic basis for the VT. In contrast to VT in patients with CAD, outflow tract VTs are uncommonly initiated with programmed stimulation but are able to be initiated by rapid-burst atrial or ventricular pacing, particularly when coupled with the infusion of isoproterenol. Outflow tract VT typically produces large monophasic R waves in the inferior frontal plane leads II, III, and aVF, and typically occurs as nonsustained bursts of VT and/or frequent premature beats. Cycle length oscillations during the tachycardia are common. Since most VT originates in the RV outflow tract, the VT typically has a left bundle branch block (LBBB) pattern in lead V1 (negative QRS vector) (Fig. 16-12). Outflow tract VTs, originating in the left ventricle, particularly those associated with an origin from the mitral valve annulus, have a right bundle branch block (RBBB) pattern in lead V1 (positive QRS vector).

Treatment

Idiopathic Outflow Tract Ventricular Tachycardia

Acute medical therapy for idiopathic outflow tract VT is rarely required because the VT is hemodynamically tolerated and is typically nonsustained. Intravenous beta blockers frequently terminate the tachycardia. Chronic therapy with beta or calcium channel blockers frequently prevents recurrent episodes of the tachycardia. The arrhythmia also appears to respond to treatment with class IA or IC agents or with sotalol. Catheter ablative

Idiopathic IV Septal VT

RVOT-VT

Idiopathic LV septal/fascicular VT

VT associated with LV dilated cardiomyopathy II

Figure 16-12 Common idiopathic ventricular tachycardia (VT) ECG patterns. Right ventricular outflow tract (RVOT) VT with typical left bundle QRS pattern in V1 and inferiorly directed frontal plane axis, and left ventricular septal VT from the inferior septum with a narrow QRS RBBB pattern in V1 and superior and leftward front plane QRS axis.

therapy has been utilized successfully to eliminate the tachycardia with success rates >90%. Because of the absence of structural heart disease and the focal nature of these arrhythmias, the 12-lead ECG pattern during VT can help localize the site of origin of the arrhythmia and help facilitate catheter ablation. Efficacy of therapy is assessed with treadmill testing and/or ECG monitoring, and electrophysiologic study is performed only when the diagnosis is in question or to perform catheter ablation.

Monomorphic and polymorphic VTs may occur in patients with nonischemic dilated cardiomyopathy (Chap. 21). Although the myopathic process may be diffuse, there appears to be a predilection for the development of fibrosis around the mitral and aortic valvular regions. Most uniform sustained VT can be mapped to these regions of fibrosis. Drug therapy is usually ineffective in preventing VT, and empirical trials of sotalol or amiodarone are usually initiated only for recurrent VT episodes after ICD implantation. VT associated with nonischemic dilated cardiomyopathy appears to be less amenable to catheter ablative therapy from the endocardium; frequently, the VT originates from epicardial areas of fibrosis and catheter access to the epicardium can be gained via a percutaneous pericardial puncture to improve the outcome of ablation techniques. In patients with a history of depressed myocardial dysfunction due to a nonischemic cardiomyopathy with an LV ejection fraction 90% of patients.

173

174

bundle branch reentrant VT typically has a QRS morphology with a left bundle branch block type of pattern and a leftward superior axis (Fig. 16-13). The circuit for bundle branch (LBB) reentrant VT can occasionally rotate in the opposite direction, antegrade through the left bundle and retrograde through the right bundle, in which case an RBBB pattern during VT will be manifest. It is important to recognize bundle branch reentrant VT because it is readily amenable to ablative therapy that targets a component of the His-Purkinje system, typically the right bundle, to block the VT circuit. Less commonly, bundle branch reentry may occur in the absence of structural heart disease or in the setting of CAD. The use of adjunctive ICD therapy is dictated by the ability to eliminate the VT successfully and the severity of the LV dysfunction.

SECTION III

VT associated with hypertrophic cardiomyopathy

Heart Rhythm Disturbances

(See also Chap. 21) VT and VF have also been associated with hypertrophic cardiomyopathy. In patients with hypertrophic cardiomyopathy and a history of sustained VT/VF, unexplained syncope, a strong family history of SCD, LV septal thickness >30 mm, or nonsustained spontaneous VT, the risk of SCD is high and ICD implantation is usually indicated. Amiodarone, sotalol, and beta blockers have been used to control recurrent

His

LBBB VT

I II

LPF

III aVR aVL aVF

aVL aVF V1

His LB

aVR

III

RV site of stimulation

An increased arrhythmia risk has been identified when cardiac involvement occurs in a variety of infiltrative diseases and neuromuscular disorders (Table 16-7). Many patients manifest AV conduction disturbances and may require permanent pacemaker insertion. The decision to implant an ICD device should follow current established guidelines for patients with nonischemic cardiomyopathy, which include an LV ejection fraction 240 ms, QRS 120 ms, or heart block and type 1 myotonic dystrophy as predicting a risk of sudden death. Additional study will be required to determine if patients with lesser degrees of LV dysfunction or other more diffuse myopathic disease processes also have identifiable risk and warrant primary ICD implantation. A potential proarrhythmic risk of antiarrhythmic drug therapy should be acknowledged, and drug therapy should be reserved for symptomatic arrhythmias and limited to amiodarone or sotalol if an ICD is not present. Arrhythmogenic RV cardiomyopathy/dysplasia (ARVCM/D) (See also Chap. 21) ARVCM/D due to a genetically determined dysplastic process or after a suspected viral myocarditis is also associated with VT/VF. The sporadic nonfamilial/nondysplastic form of RV cardiomyopathy Table 16-7 Infiltrative/Inflammatory and Neuromuscular Disorders Associated With an Increased Ventricular Arrhythmia Risk

V2 V3

LAF RB

VT associated with other infiltrative cardiomyopathies and neuromuscular disorders

RBBB VT

LAF

I II

VT. Experience with ablative therapy is limited because of the infrequency with which the VT is tolerated hemodynamically. Ablation procedures that target the substrate for VT/VF and ablate areas of low voltage consistent with fibrosis, which frequently are located in apical aneurysms, appear to have promise in this setting. WPW syndrome has been observed in patients with hypertrophic cardiomyopathy associated with PRKAG2 mutations.

V4 LPF

LV site of stimulation

Sarcoidosisa

Emery-Dreyfuss muscular dystrophya

Chagas’ diseasea

Limb-girdle muscular dystrophya

Amyloidosisa

duch*enne muscular dystrophy

Fabry disease

Becker muscular dystrophy

Hemochromatosis

Kearn-Sayre syndromea

Myotonic muscular dystrophya

Friedreich’s ataxia

Figure 16-13 Bundle branch reentrant ventricular tachycardia (VT) showing typical QRS morphologies when VT is initiated with stimulation from the right ventricle (left bundle branch block [LBBB] VT pattern) or left ventricle (right bundle branch block [RBBB] VT pattern) and schema for circuit involving the HisPurkinje network.

High frequency of ventricular arrhythmias noted.

Treatment

A rrhythmogenic Right Ventricular Cardiomyopathy/Dysplasia

The threshold for ICD implantation in patients with an established diagnosis of ARVCM/D is low. An ICD typically is implanted in patients deemed to have a persistent VT risk, those who have had spontaneous or inducible rapid VTs, and those who show concomitant LV cardiomyopathy. Treatment options for recurrent VT in patients with ARVCM/D include the use of the antiarrhythmic agent sotalol. Beta blockers serve as useful adjunctive therapy when coupled with other antiarrhythmic agents. Catheter ablative therapy directed at mappable sustained ventricular arrhythmias is also highly successful in controlling recurrent VT. In selected patients with multiple VT morphologies and unstable VT, linear ablation lesions directed at endocardial scars and, if required, targeting late potentials in epicardial scars, defined by catheterbased bipolar voltage mapping, provide significant amelioration of the recurrent VT episodes.

Figure 16-14 Leads V1 to V3 in sinus rhythm from a normal subject (A), from a patient with arrhythmogenic right ventricular cardiomyopathy showing epsilon waves (arrow) and T-wave inversion

175

(B), and from a patient with Brugada syndrome with STsegment elevation in V1 and V2 (C).

The Tachyarrhythmias

not identify the presence of fatty replacement or fibrosis unless directed to the basal RV free wall. The familial forms of this syndrome have been linked to a number of desmosomal protein mutations. A distinct genetic form of this syndrome, Naxos disease, consists of arrhythmogenic RV dysplasia coupled with palmar-plantar keratosis and woolly hair and is associated with a high risk of SCD in adolescents and young adults.

CHAPTER 16

appears to be more common; however, this may vary with ethnicity. In patients predisposed to VT, there appears to be a predominance of perivalvular fibrosis involving mostly the free wall of the right ventricle in proximity to the tricuspid and pulmonic valves. The surface ECG leads that reflect RV activation, including V1−V3, may show terminal notching of the QRS complex and inverted T waves in sinus rhythm. When the terminal notching is distinct and appears separated from the QRS complex, it is referred to as an epsilon wave (Fig. 16-14). Epsilon waves are consistent with markedly delayed ventricular activation in the region of the RV free wall near the base of the tricuspid and pulmonic valves in areas of extensive fibrosis. In patients with ARVCM/D, echocardiography demonstrates RV enlargement with RV wall motion abnormalities and RV apical aneurysm formation. MRI may show fatty replacement of the ventricle, thinning of the RV free wall with increased fibrosis, and associated wall motion abnormalities. Because of the presence of extensive amounts of fat normally covering the epicardium in the region of the RV, caution must be used to avoid overinterpreting the MRI in trying to determine the appropriate diagnosis. Patients tend to have multiple VT morphologies. The VT will typically have an LBBB type QRS pattern in V1 and tend to have poor R-wave progression in V1 through V6, consistent with an RV free-wall origin. Areas of low electrogram voltage that are identified during RV catheter endocardial sinus rhythm voltage mapping may be helpful in confirming the diagnosis. Importantly, endocardial biopsy may

176

VT after operative tetralogy of Fallot repair VT may also occur after surgical repair of tetralogy of Fallot. Patients typically develop VT many years after the surgery. VT tends to occur in patients with evidence of RV systolic dysfunction. The VT mechanism and location are typically a macroreentrant circuit around the right ventriculotomy scar to the valve annuli. Catheter ablation creating linear lesions that extend from either the pulmonic or the tricuspid annulus to the ventriculotomy scar is typically effective in preventing arrhythmia recurrences. An ICD is usually implanted in patients who manifest rapid VT, have persistent inducible VT after ablation, or have concomitant LV dysfunction.

SECTION III

Fascicular tachycardia caused by digoxin toxicity

Heart Rhythm Disturbances

Digoxin toxicity can produce increased ventricular ectopy and, when coupled with bradyarrhythmias caused by digoxin toxicity, may predispose to sustained polymorphic ventricular arrhythmias and VF. The signature VT associated with digoxin toxicity is bidirectional VT (Fig. 16-15). This unique VT is due to triggered activity associated with calcium overload resulting from the inhibition of Na+, K+-ATPase by digoxin. Bidirectional VT originates from the left anterior and posterior fascicles, creating a relatively narrow QRS right bundle branch (RBB) configuration with a beat-to-beat alternating right and left frontal plane QRS axis. This VT seldom is observed in the absence of digoxin toxicity. Treatment for bidirectional VT or other hemodynamically significant arrhythmias due to digoxin excess includes correction of electrolyte disorders and IV infusion of digoxin-specific Fab fragments. The antibody fragments will, over the course of 1 h, bind digoxin and eliminate toxic effects. In the setting of normal renal function, the bound complex is secreted.

Genetically Determined Abnormalities That Predispose to Polymorphic Ventricular Arrhythmias Ion channel defects that affect cardiac depolarization and repolarization may predispose to life-threatening polymorphic VT and SCD. These defects frequently produce unique ECG characteristics during sinus rhythm that facilitate the diagnosis. Long QT syndrome The congenital form of LQTS consists of defects in cardiac ion channels that are responsible for cardiac repolarization. Defects that enhance sodium or calcium inward currents or inhibit outward potassium currents during

Figure 16-15 Digoxin toxic bidirectional fascicular tachycardia.

the plateau phase of the action potential lengthen action potential duration and, hence, the QT interval. Of the eight genetic mutations identified to date, five affect the α or β subunits of the three different potassium channels involved with repolarization (Table 16-8). Since many patients with QT prolongation do not have one of the defined mutations, it is anticipated that other genetic abnormalities affecting repolarization channel function will be identified. The triggers for the ventricular arrhythmias are thought to be due to early afterdepolarizations potentiated by intracellular calcium accumulation from a prolonged action potential plateau. Heterogeneity of myocardial repolarization indexed by a longer QT interval predisposes to polymorphic ventricular arrhythmias in response to the triggers (Fig. 16-9). In most patients with LQTS, the QT interval corrected for heart rate using Bazett’s formula is >460 ms in men and >480 ms in women with LQTS. Marked lengthening of the QT interval to >500 ms is clearly

Table 16-8

177

Inherited Arrhythmia Disorders: “Channelopathies” With High Risk of Ventricular Arrhythmias Disorder

Gene

Protein/Channel Affected

KCNQ1

Iks channel α subunit

KCNH2 (HERG)

IKr channel α subunit

LQT3

SCN5A

Ina channel α subunit

LQT4

ANK2

Ankyrin-B

LQT5

KCNE1

IKs channel β subunit

LQT6

KCNE2

IKr channel β subunit

LQT7

KCNJ2

IK1 channel α subunit

LQT8

CACNA1C

ICa channel α subunit

Jervell LN1

KCNQ1

IKs channel β subunit

Jervell LN2

KCNE1

IKr channel β subunit

Brugada syndrome

SCN5A

INa channel

Catecholaminergic VT

Ry R2

Ryanodine receptor, calsequestrin receptor

SQTS1

KCNH2 (HERG)

IKr channel α subunit

SQTS2

KCNQ1(KvLQT1)

IKs channel α subunit

SQTS3

KCNJ2

IK1 channel

associated with a greater arrhythmia risk in patients with LQTS. Many affected individuals may have QT intervals that intermittently measure within a normal range or fail to shorten appropriately with exercise. Some individuals manifest the syndrome only when exposed to a drug, such as sotalol, that alters channel function. The genotype associated with LQTS appears to influence prognosis, and identification of the genotype appears to help optimize clinical management. The first three genotypic designations of the mutations identified, LQT1, LQT2, and LQT3, appear to account for >99% of patients with clinically relevant LQTSs. Surface ECG characteristics may be helpful in distinguishing the three most common genotypes, with genetic testing being definitive. LQT1 represents the most common genotypic abnormality. Patients with LQT1 fail to shorten or actually prolong their QT interval with exercise. The T wave in patients with LQT1 tends to be broad and constitutes the majority of the prolonged QT interval. The most common trigger for potentiating cardiac arrhythmias in patients with LQT1 is exercise, followed by emotional stress. More than 80% of male patients have their first cardiac event by age 20, so competitive exercise should be restricted and swimming avoided for these patients. Patients tend to respond to beta blocker therapy. Patients with two LQT1 alleles have Jervell and Lange-Nielsen syndrome, with more dramatic QT prolongation and deafness and a worse arrhythmia prognosis.

LQT2 is the second most common genotypic abnormality. The T wave tends to be notched and bifid. In LQT2 patients, the most common precipitant is emotional stress, followed by sleep or auditory stimulation. Despite the occurrence during sleep, patients typically respond to beta blocker therapy. LQT3 is due to a mutation in the gene that encodes the cardiac sodium channel on chromosome 3. Prolongation of the action potential duration occurs because of failure to inactivate this channel. LQT3 patients have either late-onset peaked biphasic T waves or asymmetric peaked T waves. The arrhythmia events tend to be more life threatening, and thus the prognosis for LQT3 is the poorest of all the LQTs. Male patients appear to have the worst prognosis among patients with LQT3. Most events in LQT3 patients occur during sleep, suggesting that they are at higher risk during periods of slow heart rates. Beta blockers are not recommended, and exercise is not restricted in LQT3.

Treatment

Long QT Syndrome

The institution of ICD therapy should be strongly considered in any patient with LQTS who has demonstrated any life-threatening arrhythmia. Patients with syncope with a confirmed diagnosis based on unequivocal ECG criteria or positive genetic testing should also be given the same strong consideration. Primary prevention with

The Tachyarrhythmias

Abbreviations: LQT, long QT (interval); SQT, short QT (interval).

CHAPTER 16

LQT1 LQT2

178

prophylactic ICD implantation should be considered in male patients with LQT3 and in all patients with marked QT prolongation (>500 ms), particularly when coupled with an immediate family history of SCD. Future epidemiologic investigation may provide firmer guidelines to sort patients further on the basis of risks such as age, gender, arrhythmia history, and genetic characteristics. In all patients with documented or suspected LQTS, drugs that prolong the QT interval must be avoided. For an updated list of drugs, see www.qtdrugs.org.

Acquired LQTS

SECTION III Heart Rhythm Disturbances

Patients with a genetic predisposition related to what appear to be sporadic mutations and/or single nucleotide polymorphisms can develop marked QT prolongation in response to drugs that alter repolarization currents. The QT prolongation and associated polymorphic ventricular tachycardia (TDP) are seen more frequently in women and may be a manifestation of subclinical LQTS. Drug-induced long QT and TDP frequently are potentiated by the development of hypokalemia and bradycardia. The offending drugs typically block the potassium IKr channel (Table 16-5). Since most drug effects are dose dependent, important drugdrug interactions that alter metabolism and/or alterations in elimination kinetics because of hepatic or renal dysfunction frequently contribute to the arrhythmias.

Treatment

Acquired Long QT Syndrome

Acute therapy for acquired LQTS is directed at eliminating the offending drug therapy, reversing metabolic abnormalities by the infusion of magnesium and/or potassium, and preventing pause-dependent arrhythmias by temporary pacing or the cautious infusion of isoproterenol. Class IB antiarrhythmic agents (e.g., lidocaine) that do not cause QT prolongation may also be used, though they are frequently ineffective. Supportive therapy to allay anxiety and prevent pain with required DC shock therapy for sustained arrhythmias and efforts to facilitate drug elimination are important.

Double counting of QRS and T waves may lead to inappropriate ICD shocks. Drug therapy with quinidine has been used to lengthen the QT interval and reduce the amplitude of the T wave. This therapy is being evaluated to determine long-term efficacy in preventing arrhythmias in this syndrome. Brugada syndrome The major clinical features of Brugada syndrome include manifest, transient, or concealed ST segment elevation in V1 to V3 that typically can be provoked with the sodium channel-blocking drugs ajmaline, flecainide, and procainamide and a risk of polymorphic ventricular arrhythmias. It appears that a diminished inward sodium current in the region of the RV outflow tract epicardium is responsible for Brugada syndrome (Table 16-8). A loss of the action potential dome in the RV epicardium due to unopposed ITo potassium outward current results in dramatic shortening of the action potential. The large potential difference between the normal endocardium and rapidly depolarized RV outflow epicardium gives rise to ST-segment elevation in V1−V3 in sinus rhythm and predisposes to local ventricular reentry (Fig. 16-14). The majority of genetic abnormalities responsible for the syndrome have not been described; however, in ∼20% of patients, mutations of SCN5A genes have been identified. Although identified in both genders and all races with an autosomal dominant inheritance pattern, the arrhythmia syndrome is most common in young male patients (∼75%) and is thought to be responsible for the sudden and unexpected nocturnal death syndrome (SUDS) described in Southeast Asian men. The ventricular arrhythmia characteristically occurs with rest or during sleep. Fever and other sodium channel-blocking drugs have also precipitated ventricular arrhythmias. The presence of spontaneous coved-type ST elevation in the right precordial leads and a history of syncope or aborted sudden cardiac death are predictors of an adverse outcome. Because of the overlap in SCN5A mutations, the association of Brugada syndrome with phenotypic LQT3 and conduction disturbances has been noted.

Short QT syndrome A gain in function of repolarization currents can result in a shortening of atrial and ventricular refractoriness and marked QT shortening on the surface ECG (Table 16-8). The T wave tends to be tall and peaked. A QT interval 0.47 s in men, >0.48 s in women

Brugada syndrome

Low-intensity competitive sports

Catecholaminergic polymorphic VT Asymptomatic Wolff-Parkinson-White syndrome

Low-intensity competitive sports No competitive sports

Electrophysiological study not mandatory

Premature ventricular complexes

All sports except restriction in dangerous environments All competitive sports when no increase in PVCs or symptoms occur with exercise

Nonsustained ventricular tachycardia

No structural heart disease

All competitive sports

Nonsustained ventricular tachycardia

Structural heart disease

Only low-intensity competitive sports

SECTION III

Source: Adapted from ACC Bethesda Conference #36 from Pelliccia et al: J Am Coll Cardiol 52:1990–1996, 2008.

Heart Rhythm Disturbances

been promulgated on the basis of expert consensus and evidence-based data and can facilitate management once a diagnosis has been established (Table 16-9). Treatment should be based on standards established for each arrhythmia syndrome. Curative catheter ablative therapy should be applied if indicated. ICD therapy, if

required, is incompatible with contact sports because of the potential for blunt trauma and consequent damage to the device. Although ICDs are effective, their psychosocial impact, the potential for inappropriate shocks for sinus tachycardia, and lead-related complications must be recognized.

SECTION IV

Disorders of the heart

CHaPTer 17

HEART FAILURE AND COR PULMONALE Douglas L. Mann

■

Murali Chakinala

(1) HF with a depressed EF (commonly referred to as systolic failure) or (2) HF with a preserved EF (commonly referred to as diastolic failure).

HearT FaIlure DEfINITION Heart failure (HF) is a clinical syndrome that occurs in patients who, because of an inherited or acquired abnormality of cardiac structure and/or function, develop a constellation of clinical symptoms (dyspnea and fatigue) and signs (edema and rales) that lead to frequent hospitalizations, a poor quality of life, and a shortened life expectancy.

ETIOlOgY As shown in Table 17-1, any condition that leads to an alteration in LV structure or function can predispose a patient to developing HF. Although the etiology of HF in patients with a preserved EF differs from that of patients with depressed EF, there is considerable overlap between the etiologies of these two conditions. In industrialized countries, coronary artery disease (CAD) has become the predominant cause in men and women and is responsible for 60–75% of cases of HF. Hypertension contributes to the development of HF in 75% of patients, including most patients with CAD. Both CAD and hypertension interact to augment the risk of HF, as does diabetes mellitus. In 20–30% of the cases of HF with a depressed EF, the exact etiologic basis is not known. These patients are referred to as having nonischemic, dilated, or idiopathic cardiomyopathy if the cause is unknown (Chap. 21). Prior viral infection or toxin exposure (e.g., alcoholic or chemotherapeutic) also may lead to a dilated cardiomyopathy. Moreover, it is becoming increasingly clear that a large number of cases of dilated cardiomyopathy are secondary to specific genetic defects, most notably those in the cytoskeleton. Most forms of familial dilated cardiomyopathy are inherited in an autosomal dominant fashion. Mutations of genes that encode cytoskeletal proteins (desmin, cardiac myosin, vinculin) and nuclear membrane proteins (laminin) have been identified thus far. Dilated cardiomyopathy also is associated with duch*enne’s, Becker’s, and limb-girdle muscular dystrophies. Conditions that lead to a high cardiac output (e.g., arteriovenous fistula, anemia) are seldom responsible for the development of HF in a normal heart;

EPIDEmIOlOgY HF is a burgeoning problem worldwide, with more than 20 million people affected. The overall prevalence of HF in the adult population in developed countries is 2%. HF prevalence follows an exponential pattern, rising with age, and affects 6–10% of people over age 65. Although the relative incidence of HF is lower in women than in men, women constitute at least one-half the cases of HF because of their longer life expectancy. In North America and Europe, the lifetime risk of developing HF is approximately one in five for a 40-year-old. The overall prevalence of HF is thought to be increasing, in part because current therapies for cardiac disorders, such as myocardial infarction (MI), valvular heart disease, and arrhythmias, are allowing patients to survive longer. Very little is known about the prevalence or risk of developing HF in emerging nations because of the lack of population-based studies in those countries. Although HF once was thought to arise primarily in the setting of a depressed left ventricular (LV) ejection fraction (EF), epidemiologic studies have shown that approximately one-half of patients who develop HF have a normal or preserved EF (EF ≥40–50%). Accordingly, HF patients are now broadly categorized into one of two groups:

182

Table 17-1 Etiologies of Heart Failure Depressed Ejection Fraction (40–50%) Pathologic hypertrophy Primary (hypertrophic cardiomyopathies) Secondary (hypertension) Aging

Restrictive cardiomyopathy Infiltrative disorders (amyloidosis, sarcoidosis) Storage diseases (hemochromatosis) Fibrosis Endomyocardial disorders

Cor pulmonale Pulmonary vascular disorders

Prognosis Despite many recent advances in the evaluation and management of HF, the development of symptomatic HF still carries a poor prognosis. Community-based studies indicate that 30–40% of patients die within 1 year of diagnosis and 60–70% die within 5 years, mainly from worsening HF or as a sudden event (probably because of a ventricular arrhythmia). Although it is difficult to predict prognosis in an individual, patients with symptoms at rest (New York Heart Association [NYHA] class IV) have a 30–70% annual mortality rate, whereas patients with symptoms with moderate activity (NYHA class II) have an annual mortality rate of 5–10%. Thus, functional status is an important predictor of patient outcome (Table 17-2). Table 17-2 New York Heart Association Classification Objective Assessment

Class I

Patients with cardiac disease but without resulting limitation of physical activity. Ordinary physical activity does not cause undue fatigue, palpitations, dyspnea, or anginal pain.

Thyrotoxicosis Nutritional disorders (beriberi)

Excessive blood-flow requirements Systemic arteriovenous shunting Chronic anemia

Class II

Patients with cardiac disease resulting in slight limitation of physical activity. They are comfortable at rest. Ordinary physical activity results in fatigue, palpitation, dyspnea, or anginal pain.

Class III

Patients with cardiac disease resulting in marked limitation of physical activity. They are comfortable at rest. Less than ordinary activity causes fatigue, palpitation, dyspnea, or anginal pain.

Class IV

Patients with cardiac disease resulting in inability to carry on any physical activity without discomfort. Symptoms of heart failure or the anginal syndrome may be present even at rest. If any physical activity is undertaken, discomfort is increased.

Indicates conditions that can also lead to heart failure with a preserved ejection fraction.

however, in the presence of underlying structural heart disease, these conditions can lead to overt HF.

Global Considerations Rheumatic heart disease remains a major cause of HF in Africa and Asia, especially in the young. Hypertension is an important cause of HF in the African and African-American populations. Chagas’ disease is still a major cause of HF in South America. Not surprisingly, anemia is a frequent concomitant factor in HF in many developing nations. As developing nations undergo socioeconomic development, the epidemiology of HF is becoming similar to that of Western Europe and North America, with CAD

Source: Adapted from New York Heart Association, Inc., Diseases of the Heart and Blood Vessels: Nomenclature and Criteria for Diagnosis, 6th ed. Boston, Little Brown, 1964, p. 114.

Heart Failure and Cor Pulmonale

Functional Capacity

High-Output States Metabolic disorders

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CHAPTER 17

Pulmonary Heart Disease

emerging as the single most common cause of HF. Although the contribution of diabetes mellitus to HF is not well understood, diabetes accelerates atherosclerosis and often is associated with hypertension.

Pathogenesis

SECTION IV

Figure 17-1 provides a general conceptual framework for considering the development and progression of HF with a depressed EF. As shown, HF may be viewed as a progressive disorder that is initiated after an index event either damages the heart muscle, with a resultant loss of functioning cardiac myocytes, or, alternatively, disrupts the ability of the myocardium to generate force, thereby preventing the heart from contracting normally. This index event may have an abrupt onset, as in the case of a myocardial infarction (MI); it may have a gradual or insidious onset, as in the case of hemodynamic pressure or volume overloading; or it may be hereditary, as in the case of many of the genetic cardiomyopathies. Regardless of the nature of the inciting event, the feature that is common to each of these index events is that they all in some manner produce a decline in the pumping capacity of the heart. In most instances, patients remain asymptomatic or minimally symptomatic after the initial decline in pumping capacity of the heart or develop symptoms only after the dysfunction has been present for some time. Although the precise reasons why patients with LV dysfunction may remain asymptomatic is not certain,

Inde x ev ent

Compensatory mechanisms

Disorders of the Heart

60% Ejection fraction

184

Secondary damage

20% Time, years Asymptomatic

Symptomatic

Figure 17-1 Pathogenesis of heart failure with a depressed ejection fraction. Heart failure begins after an index event produces an initial decline in the heart’s pumping capacity. After this initial decline in pumping capacity, a variety of compensatory mechanisms are activated, including the adrenergic nervous system, the renin-angiotensin-aldosterone system, and the cytokine system. In the short term, these systems are able to restore cardiovascular function to a normal homeostatic range with the result that the patient remains asymptomatic. However, with time the sustained activation of these systems can lead to secondary end-organ damage within the ventricle, with worsening left ventricular remodeling and subsequent cardiac decompensation. (From D Mann: Circulation 100:999, 1999.)

one potential explanation is that a number of compensatory mechanisms become activated in the presence of cardiac injury and/or LV dysfunction allowing patients to sustain and modulate LV function for a period of months to years. The list of compensatory mechanisms that have been described thus far include (1) activation of the renin-angiotensin-aldosterone (RAA) and adrenergic nervous systems, which are responsible for maintaining cardiac output through increased retention of salt and water (Fig. 17-2), and (2) increased myocardial contractility. In addition, there is activation of a family of countervailing vasodilatory molecules, including the atrial and brain natriuretic peptides (ANP and BNP), prostaglandins (PGE2 and PGI2), and nitric oxide (NO), that offsets the excessive peripheral vascular vasoconstriction. Genetic background, sex, age, or environment may influence these compensatory mechanisms, which are able to modulate LV function within a physiologic/ homeostatic range so that the functional capacity of the patient is preserved or is depressed only minimally. Thus, patients may remain asymptomatic or minimally symptomatic for a period of years; however, at some point patients become overtly symptomatic, with a resultant striking increase in morbidity and mortality rates. Although the exact mechanisms that are responsible for this transition are not known, as will be discussed later in this chapter, the transition to symptomatic HF is accompanied by increasing activation of neurohormonal, adrenergic, and cytokine systems that lead to a series of adaptive changes within the myocardium collectively referred to as LV remodeling. In contrast to our understanding of the pathogenesis of HF with a depressed EF, our understanding of the mechanisms that contribute to the development of HF with a preserved EF is still evolving. That is, although diastolic dysfunction (see later in this chapter) was thought to be the only mechanism responsible for the development of HF with a preserved EF, communitybased studies suggest that additional extracardiac mechanisms may be important, such as increased vascular stiffness and impaired renal function.

Basic Mechanisms of Heart Failure Systolic dysfunction LV remodeling develops in response to a series of complex events that occur at the cellular and molecular levels (Table 17-3). These changes include (1) myocyte hypertrophy, (2) alterations in the contractile properties of the myocyte, (3) progressive loss of myocytes through necrosis, apoptosis, and autophagic cell death, (4) β-adrenergic desensitization, (5) abnormal myocardial energetics and metabolism, and (6) reorganization of the extracellular matrix with dissolution of the

Baroreceptor dysfunction

Table 17-3 Afferent inhibitory signals

Renin secretion

Alterations in Myocyte Biology Excitation-contraction coupling Myosin heavy chain (fetal) gene expression β-adrenergic desensitization Hypertrophy Myocytolysis Cytoskeletal proteins

Vasomotor center

Sympathetic nervous system activity

185

Overview of Left Ventricular Remodeling

Myocardial Changes Vasopressin secretion

Angiotensin II

Myocyte loss Necrosis Apoptosis Autophagy Alterations in Extracellular Matrix Matrix degradation Myocardial fibrosis Alterations in Left Ventricular Chamber Geometry Left ventricular (LV) dilation Increased LV sphericity LV wall thinning Mitral valve incompetence

organized structural collagen weave surrounding myocytes and subsequent replacement by an interstitial collagen matrix that does not provide structural support to the myocytes. The biologic stimuli for these profound changes include mechanical stretch of the myocyte, circulating neurohormones (e.g., norepinephrine, angiotensin II), inflammatory cytokines (e.g., tumor necrosis factor [TNF]), other peptides and growth factors (e.g., endothelin), and reactive oxygen species (e.g., superoxide). The sustained overexpression of these biologically active molecules is believed to contribute to the progression of HF by virtue of the deleterious effects they exert on the heart and circulation. Indeed, this insight forms the clinical rationale for using pharmacologic agents that antagonize these systems (e.g., angiotensin-converting enzyme [ACE] inhibitors and beta blockers) in treating patients with HF. In order to understand how the changes that occur in the failing cardiac myocyte contribute to depressed LV systolic function in HF, it is instructive first to review the biology of the cardiac muscle cell (Chap. 1). Sustained neurohormonal activation and mechanical overload result in transcriptional and posttranscriptional changes in the genes and proteins that regulate excitation-contraction coupling and cross-bridge interaction (see Figs. 1-6 and 1-7). The changes that regulate excitation-contraction include decreased function

Heart Failure and Cor Pulmonale

Figure 17-2 Activation of neurohormonal systems in heart failure. The decreased cardiac output in HF patients results in an “unloading” of high-pressure baroceptors (circles) in the left ventricle, carotid sinus, and aortic arch. This unloading of the peripheral baroreceptors leads to a loss of inhibitory parasympathetic tone to the central nervous system (CNS), with a resultant generalized increase in efferent sympathetic tone, and nonosmotic release of arginine vasopressin (AVP) from the pituitary. AVP (or antidiuretic hormone [ADH]) is a powerful vasoconstrictor that increases the permeability of the renal collecting ducts, leading to the reabsorption of free water. These afferent signals to the CNS also activate efferent sympathetic nervous system pathways that innervate the heart, kidney, peripheral vasculature, and skeletal muscles. Sympathetic stimulation of the kidney leads to the release of renin, with a resultant increase in the circulating levels of angiotensin II and aldosterone. The activation of the reninangiotensin-aldosterone system promotes salt and water retention and leads to vasoconstriction of the peripheral vasculature, myocyte hypertrophy, myocyte cell death, and myocardial fibrosis. Although these neurohormonal mechanisms facilitate shortterm adaptation by maintaining blood pressure, and hence perfusion to vital organs, the same neurohormonal mechanisms are believed to contribute to end-organ changes in the heart and the circulation and to the excessive salt and water retention in advanced HF. (Modified from A Nohria et al: Neurohormonal, renal and vascular adjustments, in Atlas of Heart Failure: Cardiac Function and Dysfunction, 4th ed, WS Colucci [ed]. Philadelphia, Current Medicine Group 2002, p. 104.)

Source: Adapted from D Mann: Pathophysiology of heart failure, in Braunwald’s Heart Disease, 8th ed, PL Libby et al (eds). Philadelphia, Elsevier, 2008, p. 550.

CHAPTER 17

Limb blood flow

Renal blood flow Aldosterone Sodium reabsorption H2O reabsorption

186

of sarcoplasmic reticulum Ca2+ adenosine triphosphatase (SERCA2A), resulting in decreased calcium uptake into the sarcoplasmic reticulum (SR), and hyperphosphorylation of the ryanodine receptor, leading to calcium leakage from the SR. The changes that occur in the cross-bridges include decreased expression of α-myosin heavy chain and increased expression of β-myosin heavy chain, myocytolysis, and disruption of the cytoskeletal links between the sarcomeres and the extracellular matrix. Collectively, these changes impair the ability of the myocyte to contract and therefore contribute to the depressed LV systolic function observed in patients with HF.

(1) hypoperfusion of the subendocardium, with resultant worsening of LV function, (2) increased oxidative stress, with the resultant activation of families of genes that are sensitive to free radical generation (e.g., TNF and interleukin 1β), and (3) sustained expression of stretchactivated genes (angiotensin II, endothelin, and TNF) and/or stretch activation of hypertrophic signaling pathways. Increasing LV dilation also results in tethering of the papillary muscles with resulting incompetence of the mitral valve apparatus and functional mitral regurgitation, which in turn leads to further hemodynamic overloading of the ventricle. Taken together, the mechanical burdens that are engendered by LV remodeling contribute to the progression of HF.

Diastolic dysfunction

SECTION IV Disorders of the Heart

Myocardial relaxation is an adenosine triphosphate (ATP)-dependent process that is regulated by uptake of cytoplasmic calcium into the SR by SERCA2A and extrusion of calcium by sarcolemmal pumps (see Fig. 1-7). Accordingly, reductions in ATP concentration, as occurs in ischemia, may interfere with these processes and lead to slowed myocardial relaxation. Alternatively, if LV filling is delayed because LV compliance is reduced (e.g., from hypertrophy or fibrosis), LV filling pressures will similarly remain elevated at end diastole (see Fig. 1-11). An increase in heart rate disproportionately shortens the time for diastolic filling, which may lead to elevated LV filling pressures, particularly in noncompliant ventricles. Elevated LV end-diastolic filling pressures result in increases in pulmonary capillary pressures, which can contribute to the dyspnea experienced by patients with diastolic dysfunction. In addition to impaired myocardial relaxation, increased myocardial stiffness secondary to cardiac hypertrophy and increased myocardial collagen content may contribute to diastolic failure. Importantly, diastolic dysfunction can occur alone or in combination with systolic dysfunction in patients with HF. Left ventricular remodeling Ventricular remodeling refers to the changes in LV mass, volume, and shape and the composition of the heart that occur after cardiac injury and/or abnormal hemodynamic loading conditions. LV remodeling may contribute independently to the progression of HF by virtue of the mechanical burdens that are engendered by the changes in the geometry of the remodeled LV. In addition to the increase in LV end-diastolic volume, LV wall thinning occurs as the left ventricle begins to dilate. The increase in wall thinning, along with the increase in afterload created by LV dilation, leads to a functional afterload mismatch that may contribute further to a decrease in stroke volume. Moreover, the high end-diastolic wall stress might be expected to lead to

Clinical Manifestations Symptoms The cardinal symptoms of HF are fatigue and shortness of breath. Although fatigue traditionally has been ascribed to the low cardiac output in HF, it is likely that skeletal-muscle abnormalities and other noncardiac comorbidities (e.g., anemia) also contribute to this symptom. In the early stages of HF, dyspnea is observed only during exertion; however, as the disease progresses, dyspnea occurs with less strenuous activity, and it ultimately may occur even at rest. The origin of dyspnea in HF is probably multifactorial (Chap. 5). The most important mechanism is pulmonary congestion with accumulation of interstitial or intraalveolar fluid, which activates juxtacapillary J receptors, which in turn stimulate the rapid, shallow breathing characteristic of cardiac dyspnea. Other factors that contribute to dyspnea on exertion include reductions in pulmonary compliance, increased airway resistance, respiratory muscle and/or diaphragm fatigue, and anemia. Dyspnea may become less frequent with the onset of right ventricular (RV) failure and tricuspid regurgitation. Orthopnea

Orthopnea, which is defined as dyspnea occurring in the recumbent position, is usually a later manifestation of HF than is exertional dyspnea. It results from redistribution of fluid from the splanchnic circulation and lower extremities into the central circulation during recumbency, with a resultant increase in pulmonary capillary pressure. Nocturnal cough is a common manifestation of this process and a frequently overlooked symptom of HF. Orthopnea generally is relieved by sitting upright or sleeping with additional pillows. Although orthopnea is a relatively specific symptom of HF, it may occur in patients with abdominal obesity or ascites and patients with pulmonary disease whose lung mechanics favor an upright posture.

Paroxysmal nocturnal dyspnea (PND)

This term refers to acute episodes of severe shortness of breath and coughing that generally occur at night and awaken the patient from sleep, usually 1–3 h after the patient retires. PND may be manifest by coughing or wheezing, possibly because of increased pressure in the bronchial arteries leading to airway compression, along with interstitial pulmonary edema that leads to increased airway resistance. Whereas orthopnea may be relieved by sitting upright at the side of the bed with the legs in a dependent position, patients with PND often have persistent coughing and wheezing even after they have assumed the upright position. Cardiac asthma is closely related to PND, is characterized by wheezing secondary to bronchospasm, and must be differentiated from primary asthma and pulmonary causes of wheezing. Cheyne-Stokes respiration

Other symptoms Patients with HF also may present with gastrointestinal symptoms. Anorexia, nausea, and early satiety associated with abdominal pain and fullness are common complaints and may be related to edema of the bowel wall and/or a congested liver. Congestion of the liver and stretching of its capsule may lead to right-upperquadrant pain. Cerebral symptoms such as confusion, disorientation, and sleep and mood disturbances may be observed in patients with severe HF, particularly elderly patients with cerebral arteriosclerosis and reduced cerebral perfusion. Nocturia is common in HF and may contribute to insomnia.

Physical Examination A careful physical examination is always warranted in the evaluation of patients with HF. The purpose of the examination is to help determine the cause of HF as

General appearance and vital signs In mild or moderately severe HF, the patient appears to be in no distress at rest except for feeling uncomfortable when lying flat for more than a few minutes. In more severe HF, the patient must sit upright, may have labored breathing, and may not be able to finish a sentence because of shortness of breath. Systolic blood pressure may be normal or high in early HF, but it generally is reduced in advanced HF because of severe LV dysfunction. The pulse pressure may be diminished, reflecting a reduction in stroke volume. Sinus tachycardia is a nonspecific sign caused by increased adrenergic activity. Peripheral vasoconstriction leading to cool peripheral extremities and cyanosis of the lips and nail beds is also caused by excessive adrenergic activity. Jugular veins (See also Chap. 9) Examination of the jugular veins provides an estimation of right atrial pressure. The jugular venous pressure is best appreciated with the patient lying recumbent, with the head tilted at 45°. The jugular venous pressure should be quantified in centimeters of water (normal ≤8 cm) by estimating the height of the venous column of blood above the sternal angle in centimeters and then adding 5 cm. In the early stages of HF, the venous pressure may be normal at rest but may become abnormally elevated with sustained (∼1 min) pressure on the abdomen (positive abdominojugular reflux). Giant v waves indicate the presence of tricuspid regurgitation. Pulmonary examination Pulmonary crackles (rales or crepitations) result from the transudation of fluid from the intravascular space into the alveoli. In patients with pulmonary edema, rales may be heard widely over both lung fields and may be accompanied by expiratory wheezing (cardiac asthma). When present in patients without concomitant lung disease, rales are specific for HF. Importantly, rales are frequently absent in patients with chronic HF, even when LV filling pressures are elevated, because of increased lymphatic drainage of alveolar fluid. Pleural effusions result from the elevation of pleural capillary pressure and the resulting transudation of fluid into the pleural cavities. Since the pleural veins drain into both the systemic and the pulmonary veins, pleural

Heart Failure and Cor Pulmonale

Acute pulmonary edema

See Chap. 28.

187

CHAPTER 17

Also referred to as periodic respiration or cyclic respiration, Cheyne-Stokes respiration is present in 40% of patients with advanced HF and usually is associated with low cardiac output. Cheyne-Stokes respiration is caused by a diminished sensitivity of the respiratory center to arterial Pco2. There is an apneic phase, during which arterial Po2 falls and arterial Pco2 rises. These changes in the arterial blood gas content stimulate the depressed respiratory center, resulting in hyperventilation and hypocapnia, followed by recurrence of apnea. CheyneStokes respirations may be perceived by the patient or the patient’s family as severe dyspnea or as a transient cessation of breathing.

well as to assess the severity of the syndrome. Obtaining additional information about the hemodynamic profile and the response to therapy and determining the prognosis are important additional goals of the physical examination.

188

effusions occur most commonly with biventricular failure. Although pleural effusions are often bilateral in HF, when they are unilateral, they occur more frequently in the right pleural space. Cardiac examination

SECTION IV

Examination of the heart, although essential, frequently does not provide useful information about the severity of HF. If cardiomegaly is present, the point of maximal impulse (PMI) usually is displaced below the fifth intercostal space and/or lateral to the midclavicular line, and the impulse is palpable over two interspaces. Severe LV hypertrophy leads to a sustained PMI. In some patients, a third heart sound (S3) is audible and palpable at the apex. Patients with enlarged or hypertrophied right ventricles may have a sustained and prolonged left parasternal impulse extending throughout systole. An S3 (or protodiastolic gallop) is most commonly present in patients with volume overload who have tachycardia and tachypnea, and it often signifies severe hemodynamic compromise. A fourth heart sound (S4) is not a specific indicator of HF but is usually present in patients with diastolic dysfunction. The murmurs of mitral and tricuspid regurgitation are frequently present in patients with advanced HF. Abdomen and extremities

Disorders of the Heart

Hepatomegaly is an important sign in patients with HF. When it is present, the enlarged liver is frequently tender and may pulsate during systole if tricuspid regurgitation is present. Ascites, a late sign, occurs as a consequence of increased pressure in the hepatic veins and the veins draining the peritoneum. Jaundice, also a late finding in HF, results from impairment of hepatic function secondary to hepatic congestion and hepatocellular hypoxemia and is associated with elevations of both direct and indirect bilirubin. Peripheral edema is a cardinal manifestation of HF, but it is nonspecific and usually is absent in patients who have been treated adequately with diuretics. Peripheral edema is usually symmetric and dependent in HF and occurs predominantly in the ankles and the pretibial region in ambulatory patients. In bedridden patients, edema may be found in the sacral area (presacral edema) and the scrotum. Long-standing edema may be associated with indurated and pigmented skin. Cardiac cachexia With severe chronic HF, there may be marked weight loss and cachexia. Although the mechanism of cachexia is not entirely understood, it is probably multifactorial and includes elevation of the resting metabolic

rate; anorexia, nausea, and vomiting due to congestive hepatomegaly and abdominal fullness; elevation of circulating concentrations of cytokines such as TNF; and impairment of intestinal absorption due to congestion of the intestinal veins. When present, cachexia augurs a poor overall prognosis.

Diagnosis The diagnosis of HF is relatively straightforward when the patient presents with classic signs and symptoms of HF; however, the signs and symptoms of HF are neither specific nor sensitive. Accordingly, the key to making the diagnosis is to have a high index of suspicion, particularly for high-risk patients. When these patients present with signs or symptoms of HF, additional laboratory testing should be performed. Routine laboratory testing Patients with new-onset HF and those with chronic HF and acute decompensation should have a complete blood count, a panel of electrolytes, blood urea nitrogen, serum creatinine, hepatic enzymes, and a urinalysis. Selected patients should have assessment for diabetes mellitus (fasting serum glucose or oral glucose tolerance test), dyslipidemia (fasting lipid panel), and thyroid abnormalities (thyroid-stimulating hormone level). Electrocardiogram (ECG) A routine 12-lead ECG is recommended. The major importance of the ECG is to assess cardiac rhythm and determine the presence of LV hypertrophy or a prior MI (presence or absence of Q waves) as well as to determine QRS width to ascertain whether the patient may benefit from resynchronization therapy (see later). A normal ECG virtually excludes LV systolic dysfunction. Chest x-ray A chest x-ray provides useful information about cardiac size and shape, as well as the state of the pulmonary vasculature, and may identify noncardiac causes of the patient’s symptoms. Although patients with acute HF have evidence of pulmonary hypertension, interstitial edema, and/or pulmonary edema, the majority of patients with chronic HF do not. The absence of these findings in patients with chronic HF reflects the increased capacity of the lymphatics to remove interstitial and/or pulmonary fluid. Assessment of LV function Noninvasive cardiac imaging (Chap. 12) is essential for the diagnosis, evaluation, and management of

Circulating levels of natriuretic peptides are useful adjunctive tools in the diagnosis of patients with HF. Both B-type natriuretic peptide (BNP) and N-terminal pro-BNP, which are released from the failing heart, are relatively sensitive markers for the presence of HF with depressed EF; they also are elevated in HF patients with a preserved EF, albeit to a lesser degree. However, it is important to recognize that natriuretic peptide levels increase with age and renal impairment, are more elevated in women, and can be elevated in right HF from any cause. Levels can be falsely low in obese patients and may normalize in some patients after appropriate treatment. At present, serial measurements of BNP are not recommended as a guide to HF therapy. Other biomarkers, such as troponin T and I, C-reactive protein, TNF receptors, and uric acid, may be elevated in HF and provide important prognostic information. Serial measurements of one or more biomarkers ultimately may help guide therapy in HF, but they are not currently recommended for this purpose.

189

Treadmill or bicycle exercise testing is not routinely advocated for patients with HF, but either is useful for assessing the need for cardiac transplantation in patients with advanced HF (Chap. 18). A peak oxygen uptake (Vo2) 30–50%). Both atria are enlarged, sometimes massively. Modest left ventricular dilation can be present, usually with an end-diastolic dimension 1500 eos/mm3 for at least 6 months can cause an acute phase of eosinophilic injury in the endocardium, with systemic illness and injury to other organs. There is usually no obvious cause, but the hypereosinophilia can occasionally be explained by allergic, parasitic, or malignant disease. It is postulated to be followed by a period in which cardiac inflammation is replaced by evidence of fibrosis with superimposed thrombosis. In severe disease, the dense fibrotic layer can obliterate the ventricular apices and extend to thicken and tether the atrioventricular valve leaflets. The clinical disease may present with heart failure, embolic events, and atrial arrhythmias. While plausible, the sequence of transition has not been clearly demonstrated. In tropical countries, up to one-quarter of heart failure may be due to endomyocardial fibrosis, affecting either or both ventricles. This condition shares with the previous condition the partial obliteration of the ventricular apex with fibrosis extending into the valvular inflow tract and leaflets; however, it is not clear that the etiologies are the same for all cases. Pericardial effusions frequently accompany endomyocardial fibrosis but are not common in Löffler’s endocarditis. For endomyocardial fibrosis, there is no gender difference, but a higher prevalence in African-American populations. While tropical endomyocardial fibrosis could represent the end stage of previous hypereosinophilic disease triggered by endemic parasites, neither prior parasitic infection nor hypereosinophilia is usually documented. Geographic nutritional deficiencies have also been proposed as an etiology. Medical treatment focuses on glucocorticoids and chemotherapy to suppress hypereosinophilia when present. Fluid retention may become increasingly resistant to diuretic therapy. Anticoagulation is recommended. Atrial fibrillation is associated with worse symptoms and prognosis, but may be difficult to suppress. Surgical resection of the apices and replacement of the fibrotic valves can improve symptoms, but surgical morbidity and mortality and later recurrence rates are high. The serotonin secreted by carcinoid tumors can produce fibrous plaques in the endocardium and rightsided cardiac valves, occasionally affecting left-sided valves, as well. Valvular lesions may be stenotic or regurgitant. Systemic symptoms include flushing and diarrhea. Liver disease from hepatic metastases may play a role by limiting hepatic function and thereby allowing more serotonin to reach the venous circulation.

Hypertrophic Cardiomyopathy Hypertrophic cardiomyopathy is characterized by marked left ventricular hypertrophy in the absence of other causes, such as hypertension or valve disease (Figs. 21-14 and 21-15). The systolic function as measured by

269

Tricuspid valve

Mitral valve

LV RV free wall

Septum MV

LV free wall RV Chamber LV Chamber

IVS

Figure 21-15 Hypertrophic cardiomyopathy. This echocardiogram of hypertrophic cardiomyopathy shows asymmetric hypertrophy of the septum compared to the lateral wall of the left ventricle (LV). The mitral valve is moving anteriorly toward the hypertrophied septum in systole. The left atrium (LA) is enlarged. Note that the echocardiographic and pathologic images are vertically opposite, such that the LV is by convention on the top right in the echocardiographic image and bottom right in the pathologic images. (Image courtesy of Justina Wu, MD, Brigham and Women’s Hospital, Boston.)

characterized genetic cardiomyopathy, for which more than 400 individual mutations have been identified in 11 sarcomeric genes. More than 80% of the mutations are in the beta-myosin heavy chain, the cardiac myosinbinding protein C, or cardiac troponin T. Some families may demonstrate a higher incidence of early progression to end-stage heart failure or death, suggesting that their mutations are more “malignant.” However, the heterogeneity of phenotypic expression within and between families confirms the influence of modifying factors from other genes and the environment. Hypertrophic cardiomyopathy is characterized hemo dynamically by diastolic dysfunction, originally attributed to the hypertrophy, fibrosis, and intraventricular gradient when present. However, studies of asymptomatic family members indicate that diastolic dysfunction is a more fundamental abnormality that can precede evidence of hypertrophy. Resting ejection fraction and cardiac output are usually normal, but peak cardiac

Cardiomyopathy and Myocarditis

ejection fraction is often supranormal, at times with virtual obliteration of the left ventricular cavity during systole. The hypertrophy may be asymmetric, involving the septum more than the free wall of the ventricle. Approximately one-third of symptomatic patients demonstrate a resting intraventricular gradient that impedes outflow during systole and is exacerbated by increased contractility. This was previously termed hypertrophic obstructive cardiomyopathy (HOCM), as distinguished from nonobstructive hypertrophic cardiomyopathy. Other terms that have been used include asymmetric septal hypertrophy (ASH) and idiopathic hypertrophic subaortic stenosis (IHSS). However, the accepted terminology is now hypertrophic cardiomyopathy with or without an obstructive gradient. Classically, the microscopic picture shows marked disarray of individual fibers in a characteristic whorled pattern and disarray, also at the level of the larger bundles, interspersed with fibrosis (Fig. 21-16). The prevalence of hypertrophic cardiomyopathy is 1:500 adults. Approximately one-half of these cases occur in a recognizable autosomal dominant pattern, and spontaneous mutations also arise. This is the best

CHAPTER 21

Figure 21-14 Hypertrophic cardiomyopathy. Gross specimen of a heart with hypertrophic cardiomyopathy removed at the time of transplantation, showing asymmetric septal hypertrophy (septum much thicker than left ventricular free wall) with the septum bulging into the left ventricular outflow tract causing obstruction. The forceps are retracting the anterior leaflet of the mitral valve, demonstrating the characteristic plaque of systolic anterior motion, manifest as endocardial fibrosis on the interventricular septum in a mirror-image pattern to the valve leaflet. There is patchy replacement fibrosis, and small thick walled arterioles can be appreciated grossly, especially in the interventricular septum. IVS, interventricular septum; LV, left ventricle; RV, right ventricle. (Image courtesy of Robert Padera, MD, PhD, Department of Pathology, Brigham and Women’s Hospital, Boston.)

270

Figure 21-16 Hypertrophic cardiomyopathy. Microscopic image of hypertrophic cardiomyopathy showing the characteristic disordered myocyte architecture with swirling and branching rather than the usual parallel arrangement of myocyte fibers. Myocyte nuclei vary markedly in size and interstitial fibrosis is present. (Image courtesy of Robert Padera, MD, PhD, Department of Pathology, Brigham and Women’s Hospital, Boston.)

Section IV

output during exercise may be reduced due to inadequate ventricular filling at high heart rates.

Diagnosis

Disorders of the Heart

Hypertrophic cardiomyopathy usually presents between the ages of 20 and 40 years. Dyspnea on exertion is the most common presenting symptom, reflecting elevated intracardiac filling pressures. Chest pain with either an atypical or typical exertional pattern occurs in more than half of symptomatic patients and is attributed to myocardial ischemia from high demand and abnormal intramural coronary arteries in the hypertrophied myocardium. Palpitations may result from atrial fibrillation or ventricular arrhythmias. Much less common are episodes of presyncope or syncope, often related to heavy exertion. Of grave concern is the possibility that the first manifestation of disease may be sudden death from ventricular tachycardia or fibrillation. Hypertrophic cardiomyopathy is the most common lesion found at autopsy of young athletes dying suddenly. The physical examination typically reveals a harsh murmur heard best at the left lower sternal border, arising from both the outflow tract turbulence during ventricular ejection and the commonly associated mitral regurgitation. The gradient and the murmur may be enhanced by maneuvers that decrease ventricular volume, such as the Valsalva maneuver, or standing after squatting. They may be decreased by increasing ventricular volume or vascular resistance, such as with squatting

or hand grip. A fourth heart sound is commonly heard due to decreased ventricular compliance. In patients with a significant outflow tract gradient, palpation of the carotid pulse may reveal a bifid systolic impulse, from early and delayed ejection. Patients with chronic, severe elevations in filling pressures may show signs of systemic fluid retention. The electrocardiogram usually shows left ventricular hypertrophy, often with prominent septal Q waves that can be misdiagnosed as indicative of infarction. The diagnosis of hypertrophic cardiomyopathy is confirmed by echocardiography demonstrating left ventricular hypertrophy, which may or may not be more marked in the septum (Fig. 21-15). Intraventricular gradients to outflow can be identified by Doppler echocardiography at rest or during provocative maneuvers, such as the Valsalva maneuver. Systolic anterior motion (SAM) of the mitral valve is a classic finding on the echocardiogram. Mitral regurgitation may become severe. Cardiac catheterization can be performed to quantify the gradient, which characteristically increases after a premature ventricular contraction. Apical hypertrophic cardiomyopathy is a variant that is uncommon in the United States; however, this variant accounts for about one-fourth of patients with hypertrophic cardiomyopathy in Japan. The electrocardiogram shows deep T-wave inversions in the precordial leads, and the echocardiogram shows a characteristic spade-like appearance with apical obliteration. It has been associated with a specific genetic defect in cardiac actin (Glu 101 Lys), but may occur with other sarcomere mutations. The differential diagnosis of hypertrophic cardiomyopathy is limited in most patients once other cardiovascular causes for secondary hypertrophy are excluded. However, other diseases that result in thickened myocardium can appear indistinguishable on echocardiography, and are considered “pseudohypertrophic,” particularly the inherited metabolic diseases (Table 21-4). The differential diagnosis between hypertrophic and restrictive cardiomyopathy may be particularly difficult when considering a diagnosis of “burned-out” hypertrophic cardiomyopathy in which systolic function has decreased. Overlap with infiltrative and restrictive myocardial diseases should be considered in the evaluation of increased left ventricular wall thickness on echocardiography, particularly when clinical features are atypical for classic hypertrophic cardiomyopathy. The metabolic defects in PRKAG2, alpha-galactosidase (Fabry’s disease), and LAMP2 mutations (Tables 21-3 and 21-4) should routinely be considered during evaluation of apparent hypertrophic cardiomyopathy. With late onset without a family history of hypertrophic cardiomyopathy, amyloidosis should be carefully considered.

Treatment

Hypertrophic Cardiomyopathy

will usually be necessary, but requires careful titration to avoid hypovolemia, particularly in the presence of a resting or inducible obstruction to ventricular outflow. When symptoms persist and an outflow gradient is present, addition of disopyramide is sometimes effective. Amiodarone can also improve symptoms, but is usually initiated for control of arrhythmias rather than symptoms. Anticoagulation is recommended to prevent embolic events for patients who have had atrial fibrillation. Symptoms that limit routine daily life despite adjustment of medical therapies develop in fewer than 5–10% of patients, generally those with substantial obstruction to ventricular outflow. Further therapies are directed to reduce this obstruction by changing ventricular

Therapy of hypertrophic cardiomyopathy is directed to symptom management and the prevention of sudden death (Fig. 21-17); it is not known whether treatment will decrease disease progression in asymptomatic family members. Exertional dyspnea and chest pain are treated by medication to reduce heart rate and ventricular contractility with hopes of improving diastolic filling patterns. Beta-adrenergic blocking drugs and verapamil are most commonly used as initial therapy. These agents both act to decrease heart rate and increase the length of time for diastolic filling, as well as to decrease the inotropic state. If there is fluid retention, diuretic therapy

271

Hypertrophic cardiomyopathy

In all pts, evaluate risk for sudden death

Symptomatic? Yes

If low follow with serial evaluation

Evidence of fluid retention? Yes

Titrate beta blocker or calcium channel blocker

Persistent symptoms

Outflow gradient?

No Evidence of severe progressive LV dysfunction?

Reevaluate cause of symptoms

Yes Try disopyramide or amiodarone

Yes Rarely, consider cardiac transplantation

Refractory severe symptoms Consider procedure

Septal ablation

Mitral surgery

Figure 21-17

Treatment algorithm for hypertrophic cardiomyopathy depending on the presence and severity of symptoms, and the presence of an intraventricular gradient with obstruction to outflow. Note that all patients with

hypertrophic cardiomyopathy should be evaluated for risk of sudden death, whether or not they require treatment for symptoms. ICD, implantable cardioverter-defibrillator; LV, left ventricular.

Cardiomyopathy and Myocarditis

Use diuretics with caution to avoid hypovolemia, particularly in presence of outflow gradient

CHAPTER 21

If high, consider ICD

272

Table 21-7 Risk Factors for Sudden Death in Hypertrophic Cardiomyopathy Major Risk Factor

Screening Technique

History of cardiac arrest or spontaneous sustained ventricular tachycardia

History

Syncope

Usually with or after exertion

History

Family history of sudden cardiac death

Or possibly with a documented gene mutation associated with high risk

Family history

Spontaneous nonsustained ventricular tachycardia

>3 beats at rate >120

Exercise or 24–48 h ambulatory recording

LV thickness >30 mm

Present in about 10% of patients, but many sudden deaths occur with wall thickness 30 mm, recurrent syncope, exerciseinduced hypotension, and nonsustained ventricular tachycardia are also risk factors. Areas of ventricular fibrosis detected on MRI may further identify susceptibility to life-threatening arrhythmias. Implantable cardioverter-defibrillators should be considered for those at highest risk (Table 21-7). Although lowrisk patients can engage in regular physical activity with casual intent, it has been recommended that all patients with hypertrophic cardiomyopathy avoid intense training and competition.

ChaPter 22

PERICARDIAL DISEASE Eugene Braunwald often absent in slowly developing tuberculous, postirradiation, neoplastic, and uremic pericarditis. The pain of acute pericarditis is often severe, retrosternal and left precordial, and referred to the neck, arms, or left shoulder. Often the pain is pleuritic, consequent to accompanying pleural inflammation (i.e., sharp and aggravated by inspiration and coughing), but sometimes it is a steady, constricting pain that radiates into either arm or both arms and resembles that of myocardial ischemia; therefore, confusion with acute myocardial infarction (AMI) is common. Characteristically, however, pericardial pain may be relieved by sitting up and leaning forward and is intensified by lying supine. The differentiation of AMI from acute pericarditis becomes perplexing when, with acute pericarditis, serum biomarkers of myocardial damage such as creatine kinase and troponin rise, presumably because of concomitant involvement of the epicardium in the inflammatory process (an epi-myocarditis) with resulting myocyte necrosis. However, these elevations, if they occur, are quite modest given the extensive electrocardiographic ST-segment elevation in pericarditis. This dissociation is useful in differentiating between these conditions. 2. A pericardial friction rub is audible in about 85% of these patients, may have up to three components per cardiac cycle, is high pitched, and is described as rasping, scratching, or grating (Chap. 9); it can be elicited sometimes when the diaphragm of the stethoscope is applied firmly to the chest wall at the left lower sternal border. It is heard most frequently at end expiration with the patient upright and leaning forward. The rub is often inconstant, and the

normal funCtions of the PeriCardium The normal pericardium is a double-layered sac; the visceral pericardium is a serous membrane that is separated by a small quantity (15–50 mL) of fluid, an ultrafiltrate of plasma, from the fibrous parietal pericardium. The normal pericardium, by exerting a restraining force, prevents sudden dilation of the cardiac chambers, especially the right atrium and ventricle, during exercise and with hypervolemia. It also restricts the anatomic position of the heart, minimizes friction between the heart and surrounding structures, prevents displacement of the heart and kinking of the great vessels, and probably retards the spread of infections from the lungs and pleural cavities to the heart. Nevertheless, total absence of the pericardium, either congenital or after surgery, does not produce obvious clinical disease. In partial left pericardial defects, the main pulmonary artery and left atrium may bulge through the defect; very rarely, herniation and subsequent strangulation of the left atrium may cause sudden death.

aCute PeriCarditis Acute pericarditis, by far the most common pathologic process involving the pericardium, may be classified both clinically and etiologically (Table 22-1). There are four principal diagnostic features: 1. Chest pain is an important but not invariable symptom in various forms of acute pericarditis (Chap. 4); it is usually present in the acute infectious types and in many of the forms presumed to be related to hypersensitivity or autoimmunity. Pain is

273

274

Table 22-1 Classification of Pericarditis Clinical Classification

I. Acute pericarditis (6 months) A. Constrictive B. Effusive C. Adhesive (nonconstrictive) Etiologic Classification

SECTION IV

I. Infectious pericarditis A. Viral (coxsackievirus A and B, echovirus, mumps, adenovirus, hepatitis, HIV) B. Pyogenic (pneumococcus, streptococcus, staphylococcus, Neisseria, Legionella) C. Tuberculous D. Fungal (histoplasmosis, coccidioidomycosis, Candida, blastomycosis) E. Other infections (syphilitic, protozoal, parasitic) II. Noninfectious pericarditis A. Acute myocardial infarction B. Uremia C. Neoplasia 1. Primary tumors (benign or malignant, mesothelioma) 2. Tumors metastatic to pericardium (lung and breast cancer, lymphoma, leukemia) D. Myxedema E. Cholesterol F. Chylopericardium G. Trauma 1. Penetrating chest wall 2. Nonpenetrating H. Aortic dissection (with leakage into pericardial sac) I. Postirradiation J. Familial Mediterranean fever K. Familial pericarditis 1. Mulibrey nanisma L. Acute idiopathic M. Whipple’s disease N. Sarcoidosis III. Pericarditis presumably related to hypersensitivity or autoimmunity A. Rheumatic fever B. Collagen vascular disease (systemic lupus erythematosus, rheumatoid arthritis, ankylosing spondylitis, scleroderma, acute rheumatic fever, granulomatosis with polyangiitis (Wegener’s) C. Drug-induced (e.g., procainamide, hydralazine, phenytoin, isoniazide, minoxidil, anticoagulants, methysergide) D. Post-cardiac injury 1. Postmyocardial infarction (Dressler’s syndrome) 2. Postpericardiotomy 3. Posttraumatic

Disorders of the Heart a

An autosomal recessive syndrome characterized by growth failure, muscle hypotonia, hepatomegaly, ocular changes, enlarged cerebral ventricles, mental retardation, ventricular hypertrophy, and chronic constrictive pericarditis.

loud to-and-fro leathery sound may disappear within a few hours, possibly to reappear on the next day. A pericardial rub is heard throughout the respiratory cycle, whereas a pleural rub disappears when respiration is suspended. 3. The electrocardiogram (ECG) in acute pericarditis without massive effusion usually displays changes secondary to acute subepicardial inflammation (Fig. 22-1). It typically evolves through four stages. In stage 1, there is widespread elevation of the ST segments, often with upward concavity, involving two or three standard limb leads and V2 to V6, with reciprocal depressions only in aVR and sometimes V1, as well as depression of the PR segment below the TP segment reflecting atrial involvement. Usually, there are no significant changes in QRS complexes. In stage 2, after several days, the ST segments return to normal, and only then, or even later, do the T waves become inverted (stage 3). Ultimately, weeks or months after the onset of acute pericarditis, the ECG returns to normal in stage 4. In contrast, in AMI, ST elevations are convex, and reciprocal depression is usually more prominent; QRS changes occur, particularly the development of Q waves, as well as notching and loss of R-wave amplitude, and T-wave inversions are usually seen within hours before the ST segments have become isoelectric. Sequential ECGs are useful in distinguishing acute pericarditis from AMI. In the latter, elevated ST segments return to normal within hours (Chaps. 34 and 35). Early repolarization is a normal variant and may also be associated with widespread ST-segment elevation, most prominent in left precordial leads. However, in this condition the T waves are usually tall and the ST/T ratio is 2000 mL in slowly developing effusions when the pericardium has had the opportunity to stretch and adapt to an increasing volume. Tamponade may also develop more slowly, and in these circ*mstances the clinical manifestations may resemble those of heart failure, including dyspnea, orthopnea, and hepatic engorgement. A high index of suspicion for cardiac tamponade is required since in many instances no obvious cause for pericardial disease is apparent, and it should be considered in any patient with otherwise unexplained enlargement of the cardiac silhouette, hypotension, and elevation of jugular venous pressure. There may be reduction in amplitude of the QRS complexes, and electrical alternans of the P, QRS, or T waves should raise the suspicion of cardiac tamponade. Table 22-2 lists the features that distinguish acute cardiac tamponade from constrictive pericarditis. Paradoxical pulse This important clue to the presence of cardiac tamponade consists of a greater than normal (10 mmHg) inspiratory decline in systolic arterial pressure. When severe, it may be detected by palpating weakness or disappearance of the arterial pulse during inspiration, but usually sphygmomanometric measurement of systolic pressure during slow respiration is required. Since both ventricles share a tight incompressible covering, i.e., the pericardial sac, the inspiratory enlargement of the right ventricle in cardiac tamponade compresses and reduces left ventricular volume; leftward bulging of the interventricular septum further reduces the left ventricular cavity as the right ventricle enlarges during inspiration. Thus, in cardiac tamponade the normal inspiratory augmentation of right ventricular volume causes an exaggerated reciprocal reduction in left ventricular volume. Also, respiratory distress increases the fluctuations in intrathoracic pressure, which exaggerates the mechanism just described. Right ventricular infarction (Chap. 35) may resemble cardiac tamponade with hypotension, elevated jugular venous pressure, an absent y descent in the jugular venous pulse, and, occasionally, pulsus paradoxus. The differences between these two conditions are shown in Table 22-2. Paradoxical pulse occurs not only in cardiac tamponade but also in approximately one-third of patients with constrictive pericarditis (see later). This physical finding is not pathognomonic of pericardial disease because it may be observed in some cases of hypovolemic shock,

Table 22-2

277

Features That Distinguish Cardiac Tamponade from Constrictive Pericarditis and Similar Clinical Disorders Tamponade

Constrictive Pericarditis

Restrictive Cardiomyopathy

RVMI

Common

Usually absent

Rare

Prominent y descent

Absent

Usually present

Rare

Prominent x descent

Present

Usually present

Present

Rare

Kussmaul’s sign

Absent

Present

Third heart sound

Absent

Rare

May be present

Pericardial knock

Absent

Often present

Absent

Low ECG voltage

May be present

Absent

Electrical alternans

May be present

Absent

Thickened pericardium

Absent

Present

Absent

Pericardial calcification

Absent

Often present

Absent

Pericardial effusion

Present

Absent

RV size

Usually small

Usually normal

Enlarged

Myocardial thickness

Normal

Usually increased

Normal

Right atrial collapse and RVDC

Present

Absent

Increased early filling, ↑ mitral flow velocity

Absent

Present

May be present

Exaggerated respiratory variation in flow velocity

Present

Absent

Present

Absent

Equalization of diastolic pressures

Usually present

Usually absent

Absent or present

Cardiac biopsy helpful?

Sometimes

Characteristic

Clinical Pulsus paradoxus Jugular veins

Electrocardiogram

Echocardiography

Cardiac catheterization

Abbreviations: ECG, electrocardiograph; RV, right ventricle; RVDC, right ventricular diastolic collapse; RVMI, right ventricular myocardial infarction. Source: From GM Brockington et al: Cardiol Clin 8:645, 1990; with permission.

acute and chronic obstructive airway disease, and pulmonary embolus. Low-pressure tamponade refers to mild tamponade in which the intrapericardial pressure is increased from its slightly subatmospheric levels to +5 to +10 mmHg; in some instances, hypovolemia coexists. As a consequence, the central venous pressure is normal or only slightly elevated, whereas arterial pressure is unaffected and there is no paradoxical pulse. These patients are asymptomatic or complain of mild weakness and

dyspnea. The diagnosis is aided by echocardiography, and both hemodynamic and clinical manifestations improve after pericardiocentesis. Diagnosis Since immediate treatment of cardiac tamponade may be lifesaving, prompt measures to establish the diagnosis by echocardiography should be undertaken (Fig.22-3). When pericardial effusion causes tamponade, Doppler

Pericardial Disease

Thickened/calcific pericardium

CHAPTER 22

CT/MRI

278

ultrasound shows that tricuspid and pulmonic valve flow velocities increase markedly during inspiration, whereas pulmonic vein, mitral, and aortic flow velocities diminish. Often the right ventricular cavity is reduced in diameter, and there is late diastolic inward motion (collapse) of the right ventricular free wall and the right atrium. Transesophageal echocardiography may be necessary to diagnose a loculated or hemorrhagic effusion responsible for cardiac tamponade. treatment

Cardiac Tamponade

Patients with acute pericarditis should be observed frequently for the development of an effusion; if a large effusion is present, the patient should be hospitalized and pericardiocentesis carried out or the patient should be watched closely for signs of tamponade. Arterial and venous pressures and heart rate should be monitored or followed carefully, and serial echocardiograms obtained. Pericardiocentesis If manifestations of tam-

SECTION IV Disorders of the Heart

ponade appear, echocardiographically or fluoroscopically guided pericardiocentesis using an apical, parasternal, or, most commonly, subxiphoid approach must be carried out at once as reduction of the elevated intrapericardial pressure may be lifesaving. Intravenous saline may be administered as the patient is being readied for the procedure, but the pericardiocentesis must not be delayed. If possible, intrapericardial pressure should be measured before fluid is withdrawn, and the pericardial cavity should be drained as completely as possible. A small, multiholed catheter advanced over the needle inserted into the pericardial cavity may be left in place to allow draining of the pericardial space if fluid reaccumulates. Surgical drainage through a limited (subxiphoid) thoracotomy may be required in recurrent tamponade, when it is necessary to remove loculated effusions, and/or when it is necessary to obtain tissue for diagnosis. Pericardial fluid obtained from an effusion often has the physical characteristics of an exudate. Bloody fluid is most commonly due to neoplasm in the United States and tuberculosis in developing nations but may also be found in the effusion of acute rheumatic fever, postcardiac injury, and postmyocardial infarction, as well as in the pericarditis associated with renal failure or dialysis. Transudative pericardial effusions may occur in heart failure. The pericardial fluid should be analyzed for red and white blood cells, and cytologic studies for cancer, microscopic studies, and cultures should be obtained. The presence of DNA of Mycobacterium tuberculosis determined by polymerase chain reaction or an elevated adenosine deaminase activity (>30 U/L) strongly supports the diagnosis of tuberculous pericarditis.

Viral or Idiopathic Form of Acute Pericarditis In many instances, acute pericarditis occurs in association with illnesses of known or presumed viral origin and probably is caused by the same agent. Commonly, there is an antecedent infection of the respiratory tract, and viral isolation and serologic studies are negative. In some cases, coxsackievirus A or B or the virus of influenza, echovirus, mumps, herpes simplex, chickenpox, adenovirus, cytomegalovirus, Epstein-Barr, or HIV has been isolated from pericardial fluid and/or appropriate elevations in viral antibody titers have been noted. Pericardial effusion is a common cardiac manifestation of HIV; it is usually secondary to infection (often mycobacterial) or neoplasm, most frequently lymphoma. Most frequently, a viral causation cannot be established; the term idiopathic acute pericarditis is then appropriate. Viral or idiopathic acute pericarditis occurs at all ages but is more common in young adults and is often associated with pleural effusions and pneumonitis. The almost simultaneous development of fever and precordial pain, often 10 to 12 days after a presumed viral illness, constitutes an important feature in the differentiation of acute pericarditis from AMI, in which chest pain precedes fever. The constitutional symptoms are usually mild to moderate, and a pericardial friction rub is often audible. The disease ordinarily runs its course in a few days to 4 weeks. The ST-segment alterations in the ECG usually disappear after 1 or more weeks, but the abnormal T waves may persist for several years and be a source of confusion in persons without a clear history of pericarditis. Pleuritis and pneumonitis frequently accompany pericarditis. Accumulation of some pericardial fluid is common, and both tamponade and constrictive pericarditis are possible complications. Recurrent (relapsing) pericarditis occurs in about one-fourth of patients with acute idiopathic pericarditis. In a smaller number, there are multiple recurrences. treatment

Idiopathic Acute Pericarditis

In acute idiopathic pericarditis there is no specific therapy, but bed rest and anti-inflammatory treatment with aspirin (2–4 g/d) may be given. If this is ineffective, one of the nonsteroidal anti-inflammatory drugs (NSAIDs), such as ibuprofen (400–600 mg tid), indomethacin (25– 50 mg tid), or colchicine (0.6 mg bid), is often effective. Glucocorticoids (e.g., prednisone, 40–80 mg daily) usually suppress the clinical manifestations of the acute illness and may be useful in patients in whom purulent bacterial pericarditis has been excluded and in patients with pericarditis secondary to connective tissue disorders and renal failure (see later). Anticoagulants

should be avoided since their use could cause bleeding into the pericardial cavity and tamponade. After the patient has been asymptomatic and afebrile for about a week, the dose of the NSAID may be tapered gradually. Colchicine may prevent recurrences, but when recurrences are multiple, frequent, and disabling; continued beyond 2 years; and are not controlled by glucocorticoids, pericardiectomy may be necessary to terminate the illness.

Postcardiac injury syndrome

Since there is no specific test for acute idiopathic pericarditis, the diagnosis is one of exclusion. Consequently, all other disorders that may be associated with acute fibrinous pericarditis must be considered. A common diagnostic error is mistaking acute viral or idiopathic

Pericardial Disease

Differential Diagnosis

279

CHAPTER 22

Acute pericarditis may appear in a variety of circ*mstances that have one common feature: previous injury to the myocardium with blood in the pericardial cavity. The syndrome may develop after a cardiac operation (postpericardiotomy syndrome), after blunt or penetrating cardiac trauma (Chap. 23), or after perforation of the heart with a catheter. Rarely, it follows AMI. The clinical picture mimics acute viral or idiopathic pericarditis. The principal symptom is the pain of acute pericarditis, which usually develops 1 to 4 weeks after the cardiac injury (1 to 3 days after AMI) but sometimes appears only after an interval of months. Recurrences are common and may occur up to 2 years or more after the injury. Pericarditis, fever with temperature up to 39°C (102.2°F), pleuritis, and pneumonitis are the outstanding features, and the bout of illness usually subsides in 1 or 2 weeks. The pericarditis may be of the fibrinous variety, or it may be a pericardial effusion, which is often serosanguineous but rarely causes tamponade. Leukocytosis, an increased sedimentation rate, and ECG changes typical of acute pericarditis may also occur. This syndrome is probably the result of a hypersensitivity reaction to antigen that originates from injured myocardial tissue and/or pericardium. Circulating myocardial antisarcolemmal and antifibrillar autoantibodies occur frequently, but their precise role in the development of this syndrome has not been defined. Viral infection may also play an etiologic role, since antiviral antibodies are often elevated in patients who develop this syndrome after cardiac surgery. Often no treatment is necessary aside from aspirin and analgesics. When the illness is followed by a series of disabling recurrences, therapy with an NSAID, colchicine, or a glucocorticoid is usually effective.

pericarditis for AMI and vice versa. When acute fibrinous pericarditis is associated with AMI (Chap. 35), it is characterized by fever, pain, and a friction rub in the first 4 days after the development of the infarct. ECG abnormalities (such as the appearance of Q waves, brief ST-segment elevations with reciprocal changes, and earlier T-wave changes in AMI) and the extent of the elevations of myocardial enzymes are helpful in differentiating pericarditis from AMI. Pericarditis secondary to postcardiac injury is differentiated from acute idiopathic pericarditis chiefly by timing. If it occurs within a few days or weeks of an AMI, a chest blow, a cardiac perforation, or a cardiac operation, it may be justified to conclude that the two are probably related. It is important to distinguish pericarditis due to collagen vascular disease from acute idiopathic pericarditis. Most important in the differential diagnosis is the pericarditis due to systemic lupus erythematosus (SLE) or druginduced (procainamide or hydralazine) lupus. When pericarditis occurs in the absence of any obvious underlying disorder, the diagnosis of SLE may be suggested by a rise in the titer of antinuclear antibodies. Acute pericarditis is an occasional complication of rheumatoid arthritis, scleroderma, and polyarteritis nodosa, and other evidence of these diseases is usually obvious. Asymptomatic pericardial effusion is also common in these disorders. The pericarditis of acute rheumatic fever is generally associated with evidence of severe pancarditis and with cardiac murmurs (Chap. 26). Pyogenic (purulent) pericarditis is usually secondary to cardiothoracic operations, by extension of infection from the lungs or pleural cavities, from rupture of the esophagus into the pericardial sac, or from rupture of a ring abscess in a patient with infective endocarditis, or it can occur if septicemia complicates aseptic pericarditis. It is usually accompanied by fever, chills, septicemia, and evidence of infection elsewhere and generally has a poor prognosis. The diagnosis is made by examination of the pericardial fluid. Acute pericarditis may also complicate the viral, pyogenic, mycobacterial, and fungal infections that occur with HIV infection. Pericarditis of renal failure occurs in up to one-third of patients with chronic uremia (uremic pericarditis), is also seen in patients undergoing chronic dialysis with normal levels of blood urea and creatinine, and is termed dialysis-associated pericarditis. These two forms of pericarditis may be fibrinous and are generally associated with an effusion that may be sanguineous. A pericardial friction rub is common, but pain is usually absent or mild. Treatment with an NSAID and intensification of dialysis are usually adequate. Occasionally, tamponade occurs and pericardiocentesis is required. When the pericarditis of renal failure is recurrent or persistent, a pericardial window should be created or pericardiectomy may be necessary.

280

Pericarditis due to neoplastic diseases results from extension or invasion of metastatic tumors (most commonly carcinoma of the lung and breast, malignant melanoma, lymphoma, and leukemia) to the pericardium; pain, atrial arrhythmias, and tamponade are complications that occur occasionally. Diagnosis is made by pericardial fluid cytology or pericardial biopsy. Mediastinal irradiation for neoplasm may cause acute pericarditis and/or chronic constrictive pericarditis. Unusual causes of acute pericarditis include syphilis, fungal infection (histoplasmosis, blastomycosis, aspergillosis, and candidiasis), and parasitic infestation (amebiasis, toxoplasmosis, echinococcosis, trichinosis).

Chronic Pericardial Effusions Chronic pericardial effusions are sometimes encountered in patients without an antecedent history of acute pericarditis. They may cause few symptoms per se, and their presence may be detected by finding an enlarged cardiac silhouette on chest roentgenogram. Tuberculosis is a common cause.

SECTION IV

Other causes

Disorders of the Heart

Myxedema may be responsible for chronic pericardial effusion that is sometimes massive but rarely, if ever, causes cardiac tamponade. The cardiac silhouette is markedly enlarged, and an echocardiogram distinguishes cardiomegaly from pericardial effusion. The diagnosis of myxedema can be confirmed by tests for thyroid function. Myxedematous pericardial effusion responds to thyroid hormone replacement. Neoplasms, systemic lupus erythematosus (SLE), rheumatoid arthritis, mycotic infections, radiation therapy to the chest, pyogenic infections, and chylopericardium may also cause chronic pericardial effusion and should be considered and specifically sought in such patients. Aspiration and analysis of the pericardial fluid are often helpful in diagnosis. Pericardial fluid should be analyzed as described earlier. Grossly sanguineous pericardial fluid results most commonly from a neoplasm, tuberculosis, renal failure, or slow leakage from an aortic aneurysm. Pericardiocentesis may resolve large effusions, but pericardiectomy may be required with recurrence. Intrapericardial instillation of sclerosing agents or antineoplastic agents may be used to prevent reaccumulation of fluid.

Chronic Constrictive Pericarditis This disorder results when the healing of an acute fibrinous or serofibrinous pericarditis or the resorption

of a chronic pericardial effusion is followed by obliteration of the pericardial cavity with the formation of granulation tissue. The latter gradually contracts and forms a firm scar, which may be calcified, encasing the heart and interfering with filling of the ventricles. In developing nations where the condition is prevalent, a high percentage of cases are of tuberculous origin, but this is now an uncommon cause in North America. Chronic constrictive pericarditis may follow acute or relapsing viral or idiopathic pericarditis, trauma with organized blood clot, cardiac surgery of any type, mediastinal irradiation, purulent infection, histoplasmosis, neoplastic disease (especially breast cancer, lung cancer, and lymphoma), rheumatoid arthritis, SLE, and chronic renal failure with uremia treated by chronic dialysis. In many patients the cause of the pericardial disease is undetermined, and in them an asymptomatic or forgotten bout of viral pericarditis, acute or idiopathic, may have been the inciting event. The basic physiologic abnormality in patients with chronic constrictive pericarditis is the inability of the ventricles to fill because of the limitations imposed by the rigid, thickened pericardium. In constrictive pericarditis, ventricular filling is unimpeded during early diastole but is reduced abruptly when the elastic limit of the pericardium is reached, whereas in cardiac tamponade, ventricular filling is impeded throughout diastole. In both conditions, ventricular end-diastolic and stroke volumes are reduced and the end-diastolic pressures in both ventricles and the mean pressures in the atria, pulmonary veins, and systemic veins are all elevated to similar levels (i.e., within 5 mmHg of one another). Despite these hemodynamic changes, myocardial function may be normal or only slightly impaired in chronic constrictive pericarditis. However, the fibrotic process may extend into the myocardium and cause myocardial scarring and atrophy, and venous congestion may then be due to the combined effects of the pericardial and myocardial lesions. In constrictive pericarditis, the right and left atrial pressure pulses display an M-shaped contour, with prominent x and y descents. The y descent, which is absent or diminished in cardiac tamponade, is the most prominent deflection in constrictive pericarditis; it reflects rapid early filling of the ventricles. The y descent is interrupted by a rapid rise in atrial pressure during early diastole, when ventricular filling is impeded by the constricting pericardium. These characteristic changes are transmitted to the jugular veins, where they may be recognized by inspection. In constrictive pericarditis, the ventricular pressure pulses in both ventricles exhibit characteristic “square root” signs during diastole. These hemodynamic changes, although characteristic, are not pathognomonic of constrictive pericarditis and may also be observed in cardiomyopathies characterized by restriction of ventricular filling (Chap. 21) (Table 22-2).

Clinical and Laboratory Findings

281

Differential Diagnosis

Inspiration E A

Septum

Expiration E

Septum A

MV RV

Doppler transvalvular inflow patterns Thickened pericardium

Pulmonary vein

LA DIASTOLE

DIASTOLE

IVC and hepatic veins Apical 4-chamber views

Figure 22-5 Constrictive pericarditis. Doppler schema of respirophasic changes in mitral and tricuspid inflow. Reciprocal patterns of ventricular filling are assessed on pulsed Doppler examination of mitral valve (MV) and tricuspid valve (TV) inflow. (Courtesy of Bernard E. Bulwer, MD; with permission.)

Pericardial Disease

Like chronic constrictive pericarditis, cor pulmonale (Chap. 17) may be associated with severe systemic venous hypertension but little pulmonary congestion; the heart is usually not enlarged, and a paradoxical pulse may be present. However, in cor pulmonale, advanced parenchymal pulmonary disease is usually obvious and venous pressure falls during inspiration (i.e., Kussmaul’s sign is negative). Tricuspid stenosis (Chap. 20) may also simulate chronic constrictive pericarditis; congestive hepatomegaly, splenomegaly, ascites, and venous distention may be equally prominent. However, in tricuspid stenosis, a characteristic murmur as well as the murmur of accompanying mitral stenosis is usually present. Because constrictive pericarditis can be corrected surgically, it is important to distinguish chronic

CHAPTER 22

Weakness, fatigue, weight gain, increased abdominal girth, abdominal discomfort, a protuberant abdomen, and edema are common. The patient often appears chronically ill, and in advanced cases there are anasarca, skeletal muscle wasting, and cachexia. Exertional dyspnea is common, and orthopnea may occur, although it is usually not severe. Acute left ventricular failure (acute pulmonary edema) is very uncommon. The cervical veins are distended and may remain so even after intensive diuretic treatment, and venous pressure may fail to decline during inspiration (Kussmaul’s sign). The latter is common in chronic pericarditis but may also occur in tricuspid stenosis, right ventricular infarction, and restrictive cardiomyopathy. The pulse pressure is normal or reduced. In about one-third of cases, a paradoxical pulse can be detected. Congestive hepatomegaly is pronounced and may impair hepatic function and cause jaundice; ascites is common and is usually more prominent than dependent edema. The apical pulse is reduced and may retract in systole (Broadbent’s sign). The heart sounds may be distant; an early third heart sound (i.e., a pericardial knock, occurring at the cardiac apex 0.09–0.12 s after aortic valve closure) is often conspicuous; it occurs with the abrupt cessation of ventricular filling. A systolic murmur of tricuspid regurgitation may be present. The ECG frequently displays low voltage of the QRS complexes and diffuse flattening or inversion of the Twaves. Atrial fibrillation is present in about one-third of patients. The chest roentgenogram shows a normal or slightly enlarged heart; pericardial calcification is most common in tuberculous pericarditis. Pericardial calcification may, however, occur in the absence of constriction. Inasmuch as the usual physical signs of cardiac disease (murmurs, cardiac enlargement) may be inconspicuous or absent in chronic constrictive pericarditis, hepatic enlargement and dysfunction associated with jaundice and intractable ascites may lead to a mistaken diagnosis of hepatic cirrhosis. This error can be avoided if the neck veins are inspected carefully in patients with ascites and hepatomegaly. Given a clinical picture resembling hepatic cirrhosis, but with the added feature of distended neck veins, a careful search for thickening of the pericardium by imaging (see Fig. 12-6) should be carried out and may disclose this curable or remediable form of heart disease. The transthoracic echocardiogram typically shows pericardial thickening, dilation of the inferior vena cava and hepatic veins, and a sharp halt in ventricular filling in early diastole, with normal ventricular systolic function and flattening of the left ventricular posterior wall. Atrial enlargement may be seen, especially in patients with long-standing constrictive physiology. There is a distinctive pattern of transvalvular flow velocity on

Doppler flow-velocity echocardiography. During inspiration there is an exaggerated reduction in blood flow velocity in the pulmonary veins and across the mitral valve and a leftward shift of the ventricular septum; the opposite occurs during expiration. Diastolic flow velocity in the vena cavae into the right atrium and across the tricuspid valve increases in an exaggerated manner during inspiration and declines during expiration (Fig.22-5). However, echocardiography cannot definitively exclude the diagnosis of constrictive pericarditis. MRI and CT scanning (Fig. 22-6) are more accurate than echocardiography in establishing or excluding the presence of a thickened pericardium. Pericardial thickening and even pericardial calcification, however, are not synonymous with constrictive pericarditis since they may occur without seriously impairing ventricular filling.

282

Figure 22-6 Cardiovascular magnetic resonance in a patient with constrictive pericarditis. On the right is a basal short-axis view of the ventricles showing a thickened pericardium encasing the heart (arrows). On the left is a transaxial view, again showing the thickened pericardium, particularly over

SECTION IV Disorders of the Heart

constrictive pericarditis from restrictive cardiomyopathy (Chap. 21), which has a similar physiologic abnormality (i.e., restriction of ventricular filling). In many patients with restrictive cardiomyopathy the ventricular wall is thickened as shown on echocardiographic examination (Table 22-2). The features favoring the diagnosis of restrictive cardiomyopathy over chronic constrictive pericarditis include a well-defined apex beat, cardiac enlargement, and pronounced orthopnea with attacks of acute left ventricular failure, left ventricular hypertrophy, gallop sounds (in place of a pericardial knock), bundle branch block, and, in some cases, abnormal Q waves on the ECG. The typical echocardiographic features of constrictive pericarditis (see earlier) are useful in the differential diagnosis in chronic constrictive pericarditis (Fig. 22-5). CT imaging (usually with contrast) and MRI are key in distinguishing between restrictive cardiomyopathy and chronic constrictive pericarditis. In the former, the ventricular walls are hypertrophied, whereas in the latter, the pericardium is thickened and sometimes calcified. When a patient has progressive, disabling, and unresponsive congestive heart failure and displays any of the features of constrictive heart disease, Doppler echocardiography to record respiratory effects on transvalvular flow and an MRI or CT scan should be obtained to detect or exclude constrictive pericarditis, since the latter is usually curable. treatment

Constrictive Pericarditis

Pericardial resection is the only definitive treatment of constrictive pericarditis and should be as complete as possible. Dietary sodium restriction and diuretics

the right heart, but also a pleural effusion (Pl Eff). LV, left ventricle; RV, right ventricle. (From D Pennell: Cardiovascular Magnetic Resonance, in P Libby et al [eds]: Braunwald’s Heart Disease, 8th ed. Philadelphia, Elsevier, 2005.)

are useful during preoperative preparation. Coronary arteriography should be carried out preoperatively in patients older than 50 years of age to exclude unsuspected coronary artery disease. The benefits derived from cardiac decortication are usually progressive over a period of months. The risk of this operation depends on the extent of penetration of the myocardium by the fibrotic and calcific process, the severity of myocardial atrophy, the extent of secondary impairment of hepatic and/or renal function, and the patient’s general condition. Operative mortality is in the range of 5% to 10%; the patients with the most severe disease are at highest risk. Therefore, surgical treatment should, if possible, be carried out relatively early in the course.

Subacute effusive-constrictive pericarditis This form of pericardial disease is characterized by the combination of a tense effusion in the pericardial space and constriction of the heart by thickened pericardium. It shares a number of features both with chronic pericardial effusion producing cardiac compression and with pericardial constriction. It may be caused by tuberculosis (see later), multiple attacks of acute idiopathic pericarditis, radiation, traumatic pericarditis, renal failure, scleroderma, and neoplasms. The heart is generally enlarged, and a paradoxical pulse and a prominent x descent (without a prominent y descent) are present in the atrial and jugular venous pressure pulses. After pericardiocentesis, the physiologic findings may change from those of cardiac tamponade to those of pericardial constriction. Furthermore, the intrapericardial pressure and the central venous pressure may decline, but not to normal. The diagnosis can be established by pericardiocentesis followed by pericardial biopsy.

Wide excision of both the visceral and parietal pericardium is usually effective therapy.

constriction should be treated surgically while the patient is receiving antituberculous chemotherapy.

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Tuberculous pericardial disease This chronic infection is a common cause of chronic pericardial effusion, although less so in the United States than in Africa, Asia, the Middle East, and other parts of the developing world where active tuberculosis is endemic. The clinical picture is that of a chronic, systemic illness in a patient with pericardial effusion. It is important to consider this diagnosis in a patient with known tuberculosis, with HIV, and with fever, chest pain, weight loss, and enlargement of the cardiac silhouette of undetermined origin. If the etiology of chronic pericardial effusion remains obscure despite detailed analysis of the pericardial fluid (see earlier), a pericardial biopsy, preferably by a limited thoracotomy, should be performed. If definitive evidence is still lacking but the specimen shows granulomas with caseation, antituberculous chemotherapy is indicated. If the biopsy specimen shows a thickened pericardium, pericardiectomy should be carried out to prevent the development of constriction. Tubercular cardiac

Other Disorders of the Pericardium Pericardial cysts appear as rounded or lobulated deformities of the cardiac silhouette, most commonly at the right cardiophrenic angle. They do not cause symptoms, and their major clinical significance lies in the possibility of confusion with a tumor, ventricular aneurysm, or massive cardiomegaly. Tumors involving the pericardium are most commonly secondary to malignant neoplasms originating in or invading the mediastinum, including carcinoma of the bronchus and breast, lymphoma, and melanoma. The most common primary malignant tumor is the mesothelioma. The usual clinical picture of malignant pericardial tumor is an insidiously developing, often bloody pericardial effusion. Surgical exploration is required to establish a definitive diagnosis and to carry out definitive or, more commonly, palliative treatment.

CHAPTER 22 Pericardial Disease

CHAPTER 23

TUMORS AND TRAUMA OF THE HEART Eric H. Awtry

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Wilson S. Colucci

TABLE 23-1

TUMORS OF THE HEART

RELATIVE INCIDENCE OF PRIMARY TUMORS OF THE HEART

PRIMARY TUMORS

TYPE

Primary tumors of the heart are rare. Approximately three-quarters are histologically benign, and the majority of these tumors are myxomas. Malignant tumors, almost all of which are sarcomas, account for 25% of primary cardiac tumors (Table 23-1). All cardiac tumors, regardless of pathologic type, have the potential to cause life-threatening complications. Many tumors are now surgically curable; thus, early diagnosis is imperative.

Benign

NUMBER

PERCENT

199

58.0

114

33.2

Rhabdomyoma

5.8

Fibroma

5.8

Hemangioma

5.0

Atrioventricular nodal

2.9

Granular cell

1.2

Lipoma

0.6

Clinical presentation

Paraganglioma

0.6

Cardiac tumors may present with a wide array of cardiac and noncardiac manifestations. These manifestations depend in large part on the location and size of the tumor and are often nonspecific features of more common forms of heart disease, such as chest pain, syncope, heart failure, murmurs, arrhythmias, conduction disturbances, and pericardial effusion with or without tamponade. Additionally, embolic phenomena and constitutional symptoms may occur.

Myocytic hamartoma

0.6

Histiocytoid cardiomyopathy

0.6

Myxoma

Inflammatory psuedotumor

0.6

Other benign tumors

1.2

Malignant

144

42.0

Sarcoma

137

39.9

2.1

Lymphoma

Myxoma

Source: Modified from A Burke, R Virmani: Atlas of Tumor Pathology: Tumors of the Heart and Great Vessels. Washington, DC, Armed Forces Institute of Pathology 1996, p. 231; with permission.

Myxomas are the most common type of primary cardiac tumor in all age groups, accounting for one-third to one-half of all cases at postmortem and about threequarters of the tumors treated surgically. They occur at all ages, most commonly in the third through sixth decades, with a female predilection. Approximately 90% of myxomas are sporadic; the remainder are familial with autosomal dominant transmission. The familial variety often occurs as part of a syndrome complex

(Carney complex) that includes (1) myxomas (cardiac, skin, and/or breast), (2) lentigines and/or pigmented nevi, and (3) endocrine overactivity (primary nodular adrenal cortical disease with or without Cushing’s syndrome, testicular tumors, and/or pituitary adenomas with gigantism or acromegaly). Certain constellations of findings have been referred to as the NAME syndrome (nevi, atrial myxoma, myxoid neurofibroma,

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erythrocyte sedimentation rate, thrombocytopenia, and thrombocytosis. These factors account for the frequent misdiagnosis of patients with myxomas as having endocarditis, collagen vascular disease, or a paraneoplastic syndrome. Two-dimensional transthoracic or omniplane transesophageal echocardiography is useful in the diagnosis of cardiac myxoma and allows assessment of tumor size and determination of the site of tumor attachment, both of which are important considerations in the planning of surgical excision (Fig. 23-1). CT and MRI may provide important information regarding size, shape, composition, and surface characteristics of the tumor (Fig. 23-2). Although cardiac catheterization and angiography were previously performed routinely before tumor resection, they no longer are considered mandatory when adequate noninvasive information is available and other cardiac disorders (e.g., coronary artery disease) are not considered likely. Additionally, catheterization of the chamber from which the tumor arises carries the risk of tumor embolization. Because myxomas may be familial, echocardiographic screening of first-degree relatives is appropriate, particularly if the patient is young and has multiple tumors or evidence of myxoma syndrome.

treatment

Myxoma

Figure 23-1 Transthoracic echocardiogram demonstrating a large atrial myxoma. The myxoma (Myx) fills the entire left atrium in systole (panel A) and prolapses across the mitral valve and into the left ventricle (LV) during diastole (panel B). RA, right atrium; RV, right ventricle. (Courtesy of Dr. Michael Tsang; with permission.)

Tumors and Trauma of the Heart

Surgical excision utilizing cardiopulmonary bypass is indicated regardless of tumor size and is generally curative. Myxomas recur in 12–22% of familial cases but in only 1–2% of sporadic cases. Tumor recurrence most likely is due to multifocal lesions in the former and inadequate resection in the latter.

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CHAPTER 23

and ephelides) or the LAMB syndrome (lentigines, atrial myxoma, and blue nevi), although these syndromes probably represent subsets of the Carney complex. The genetic basis of this complex has not been elucidated completely; however, patients frequently have inactivating mutations in the tumor-suppressor gene PRKAR1A, which encodes the protein kinase A type I-α regulatory subunit. Pathologically, myxomas are gelatinous structures that consist of myxoma cells embedded in a stroma rich in glycosaminoglycans. Most are solitary, are located in the atria (particularly the left atrium, where they usually arise from the interatrial septum in the vicinity of the fossa ovalis), and are often pedunculated on a fibrovascular stalk. In contrast to sporadic tumors, familial or syndromic tumors tend to occur in younger individuals, are often multiple, may be ventricular in location, and are more likely to recur after initial resection. Myxomas commonly present with obstructive signs and symptoms. The most common clinical presentation mimics that of mitral valve disease: either stenosis owing to tumor prolapse into the mitral orifice or regurgitation resulting from tumor-induced valvular trauma. Ventricular myxomas may cause outflow obstruction similar to that caused by subaortic or subpulmonic stenosis. The symptoms and signs of myxoma may be sudden in onset or positional in nature, owing to the effects of gravity on tumor position. A characteristic low-pitched sound, a “tumor plop,” may be appreciated on auscultation during early or mid-diastole and is thought to result from the impact of the tumor against the mitral valve or ventricular wall. Myxomas also may present with peripheral or pulmonary emboli or with constitutional signs and symptoms, including fever, weight loss, cachexia, malaise, arthralgias, rash, digital clubbing, Raynaud’s phenomenon, hypergammaglobulinemia, anemia, polycythemia, leukocytosis, elevated

disturbances and even sudden death as a result of their propensity to develop in the region of the AV node. Other benign tumors arising from the heart include teratoma, chemodectoma, neurilemoma, granular cell myoblastoma, and bronchogenic cysts.

286

Sarcoma

Figure 23-2 Cardiac MRI demonstrating a rounded mass (M) within the left atrium (LA). Pathologic evaluation at the time of surgery revealed it to be an atrial myxoma. LV, left ventricle; RA, right atrium; RV, right ventricle.

SECTION IV

Other benign tumors

Disorders of the Heart

Cardiac lipomas, although relatively common, are usually incidental findings at postmortem examination; however, they may grow as large as 15 cm and may present with symptoms owing to mechanical interference with cardiac function, arrhythmias, or conduction disturbances or as an abnormality of the cardiac silhouette on chest x-ray. Papillary fibroelastomas are the most common tumors of the cardiac valves. Although usually clinically silent, they can cause valve dysfunction and may embolize distally, resulting in transient ischemic attacks, stroke, or myocardial infarction. Therefore, these tumors should be resected even when asymptomatic. Rhabdomyomas and fibromas are the most common cardiac tumors in infants and children and usually occur in the ventricles, where they may produce mechanical obstruction to blood flow, thereby mimicking valvular stenosis, congestive heart failure (CHF), restrictive or hypertrophic cardiomyopathy, or pericardial constriction. Rhabdomyomas are probably hamartomatous growths, are multiple in 90% of cases, and are strongly associated with tuberous sclerosis. These tumors have a tendency to regress completely or partially; only tumors that cause obstruction require surgical resection. Fibromas are usually single, are often calcified, tend to grow and cause obstructive symptoms, and should be resected. Hemangiomas and mesotheliomas are generally small tumors, most often intramyocardial in location, and may cause atrioventricular (AV) conduction

Almost all primary cardiac malignancies are sarcomas, which may be of several histologic types. In general, these tumors are characterized by rapid progression that culminates in the patient’s death within weeks to months from the time of presentation as a result of hemodynamic compromise, local invasion, or distant metastases. Sarcomas commonly involve the right side of the heart, are characterized by rapid growth, frequently invade the pericardial space, and may obstruct the cardiac chambers or venae cavae. Sarcomas also may occur on the left side of the heart and may be mistaken for myxomas.

treatment

Sarcoma

At the time of presentation these tumors have often spread too extensively to allow for surgical excision. Although there are scattered reports of palliation with surgery, radiotherapy, and/or chemotherapy, the response of cardiac sarcomas to these therapies is generally poor. The one exception appears to be cardiac lymphosarcomas, which may respond to a combination of chemo- and radiotherapy.

Tumors Metastatic to the Heart Tumors metastatic to the heart are much more common than primary tumors, and their incidence is likely to increase as the life expectancy of patients with various forms of malignant neoplasms is extended by more effective therapy. Although cardiac metastases may occur with any tumor type, the relative incidence is especially high in malignant melanoma and, to a somewhat lesser extent, leukemia and lymphoma. In absolute terms, the most common primary originating sites of cardiac metastases are carcinoma of the breast and lung, reflecting the high incidence of those cancers. Cardiac metastases almost always occur in the setting of widespread primary disease, and most often there is either primary or metastatic disease elsewhere in the thoracic cavity. Nevertheless, cardiac metastasis occasionally may be the initial presentation of an extrathoracic tumor. Cardiac metastases may occur via hematogenous or lymphangitic spread or by direct tumor invasion. They generally manifest as small, firm nodules; diffuse infiltration also may occur, especially with sarcomas or

Tumors Metastatic to the Heart

Most patients with cardiac metastases have advanced malignant disease; thus, therapy is generally palliative and consists of treatment of the primary tumor. Symptomatic malignant pericardial effusions should be drained by pericardiocentesis. Concomitant instillation of a sclerosing agent (e.g., tetracycline) may delay or prevent reaccumulation of the effusion, and creation of a pericardial window allows drainage of the effusion to the pleural space.

Traumatic Cardiac Injury Traumatic cardiac injury may be caused by either penetrating or nonpenetrating trauma. Penetrating injuries most often result from gunshot or knife wounds, and the site of entry is usually obvious. Nonpenetrating injuries most often occur during motor vehicle accidents, either from a rapid deceleration injury or from impact of the chest against the steering wheel, and may be associated with significant cardiac injury even in the absence of external signs of thoracic trauma.

287

Tumors and Trauma of the Heart

treatment

Myocardial contusions are the most common form of nonpenetrating cardiac injury and may initially be overlooked in trauma patients as the clinical focus is directed toward other, more obvious injuries. Myocardial necrosis may occur as a direct result of the blunt injury or as a result of traumatic coronary laceration or thrombosis. The contused myocardium is pathologically similar to infarcted myocardium and may be associated with atrial or ventricular arrhythmias; conduction disturbances, including bundle branch block; or ECG abnormalities resembling those of infarction or pericarditis. Thus, it is important to consider contusion as a cause of otherwise unexplained ECG changes in a trauma patient. Serum creatine kinase, myocardial bound (CK-MB) isoenzyme levels are increased in ∼20% of patients who experience blunt chest trauma but may be falsely elevated in the presence of massive skeletal muscle injury. Cardiac troponin levels are more specific for identifying cardiac injury in this setting. Echocardiography is useful in detecting structural and functional sequelae of contusion, including wall motion abnormalities, pericardial effusion, valvular dysfunction, and ventricular rupture. Rupture of the cardiac valves or their supporting structures, most commonly of the tricuspid or mitral valve, leads to acute valvular incompetence. This complication is usually heralded by the development of a loud murmur, may be associated with rapidly progressive heart failure, and can be diagnosed by either transthoracic or transesophageal echocardiography. The most serious consequence of nonpenetrating cardiac injury is myocardial rupture, which may result in hemopericardium and tamponade (free wall rupture) or intracardiac shunting (ventricular septal rupture). Although it generally is fatal, up to 40% of patients with cardiac rupture have been reported to survive long enough to reach a specialized trauma center. Hemopericardium also may result from traumatic rupture of a pericardial vessel or a coronary artery. Additionally, a pericardial effusion may develop weeks or even months after blunt chest trauma as a manifestation of the postcardiac injury syndrome, which resembles the post-pericardiotomy syndrome (Chap. 22). Blunt, nonpenetrating, often innocent-appearing injuries to the chest may trigger ventricular fibrillation even in absence of overt signs of injury. This syndrome, referred to as commotio cordis, occurs most often in adolescents during sporting events (e.g., baseball, hockey, football, and lacrosse) and probably results from an impact to the chest wall overlying the heart during the susceptible phase of repolarization just before the peak of the T wave. Survival depends on prompt defibrillation. Rupture of the aorta, usually just above the aortic valve or at the site of the ligamentum arteriosum, is a common consequence of nonpenetrating chest trauma and is the most common vascular deceleration injury.

CHAPTER 23

hematologic neoplasms. The pericardium is most often involved, followed by myocardial involvement of any chamber and, rarely, by involvement of the endocardium or cardiac valves. Cardiac metastases are clinically apparent only ∼10% of the time, are usually not the cause of the patient’s presentation, and rarely are the cause of death. The vast majority occur in the setting of a previously recognized malignant neoplasm. When symptomatic, cardiac metastases may result in a variety of clinical features, including dyspnea, acute pericarditis, cardiac tamponade, ectopic tachyarrhythmias, heart block, and CHF. As with primary cardiac tumors, the clinical presentation reflects more the location and size of the tumor than its histologic type. Many of these signs and symptoms may also result from myocarditis, pericarditis, or cardiomyopathy induced by radiotherapy or chemotherapy. Electrocardiographic (ECG) findings are nonspecific. On chest x-ray, the cardiac silhouette is most often normal but may be enlarged or exhibit a bizarre contour. Echocardiography is useful for identifying pericardial effusions and visualizing larger metastases, although CT and radionuclide imaging with gallium or thallium may define the tumor burden more clearly. Cardiac MRI offers superb image quality and plays a central role in the diagnostic evaluation of cardiac metastases and cardiac tumors in general. Pericardiocentesis may allow for a specific cytologic diagnosis in patients with malignant pericardial effusions. Angiography is rarely necessary but may delineate discrete lesions.

288

SECTION IV Disorders of the Heart

The clinical presentation is similar to that of aortic dissection (Chap. 38); the arterial pressure and pulse amplitude may be increased in the upper extremities and decreased in the lower extremities, and chest x-ray may reveal mediastinal widening. Occasionally, aortic rupture is contained by the aortic adventitia, resulting in a false, or pseudo-, aneurysm that may be discovered months or years after the initial injury. Sudden emotional or physical trauma may precipitate a transient catecholamine-mediated cardiomyopathy referred to as Tako-Tsubo syndrome or the apical ballooning syndrome (Chap. 21). Penetrating injuries of the heart produced by knife or bullet wounds usually result in rapid clinical deterioration and frequently in death as a result of hemopericardium/pericardial tamponade or massive hemorrhage. Nonetheless, up to half of such patients may survive long enough to reach a specialized trauma center if immediate resuscitation is performed. Prognosis in these patients relates to the mechanism of injury, their clinical condition at presentation, and the specific cardiac chamber(s) involved. Iatrogenic cardiac or coronary arterial perforation may complicate placement of central venous or intracardiac catheters, pacemaker leads, or intracoronary stents and is associated with a better prognosis than are other forms of penetrating cardiac trauma. Traumatic rupture of a great vessel from penetrating injury is usually associated with hemothorax and, less often, hemopericardium. Local hematoma formation may compress major vessels and produce ischemic symptoms, and AV fistulas may develop, occasionally resulting in high-output CHF.

Occasionally, patients who survive penetrating cardiac injuries may subsequently present with a new cardiac murmur or CHF as a result of mitral regurgitation or an intracardiac shunt (i.e., ventricular or atrial septal defect, aortopulmonary fistula, or coronary AV fistula) that was undetected at the time of the initial injury or developed subsequently. Therefore, trauma patients should be examined carefully several weeks after the injury. If a mechanical complication is suspected, it can be confirmed by echocardiography or cardiac catheterization.

treatment

Traumatic Cardiac Injury

The treatment of an uncomplicated myocardial contusion is similar to the medical therapy for a myocardial infarction, except that anticoagulation is contraindicated, and should include monitoring for the development of arrhythmias and mechanical complications such as cardiac rupture (Chap. 35). Acute myocardial failure resulting from traumatic valve rupture usually requires urgent operative correction. Immediate thoracotomy should be carried out for most cases of penetrating injury or if there is evidence of cardiac tamponade and/or shock regardless of the type of trauma. Pericardiocentesis may be lifesaving in patients with tamponade but is usually only a temporizing measure while awaiting definitive surgical therapy. Pericardial hemorrhage often leads to constriction (Chap. 22), which must be treated by surgical decortication.

CHAPTER 24

CARDIAC MANIFESTATIONS OF SYSTEMIC DISEASE Eric H. Awtry

■

Wilson S. Colucci and probably have improved survival when treated with surgical bypass compared with PCI for multivessel CAD. Patients with diabetes mellitus also may have abnormal left ventricular systolic and diastolic function, reflecting concomitant epicardial CAD and/or hypertension, coronary microvascular disease, endothelial dysfunction, ventricular hypertrophy, and autonomic dysfunction. A restrictive cardiomyopathy may be present with abnormal myocardial relaxation and elevated ventricular filling pressures. Histologically, interstitial fibrosis is seen, and intramural arteries may demonstrate intimal thickening, hyaline deposition, and inflammatory changes. Diabetic patients have an increased risk of developing clinical heart failure, which probably contributes to their excessive cardiovascular morbidity and mortality rates. There is some evidence that insulin therapy may ameliorate diabetes-related myocardial dysfunction.

The common systemic disorders that have associated cardiac manifestations are summarized in Table 24-1.

DIABETES MELLITUS Diabetes mellitus, both insulin- and non-insulin-dependent, is an independent risk factor for coronary artery disease (CAD; Chap. 30) and accounts for 14–50% of new cases of cardiovascular disease. Furthermore, CAD is the most common cause of death in adults with diabetes mellitus. In the diabetic population the incidence of CAD relates to the duration of diabetes and the level of glycemic control, and its pathogenesis involves endothelial dysfunction, increased lipoprotein peroxidation, increased inflammation, a prothrombotic state, and associated metabolic abnormalities. Diabetic patients are more likely to have a myocardial infarction, have a greater burden of CAD, have larger infarct size, and have more postinfarct complications, including heart failure, shock, and death, than are nondiabetics. Importantly, diabetic patients are more likely to have atypical ischemic symptoms; nausea, dyspnea, pulmonary edema, arrhythmias, heart block, or syncope may be their anginal equivalent. Additionally, “silent ischemia,” resulting from autonomic nervous system dysfunction, is more common in diabetic patients, accounting for up to 90% of their ischemic episodes. Thus, one must have a low threshold for suspecting CAD in diabetic patients. The treatment of diabetic patients with CAD must include aggressive risk factor management. Pharmacologic therapy and revascularization are similar in diabetic patients and nondiabetics except that diabetic patients have higher morbidity and mortality rates associated with revascularization, have an increased risk of restenosis after percutaneous coronary intervention (PCI),

malnutrition anD Vitamin DefiCienCy Malnutrition In patients whose intake of protein, calories, or both is severely deficient, the heart may become thin, pale, and hypokinetic with myofibrillar atrophy and interstitial edema. The systolic pressure and cardiac output fall, and the pulse pressure narrows. Generalized edema is common and relates to a variety of factors, including reduced serum oncotic pressure and myocardial dysfunction. Such profound states of protein and calorie malnutrition, termed kwashiorkor and marasmus, respectively, are most common in underdeveloped countries. However, significant nutritional heart disease also may occur in developed nations, particularly in patients with chronic diseases such as AIDS, patients with

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Table 24-1 Common Systemic Disorders and Their Associated Cardiac Manifestations Systemic Disorder

Common Cardiac Manifestations

Diabetes mellitus Protein-calorie malnutrition Thiamine deficiency Hyperhom*ocysteinemia Obesity Hyperthyroidism Hypothyroidism Malignant carcinoid Pheochromocytoma Acromegaly Rheumatoid arthritis Seronegative arthropathies Systemic lupus erythematosus HIV Amyloidosis Sarcoidosis Hemochromatosis Marfan syndrome Ehlers-Danlos syndrome

CAD, atypical angina, CMP, systolic or diastolic CHF Dilated CMP, CHF High-output failure, dilated CMP Premature atherosclerosis CMP, systolic or diastolic CHF Palpitations, SVT, atrial fibrillation, hypertension Hypotension, bradycardia, dilated CMP, CHF, pericardial effusion Tricuspid and pulmonary valve disease, right heart failure Hypertension, palpitations, CHF Systolic or diastolic heart failure Pericarditis, pericardial effusions, coronary arteritis, myocarditis, valvulitis Aortitis, aortic and mitral insufficiency, conduction abnormalities Pericarditis, Libman-Sacks endocarditis, myocarditis, arterial and venous thrombosis Myocarditis, dilated CMP, pericardial effusion CHF, restrictive CMP, valvular regurgitation, pericardial effusion CHF, dilated or restrictive CMP, ventricular arrhythmias, heart block CHF, arrhythmias, heart block Aortic aneurysm and dissection, aortic insufficiency, mitral valve prolapse Aortic and coronary aneurysms, mitral and tricuspid valve prolapse

Abbreviations: CAD, coronary artery disease; CHF, congestive heart failure; CMP, cardiomyopathy; SVT, supraventricular tachycardia.

SECTION IV Disorders of the Heart

anorexia nervosa, and patients with severe cardiac failure in whom gastrointestinal hypoperfusion and venous congestion may lead to anorexia and malabsorption. Open-heart surgery poses increased risk in malnourished patients, and those patients may benefit from preoperative hyperalimentation. Thiamine deficiency (beriberi) Generalized malnutrition often is accompanied by thiamine deficiency; however, this hypovitaminosis also may occur in the presence of an adequate protein and caloric intake, particularly in the Far East, where polished rice deficient in thiamine may be a major dietary component. In Western nations where the use of thiamineenriched flour is widespread, clinical thiamine deficiency is limited primarily to alcoholics, food faddists, and patients receiving chemotherapy. Nonetheless, when thiamine stores are measured using the thiaminepyrophosphate effect (TPPE), thiamine deficiency has been found in 20–90% of patients with chronic heart failure. This deficiency appears to result from both reduced dietary intake and a diuretic-induced increase in the urinary excretion of thiamine. The acute administration of thiamine to these patients increases the left ventricular ejection fraction and the excretion of salt and water. Clinically, patients with thiamine deficiency usually have evidence of generalized malnutrition, peripheral neuropathy, glossitis, and anemia. The classic associated

cardiovascular syndrome is characterized by high-output heart failure, tachycardia, and often elevated biventricular filling pressures. The major cause of the high-output state is vasomotor depression leading to reduced systemic vascular resistance, the precise mechanism of which is not understood. The cardiac examination reveals a wide pulse pressure, tachycardia, a third heart sound, and, frequently, an apical systolic murmur. The electrocardiogram (ECG) may reveal decreased voltage, a prolonged QT interval, and T-wave abnormalities. The chest x-ray generally reveals cardiomegaly and signs of congestive heart failure (CHF). The response to thiamine is often dramatic, with an increase in systemic vascular resistance, a decrease in cardiac output, clearing of pulmonary congestion, and a reduction in heart size often occurring in 12–48 h. Although the response to inotropes and diuretics may be poor before thiamine therapy, these agents may be important after thiamine is given, since the left ventricle may not be able to handle the increased work load presented by the return of vascular tone. Vitamins B6 , B12 , and folate deficiency Vitamins B6, B12, and folate are cofactors in the metabolism of hom*ocysteine. Their deficiency probably contributes to the majority of cases of hyperhom*ocysteinemia, a disorder associated with increased atherosclerotic risk. Supplementation of these vitamins has reduced the incidence of hyperhom*ocysteinemia in the United States; however, the clinical cardiovascular

benefit of normalizing elevated hom*ocysteine levels has not been proved.

Obesity

Thyroid hormone exerts a major influence on the cardiovascular system by a number of direct and indirect mechanisms, and, not surprisingly, cardiovascular effects are prominent in both hypo- and hyperthyroidism. Thyroid hormone causes increases in total-body metabolism and oxygen consumption that indirectly increase the cardiac workload. In addition, thyroid hormone exerts direct inotropic, chronotropic, and

Hyperthyroidism Common cardiovascular manifestations of hyperthyroidism include palpitations, systolic hypertension, and fatigue. Sinus tachycardia is present in ∼40% of hyperthyroid patients, and atrial fibrillation in ∼15%. Physical examination may reveal a hyperdynamic precordium, a widened pulse pressure, increases in the intensity of the first heart sound and the pulmonic component of the second heart sound, and a third heart sound. An increased incidence of mitral valve prolapse has been described in hyperthyroid patients, in which case a midsystolic murmur may be heard at the left sternal border with or without a mid-systolic click. A systolic pleuropericardial friction rub (Means-Lerman scratch) may be heard at the left second intercostal space during expiration and is thought to result from the hyperdynamic cardiac motion. Elderly patients with hyperthyroidism may present with only cardiovascular manifestations of thyrotoxicosis such as sinus tachycardia, atrial fibrillation, and hypertension, all of which may be resistant to therapy until the hyperthyroidism is controlled. Angina pectoris and CHF are unusual with hyperthyroidism unless there is coexistent heart disease; in such cases, symptoms often resolve with treatment of the hyperthyroidism. Hypothyroidism Cardiac manifestations of hypothyroidism include a reduction in cardiac output, stroke volume, heart rate, blood pressure, and pulse pressure. Pericardial effusions are present in about one-third of patients, rarely progress to tamponade, and probably result from increased capillary permeability. Other clinical signs include cardiomegaly, bradycardia, weak arterial pulses, distant heart sounds, and pleural effusions. Although the signs and symptoms of myxedema may mimic those of CHF, in the absence of other cardiac disease, myocardial failure is uncommon. The ECG generally reveals sinus bradycardia and low voltage and may show prolongation of the QT interval, decreased P-wave voltage, prolonged AV conduction time, intraventricular conduction disturbances, and nonspecific ST-T-wave abnormalities. Chest x-ray may show cardiomegaly, often with a “water bottle” configuration; pleural effusions; and, in some cases, evidence of CHF. Pathologically, the heart is pale and dilated and often demonstrates myofibrillar swelling, loss of striations, and interstitial fibrosis.

Cardiac Manifestations of Systemic Disease

Thyroid Disease

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CHAPTER 24

Severe obesity, especially abdominal obesity, is associated with an increase in cardiovascular morbidity and mortality rates. Although obesity itself is not considered a disease, it is associated with an increased prevalence of hypertension, glucose intolerance, and atherosclerotic CAD. In addition, obese patients have a distinct cardiovascular abnormality characterized by increased total and central blood volumes, increased cardiac output, and elevated left ventricular filling pressure. The elevated cardiac output appears to be required to support the metabolic demands of the excess adipose tissue. Left ventricular filling pressure is often at the upper limits of normal at rest and rises excessively with exercise. In part as a result of chronic volume overload, eccentric cardiac hypertrophy with cardiac dilation and ventricular dysfunction may develop. In addition, altered levels of adipokines secreted by adipose tissue may contribute to adverse myocardial remodeling via direct effects on cardiac myocytes and other cells. Pathologically, there is left and, in some cases, right ventricular hypertrophy and generalized cardiac dilation. Pulmonary congestion, peripheral edema, and exercise intolerance may all ensue; however, the recognition of these findings may be difficult in massively obese patients. Weight reduction is the most effective therapy and results in reduction in blood volume and the return of cardiac output toward normal. However, rapid weight reduction may be dangerous, as cardiac arrhythmias and sudden death owing to electrolyte imbalance have been described. Treatment with angiotensin-converting enzyme inhibitors, sodium restriction, and diuretics may be useful to control heart failure symptoms. This form of heart disease should be distinguished from Pickwickian syndrome, which may share several of the cardiovascular features of heart disease secondary to severe obesity but, in addition, frequently has components of central apnea, hypoxemia, pulmonary hypertension, and cor pulmonale.

dromotropic effects that are similar to those seen with adrenergic stimulation (e.g., tachycardia, increased cardiac output); they are mediated at least partly by both transcriptional and nontranscriptional effects of thyroid hormone on myosin, calcium-activated ATPase, Na+-K+ATPase, and myocardial β-adrenergic receptors.

292

Patients with hypothyroidism frequently have elevations of cholesterol and triglycerides, resulting in premature atherosclerotic CAD. Before treatment with thyroid hormone, patients with hypothyroidism frequently do not have angina pectoris, presumably because of the low metabolic demands caused by their condition. However, angina and myocardial infarction may be precipitated during initiation of thyroid hormone replacement, especially in elderly patients with underlying heart disease. Therefore, replacement should be done with care, starting with low doses that are increased gradually.

Malignant Carcinoid

SECTION IV Disorders of the Heart

Carcinoid tumors most often originate in the small bowel and elaborate a variety of vasoactive amines (e.g., serotonin), kinins, indoles, and prostaglandins that are believed to be responsible for the diarrhea, flushing, and labile blood pressure that characterize the carcinoid syndrome. Some 50% of patients with carcinoid syndrome have cardiac involvement, usually manifesting as abnormalities of the right-sided cardiac structures. These patients invariably have hepatic metastases that allow vasoactive substances to circumvent hepatic metabolism. Left-sided cardiac involvement is rare and indicates either pulmonary carcinoid or an intracardiac shunt. Pathologically, carcinoid lesions are fibrous plaques that consist of smooth-muscle cells embedded in a stroma of glycosaminoglycans and collagen. They occur on the cardiac valves, where they cause valvular dysfunction, as well as on the endothelium of the cardiac chambers and great vessels. Carcinoid heart disease most often presents as tricuspid regurgitation, pulmonic stenosis, or both. In some cases a high cardiac output state may occur, presumably as a result of a decrease in systemic vascular resistance resulting from vasoactive substances released by the tumor. Treatment with somatostatin analogues (e.g., octreotide) or interferon α improves symptoms and survival in patients with carcinoid heart disease but does not appear to improve valvular abnormalities. In some severely symptomatic patients, valve replacement is indicated. Coronary artery spasm, presumably due to a circulating vasoactive substance, may occur in patients with carcinoid syndrome.

Pheochromocytoma In addition to causing labile or sustained hypertension, the high circulating levels of catecholamines resulting from a pheochromocytoma may cause direct myocardial injury. Focal myocardial necrosis and inflammatory cell infiltration are present in ∼50% of patients who die with pheochromocytoma and may contribute to clinically

significant left ventricular failure and pulmonary edema. In addition, associated hypertension results in left ventricular hypertrophy. Left ventricular dysfunction and CHF may resolve after removal of the tumor.

Acromegaly Exposure of the heart to excessive growth hormone may cause CHF as a result of high cardiac output, diastolic dysfunction owing to ventricular hypertrophy (with increased left ventricular chamber size or wall thickness), or global systolic dysfunction. Hypertension occurs in up to one-third of patients with acromegaly and is characterized by suppression of the reninangiotensin-aldosterone axis and increases in total-body sodium and plasma volume. Some form of cardiac disease occurs in about one-third of patients with acromegaly and is associated with a doubling of the risk of cardiac death.

Rheumatoid Arthritis and the Collagen Vascular Diseases Rheumatoid arthritis Rheumatoid arthritis may be associated with inflammatory changes in any or all cardiac structures, although pericarditis is the most common clinical entity. Pericardial effusions are found on echocardiography in 10–50% of patients with rheumatoid arthritis, particularly those with subcutaneous nodules. Nonetheless, only a small fraction of these patients have symptomatic pericarditis, and when present, it usually follows a benign course, only occasionally progressing to cardiac tamponade or constrictive pericarditis. The pericardial fluid is generally exudative, with decreased concentrations of complement and glucose and elevated cholesterol. Coronary arteritis with intimal inflammation and edema is present in ∼20% of cases but only rarely results in angina pectoris or myocardial infarction. Inflammation and granuloma formation may affect the cardiac valves, most often the mitral and aortic valves, and may cause clinically significant regurgitation owing to valve deformity. Myocarditis is uncommon and rarely results in cardiac dysfunction. Treatment is directed at the underlying rheumatoid arthritis and may include glucocorticoids. Urgent pericardiocentesis should be performed in patients with tamponade, but pericardiectomy usually is required in cases of pericardial constriction. Seronegative arthropathies The seronegative arthropathies, including ankylosing spondylitis, reactive arthritis, psoriatic arthritis, and the arthritides associated with ulcerative colitis and regional

enteritis, are all strongly associated with the HLA-B27 histocompatibility antigen and may be accompanied by a pancarditis and proximal aortitis. The aortic inflammation usually is limited to the aortic root but may extend to involve the aortic valve, mitral valve, and ventricular myocardium, resulting in aortic and mitral regurgitation, conduction abnormalities, and ventricular dysfunction. One-tenth of these patients have significant aortic insufficiency, and one-third have conduction disturbances; both are more common in patients with peripheral joint involvement and long-standing disease. Treatment with aortic valve replacement and permanent pacemaker implantation may be required. Occasionally, aortic regurgitation precedes the onset of arthritis, and therefore, the diagnosis of a seronegative arthritis should be considered in young males with isolated aortic regurgitation. Systemic lupus erythematosus (SLE) A significant percentage of patients with SLE have cardiac involvement. Pericarditis is common, occurring in about two-thirds of patients, and generally follows a

benign course, although rarely tamponade or constriction may result. The characteristic endocardial lesions of SLE are verrucous valvular abnormalities known as LibmanSacks endocarditis. They most often are located on the left-sided cardiac valves, particularly on the ventricular surface of the posterior mitral leaflet, and are made up almost entirely of fibrin. These lesions may embolize or become infected but rarely cause hemodynamically important valvular regurgitation. Myocarditis generally parallels the activity of the disease and, although common histologically, seldom results in clinical heart failure unless associated with hypertension. Although arteritis of epicardial coronary arteries may occur, it rarely results in myocardial ischemia. There is, however, an increased incidence of coronary atherosclerosis that probably is related more to associated risk factors and glucocorticoid use than to SLE itself. Patients with the antiphospholipid antibody syndrome may have a higher incidence of cardiovascular abnormalities, including valvular regurgitation, venous and arterial thrombosis, premature stroke, myocardial infarction, pulmonary hypertension, and cardiomyopathy.

293

CHAPTER 24 Cardiac Manifestations of Systemic Disease

CHAPTER 25

INFECTIVE ENDOCARDITIS Adolf W. Karchmer progresses to death within weeks. Subacute endocarditis follows an indolent course; causes structural cardiac damage only slowly, if at all; rarely metastasizes; and is gradually progressive unless complicated by a major embolic event or ruptured mycotic aneurysm. In developed countries, the incidence of endocarditis ranges from 2.6 to 7 cases per 100,000 population per year and has remained relatively stable during recent decades. While congenital heart diseases remain a constant predisposition, predisposing conditions in developed countries have shifted from chronic rheumatic heart disease (which remains a common predisposition in developing countries) to illicit IV drug use, degenerative valve disease, and intracardiac devices. The incidence of endocarditis is notably increased among the elderly. In developed countries, 30–35% of cases of native valve endocarditis (NVE) are associated with health care, and 16–30% of all cases of endocarditis involve prosthetic valves. The risk of prosthesis infection is greatest during the first 6–12 months after valve replacement; gradually declines to a low, stable rate thereafter; and is similar for mechanical and bioprosthetic devices.

The prototypic lesion of infective endocarditis, the vegetation (Fig. 25-1), is a mass of platelets, fibrin, microcolonies of microorganisms, and scant inflammatory cells. Infection most commonly involves heart valves (either native or prosthetic) but may also occur on the low-pressure side of a ventricular septal defect, on the mural endocardium where it is damaged by aberrant jets of blood or foreign bodies, or on intracardiac devices themselves. The analogous process involving arteriovenous shunts, arterioarterial shunts (patent ductus arteriosus), or a coarctation of the aorta is called infective endarteritis. Endocarditis may be classified according to the temporal evolution of disease, the site of infection, the cause of infection, or a predisposing risk factor such as injection drug use. While each classification criterion provides therapeutic and prognostic insight, none is sufficient alone. Acute endocarditis is a hectically febrile illness that rapidly damages cardiac structures, hematogenously seeds extracardiac sites, and, if untreated,

ETIOLOGY Although many species of bacteria and fungi cause sporadic episodes of endocarditis, a few bacterial species cause the majority of cases (Table 25-1). Because of their different portals of entry, the pathogens involved vary somewhat with the clinical types of endocarditis. The oral cavity, skin, and upper respiratory tract are the respective primary portals for the viridans streptococci, staphylococci, and HACEK organisms (Haemophilus, Actinobacillus, Cardiobacterium, Eikenella, and Kingella; Haemophilus aphrophilus and Actinobacillus actinomycetemcomitans have been reclassified into the genus Aggregatibacter). Streptococcus gallolyticus (formerly S. bovis) originates from the gastrointestinal tract, where it is associated with polyps and colonic tumors, and

FIGURE 25-1 Vegetations (arrows) due to viridans streptococcal endocarditis involving the mitral valve.

294

Table 25-1

295

Organisms Causing Major Clinical Forms of Endocarditis Percentage of Cases

Native Valve Endocarditis

Prosthetic Valve Endocarditis at Indicated Time of Onset (Months) after Valve Surgery

Endocarditis in Injection Drug Users

Organism

Community- Health Care– Acquired Associated (n = 1718) (n = 788)

12 (n = 194)

RightSided (n = 346)

LeftSided (n = 204)

Total (n = 675)a

Streptococcib

Pneumococci

—

Enterococci

Coagulase-negative staphylococci

—

Fastidious gramnegative coccobacilli (HACEK group)d

—

Gram-negative bacilli

Candida spp.

Rheumatoid factor

Circulating immune complexes

65–100

Decreased serum complement

5–40

involving a normal valve, murmurs may be absent initially but ultimately are detected in 85% of cases. Congestive heart failure (CHF) develops in 30–40% of patients; it is usually a consequence of valvular dysfunction but occasionally is due to endocarditis-associated myocarditis or an intracardiac fistula. Heart failure due to aortic valve dysfunction progresses more rapidly than does that due to mitral valve dysfunction. Extension of infection beyond valve leaflets into adjacent annular or myocardial tissue results in perivalvular abscesses, which in turn may cause intracardiac fistulae with new murmurs. Abscesses may burrow from the aortic valve annulus through the epicardium, causing pericarditis, or into the upper ventricular septum, where they may interrupt the conduction system, leading to varying degrees of heart block. Perivalvular abscesses arising from the mitral valve rarely interrupt conduction pathways near the atrioventricular node or in the proximal bundle of His. Emboli to a coronary artery occur in 2% of patients and may result in myocardial infarction.

Figure 25-2 Septic emboli with hemorrhage and infarction due to acute Staphylococcus aureus endocarditis. (Used with permission of L. Baden.)

Infective Endocarditis

Elevated C-reactive protein level

CHAPTER 25

Anemia

The classic nonsuppurative peripheral manifestations of subacute endocarditis are related to the duration of infection and, with early diagnosis and treatment, have become infrequent. In contrast, septic embolization mimicking some of these lesions (subungual hemorrhage, Osler’s nodes) is common in patients with acute S. aureus endocarditis (Fig. 25-2). Musculoskeletal pain usually remits promptly with treatment but must be distinguished from focal metastatic infections (e.g., spondylodiscitis), which may complicate 10–15% of cases. Hematogenously seeded focal infection is most often clinically evident in the skin, spleen, kidneys, skeletal system, and meninges. Arterial emboli are clinically apparent in up to 50% of patients. Endocarditis caused by S. aureus, vegetations >10 mm in diameter (as measured by echocardiography), and infection involving the mitral valve are independently associated with an increased risk of embolization. Emboli occurring late, during, or after effective therapy do not in themselves constitute evidence of failed antimicrobial treatment. Cerebrovascular emboli presenting as strokes or occasionally as encephalopathy complicate 15–35% of cases of endocarditis. One-half of these events precede the diagnosis of endocarditis. The frequency of stroke is 8per 1000 patient-days during the week prior to diagnosis; the figure falls to 4.8 and 1.7 per 1000 patientdays during the first and second weeks of effective antimicrobial therapy, respectively. This decline exceeds that which can be attributed to change in vegetation size. Only 3% of strokes occur after 1 week of effective therapy. Other neurologic complications include aseptic or purulent meningitis, intracranial hemorrhage due to hemorrhagic infarcts or ruptured mycotic aneurysms, and seizures. (Mycotic aneurysms are focal dilations of arteries occurring at points in the artery wall that have been

297

298

weakened by infection in the vasa vasorum or where septic emboli have lodged.) Microabscesses in brain and meninges occur commonly in S. aureus endocarditis; surgically drainable intracerebral abscesses are infrequent. Immune complex deposition on the glomerular basem*nt membrane causes diffuse hypocomplementemic glomerulonephritis and renal dysfunction, which typically improve with effective antimicrobial therapy. Embolic renal infarcts cause flank pain and hematuria but rarely cause renal dysfunction.

antimicrobial therapy yields no histologic evidence of endocarditis. Illnesses not classified as definite endocarditis or rejected as such are considered cases of possible infective endocarditis when either one major criterion Table 25-3 The Duke Criteria for the Clinical Diagnosis of Infective Endocarditisa Major Criteria 1. Positive blood culture Typical microorganism for infective endocarditis from two separate blood cultures Viridans streptococci, Streptococcus gallolyticus, HACEK group, Staphylococcus aureus, or Community-acquired enterococci in the absence of a primary focus, or Persistently positive blood culture, defined as recovery of a microorganism consistent with infective endocarditis from: Blood cultures drawn >12 h apart; or All of 3 or a majority of ≥4 separate blood cultures, with first and last drawn at least 1 h apart Single positive blood culture for Coxiella burnetii or phase I IgG antibody titer of >1:800 2. Evidence of endocardial involvement Positive echocardiogramb Oscillating intracardiac mass on valve or supporting structures or in the path of regurgitant jets or in implanted material, in the absence of an alternative anatomic explanation, or Abscess, or New partial dehiscence of prosthetic valve, or New valvular regurgitation (increase or change in preexisting murmur not sufficient)

Manifestations of specific predisposing conditions

SECTION IV Disorders of the Heart

Almost 50% of endocarditis cases associated with injection drug use are limited to the tricuspid valve and present with fever but with faint or no murmur. In 75% of cases, septic emboli cause cough, pleuritic chest pain, nodular pulmonary infiltrates, or occasionally pyopneumothorax. Infection of the aortic or mitral valves on the left side of the heart presents with the typical clinical features of endocarditis. Health care–associated endocarditis has typical manifestations if it is not associated with a retained intracardiac device or masked by the symptoms of concurrent comorbid illness. Transvenous pacemaker– or implanted defibrillator–associated endocarditis may be associated with obvious or cryptic generator pocket infection and results in fever, minimal murmur, and pulmonary symptoms due to septic emboli. Late-onset PVE presents with typical clinical features. In cases arising within 60 days of valve surgery (early onset), typical symptoms may be obscured by comorbidity associated with recent surgery. In both earlyonset and more delayed presentations, paravalvular infection is common and often results in partial valve dehiscence, regurgitant murmurs, CHF, or disruption of the conduction system.

Minor Criteria 1. Predisposition: predisposing heart condition or injection drug use 2. Fever ≥38.0°C (≥100.4°F) 3. Vascular phenomena: major arterial emboli, septic pulmonary infarcts, mycotic aneurysm, intracranial hemorrhage, conjunctival hemorrhages, Janeway lesions 4. Immunologic phenomena: glomerulonephritis, Osler’s nodes, Roth’s spots, rheumatoid factor 5. Microbiologic evidence: positive blood culture but not meeting major criterion as noted previouslyc or serologic evidence of active infection with organism consistent with infective endocarditis

Diagnosis The Duke criteria The diagnosis of infective endocarditis is established with certainty only when vegetations are examined histologically and microbiologically. Nevertheless, a highly sensitive and specific diagnostic schema—known as the Duke criteria—has been developed on the basis of clinical, laboratory, and echocardiographic findings (Table 25-3). Documentation of two major criteria, of one major criterion and three minor criteria, or of five minor criteria allows a clinical diagnosis of definite endocarditis. The diagnosis of endocarditis is rejected if an alternative diagnosis is established, if symptoms resolve and do not recur with ≤ 4 days of antibiotic therapy, or if surgery or autopsy after ≤ 4 days of

Definite endocarditis is defined by documentation of two major criteria, of one major criterion and three minor criteria, or of five minor criteria. See text for further details. b Transesophageal echocardiography is recommended for assessing possible prosthetic valve endocarditis or complicated endocarditis. c Excluding single positive cultures for coagulase-negative staphylococci and diphtheroids, which are common culture contaminants, and organisms that do not cause endocarditis frequently, such as gram-negative bacilli. Note: HACEK, Haemophilus spp., Aggregatibacter actinomycetemcomitans, Cardiobacterium hominis, Eikenella corrodens, Kingella spp. Source: Adapted from JS Li et al: Clin Infect Dis 30:633, 2000, with permission from the University of Chicago Press.

and one minor criterion or three minor criteria are fulfilled. Requiring the identification of clinical features of endocarditis for classification as possible infective endocarditis increases the specificity of the schema without significantly reducing its sensitivity. The roles of bacteremia and echocardiographic findings in the diagnosis of endocarditis are emphasized in the Duke criteria. The requirement for multiple positive blood cultures over time is consistent with the continuous low-density bacteremia characteristic of endocarditis. Among patients with untreated endocarditis who ultimately have a positive blood culture, 95% of all blood cultures are positive. The diagnostic criteria attach significance to the species of organism isolated from blood cultures. To fulfill a major criterion, the isolation of an organism that causes both endocarditis and bacteremia in the absence of endocarditis (e.g., S. aureus, enterococci) must take place repeatedly (i.e., persistent bacteremia) and in the absence of a primary focus of infection. Organisms that rarely cause endo carditis but commonly contaminate blood cultures (e.g., diphtheroids, CoNS) must be isolated repeatedly if their isolation is to serve as a major criterion.

Non-blood-culture tests Serologic tests can be used to implicate causally some organisms that are difficult to recover by blood culture: Brucella, Bartonella, Legionella, Chlamydophila psittaci, and C. burnetii. Pathogens can also be identified in vegetations by culture, microscopic examination with special stains (i.e., the periodic acid–Schiff stain for T. whipplei),

Echocardiography Echocardiography allows anatomic confirmation of infective endocarditis, sizing of vegetations, detection of intracardiac complications, and assessment of cardiac function (Fig. 25-3). Transthoracic echocardiography (TTE) is noninvasive and exceptionally specific; however, it cannot image vegetations 90% of patients with definite endocarditis; nevertheless, initial studies may be false-negative in 6–18% of endocarditis patients. When endocarditis is likely, a negative TEE result does not exclude the diagnosis but rather warrants repetition of the study in 7–10 days. TEE is the optimal method for the diagnosis of PVE or the detection of myocardial abscess, valve perforation, or intracardiac fistulae. Experts favor echocardiographic evaluation of all patients with a clinical diagnosis of endocarditis; however, the test should not be used to screen patients with a low probability of endocarditis (e.g., patients with unexplained fever). An American Heart Association approach to the use of echocardiography for evaluation of patients with suspected endocarditis is illustrated in Fig. 25-4. Other studies Many laboratory studies that are not diagnostic—i.e., complete blood count, creatinine determination, liver function tests, chest radiography, and electrocardiography—are nevertheless important in the management of patients with endocarditis. The erythrocyte sedimentation rate, C-reactive protein level, and circulating immune complex titer are commonly increased in endocarditis (Table 25-2). Cardiac catheterization is useful primarily to assess coronary artery patency in older individuals who are to undergo surgery for endocarditis.

treatment

Infective Endocarditis

Antimicrobial Therapy It is difficult to eradicate bacteria from the vegetation because local host defenses are deficient and because the largely nongrowing, metabolically inactive bacteria are less easily

Infective Endocarditis

Isolation of the causative microorganism from blood cultures is critical for diagnosis, determination of antimicrobial susceptibility, and planning of treatment. In the absence of prior antibiotic therapy, three 2-bottle blood culture sets, separated from one another by at least 1 h, should be obtained from different venipuncture sites over 24 h. If the cultures remain negative after 48–72 h, two or three additional blood culture sets should be obtained, and the laboratory should be consulted for advice regarding optimal culture techniques. Pending culture results, empirical antimicrobial therapy should be withheld initially from hemodynamically stable patients with suspected subacute endocarditis, especially those who have received antibiotics within the preceding 2 weeks; thus, if necessary, additional blood culture sets can be obtained without the confounding effect of empirical treatment. Patients with acute endocarditis or with deteriorating hemodynamics who may require urgent surgery should be treated empirically immediately after three sets of blood cultures are obtained over several hours.

299

CHAPTER 25

Blood cultures

or direct fluorescence antibody techniques and by the use of polymerase chain reaction (PCR) to recover unique microbial DNA or 16S rRNA that, when sequenced, allows identification of organisms.

300

Figure 25-3 Imaging of a mitral valve infected with Staphylococcus aureus by low-esophageal four-chamber-view transesophageal echocardiography (TEE). A. Two-dimensional echocardiogram showing a large vegetation with an adjacent echolucent abscess cavity. B. Color-flow Doppler image showing

severe mitral regurgitation through both the abscess-fistula and the central valve orifice. A, abscess; A-F, abscess-fistula; L, valve leaflets; LA, left atrium; LV, left ventricle; MR, mitral central valve regurgitation; RV, right ventricle; veg, vegetation. (With permission of Andrew Burger, MD)

SECTION IV

High initial patient risk†; moderate to high clinical suspicion or difficult imaging candidate

IE suspected

Low initial patient risk and low clinical suspicion

Initial TTE

Disorders of the Heart

–

Initial TEE

–

Low suspicion persists

Increased suspicion during clinical course

TEE

–

Look for other source

High suspicion persists

High-risk echo features *

No high-risk echo features

TEE for detection of complications

No TEE unless clinical status deteriorates

Figure 25-4 The diagnostic use of transesophageal and transtracheal echocardiography (TEE and TTE, respectively). †High initial patient risk for endocarditis as listed in Table 25-8 or evidence of intracardiac complications (new regurgitant murmur, new electrocardiographic conduction changes, or congestive heart failure). *High-risk echocardiographic features

Look for other source of symptoms

–

Repeat TEE

–

+ Rx

+ Alternative diagnosis established

Look for other source Follow-up TEE or TTE to reassess vegetations, complications, or Rx response as clinically indicated

include large vegetations, valve insufficiency, paravalvular infection, or ventricular dysfunction. Rx indicates initiation of antibiotic therapy. (Reproduced with permission from Diagnosis and Management of Infective Endocarditis and Its Complications. Circulation 98:2936, 1998. © 1998 American Heart Association.)

killed by antibiotics. To cure endocarditis, all bacteria in the vegetation must be killed; therefore, therapy must be bactericidal and prolonged. Antibiotics are generally given parenterally to achieve serum concentrations that, through passive diffusion, lead to effective concentrations in the depths of the vegetation. To select effective therapy requires knowledge of the susceptibility of the causative microorganisms. The decision to initiate treatment empirically must balance the need to establish a microbiologic diagnosis against the potential progression of disease or the need for urgent surgery (see “Blood Cultures,” earlier). Simultaneous infection at other sites (such as meningitis), allergies, end-organ dysfunction, interactions with concomitant medications, and risks of adverse events must be considered in the selection of therapy. Although given for several weeks longer, the regimens recommended for the treatment of endocarditis involving prosthetic valves (except for staphylococcal infections) are similar to those used to treat NVE (Table 25-4). Recommended doses and durations of therapy should be adhered to unless alterations are required by end-organ dysfunction or adverse events.

Enterococci Enterococci are resistant to oxacillin,

nafcillin, and the cephalosporins and are only inhibited—not killed—by penicillin, ampicillin, teicoplanin (not available in the United States), and vancomycin. To kill enterococci requires the synergistic interaction of a cell wall–active antibiotic (penicillin, ampicillin, vancomycin, or teicoplanin) that is effective at achievable serum concentrations and an aminoglycoside (gentamicin or streptomycin) to which the isolate does not exhibit high-level resistance. An isolate’s resistance to cell wall–active agents or its ability to replicate in the presence of gentamicin at ≥500 μg/mL or streptomycin at 1000–2000 μg/mL—a phenomenon called high-level aminoglycoside resistance—indicates that the ineffective

Staphylococci The regimens used to treat staphy-

lococcal endocarditis (Table 25-4) are based not on coagulase production but rather on the presence or absence of a prosthetic valve or foreign device, the native valve(s) involved, and the susceptibility of the isolate to penicillin, methicillin, and vancomycin. All staphylococci are considered penicillin resistant until shown

Infective Endocarditis

Streptococci Optimal therapy for streptococcal endocarditis is based on the minimal inhibitory concentration (MIC) of penicillin for the causative isolate (Table 25-4). The 2-week penicillin/gentamicin or ceftriaxone/gentamicin regimens should not be used to treat complicated NVE or PVE. The regimen recommended for relatively penicillin-resistant streptococci is advocated for treatment of group B, C, or G streptococcal endocarditis. Nutritionally variant organisms (Granulicatella or Abiotrophia species) and Gemella morbillorum are treated with the regimen for moderately penicillinresistant streptococci, as is PVE caused by these organisms or by streptococci with a penicillin MIC of >0.1 μg/ mL (Table 25-4).

301

CHAPTER 25

Organism-Specific Therapies

antimicrobial agent cannot participate in the interaction to produce killing. High-level resistance to gentamicin predicts that tobramycin, netilmicin, amikacin, and kanamycin also will be ineffective. In fact, even when enterococci are not highly resistant to gentamicin, it is difficult to predict the ability of these other aminoglycosides to participate in synergistic killing; consequently, they should not in general be used to treat enterococcal endocarditis. High concentrations of ampicillin plus ceftriaxone or cefotaxime, by expanded binding of penicillin-binding proteins, kill E. faecalis in vitro and in animal models of endocarditis. Enterococci causing endocarditis must be tested for high-level resistance to streptomycin and gentamicin, β-lactamase production, and susceptibility to penicillin and ampicillin (MIC, 0.1 μg/mL

• Penicillin G (4–5 mU IV q4h) plus Gentamicind (1 mg/kg IV q8h), both for 4–6 weeks • Ampicillin (2 g IV q4h) plus Gentamicind (1 mg/kg IV q8h), both for 4–6 weeks • Vancomycinc (15 mg/kg IV q12h) plus Gentamicind (1 mg/kg IV q8h), both for 4–6 weeks

Can use streptomycin (7.5 mg/kg q12h) in lieu of gentamicin if there is not highlevel resistance to streptomycin —

• Nafcillin or oxacillin (2 g IV q4h for 4–6 weeks)

Can use penicillin (4 mU q4h) if isolate is penicillin susceptible (does not produce β-lactamase) Can use cefazolin regimen for patients with nonimmediate penicillin allergy Use vancomycin for patients with immediate (urticarial) or severe penicillin allergy

—

Enterococci

Use vancomycin plus gentamicin for penicillin-allergic patients, or desensitize to penicillin

Staphylococci Methicillin-susceptible, infecting native valves (no foreign devices)

• Cefazolin (2 g IV q8h for 4–6 weeks) • Vancomycinc (15 mg/kg IV q12h for 4–6 weeks) Methicillin-resistant, infecting native valves (no foreign devices)

• Vancomycinc (15 mg/kg IV q8–12h for 4–6 weeks)

No role for routine use of rifampin

Methicillin-susceptible, infecting prosthetic valves

• Nafcillin or oxacillin (2 g IV q4h for 6–8 weeks) plus Gentamicind (1 mg/kg IM or IV q8h for 2 weeks) plus Rifampini (300 mg PO q8h for 6–8 weeks)

Use gentamicin during initial 2 weeks; determine susceptibility to gentamicin before initiating rifampin (see text); if patient is highly allergic to penicillin, use regimen for methicillin-resistant staphylococci; if β-lactam allergy is of the minor, nonimmediate type, can substitute cefazolin for oxacillin/nafcillin

Methicillin-resistant, infecting prosthetic valves

• Vancomycinc (15 mg/kg IV q12h for 6–8 weeks) plus Gentamicind (1 mg/kg IM or IV q8h for 2 weeks) plus Rifampini (300 mg PO q8h for 6–8 weeks)

Use gentamicin during initial 2 weeks; determine gentamicin susceptibility before initiating rifampin (see text) (continued )

Table 25-4

303

Antibiotic Treatment for Infective Endocarditis Caused by Common Organismsa (continued) Organism

Drug (Dose, Duration)

Comments

• Ceftriaxone (2 g/d IV as a single dose for 4 weeks) • Ampicillin/sulbactam (3 g IV q6h for 4 weeks)

Can use another third-generation cephalosporin at comparable dosage —

HACEK Organisms

Doses are for adults with normal renal function. Doses of gentamicin, streptomycin, and vancomycin must be adjusted for reduced renal function. Ideal body weight is used to calculate doses of gentamicin and streptomycin per kilogram (men = 50 kg + 2.3 kg per inch over 5 feet; women = 45.5 kg + 2.3 kg per inch over 5 feet). b MIC, ≤0.1 μg/mL. c Vancomycin dose is based on actual body weight. Adjust for trough level of 10–15 μg/mL for streptococcal and enterococcal infections and 15–20 μg/mL for staphylococcal infections. d Aminoglycosides should not be administered as single daily doses for enterococcal endocarditis and should be introduced as part of the initial treatment. Target peak and trough serum concentrations of divided-dose gentamicin 1 h after a 20- to 30-min infusion or IM injection are ∼3.5 μg/mL and ≤1 μg/mL, respectively; target peak and trough serum concentrations of streptomycin (timing as with gentamicin) are 20–35 μg/mL and 0.1 μg/mL and 10-mm diameter) hypermobile vegetations with increased risk of embolism Persistent unexplained fever (≥10 days) in culture-negative native valve endocarditis Poorly responsive or relapsed endocarditis due to highly antibiotic-resistant enterococci or gram-negative bacilli a

Surgery must be carefully considered; findings are often combined with other indications to prompt surgery.

CHAPTER 25

tral nervous system complications of endocarditis are important causes of morbidity and death. In some cases, effective treatment for these complications requires surgery. The indications for cardiac surgical treatment of endocarditis (Table 25-5) have been derived from observational studies and expert opinion. The strength of individual indications vary; thus, the risks and benefits as well as the timing of surgery must be individualized (Table 25-6). From 25% to 40% of patients with leftsided endocarditis undergo cardiac surgery during active infection, with slightly higher surgery rates with PVE than with NVE. Clinical events resulting from intracardiac complications, which are most reliably detected by TEE, justify most surgery. In the absence of randomized trials to evaluate a survival benefit for surgical intervention, the effect of surgery has been assessed in studies comparing populations of medically and surgically treated patients matched for the necessity of surgery (indication), with adjustments for predictors of death (comorbidity) and time of the surgical intervention. Although study results vary, surgery for currently advised indications appears to convey a significant survival benefit (27–55%) that becomes apparent only with follow-up for ≥6 months after the intervention. During the initial weeks after surgery, mortality risk is actually increased (disease-plus

Table 25-5

Table 25-6 Indication for Surgical Intervention Conflicting Evidence, but Majority of Opinions Favor Surgery

Timing

Strong Supporting Evidence

Emergent (same day)

Acute aortic regurgitation plus preclosure of mitral valve Sinus of Valsalva abscess ruptured into right heart Rupture into pericardial sac

Urgent (within 1–2 days)

Valve obstruction by vegetation Unstable (dehisced) prosthesis Acute aortic or mitral regurgitation with heart failure (New York Heart Association class III or IV) Septal perforation Perivalvular extension of infection with/without new electrocardiographic conduction system changes Lack of effective antibiotic therapy

Major embolus plus persisting large vegetation (>10 mm in diameter)

Elective (earlier usually preferred)

Progressive paravalvular prosthetic regurgitation Valve dysfunction plus persisting infection after ≥7–10 days of antimicrobial therapy Fungal (mold) endocarditis

Staphylococcal PVE Early PVE (≤2 months after valve surgery) Fungal endocarditis (Candida spp.) Antibiotic-resistant organisms

Note: PVE, prosthetic valve endocarditis. Source: Adapted from L Olaison, G Pettersson: Infect Dis Clin North Am 16:453, 2002.

Infective Endocarditis

Timing of Cardiac Surgical Intervention in Patients With Endocarditis

306

surgery-related mortality). With less demanding surgical indications, this combined mortality risk may erode potential long-term benefits. Benefit is greatest for NVE complicated by heart failure or myocardial abscess and is less clear for PVE; this difference may reflect sample size in the relevant studies. Congestive Heart Failure Moderate to severe

refractory CHF caused by new or worsening valve dysfunction is the major indication for cardiac surgical treatment of endocarditis. At 6 months of follow-up, patients with left-sided endocarditis and moderate to severe heart failure due to valve dysfunction who are treated only medically have a 50% mortality rate; the figure is 15% among matched patients who undergo surgery. The survival benefit with surgery is seen in both NVE and PVE. Surgery can relieve functional stenosis due to large vegetations or restore competence to damaged regurgitant valves by repair or replacement. Perivalvular Infection This complication, which

SECTION IV Disorders of the Heart

is most common with aortic valve infection, occurs in 10–15% of native valve and 45–60% of prosthetic valve infections. It is suggested by persistent unexplained fever during appropriate therapy, new electrocardiographic conduction disturbances, and pericarditis. TEE with color Doppler is the test of choice to detect perivalvular abscesses (sensitivity, ≥85%). For optimal outcome, surgery is required, especially when fever persists, fistulae develop, prostheses are dehisced and unstable, and invasive infection relapses after appropriate treatment. Cardiac rhythm must be monitored since highgrade heart block may require insertion of a pacemaker. Uncontrolled Infection Continued positive blood

cultures or otherwise-unexplained persistent fevers (in patients with either blood culture–positive or –negative endocarditis) despite optimal antibiotic therapy may reflect uncontrolled infection and may warrant surgery. Surgical treatment is also advised for endocarditis caused by organisms for which experience indicates that effective antimicrobial therapy is lacking (e.g., yeasts, fungi, P. aeruginosa, other highly resistant gram-negative bacilli, Brucella species, and probably C. burnetii). S. aureus Endocarditis The mortality rate for S. aureus PVE exceeds 50% with medical treatment but is reduced to 25% with surgical treatment. In patients with intracardiac complications associated with S. aureus PVE, surgical treatment reduces the mortality rate twentyfold. Surgical treatment should be considered for patients with S. aureus native aortic or mitral valve infection who have TTE-demonstrable vegetations and remain septic during the initial week of therapy. Isolated tricuspid valve endocarditis, even with persistent fever, rarely requires surgery.

Prevention of Systemic Emboli Death and persisting morbidity due to emboli are largely limited to patients suffering occlusion of cerebral or coronary arteries. Echocardiographic determination of vegetation size and anatomy, although predictive of patients at high risk of systemic emboli, does not identify those patients in whom the benefits of surgery to prevent emboli clearly exceed the risks of the surgical procedure. Net benefits from surgery to prevent emboli are most likely when other surgical benefits can be achieved simultaneously—e.g., repair of a moderately dysfunctional valve or debridement of a paravalvular abscess. Only 3.5% of patients undergo surgery solely to prevent systemic emboli. Valve repair avoiding insertion of a prosthesis makes the benefit-to-risk ratio of surgery to address vegetations more favorable. Timing of Cardiac Surgery In general, when

indications for surgical treatment of infective endocarditis are identified, surgery should not be delayed simply to permit additional antibiotic therapy, since this course of action increases the risk of death (Table 25-6). After 14 days of recommended antibiotic therapy, excised valves are culture-negative in 99% and 50% of patients with streptococcal and S. aureus endocarditis, respectively. Recrudescent endocarditis on a new implanted prosthetic valve follows surgery for active NVE and PVE in 2% and 6–15% of patients, respectively. These frequencies do not justify the risk of adverse outcome with delayed surgery, particularly in patients with severe heart failure, valve dysfunction, and staphylococcal infections. Delay is justified only when infection is controlled and CHF is resolved with medical therapy. Among patients who have experienced a neurologic complication of endocarditis, further neurologic deterioration can occur as a consequence of cardiac surgery. The risk of neurologic deterioration is related to the type of neurologic complication and the interval between the complication and surgery. Whenever feasible, cardiac surgery should be delayed for 2–3 weeks after a nonhemorrhagic embolic infarction and for 4 weeks after a cerebral hemorrhage. A ruptured mycotic aneurysm should be treated before cardiac surgery. Antibiotic Therapy after Cardiac Surgery

Bacteria visible in Gram-stained preparations of excised valves do not necessarily indicate a failure of antibiotic therapy. Organisms have been detected on Gram’s stain—or their DNA has been detected by PCR—in excised valves from 45% of patients who have successfully completed the recommended therapy for endocarditis. In only 7% of these patients are the organisms, most of which are unusual and antibiotic resistant, cultured from the valve. Despite the detection of organisms or their DNA, relapse of endocarditis after surgery

is uncommon. Thus, when valve cultures are negative in uncomplicated NVE caused by susceptible organisms, the duration of preoperative plus postoperative treatment should equal the total duration of recommended therapy, with ∼2 weeks of treatment administered after surgery. For endocarditis complicated by paravalvular abscess, partially treated PVE, or cases with culturepositive valves, a full course of therapy should be given postoperatively. Extracardiac Complications Splenic abscess develops in 3–5% of patients with endocarditis. Effective therapy requires either image-guided percutaneous drainage or splenectomy. Mycotic aneurysms occur in 2–15% of endocarditis patients; one-half of these cases involve the cerebral arteries and present as headaches, focal neurologic symptoms, or hemorrhage. Cerebral aneurysms should be monitored by angiography. Some will resolve with effective antimicrobial therapy, but those that persist, enlarge, or leak should be treated surgically if possible. Extracerebral aneurysms present as local pain, a mass, local ischemia, or bleeding; these aneurysms are treated by resection.

Table 25-7 Antibiotic Regimens for Prophylaxis of Endocarditis in Adults With High-Risk Cardiac Lesionsa,b A. Standard oral regimen 1. Amoxicillin: 2 g PO 1 h before procedure B. Inability to take oral medication 1. Ampicillin: 2 g IV or IM within 1 h before procedure C. Penicillin allergy 1. Clarithromycin or azithromycin: 500 mg PO 1 h before procedure 2. Cephalexinc: 2 g PO 1 h before procedure 3. Clindamycin: 600 mg PO 1 h before procedure D. Penicillin allergy, inability to take oral medication 1. Cefazolinc or ceftriaxonec: 1 g IV or IM 30 min before procedure 2. Clindamycin: 600 mg IV or IM 1 h before procedure

Prevention In the past, in an effort to prevent endocarditis (long a goal in clinical practice), expert committees have supported systemic antibiotic administration prior to many bacteremia-inducing procedures. In the absence of human trials, a reappraisal of the indirect evidence for antibiotic prophylaxis for endocarditis by the American Heart Association has culminated in guidelines that reverse prior recommendations and restrict prophylactic antibiotic use. At best, the benefit of antibiotic

Dosing for children: for amoxicillin, ampicillin, cephalexin, or cefadroxil, use 50 mg/kg PO; cefazolin, 25 mg/kg IV; clindamycin, 20 mg/kg PO, 25 mg/kg IV; clarithromycin, 15 mg/kg PO; and vancomycin, 20 mg/kg IV. b For high-risk lesions, see Table 25-8. Prophylaxis is not advised for other lesions. c Do not use cephalosporins in patients with immediate hypersensitivity (urticaria, angioedema, anaphylaxis) to penicillin. Source: W Wilson et al: Circulation 116:1736, 2007.

Infective Endocarditis

Older age, severe comorbid conditions and diabetes, delayed diagnosis, involvement of prosthetic valves or the aortic valve, an invasive (S. aureus) or antibioticresistant (P. aeruginosa, yeast) pathogen, intracardiac and major neurologic complications, and an association with health care adversely affect outcome. Death and poor outcome often are related not to failure of antibiotic therapy but rather to the interactions of comorbidities and endocarditis-related end-organ complications. Overall survival rates for patients with NVE caused by viridans streptococci, HACEK organisms, or enterococci (susceptible to synergistic therapy) are 85–90%. For S. aureus NVE in patients who do not inject drugs, survival rates are 55–70%, whereas 85–90% of injection drug users survive this infection. PVE beginning within 2 months of valve replacement results in mortality rates of 40–50%, whereas rates are only 10–20% in later-onset cases.

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CHAPTER 25

Outcome

prophylaxis is minimal. Most endocarditis cases do not follow a procedure. In case-control studies, dental treatments—widely considered as predisposing to endocarditis—occur no more frequently before endocarditis than in matched controls. Furthermore, the frequency and magnitude of bacteremia associated with dental procedures and routine daily activities (e.g., tooth brushing and flossing) are similar. Because dental procedures are infrequent, exposure of cardiac structures to bacteremic oral-cavity organisms is notably greater from routine daily activities than from dental care. The relation of gastrointestinal and genitourinary procedures to subsequent endocarditis is more tenuous than that of dental procedures. In addition, cost-effectiveness and cost-benefit estimates suggest that antibiotic prophylaxis represents a poor use of resources. Studies in animal models suggest that antibiotic prophylaxis may be effective. Thus it is possible that rare cases of endocarditis are prevented. Weighing the potential benefits, potential adverse events, and costs associated with antibiotic prophylaxis, the American Heart Association and the European Society of Cardiology now recommend prophylactic antibiotics (Table 25-7) only for those patients at highest risk for severe morbidity or death from endocarditis (Table 25-8). Maintaining good dental hygiene is essential. Prophylaxis is recommended only when there is manipulation of gingival tissue or the periapical region of the teeth or perforation of the oral mucosa (including surgery on the respiratory tract). Prophylaxis is not advised for patients undergoing

308

Table 25-8 High-Risk Cardiac Lesions for Which Endocarditis Prophylaxis Is Advised Before Dental Procedures Prosthetic heart valves Prior endocarditis Unrepaired cyanotic congenital heart disease, including palliative shunts or conduits Completely repaired congenital heart defects during the 6 months after repair Incompletely repaired congenital heart disease with residual defects adjacent to prosthetic material Valvulopathy developing after cardiac transplantation Source: W Wilson et al: Circulation 116:1736, 2007.

gastrointestinal or genitourinary tract procedures. Highrisk patients should be treated before or when they undergo procedures on an infected genitourinary tract or on infected skin and soft tissue. The British Society for Antimicrobial Chemotherapy continues to recommend prophylaxis for at-risk patients undergoing selected gastrointestinal and genitourinary procedures. In contrast, the National Institute for Health and Clinical Excellence in the United Kingdom found no convincing evidence that antibiotic prophylaxis was cost-effective and advised discontinuation of the practice (see www.nice.org.uk/ guidance/CG64).

SECTION IV Disorders of the Heart

CHaPter 26

ACUTE RHEUMATIC FEVER Jonathan R. Carapetis Acute rheumatic fever (ARF) is a multisystem disease resulting from an autoimmune reaction to infection with group A streptococcus. Although many parts of the body may be affected, almost all of the manifestations resolve completely. The exception is cardiac valvular damage (rheumatic heart disease [RHD]), which may persist after the other features have disappeared.

developing countries do not currently have coordinated, register-based RHD control programs, which are proven to be cost-effective in reducing the burden of RHD. Enhancing awareness of RHD and mobilizing resources for its control in developing countries is an issue requiring international attention.

gloBal ConsiDerations

ePiDeMiologY

ARF and RHD are diseases of poverty. They were common in all countries until the early twentieth century, when their incidence began to decline in industrialized nations. This decline was largely attributable to improved living conditions— particularly less crowded housing and better hygiene— which resulted in reduced transmission of group A streptococci. The introduction of antibiotics and improved systems of medical care had a supplemental effect. Recurrent outbreaks of ARF began in the 1980s in the Rocky Mountain states of the United States, where elevated rates persist. The virtual disappearance of ARF and reduction in the incidence of RHD in industrialized countries during the twentieth century unfortunately was not replicated in developing countries, where these diseases continue unabated. RHD is the most common cause of heart disease in children in developing countries and is a major cause of mortality and morbidity in adults as well. It has been estimated that between 15 and 19 million people worldwide are affected by RHD, with approximately one-quarter of a million deaths occurring each year. Some 95% of ARF cases and RHD deaths now occur in developing countries. Although ARF and RHD are relatively common in all developing countries, they occur at particularly elevated rates in certain regions. These “hot spots” are sub-Saharan Africa, Pacific nations, Australasia, and the Indian subcontinent (Fig. 26-1). Unfortunately, most

ARF is mainly a disease of children aged 5–14 years. Initial episodes become less common in older adolescents and young adults and are rare in persons aged >30 years. By contrast, recurrent episodes of ARF remain relatively common in adolescents and young adults. This pattern contrasts with the prevalence of RHD, which peaks between 25 and 40 years. There is no clear gender association for ARF, but RHD more commonly affects females, sometimes up to twice as frequently as males.

PatHogenesis organIsm factors Based on currently available evidence, ARF is exclusively caused by infection of the upper respiratory tract with group A streptococci. Although classically, certain M-serotypes (particularly types 1, 3, 5, 6, 14, 18, 19, 24, 27, and 29) were associated with ARF, in high-incidence regions, it is now thought that any strain of group A streptococcus has the potential to cause ARF. Potential role of skin infection and of groups C and G streptococci are currently being investigated.

Host factors Approximately 3–6% of any population may be susceptible to ARF, and this proportion does not vary dramatically between populations. Findings of familial

309

310

Prevalence of rheumatic heart disease (cases per 1000) 0–3

1– 0

1– 3

3– 5

0–8

1– 8

2– 2

5– 7

Figure 26-1 Prevalence of rheumatic heart disease in children aged 5–14 years. Circles within Australia and New Zealand represent indigenous populations, and also Pacific Islanders in

SECTION IV Disorders of the Heart

clustering of cases and concordance in monozygotic twins—particularly for chorea—confirm that susceptibility to ARF is an inherited characteristic. Particular human leukocyte antigen (HLA) class II alleles appear to be strongly associated with susceptibility. Associations have also been described with high levels of circulating mannose-binding lectin and polymorphisms of transforming growth factor β1 gene and immunoglobulin genes. High-level expression of a particular alloantigen present on B cells, D8-17, has been found in patients with a history of ARF in many populations, with intermediate-level expression in first-degree family members, suggesting that this may be a marker of inherited susceptibility.

The Immune Response When a susceptible host encounters a group A streptococcus, an autoimmune reaction results, which leads to damage to human tissues as a result of cross-reactivity between epitopes on the organism and the host (Fig. 26-2). Cross-reactive epitopes are present in the streptococcal M protein and the N-acetylglucosamine of group A streptococcal carbohydrate and are immunologically similar to molecules in human myosin, tropomyosin, keratin, actin, laminin, vimentin, and N-acetylglucosamine. It is currently thought that the initial damage is due to cross-reactive antibodies attaching at the cardiac valve endothelium, allowing the entry of primed CD4+ T cells, leading to subsequent T cellmediated inflammation.

Clinical Features There is a latent period of ∼3 weeks (1–5 weeks) between the precipitating group A streptococcal infection and the appearance of the clinical features of ARF. The exceptions are chorea and indolent carditis, which may follow prolonged latent periods lasting up to 6 months. Although many patients report a prior sore throat, the preceding group A streptococcal infection is commonly subclinical; in these cases it can only be confirmed using streptococcal antibody testing. The most common clinical presentation of ARF is polyarthritis and fever. Polyarthritis is present in 60–75% of cases and carditis in 50–60%. The prevalence of chorea in ARF varies substantially between populations, ranging from 1000) mutations in the LDL receptor gene. It has a higher incidence in certain founder populations, such as Afrikaners, Christian Lebanese, and French Canadians. The elevated levels of LDL-C in FH are due to an increase in the production of LDL from IDL (since a portion of IDL is normally cleared by LDL receptor–mediated endocytosis) and a delayed removal of LDL from the blood. Individuals with two mutated LDL receptor alleles (FH hom*ozygotes) have much higher LDL-C levels than those with one mutant allele (FH heterozygotes). hom*ozygous FH occurs in approximately 1 in 1 million persons worldwide. Patients with hom*ozygous FH can be classified into one of two groups based on the amount of LDL receptor activity measured in their skin fibroblasts: those patients with 500 mg/dL and can be higher

Table 31-4 Primary Hyperlipoproteinemias Caused by Known Single Gene Mutations Protein (Gene) Defect

Lipoproteins Elevated

Lipoprotein lipase deficiency

LPL (LPL)

Chylomicrons

Familial apolipoprotein C-II deficiency

ApoC-II (APOC2) Chylomicrons

ApoA-V deficiency

ApoA-V (APOA5)

Chylomicrons, VLDL

GPIHBP1 deficiency

GDIHBP1

Chylomicrons

Familial hepatic lipase deficiency Familial dysbetalipoproteinemia Familial hypercholesterolemia Familial defective apoB-100

Hepatic lipase (LIPC) ApoE (APOE)

Autosomal dominant hypercholesterolemia Autosomal recessive hypercholesterolemia Sitosterolemia

Genetic Disorder

Genetic Transmission

Estimated Incidence

Eruptive xanthomas, hepatosplenomegaly, pancreatitis Eruptive xanthomas, hepatosplenomegaly, pancreatitis

1/1,000,000

95th percentile for age, sex, and height. Blood pressures between the 90th and 95th percentiles are considered prehypertensive and are an indication for lifestyle interventions. Home blood pressure and average 24-h ambulatory blood pressure measurements are generally lower than clinic blood pressures. Because ambulatory blood pressure recordings yield multiple readings throughout the day and night, they provide a more comprehensive assessment of the vascular burden of hypertension than do a limited number of office readings. Increasing evidence suggests that home blood pressures, including

Table 37-1 Blood Pressure Classification Blood Pressure Classification

Systolic, mmHg

Diastolic, mmHg

Normal

5.5–6 cm or the descending thoracic aortic diameter is >6.5–7 cm, and those with an aneurysm that has increased by >1 cm per year. In patients with Marfan syndrome or bicuspid aortic valve, ascending thoracic aortic aneurysms >5 cm should be considered for surgery. Endovascular repair is an alternative treatment for some patients with descending thoracic aortic aneurysms.

Abdominal Aortic Aneurysms Abdominal aortic aneurysms occur more frequently in males than in females, and the incidence increases with age. Abdominal aortic aneurysms ≥4.0 cm may affect 1–2% of men older than 50 years. At least 90% of all abdominal aortic aneurysms >4.0 cm are related to atherosclerotic disease, and most of these aneurysms are below the level of the renal arteries. Prognosis is related to both the size of the aneurysm and the severity of coexisting coronary artery and cerebrovascular disease. The risk of rupture increases with the size of the aneurysm: the 5-year risk for aneurysms 5 cm in diameter. The formation of mural thrombi within aneurysms may predispose to peripheral embolization. An abdominal aortic aneurysm commonly produces no symptoms. It usually is detected on routine examination as a palpable, pulsatile, expansile, and nontender mass, or it is an incidental finding observed on an abdominal x-ray or ultrasound study performed for other reasons. As abdominal aortic aneurysms expand, however, they may become painful. Some patients complain of strong pulsations in the abdomen; others experience pain in the chest, lower back, or scrotum. Aneurysmal pain is usually a harbinger of rupture and represents a medical emergency. More often, acute rupture occurs without any prior warning, and this complication is always life threatening. Rarely, there is leakage of the aneurysm with severe pain and tenderness. Acute pain and hypotension occur with rupture of the aneurysm, which requires an emergency operation. Abdominal radiography may demonstrate the calcified outline of the aneurysm; however, about 25% of aneurysms are not calcified and cannot be visualized by x-ray imaging. An abdominal ultrasound can delineate the transverse and longitudinal dimensions of an abdominal aortic aneurysm and may detect mural thrombus.

Figure 38-3 A computed tomographic angiogram (CTA) depicting a fusiform abdominal aortic aneurysm that has been treated with a bifurcated stent graft.

Abdominal ultrasound is useful for serial documentation of aneurysm size and can be used to screen patients at risk for developing an aortic aneurysm. In one large study, ultrasound screening of men age 65–74 years was associated with a risk reduction in aneurysm-related death of 42%. For this reason, screening by ultrasonography is recommended for men age 65–75 years who have ever smoked. In addition, siblings or offspring of persons with abdominal aortic aneurysms, as well as individuals with thoracic aortic or peripheral arterial aneurysms, should be considered for screening for abdominal aortic aneurysms. CT with contrast and MRI are accurate noninvasive tests to determine the location and size of abdominal aortic aneurysms and to plan endovascular or open surgical repair (Fig. 38-3). Contrast aortography may be used for the evaluation of patients with aneurysms, but the procedure carries a small risk of complications such as bleeding, allergic reactions, and atheroembolism. Since the presence of mural thrombi may reduce the luminal size, aortography may underestimate the diameter of an aneurysm. Treatment

Abdominal Aortic Aneurysms

Operative repair of the aneurysm with insertion of a prosthetic graft or endovascular placement of an aortic stent graft (Fig. 38-3) is indicated for abdominal aortic aneurysms of any size that are expanding rapidly or are

The four major acute aortic syndromes are aortic rupture (discussed earlier), aortic dissection, intramural hematoma, and penetrating atherosclerotic ulcer. Aortic dissection is caused by a circumferential or, less frequently, transverse tear of the intima. It often occurs along the right lateral wall of the ascending aorta where the hydraulic shear stress is high. Another common site is the descending thoracic aorta just below the ligamentum arteriosum. The initiating event is either a primary intimal tear with secondary dissection into the media or a medial hemorrhage that dissects into and disrupts the intima. The pulsatile aortic flow then dissects along the elastic lamellar plates of the aorta and creates a false lumen. The dissection usually propagates distally down the descending aorta and into its major branches, but it may propagate proximally. Distal propagation may be limited by atherosclerotic plaque. In some cases, a secondary distal intimal disruption occurs, resulting in the reentry of blood from the false to the true lumen.

Clinical Manifestations The peak incidence of aortic dissection is in the sixth and seventh decades. Men are more affected than women by a ratio of 2:1. The presentations of aortic dissection and its variants are the consequences of intimal tear, dissecting hematoma, occlusion of involved arteries, and compression of adjacent tissues. Acute aortic dissection presents with the sudden onset of pain (Chap. 4), which often is described as very severe

471

Diseases of the Aorta

Acute Aortic Syndromes

There are at least two important pathologic and radiologic variants of aortic dissection: intramural hematoma without an intimal flap and penetrating atherosclerotic ulcer. Acute intramural hematoma is thought to result from rupture of the vasa vasorum with hemorrhage into the wall of the aorta. Most of these hematomas occur in the descending thoracic aorta. Acute intramural hematomas may progress to dissection and rupture. Penetrating atherosclerotic ulcers are caused by erosion of a plaque into the aortic media, are usually localized, and are not associated with extensive propagation. They are found primarily in the middle and distal portions of the descending thoracic aorta and are associated with extensive atherosclerotic disease. The ulcer can erode beyond the internal elastic lamina, leading to medial hematoma, and may progress to false aneurysm formation or rupture. Several classification schemes have been developed for thoracic aortic dissections. DeBakey and colleagues initially classified aortic dissections as type I, in which an intimal tear occurs in the ascending aorta but involves the descending aorta as well; type II, in which the dissection is limited to the ascending aorta; and type III, in which the intimal tear is located in the descending aorta with distal propagation of the dissection (Fig. 38-4). Another classification (Stanford) is that of type A, in which the dissection involves the ascending aorta (proximal dissection), and type B, in which it is limited to the descending aorta (distal dissection). From a management standpoint, classification of aortic dissections and intramural hematomas into type A or B is more practical and useful, since DeBakey types I and II are managed in a similar manner. The factors that predispose to aortic dissection include systemic hypertension, a coexisting condition in 70% of patients, and cystic medial necrosis. Aortic dissection is the major cause of morbidity and mortality in patients with Marfan syndrome and similarly may affect patients with Ehlers-Danlos syndrome. The incidence also is increased in patients with inflammatory aortitis (i.e., Takayasu’s arteritis, giant cell arteritis), congenital aortic valve anomalies (e.g., bicuspid valve), coarctation of the aorta, and a history of aortic trauma. In addition, the risk of dissection is increased in otherwise normal women during the third trimester of pregnancy.

CHAPTER 38

associated with symptoms. For asymptomatic aneurysms, abdominal aortic aneurysm repair is indicated if the diameter is >5.5 cm. In randomized trials of patients with abdominal aortic aneurysms 90%. They are useful in recognizing intramural hemorrhage and penetrating ulcers. MRI also can detect blood flow, which may be useful in characterizing antegrade versus retrograde dissection. The relative utility of transesophageal echocardiography, CT, and MRI depends on the availability and expertise in individual institutions as well as on the hemodynamic stability of the patient, with CT and MRI obviously less suitable for unstable patients.

Treatment

Aortic Dissection

Atherosclerosis may affect the thoracic and abdominal aorta. Occlusive aortic disease caused by atherosclerosis usually is confined to the distal abdominal aorta below the renal arteries. Frequently, the disease extends to the iliac arteries (Chap. 39). Claudication characteristically involves the buttocks, thighs, and calves and may be associated with impotence in males (Leriche syndrome). The severity of the symptoms depends on the adequacy of collaterals. With sufficient collateral blood flow, a complete occlusion of the abdominal aorta may occur without the development of ischemic symptoms. The physical findings include the absence of femoral and other distal pulses bilaterally and the detection of an audible bruit over the abdomen (usually at or below the umbilicus) and the common femoral arteries. Atrophic skin, loss of hair, and coolness of the lower extremities usually are observed. In advanced ischemia, rubor on dependency and pallor on elevation can be seen. The diagnosis usually is established by physical examination and noninvasive testing, including leg pressure measurements, Doppler velocity analysis, pulse volume recordings, and duplex ultrasonography. The anatomy may be defined by MRI, CT, or conventional aortography, typically performed when one is considering revascularization. Catheter-based endovascular or operative treatment is indicated in patients with lifestyle-limiting or debilitating symptoms of claudication and patients with critical limb ischemia.

Acute Aortic Occlusion Acute occlusion in the distal abdominal aorta constitutes a medical emergency because it threatens the viability of the lower extremities; it usually results from an occlusive (saddle) embolus that almost always originates from the heart. Rarely, acute occlusion may occur as the result of in situ thrombosis in a preexisting severely narrowed segment of the aorta. The clinical picture is one of acute ischemia of the lower extremities. Severe rest pain, coolness, and pallor of the lower extremities and the absence of distal pulses bilaterally are the usual manifestations. Diagnosis should be established rapidly by MRI, CT, or aortography. Emergency thrombectomy or revascularization is indicated.

Diseases of the Aorta

Chronic Atherosclerotic Occlusive Disease

473

CHAPTER 38

Medical therapy should be initiated as soon as the diagnosis is considered. The patient should be admitted to an intensive care unit for hemodynamic monitoring. Unless hypotension is present, therapy should be aimed at reducing cardiac contractility and systemic arterial pressure, and thus shear stress. For acute dissection, unless contraindicated, β-adrenergic blockers should be administered parenterally, using intravenous propranolol, metoprolol, or the short-acting esmolol to achieve a heart rate of approximately 60 beats/min. This should be accompanied by sodium nitroprusside infusion to lower systolic blood pressure to ≤120 mmHg. Labetalol (Chap. 37), a drug with both β- and α-adrenergic blocking properties, also may be used as a parenteral agent in acute therapy for dissection. The calcium channel antagonists verapamil and diltiazem may be used intravenously if nitroprusside or β-adrenergic blockers cannot be employed. The addition of a parenteral angiotensin-converting enzyme (ACE) inhibitor such as enalaprilat to a β-adrenergic blocker also may be considered. Isolated use of a direct vasodilator such as hydralazine is contraindicated because these agents can increase hydraulic shear and may propagate the dissection. Emergent or urgent surgical correction is the preferred treatment for acute ascending aortic dissections and intramural hematomas (type A) and for complicated type B dissections, including those characterized by propagation, compromise of major aortic branches, impending rupture, or continued pain. Surgery involves excision of the intimal flap, obliteration of the false lumen, and placement of an interposition graft. A composite valve-graft conduit is used if the aortic valve is disrupted. The overall in-hospital mortality rate after surgical treatment of patients with aortic dissection is reported to be 15–25%. The major causes of perioperative mortality and morbidity include myocardial infarction, paraplegia, renal failure, tamponade, hemorrhage, and sepsis. Endoluminal stent grafts may be considered in selected patients. Other transcatheter techniques, such as fenestration of the intimal flaps and stenting of narrowed branch vessels to increase flow to compromised organs, are used in selected patients. For uncomplicated and stable distal dissections and intramural hematomas (type B), medical therapy is the preferred treatment. The in-hospital mortality rate of medically treated patients with type B dissection is 10–20%. Longterm therapy for patients with aortic dissection and intramural hematomas (with or without surgery) consists of control of hypertension and reduction of cardiac contractility with the use of beta blockers plus other antihypertensive agents, such as ACE inhibitors or calcium antagonists. Patients with chronic type B dissection and

intramural hematomas should be followed on an outpatient basis every 6–12 months with contrast-enhanced CT or MRI to detect propagation or expansion. Patients with Marfan syndrome are at high risk for postdissection complications. The long-term prognosis for patients with treated dissections is generally good with careful followup; the 10-year survival rate is approximately 60%.

474

Aortitis

SECTION V Disorders of the Vasculature

Aortitis, a term referring to inflammatory disease of the aorta, may be caused by large vessel vasculitides such as Takayasu’s arteritis and giant cell arteritis, rheumatic and HLA-B27–associated spondyloarthropathies, Behçet’s syndrome, antineutrophil cytoplasmic antibodies (ANCA)associated vasculitides, Cogan’s syndrome, and infections such as syphilis, tuberculosis, and Salmonella, or may be associated with retroperitoneal fibrosis. Aortitis may result in aneurysmal dilation and aortic regurgitation, occlusion of the aorta and its branch vessels, or acute aortic syndromes.

Takayasu’s Arteritis This inflammatory disease often affects the ascending aorta and aortic arch, causing obstruction of the aorta and its major arteries. Takayasu’s arteritis is also termed pulseless disease because of the frequent occlusion of the large arteries originating from the aorta. It also may involve the descending thoracic and abdominal aorta and occlude large branches such as the renal arteries. Aortic aneurysms also may occur. The pathology is a panarteritis characterized by mononuclear cells and occasionally giant cells, with marked intimal hyperplasia, medial and adventitial thickening, and, in the chronic form, fibrotic occlusion. The disease is most prevalent in young females of Asian descent but does occur in women of other geographic and ethnic origins and also in young men. During the acute stage, fever, malaise, weight loss, and other systemic symptoms may be evident. Elevations of the erythrocyte sedimentation rate and C-reactive protein are common. The chronic stages of the disease, which is intermittently active, present with symptoms related to large artery occlusion, such as upper extremity claudication, cerebral ischemia, and syncope. The process is progressive, and there is no definitive therapy. Glucocorticoids and immunosuppressive agents have been reported to be effective in some patients during the acute phase. Surgical bypass or endovascular intervention of a critically stenotic artery may be necessary.

Giant Cell Arteritis This vasculitis occurs in older individuals and affects women more often than men. Primarily large and medium-size arteries are affected. The pathology is that of focal granulomatous lesions involving the entire arterial wall; it may be associated with polymyalgia rheumatica. Obstruction of medium-size arteries (e.g., temporal and ophthalmic arteries) and major branches of the aorta and the development of aortitis and aortic regurgitation are important complications of the disease.

High-dose glucocorticoid therapy may be effective when given early.

Rheumatic Aortitis Rheumatoid arthritis, ankylosing spondylitis, psoriatic arthritis, reactive arthritis (formerly known as Reiter’s syndrome), relapsing polychondritis, and inflammatory bowel disorders may all be associated with aortitis involving the ascending aorta. The inflammatory lesions usually involve the ascending aorta and may extend to the sinuses of Valsalva, the mitral valve leaflets, and adjacent myocardium. The clinical manifestations are aneurysm, aortic regurgitation, and involvement of the cardiac conduction system.

Idiopathic Aortitis Idiopathic abdominal aortitis is characterized by adventitial and periaortic inflammation with thickening of the aortic wall. It is associated with abdominal aortic aneurysms and idiopathic retroperitoneal fibrosis. Affected individuals may present with vague constitutional symptoms, fever, and abdominal pain. Retroperitoneal fibrosis can cause ureteral obstruction and hydronephrosis. Glucocorticoids and immunosuppressive agents may reduce the inflammation.

Infective Aortitis Infective aortitis may result from direct invasion of the aortic wall by bacterial pathogens such as Staphylococcus, Streptococcus, and Salmonella or by fungi. These bacteria cause aortitis by infecting the aorta at sites of atherosclerotic plaque. Bacterial proteases lead to degradation of collagen, and the ensuing destruction of the aortic wall leads to the formation of a saccular aneurysm referred to as a mycotic aneurysm. Mycotic aneurysms have a predilection for the suprarenal abdominal aorta. The pathologic characteristics of the aortic wall include acute and chronic inflammation, abscesses, hemorrhage, and necrosis. Mycotic aneurysms typically affect the elderly and occur in men three times more frequently than in women. Patients may present with fever, sepsis, and chest, back, or abdominal pain; there may have been a preceding diarrheal illness. Blood cultures are positive in the majority of patients. Both CT and MRI are useful to diagnose mycotic aneurysms. Treatment includes antibiotic therapy and surgical removal of the affected part of the aorta and revascularization of the lower extremities with grafts placed in uninfected tissue. Syphilitic aortitis is a late manifestation of luetic infection that usually affects the proximal ascending aorta, particularly the aortic root, resulting in aortic dilation and aneurysm formation. Syphilitic aortitis occasionally

475

Diseases of the Aorta

scar formation, and calcification. These changes account for the characteristic radiographic appearance of linear calcification of the ascending aorta. The disease typically presents as an incidental chest radiographic finding 15–30 years after initial infection. Symptoms may result from aortic regurgitation, narrowing of coronary ostia due to syphilitic aortitis, compression of adjacent structures (e.g., esophagus), or rupture. Diagnosis is established by a positive serologic test, i.e., rapid plasmin reagin (RPR) or fluorescent treponemal antibody. Treatment includes penicillin and surgical excision and repair.

CHAPTER 38

may involve the aortic arch or the descending aorta. The aneurysms may be saccular or fusiform and are usually asymptomatic, but compression of and erosion into adjacent structures may result in symptoms; rupture also may occur. The initial lesion is an obliterative endarteritis of the vasa vasorum, especially in the adventitia. This is an inflammatory response to the invasion of the adventitia by the spirochetes. Destruction of the aortic media occurs as the spirochetes spread into this layer, usually via the lymphatics accompanying the vasa vasorum. Destruction of collagen and elastic tissues leads to dilation of the aorta,

chapter 39

VASCULAR DISEASES OF THE EXTREMITIES Mark A. Creager

■

Joseph Loscalzo Clinical evaluation

arteriaL DisorDers

Fewer than 50% of patients with PAD are symptomatic, although many have a slow or impaired gait. The most common symptom is intermittent claudication, which is defined as a pain, ache, cramp, numbness, or a sense of fatigue in the muscles; it occurs during exercise and is relieved by rest. The site of claudication is distal to the location of the occlusive lesion. For example, buttock, hip, and thigh discomfort occurs in patients with aortoiliac disease, whereas calf claudication develops in patients with femoral-popliteal disease. Symptoms are far more common in the lower than in the upper extremities because of the higher incidence of obstructive lesions in the former region. In patients with severe arterial occlusive disease in whom resting blood flow cannot accommodate basal nutritional needs of the tissues, critical limb ischemia may develop. Patients complain of rest pain or a feeling of cold or numbness in the foot and toes. Frequently, these symptoms occur at night when the legs are horizontal and improve when the legs are in a dependent position. With severe ischemia, rest pain may be persistent. Important physical ﬁndings of PAD include decreased or absent pulses distal to the obstruction, the presence of bruits over the narrowed artery, and muscle atrophy. With more severe disease, hair loss, thickened nails, smooth and shiny skin, reduced skin temperature, and pallor or cyanosis are common physical signs. In patients with critical limb ischemia, ulcers or gangrene may occur. Elevation of the legs and repeated flexing of the calf muscles produce pallor of the soles of the feet, whereas rubor, secondary to reactive hyperemia, may develop when the legs are dependent. The time required for rubor to develop or for the veins in the foot to fill when the patient’s legs are transferred from an elevated to a dependent position is related to the severity of the ischemia and the presence of collateral vessels.

peripheral arTery Disease Peripheral artery disease (PAD) is defined as a clinical disorder in which there is a stenosis or occlusion in the aorta or the arteries of the limbs. Atherosclerosis is the leading cause of PAD in patients >40 years old. Other causes include thrombosis, embolism, vasculitis, fibromuscular dysplasia, entrapment, cystic adventitial disease, and trauma. The highest prevalence of atherosclerotic PAD occurs in the sixth and seventh decades of life. As in patients with atherosclerosis of the coronary and cerebral vasculature, there is an increased risk of developing PAD in cigarette smokers and in persons with diabetes mellitus, hypercholesterolemia, hypertension, or hyperhom*ocysteinemia. Pathology (See also Chap. 30) Segmental lesions that cause stenosis or occlusion are usually localized to large and medium-size vessels. The pathology of the lesions includes atherosclerotic plaques with calcium deposition, thinning of the media, patchy destruction of muscle and elastic fibers, fragmentation of the internal elastic lamina, and thrombi composed of platelets and fibrin. The primary sites of involvement are the abdominal aorta and iliac arteries (30% of symptomatic patients), the femoral and popliteal arteries (80–90% of patients), and the more distal vessels, including the tibial and peroneal arteries (40–50% of patients). Atherosclerotic lesions occur preferentially at arterial branch points, which are sites of increased turbulence, altered shear stress, and intimal injury. Involvement of the distal vasculature is most common in elderly individuals and patients with diabetes mellitus.

476

Noninvasive testing

Figure 39-1 Magnetic resonance angiography of a patient with intermittent claudication, showing stenoses of the distal abdominal aorta and right iliac common iliac artery (A) and stenoses of

Prognosis The natural history of patients with PAD is influenced primarily by the extent of coexisting coronary artery and cerebrovascular disease. Approximately one-third to

the right and left superficial femoral arteries (B). (Courtesy of Dr. Edwin Gravereaux; with permission.)

477

Vascular Diseases of the Extremities

The history and physical examination are often sufficient to establish the diagnosis of PAD. An objective assessment of the presence and severity of disease is obtained by noninvasive techniques. Arterial pressure can be recorded noninvasively in the legs by placement of sphygmomanometric cuffs at the ankles and the use of a Doppler device to auscultate or record blood flow from the dorsalis pedis and posterior tibial arteries. Normally, systolic blood pressure in the legs and arms is similar. Indeed, ankle pressure may be slightly higher than arm pressure due to pulse-wave amplification. In the presence of hemodynamically significant stenoses, the systolic blood pressure in the leg is decreased. Thus, the ratio of the ankle and brachial artery pressures (termed the ankle:brachial index, or ABI) is ≥1.0 in normal individuals and 3 months Includes: • Chronic pulmonary thromboembolism • Nonthrombotic pulmonary embolism (tumor, foreign material) Category 5. Miscellaneous Key feature: elevation in PAP in association with a systemic disease where a causal relationship is not clearly understood Includes: • Sarcoidosis • Chronic anemias • Histiocytosis X • Lymphangiomatosis • Schistosomiasis

Inflammation

Thrombosis Hyperpolarized mitochondria

NFAT activation

HIF-1α activation

KV 1.5 down regulation

Increased tissue factor

BMPR-2 insufficiency Suppressed apoptosis

Constriction

Overexpressed serotonin transporter

Proliferation

Figure 40-2 Multiple biologic pathways that can lead to pulmonary arterial hypertension. Some of the better-characterized ones are illustrated. Because of the redundancy in these pathways and the spectrum of abnormalities that may coexist, it is unlikely that a single agent will produce disease reversal. BMPR-2, bone morphogenetic protein receptor-2; HIF, hypoxia inducible factor; KV 1.5, voltage-regulated potassium channel 1.5; NFAT, nuclear factor of activated T cells.

the gene that code the type II bone morphogenetic protein receptor (BMPR II), a member of the transforming growth factor (TGF) β superfamily, appear to account for most cases of familial IPAH. The TGF-β superfamilies include multifunctional proteins that initiate diverse cellular responses by binding to and activating serine/ threonine kinase receptors. The low gene penetrance indicates that other risk factors or abnormalities are necessary to manifest clinical disease. Germ-line mutations in the activin-like kinase gene and endoglin gene, which have been linked to hereditary hemorrhagic telangiectasia, coexist in some patients with familial IPAH.

Natural History The natural history of IPAH is uncertain, but the disease typically is diagnosed late in its course. Before current therapies, a mean survival of 2–3 years from the time of diagnosis was reported. Functional class remains a strong predictor of survival, with patients who are in New York Heart Association (NYHA) functional class IV having a mean survival of 20 μg/mL

(continued)

Table 3

561

Toxicology and Therapeutic Drug Monitoring (CONTINUED) Therapeutic Range

Toxic Level

SI Units

Conventional Units

SI Units

Conventional Units

Ethosuximide Everolimus

280–700 μmol/L 3.13–8.35 nmol/L

40–100 μg/mL 3–8 ng/mL

>700 μmol/L >12.5 nmol/L

>100 μg/mL >12 ng/mL

Flecainide Gentamicin Peak Trough

0.5–2.4 μmol/L

0.2–1.0 μg/mL

>3.6 μmol/L

>1.5 μg/mL

10–21 μmol/mL 0–4.2 μmol/mL

5–10 μg/mL 0–2 μg/mL

>25 μmol/mL >4.2 μmol/mL

>12 μg/mL >2 μg/mL

49–243 μmol/L

10–50 μg/mL

>700 μmol/L >970 μmol/L

>200 ng/mL (as morphine) >200 μg/mL

375–1130 nmol/L 563–1130 nmol/L

100–300 ng/mL 150–300 ng/mL

>1880 nmol/L >1880 nmol/L

>500 ng/mL >500 ng/mL

Lamotrigine Lidocaine Lithium

11.7–54.7 μmol/L 5.1–21.3 μmol/L 0.5–1.3 mmol/L

3–14 μg/mL 1.2–5.0 μg/mL 0.5–1.3 meq/L

>58.7 μmol/L >38.4 μmol/L >2 mmol/L

>15 μg/mL >9.0 μg/mL >2 meq/L

Methadone Methamphetamine Methanol

1.0–3.2 μmol/L 0.07–0.34 μmol/L

0.3–1.0 μg/mL 0.01–0.05 μg/mL

>6.5 μmol/L >3.35 μmol/L >6 mmol/L

>2 μg/mL >0.5 μg/mL >20 mg/dL

Methotrexate Low-dose High-dose (24 h) High-dose (48 h) High-dose (72 h)

0.01–0.1 μmol/L 5.0 μmol/L >0.5 μmol/L >0.1 μmol/L

Morphine Mycophenolic acid Nitroprusside (as thiocyanate) Nortriptyline Phenobarbital

232–286 μmol/L 3.1–10.9 μmol/L 103–499 μmol/L 190–569 nmol/L 65–172 μmol/L

65–80 ng/mL 1.0–3.5 ng/mL 6–29 μg/mL 50–150 ng/mL 15–40 μg/mL

>720 μmol/L >37 μmol/L 860 μmol/L >1900 nmol/L >258 μmol/L

>200 ng/mL >12 ng/mL >50 μg/mL >500 ng/mL >60 μg/mL

Phenytoin Phenytoin, free % Free

40–79 μmol/L 4.0–7.9 μg/mL 0.08–0.14

10–20 μg/mL 1–2 μg/mL 8–14%

>158 μmol/L >13.9 μg/mL

>40 μg/mL >3.5 μg/mL

Primidone and metabolite Primidone Phenobarbital

23–55 μmol/L 65–172 μmol/L

5–12 μg/mL 15–40 μg/mL

>69 μmol/L >215 μmol/L

>15 μg/mL >50 μg/mL

Procainamide Procainamide NAPA (N-acetylprocainamide)

17–42 μmol/L 22–72 μmol/L

4–10 μg/mL 6–20 μg/mL

>43 μmol/L >126 μmol/L

>10 μg/mL >35 μg/mL

6.2–15.4 μmol/L 145–2100 μmol/L

2.0–5.0 μg/mL 2–29 mg/dL

>19 μmol/L >2900 μmol/L

>6 μg/mL >40 mg/dL

4.4–15.4 nmol/L

4–14 ng/mL

>16 nmol/L

>15 ng/mL

12–19 nmol/L

10–15 ng/mL

>25 nmol/L

>20 ng/mL

6–12 nmol/L

5–10 ng/mL

>25 nmol/L

>20 ng/mL

19–25 nmol/L 6–12 nmol/L

15–20 ng/mL 5–10 ng/mL

Heroin (diacetyl morphine) Ibuprofen Imipramine (and metabolite) Desimipramine Total imipramine + desimipramine

Tacrolimus (FK506) (trough) Kidney and liver Initiation Maintenance Heart Initiation Maintenance

Laboratory Values of Clinical Importance

Quinidine Salicylates Sirolimus (trough level) Kidney transplant

APPENDIX

Drug

(continued)

562

Table 3 Toxicology and Therapeutic Drug Monitoring (CONTINUED) Therapeutic Range

Toxic Level

APPENDIX

Drug

SI Units

Conventional Units

SI Units

Conventional Units

Theophylline Thiocyanate After nitroprusside infusion Nonsmoker Smoker

56–111 μg/mL

10–20 μg/mL

>168 μg/mL

>30 μg/mL

103–499 μmol/L 17–69 μmol/L 52–206 μmol/L

6–29 μg/mL 1–4 μg/mL 3–12 μg/mL

860 μmol/L

>50 μg/mL

Tobramycin Peak Trough

11–22 μg/L 0–4.3 μg/L

5–10 μg/mL 0–2 μg/mL

>26 μg/L >4.3 μg/L

>12 μg/mL >2 μg/mL

Valproic acid

346–693 μmol/L

50–100 μg/mL

>693 μmol/L

>100 μg/mL

Vancomycin Peak Trough

14–28 μmol/L 3.5–10.4 μmol/L

20–40 μg/mL 5–15 μg/mL

>55 μmol/L >14 μmol/L

>80 μg/mL >20 μg/mL

Laboratory Values of Clinical Importance

Table 4 Vitamins and Selected Trace Minerals Reference Range Specimen

Analyte

SI Units

Conventional Units

Aluminum

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References