Tresch and Aronow's cardiovascular disease in the elderly [Sixth edition] 9781138558298, 113855829X

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Content: PrefaceAcknowledgments1. Structure and function of skin 2. Free radicals in biology 3. The skin's endogenous antioxidant network 4. Effects of solar radiation, air pollution, and artificial blue light on the skin 5. Lipid peroxidation and its measurement 6. Antioxidant assays 7. Electron spin resonance of skin 8. Treatment of skin with antioxidants 9. Antioxidant properties and application information Appendix 1: Glossary of terms Appendix 2: Biologically important molecules and mechanisms Appendix 3: Cellular signaling in skin Appendix 4: Thermodynamic and kinetic factors that contribute to antioxidant behavior Index

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Tresch and Aronow’s Cardiovascular Disease in the Elderly

Tresch and Aronow’s Cardiovascular Disease in the Elderly Sixth Edition

Edited by

Wilbert S. Aronow, MD

Professor of Medicine and Director of Cardiology Research Westchester Medical Center/New York Medical College

Jerome L. Fleg, MD

Division of Cardiovascular Sciences, National Heart, Lung, and Blood Institute, National Institutes of Health

Michael W. Rich, MD

Professor of Medicine Washington University School of Medicine

CRC Press Taylor & Francis Group 6000 Broken Sound Parkway NW, Suite 300 Boca Raton, FL 33487-2742 © 2019 by Taylor & Francis Group, LLC CRC Press is an imprint of Taylor & Francis Group, an Informa business No claim to original U.S. Government works Printed on acid-free paper International Standard Book Number-13: 978-1-138-55829-8 (Hardback) This book contains information obtained from authentic and highly regarded sources. Reasonable efforts have been made to publish reliable data and information, but the author and publisher cannot assume responsibility for the validity of all materials or the consequences of their use. The authors and publishers have attempted to trace the copyright holders of all material reproduced in this publication and apologize to copyright holders if permission to publish in this form has not been obtained. If any copyright material has not been acknowledged please write and let us know so we may rectify in any future reprint. Except as permitted under U.S. Copyright Law, no part of this book may be reprinted, reproduced, transmitted, or utilized in any form by any electronic, mechanical, or other means, now known or hereafter invented, including photocopying, microfilming, and recording, or in any information storage or retrieval system, without written permission from the publishers. For permission to photocopy or use material electronically from this work, please access www.copyright.com (http://www.copyright.com/) or contact the Copyright Clearance Center, Inc. (CCC), 222 Rosewood Drive, Danvers, MA 01923, 978-750-8400. CCC is a not-for-profit organization that provides licenses and registration for a variety of users. For organizations that have been granted a photocopy license by the CCC, a separate system of payment has been arranged. Trademark Notice: Product or corporate names may be trademarks or registered trademarks, and are used only for identification and explanation without intent to infringe. Library of Congress Cataloging‑in‑Publication Data Names: Aronow, Wilbert S., editor. | Fleg, Jerome L., editor. | Rich, Michael W., editor. Title: Tresch and Aronow’s cardiovascular disease in the elderly / edited by Wilbert S. Aronow, Jerome L. Fleg, and Michael W. Rich. Other titles: Cardiovascular disease in the elderly Description: Sixth edition. | Boca Raton, FL : CRC Press/Taylor & Francis Group, [2019] | Includes bibliographical references and index. Identifiers: LCCN 2018035161 | ISBN 9781138558298 (hardback : alk. paper) Subjects: | MESH: Cardiovascular Diseases--physiopathology | Cardiovascular Diseases--therapy | Aged Classification: LCC RC669 | NLM WG 120 | DDC 618.97/61--dc23 LC record available at https://lccn.loc.gov/2018035161 Visit the Taylor & Francis Web site at http://www.taylorandfrancis.com and the CRC Press Web site at http://www.crcpress.com

Contents

Foreword vii Preface ix Editors xi Contributors xiii 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19

Cardiovascular changes with aging Jerome L. Fleg Morphologic features and pathology of the elderly heart Atsuko Seki, Gregory A. Fishbein, and Michael C. Fishbein General principles on caring for older adults Dae Hyun Kim and Sandra M. Shi Cardiovascular drug therapy in the elderly William H. Frishman, Wilbert S. Aronow, and Angela Cheng-Lai Systemic hypertension in the elderly Wilbert S. Aronow and William H. Frishman Disorders of lipid metabolism Mays T. Ali and Seth S. Martin Diabetes mellitus and cardiovascular disease in the elderly Samuel C. Durso Epidemiology and prevention of coronary heart disease in older adults Nathan D. Wong, David Tehrani, and Stanley S. Franklin Diagnosis of coronary heart disease in the elderly Wilbert S. Aronow and Jerome L. Fleg Angina pectoris in the elderly Wilbert S. Aronow and William H. Frishman Therapy of acute myocardial infarction Joshua M. Stolker and Michael W. Rich Management of the older patient after myocardial infarction Howard A. Cooper, Julio A. Panza, and Wilbert S. Aronow Surgical management of coronary artery disease Melissa M. Anastacio, Alejandro Suarez Pierre, and Jennifer S. Lawton Percutaneous coronary intervention in the elderly Kashish Goel and David R. Holmes Exercise training and comprehensive cardiac rehabilitation in older cardiac patients Daniel E. Forman Aortic valve disease in the elderly Madhur A. Roberts, Ryan K. Kaple, and Wilbert S. Aronow Mitral regurgitation, mitral stenosis, and mitral annular calcification in the elderly Hasan Ahmad and Wilbert S. Aronow Infective endocarditis in older adults Sairia Dass and Lona Mody Cardiomyopathies in the elderly John Arthur McClung, Srihari S. Naidu, and Wilbert S. Aronow

1 28 49 64 95 111 128 149 166 187 206 239 255 266 282 293 323 353 366 v

vi Contents

20 21 22 23 24 25 26 27 28 29 30 31 32

Thyroid heart disease in the elderly Myron Miller and Steven R. Gambert Heart failure with reduced ejection fraction in older adults Ali Ahmed and Jerome L. Fleg Heart failure with preserved ejection fraction in older adults Bharathi Upadhya and Dalane W. Kitzman Supraventricular tachyarrhythmias in the elderly Jason T. Jacobson, Sei Iwai, Ali Ahmed, and Wilbert S. Aronow Ventricular arrhythmias in the elderly Jason T. Jacobson, Sei Iwai, and Wilbert S. Aronow Bradyarrhythmias and cardiac pacemakers in the elderly Naktal Hamoud, Fernando Tondato, and Win-Kuang Shen Cerebrovascular disease in the elderly patient Laura Stein and Jesse Weinberger Evaluation and management of syncope and related disorders in the elderly Andrea Ungar, Martina Rafanelli, and Michele Brignole Pericardial disease in the elderly Massimo Imazio Venous thromboembolic disease in older adults Laurie G. Jacobs, Justin B. Kaplan, and Ruchi Jain Management of peripheral arterial disease in the elderly Wilbert S. Aronow Perioperative cardiovascular evaluation and treatment of elderly patients undergoing noncardiac surgery Dipika Gopal, Monika Sanghavi, and Lee A. Fleisher Ethical decisions and end-of-life care in older patients with cardiovascular disease Esther S. Pak, James N. Kirkpatrick, Craig Tanner, and Sarah J. Goodlin

383 406 422 442 468 490 512 530 544 563 584 602 626

Index 639

Foreword

It is indeed a pleasure to write this foreword for the new sixth edition of Tresch and Aronow’s Cardiovascular Disease in the Elderly. This work has now become a classic in the field of geriatric cardiology, and the new edition contains a great deal of up-to-date information concerning the diagnosis and therapy of cardiovascular disease in this everexpanding segment of our population. All of the chapters have been revised to reflect the latest research in this large and complex field. Excellent summaries are found at the outset of each chapter in order to facilitate easy reading, and there is a comprehensive bibliography for readers interested in delving more deeply into a particular topic. Contemporary evidence-based recommendations are suggested when available, and there is continued strong

emphasis on new research findings. For example, readers will find an extensive discussion of the direct-acting antithrombotic agents that are rapidly replacing warfarin. This is truly a lovely book that should be studied by medical practitioners throughout the world, given the remarkable increase in the number of elderly patients with cardiac and vascular disorders in recent years. The editors and authors are to be congratulated for this outstanding contribution to the scientific understanding and clinical care of older patients with cardiovascular disease. Joseph S. Alpert, MD University of Arizona College of Medicine Editor-in-Chief, The American Journal of Medicine

vii

Preface

In 2010, the first of the baby boomers turned 65 years old, and we are now in the midst of an explosive growth in the older adult population in the United States, from 49 million in 2016 to approximately 73  million by 2030, with a further increase to 86  million by 2050.1 Moreover, the most rapid growth will occur in the subgroup 85 years of age or older—from 6.4  million in 2016 to 9.0  million in 2030 and 18.6 million by 2050, an almost threefold rise. Similar demographic shifts are occurring in many countries around the world. Accompanying this graying of the population is a dramatic rise in the number of older persons with cardiovascular disorders, including hypertension, coronary artery disease, valvular heart disease, heart failure, and cardiac rhythm disturbances. Since persons over age 65 already account for more than 80% of all deaths attributable to cardiovascular disease, it is essential for all clinicians involved in the care of older adults—not just primary care physicians, geriatricians, and cardiologists, but also surgeons, anesthesiologists, other medical subspecialists, and nurse practitioners—to have a basic understanding of the effects of aging on cardiovascular structure and function, as well as the impact of aging and prevalent comorbid conditions on the clinical presentation, diagnosis, and response to therapy in older adults with cardiovascular disease. As with prior editions, the primary objective of the present volume is to provide an up-to-date and in-depth, yet clinically relevant and readable overview of the epidemiology, pathophysiology, evaluation, and treatment of cardiovascular disorders in older adults. To the extent possible, clinical recommendations are evidence based, but it is also acknowledged that existing data are often quite limited or nonexistent in the very elderly (persons 85 years of age or older), and especially in older adults with multiple coexisting conditions and/or frailty. Thus, careful consideration of each patient’s unique clinical and psychosocial circumstances, medical and nonmedical needs, and personal preferences is required in designing an individualized care plan.

Indeed, it is perhaps in the compassionate management of these challenging patients where the “art” of medicine most clearly flourishes. This edition appears 4  years after the fifth edition, which was published in 2014. During the intervening period, an extensive body of new research relevant to the ­diagnosis and treatment of cardiovascular disorders in older adults has been reported. In addition to an expanding literature derived from population-based observational studies, an increasing number of clinical trials focusing on older adults have been undertaken, practice guidelines are increasingly providing explicit commentary on the diagnosis and management of older adults, and both  the American College  of Cardiology and the American  Heart  Association have established sections focusing on issues relevant to older adults with cardiovascular disease. With the sixth edition of this work, we have added a new chapter entitled “General Principles on Caring for Older Adults,” which subsumes and expands the chapter on disability and frailty from the fifth edition. We also expanded the chapter on heart failure to two chapters addressing “Heart Failure with Reduced Ejection Fraction in Older Adults” and “Heart Failure with Preserved Ejection Fraction in Older Adults” in recognition of the importance of the latter form of heart failure in older patients. In addition, all chapters have been thoroughly revised and updated by recognized experts to incorporate the most recent knowledge in the field. We would like to thank all of the contributors for their outstanding work. We also wish to express our gratitude to Ben O’Hara, Shivangi Pramanik, and Mouli Sharma at Taylor & Francis Group for their dedication and support in bringing this sixth edition to fruition. Finally, we want to thank you, the reader, for your commitment to providing the best possible care for your older patients with cardiovascular disease. We hope you will find this volume to be a valuable resource as you strive to help your older patients enjoy both longer and fuller lives. We welcome any comments you may have.

US Census Bureau. 2017 National Population Projections Tables. Available at: https://www.census.gov/data/tables/2017/demo/ popproj/2017-summary-tables.html (accessed July 23, 2018).

Michael W. Rich, MD, FACC, AGSF Wilbert S. Aronow, MD, FACC, FAHA Jerome L. Fleg, MD, FACC, FAHA

1

ix

Editors

Wilbert S. Aronow, MD is currently Professor of Medicine and Director of Cardiology Research at Westchester Medical Center and New York Medical College. He received his MD from Harvard Medical School. He has edited 16 books; has authored or coauthored 1,657 papers or book chapters, 518 commentaries, 47 Letters to the Editor, and 1,102 abstracts; and has presented or copresented 1,473 talks at meetings. Dr. Aronow is a Fellow of the ACC, the AHA, the ACP, ACCP, the ASPC, the AGS (Founding Fellow of Western Section), and the GSA. He also received a Distinguished Fellowship Award from the International Academy of Cardiology. He has been a member of 172 editorial boards of medical journals. He has received numerous teaching and research awards. He has been a member of four national guidelines committees, including being a coauthor of the 2010 American Medical Director Association guidelines for heart failure, a co-chair of the 2011 ACC/AHA expert consensus document on hypertension in the elderly, a coauthor of the 2015 AHA/ACC/ASH scientific statement on treatment of hypertension in patients with coronary artery disease, and a coauthor of the 2017 ACC/AHA/AAPA/ABC/ ACPM/AGS/APhA/ASH/ASPC/NMA/PCNA guideline for the prevention, detection, evaluation, and management of high blood pressure in adults.

Jerome L. Fleg, MD, FACC, FAHA is a Medical Officer, Division of Cardiovascular Sciences, National Heart, Lung, and Blood Institute, Bethesda, Maryland and Guest Researcher, Laboratory of Cardiovascular Science, Gerontology Research Center, National Institute on Aging, Baltimore, Maryland. Dr. Fleg received his MD from the University of Cincinnati College of Medicine and has authored over 350 peer-reviewed articles, book chapters, reviews, and editorials related to cardiovascular aging and disease. He serves on multiple journal editorial boards and is an associate editor for the Journal of Cardiopulmonary Rehabilitation and Prevention and Aging: Clinical and Experimental Research. Michael W. Rich, MD, FACC, FAHA, AGSF is Professor of Medicine, Washington University School of Medicine, and Director, Cardiac Rapid Evaluation Unit, Barnes–Jewish Hospital, St. Louis, Missouri. Dr. Rich received his MD from the University of Illinois College of Medicine, Chicago. He has published over 300 journal articles and more than 70 books and book chapters. Dr. Rich is Senior Associate Editor for the Journal of Cardiac Failure, Associate Editor for The American Journal of Medicine, and Consulting Editor for the Journal of the American Geriatrics Society.

xi

Contributors

Hasan Ahmad Division of Cardiology Westchester Medical Center and Assistant Professor of Medicine New York Medical College Valhalla, New York Ali Ahmed Veterans Affairs Medical Center and Department of Medicine George Washington University Washington, District of Columbia

Howard A. Cooper Division of Cardiology Westchester Medical Center and New York Medical College Valhalla, New York Sairia Dass Division of Geriatric Medicine and Gerontology Johns Hopkins University School of Medicine Baltimore, Maryland Samuel C. Durso Division of Geriatric Medicine and Gerontology Johns Hopkins University School of Medicine Baltimore, Maryland

Mays T. Ali Department of Medicine Division of Cardiology The Johns Hopkins University School of Medicine Baltimore, Maryland

Gregory A. Fishbein Department of Pathology and Laboratory Medicine David Geffen School of Medicine at UCLA Los Angeles, California

Melissa M. Anastacio MedStar Washington Hospital Center Washington, District of Columbia

Michael C. Fishbein Department of Pathology and Laboratory Medicine David Geffen School of Medicine at UCLA Los Angeles, California

Wilbert S. Aronow Divisions of Cardiology, Geriatrics and Pulmonary/Critical Care Department of Medicine Westchester Medical Center and New York Medical College Valhalla, New York Michele Brignole Department of Cardiology Arrhythmologic Centre Lavagna, Italy Angela Cheng-Lai Department of Pharmacy Montefiore Medical Center Bronx, New York

Jerome L. Fleg Division of Cardiovascular Diseases National Heart, Lung, and Blood Institute National Institutes of Health Bethesda, Maryland Lee A. Fleisher Department of Anesthesiology and Critical Care University of Pennsylvania School of Medicine Philadelphia, Pennsylvania Daniel E. Forman Section of Geriatric Cardiology University of Pittsburgh Medical Center (UPMC) Pittsburgh, Pennsylvania

xiii

xiv Contributors

Stanley S. Franklin Heart Disease Prevention Program Division of Cardiology University of California Irvine, California William H. Frishman Division of Cardiology Department of Medicine Westchester Medical Center and New York Medical College Valhalla, New York Steven R. Gambert Department of Medicine University of Maryland School of Medicine and Department of Medicine The Johns Hopkins University School of Medicine Baltimore, Maryland Kashish Goel Division of Cardiovascular Diseases Vanderbilt University Nashville, Tennessee Sarah J. Goodlin Professor, Oregon Health and Science University and Chief, Geriatrics and Palliative Medicine VA Portland Healthcare System Portland, Oregon

Sei Iwai Director, Cardiac Electrophysiology Program Westchester Medical Center Valhalla, New York Laurie G. Jacobs Professor and Chair, Department of Internal Medicine Hackensack Meridian School of Medicine at Seton Hall Nutley, New Jersey and Chair, Department of Internal Medicine Hackensack University Medical Center Hackensack, New Jersey Jason T. Jacobson Associate Professor, New York Medical College and Director, Complex Arrhythmia Ablation Program Westchester Medical Center Valhalla, New York Ruchi Jain Critical Care Pharmacy Specialist Hackensack University Medical Center Hackensack, New Jersey Justin B. Kaplan Clinical Pharmacy Specialist – Critical Care Overlook Medical Center/Atlantic Health System Summit, New Jersey

Dipika Gopal Department of Medicine Division of Cardiology University of Pennsylvania Philadelphia, Pennsylvania

Ryan K. Kaple Yale School of Medicine Yale New Haven Hospital New Haven, Connecticut

Naktal Hamoud Department of Medicine University of Arizona College of Medicine Tucson, Arizona

Dae Hyun Kim Department of Medicine Harvard Medical School Boston, Massachusetts

David R. Holmes Department of Cardiovascular Diseases Mayo Clinic Rochester, Minnesota

James N. Kirkpatrick University of Washington Division of Cardiology Department of Bioethics and Humanities Seattle, Washington

Massimo Imazio Azienda Ospedaliera Città della Salute e della Scienza di Torino University Cardiology Turin, Italy

Dalane W. Kitzman Cardiovascular Medicine Section Department of Internal Medicine Wake Forest School of Medicine Winston-Salem, North Carolina

Contributors xv

Jennifer S. Lawton Division of Cardiac Surgery The Johns Hopkins University School of Medicine Baltimore, Maryland Seth S. Martin Department of Medicine Division of Cardiology The Johns Hopkins University School of Medicine Baltimore, Maryland John Arthur McClung Professor of Clinical Medicine and Professor of Clinical Public Health New York Medical College Valhalla, New York Myron Miller Department of Medicine Sinai Hospital of Baltimore and Department of Medicine The Johns Hopkins University School of Medicine Baltimore, Maryland Lona Mody Amanda Sanford Hickey Professor of Internal Medicine and Associate Division Chief, Geriatric and Palliative Care Medicine and Director, UM Pepper Center Pilot and Exploratory Studies Core and Associate Director, Clinical and Translational Research, Geriatrics Center University of Michigan Geriatrics Ann Arbor, Michigan Srihari S. Naidu Professor of Medicine New York Medical College and Director of Cardiac Cath Labs and Director of Hypertrophic Cardiomyopathy Center Westchester Medical Center Valhalla, New York Esther S. Pak University of Pennsylvania Division of Cardiovascular Medicine Philadelphia, Pennsylvania

Julio A. Panza Division of Cardiology Westchester Medical Center and New York Medical College Valhalla, New York Martina Rafanelli Syncope Unit Department of Geriatrics Careggi University Hospital Florence, Italy Michael W. Rich Mercy Clinic Heart and Vascular Washington, Missouri and Washington University School of Medicine St. Louis, Missouri Madhur A. Roberts Internal Medicine Piedmont Atlanta Hospital Atlanta, Georgia Monika Sanghavi Department of Medicine Division of Cardiology University of Pennsylvania Philadelphia, Pennsylvania Atsuko Seki Department of Pathology and Laboratory Medicine Cleveland Clinic Cleveland, Ohio Win-Kuang Shen Department of Cardiovascular Diseases Mayo Clinic Phoenix, Arizona and Mayo Clinic College of Medicine Rochester, Minnesota Sandra M. Shi Geriatric Medicine Harvard Medical School Boston, Massachusetts Laura Stein Department of Neurology Icahn School of Medicine at Mount Sinai New York City, New York

xvi Contributors

Joshua M. Stolker Mercy Clinic Heart and Vascular Washington, Missouri Alejandro Suarez Pierre Division of Cardiac Surgery The Johns Hopkins University School of Medicine Baltimore, Maryland Craig Tanner Medical Director, Legacy Hospice Legacy Health System Portland, Oregon David Tehrani Heart Disease Prevention Program Division of Cardiology University of California Irvine, California Fernando Tondato Cardiac Electrophysiology Kaiser Permanente Portland, Oregon

Andrea Ungar Syncope Unit Department of Geriatrics Careggi University Hospital Florence, Italy Bharathi Upadhya Cardiovascular Medicine Section Department of Internal Medicine Wake Forest School of Medicine Winston-Salem, North Carolina Jesse Weinberger Department of Neurology Icahn School of Medicine at Mount Sinai New York City, New York Nathan D. Wong Heart Disease Prevention Program Division of Cardiology University of California Irvine, California

1 Cardiovascular changes with aging JEROME L. FLEG Introduction 1 Methodological issues 2 Arterial changes: The root cause of unsuccessful aging 2 Intimal medial thickening 2 Endothelial dysfunction 3 Arterial stiffness and compliance 4 Pulse wave velocity 4 Reflected pulse waves 4 Systolic, diastolic, and pulse pressure 6 Interventions to retard or prevent accelerated arterial aging 6 Cardiac structure and resting function 7 CV physical findings in older adults 9 CV response to stress 9 Orthostatic stress 10 Pressor stress 10 Aerobic exercise capacity 10 Mechanisms of impaired LV ejection during maximal aerobic exercise in healthy older adults 13 Myocardial contractility 13

LV afterload 13 Arterial/ventricular load matching 13 Sympathetic modulation 14 Sympathetic neurotransmitters 14 Deficits in cardiac β-adrenergic receptor signaling 14 Relevant aging changes in other organ systems 14 Electrocardiography and arrhythmias 14 Anatomical conduction system changes 14 Electrocardiography 15 Sinus node function 15 P waves 15 P–R interval 16 QRS complex 16 Repolarization 17 Arrhythmias 17 Atrial arrhythmias 17 Atrial fibrillation 17 Paroxysmal supraventricular tachycardia 18 Ventricular arrhythmias 18 References 20

INTRODUCTION

Nevertheless, it is important to define normal CV structure and function in older adults to facilitate the accurate diagnosis of CV disease in this rapidly growing segment of society. Another important goal of this chapter will be to demonstrate how aging changes in the CV system may themselves predispose individuals to the development of CV disease. The enhanced CV risk associated with age indicates important interactions between mechanisms that underlie aging and those that underlie diseases. The nature of these interactions is complex and involves not only mechanisms of aging but also multiple defined and undefined risk factors. Yet quantitative information on age-associated alterations in CV structure and function is essential to define and target the specific characteristics of CV aging that render it such a major risk factor. Such information is also required to differentiate between the limitations of an elderly person that relate to disease and those that are within expected normal limits.

As longevity increases throughout the world, disorders and diseases associated with aging assume increasing importance. In the United States, approximately 13% of the population is 65  years and older; this proportion is expected to reach nearly 20% by the year 2030, comprising over 70 ­million people (1). The fastest-growing age group, comprising those 85 years or older, has more than quadrupled since 1960 and will exceed 20 million by 2060 (Figure 1.1). Because both the prevalence and incidence of cardiovascular (CV) disease increase dramatically with age, this “graying” of the population has created a huge number of older adults requiring treatment. However, aging per se is not necessarily accompanied by CV disease. This chapter will set the stage for those that follow by delineating the changes in the CV system that occur during the aging process in the absence of detectable CV disease. This is a challenging task, given the many factors that blur their separation.

1

2  Cardiovascular changes with aging

From Pyramid to Pillar: A Century of Change Ages 85+ 80–84 75–79 70–74 65–69 60–64 55–59 50–54 45–49 40–44 35–39 30–34 25–29 20–24 15–19 10–14 5–9 0–4 15

1960 Male Female

10 5 0 5 10 Millions of people

2060 Male Female

15

15

10 5 0 5 10 Millions of people

15

Figure 1.1  Projected growth of the U.S. population between 1960 and 2060, stratified by age group. (From United States Bureau of the Census, www.census.gov/population/www/ estimates/popest.html. March 13, 2018.)

METHODOLOGICAL ISSUES There are multiple methodological issues that must be addressed in defining “normal” aging. Because the population sample from which norms are derived will strongly influence the results obtained, it should be representative of the general population. Thus, neither a seniors cycling club nor nursing home residents would provide appropriate normal values for maximal exercise capacity that could be applied to the majority of elders. In addition, the degree of screening used to define “normal” can profoundly influence the results. In clinically healthy older adults, a resting electrocardiogram (ECG), echocardiogram, or exercise perfusion imaging study will often identify silent CV disease, especially coronary artery disease (CAD). If multiple screening tests are used, only a small proportion of the older population may qualify as normal, limiting the applicability of findings to the majority of older adults. Furthermore, the inclusion limits chosen for body fatness, blood pressure, smoking status, and other constitutional or lifestyle variables will significantly influence the normal range for CV variables. For example, if a systolic pressure of ≥130 mmHg is considered hypertension as per recent guidelines, and if hypertension is considered a disease, then individuals with a systolic pressure between 130 and 140 mmHg, who were previously considered normotensive, are now identified as having CV disease. Numerous studies have shown that individuals who manifest even modest elevations in systolic and pulse pressures are more likely to develop overt CV disease or die from it. Further methodological issues can affect the definitions of normal aging. Cross-sectional studies, which study individuals across a wide age range at a single time point, may underestimate the magnitude of age-associated changes because older normal persons included in such studies

represent “survival of the fittest.” True age-induced changes are better estimated by longitudinal studies, in which individuals are examined serially over time. A reality of aging research, however, is that most data are derived from crosssectional studies because they are easier to perform. Even longitudinal studies have their limitations—changes in methodology or measurement drift over time and development of disease in previously healthy persons. Finally, secular trends such as the downward drift in serum cholesterol or increasing obesity of Americans can alter age-related longitudinal changes. In this chapter, emphasis will be given to data obtained from community-dwelling persons screened for the absence of clinical, and in some cases subclinical, CV disease as well as major systemic disorders. A substantial portion of the data presented derives from studies over the past three decades in community-based volunteers from the Baltimore Longitudinal Study of Aging (BLSA).

ARTERIAL CHANGES: THE ROOT CAUSE OF UNSUCCESSFUL AGING Intimal medial thickening Age-associated changes in the arterial tree of apparently healthy individuals may have relevance to the exponential increase in CV disease with aging. Cross-sectional studies in humans have found that wall thickening and dilatation are prominent structural changes that occur within large elastic arteries during aging (2). Postmortem studies indicate that aortic wall thickening with aging consists mainly of intimal thickening, even in populations with a low incidence of atherosclerosis (3). Noninvasive measurements made within the context of several epidemiological studies indicate that the carotid wall intimal-medial (IM) thickness increases nearly threefold between 20 and 90 years of age, which is also the case in BLSA individuals rigorously screened to exclude carotid or coronary arterial disease (Figure 1.2a). Some investigators believe that the age-associated increase in IM thickness in humans represents an early stage of atherosclerosis (4). Indeed, excessive IM thickening at a given age predicts silent CAD (4). Since silent CAD often progresses to clinical CAD, it is not surprising that increased IM thickness predicts future clinical CV disease. Multiple epidemiological studies of individuals not initially screened to exclude occult CV disease have shown that increased IM thickness is an independent predictor of future CV events. Note in Figure 1.2b that the degree of risk varies with the degree of vascular thickening and that the risk gradation among quintiles of IM thickening is nonlinear, with the greatest risk occurring in the upper quintile (5). Thus, older adults in the upper quintile of IM thickness may be considered to have aged “unsuccessfully” or to have “subclinical” vascular disease. The potency of IM thickness as a risk factor in older individuals equals or exceeds that of most other, more traditional, risk factors.

Arterial changes: The root cause of unsuccessful aging  3

95

1st quintile

It is currently believed that additional risk factors (e.g., hypertension, smoking, dyslipidemia, diabetes, diet, or as-yet-unidentified genetic factors) are required to interact with vascular aging (as described above) to activate a preexisting atherosclerotic plaque. According to this view, atherosclerosis that increases with aging is not a specific disease, but an interaction between atherosclerotic plaque and intrinsic features related to vascular aging modulated by atherosclerotic risk factors. Evidence supporting this view comes from studies in which an atherogenic diet caused markedly more severe atherosclerotic lesions in older versus younger rabbits and nonhuman primates despite similar elevations of serum lipids (7,8). However, studies in populations with clinically defined vascular disease have demonstrated that pharmacological and lifestyle (diet, physical activity) interventions can retard the progression of IM thickening (9–14).

90

2nd quintile 3rd quintile

Endothelial dysfunction

85

4th quintile

Intimal medial thickness (cm)

0.12 Male

0.10

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0.08 0.06 0.04 0.02 0.00

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(a)

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3 Years

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Figure 1.2  (a) The common carotid intimal-medial thickness in healthy BLSA volunteers as a function of age. (b) Common carotid intimal-medial thickness predicts future cardiovascular events in the Cardiovascular Health Study. Abbreviation: BLSA, Baltimore Longitudinal Study of Aging. ([a] From Nagai, Y. et al., Circulation, 98, 1504– 1509, 1998. [b] From O’Leary, D.H. et al. N. Engl. J. Med., 340, 14–22, 1999.)

The common finding of age-associated IM thickening in the absence of atherosclerosis, both in laboratory animals and in humans (3) suggests that such excessive IM thickening is not necessarily “early” atherosclerosis. Rather, “subclinical CV disease” is strongly correlated with arterial aging. Interpreted in this way, the increase in IM thickness with age is analogous to the intimal hyperplasia that develops in aortocoronary saphenous vein grafts, which is independent of atherosclerosis but predisposes to its later development (6). Age-associated endothelial dysfunction, arterial stiffening, and arterial pulse pressure widening can also be interpreted similarly. Combinations of these processes occurring to varying degrees determine the overall vascular aging profile of a given individual (i.e., the degree of “unsuccessful” vascular aging). Animal data suggest that oxidative stress, inflammation, and defective cellular signaling underlie these adverse processes, initiating a vicious cycle between vascular remodeling and increasing arterial stiffness and blood pressure.

The endothelial monolayer that lines the luminal ­surface of the vascular tree plays a pivotal role in regulating m ­ ultiple arterial properties, including vessel tone, permeability, response to inflammation, and angiogenesis. Several of these functions undergo important age-­ associated ­a lterations. Endothelium-derived mediators such as nitric oxide (NO) and endothelin-1 are determinants of arterial tone and compliance, suggesting that endothelial cells may modulate arterial stiffness. Brachial arterial flow-mediated dilation, mediated in large part by NO, declines with age in both sexes, even in the absence of other CV risk factors (15). A decline of ~75% in this flow-mediated vasodilation occurs in men between the ages of 40 and 70  years. This decline begins approximately a decade later in women, perhaps because of the protective effect of estrogen, but is nearly 2.5  times as steep compared with men (15). The impairment of ­endothelial-mediated vasodilatation with aging in humans can be partially reversed by L-arginine administration, suggesting that NO p ­ roduction becomes reduced with aging  (16). Plasma ­ levels of a­symmetric dimethyl arginine, which reduces NO synthase (NOS) ­activity, also increase with age in humans (16). A ­ ge-associated changes in endothelial cell integrity, shape, and surface characteristics affect the cell’s physical and chemical barrier, increasing endothelial ­ permeability, leading to aberrant macromolecular ­transport (17). In c­ontrast to endothelium-mediated v­ asodilation, the vasodilator response to sublingual ­nitroglycerin is u ­ nrelated to age (15). Several CV risk factors and disorders are associated with endothelial dysfunction, including hypertension, hypercholesterolemia, insulin resistance, cigarette smoking, CAD, and heart failure. Furthermore, impaired endothelial vasoreactivity, in both the coronary and peripheral arterial beds, is an independent predictor of future CV events (18,19). Hypertensive individuals exhibit endothelial dysfunction (20,21), and the mechanisms underlying their endothelial dysfunction are similar to those that occur with

4  Cardiovascular changes with aging

2500 Pulse wave velocity (cm/sec)

normotensive aging, albeit they appear at an earlier age (21). The normotensive offspring of hypertensives also exhibit endothelial dysfunction (22), suggesting that endothelial dysfunction may precede the development of clinical hypertension. Age-associated endothelial dysfunction, arterial stiffening, and IM thickening are risk factors for arterial diseases, even after accounting for other risk factors, such as arterial pressure, plasma lipids, smoking, and so on. The interaction between arterial wall stiffening and CV diseases may set in motion a vicious cycle. In this cycle, alterations in the mechanical properties of the vessel wall contribute to endothelial cell dysfunction and, ultimately, to arterial stiffening.

Female Male

2000 1500 1000 500 0

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Augmentation index (AI) ΔP

Arterial stiffness and compliance

Pulse wave velocity Each systolic contraction of the ventricle generates a pressure wave that propagates centrifugally down the arterial tree, slightly preceding the luminal flow wave generated during systole. The propagation velocity of this wave is proportional to the stiffness of the arterial wall. The velocity of the pulse wave in vivo is determined not only by the intrinsic stress/strain relationship (stiffness) of the vascular wall but also by the smooth muscle tone, which is reflected by the mean arterial pressure. Noninvasive measures of the velocity of this pulse wave allow for large-scale epidemiological studies to examine its determinants and prognostic importance. In both rigorously screened normal subjects (25) and populations with varying prevalence of CV disease (26,27), a significant age-associated increase in pulse wave velocity (PWV) has been observed in men and women (Figure 1.3a). In contrast to central arteries, the stiffness of muscular arteries does not increase with advancing age (28). Thus, the manifestations of arterial aging may vary among the different vascular beds, reflecting differences in the structural compositions of the arteries and, possibly, differences in the age-­associated signaling cascades that modulate the arterial properties, or differences in the response to these signals across the arterial tree. Increased PWV has traditionally been linked to structural alterations in the vascular media, such as those observed with aging. Prominent age-associated increases in PWV have been demonstrated in populations with

60 Augmentation index

The increase in arterial wall thickening and reduction in endothelial function with advancing age are accompanied by an increase in arterial stiffening and a reduction in compliance. Age-associated structural changes in the arterial media that increase vascular stiffness include increased collagen content, covalent cross-linking of the collagen, reduced elastin content, elastin fracture, and calcification (23,24). In addition, there is a substantial increase in angiotensin II levels and augmented angiotensin II signaling in aged arterial walls, which may play a pivotal role in arterial aging, given the potent pressor and mitogenic effects of angiotensin II.

PP

40 20 0 –20 –40

(b)

AI = ΔP PP (%)

Female Male

0

20

40 60 Age (years)

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Figure 1.3  Scatter plots of aortofemoral pulse wave velocity (a), and carotid artery augmentation index (b) as a function of age in healthy non-endurance-trained BLSA volunteers. A similar age-associated increase in both measures of arterial stiffness was seen in men and women. Abbreviation: BLSA, Baltimore Longitudinal Study of Aging. (From Vaitkevicius, P.V. et al., Circulation, 88, 1456–1462, 1993.)

little or no atherosclerosis, again indicating that these vascular parameters are not necessarily indicative of atherosclerosis (29). However, the data emerging from ­epidemiological studies indicate that increased large vessel stiffening also occurs in the context of atherosclerosis (30,31), ­metabolic syndrome (32), and diabetes (33,34). Thus, altered mechanical properties of the vessel wall facilitate the development of atherosclerosis, which in turn increases arterial stiffness via endothelial cell dysfunction and other mechanisms.

Reflected pulse waves In addition to the forward pulse wave, each cardiac cycle generates a reflected wave, originating at areas of arterial impedance mismatch, which travels back up the arterial tree toward the central aorta, altering the arterial pressure waveform. This reflected wave can be noninvasively assessed from recordings of the carotid (25) or radial (35) arterial pulse waveforms using applanation tonometry and high-fidelity micromanometer probes. Dividing the late

Arterial changes: The root cause of unsuccessful aging  5

systolic augmentation of the arterial pulse wave by the distance from the peak to the trough of the arterial waveform (corresponding to the pulse pressure) yields the augmentation index, representing the degree of late systolic pressure increase (24). The augmentation index, like the PWV, increases with age (Figure 1.3b) (24,25). The velocity of the reflected flow wave is proportional to the stiffness of the arterial wall. Thus, in young individuals whose vascular wall is compliant, the reflected wave does not reach the large elastic arteries until diastole. With advancing age and increasing arterial stiffening, the velocity of the reflected wave increases, and the wave reaches the central circulation earlier in the cardiac cycle, during systole. The pressure pulse augmentation provided by the early return of the reflected wave is an added load against which the aged ventricle must contract. Furthermore, the diastolic pressure augmentation seen in compliant vessels, caused by the late return of the reflected waves, is lost in the elderly, decreasing diastolic blood pressure; this decrease in

diastolic pressure may reduce coronary blood flow because most coronary flow occurs during diastole. Numerous studies (27,36–39) indicate that increased arterial stiffness, over and above blood pressure, is an independent predictor of hypertension, atherosclerosis, CV events, and mortality. Kaess et al. (38) and others have demonstrated that increased arterial stiffness precedes the development of hypertension. Thus, a “primary” increase in large artery stiffness that accompanies aging gives rise to an elevation of arterial pressure; in turn, a “secondary” increase in large artery stiffness occurs due to the increase in mean arterial pressure. Normotensive individuals who fall within the upper quartile for measures of arterial stiffness are more likely to subsequently develop hypertension. Observations such as these reinforce the concept that hypertension, at least in part, is a disease of the arterial wall. The mechanisms of age-­associated changes in vascular structure and function and the putative relationship of these changes to development of CV disease are depicted in Table 1.1.

Table 1.1  Relationship of cardiovascular human aging in health to cardiovascular disease Age-associated changes CV structural remodeling       ⇑ Vascular intimal thickness

      ⇑ Vascular stiffness

      ⇑ LV wall thickness

      ⇑ Left atrial size CV functional changes       Altered regulation of vascular tone

Plausible mechanisms

Possible relation to human disease Early stages of atherosclerosis production

⇑ Migration of and ⇑ matrix by VSMC Possible derivation of intimal cells from other sources Elastin fragmentation ⇑ Elastase activity ⇑ Collagen production by VSMC Stroke and ⇑ cross-linking of collagen Altered growth factor regulation/ tissue repair mechanisms ⇑ LV myocyte size ⇓ Myocyte number (necrotic and apoptotic death) Altered growth factor regulation Focal collagen deposition ⇑ Left atrial pressure/volume

      ⇓ CV reserve

⇓ NO production/effects ⇓ β-AR responses ⇑ Vascular load

Reduced physical activity

⇓ Intrinsic myocardial Contractility ⇓ β-Adrenergic modulation of heart rate, myocardial contractility, and vascular tone Learned lifestyle

Systolic hypertension

Atherosclerosis Retarded early diastolic cardiac filling ⇑ Cardiac filling pressure Lower threshold for dyspnea ⇑ Prevalence of lone atrial fibrillation Vascular stiffening; hypertension Lower threshold for, and increased severity of, heart failure

Exaggerated aging changes in some aspects of CV structure and function; negative impact on atherosclerotic vascular disease, hypertension, and heart failure

Abbreviations: β-AR, β-adrenergic receptor; CV, cardiovascular; LV, left ventricular; NO, nitric oxide; VSMC, vascular smooth muscle cell.

6  Cardiovascular changes with aging

Age-associated dilation of the proximal aorta has been demonstrated in normal adults. Echocardiographic aortic root diameter increased a modest 6% in BLSA men between the fourth and eighth decades (40). Similarly, the aortic knob diameter increased from 3.4 to 3.8 cm on serial chest X-rays over 17 years (41). In addition, the aortic arch lengthens with age due to arch widening (42). Both greater aortic diameter and arch length were independently associated with higher aortic arch PWV and left ventricular (LV) mass. Such aortic root dilation and lengthening provide an additional stimulus for LV hypertrophy (LVH) because the larger volume of blood in the proximal aorta represents a greater inertial load that must be overcome before LV ejection can begin.

Systolic, diastolic, and pulse pressure Arterial pressure is determined by the interplay of peripheral vascular resistance and arterial stiffness; the former raises both systolic and diastolic pressure to a similar degree, whereas the latter raises systolic but lowers diastolic pressure. A rise in average systolic blood pressure across adult age has been well documented (Figure 1.4) (43,44). In contrast, average diastolic pressure was found to rise until about 50 years of age, level off from age 50 to 60, and decline thereafter (43,44). Thus, pulse pressure (systolic minus diastolic), a useful hemodynamic indicator of conduit artery vascular stiffness, increases with age. These age-dependent changes in systolic, diastolic, and pulse pressures are consistent with the concept that blood pressure in younger people is determined largely by peripheral vascular resistance, whereas in older individuals it is determined more by central conduit vessel stiffness.

Because systolic pressure is higher whereas diastolic pressure is lower in older men and women, isolated systolic hypertension emerges as the most common form of hypertension in individuals older than 50 years (43). Isolated systolic hypertension, even when mild in severity, is associated with an appreciable increase in CV disease risk (45,46). On the basis of long-term follow-up of middle-aged and older subjects, however, Framingham researchers have found pulse pressure to be a better predictor of coronary disease risk than systolic or diastolic blood pressures (47). A subsequent Framingham investigation found that pulse pressure was especially informative of coronary risk in older subjects (48) because of the J- or U-shaped association between diastolic pressure and coronary risk. Thus, consideration of the systolic and diastolic pressures jointly, as reflected in pulse pressure, is preferable to consideration of either value alone.

INTERVENTIONS TO RETARD OR PREVENT ACCELERATED ARTERIAL AGING Despite the deleterious effects of aging on arterial structure and function, it is noteworthy that the age increases in systolic and pulse pressures are markedly blunted in ­hunter-gatherer and forager-farmer societies (49). Furthermore, increasing evidence has accrued that ­lifestyle modifications, including aerobic exercise, and dietary modifications, including reduction in sodium intake, caloric restriction, and weight loss, can prevent or retard age-­associated IM thickening (50,51) and arterial stiffening (52,53) and improve endothelial function (54–57). Perhaps, the most promising of these modifications is caloric ­restriction, which may prolong maximal life span in laboratory animals when begun in youth or middle age. Limited studies in individuals have

Men

Women

150

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140

150 140

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90

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80

0

Systolic pressure

>80

0

Diastolic pressure 18–29 30–39 40–49 50–59 60–69 70–79 Age (years)

>80

Figure 1.4  Change in blood pressure with age in healthy men and women of different ethnicities. (From Aronow, W.S. et al., Circulation, 123, 2434–2506, 2011.)

Cardiac structure and resting function  7

demonstrated decreases in CV risk factors and inflammatory markers with caloric ­restriction (51,58). In one study, 25 individuals aged 53 ± 12 years who had p ­ racticed v­ oluntary caloric restriction of ~30% for an ­average of 6.5 years showed markedly lower blood pressure and inflammatory markers compared with controls matched for age and g­ ender (58). In  addition, the calorie restricted group demonstrated higher transmittal early diastolic flow measures, similar to those of younger adults (58). Whether such beneficial effects can be derived by initiating caloric restriction at older ages remains unknown. Pharmacological intervention such as chronic a­ ngiotensinconverting enzyme inhibition or angiotensin receptor blockade, begun at an early age in animal models, markedly delays the progression of age-associated arterial remodeling. Beneficial effects include lesser IM thickening and rupture of internal elastic lamina (59,60), attenuated mitochondrial dysfunction, reduced reactive oxygen species, enhanced NO bioavailability, reduced fibrosis, and prolonged life (61–67). It is thus far unproven if such treatment can prevent or retard unsuccessful aging of the vasculature in younger to middle-aged animals or humans who exhibit excessive subclinical evidence of accelerated arterial aging. Although breaking nonenzymatic collagen cross-links with a novel thiazolium agent reduces arterial stiffness in nonhuman primates (68) and humans (69), its clinical relevance is unclear.

CARDIAC STRUCTURE AND RESTING FUNCTION Until the 1970s, autopsy was essentially the only method for obtaining reliable measurements of cardiac structure in normal persons. These studies were obviously flawed by their inherent selection bias. A large autopsy series by Linsbach et  al. (70) in 7112 patients demonstrated an increase in cardiac mass of 1–1.5  g/yr between 30 and 90 years of age. Because the study included individuals with CV disease, the age-associated increase in heart weight may have derived, at least in part, from the coexistence of cardiac pathology. An autopsy study of 765 normal hearts from persons 20 to 99 years old who were free from both hypertension and CAD showed that heart weight indexed to body surface area was not age related in men but increased with age in women, primarily between the fourth and seventh decades (71). In autopsies of hospitalized patients without evident CV disease, Olivetti et  al. (72) observed an ageassociated reduction of LV mass mediated by a decrease in estimated myocyte number, although myocyte enlargement occurred with age. These investigators subsequently found a higher prevalence of apoptotic myocytes in older male than in female hearts, which paralleled a decline of LV mass with age in men but not in women (73). Widespread application of echocardiography finally allowed accurate noninvasive assessment of age-associated changes in cardiac structure and function. In healthy normotensive BLSA men, Gerstenblith et al. (40) found a 25%

increase in echocardiographic LV posterior wall thickness between the third and eighth decades, a finding replicated by others (74,75). Because LV diastolic cavity size was not significantly age-related in the BLSA (40), calculated LV mass also increased substantially with age. However, more recent studies using magnetic resonance imaging (MRI) to estimate LV mass in three dimensions has helped to resolve the divergent finding between autopsy and echocardiographic studies. In 136  men and 200  women without CV disease, MRI-derived LV wall thickness increased with age and short-axis diastolic dimension was not age related, similar to earlier echocardiographic findings. In contrast, LV length declined with age in both sexes (i.e., the LV became more spherical) (76). Thus, MRI-derived LV mass was unrelated to age in women and demonstrated an age-associated decline in men (because of their lesser age-related increase in wall thickness), similar to autopsy findings (73). Threedimensional echocardiography has confirmed this preservation of LV mass across age in women and a reduction of LV mass in older men (77). In 5004 healthy volunteers from the MESA study, cardiac MRI revealed age-related declines in both LV diastolic and systolic volumes and an increase in the LV mass/volume ratio in both sexes (78); stroke volume decreased modestly with age. Longitudinal MRI follow-up over 10  years confirmed a modest decline in LV diastolic volume and increase in LV mass/volume ratio (79). Thus, the normal LV becomes smaller, thicker, and more spherical with advancing age. Although the mechanisms for the age-associated remodeling of the LV and increase in myocyte size are not clear, they may be adaptive responses to the arterial changes that accompany aging. Putative stimuli for cardiac cell enlargement with age are an increase in vascular load due to arterial stiffening and a stretching of cells due to dropout of neighboring apoptotic myocytes (80). Phenotypically, the age-associated increase in LV thickness resembles the LVH that develops from hypertension. This finding, coupled with the increase in systolic blood pressure that occurs over time even in healthy individuals, has led to consideration of aging as a muted form of hypertension. In older rodent hearts, which demonstrate a similar increase in LV mass and myocyte size as observed in humans, a stretching of cardiac myocytes and fibroblasts releases growth factors such as angiotension II, a known stimulus for apoptosis. As a result, the heart becomes stiffer, that is, less compliant, with age. Enhanced secretion of atrial natriuretic (81) and opioid (82) peptides is also observed. Echocardiographic LV shortening fraction (74) and radionuclide LV ejection fraction (83,84), the two most common measures of global LV systolic performance, are unaffected by age at rest in healthy normotensive persons. Because LV stroke volume (SV) is the difference of LV enddiastolic volume (EDV) and end-systolic volume (ESV), the radionuclide-determined supine resting LV stroke volume is also unrelated to age (84). Prolonged contractile activation of the thickened LV wall (85) maintains a normal ejection time in the presence of the late systolic augmentation

8  Cardiovascular changes with aging

Young LV filling

15 Peak filling rate (EDV/sec)

of aortic impedance, preserving systolic cardiac pump function at rest. However, a downside of prolonged contractile ­activation is that at the time of the mitral valve opening, myocardial relaxation is less complete in older than in younger individuals, contributing to a reduced early LV filling rate. Over the last decade, two-dimensional speckle tracking echocardiography has allowed quantitative measurement of LV myocardial deformation, that is, strain. The most widely used such measurement is global longitudinal strain (GLS). Among 1266 healthy adults from the third through ninth decades, GLS declined modestly with age, especially after 60 years (86), a finding confirmed by others (87). In contrast to the general preservation of resting LV systolic performance across the adult age span, LV diastolic performance is profoundly altered by aging. Reduced mitral valve E–F closure slope on M-mode echocardiography first documented these age changes in diastolic performance (40,74). Pulsed Doppler (88) and radionuclide (89) techniques confirmed that the transmitral early diastolic peak filling rate declined by ~50% between the ages of 20 and 80 years (Figure 1.5). Conversely, peak A-wave velocity, which represents late LV filling facilitated by atrial contraction, increases with age (88). This greater atrial contribution to LV filling is accomplished via a modest age-associated increase in left atrial size demonstrable on echocardiography. Tissue Doppler and color M-mode techniques, both less influenced by preload and afterload than pulsed Doppler, have confirmed the age-associated reduction in early diastolic filling rate and increased late filling (90). Because the resting LV EDV is preserved across adult age in BLSA volunteers, the augmented atrial contribution to LV filling in older adults can be considered a successful adaptation to the reduced early diastolic filling rate in the thicker, and presumably stiffer, senescent LV. Thus, the relative importance of early and late diastolic LV filling is reversed with aging. Reduction of early LV filling with age may derive in part from decreased LV diastolic compliance due to the increase in LV wall thickness. An age-associated reduction in ventricular compliance has been shown in animals. Studies in man have confirmed an age-associated reduction in LV compliance, which was minimally changed in older adults after a full year of endurance training (91). In both intact animal hearts and isolated cardiac muscle, studies have demonstrated prolonged isovolumic relaxation and increased myocardial diastolic stiffness. Studies in both mice and healthy volunteers have shown age-associated increases in MRI-derived extracellular volume, thought to represent myocardial fibrosis, representing another potential mechanism for reduced LV compliance with aging (92). This slower isovolumic relaxation observed in cardiac muscle from older animals (93) may be secondary to diminished rate of Ca2+ accumulation by the sarcoplasmic reticulum (94). A conceptual framework for the cardiac adaptations to age-associated arterial stiffening is shown in Figure 1.6. Although the diminished early LV diastolic filling rate with age may not compromise resting EDV or stroke volume,

12

Advanced age

9 6 Max. 3 0

Rest 20

30

40

50 60 Age (years)

70

80

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Figure 1.5  Changes with age in peak early diastolic filling rates derived from radionuclide ventriculography at rest and during maximal upright cycle ergometry. The inset shows the transmittal flow velocity profile derived from Doppler echocardiography in a young adult and older adult. Note the shift from a dominant early (E) filling wave in the young to a dominant late (A) filling wave in the elderly. (From Schulman, S.P. et al., Am. J. Physiol., 263, H1932–H1938, 1992.)

an underlying reduction of LV compliance might cause a greater rise in LV diastolic pressure in older persons, especially during stress-induced tachycardia, thereby causing a lower threshold for dyspnea than in the young. It might also be anticipated that the loss of atrial contribution to LV filling that occurs during atrial fibrillation would elicit a greater deterioration of diastolic performance in older than in younger individuals. Indeed, it is attractive to speculate that the frequent occurrence of heart failure in the elderly despite preserved LV systolic function derives, at least in part, from the age-associated impairment of early diastolic filling (Table 1.1). The difficulty in imaging the right ventricle by echocardiography has limited obtaining information regarding aging changes in right ventricular (RV) structure and function. However, cardiac MRI can provide such information. In 4204 MESA participants aged 45–84 years who were free of clinical CV disease, cardiac MRI showed declines in both RV mass and volumes but a modest increase in RV ejection fraction with age (95). RVEDV, mass, and ejection fraction were positively related to systolic blood pressure and inversely related to diastolic blood pressure. The pulmonary arteries also appear to undergo age-associated remodeling, resulting in increased pulmonary artery (PA) stiffness and PA systolic pressure. In 1413 Olmsted County, Minnesota, residents ≥45  years old, PA systolic pressure estimated by Doppler echocardiography increased modestly from 26 ± 4 mmHg in persons 45–54 years old to 30 ± 6 mmHg in those 72–96 years old (96). Higher PA systolic pressure was an independent mortality predictor (hazard ratio [HR] 1.46  per 10  mmHg) (96). Healthy adults demonstrate an exaggerated rise in PA systolic and mean pressures with age during cycle ergometry (Figure 1.7) (97).

CV response to stress  9

Arterial stiffening

Pulse wave velocity early reflected waves late peak in systolic pressure

Arterial systolic and pulse pressure

Aortic root size Aortic wall thickness

Aortic impedance and LV loading LV wall tension Prolonged myocardial contraction

LV wall thickness Normalization of LV wall tension

Myocardial contraction velocity

Preserved endsystolic volume and ejection fraction

Energetic efficiency

L atrial size Atrial filling

Slightly increased end-diastolic volume

Prolonged force bearing capacity

Early diastolic filling rate

Maintenance of ejection time

Figure 1.6  Conceptual framework for the cardiovascular adaptations to arterial stiffening that occur with aging. Abbreviation: LV, left ventricular.

mPAP

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60–80 yrs 40–59 yrs

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20–39 yrs p < 0.0001

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Figure 1.7  Age-associated changes in mean pulmonary artery pressure (mPAP) during leg raising and graded aerobic exercise (25%, 50%, and 75% of maximal oxygen consumption). (From Wolsk, E. et al., J. Am. Coll. Cardiol. HF., 5, 337–346, 2017.)

CV physical findings in older adults Several age-associated alterations in CV structure and function may manifest themselves during the CV examination. Because of the stiffening of the large arteries, ­systolic blood pressure is often elevated with a normal or low diastolic blood pressure. Therefore, the carotid artery upstroke is usually brisk in the elderly and may mask ­significant aortic valve stenosis. The apical cardiac impulse may be difficult to palpate secondary to senile ­emphysema and chest wall deformities. Respiratory s­plitting of the

s­ econd heart sound is audible in only ~30%–40% of individuals older than 60 years, presumably because of reduced compliance of the pulmonary v­ asculature. In contrast, an S4  gallop is commonly heard in older but not younger persons because of the age-­associated increase in late ­d iastolic filling mediated by vigorous atrial ­contraction into a thicker-walled, less compliant LV. A soft basal ejection murmur occurs in 30%–60% of elders. This murmur is thought to arise from a dilated, tortuous aorta or from sclerosis of the aortic valve.

CV RESPONSE TO STRESS The CV response of older adults to stress (e.g., to increases in arterial pressure, to postural maneuvers, or to physical exercise) is of considerable clinical importance for several reasons. First, physicians are often asked to provide advice and information concerning the CV potential of the elderly (e.g., the effect or importance of conditioning status on the maintenance of function). Second, the CV response to stress is important in assessing the ability of older individuals to respond to disease states. Third, the CV stress response is valuable in the diagnosis and management of older patients with CV disease. Despite the high prevalence of CV disease among older Americans, it is important to understand their exercise capabilities. Exercise testing is a diagnostic tool that is frequently utilized to detect and quantify the severity of CV disease. The utility of such diagnostic testing clearly depends on precise information regarding the normal limits of such stress testing procedures relative to age.

10  Cardiovascular changes with aging

Orthostatic stress In healthy, community-dwelling elders, arterial pressure changes little with the assumption of upright posture, and postural hypotension or acute orthostatic intolerance (i.e., dizziness or fainting when assuming an upright from a supine position or during a passive tilt) is uncommon. Orthostatic hypotension (OH), defined by a decline of systolic blood pressure by ≥20 mmHg or diastolic blood pressure by ≥10  mmHg, occurred in 16% of volunteers aged 65 and older from the Cardiovascular Health Study (CHS) (98) and in 7% of men aged 71–93 years from the Honolulu Heart Program (99); in both of these older cohorts, the prevalence of OH increased with age. In the former study, OH was associated with higher supine blood pressure, greater LV wall thickness, and smaller LV cavity size (100). In the latter study, OH was an independent predictor for mortality (relative risk [RR] = 1.64), and there was a linear relationship between the magnitude of orthostatic decline in systolic blood pressure and 4-year mortality rate (99). In contrast to healthy, community-dwelling older volunteers, OH and orthostatic intolerance are common in debilitated institutionalized elders with chronic illnesses. Within such populations, the likelihood for OH is increased among individuals who exhibit very low LV filling rates and small EDV and SV in the supine position (101). In such individuals, however, the effects of advanced age cannot be dissociated from those of profound deconditioning and multiple diseases and medications. With advancing age, the acute heart rate increase to orthostatic stress decreases in magnitude and takes longer to achieve. The baroreceptor sensitivity (i.e., the slope of the relationship of the change in heart rate versus the change in arterial pressure) is negatively correlated with age and resting arterial pressure (102). The low-pressure baroreceptor, or cardiopulmonary reflex, also decreases with age in normotensives, but not in hypertensives. Despite the lesser heart rate increase during orthostatic stress in older than in younger BLSA volunteers, the SV reduction tends to be less in the older group; thus, the postural change in cardiac output does not vary significantly with age, because a lesser reduction in SV balances the lesser increase in heart rate in older individuals (103). Similarly, some studies have found cardiac output to be reduced with age in the supine position because of a reduced SV in older versus younger men; this age effect was abolished in the sitting position because of lesser reduction in SV in the older men on sitting.

Pressor stress Acute increases in blood pressure represent another common CV stress. Sustained, isometric handgrip increases both arterial pressure and heart rate. The response varies in magnitude in proportion to the relative level and duration of effort. After sustained submaximal or maximal handgrip, heart rate was observed to increase more in younger

than in older healthy individuals, whereas blood pressure increased more in older persons (104,105). In BLSA volunteers, 3 minutes of submaximal sustained handgrip elicited mild increases in echocardiographic LV diastolic and systolic dimensions and atrial filling fraction; these increases correlated positively with age (105). Thus, pressor stress accentuated the age-associated dependence on late diastolic filling. Application of a pressor stress has also been used to assess the intrinsic myocardial reserve capacity. In healthy BLSA individuals, a 30  mmHg increase in systolic blood pressure induced by phenylephrine infusion in the presence of β-adrenergic blockade induced significant echocardiographic LV dilatation at end diastole in healthy older (60–68  years), but not in younger (18–34  years), men: the cardiac dilatation occurred in older men despite a smaller reduction in heart rate (106), analogous to the handgrip response. Thus, an apparent age-associated decrease in intrinsic myocardial contractile reserve occurs in response to an acute increase in afterload; the senescent heart dilates to preserve SV via the Frank–Starling mechanism.

Aerobic exercise capacity The ability to perform oxygen-utilizing (i.e., aerobic) activities is a fundamental requirement of independent living and is probably the best-studied CV stressor. The accepted standard for aerobic fitness is maximum oxygen consumption rate (VO2max), the product of cardiac output (the central component) and arteriovenous oxygen difference (the peripheral component) during exhaustive exercise. In healthy adults, VO2max is up to 15 times greater than resting VO2. This huge increase is accomplished by a four- to fivefold augmentation of cardiac output and up to a threefold widening of the arteriovenous oxygen difference; the latter is due to both a dramatic increase in the relative proportion of cardiac output delivered to working muscles and increased oxygen extraction by these muscles. Because the total body VO2max is strongly influenced by muscle mass, VO2max is typically compared across individuals by normalizing for body weight. Multiple studies have documented that treadmill VO2max, adjusted for body weight, declines with age. In cross-sectional studies, the decline typically approximates 50% across the adult age span (107,108). However, the extent of the VO2max decline with aging varies among studies, depending on age ranges, differences in body weight and composition, and differences in habitual physical activity among the individuals studied. Longitudinal studies generally report a more pronounced age-associated decline in VO2max than do cross-sectional studies. In BLSA volunteers rigorously screened to exclude CV or lung disease, VO2max declines by ~50% between the third and ninth decades by cross-sectional analysis (107,108). Although such cross-sectional studies are usually interpreted to indicate that VO2max declines linearly with age, a more detailed analysis in this same BLSA population demonstrated that

Longitudinal % change per decade

CV response to stress  11

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Figure 1.8  Longitudinal change in peak VO2 and its components (maximal heart rate and O2 pulse) in healthy BLSA male (a) and female (b) volunteers. In both sexes, the decline in maximal heart rate is only ~5% per decade and is relatively constant across age. However, the decline in O2 pulse, encompassing both stroke volume and peripheral oxygen delivery and utilization, declines more rapidly in older adults, paralleling the decline in peak VO2. Abbreviation: BLSA, Baltimore Longitudinal Study of Aging. (From Fleg, J.L. et al., Circulation, 112, 674–682, 2005.)

the longitudinal decline in aerobic capacity is not constant across adulthood as assumed by cross-sectional studies, but accelerates markedly with successive age decades, especially in men, regardless of physical activity levels (Figure 1.8) (109). When the components of VO2max were examined, the longitudinal decline in oxygen pulse (VO2 per heartbeat) mirrored that of VO2max, whereas maximal heart rate decreased only 4%–6% per decade regardless of starting age (Figure 1.8). Although age-associated loss of muscle mass and increase in body fat also contribute to the reduction in VO2max with aging, the pattern of accelerated VO2max decline with age persists even after normalizing it for fat-free mass rather than body weight (109). Despite the similar rates of decline in VO2max with age regardless of physical activity level, it should be emphasized that at any age the more active quartiles maintain a higher VO2max than their sedentary peers. The accelerated decline of aerobic capacity has important implications regarding functional independence and quality of life. It should be emphasized that the data in

healthy BLSA volunteers represent a best-case scenario. The superimposition of CV or pulmonary disease as well as the deconditioning and loss of muscle mass commonly seen in the elderly because of their sedentary lifestyle accentuate this decline in VO2max. Because activities of daily living typically require a fixed aerobic expenditure, they require a significantly larger percent of VO2max in an older than a younger person. Once the energy required of an activity approaches or exceeds the aerobic capacity of an elderly individual, he/she will likely be unable to perform it. Thus, it is not surprising that a low aerobic capacity, represented by slow walking speed, comprises one of the five components of the “frailty phenotype” (110). Another potential contributor to exercise intolerance with aging is a greater metabolic debt incurred during exercise that persists during recovery. For several minutes after a bout of aerobic exercise, the body continues to consume o ­ xygen at a higher rate than at rest. This “oxygen debt” incurred during recovery can comprise 14%–20% of the total aerobic expenditure. In one study, the VO2 consumed by healthy older persons during recovery from exercise exceeded that in the young by more than 30% (111). Although the precise causes of this greater VO2 use during recovery in the elderly is unclear, increased circulating catecholamine levels (112) and the higher core temperature that occur during exercise and early recovery in deconditioned older adults (113) may be contributory. Because of the difficulty in imaging the heart during treadmill exercise, cycle ergometry has been used to dissect the relative contributions of cardiac and peripheral factors in the age-associated decline in aerobic capacity (Table  1.2). During upright cycle ergometry, the peak VO2  of healthy BLSA participants averages about 80% of that during treadmill exercise, regardless of age, usually limited by leg fatigue. Peak cycle work rate and VO2 decline Table 1.2  Changes in maximal aerobic capacity and its determinants between ages 20 and 80 years in healthy volunteers Oxygen consumption (A-V)O2 difference Cardiac output Heart rate   Stroke volume  EDV  ESV Contractility Ejection fraction Vascular (SVR) Plasma catecholamines   Cardiac and vascular Responses to β-adrenergic stimulation

⇓ (50%) ⇓ (20%) ⇓ (30%) ⇓ (25%) no change ⇑ (30%) ⇑ (275%) ⇓ (60%) ⇓ (15%) ⇑ (30%) ⇑ ⇓

Abbreviations:  AV, arteriovenous; EDV, end-diastolic volume; ESV,  end-systolic volume; SVR, systemic vascular resistance.

140

Female Male r = 0.11, p = 0.23

120 100 80 60 40 20

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End-systolic volume index (mL.m–2)

End-diastolic volume index (mL.m–2)

12  Cardiovascular changes with aging

Stroke volume index (mL.m2)

80 70 60

Female r = –0.34, p = 0.0002 Male r = –0.44, p = 0.0001

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100 18

200

16

180 160 140 120 Female r = – 0.64, p = 0.0001 Male r = – 0.68, p = 0.0001

80 20

40

60 Age (years)

40

(d)

220

100

Female r = – 0.063, p = 0.49 Male r = – 0.034, p = 0.66

40 20

80

Cardiac index (L.min–2.m–1)

Ejection fraction (%)

90

50

(e)

60

100

100

60

Female r = 0.34, p = 0.0003 Male r = 0.43, p = 0.0001

(b)

110

40

70

80

(f)

80

100

Female r = – 0.46, p = 0.0001 Male r = – 0.43, p = 0.0001

14 12 10 8 6 4 2

100

60 Age (years)

20

40

60 Age (years)

80

100

Figure 1.9  Scatter plots of left ventricular volumes (a, b), ejection fraction (c), stroke volume (d), heart rate (e), and cardiac index (f) during maximal graded upright cycle exercise in healthy BLSA volunteers, carefully screened to exclude silent coronary artery disease. Note the similar age changes in men and women and the increasing heterogeneity with age in the end-systolic volume index, ejection fraction, and heart rate. Abbreviation: BLSA, Baltimore Longitudinal Study of Aging. (From Fleg, J.L. et al., J. Appl. Physiol., 78, 890–900, 1995.)

by ~50% between ages 20 and 90  years in healthy, nonathletic BLSA men and women, attributable to declines of ~30% in cardiac output and 20% in arteriovenous oxygen difference (Table 1.2) (114). The age-associated decrease in cardiac index at ­maximal effort during upright cycle exercise (Figure 1.9f) is due entirely to a reduction in heart rate (Figure 1.9e), as the LVSV index (LVSVI) does not decline with age in either gender (Figure 1.9d) (115). However, the manner in which SVI is achieved during ­maximal exercise changes importantly with aging. Although older individuals have a blunted capacity to reduce end-­ systolic volume index (ESVI) (Figure 1.9b) and to increase

LV ­ejection ­fraction (Figure 1.9c), this deficit is offset by a larger end-­ diastolic ­ volume index (EDVI) (Figure 1.9a) (115). Thus, a “stiff heart” that prohibits sufficient filling between beats during exercise does not characterize aging in healthy individuals. The larger EDVI in healthy older versus younger individuals during vigorous aerobic exercise is due in part to a longer ­diastolic interval (i.e., slower heart rate) and to a greater amount of blood ­remaining in the heart at end systole (Figure 1.9b) (115). However, an exaggerated rise in p ­ ulmonary ­capillary wedge pressure occurs during ­aerobic exercise in older adults, p ­ erhaps contributing to exercise intolerance (97).

Mechanisms of impaired LV ejection during maximal aerobic exercise in healthy older adults  13

Given the accelerated decline in VO2max with age, an important question is whether aerobic training of sedentary older adults can improve their CV reserve capacity. It has been amply documented that physical conditioning of older persons can substantially increase their maximum aerobic work capacity. In a meta-analysis of 41 trials in 2102 individuals aged 60 and older, aerobic training elicited a 16.3% mean increase in VO2max (116). The extent to which this conditioning effect results from enhanced central cardiac performance versus augmented peripheral mechanisms, including changes in skeletal muscle mass, likely varies with the characteristics of the population studied, the type and degree of conditioning achieved, gender, body position ­during study, and genetic factors. A longitudinal study of older men during upright cycle ergometry indicates that aerobic training enhances VO2max in part by increases in the maximum cardiac output due to augmented maximum SV and in part by increasing the arteriovenous oxygen difference (117). The augmentation of maximum SV is due primarily to an augmented reduction of LVESV and, thus, a concomitant increase in LV ejection fraction; however, conditioning status had minimal effect on LVEDV during exercise in older adults. This contrasts with the effect of physical conditioning in younger persons, which substantially increases EDV and SV via the Frank–Starling mechanism, as well as via an enhanced LV ejection fraction. However, the maximal heart rate of both older and younger persons does not vary with conditioning status. Thus, physical conditioning of older persons does not appear to offset the age-associated deficiency in sympathetic modulation. Rather, increased LV ejection from aerobic training in this age group appears to derive from the reduction in vascular afterload, as reflected in a reduced PWV (118) and carotid augmentation index, with possible contribution from augmented maximum intrinsic myocardial contractility. Furthermore, aerobic training in sedentary older adults reduced their oxygen debt immediately post-exercise by nearly 30%, translating into an 18% increase in exercise efficiency; in contrast, efficiency did not change in younger persons after training (111).

MECHANISMS OF IMPAIRED LV EJECTION DURING MAXIMAL AEROBIC EXERCISE IN HEALTHY OLDER ADULTS The ability to augment LV ejection fraction during v­ igorous aerobic exercise is blunted with age even after screening to exclude persons with occult CAD. The impaired ability of healthy older men and women to reduce LVESV during ­vigorous exercise accounts for their smaller increase in ­ ejection fraction from rest and their lower maximal value compared to younger individuals (Figure 1.9c) (115). A blunted LV ejection fraction response during exercise is even more prominent in older individuals with exerciseinduced silent myocardial ischemia than in those without evident ­ischemia, due to a more pronounced inability to reduce ESVI (119).

The underlying mechanisms for the age-­ associated r­eduction in maximum LV ejection fraction are multifactorial and include (i) a reduction in intrinsic myocardial ­ contractility, (ii) an increase in vascular ­ afterload, (iii) ­arterial-ventricular load mismatching, and (iv) a diminished effectiveness of the autonomic modulation of both LV contractility and arterial afterload. Although these age-­ associated changes in CV reserve per se are insufficient to produce clinical heart failure, they appear to lower the threshold for developing symptoms and signs of heart f­ ailure and adversely influence its clinical severity and prognosis for any level of disease burden (Table 1.1).

Myocardial contractility How aging affects factors that regulate intrinsic m ­ yocardial contractility in humans is incompletely understood because the effectiveness of intrinsic myocardial ­contractility in the intact circulation is difficult to separate from loading and autonomic modulatory influences on contractility. Given that the heart rate per se is a determinant of the myocardial contractile state, a ­deficit in the maximal intrinsic contractility of older persons might be expected on the basis of their reduced maximum heart rate. Supporting evidence for reduced LV ­contractility with aging during stress comes from a study in which the LV of older but not younger healthy BLSA men dilated at end diastole in response to a given increase in ­afterload during β-adrenergic blockade (106).

LV afterload Cardiac afterload has two components: one generated by the heart itself and the other by the vasculature. The cardiac component of afterload during exercise can be expected to increase slightly with age because the heart size increases in older persons throughout the cardiac cycle during exercise (115). The vascular load on the heart has four components: conduit artery compliance characteristics, reflected pulse waves, resistance, and inertance. Inertance is determined by the mass of blood in the large arteries that requires acceleration prior to LV ejection. As the central arterial diastolic diameter increases with aging (26,40), the inertance component of afterload likely increases. Thus, each of the pulsatile components of vascular load, measured at rest, increases with age.

Arterial/ventricular load matching Optimal ejection of blood from the heart occurs when ventricular and vascular loads are matched. The precise cardiac and vascular load matching that is characteristic of younger persons is thought to be preserved at older ages, at least at rest, because the increased vascular stiffness in older persons at rest is matched by increased resting ventricular stiffness (120). For the ejection fraction to increase during exercise, the LV end-systolic elastance (ELV), that is, the end systolic pressure (ESP)/ESV ratio, must increase to a greater extent

14  Cardiovascular changes with aging

than the effective vascular elastance (EA), that is, ESP/ stroke volume. With increasing age, however, ELV fails to increase in proportion to the increase in EA; hence, the EA/ ELV during exercise in older persons decreases to a lesser extent than it does in younger persons (120). This altered arterial/ventricular load matching in older versus younger persons during exercise is a mechanism for the deficit in the acute LV ejection fraction reserve that typically accompanies advancing age. Acute pharmacological reduction in both cardiac and vascular components of LV afterload by sodium nitroprusside infusions in older, healthy BLSA volunteers augments LV ejection fraction in these subjects at rest and throughout upright cycle exercise (121).

Sympathetic modulation During acute exercise and other stresses, sympathetic modulation of the CV system increases heart rate, augments myocardial contractility and relaxation, reduces LV afterload, and redistributes blood to working muscles and skin to dissipate heat. All of the factors that have been identified to play a role in the deficient CV regulation with aging—that is, heart rate, afterload (both cardiac and vascular), myocardial contractility, and redistribution of blood flow—exhibit a deficient sympathetic modulatory component.

Thus, the reduction in heart rate during exhaustive aerobic exercise in the presence of acute β-adrenergic blockade is greater in younger than in older subjects, and significant β-adrenergic blockade–induced LV dilatation occurs only in the younger group (125). In addition, the age-associated deficits in early LV diastolic filling rate, both at rest and during exercise, are abolished by acute β-adrenergic blockade (89). However, acute β-adrenergic blockade causes SVI to increase to a greater extent in younger than in older individuals, due in part to the greater increase in LV filling time in the young, caused by greater reduction in their maximal heart rate (125). When perspectives from intact humans to subcellular biochemistry in animal models are integrated, a diminished responsiveness to β-adrenergic modulation is among the most consistently observed CV changes that occur with advancing age. Age-associated alterations in CV function that exceed the identified limits for healthy elderly individuals most likely represent interactions of aging per se with severe physical deconditioning and/or CV disease, both of which are highly prevalent among older adults.

RELEVANT AGING CHANGES IN OTHER ORGAN SYSTEMS

Apparent deficits in sympathetic modulation of cardiac and arterial functions with aging occur in the presence of elevated neurotransmitter levels. Plasma levels of norepinephrine and epinephrine, during any perturbation from the supine basal state, increase to a greater extent in older than in younger healthy humans (82,112). This increase appears to be a compensatory response to the reduced cardiac β-receptor density with advancing age (122). The ageassociated increase in plasma levels of norepinephrine results from an increased cardiac spillover into the circulation and, to a lesser extent, to reduced plasma clearance. Deficient norepinephrine reuptake at nerve endings has been suggested as the primary mechanism for increased spillover. During prolonged submaximal exercise, however, diminished neurotransmitter reuptake might also be associated with reduced release and spillover in older adults (123), contributing to the age-associated deficit in cardioacceleration and LV systolic performance seen during such an exercise (124).

Because of the close relationships between the CV system and other organs, it is important to recognize some of the more salient non-CV changes that occur with age. In the lungs, loss of elastic recoil causes reduced emptying and thus reduced vital capacity and minute ventilation during vigorous exercise. Plasma and total blood volumes decline moderately with age. Age-related loss of skeletal muscle mass, termed sarcopenia, is paralleled by reduced muscle strength, a major cause of disability and reduced quality of life in the elderly. A similar loss of bone occurs with age and is exacerbated by estrogen deficiency in postmenopausal women, leading to a marked increase in fracture risk. Additionally, age-associated nephrosclerosis results in loss of renal parenchyma and reductions in renal plasma flow, creatinine clearance, plasma rennin activity, and plasma aldosterone. These renal changes decrease the elimination of renally excreted drugs, attenuate responses to sodium restriction and volume expansion, and increase the risk for hyperkalemia. Although creatinine clearance typically declines by ~50% between the third and ninth decades, serum creatinine changes minimally because of the parallel loss of muscle mass.

Deficits in cardiac β-adrenergic receptor signaling

ELECTROCARDIOGRAPHY AND ARRHYTHMIAS

Numerous studies support the concept that the efficiency of postsynaptic β-adrenergic signaling declines with aging. One line of evidence derives from the observation that acute β-AR blockade changes the exercise hemodynamic profile of younger persons to resemble that of older ones.

Anatomical conduction system changes

Sympathetic neurotransmitters

The cardiac conduction system undergoes multiple changes with age that affect its electrical properties and, when exaggerated, cause clinical disease. A generalized increase in

ELECTROCARDIOGRAPHY Alterations in cardiac anatomy and electrophysiology with age often manifest themselves on the ECG. Because the resting ECG remains the most widely used cardiac diagnostic test, a review of these aging changes is relevant to distinguish them from those imposed by disease.

Sinus node function Whereas supine resting heart rate is unrelated to age in most studies (Figure 1.10, upper panel), the phasic variation in R–R interval known as respiratory sinus arrhythmia declines with age (126,127). Similarly, a reduced prevalence of sinus bradycardia on resting ECG is evident by the fourth decade (126). Because both sinus arrhythmia and sinus bradycardia are indices of cardiac parasympathetic activity, the age-associated reduction in parasympathetic function (127) may mediate both findings. Spectral analysis of heart rate variability has confirmed an age-related reduction of high-frequency (0.15–0.45  Hz) oscillations indicative of vagal efferent activity (Figure 1.10, lower panel) (128,129). Although physical conditioning status influences autonomic tone, a cross-sectional study in BLSA volunteers demonstrated that the deconditioning that usually accompanies the aging process plays only a minor role in the age-associated blunting of these high-frequency oscillations (129). Patients with organic heart disease demonstrate a reduced respiratory sinus arrhythmia compared to age-matched normal individuals. A blunting of high-frequency oscillations in apparently healthy older volunteers is predictive of future coronary events (130) and total mortality (131). Time domain indices of heart rate variability also decline substantially with age; the pattern of decline varies with the specific time domain measure (132). Younger men generally display higher time domain indices than younger women, but this gender difference narrows or disappears at older ages. In a Swiss population of healthy persons aged 50  years and older, CV risk factors, such as hypertension, smoking, non-high-density lipoprotein

1800 1600 1400 1200 1000 800 600 400

20

30

40

20

30

40

50

60

70

80

90

70

80

90

10 RSA (In[ms]2)

elastic and collagenous tissue commonly occurs. Fat accumulates around the sinoatrial node, sometimes creating partial or complete separation of the node from the atrial tissue. In extreme cases, this may contribute to the development of sick sinus syndrome. A pronounced decline in the number of pacemaker cells generally occurs after age 60; by age 75, less than 10% of the number seen in young adults remain. A variable degree of calcification of the left side of the cardiac skeleton, which includes the aortic and mitral annuli, the central fibrous body, and the summit of the interventricular system, is observed. Because of their proximity to these structures, the atrioventricular (AV) node, AV bifurcation, and proximal left and right bundle branches may be damaged or destroyed by this process, resulting in AV or intraventricular block.

RRI (ms)

Electrocardiography 15

8 6 4 2 0

50 60 Age (years)

Figure 1.10  Mean RRI and RSA during 3 minutes of sitting in healthy BLSA men (closed circles and dashed line) and women (open circles and solid line). Whereas RRI (top) was unrelated to age in either sex, RSA (bottom) declined similarly with age in women (r = 0.61; p < 0.001) and men (r = 0.59; p 456 ms in men and >470 ms in women was associated with a 2.5-fold increased risk of sudden death after adjustment for multiple CV risk factors (165). This risk was increased eightfold in persons younger than the mean age of 68 years, but only twofold in older individuals. Increased Q–T-interval dispersion, defined as the difference between the maximum and minimum QTc among the ECG leads, was also associated with a doubled risk of sudden death in this cohort (166). Table 1.3 Table 1.3  Normal age-associated changes in resting ECG measurements Measurement R–R interval P-wave duration P–R interval QRS duration QRS axis QRS voltage Q–T interval T-wave voltage

Change with age No change Minor increase Increase No change Leftward shift Decrease Minor increase Decrease

Effect on mortality None Possible increase None None Probable increase None

summarizes those changes in resting ECG measurements thought to be secondary to normative aging.

ARRHYTHMIAS An increase in the prevalence and complexity of both supraventricular and ventricular arrhythmias, whether detected by resting ECG, ambulatory monitoring, or exercise testing, is a hallmark of normal human aging.

Atrial arrhythmias Isolated premature atrial ectopic beats (AEB) appear on the resting ECG in 5%–10% of individuals older than 60 years and are not generally associated with heart disease. Isolated AEB were detected in 6% of healthy BLSA volunteers older than 60 years at rest, in 39% during exercise testing, and in 88% during ambulatory 24-hour monitoring (167). Such isolated AEB on ambulatory monitoring, even if frequent, were not predictive of increased cardiac risk in this sample over a 10-year mean follow-up period (168). Among 1372 predominantly healthy persons ≥65 years old in the CHS, isolated AEB were found in 97% and were frequent in 18% of women and 28% of men (Table 1.4) (169).

Atrial fibrillation Atrial fibrillation (AF) is found in approximately 3%–4% of subjects over age 60  (Table 1.4), a rate 10-fold higher than the general adult population (169,170); the prevalence in octogenarians approaches 10% (171). Chronic AF is most commonly due to CAD and hypertensive heart disease, mitral valvular disorders, thyrotoxicosis, and sick sinus syndrome. The association between hyperthyroidism

Table 1.4  Arrhythmias on 24-hour ECG in 1372 ambulatory persons ≥65 years old Arrhythmia Supraventricular Any   ≥15 in any hr   PSVT (≥3 complexes) Atrial fibrillation or flutterb Ventricular Any   ≥15 in any hr VT (≥3 complexes) VT (>5 complexes)

Women (%)

Men (%)

Gender differencea

97

97

No

18 50 3

28 48 3

Yes No No

76

89

Yes

14 4 0.3

25 13 0.2

Yes Yes No

Source: Manolio, T.A. et al., J. Am. Coll. Cardiol., 23, 916–925, 1994. Abbreviations:  PSVT, paroxysmal supraventricular tachycardia; VT, ventricular tachycardia. a Defined by p 65 yr (n = 25)

80

>32 mL/m2 >65 yr (n = 55)

60 % 40

>32 mL/m2 >65 yr (n = 98) 20 0

P < 0.00001 0

1

2

3 4 5 Days after surgery

6

7

Figure 1.11  Risk of postoperative atrial fibrillation after cardiac surgery as a function of age and left atrial volume in 205 patients. (From Osranek, M. et al., J. Am. Coll. Cardiol., 48, 779–786, 2006.)

Paroxysmal supraventricular tachycardia Short bursts of paroxysmal supraventricular tachycardia (PSVT) on a resting ECG are found in 1%–2% of normal individuals older than 65 years. Twenty-four-hour ambulatory monitoring studies have demonstrated short runs of PSVT (usually 3–5 beats) in 13%–50% of clinically healthy older persons (Table 1.4) (167,169). Although the presence of nonsustained PSVT on ambulatory monitoring did not predict an increase in risk of future coronary events in BLSA participants, 2 of 13 individuals with PSVT later developed de novo AF, compared with only 1 of the 85 without PSVT (168). Exercise-induced PSVT has been observed in 3.5% of over 3000 maximal treadmill tests on apparently healthy BLSA volunteers (179). The arrhythmia increased sharply with age, from 0% in the twenties to approximately 10% in the eighties (Figure 1.12a); similar to PSVT on ambulatory ECG, the vast majority of these episodes were asymptomatic 3–5 beat salvos. Coronary risk factors and ECG or thallium scintigraphic evidence of ischemia occurred with similar prevalence in the 85 volunteers with exercise-induced PSVT as in age- and sex-matched controls. Of importance, the group with PSVT experienced no increase in subsequent coronary events over a 5.5-year mean follow-up period. However, 10% of the individuals with PSVT later developed a spontaneous atrial tachyarrhythmia compared with only 2% of controls (179), analogous to the results of the 24-hour ambulatory ECG.

Ventricular arrhythmias Both in unselected populations and in those clinically free of heart disease, an exponential increase in the prevalence of ventricular ectopic beats (VEB) occurs with advancing age. Pooled data from nearly 2500 ECGs from hospitalized patients older than 70  years revealed VEB in 8% (180). Among apparently healthy BLSA volunteers with a normal ST-segment response to treadmill exercise, isolated VEB occurred at rest in 8.6% of men over age 60  years compared with only 0.5% in those 20–40  years old (181). Of note, the prevalence of resting VEB was not age related in women. The prognostic significance of VEB detected on the resting ECG in the general elderly population is controversial. Significant increases in cardiac mortality among persons with VEB were observed in studies from Busselton (182) and Manitoba (183), with risk ratios of 3.3 and 2.4, respectively, compared with arrhythmia-free cohorts. The Framingham community, however, demonstrated no increase in the age-adjusted risk ratio for cardiac events (184). Data from the Multiple Risk Factor Intervention Trial suggest that the prognostic significance of resting VEB may vary according to age; asymptomatic white men under 50  years with frequent or complex VEB on a 2-­minute resting rhythm strip suffered a 14-fold relative risk of sudden cardiac death, while in older men the risk was not significantly increased (185).

Arrhythmias 19

12

46

Men Percent with SVT

10

Women

8

129

6 170 96

4 2

25

155 85

343 248

0 350 g in women, was found in 64% and 74% of men and women, respectively. Chamber dilatation, on the other hand, was present in only 33% of individuals. Both heart weight and chamber size tended to decrease with age.

VALVULAR HEART DISEASE Valvular heart disease is an increasingly common medical problem, affecting 1%–2% of the adult population in the United States (58). As one ages, the mean thickness of valve leaflets increases; of note, the thickness of valve leaflets is not significantly correlated with the height, weight, heart weight, or body surface area (59).

Aging change of valves Figure 2.5  Findings in hypertrophied hypertensive hearts: (a) transverse section of left ventricle showing marked concentric hypertrophy with myocardial fibrosis (white regions); (b) hypertrophic myocytes with enlarged “­boxcar” nuclei (H&E stain, ×400), and (c) interstitial ­fibrosis (H&E stain, ×200). Abbreviation: F, fibrosis.

wall thickens in response to increased pressure (51). Through a variety of mechanisms, both mechanical and neurohumoral, cardiac myocytes increase in size resulting in an increase in left ventricle mass and thickness. The result is concentric LVH. However, concentric hypertrophy is not the only morphologic phenotype of hypertensive heart disease. In fact, studies of hypertensive individuals demonstrate that eccentric hypertrophy is at least as common as concentric hypertrophy (52,53). Frequently, the hypertensive heart exhibits variable degrees of both concentric and eccentric LVH. The natural history of the hypertensive patient is variable. However, it is well established that hypertensive people who develop concentric hypertrophy may subsequently develop eccentric hypertrophy via a series of events often referred to as the “transition to failure” (54). Not surprisingly, as hypertension is a significant risk factor for other

Age-related changes are seen in all of the cardiac valves although the degree of change differs. Almost all adult aortic valves have nodular thickenings at the centers of the free edges of the cusps—the so-called nodule of Arantii or nodule of Morgagni (60). Lambl’s excrescences, hairlike projections from the nodules, are often seen in older patients. Fenestration of the cusps, firm ridgelike thickening at the bases of the cusps, is also found in elderly aortic valves. None of these changes are functionally significant. The mitral valve apparatus consists of the atrial wall, mitral valve annulus, leaflets, chordae tendineae, papillary muscles, and underlying left ventricular wall. The leaflets may display thickening with degeneration of collagen fibers, lipid accumulation, and focal calcification (59). Nodular thickening of the free edge of the anterior leaflet, referred to by some as “atheromatosis,” is seen in all adults. Severity of the lipid deposition on the leaflet also correlates with age, but there are no gender differences (60). In addition, mitral annular calcification, small scars, diffuse opacity, or hooding of leaflets (myxomatous degeneration) are often seen in the elderly (59). Mitral annular calcification may be associated with mild, usually insignificant, mitral insufficiency. Age-related changes in the pulmonary valve and tricuspid valve are minor. Nodules of Aranti and fenestrations of the cusps are sometimes present in the pulmonary valve (60).

Valvular heart disease  35

Aortic valve disease Degenerative/calcific aortic stenosis (AS), also known as aortic stenosis of the elderly, or more politically correct, agingrelated aortic stenosis, has become the most common type of valvular heart disease requiring valve surgery in industrialized countries, and is associated with significant morbidity and mortality (Figure 2.6) (61–64). Calcification of the a­ ortic valve (AV) is seen in more than one fourth of individuals over 65 years and more than half of those over 85 years (63). Among octogenarians, AS was seen in 2.4%–8.1% (64,65). The aortic valve is chronically exposed to complex shear forces. Calcification primarily occurs on the aortic side of the cusps, along the line of coaptation (61). Calcification involves the collagenous portion of the leaflets, but calcifications can erode through the endothelial surface and even embolize to other organs (66). The presence of calcification in the AV is associated with calcification at other sites, including the carotid arteries, coronary arteries, thoracic aorta, abdominal aorta, and iliac arteries. Calcification of the aortic valve and AS are associated with aging, hypertension, diabetes, elevated plasma levels of low-density lipoprotein (LDL), and smoking (61,63,64,66). AS has been said to be the result of atherosclerosis— inflammation and lipid deposition on the aortic valve (61). However, there is a discrepancy in the prevalence of coexisting calcific AS and coronary artery disease (61,64,67). Although half of patients with severe AS have severe coronary disease,

most patients with coronary artery disease do not have AS (61,64). Therefore the pathogenesis of AS is now recognized as a unique process (64). Indeed, calcification, once thought to be a nonspecific degenerative process, is now recognized as a highly regulated phenomenon. There are no specific or effective disease-modifying medical therapies for the treatment of AS (64). Without valve replacement, the 2-year mortality following the onset of symptoms is approximately 50% (68). Surgical valve replacement is an effective treatment for AS, with long-term survival comparable to the age-matched general population (69). Nevertheless, only about 70% of patients with severe AS are taken for surgery owing to contraindications and comorbidities (68). Transcatheter aortic valve implantation (TAVI) is a minimally invasive alternative to surgery. Originally reserved for high-risk surgical candidates, TAVI has demonstrated improved survival and freedom from disabling stroke compared to surgery in both high- and intermediate-risk patients (70–72). Aortic regurgitation (AR) requiring surgery is less common in older adults and usually results from infective endocarditis, rheumatic fever, aortic-root dilatation or dissection, or myxoid degeneration (73,74). Myxoid degeneration of the aortic valve is seen in 36% of cases with pure AR. There is a male predominance. Long-standing hypertension is thought to be an important underlying factor (74). In contrast to myxoid degeneration of the mitral valve (MV), myxoid degeneration of the AV is very uncommon.

Figure 2.6  Calcific aortic stenosis in a 69-year-old female: (a) the operative view of the aortic stenosis; (b) a transesophageal echocardiogram of the aortic valve short axis view during systole; (c) surgically resected cusps; (d) an X-ray of the of the same specimen. Nodular calcification is found on the cusps; (e) and (f) histology of the noncoronary cusp ([e] Elastica van Gieson stain; [f] H&E stain). Calcification destroying the elastic tissue and growth on the cuspal surface. Abbreviations: Ao, aorta; Ca, calcification; L, left coronary cusp; LA, left atrium; N, noncoronary cusp; R, right coronary cusp; RAA, right atrial appendage; RVOT, right ventricular outflow tract. Scale bar, 1 cm. (Courtesy of Drs. Takashi Nishimura, Mitsuhiro Kawata, and Jun Tanaka, Tokyo Metropolitan Geriatric Hospital.)

36  Morphologic features and pathology of the elderly heart

Mitral valve disease Clinically significant mitral valve disease affects 1%–2% of the adult population, resulting in nearly 3,000 deaths in the United States (58). Mitral valve regurgitation (MR), mitral stenosis (MS), mitral annular calcification (MAC), and mitral valve prolapse (MVP) are seen in the elderly (Figure 2.7). Classical MS, which primarily affects females, is usually postinflammatory; most cases are due to rheumatic disease (58,73). In elderly patients, especially women, severe MV annular calcification with encroachment into the orifice is an uncommon cause of functional MS. MR may be caused by myxomatous degeneration, infective endocarditis, collagen vascular disease, or spontaneous rupture of the chordae tendineae (73). MVP is the most common structural valvular cause of MR in older patients (58,75). The prevalence of MVP is estimated to be in the range of 3%–5% in healthy adults. Most patients with MVP are older than 50 years of age (76). MVP is more common in women, but clinically significant MR and chordal rupture due to MVP are more common in men. Grossly, myxomatous mitral valves are characterized by floppy leaflets with elongated or ruptured chordae tendineae (Figure 2.7a) (58,75,76). Also, the valves show an increase in leaflet thickness (77). The mitral valve consists of a fibrosa, spongiosa, and atrialis layer. Histologically, the valve with prolapse shows collagen degeneration and disorganization, elastic fiber fragmentation, and increased thickness of the spongiosa layer (58,75). In MVP, the leaflets contain more abundant proteoglycans, biglycan, and verisican (75). Ruptured

mitral chordae tendineae are seen not only in myxomatous degeneration of the MV but also in chronic rheumatic valvulitis or endocarditis. Myxomatous degeneration mainly causes posterior chordae tendineae rupture, while anterior chordae tendineae rupture is more common in chronic rheumatic valvulitis (78). The cause of myxomatous degeneration remains unclear; surgical repair is the treatment of choice in patients with severe MR (75). The incidence of MAC, or mitral ring calcification, shows a striking increase with age. MAC is rarely found in those younger than 40 years old, except in the case of a concomitant connective tissue disorder, such as Marfan syndrome, or disorder of calcium metabolism, for example, secondary hyperparathyroidism in patients with severe chronic kidney disease (CKD) (66). Risk factors include advanced age, CKD, and increased mitral stress, as occurs in hypertension, AS, or MVP (60,67,79,80). The overall incidence in individuals older than 50 years is 8.5% (67). MAC is initially more common in men, but over the age of 65 years the incidence is considerably higher in women. Heavy calcification is seen more frequently in women (Figure 2.7b) (60,79,80). The configuration of the calcified annulus may be J-, C-, U-, or O-shaped (67). MAC is usually located entirely in or below the annulus of the posterior mitral leaflet. Although the anterior leaflet has no true annulus, there can be anterior submitral calcification, seen much less frequently than in association with the posterior leaflet (81). Ulceration and extrusion of calcium through the cusp, extensive central necrosis, or endocarditis of the mitral valve are sometimes associated with MAC (79). Microscopically, MAC shows no evidence of previous endocarditis. Nonspecific chronic inflammatory changes are seen adjacent to calcium deposition. Rarely MAC extends into the His bundle of the conduction system, causing atrioventricular (AV) block (80). In one autopsy study, MAC was the cause of complete AV block in 19.4% of elderly patients (82).

INFECTIVE ENDOCARDITIS(SEE ALSO CHAPTER 18)

Figure 2.7  Mitral valve disease in the elderly: (a) mitral valve prolapse with ruptured chordea tendinea (arrow); (b) postmortem radiograph showing mitral annular ­calcification (arrow); (c) fungal endocarditis with large ­vegetation on mitral valve; and (d) nonbacterial thrombotic endocarditis with nondestructive vegetations on valve leaflet.

Infective endocarditis (IE) is a microbial infection of an endocardial surface of the heart (83,84). The clinical diagnosis of IE is based on culture of organisms from the blood and visualization of cardiac vegetations (Figure 2.7c) (85). Despite current sophisticated imaging methods, IE is frequently not diagnosed until autopsy. Risk factors in addition to older age include preexisting valvular disease, artificial heart valves, intracardiac devices, and intravenous drug use (83,86). The prevalence of IE at autopsy has been reported to be 1.3% (85), and the mean age of patients is increasing (85,86). In-hospital mortality is high—up to 20% (84). Although the most common organisms were Streptococcus species in the pre-antibiotic era, currently the predominant pathogen is Staphylococcus aureus (84–89). Endocarditis caused by S. aureus is associated with a poor prognosis (90). The etiologic organisms are not different between younger adults and older people (86). Fungal endocarditis

Cardiomyopathy 37

is not common, but results in larger vegetations and greater destruction of the tissue. Left-sided endocarditis is the more common, but endocarditis involving right-sided structures or both right- and left-sided valves is not rare (85,86). Right-sided endocarditis is often associated with intravenous drug use or pulmonary artery catheterization (85,86,89). Prosthetic valve endocarditis is a serious complication of valve surgery that often requires removal of the affected valve. Pathologically, bacterial colonies or fungal hyphae are demonstrated in untreated endocarditis. Gram stain for bacteria and Gomori methenamine silver (GMS) stain for fungi are recommended (86). Infection from a native or artificial valve may spread to adjacent structures and myocardium (85). The finding of heart block indicates spread of the infection into the cardiac conduction system, and the finding of pericarditis indicates spread through the infected valve annulus—both are ominous complications. The spleen, kidneys, brain, and mesentery are common sites of embolization of infected vegetations in cases of left-sided endocarditis; the lung is a more common site in cases of right-sided endocarditis. (85) At autopsy, gross infarction may be seen in as many as 63% of cases, but in most cases these lesions were asymptomatic. Up to one third of patients with IE have cardiac disorders that are clinically silent, such as bicuspid aortic valve (BAV) or MVP (86,87). BAV is the most common congenital cardiac abnormality, reported to be present in 1%–2% of the population (91). Patients with endocarditis and BAV are younger, have a higher frequency of aortic perivascular abscess, and usually require early surgery. Cardiac deviceassociated IE (e.g., pacemakers or ICDs) has been seen more frequently in recent years due to increased utilization of these technologies, especially in older adults (92). In one study of such patients, coexisting valve involvement was seen in 37.3%, and the most commonly infected valve was the tricuspid valve.

NONBACTERIAL THROMBOTIC ENDOCARDITIS Nonbacterial thrombotic endocarditis (NBTE) is a sterile, thrombotic vegetation of the heart valves. NBTE is found in 0.3% to 9.3% of autopsy patients (93,94). Thromboembolism may be the first manifestation; however, NBTE is usually asymptomatic, or at least not recognized clinically, in part because the patient has very severe underlying disease such as shock or metastatic malignancy. Accordingly, NBTE is usually first diagnosed at autopsy (94). Patients with NBTE are usually older, but NBTE is also observed in children and young adults (93). There is no gender predilection. NBTE is most commonly found in patients with adenocarcinomas, and it is also seen in patients with antiphospholipid syndrome (APS) or other autoimmune disorder characterized by hypercoagulability (93–95). NBTE may be seen in patients with disseminated intravascular coagulation (DIC)

of any cause. NBTE occurs on the atrial surfaces of the mitral and tricuspid valves and the ventricular surfaces of the aortic and pulmonic valves (93). The mitral and aortic valves are most commonly involved. Histologically NBTE shows agglutinated deposits of fibrin and platelets with no inflammatory reaction and no destruction of underlying valve tissue (93,95). NBTE is superficial and attached to the endocardial surface along the lines of closure of the affected valves (Figure 2.7d).

CARDIOMYOPATHY According to the 2006 AHA classification scheme, cardiomyopathy is defined as a heterogeneous group of diseases of the myocardium associated with mechanical and/or electrical dysfunction (96). Cardiomyopathies are divided into two major groups, primary and secondary. Primary cardiomyopathies are solely or predominantly confined to heart muscles and are classified as genetic, acquired, and mixed (genetic and nongenetic etiologies). Genetic research has identified more than a thousand disease-causing mutations (97). Morphological phenotypes and disease severity can be variable due to genetic heterogeneity and allelic variation. Genetic testing can assist diagnosis, guide clinical management, and be useful for screening of family members.

Hypertrophic cardiomyopathy Hypertrophic cardiomyopathy (HCM) is a clinically heterogeneous, autosomal dominant genetic heart disease characterized by unexplained hypertrophy of the left ventricle (Figure 2.8) (96,98,99). HCM is one of the most common genetic heart diseases, estimated to have a prevalence of 1 in 500 individuals (96,99). Commercial genetic testing has increasingly become more common (98). The minimal prevalence of HCM gene carriers could be greater than 1 in 200 people. Unless a known pathogenic mutation is identified, to render a diagnosis of HCM, other causes of ventricular hypertrophy, such as hypertension or aortic stenosis, must be excluded (97,100,101). HCM is the most common cause of sudden death in young individuals, including trained athletes (96,101,102), but HCM has been observed during all phases of life (101). Males and females are equally affected (102). HCM is not rare in the elderly. Maron et al. reported that the average age at diagnosis was in the fifth decade of life (103). Another study showed that approximately one quarter of HCM patients were older than 75 years (101). However, there are substantial differences in clinical manifestations across age groups. Only a minority of aged HCM patients have severe heart failure. In one study, two thirds of patients older than 75  years experienced few or no symptoms, and about 60% of those survived to age 80–96 years (104). It has also been suggested that many patients with HCM have gone undiagnosed their entire lives (103).

38  Morphologic features and pathology of the elderly heart

Dilated cardiomyopathy

Figure 2.8  Primary cardiomyopathies and takotsubo cardiomyopathy: (a) base of heart from a patient transplanted for hypertrophic cardiomyopathy (note that the septum is thicker than the left ventricular free wall); (b) characteristic myocyte disarray seen in hypertrophic cardiomyopathy (H&E stain, ×400); (c) heart from a patient transplanted for dilated cardiomyopathy (note dilation of left ventricle). A 77-year-old female with the acute phase of takotsubo cardiomyopathy. Transthoracic echocardiography showing apical ballooning in (d) end-diastole and (e) end-systole that resembles the appearance of a Japanese octopus fishing pot called a tako-tsubo (insert). Abbreviations: FW, free wall; LA, left atrium; LV, left ventricle; S, septum. (Courtesy of Dr. Jun Tanaka, Tokyo Metropolitan Geriatric Hospital.)

The clinical diagnosis of HCM is usually established by echocardiography. Although characteristic pathological findings may be identified, a diagnosis of HCM should not be made by endomyocardial biopsy. Endomyocardial biopsy is useful, however, to exclude diseases that may mimic HCM, such as infiltrative or storage diseases (105). HCM is a monogenic disorder. Pathogenic genes of HCM mostly encode sarcomere proteins (97). Grossly, left ventricular hypertrophy is characteristically asymmetric, with the anterior basal interventricular septum showing the greatest wall thickness (Figure 2.8b) (96,101,105). Subaortic obstruction is significantly more common in older HCM patients (104). Characteristic histologic features include myocyte hypertrophy, myocyte disarray, and fibrosis (100,101,106). Wall thickening and luminal narrowing of intramyocardial arteries is also seen. In elderly patients, these morphologic features are relatively mild compared to younger patients who have died from HCM (101,104).

Dilated cardiomyopathy (DCM) is characterized by ventricular chamber enlargement of the left or both ventricles, and systolic dysfunction in the absence of other identifiable causes (Figure 2.8c) (96,105,107,108). DCM may occur at any age, but there are onset peaks during childhood and mid-adulthood (105,107). DCM leads to progressive biventricular heart failure, ventricular and supraventricular arrhythmias, thromboembolism due to cardiac mural thrombi, and sudden cardiac death (96,105,107,108). The 5-year survival after diagnosis is 50% (107). Approximately 20%–50% of DCM cases have been reported to be familial (96,105,107,108). Genetic testing is recommended in familial cases (109). DCM is a phenotype, categorized as a mixed (genetic and nongenetic) cardiomyopathy in the AHA classification (96). There are a number of potential underlying causes, including gene mutation, toxins such as alcohol, cocaine, and anthracyclines, myocarditis, Chagas disease, metabolic causes, hypersensitivity myocarditis, connective tissue disease, neuromuscular disease, and pregnancy (109). The etiology of DCM is not identified in approximately 50% of cases (97). DCM may be a late sequela of myocarditis. Most cases are presumably viral, although a specific virus is rarely identified. The most commonly implicated viruses are parvovirus B19, coxsackie virus B3, and adenovirus (107). The cardiomyopathy may manifest clinically long after the acute viral illness. Endomyocardial biopsy is the gold standard examination for diagnosis and choice of subsequent treatment. Biopsies may demonstrate lymphocytic myocarditis, giant cell myocarditis, eosinophilic myocarditis, or sarcoidosis (105,107,109). In the elderly, exclusion of other causes, such as ischemic heart disease and hypertensive heart disease, is essential for the diagnosis of DCM (109). If there is greater than 75% stenosis in left main coronary artery, proximal left anterior descending artery, or more than two epicardial coronary arteries, ischemic cardiac disease is a more likely diagnosis. Macroscopically, the heart often weighs two to three times that of a normal heart; some hearts exceed 1000 grams (socalled cor bovinum) (107). The characteristic shape of the heart is globoid and somewhat spherical with rounding of the apex due to biventricular hypertrophy and marked dilation (Figure 2.8). Functional mitral regurgitation is very common in patients with DCM; mitral annular dilatation is a common finding. Mural thrombi may be seen in all cardiac chambers (105,107). As a consequence of diastolic dysfunction, left atrial dilation and atrial fibrillation may occur (109). Histological findings are nonspecific, including interstitial fibrosis, replacement fibrosis, irregular and hyperchromatic nuclei of myocytes, and sarcoplasmic degenerative changes (105,107). Replacement fibrosis is a consequence of myocyte injury or necrosis and is known to be a substrate for ventricular re-entrant arrhythmia (109). Myocardial fibrosis can predict not only the risk of sudden cardiac death but also the likelihood of LV functional recovery (109,110).

Amyloidosis 39

Takotsubo (stress) cardiomyopathy Takotsubo cardiomyopathy is an acquired cardiomyopathy in the AHA classification (96). The name refers to the shape of the heart resembling the appearance of a Japanese octopus fishing pot called a tako-tsubo (octopus-pot) (Figure 2.8d and e). This cardiomyopathy is characterized by transient regional systolic dysfunction involving the left ventricular apex and/or mid-ventricle that typically recovers within a few weeks (96,108,111,112). Right ventricular involvement has also been reported, and has been associated with longer hospital stays and more complications (113). Diagnostic criteria from the Mayo Clinic include (1)  transient akinesis or dyskinesis of the left ventricular mid segments with or without apical involvement, (2) new ECG abnormalities (ST-segment elevation or T wave inversion), (3) no ­obstructive coronary disease, and (4) absence of pheochromocytoma or myocarditis (114). Gender and age discrepancies are striking. Females comprise 90%–95% of reported cases. Most patients are elderly and postmenopausal (96,115–119). Common symptoms include abrupt onset of angina-like chest pain and dyspnea resembling acute coronary syndrome (108,112,115,116). Symptoms are usually preceded by emotional or physical stress, such as family death, abuse, a harsh argument, exhausting work, or an earthquake (108,112,115). Sympathetic hyperactivity and increased catecholamine levels may play a role in myocardial stunning and contractile dysfunction (120). Plasma catecholamine levels are elevated in patients with takotsubo cardiomyopathy (108,116,119), and the histological findings are similar to catecholamineinduced changes, including contraction-band necrosis (120). Neurologic or psychiatric disorders are more prevalent in takotsubo cardiomyopathy (118). There is also an increased prevalence of migraine headaches and affective disorders (121). A multimodal MRI study demonstrated structural and functional alterations in regions primarily involved in cardiac control and emotional processing such as the amygdala and hippocampus (122).

There are several reports of morphological changes in takotsubo cardiomyopathy. Its histology is similar to those seen in patients with ischemic electrocardiographic changes after an acute intracranial injury and cardiotoxic effects induced by catecholamines (116,123). Endomyocardial biopsies showed contraction bands, interstitial infiltrates consisting primarily of mononuclear lymphocytes and macrophages, and myocardial fibrosis, but no coagulation myocardial necrosis (112,115,119,124). This was evidenced by the absence of terminal deoxynucleotidyl transferase (TdT) dUTP nick-end labeling (TUNEL) positive myocytes, indicating the absence of apoptosis (124). An autopsy case report demonstrated patchy myofibril degeneration of the myocardium with contraction band necrosis and myocyte edema at the cardiac apex (125). A study using electron microscopy showed that the main alterations included vacuoles filled with cellular debris and myelin bodies, contraction bands, and clusters of mitochondria with abnormalities in the sizes and shapes (124). After functional recovery, the myocytes showed a nearly normal rearrangement of the intracellular structures by electron microscopy.

AMYLOIDOSIS Cardiac amyloidosis may be considered a secondary form of cardiomyopathy, as many forms of amyloidosis are systemic. Cardiac amyloidosis is characterized by infiltration of the myocardium by one of several misfolded proteins known as amyloid. Currently, there are more than 30  types of amyloid, 11 of which have been reported to involve the heart (Table 2.1) (126). Each type has different clinicopathological features including treatment and prognosis (127,128). Therefore, the identification of the specific amyloidogenic protein is essential. In the elderly, the most commonly encountered types of cardiac amyloidosis are amyloid light chain (AL), transthyretin amyloid (ATTR), and isolated atrial amyloidosis (AANF). Deposition of amyloid in the heart results in a thickened heart wall with a firm and rubbery consistency (99,127). Brown “waxy” deposits may be seen in the endocardium

Table 2.1  Amyloidoses affecting the heart Amyloid subtype AL AH ATTR AA AANF Aβ2M AApoAI AApoAII AApoAIV AGel ALys

Precursor protein

Disease/etiology

Immunoglobulin light chain Immunoglobulin heavy chain Transthyretin (prealbumin) Amyloid A protein Atrial natriuretic factor β2-Microglobulin Apolipoprotein AI Apolipoprotein AII Apolipoprotein AIV Gelsolin Lysozyme

Plasma cell dyscrasia Plasma cell dyscrasia Age-related or hereditary Chronic inflammatory disease Isolated atrial amyloidosis Chronic hemodialysis Hereditary Hereditary Age-related Hereditary Hereditary

Source: Maleszewski, J.J., Cardiovasc Pathol., 24, 343–350, 2015.

40  Morphologic features and pathology of the elderly heart

of the atria or heart valves (Figure 2.9a). The stiff heart worsens cardiac relaxation and compliance; therefore, cardiac manifestations of amyloidosis are dominated by diastolic heart failure resulting from restrictive physiology (99). Right heart failure, conduction disturbances, and arrhythmias are common (99,127). When suspected clinically, the diagnosis of amyloidosis may be confirmed by biopsy. Histologically, amyloid displays an amorphous eosinophilic appearance by hematoxylin and eosin staining, and shows characteristic apple-green and yellow birefringence with polarized light following Congo red ­ staining (Figure 2.9c and d) (127,129–131). Amyloid can also be detected using fluorescent stains, such as thioflavin T and thioflavin S, metachromatic dyes, such as crystal or methyl violet, and other histochemical stains, such as sulfated alcian blue. Once confirmation of amyloid is obtained, subtyping may be attempted by immunohistochemistry and/or immunofluorescence using antisera to amyloid A protein, kappa and lambda light chains, and transthyretin (Figure 2.9e and f) (127,129,132,133). Mass spectrometry, however, is a more reliable method that can be performed on formalin-fixed paraffin-embedded tissue (129,133). If

transthyretin amyloid is detected, DNA mutational analysis may be performed to distinguish age-related, or senile, ­systemic amyloidosis (wild-type transthyretin) from hereditary amyloidosis (mutated transthyretin) (129). AL amyloidosis is the most frequent amyloid disorder in the Western world (133). Multiple myeloma or a primary plasma cell dyscrasia are the underlying etiologies. Neoplastic plasma cells secrete monoclonal immunoglobulin light chains that form amyloid deposits in multiple organs including the heart and kidneys (127,133,134). Plasma cell dyscrasias are more frequent in the elderly and almost exclusively affect individuals older than 40 years. Cardiac involvement portends a poor prognosis. Right-heart failure caused by restrictive physiology, arrhythmia, and pericardial effusion are common cardiac manifestations (99,127,130,134). Heart failure contributes to about 40%–75% of deaths; however, 25% of deaths are sudden (127,129,134). Typical macroscopic findings are increased heart weight, diffuse, waxy, stiffening of tissues, and gross appearance mimicking HCM (127,130,131,135). Histologically, amyloid deposition is predominantly seen in interstitial tissue and vascular walls (136). Other age-related amyloidosis include age-related ATTR

Figure 2.9  Cardiac amyloidosis: (a) Gross appearance of amyloid in the left atrium (note brown “waxy” appearance (arrow); (b) H&E stain of amyloid in the myocardium; (c) Congo red stain of amyloid; (d) Congo red stain under polarized light showing characteristic green birefringence; (e) immunohistochemical staining for transthyretin from a patient with “senile” ATTR cardiac amyloidosis, ×100; and (f) immunohistochemical stain for lambda light chain from a case of AL amyloidosis in a patient with multiple myeloma. Positive immunostaining is brown (×200). Abbreviation: A, amyloid.

Atrial fibrillation  41

amyloidosis, also called senile amyloidosis, and AANF. Both are senescence-related and prevalence increases with aging (129). The amyloid protein of ATTR is composed of wild-type transthyretin, and that of AANF is atrial natriuretic factor (a.k.a. atrial natriuretic peptide or ANP) (127,129,137). ATTR occurs in 11.5%–25% of people over the age of 80 years (127,128,138). Wild-type transthyretin forms amyloid deposits in various organs (131), although the heart is most commonly affected (127,132,139). Both the atria and ventricles are involved. Compared to AL, ATTR is less commonly associated with cardiomegaly, heart failure, or arrhythmia (127,132,136,138). Histologically, large, diffuse or multifocal, predominantly nodular amyloid deposits are present between muscle bundles. Usually the conduction system is not affected (127,128,136). AANF is a common postmortem finding in the elderly. AANF occurs in as many as 80%–90% of individuals older than 90 years (127,138). AANF is seen in conditions associated with increased plasma concentrations of atrial natriuretic factor, such as heart failure and atrial fibrillation. Grossly, deposits of amyloid are only found in the atria, predominantly in the appendages, and beneath the endocardium (127). Histologically, amyloid deposits surround cardiac myocyte (127,128,137,138). Localized valvular amyloid may also be found in the elderly. This amyloid deposition is associated with AV sclerosis and, less commonly, with MV dysfunction (regurgitation and stenosis) (127,140). The exact amyloid subtype is unclear, but valvular amyloid seems to be associated with athero-inflammatory risk factors such as high shear-stress hemodynamics (140).

AGING CHANGES IN THE CONDUCTION SYSTEM AND ARRHYTHMIA The prevalence rates of both conduction disturbances and arrhythmias increase with age (82). The major components of the conduction system of the heart consist of the sinoatrial (SA) node, AV node, His bundle, and bundle branches. Dysfunction of the SA node progressively increases with age regardless of gender (141). Even in the healthy elderly, there is an intrinsic decline in endogenous pacemaker function. In the adult SA node, the percentage of collagen fibers, reticular fibers, and elastic fibers increases significantly with age (13,82,142,143). Mature adipose tissue also increases with age (142–147). The number of SA nodal cells declines with aging (82,144,148). Nodal cells occupy 20%–30% of the area of the SA node in adults 30–39 years old, but this declines to less than 10% among those older than 100 years (82). The AV node in the elderly also shows replacement by adipose tissue and an increase in elastic fibers (82,144). However, these changes are usually not extensive enough to lead to clinical problems (144). The His bundle and bundle branches also have more fibrous tissue in the aged (82).

SICK SINUS SYNDROME Patients with sick sinus syndrome (SSS) show sinus arrest, sinoatrial exit block, or persistent sinus bradycardia. The majority of patients ultimately require implantation of a permanent pacemaker. Symptomatic SSS is mostly seen in elderly people and is the leading cause of pacemaker implantation. Reduction in the number of conduction cells, increased fibrosis (Figure 2.10), and infiltration of adipose tissue may contribute to SSS (82,147,144). In older SSS patients, there is a loss of SA node cells, resulting in decreased cellularity in the region of the SA node (82). Marked fibrosis of the SA node is found in elderly patients requiring permanent pacemakers for SSS (144). In cases without marked fibrosis, severe fatty infiltration is seen. Excessive fatty infiltration in the atrionodal transitional area leads to reduced atrionodal conduction with atrophy of the AV node. Fibrosis of right atrial muscle may also be present (82).

ATRIAL FIBRILLATION Atrial fibrillation (AF) is the most common clinically significant cardiac arrhythmia, and the prevalence of AF increases markedly with age (149). Additionally, as the population ages worldwide, its prevalence is increasing (149,150). There are regional and ethnic variations in the prevalence of AF; the prevalence of AF is significantly higher in individuals of European ancestry (150). Additionally, the age distribution differs between regions. More than 70% of patients with AF are older than age 65  in North America and western Europe. Patients with AF have higher mortality rates and are at increased risk for stroke, myocardial infarction, and heart failure. AF was also associated with grossly observed cerebral infarction in a population-based autopsy study (151). In addition to age, risk factors for AF include obesity, smoking, hypertension, diabetes mellitus, myocardial infarction, valvular heart disease, and rheumatic heart disease (150). A recent report from the Framingham Heart Study suggested that a higher pericardial fat volume detected by multidetector computed tomography was associated with a higher incidence of AF (152). However, AF in the elderly is often multifactorial or idiopathic, that is, not associated with any specific cause (143). Macroscopically, atrial cavity dilation is seen in hearts with AF (Figure  2.1a) (13,82,143). Microscopic findings show sinoatrial muscle cell loss or fibrosis, disruption of the internodal atrial musculature by fibrosis and/or adipose tissue, or vascular occlusion of the SA nodal artery (82,143). Catheter ablation and the Cox maze procedure are sometimes employed for symptomatic paroxysmal or persistent AF (153). Macroscopically, following ablation the pulmonary vein orifices may show narrowing and there are yellow to white lesions on the endocardium several years after the procedures (Figure 2.10) (154,155). Microscopic examination shows that nontransmural-to-transmural coagulative necrosis, inflammation, and fibrosis depend on the time after the procedure.

42  Morphologic features and pathology of the elderly heart

Figure 2.10  An 80-year-old male who demonstrated sinus arrest and premature atrial contractions (a) and who underwent pacemaker implantation 8 years before death. Decreased cellularity of the sinoatrial node and increased fibrosis are present (b–d). An 86-year-old male who demonstrated atrial flutter (e) and who underwent a catheter ablation 2 years before death; (f) an electrocardiogram taken 3 months after the procedure, showing sinus rhythm; (g) macroscopic view of the right atrium 2 years after the ablation, demonstrating a white, thickened endocardium (arrowheads) between the coronary sinus and the tricuspid annulus; (h) and (i) histology of the ablation site showing thickened fibrotic tissue (arrowheads) without viable cardiomyocytes ([b and i], H&E stain; [c] Elastica van Gieson; [d and h] Azan). Abbreviations: CS, coronary sinus; IVC, inferior vena cava; RA, right atrium; RV, right ventricle; SAN, sinoatrial node; TV, tricuspid valve. White bar, 1 cm; black bar, 500 µm. (Courtesy of Dr. Koji Chida, Tokyo Metropolitan Geriatric Hospital.)

ATRIOVENTRICULAR BLOCK AV block is defined as a delay or interruption in the transmission of an impulse from the atria to the ventricles through the conduction system. AV block can be caused by anatomical abnormalities, functional disorders, drugs, or electrolyte disturbances (156,157). Morphological changes are seen in the AV junctional area, bifurcating His bundle, or right or left bundle branch (156). In the elderly, acute and old myocardial infarction, calcific valvular disease, endocarditis,

myocarditis, amyloidosis, and metastatic or primary tumors may be associated with AV block (82,156,157). Lev’s disease and Lenègre’s disease are common causes of AV block in the elderly. These disorders are characterized by idiopathic progressive cardiac conduction system disease without other evidence of organic heart disease (158). According to Lev, the heart begins to show fibrosis, hyalinization, and calcification with aging in various regions, including the conduction system (159). These age-related degenerative changes lead to interruption of the conduction fibers and AV block (158,159).

References 43

Lev reported that sclero-fibrotic changes involving the central fibrous body can cause chronic atrioventricular block (159). Fibrosis and sclero-calcification is characteristically found in the bundle of His or the proximal bundle branches (159,160). In contrast, diffuse fibrotic degeneration of the conduction system is mainly seen in the distal parts of the bundle branches in the disease credited to Lenègre. Recently, a splicing mutation was found in Lenègre’s disease, and the disease is now thought to be hereditary. Lenègre’s disease appears to be due to a loss-of-function mutation in the gene coding the main cardiac Na channel, SCN5A (158). Whether Lev’s disease and Lenègre’s disease are the same or different entities is debatable (158–160). However, a combination of the SCN5A mutation and additional degenerative age-related changes may explain the progressive alteration of conduction velocity in both disorders (158). In one autopsy study of elderly patients with complete AV block without any identifiable cause, the most common site of complete AV block with narrow QRS and prolonged AH interval (i.e., block proximal to the His bundle deflection) was at the branching of the His bundle (161). Complete AV block with wide QRS and prolonged HV interval (block distal to the His bundle deflection) was caused by lesions in both bundle branches. As the main penetrating bundle of His is located near the noncoronary cusp of the aortic valve and near the base of the anterior leaflet of the mitral valve, calcific deposits in either the aortic or mitral valve may cause AV block (157).

BUNDLE BRANCH BLOCK Right bundle branch block (RBBB) and left bundle branch block (LBBB) occur at various levels of the branches of the His-Purkinje system. The prevalence of both RBBB and LBBB increase with age. RBBB and LBBB are associated with a wide range of diseases (157).

PERICARDIAL DISEASE The human heart is surrounded by pericardial tissue. The pericardium provides structural support and reduces friction (162). There is a potential cavity between the visceral and parietal pericardium, usually containing 15–50 mL of serous fluid (162,163). The elderly are not particularly prone to pericardial disease. The most common cause of acute pericarditis in the elderly is thought to be viral, although the etiologic agent is usually not identified. In elderly patients with chest pain, the pericardium as the source of pain may not be considered in the initial differential diagnosis. Pericardial diseases include acute and recurrent pericarditis, pericardial effusion, cardiac tamponade, pericardial constriction, and pericardial tumors. Primary malignant pericardial tumors are rare, with mesothelioma being the most common type (163). In contrast, the pericardium is a common site of metastasis, especially from lung or breast primaries. Acute pericarditis is caused by a wide range of disorders (162,163). The acute inflammatory response in pericarditis

produces serous or purulent pericardial effusions or dense fibrinous exudates (164). Viral infection tends to cause serous, low-volume pericardial effusions. Neoplasms and tuberculous pericarditis cause exudative, hemorrhagic effusions. Bacterial infections cause purulent pericarditis. The cause of acute pericarditis is unclear in most patients, but often presumed to be viral (162). Pericardial constriction (less properly referred to as constrictive pericarditis) differs in developed countries and developing countries (162,165). Pericardial constriction is thought to be the result of chronic pericardial inflammation caused by any pericardial disease (162,163). However, when the pericardial tissue is examined, little if any inflammation is present. In developed countries, most cases are idiopathic (often thought to be viral) or related to previous cardiac surgery or irradiation. (162) Grossly, pericardial constriction is associated with thickened pericardium, fibrosis and calcification, and adhesion to the adjacent myocardium (162,163). In contrast, in developing countries approximately 70% of large pericardial effusions and most cases of pericardial constriction are caused by tuberculosis. Mortality of tuberculous pericarditis is high, 17%–40% (165). Tuberculous pericarditis develops by retrograde lymphatic spread rather than contiguous spread from tuberculous lesions in the lungs or pleurae. The immune response to the M. tuberculosis bacilli penetrating the pericardium plays a fundamental role in the pathogenesis of tuberculous pericarditis. Four ­pathological stages of tuberculous pericarditis have been recognized: (1)  fibrinous exudation with initial polymorphonuclear leukocytosis, abundant mycobacteria, and early granuloma formation; (2) serosanguineous effusion with a predominantly lymphocytic exudate with monocytes and foam cells; (3) absorption of effusion with granuloma formation, pericardial thickening, and subsequent fibrosis; and (4) constrictive scarring (165). Patients with HIVassociated tuberculous pericarditis often have associated with myocarditis.

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44  Morphologic features and pathology of the elderly heart

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3 General principles on caring for older adults DAE HYUN KIM AND SANDRA M. SHI Introduction 49 Physiologic changes of aging 49 Geriatric syndromes in older adults with CVD 50 Multimorbidity 50 Polypharmacy 53 Frailty 54 Cognitive impairment 54 Delirium 55 Functional decline 55 Falls 56

Urinary incontinence 56 Approaches to evaluation and management of older adults with CVD 57 Limitations of clinical trial evidence and clinical practice guidelines 57 Adopting patient-centered goals-directed care 57 Assessing time to benefit and prognosis 58 Communicating evidence for treatment decision making 58 Summary 58 References 59

INTRODUCTION

due to CVD and other chronic and geriatric conditions, functional limitations, and limited social and economic resources. Therefore, it is crucial to consider age-associated physiologic changes, concurrent geriatric conditions (e.g., multimorbidity, polypharmacy, frailty), and other contextual factors (e.g., financial status, social support) in the process of evaluation and management of CVD in older adults. The goal is to help patients achieve their desired health outcomes through active collaboration and shared decision-making.

In the United States, nearly 70% of men and women 60–79 years old and 85% of those 80 years and older have some form of cardiovascular disease (CVD) (1). Despite efforts to control major risk factors and advancements in therapies for CVD, it remains the leading cause of death, accounting for approximately one in three deaths. It is also a leading cause of health care utilization and functional limitations. Over 7  million inpatient operations and procedures are performed every year, and more than half of those procedures are done in people 65 years and older. The estimated total annual cost for CVD is more than $300  billion. Population aging is a global demographic trend that has important implications for managing older adults with CVDs. In the United States, the number of people 65 years and older is projected to more than double in the next 50  years, and one in four Americans will be 65 years and older in 2060 (2). Similar trends are observed in other developed and less developed countries. Population aging was mainly responsible for an increase in CVD mortality globally between 1990 and 2013 (3). In addition, economic disparities exist across subgroups of the older population, and higher proportions of older people are living alone or requiring institutional care (2). These consequences of population aging present significant challenges to clinicians in providing care for people who have complex needs

PHYSIOLOGIC CHANGES OF AGING Aging is characterized by gradual loss and alterations in function in multiple organ systems. The rate of these changes varies among people and can be accelerated by an individual’s lifestyle, risk factors and diseases, and environment, which culminates in the considerable heterogeneity of older populations. As these changes accumulate, an individual’s physiologic capacity to withstand stressors and maintain homeostasis is diminished, a state referred to as “homeostenosis.” Consequently, older individuals become more vulnerable to diseases as well as adverse effects of drug therapy and invasive procedures. Age-associated changes in the anatomy and physiology of the cardiovascular system are described in Chapters 1 and 2. Decreased elasticity and increased stiffness of the arterial system leads to isolated systolic hypertension. Stiffness and

49

50  General principles on caring for older adults

delayed relaxation of the left ventricle predispose to diastolic heart failure. Reduced responsiveness to beta-adrenergic stimulation and circulating catecholamines limits the maximum heart rate response and peak cardiac output, contributing to decreased exercise tolerance. Fibrosis of the cardiac skeleton and conduction system, and decrease in the sinus node pacemaker cells increase the risk of atrial fibrillation and other arrhythmias. Calcification of fibrous valve rings increases the prevalence of calcific aortic and mitral stenosis. Decreased sensitivity of carotid baroreceptors predisposes to orthostatic hypotension, syncope, falls, and adverse effects of cardiovascular drug therapy (e.g., diuretics, beta-blockers). Age-associated changes in other systems interact with the manifestations and management of CVD. Aging is associated with progressive decline in glomerular surface area for filtration in the kidney and decreased ability to maintain fluid and electrolyte balance. Age-associated decline in glomerular filtration rate (8 mL/min/1.73 m2 per decade after age 40) (4) is often underappreciated. Older adults are at increased risk for volume overload, electrolyte imbalance, and cardiorenal syndrome. Because several cardiovascular drugs, such as renin-angiotensin system inhibitors and diuretics, can impair renal function and cause electrolyte disorders, close monitoring is appropriate when these drugs are used. In the respiratory system, aging is associated with increased collapsibility of the alveoli and terminal conducting airways, and increased ventilation-perfusion mismatch. The ventilatory response to hypoxic or hypercapnic stimuli is blunted. These changes contribute to dyspnea and reduced exercise capacity. Changes in the neurohumoral system include impaired autoregulation of cerebral perfusion, diminished reflexes and proprioception, and impaired thirst mechanisms, all of which can increase the risk of syncope, falls, and volume depletion in response to cardiovascular drug therapy. In addition, anemia is prevalent in older adults with CVD due to ineffective erythropoiesis and inflammation. Increased levels of coagulation factors, increased platelet activity, and inhibition of fibrinolysis may predispose them to the risk of arterial and venous thrombosis. The risk of bleeding with antiplatelet, anticoagulant, and fibrinolytic therapy is increased (5), in part due to high prevalence of risk factors for bleeding, such as decreased renal function, higher risk of falls, and drug-drug interactions. Decreased lean body mass and increased body fat  can alter pharmacokinetic and pharmacodynamic properties of drugs, which confers greater susceptibility to treatment-related adverse events. Finally, the high prevalence of vision and hearing impairment may present as a barrier to communication and implementation of treatment plan in older adults with CVD. In summary, understanding age-associated changes to the structure and function of the cardiovascular system as well as other organ systems is fundamental to individualizing treatment decisions and to delivering effective and safe therapy for CVD.

GERIATRIC SYNDROMES IN OLDER ADULTS WITH CVD Geriatric syndromes refer to common multifactorial conditions in older adults, such as frailty, falls, functional decline, cognitive impairment, delirium, and incontinence, that do not fit into classic disease categories (6). Although age-­ associated physiologic changes by themselves do not represent pathology, accumulation of such changes and diseases in multiple organ systems, including CVD and noncardiovascular conditions, predispose to geriatric syndromes. The presence of one geriatric syndrome may increase the risk of another geriatric syndrome (e.g., hospitalization-associated delirium may lead to falls). Furthermore, geriatric syndromes are associated with poor outcomes of CVD (7–9), suggesting a bidirectional relationship. Coexistence of CVD and noncardiovascular conditions may increase the risk of geriatric syndromes and adverse clinical outcomes (disease-disease interaction). In addition, a drug therapy for CVD may worsen noncardiovascular condition or geriatric syndrome, and vice versa (drug-­ disease interaction). Two drugs for different conditions may synergistically heighten the risk of treatment-related adverse events (drug-drug interaction). The likelihood of such interactions increases with the number of conditions and medications a patient has. Importantly, older adults with multiple chronic conditions and geriatric syndromes have limited remaining life expectancy, such that they may derive little benefit from preventive cardiovascular therapy or may not tolerate the acute stress from hospitalizations, invasive procedures, and adverse drug reactions. Therefore, clinicians should be able to identify and understand the impact of common geriatric syndromes that affect CVD management (Table 3.1).

Multimorbidity More than two thirds of older adults have two or more chronic conditions, or multimorbidity (10). Individuals with multimorbidity are at increased risk for death, disability, hospitalization, nursing facility stay, and health care utilization. The prevalence of multimorbidity increases with age; over 80% of people 85 years and older have at least two conditions and approximately 50% have at least four conditions. The most common pattern of multimorbidity is coexistence of cardio-metabolic disease and osteoarthritis (11). More than 50% of older individuals with heart failure, stroke, and atrial fibrillation have five or more chronic conditions (12). Common noncardiovascular conditions in those with CVD are arthritis, anemia, chronic kidney disease, cataracts, chronic obstructive pulmonary disease, dementia, and depression (12), which add to the complexity of CVD management in older adults. These non-­cardiovascular conditions account for almost half of readmissions after an index admission for heart failure or myocardial infarction (13).

Cognitive impairment

Frailty

Polypharmacy

Multimorbidity

Condition

• Older patients with multimorbidity excluded from clinical trials of CVD treatments • Guideline-based CVD treatments may not be feasible or effective • CVD treatment may worsen coexisting conditions • Non-CVD conditions account for almost half of readmissions after CVD admissions • CVD medications are responsible for 25% of preventable drug-related adverse events. • ↑Risk of drug-drug interactions • ↑Risk of drug-disease interactions • ↓Treatment adherence • ↑Financial burden • ↑Caregiver stress • Underdiagnosed • CVD is a risk factor for frailty • ↑Risk for hospitalization, nursing home admission, functional decline, and mortality • Useful for risk stratification before invasive procedure (e.g., transcatheter aortic valve replacement) • Underdiagnosed • CVD is a risk factor for cognitive impairment • ↓Treatment adherence and disease monitoring • ↑Risk for hospitalization and mortality in heart failure

Significance

• Adopt patient-centered care that aligns treatments with personal goals and preference • Consider the following aspects: • Likelihood of benefits vs. harms • Prognosis (life expectancy) • Functional impairment and frailty • Treatment feasibility • Identify medications with high likelihood of harms and questionable benefits using an expert consensus checklist (e.g., Beers criteria) • Discontinue nonessential treatments to maximize adherence to essential treatments

• No effective pharmacological interventions exist for prevention or treatment of frailty • Comprehensive geriatric assessment and exercise program can prevent functional decline and nursing home admission • Use frailty assessment to predict prognosis and guide individualized treatment decisions • Simplify CVD treatments for better adherence • Utilize support system to improve adherence and disease monitoring

• Identify coexisting non-CVD conditions requiring treatments that may compete with CVD treatments

• Assess total treatment burden from • Nonpharmacological treatment • Pharmacological treatment (total number of medications and treatment complexity) • Assess treatment adherence • Use a validated frailty assessment: • Timed Up and Go test • Gait speed • Short physical performance battery • Frailty phenotype • Comprehensive geriatric assessment • Use a validated cognitive screening tool: • Mini-Mental State Examination • Montreal Cognitive Assessment • Mini-Cog test

(Continued)

Management

Assessment

Table 3.1  Common geriatric conditions and implications for cardiovascular care

Geriatric syndromes in older adults with CVD  51

• Ask about urinary incontinence

• Start CVD medications at low dose and gradually increase • Refer high-risk patients to gait and balance training program or to a fall specialist for multidisciplinary assessment and targeted interventions • Discuss the impact of worsening incontinence by CVD treatments • Initiate nonpharmacological interventions for incontinent patients • Refer selected patients to a specialist if nonpharmacological interventions are not effective

• Utilize support system to improve adherence and disease monitoring

• Use a validated instrument: • Katz index of activities of daily living • Lawton index of instrumental activities of daily living • Nagi scale • Use a validated screening tool: • Number of falls in the past year • Self-reported difficulty in gait or balance • Timed Up and Go test

Management • Use nonpharmacological interventions to prevent delirium • No effective pharmacological interventions exist for prevention or treatment of delirium

Assessment • Use the Confusion Assessment Method (CAM) for diagnosis in hospitalized older patients

Abbreviations:  ACEI, angiotensin-converting enzyme inhibitor; CVD, cardiovascular disease.

Urinary incontinence

Falls

• Underdiagnosed • CVD medications may contribute to the risk (especially diuretics and ACEI cough) • ↓Quality of life

• Under-diagnosed • ↑Risk for hospitalization, nursing home admission, functional decline, and mortality • May lead to persistent cognitive impairment after cardiac surgery • Underdiagnosed • CVD can cause functional decline • ↓Treatment adherence and disease monitoring • ↓Risk for hospitalization, nursing home admission, and mortality • Underdiagnosed • Symptomatic heart failure and certain CVD medications may contribute to fall risk • ↓Adherence to exercise intervention

Delirium

Functional decline

Significance

Condition

Table 3.1 (Continued)  Common geriatric conditions and implications for cardiovascular care

52  General principles on caring for older adults

Geriatric syndromes in older adults with CVD  53

Moreover, older adults with multimorbidity are frequently excluded from clinical trials of cardiovascular therapy. Therefore, it remains unclear whether clinical trial evidence on the benefits and risks can be generalized to patients with multimorbidity. Some evidence suggests that those with certain multimorbidity patterns may benefit less from guideline-recommended therapy (14). Although multimorbidity and comorbidity are related concepts, a multimorbidity-based framework provides a useful approach to managing older adults with CVD (Figure 3.1). In the comorbidity framework, CVD is the disease of interest and all other conditions are considered as secondary entities (e.g., consequences of CVD, complications of cardiovascular therapy, or unrelated coexistence) (15). Treatment is focused on the CVD, although coexisting conditions may affect the choice of cardiovascular therapy. Most CVD clinical practice guidelines were developed under this construct. By contrast, in the multimorbidity framework, the patient is the main focus and all conditions can be considered equally important as long as they impact patient-centered outcomes, such as quality of life and function (15). Treatment is targeted at multiple conditions simultaneously with a goal to optimize these measures. To effectively achieve this goal, identifying common patterns of conditions provides a useful context to consider trade-offs between different conditions. Clinicians should prioritize interventions for CVD and other coexisting noncardiovascular conditions that have the highest impact on patient-centered outcomes.

Polypharmacy Medications frequently used by older adults in the United States include cardiovascular drugs, antacids, diabetes (a) Comorbidity Framework

drugs, anticoagulants, analgesics, and antidepressants (16). Approximately 40% of older individuals concomitantly take five or more medications, which is referred to as polypharmacy (16). Polypharmacy is strongly associated with multimorbidity and prescribing practices aligned with disease-based clinical practice guidelines (14,16). The rate of polypharmacy has been rising, in part, due to increased use of cardiovascular therapy, such as statins, antiplatelet agents, and omega-3 fish oils (17). The consequences of polypharmacy are broad and potentially serious. In a 2011 national survey, 15% of older adults were at risk for a major drug-drug interaction; the most common interacting regimen involving prescription medications was concurrent use of amlodipine and simvastatin (17). In a national study of Medicare beneficiaries, 23% were taking at least one medication that could potentially worsen a coexisting condition. For example, use of nonsteroidal anti-inflammatory drugs for osteoarthritis may increase the risk of CVD and reduce the efficacy of cardiovascular therapy (e.g., angiotensinconverting enzyme inhibitors, angiotensin receptor blockers, diuretics) in patients with CVD (18). Cardiovascular drugs are responsible for 25% of preventable adverse events (19). Other consequences of polypharmacy include lower adherence, financial burden, and caregiver stress (20,21). When a new cardiovascular drug is considered, clinicians should assess the incremental benefit and harm of the new drug in older patients who already receive a complex regimen. A post hoc analysis of a clinical trial of anticoagulation therapy in patients with atrial fibrillation showed that the efficacy of apixaban compared with warfarin on thromboembolic events was consistent across the number of concomitant drugs used, but the protective effect of apixaban on major bleeding diminished with increasing numbers of concomitant drugs (22). Since clinical trials (b) Multimorbidity Framework Cardiovascular disease

Diabetes

Osteoarthritis

Cardiovascular disease

COPD

Chronic kidney disease

Diabetes

Osteoarthritis

Patient

Chronic kidney disease

COPD

Figure 3.1  Comorbidity and multimorbidity in older adults with cardiovascular disease. In the comorbidity framework (a), cardiovascular disease is the disease of interest and all other conditions are considered as secondary entities. Treatment is focused on cardiovascular disease and coexisting conditions may affect the choice of cardiovascular therapy. In the multimorbidity framework (b), the patient is the main focus and all conditions can be considered equally important as long as they impact patient-centered outcomes, such as the quality of life and function. Treatment is targeted at multiple conditions simultaneously with a goal to optimize patient-centered outcomes. Patient-centered outcomes depend on the net effect of complex interactions among multimorbidity, polypharmacy, and geriatric syndromes. Therefore, treatment to improve cardiovascular disease, whose effects can be offset by worsening noncardiovascular or geriatric conditions and treatment-related adverse events, may not result in a proportional improvement in patient-centered outcomes. Abbreviation: COPD, chronic obstructive pulmonary disease.

54  General principles on caring for older adults

often exclude patients with polypharmacy, the possibility of differential benefit and harm by the number of concomitant drugs remains uncertain for most cardiovascular drugs. In addition to the increased likelihood of drug-drug or drug-disease interaction with polypharmacy, patients with polypharmacy—who are more likely to have multimorbidity and frailty—may not live long enough to benefit from a preventive cardiovascular therapy. In a clinical trial of patients who had an estimated life expectancy less than a year and were taking statins for primary or secondary prevention, discontinuing statins resulted in better quality of life and cost savings without increasing the risk of CVD events or death (23). When there is a major change in the patient’s general health or functional status (e.g., falls, functional decline, cognitive decline, delirium, hospitalization, institutionalization), clinicians should reassess the ongoing need for each medication and consider deprescribing medications with questionable benefit or high risk of harm. Standard checklists, such as the American Geriatrics Society Beers list (24) or STOPP/START criteria (25), can be used to identify high-risk medications. A time-limited withdrawal may help clinicians determine the need for ongoing therapy when the indication for a medication is unclear. When deprescribing cardiovascular drugs, a gradual tapering off may be necessary to reduce rebound or withdrawal symptoms.

Frailty Frailty is a vulnerable state characterized by decreased physiologic reserve to maintain homeostasis after a stressor and increased susceptibility to adverse health outcomes. The prevalence of frailty in the general population is 10–15%, although it may vary from less than 5% to over 50% depending on the diagnostic criteria used (26). Among older adults with CVD, prevalence estimates were 21% in patients with coronary artery disease (27), 51% in patients with heart failure (9), and up to 70% in patients undergoing transcatheter aortic valve replacement (28,29). While frailty is a consequence of accumulated age-associated changes and diseases in multiple physiologic systems (30), CVD seems to play an important role in the development of frailty. In the Cardiovascular Health Study, frailty was associated with clinical CVD as well as subclinical CVD (e.g., carotid stenosis, low anklebrachial index, left ventricular hypertrophy, infarct-like lesions on brain magnetic resonance imaging) (31). In particular, the strongest association was found for heart failure. Individuals with frailty are more likely to develop heart failure (32), and frailty was associated with poor outcomes in heart failure (7–9). Frailty also predicts mortality and poor functional status after major cardiac surgery and transcatheter aortic valve replacement (33,34). Given the bidirectional relationship between frailty and CVD, there is a growing interest to lessen frailty by optimizing CVD management. In a small study of older patients with advanced heart failure, the components of frailty lessened

after 3–6 months following implantation of a left ventricular assist device (35). More research is needed to study whether treatment of CVD can reverse frailty or treatment of frailty can improve CVD outcomes. Frailty assessment can be useful in individualizing cardiovascular therapy, since older adults with CVD and severe frailty have a shorter remaining life expectancy and increased risk for treatment-related harms. There are a number of validated instruments to measure frailty (36). The frailty phenotype is the most widely used assessment that is based on unintentional weight loss, weak grip strength, exhaustion, slow gait, and physical inactivity (37). It classifies individuals into robust (0 of 5 components), prefrail (1–2 components), and frail state (≥3 components). Each component of frailty phenotype can be targeted by interventions. The deficit-accumulation frailty index is an alternative measure that quantifies frailty as a proportion of deficits (e.g., symptoms, signs, diseases, diagnostic test abnormalities, functional limitations) in medical, physical, cognitive, emotional, and sensory domains from a survey, medical record, or comprehensive geriatric assessment (38,39). Although the frailty index can take a value between 0 and 1, very few people have a frailty index greater than 0.6, suggesting that an individual with more than 60% of deficits has very high mortality risk (40). In other words, a patient whose frailty index is close to 0.6 has little reserve to withstand additional stress from adverse drug reactions, invasive procedures, or hospitalizations. Compared with frailty phenotype, the frailty index offers better prediction of adverse health outcomes (41). In choosing a frailty instrument for clinical use, feasibility (e.g., need for equipment, space, time, additional training) and specific characteristics of patients that may influence their participation in the assessment should be considered. As an alternative to assessments of frailty phenotype or frailty index, simple instruments are available. Such instruments include Timed Up-and-Go test (42), gait speed (43), Clinical Frailty Scale (44), FRAIL questionnaire (45), and self-administered PRISMA-7 questionnaire (43). Since these simple instruments generally have high sensitivity and moderate specificity (43), a positive test should be followed by a comprehensive geriatric assessment. The performance of a frailty instrument may differ depending on the population (general population vs. specific disease population) or the clinical setting (e.g., ambulatory clinic, preoperative assessment, hospital). One should keep in mind that modifications to the frailty criteria or applying different cut-points from the original definitions may affect the accuracy of assessment and predictive ability (46,47).

Cognitive impairment The prevalence of dementia is 14% in the older population of the United States, ranging from 5% in people 71–79 years of age to 37% in people 90 years and older (48). More people have mild cognitive impairment, a less severe but measurable cognitive decline that may progress to dementia at an

Geriatric syndromes in older adults with CVD  55

annual rate of 12% (49). Cognitive impairment is more common in older adults with CVD, affecting 35% of patients undergoing coronary artery bypass grafting (50) and 47% of those with heart failure (51). Risk factors of CVD, such as hypertension, diabetes, hyperlipidemia, smoking, and obesity, are associated with cerebral infarcts, microhemorrhage, hypoperfusion, inflammation, and oxidative stress (52). These changes lead to gray matter atrophy, white matter lesions, and damage to subcortical white matter pathways (53). Cognitive impairment associated with CVD is characterized by executive dysfunction that is critical in maintaining independence. Those with executive dysfunction have more difficulty following complex treatment regimens, contributing to low adherence, readmission, and mortality (51,54,55). Among several validated instruments to assess cognitive function, the Mini-Cog test is a brief screening tool that consists of a three-word recall test for memory and a clock drawing test for executive function. It is as accurate as the Mini-Mental State Examination in detecting clinically significant cognitive impairment, while being less influenced by education level or literacy (56). Poor performance on the Mini-Cog test predicts readmission or mortality after heart failure hospitalization (57).

Delirium Delirium is an acute confusional state that affects up to 35% of older patients on general medical wards, 50% of cardiac surgical patients (58), and 75% of patients in an intensive care unit (59). It develops as a result of a complex interaction between predisposing factors (e.g., preexisting cognitive impairment, functional limitations, multimorbidity) and precipitating factors (e.g., psychoactive drugs, surgery, anesthesia, severe pain, dehydration, sleep-wake cycle reversal, acute medical illness, inflammation) (60). Delirium is associated with prolonged hospitalization, functional and cognitive decline, institutionalization, mortality, and increased health care costs (60). Although delirium has traditionally been considered transient, emerging literature suggests otherwise: persistent delirium is common, with 33% of cases at 1 month and 21% at 6 months after discharge (61). Delirium was associated with persistently lower cognitive function at 1 year after cardiac surgery (62) and increased risk of dementia over 4 years (63). Despite these clinical and public health implications, delirium is under-recognized by clinicians, especially in the case of hypoactive delirium. However, hypoactive delirium is more common and associated with worse prognosis than hyperactive delirium (58). The Confusion Assessment Method (CAM) is the most widely used diagnostic algorithm; it has a sensitivity of 94%–100% and specificity of 90%–95% against a reference standard clinical examination (64,65). A brief cognitive assessment (e.g., testing of orientation and sustained attention) is required for accurate scoring. This algorithm evaluates four features of delirium: (1) acute onset and fluctuating course; (2) inattention; (3) disorganized thinking; and (4) altered level of consciousness (66). Brief instruments, such

as the CAM for Intensive Care Unit (67), the 3-Minute Diagnostic Assessment (68), or 4 A’s Test (69), can be adopted in busy clinical practice. A CAM-based severity score (70,71) can be used to track clinical course and recovery, and to monitor treatment response. Currently, no pharmacological interventions are proven effective for prevention or treatment of delirium. Therefore, prevention is the key to avoid negative ramifications (72). There is strong evidence to recommend nonpharmacological multifactorial interventions to address cognitive impairment, sleep deprivation, immobility, dehydration, and sensory impairment (72). Medications that are associated with increased risk of delirium (e.g., drugs with anticholinergic properties, benzodiazepines, sedatives) should be avoided. Due to inconsistent efficacy and concerns for serious harms, such as cardiac arrhythmias, sedation, extrapyramidal side effects, aspiration pneumonitis, stroke, and even mortality, antipsychotics should not be routinely used for prevention or treatment. In case of severe agitation that presents substantial harms to self or others, they should be prescribed at the lowest effective dose for the shortest duration possible (73). Commonly used antipsychotics include haloperidol, quetiapine, olanzapine, and risperidone. Because these agents appear to have similar efficacy, the choice is often based on adverse effects (74). Adequate management of precipitating factors, such as pain and acute medical illness, is also key in mitigating duration and severity of delirium.

Functional decline Patients with a higher burden of clinical and subclinical CVD experience accelerated functional decline and spend more years with disability (75,76). Those who experience functional decline are more likely to develop CVD events (77). In particular, the risk of functional decline is high when older adults are hospitalized with an acute illness. In addition to the negative effect of acute illness and its complications (e.g., delirium), hospitalization is associated with restricted mobility, enforced dependence and limited encouragement of independence (e.g., fall alarms and bed rest), limited access to food and liquids (e.g., “Nil per os” orders), and polypharmacy (78). The effect of bed rest on sarcopenia, defined as loss in skeletal muscle mass and function, and aerobic capacity is well documented (79,80). In healthy older adults, bed rest resulted in a loss of 630 grams of muscle mass per week compared with 100–200 grams per week in younger adults (79). The loss in knee extensor peak torque after a 10-day bed rest was consistent with a meaningful reduction in stair-climbing power (80). The effect of bed rest on sarcopenia is expected to be more substantial in hospitalized patients with an acute illness (e.g., acute CVD event) that is associated with high catabolic state (81). As a result, functional decline acquired during an acute hospitalization may require rehabilitation discharge or home health services. The period of restricted activity may persist after hospital discharge, and this can precipitate new or worsening disability in frail older adults who have limited

56  General principles on caring for older adults

reserve (82). Additionally, reduced physical activity during hospitalization, measured using a wearable device, was associated with readmission after cardiac surgery (83). Frail patients are more likely to experience functional decline than non-frail patients even after less invasive transcatheter aortic valve replacement (34). Clinicians can measure functional status using a validated questionnaire, such as the Nagi scale (84), activity of daily living scale (85), or instrumental activity of daily living scale (86), at ambulatory clinic visit or inpatient encounter. Functional status can be a prognostic indicator as well as an outcome to evaluate the effect of cardiovascular therapy. It is important to identify individuals at high risk for functional decline, such as people with frailty, preexisting functional limitations, and cognitive impairment. Considering the multifactorial nature of functional decline, preventing it requires a multicomponent intervention. Evidence supports that consumption of a moderate amount of high-quality protein (25–30 grams per meal) and exercise in close temporal proximity to protein-enriched meals are effective in preventing muscle loss due to bed rest (81). Nonpharmacological interventions to prevent delirium can reduce delirium, functional decline, and hospital falls (72,87). In the absence of medical contraindications, these interventions should be routinely recommended to hospitalized older adults with CVD. In older adults who are scheduled for a cardiovascular procedure, a prehabilitation program that addresses modifiable risk factors for functional decline prior to procedure has potential to improve postoperative outcomes and facilitate functional recovery (88). Such programs should be individualized based on patient characteristics, available expertise, resources, and costs. As facility-based programs may not be cost-effective or feasible for many patients, a home-based program may be a suitable alternative. More research is needed to identify the best prehabilitation model for patients undergoing cardiovascular procedures.

Falls One in three older adults in the community falls every year. As the leading cause of injury (e.g., soft tissue injury, hip fracture, head trauma) in people 65 years and older (89), falls have major consequences on older individuals’ independence, quality of life, and medical costs. The average medical cost of a hospitalization due to fall-related injuries exceeds that of a hospitalization for acute myocardial infarction or heart failure (89). Most falls are multifactorial, with major risk factors including gait and balance impairment, weak muscle strength, sensory impairment, medications, orthostatic hypotension, functional limitations, cognitive impairment, and urinary incontinence (90). Patients with clinical CVD, in particular hypotension, heart failure, and arrhythmia, are at increased risk for falls (91). Other cardiovascular conditions related to falls include carotid sinus hypersensitivity, vasovagal syncope, and postprandial hypotension. Symptomatic CVD can cause mobility impairment, weak muscle strength,

functional limitation, and cognitive impairment, thereby contributing to the risk of falls. Moreover, medications commonly consumed by older adults with CVD, such as antihypertensives (92,93), loop diuretics (94), and psychoactive drugs (92,95), have been linked to falls. The risk may be higher after initiation of a new cardiovascular drug or dose increase compared with chronic use. On the other hand, fall history can influence CVD management. Individuals with fall history or fear of falling may limit their participation in physical activity. Concerns about falling are the most commonly cited reason by clinicians for not initiating anticoagulation in older adults with atrial fibrillation (96). Since the risk of major bleeding and intracranial bleeding is higher in older adults with fall history than those without, it is important to assess fall risk before anticoagulation therapy (97). To assess fall risk, clinicians should first ask about history of falls in the past year and difficulty with walking or balance. A mobility test, such as Timed Up and Go test, can be useful (98). Patients at high risk for falls should receive a comprehensive evaluation followed by targeted interventions, including gait and balance training (99).

Urinary incontinence The prevalence of urinary incontinence is higher than that of heart disease and diabetes, affecting almost 4 million older men and 10 million older women (100). It has negative effect on the quality of life and increases the risk of depression, functional limitations, falls, and nursing home placement (101). Despite the population burden and significant health impact, it remains underdiagnosed and undertreated; only a quarter of patients with incontinence seek medical care (102). The risk factors of urinary incontinence may differ by types of incontinence (stress, urgency, and mixed type). Common contributing causes include conditions affecting lower urinary tract (e.g., atrophic vaginal tissue, urinary tract infection, fecal impaction), increased urine volume (e.g., volume overload, diuretic use, caffeine intake, hyperglycemia), impaired mobility, dementia and delirium, depression, and external factors (e.g., restraint use, availability of restroom and toilet aids). Medications used to manage CVD can affect several of these factors. Cough, a common side effect from angiotensin-converting enzyme inhibitors, may cause stress incontinence. Increase urine volume from loop diuretics can lead to urgency incontinence. Calcium channel blockers may worsen urgency incontinence by causing urinary retention and constipation. Clinical management of urinary incontinence should begin by asking patients about urinary incontinence. Use of a simple screening question can lead to an increase in appropriate care (103). A careful history and examination can identify reversible causes, such as infection, uncontrolled diabetes, decompensated heart failure, medications, and depression. Once reversible causes are adequately managed, nonpharmacological treatment (e.g., lifestyle interventions for weight loss, pelvic muscle exercise, and bladder training including timed/scheduled voiding) should be offered. Medications

Approaches to evaluation and management of older adults with CVD  57

are second-line treatment for urgency incontinence. Use of anticholinergics (darifenacin, fesoterodine, oxybutynin, solifenacin, tolterodine, and trospium) is frequently limited by constipation and dry mouth. In older adults, anticholinergics were associated with increased brain atrophy and cognitive decline (104). The beta-3 adrenergic agonist mirabegron, which is indicated for urgency incontinence, can worsen hypertension. Specialist referral is indicated under selected circumstances (e.g., anatomic abnormalities, diagnostic uncertainty, suspicion for neurological diseases, recurrent infections, urinary retention) (101).

APPROACHES TO EVALUATION AND MANAGEMENT OF OLDER ADULTS WITH CVD The main goal of cardiovascular therapy is to improve quality of life, functional status, and survival by reducing CVD symptoms and preventing future CVD events. Patient-centered outcomes, such as quality of life, functional status, and overall survival (rather than CVD-free survival), are determined by the net effect of multimorbidity, polypharmacy, geriatric syndromes, and their interactions (Figure 3.2). Consequently, the actual benefit of cardiovascular therapy on patient-centered outcomes may be offset by exacerbation of noncardiovascular or geriatric conditions, treatment-related adverse events, and decreased adherence to complex treatment regimens. Evaluation of older adults with CVD should include assessment of the severity and prognosis related to CVD as well as the impact of noncardiovascular conditions and geriatric syndromes on the overall quality of life, functional status, and prognosis. Before prescribing medications or recommending invasive procedures for CVD, clinicians should understand the limitations of current evidence and clinical practice guidelines, and acquire competency in the principles of patient-centered care.

Limitations of clinical trial evidence and clinical practice guidelines The management of CVD is driven by evidence from clinical trials. Yet exclusion of multimorbid older adults from clinical trials leads to uncertainty for a large fraction of the patient population. A study comparing Medicare

beneficiaries to the participants of 141 trials referenced by CVD guidelines found that trial participants were younger and more likely to be male (105). A simulation study estimated that, in younger patients, 9–25 patients would need to be treated with angiotensin-converting enzyme inhibitors and angiotensin receptor blockers for 3 years to prevent one case of end-stage renal disease, whereas the corresponding number in patients aged 70 or older ranged from 16 to 2500 (106). In addition, since clinical trials primarily focus on mortality or cardiovascular events, the effect of therapeutic and preventative interventions on quality of life or functional status is not well studied. While a patient’s willingness to take a medication for primary prevention may be influenced by the risk of adverse effects rather than potential benefit (107), clinical trials do not provide sufficient evidence on treatment harms. Clinical practice guidelines derived from clinical trial evidence carry similar limitations. Although many guidelines mention age, few guidelines discuss conflicting recommendations or need for treatment modifications in the presence of multimorbidity (20). Such myopic focus on a single disease is not only impractical but potentially harmful. Therapeutic competition, a term which refers to the potential for standard of care treatment of one condition to introduce harm in the context of another illness, was observed in 23% of community-dwelling older adults (18). In general, clinical practice guidelines fail to address patient preferences, which may contribute to low adherence and less optimal care (20). A review of 65 guidelines found that only 6% of references from clinical practice guidelines pertained to patient preferences, compared to 37% of references addressing treatment effectiveness (108). None of the reviewed guidelines discussed the patient’s goals. Failure to consider and incorporate the patient’s preferences not only limits applicability of clinical practice guidelines, but is potentially obstructive to providing individualized care. Treatment burden on patients and their caregivers are rarely addressed.

Adopting patient-centered goals-directed care The current health care delivery model is ineffective, inadequate, and potentially harmful to multimorbid older adults. A typical Medicare beneficiary sees two primary

Multimorbidity - CVD - non-CVD

Polypharmacy

Patient-Centered Outcomes Quality of life

Aging

Functional status Geriatric syndromes

Survival

Figure 3.2  Interactions among multimorbidity, polypharmacy, and geriatric syndromes and patient-centered outcomes.

58  General principles on caring for older adults

care providers and five specialists in four different practices in a year, and the number of providers increases with the number of conditions (109). Fragmented care, combined with clinical practice guidelines under the comorbidity framework, often leads to conflicting recommendations. Recently, a patient-centered goal-directed care model has been proposed as a potential remedy to the above issues. Patient goals–directed care is centered on achievement of patient-defined health outcome goals and care preferences (110–112). Health outcome goals refer to specific outcomes which patients aim to accomplish through their health and health care (e.g., improvement of function, symptom relief). Care preferences are essentially what trade-offs are allowed (e.g., frequent lab monitoring, dietary changes, financial limitations), which weigh into what an individual patient is willing to do. By centering goals on patient-defined outcomes and preferences rather than individual diseases, the health care team is united in its efforts to achieve the same outcomes. The process starts with the identification of patient goals by a member of the health care team. Here the position of the member is less important than their communication skills and ability to guide an interaction and craft meaningful goals with patients and their caregivers. Outcomes should be specific, measurable, actionable, reliable, and time bound (“SMART”) (110). Specific roles can then be established, with responsibilities delegated to the most appropriate members of the health care team and one clinician taking responsibility to coordinate care in general. Working with geriatricians and other clinicians with experience and expertise in caring for older patients is critical to the success of this model. Developing quality metrics that reflect high-value care from the patient’s perspective can facilitate patient goals–directed care (113).

Assessing time to benefit and prognosis Another important consideration in treatment decision is to assess the likelihood of a clinically meaningful treatment benefit. This involves comparing the patient’s remaining life expectancy with the time to benefit from a treatment (114). Several prognostic models exist to estimate the mortality risk at a specified time period or the remaining life expectancy (115). The time to benefit represents the length of time needed to accrue a clinically meaningful benefit in a specific outcome (114). Likewise, the time to harm can be defined as the length of time until a clinically meaningful adverse event occurs. If a patient’s remaining life expectancy is shorter than the time to benefit from a treatment, the treatment is unlikely to provide a meaningful benefit and may be futile; if the remaining life expectancy is longer than the time to benefit, the treatment can be recommended. If the two estimates are similar, the decision should be guided by the patient’s goals and preferences. While this concept is potentially useful to prioritize multiple, competing treatments in multimorbid patients, time to benefit (or harm) is rarely reported in clinical trials.

Although the time to benefit has been operationalized by a few researchers (116–118), these methods rely on statistical interpretation of benefit, rather than clinically meaningful benefit, or result in estimates that are often too uncertain (i.e., wide confidence intervals) to impact treatment decision making.

Communicating evidence for treatment decision making Appropriate interpretation and effective communication of the evidence are essential to treatment decision making. Evidence suggests that how evidence is presented to patients affects their treatment choice. Typically, the benefit and harm of a treatment are summarized in terms of relative risk reduction (e.g., relative risk or hazard ratio) and absolute risk reduction. The number needed to treat (or harm) can be derived from absolute risks at a specified time point. Despite their widespread use in medical literature, these statistics are not intuitive for clinicians and patients to understand or communicate (119,120). Presenting relative risk reduction alone without absolute risk information can be misleading and tends to bias patients toward accepting treatment (121). For instance, patients who have diabetes but low cardiovascular risk were 70% less likely to choose statin treatment after being presented with information about the small absolute risk reduction (122). However, the number needed to treat has a negative effect on patients’ understanding about the evidence (121). Therefore, it is recommended to use natural frequencies with the denominator of 1000  people (e.g., 50 in 1,000  people, instead of 5%, develop an event in 5 years) when expressing benefits and harms; avoid number needed to treat; and present both absolute and relative risk reductions (121,123–128). Use of visual decision aids can be helpful. Alternative measures of treatment effect, such as event-free or disability-free time gained or lost due to treatment (129,130), may allow more intuitive interpretation of clinical trial results than conventional measures.

SUMMARY With population aging, CVD affects a large number of older people and remains a significant cause of mortality and morbidity. Due to accumulation of age-associated structural and functional changes, multiple diseases affecting the cardiovascular and other organ systems, and prevalent geriatric conditions, it is challenging to evaluate and manage the treatment of older adults with CVD. It is important to recognize that clinical trial evidence and recommendations from disease-specific clinical practice guidelines are inadequate for multimorbid or frail older adults because the net benefit of treatment to optimize CVD-specific outcomes may be negated by its adverse effect on other conditions that are equally important for quality of life and functioning. When such a trade-off is inevitable, clinicians should begin by asking about the patient’s

References 59

goals and preferences, and prioritize and align treatments accordingly. Under the patient goals–directed care model, the emphasis is to maximize the chance of achieving the patient-defined goals, not to manage each disease according to the clinical practice guidelines. Additional research is needed to generate evidence on patient-centered outcomes and improve evidence communication strategies for informed decision making.

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4 Cardiovascular drug therapy in the elderly WILLIAM H. FRISHMAN, WILBERT S. ARONOW, AND ANGELA CHENG-LAI Introduction 64 Pharmacokinetic considerations in the elderly 64 Absorption 64 Bioavailability 64 Drug distribution 64 Half-life 65 Drug metabolism 65 Drug excretion 65 Pharmacodynamics 71 Use of cardiovascular drugs in the elderly 72 Digoxin 72 Diuretics 73 Beta-adrenergic blockers 74 ACE inhibitors 76

Angiotensin II receptor blockers 76 Direct renin inhibitors 76 Nitrates 77 Calcium channel blockers 77 Alpha-adrenergic blockers 77 Lidocaine 77 Other antiarrhythmic drugs 78 Lipid-lowering drugs 78 Anticoagulants 80 Herbal remedies 80 Adverse effects of drugs in the elderly 80 Medications best to avoid in the elderly 80 Prudent use of medication in the elderly 87 References 87

INTRODUCTION

Bioavailability

Cardiovascular disease is the greatest cause of morbidity and mortality in the elderly, and cardiovascular drugs are the most widely prescribed drugs in this population. Since many cardiovascular drugs have narrow therapeutic windows in the elderly, the incidence of adverse effects from using these drugs is also highest in the elderly. The appropriate use of cardiovascular drugs in the elderly requires knowledge of age-related physiologic changes, the effects of concomitant diseases that alter the pharmacokinetic and pharmacodynamic effects of cardiovascular drugs, and drug-drug interactions.

There are almost no data available for age-related changes in drug bioavailability for routes of administration other than the oral route (2). The bioavailability of cardiovascular drugs depends on the extent of drug absorption and on first-pass metabolism by the liver and/or the wall of the gastrointestinal (GI) tract. In the elderly, the absolute bioavailability of drugs such as propranolol, verapamil, and labetalol is increased because of reduced first-pass hepatic extraction (3). However, the absolute bioavailability of prazosin in the elderly is reduced (4).

PHARMACOKINETIC CONSIDERATIONS IN THE ELDERLY

Drug distribution

Absorption Age-related physiologic changes that may affect absorption include reduced gastric secretion of acid, decreased gastric emptying rate, reduced splanchnic blood flow, and decreased mucosal absorptive surface area (Table 4.1). Despite these physiologic changes, the oral absorption of cardiovascular drugs is not significantly affected by aging, probably because most drugs are absorbed passively (1). 64

With aging there is a reduction in lean body mass (5) and in total body water (6), causing a decrease in volume of distribution (Vd) of hydrophilic drugs. This leads to higher plasma concentrations of hydrophilic drugs such as digoxin and angiotensin converting enzyme (ACE) inhibitors with the first dose in the elderly (7). The increased proportion of body fat that occurs with aging also causes an increased Vd for lipophilic drugs. This leads to lower initial plasma concentrations for lipophilic drugs such as most beta-blockers, antihypertensive drugs, and central alpha-agonists.

Pharmacokinetic considerations in the elderly  65

Table 4.1  Physiologic changes with aging potentially affecting cardiovascular drug Process Absorption

Physiologic change Reduced gastric acid production

Reduced gastric emptying rate Reduced GI mobility, GI blood flow, absorptive surface Distribution Decreased total body mass; increased proportion of body fat Decreased proportion of body water Decreased plasma albumin, diseaserelated increased α1-acid glycoprotein, altered relative tissue perfusion Metabolism Reduced liver mass, liver blood flow, and hepatic metabolic capacity

Excretion

Result

Drugs affected

Reduced tablet dissolution and decreased solubility of basic drugs Decreased absorption for acidic drugs Less opportunity for drug absorption Increased Vd of highly lipid-soluble drugs Decreased Vd of hydrophilic drugs Changed % of free drug, Vd, and measured levels of bound drugs Accumulation of metabolized drugs

Reduced glomerular filtration, renal Accumulation of renally cleared drugs tubular function, and renal blood flow

↓ β-blockers, central α agonists ↑ digoxin & ACE inhibitors ↑ disopyramide and warfarin, lidocaine, propranolol ↑ propranolol, nitrates, lidocaine, diltiazem, warfarin, labetalol, verapamil, mexiletine ↑ digoxin, ACE inhibitors, antiarrhythmic drugs, atenolol, sotalol, nadolol

Source: The American Geriatrics Society 2015 Beers Criteria Update Expert Panel, J. Am. Geriatr. Soc., 63, 2227–2246, 2015. Abbreviations:  GI, gastrointestinal; Vd, volume of distribution; ACE, angiotensin converting enzyme.

The level of alpha1-acid glycoprotein increases in the elderly  (8). Weak bases such as disopyramide, lidocaine, and propranolol bind to alpha1-acid glycoprotein. This may cause a reduction in the free fraction of these drugs in the circulation, a decreased Vd, and a higher initial plasma concentration (9). In the elderly, there is also a tendency for plasma albumin concentration to be reduced (10). Weak acids, such as salicylates and warfarin, bind extensively to albumin. Decreased binding of drugs such as warfarin to plasma albumin may result in increased free-drug concentrations, resulting in more intense drug effects (11).

Half-life The half-life of a drug (or of its major metabolite) is the length of time in hours that it takes for the serum concentration of that drug to decrease to half of its peak level. This can be described by the kinetic equation: t1/2  =  (0.693 × Vd)/Cl, where t1/2  is directly related to drug distribution and inversely to clearance. Therefore, changes in Vd and/or Cl due to aging, as previously mentioned, can affect the half-life of a drug. In elderly patients, an increased half-life of a drug means a longer time until steadystate conditions are achieved. With a prolonged half-life of a drug, there may be an initial delay in maximum effects of the drug and prolonged adverse effects. Table 4.2 lists the pharmacokinetic changes, routes of elimination and dosage adjustment for common cardiovascular drugs used in the elderly.

Drug metabolism Decreased hepatic blood flow, liver mass, liver volume, and hepatic metabolic capacity occur in the elderly (12). There

is a reduction in the rate of many drug oxidation reactions (phase  1) and little change in drug conjugation reactions (phase 2). These changes in the elderly may result in higher serum concentrations of cardiovascular drugs that are metabolized in the liver, including propranolol, lidocaine, labetalol, verapamil, diltiazem, nitrates, warfarin, and mexiletine.

Drug excretion With aging there is a reduction in the total numbers of functioning nephrons and thereby a parallel decline in both glomerular filtration rate and renal plasma flow (13,14). The age-related decline in renal function is likely the single most important physiologic change causing pharmacokinetic alterations in the elderly. The change in renal function with aging is insidious and poorly characterized by serum creatinine determinations, although serum creatinine measurements remain one of the most widely used tests for gauging renal function. To estimate renal function from a serum creatinine value requires its being indexed for muscle mass, which is difficult in even the most skilled hands. Creatinine is a by-product of creatine metabolism in muscle and its daily production correlates closely with muscle mass. Thus, the greater the muscle mass, the higher the “normal serum creatinine.” For example, in a heavily muscled male, a serum creatinine value of 1.4 mg/dL might be considered normal, though such a value may be considered grossly abnormal in an individual with less muscle, such as an aged individual. A safer way to estimate renal function in the elderly is by use of a urine-free formula such as the Cockcroft–Gault ­formula (15):

66  Cardiovascular drug therapy in the elderly

Table 4.2  Pharmacokinetic changes, route of elimination, and dosage adjustment of selected cardiovascular drugs in the elderly Drug

T½

VD

Cl

Primary route(s) of elimination

Dosage adjustment

Alpha-Adrenergic Agonists Centrally Acting Clonidine – – – Guanabenz – – – Guanfacine ↑ – ↓ Methyldopa – – –

Hepatic/renal Hepatic Hepatic/renal Hepatic

Initiate at lowest dose; titrate to response Initiate at lowest dose; titrate to response Initiate at lowest dose; titrate to response Initiate at lowest dose; titrate to response

Alpha-/Beta Agonist Droxidopa

Renal

Use usual dose with caution

–

–

–

Alpha1 Selective Adrenergic Antagonists Peripherally Acting Doxazosin ↑ ↑ ↑* Hepatic Prazosin ↑ – – Hepatic Terazosin ↑ – – Hepatic

Initiate at lowest dose; titrate to response Initiate at lowest dose; titrate to response Initiate at lowest dose; titrate to response

Angiotensin Converting Enzyme Inhibitors Benazepril ↑ – ↓ Captopril NS – ↓ Enalapril – – – Fosinopril – – – Lisinopril ↑ NS ↓ Moexipril – – – Perindopril – – ↓ Quinapril – – – Ramipril – – – Trandolapril – – –

Renal Renal Renal Hepatic/renal Renal Hepatic/renal Renal Renal Renal Hepatic/renal

No adjustment needed Initiate at lowest dose; titrate to response Initiate at lowest dose; titrate to response No adjustment needed Initiate at lowest dose; titrate to response Initiate at lowest dose; titrate to response Initiate at lowest dose; titrate to response Initiate at lowest dose; titrate to response Initiate at lowest dose; titrate to response Initiate at lowest dose; titrate to response

Angiotensin II Receptor Blockers Azilsartan – – Candesartan – – Eprosartan – – Irbesartan NS – Losartan – – Olmesartan – – Telmisartan – – Valsartan ↑ –

Hepatic/renal Hepatic/renal Hepatic/biliary/renal Hepatic Hepatic Renal/biliary Hepatic/biliary Hepatic

No adjustment needed No adjustment needed No adjustment needed No adjustment needed No adjustment needed No adjustment needed No adjustment needed No adjustment needed

– – ↓ – – – – –

Angiotensin II Receptor Blocker/Neprilysin Inhibitor Sacubitril/valsartan NS NS NS Hepatic/renal

Use usual dose with caution

Antianginal Agent Ranolazine

NS

NS

NS

Hepatic

Initiate at lowest dose; titrate to response

Antiarrhythmic Agents    Class I       Disopyramide       Flecainide       Lidocaine       Mexilitine       Moricizine       Procainamide       Propafenone       Quinidine       Tocainide

↑ ↑ ↑ – – – – ↑ ↑

– ↑ ↑ – – – – NS –

↓ ↓ NS – – ↓ – ↓ ↓

Renal Hepatic/renal Hepatic Hepatic Hepatic Renal Hepatic Hepatic Hepatic/renal

Initiate at lowest dose; titrate to response Initiate at lowest dose; titrate to response Initiate at lowest dose; titrate to response No adjustment needed No adjustment needed Initiate at lowest dose; titrate to response No adjustment needed Initiate at lowest dose; titrate to response No adjustment needed (Continued)

Pharmacokinetic considerations in the elderly  67

Table 4.2 (Continued)  Pharmacokinetic changes, route of elimination, and dosage adjustment of selected cardiovascular drugs in the elderly Drug

T½

VD

Cl

   Class II (see β-Blockers)    Class III       Amiodarone       Bretylium       Dofetilide       Dronedarone       Ibutilide       Sotalol

– – – – – –

– – – – – –

– – – – – –

   Class IV (see Calcium Channel Blockers)    Other Antiarrhythmics       Adenosine – – –

Primary route(s) of elimination

Dosage adjustment

Hepatic/biliary Renal Renal Hepatic Hepatic Renal

No adjustment needed Initiate at lowest dose; titrate to response Adjust dose based on renal function No adjustment needed No adjustment needed Adjust dose based on renal function

No adjustment needed Use usual dose with caution

      Atropine

–

–

–

Erythrocytes/vascular endothelial cells Hepatic/renal

Antidote Idarucizumab

–

–

–

Biodegradation/renal

No adjustment needed

Antithrombotics    Anticoagulants       Apixaban       Argatroban

– –

– –

– –

Hepatic/renal Hepatic/biliary

Use usual dose with caution Use usual dose with caution

      Bivalirudin

–

–

–

Adjust dose based on renal function

      Dabigatran

–

–

–

Renal/proteolytic cleavage Renal

      Dalteparin       Desirudin       Edoxaban       Enoxaparin       Fondaparinux       Heparin

– – – – ↑ –

– – – – – –

– – – – ↓ –

      Lepirudin       Rivaroxaban

↑ –

– –

↓ –

Renal Renal Renal Renal Renal Hepatic/ reticuloendothelial system Renal Renal/hepatic

      Tinzaparin       Warfarin

– NS

– NS

– NS

Renal Hepatic

   Antiplatelets       Abciximab       Aspirin       Clopidogrel       Cangrelor

– – NS –

– – – –

– – – –

      Dipyridamole       Eptifibatide

– –

– –

– –

Unknown ↓ Hepatic/renal Hepatic Dephosphorylation (in circulation) Hepatic/biliary Renal/plasma

No adjustment needed unless renal impairment Use usual dose with caution Adjust dose based on renal function Adjust dose based on renal function Adjust dose based on renal function Use usual dose with caution Use usual dose with caution

Adjust dose based on renal function No adjustment needed unless renal impairment Use usual dose with caution Initiate at lowest dose; titrate to response Use usual dose with caution Use usual dose with caution Use usual dose with caution No adjustment necessary Use usual dose with caution Use usual dose with caution (Continued )

68  Cardiovascular drug therapy in the elderly

Table 4.2 (Continued)  Pharmacokinetic changes, route of elimination, and dosage adjustment of selected cardiovascular drugs in the elderly Drug

T½

VD

Cl

      Prasugrel       Ticagrelor

– –

– –

– –

Hepatic Hepatic

Use usual dose with caution Use usual dose with caution

      Ticlopidine       Tirofiban    Thrombolytics       Alteplase       Anistreplase       Reteplase       Streptokinase

– ↑

– –

↓ ↓

Hepatic Renal

Use usual dose with caution Use usual dose with caution

– – – –

– – – –

– – – –

Use usual dose with caution Use usual dose with caution Use usual dose with caution Use usual dose with caution

      Tenecteplase       Urokinase

– –

– –

– –

Hepatic Unknown Hepatic Circulating antibodies/ reticuloendothelial system Hepatic Hepatic

Use usual dose with caution Use usual dose with caution

– NS –

– ↓ –

Renal Hepatic Hepatic

Initiate at lowest dose; titrate to response Initiate at lowest dose; titrate to response Initiate at lowest dose; titrate to response

NS – – –

↓ – – –

Renal Hepatic Hepatic/renal Erythrocytes

Initiate at lowest dose; titrate to response Initiate at lowest dose; titrate to response Initiate at lowest dose; titrate to response Use usual dose with caution

NS –

NS –

NS –

Hepatic Hepatic/renal

Initiate at lowest dose; titrate to response No adjustment necessary

↑

↓

–

Hepatic/biliary

Initiate at lowest dose; titrate to response

– – –

– – –

– – –

Renal Hepatic Hepatic/renal

Initiate at lowest dose; titrate to response Initiate at lowest dose; titrate to response Initiate at lowest dose; titrate to response

– –

– –

– NS

Hepatic/biliary Hepatic

Initiate at lowest dose; titrate to response Initiate at lowest dose; titrate to response

↑ – ↑ – – NS ↑ – – ↑

– – NS NS – – NS – – NS

↓ – ↓ ↓ – – ↓ – – ↓

Hepatic Blood/extravascular tissue Hepatic Hepatic Hepatic Hepatic Hepatic Hepatic Hepatic Hepatic

Initiate at lowest dose; titrate to response Use usual dose with caution Initiate at lowest dose; titrate to response Initiate at lowest dose; titrate to response Initiate at lowest dose; titrate to response No initial adjustment needed Initiate at lowest dose; titrate to response Use usual dose with caution Initiate at lowest dose; titrate to response Initiate at lowest dose; titrate to response (Continued)

β-Adrenergic Blockers    Nonselective without ISA       Nadolol NS       Propranolol ↑       Timolol –    β1 Selective without ISA       Atenolol ↑       Betaxolol –       Bisoprolol –       Esmolol –       Metoprolol       Nebivolol    β1 Selective with ISA       Acebutolol    Nonselective with ISA       Carteolol       Penbutolol       Pindolol    Dual Acting       Carvedilol       Labetalol Calcium Channel Blockers Amlodipine Clevidipine Diltiazem Felodipine Isradipine Nicardipine Nifedipine Nimodipine Nisoldipine Verapamil

Primary route(s) of elimination

Dosage adjustment

Pharmacokinetic considerations in the elderly  69

Table 4.2 (Continued)  Pharmacokinetic changes, route of elimination, and dosage adjustment of selected cardiovascular drugs in the elderly Drug

T½

VD

Cl

Direct Renin Inhibitor Aliskiren

–

–

–

Renal/biliary

No initial dosage adjustment is needed

Diuretics    Loop       Bumetanide       Ethacrynic Acid       Furosemide       Torsemide

– – ↑ –

NS – NS –

– – ↓ –

Renal/hepatic Hepatic Renal Hepatic

No initial adjustment needed No initial adjustment needed No initial adjustment needed No initial adjustment needed

– – – – – – – – – – –

– – – – – – – – – – –

– – – – ↓ – – – – – –

Renal Unknown Renal Renal Renal Unknown Hepatic Renal Renal Unknown Unknown

No initial adjustment needed No initial adjustment needed No initial adjustment needed No initial adjustment needed No initial adjustment needed No initial adjustment needed No initial adjustment needed No initial adjustment needed No initial adjustment needed No initial adjustment needed No initial adjustment needed

– ↑

– –

↓ –

Renal Hepatic/renal

No initial adjustment needed Initiate at lowest dose; titrate to response

Aldosterone Receptor Antagonist Eplerenone – – Spironolactone – –

– –

Hepatic Hepatic/biliary/renal

No initial adjustment needed No initial adjustment needed

Endothelin Receptor Antagonist Ambrisentan – – Bosentan – – Macitentan – –

– – –

Hepatic/biliary Hepatic/biliary Hepatic/biliary

Use usual dose with caution Use usual dose with caution Use usual dose with caution

Inotropic & Vasopressor Agents Digoxin ↑ Dobutamine – Dopamine – Epinephrine –

↓ – – –

↓ – – –

Initiate at lowest dose; titrate to response Initiate at lowest dose; titrate to response Initiate at lowest dose; titrate to response Initiate at lowest dose; titrate to response

Isoproterenol Midodrine Milrinone Norepinephrine

– – – –

– – – –

– – – –

Phenylephrine Vasopressin

– –

– –

– –

Renal Hepatic/tissue Renal/hepatic/plasma Sympathetic nerve endings/plasma Renal Tissue/hepatic/renal Renal Sympathetic nerve endings/hepatic Hepatic/intestinal Hepatic

   Thiazides       Bendroflumethiazide       Benthiazide       Chlorothiazide       Chlorthalidone       Hydrochlorothiazide       Hydroflumethiazide       Indapamide       Methyclothiazide       Metolazone       Polythiazide       Trichlormethiazide    Potassium-Sparing       Amiloride       Triamterene

Primary route(s) of elimination

Dosage adjustment

Initiate at lowest dose; titrate to response No initial adjustment needed Adjust based on renal function Initiate at lowest dose; titrate to response Initiate at lowest dose; titrate to response Use usual dose with caution (Continued)

70  Cardiovascular drug therapy in the elderly

Table 4.2 (Continued)  Pharmacokinetic changes, route of elimination, and dosage adjustment of selected cardiovascular drugs in the elderly Drug

T½

VD

Lipid-Lowering Agents    BAS       Cholestyramine – –       Colestipol – –       Colesevelam – –    Cholesterol Absorption Inhibitor       Ezetimibe – –    FADS       Fenofibrate – –       Gemfibrozil – –    Nicotinic Acid       Niacin – –    HMG-CoA Reductase Inhibitors       Atorvastatin ↑ –       Fluvastatin – –       Lovastatin – –       Pitavastatin – –       Pravastatin – –       Rosuvastatin – –       Simvastatin – –    Omega-3 Fatty Acids       Omega-3 acid ethyl       Esters    PCSK9 Inhibitors       Alirocumab       Evolocumab

Cl

Primary route(s) of elimination

Dosage adjustment

– – –

Not absorbed in GI tract Not absorbed in GI tract Not absorbed in GI tract

No adjustment needed No adjustment needed No adjustment needed

–

Small intestine/hepatic/ biliary

No adjustment needed

– –

Renal Hepatic/renal

Initiate at lowest dose; titrate to response No adjustment necessary

–

Hepatic/renal

No initial adjustment needed

– – – – – – –

Hepatic/biliary Hepatic Hepatic/fecal Hepatic/fecal/renal Hepatic Hepatic/fecal Hepatic/fecal

No initial adjustment needed No initial adjustment needed No initial adjustment needed No initial adjustment needed No initial adjustment needed No initial adjustment needed Initiate at lowest dose; titrate to response

–

–

–

Hepatic

No adjustment needed

– –

– –

– –

Proteolysis Proteolysis

No adjustment needed No adjustment needed

Neuronal and Ganglionic Blockers Guanadrel – – Guanethidine – – Mecamylamine – – Reserpine – –

– – – –

Hepatic/renal Hepatic/renal Renal Hepatic/fecal

Initiate at lowest dose; titrate to response Initiate at lowest dose; titrate to response Initiate at lowest dose; titrate to response Initiate at lowest dose; titrate to response

PDE5 Enzyme Inhibitors Sildenafil Tadalafil

– –

– –

↓ ↓

Hepatic/fecal Hepatic/fecal/renal

Use usual dose with caution No adjustment needed

Sinus Node Modulator Ivabradine

–

–

–

Intestinal/hepatic

No adjustment needed

Soluble Guanylate Cyclase Stimulator Riociguat – – –

Hepatic

Use usual dose with caution

Vasodilators Alprostadil Cilostazol

Pulmonary/renal Hepatic/renal

Initiate at lowest dose; titrate to response No adjustment necessary (Continued)

– –

– –

– –

Pharmacodynamics 71

Table 4.2 (Continued)  Pharmacokinetic changes, route of elimination, and dosage adjustment of selected cardiovascular drugs in the elderly Drug

T½

VD

Cl

Primary route(s) of elimination

Diazoxide Epoprostenol Fenoldopam Hydralazine Iloprost ISDN ISMN Isoxsuprine Minoxidil Nitroglycerin Nitroprusside

– – – – – – NS – – – –

– – – – – – – – – – –

– – – – – – NS – – – –

Papaverine Pentoxifylline

– –

– –

– ↓

Hepatic/renal Hepatic/renal Hepatic Hepatic Hepatic Hepatic Hepatic Renal Hepatic Hepatic Hepatic/renal/ erythrocytes Hepatic Hepatic/renal

Vasopressin Antagonists       Conivaptan –       Tolvaptan –

– –

– –

Hepatic Hepatic

Dosage adjustment Initiate at lowest dose; titrate to response Initiate at usual dose with caution No adjustment necessary Initiate at lowest dose; titrate to response No adjustment necessary Initiate at lowest dose; titrate to response No adjustment necessary Initiate at lowest dose; titrate to response Initiate at lowest dose; titrate to response Initiate at lowest dose; titrate to response Use usual dose with caution Initiate at lowest dose; titrate to response Use usual dose with caution; dose reduction may be needed No adjustment needed No adjustment needed

Source: Johnson, J.F., PCS Health. Syst. Eli. Lilly & Co., 1, 98, 1998. * Increase in Cl is small compared to increase in V ; T ½  =  half-life. Abbreviations: V ,  volume of distribution; Cl,  clearance; ↑  =  increase; D D ↓ = decrease; – = no information or not relevant; NS, no significant change; LMWH, low molecular weight heparin; ISA, intrinsic sympathomimetic activity; GI, gastrointestinal; BAS, bile acid sequestrants; FADS, fibric acid derivatives; HMG-CoA, hydroxymethylglutaryl coenzyme A; PDE5, phosphodiesterase 5; ISDN, isosorbide dinitrate; ISMN, isosorbide mononitrate; PCSK9, proprotein convertase subtilisin kexin type 9.

Creatinine clearance (mL/min) = [(140 – age) × body weight (kg)]/[72 × Screat (mg/dL)] For females, the results of this equation can be multiplied by 0.85 to account for the small muscle mass in most females. It should be appreciated that creatinine clearance is reciprocally related to serum creatinine concentrations, such that a doubling of serum creatinine represents an approximate halving of renal function. The axiom that glomerular filtration rate is reciprocally related to serum creatinine is most important with the first doubling of serum creatinine. For example, a serum creatinine value of 0.6-mg/dL in an elderly subject doubles to 1.2-mg/dL and with this doubling creatinine clearance falls from 80 cc/min to about 40 cc/min, The National Kidney Foundation guidelines use the Modification of Diet in Renal Disease Study (MDRD) equation to estimate glomerular filtration rate (16). The MDRD equation is as follows: Glomerular filtration rate (mL/min/1.73 m2) = 175 × (Screat)−1.154 × (age)−0.203 × (0.742 if female) or × (1.212 African American) The reduced clearance of many drugs primarily excreted by the kidneys causes their half-life to be increased in the elderly. Cardiovascular drugs known to be excreted by the kidney, via various degrees of filtration and tubular secretion, include digoxin, diuretics, ACE inhibitors, antiarrhythmic medications (bretylium, disopyramide, flecainide, procainamide,

tocainide), and the beta-blockers (atenolol, bisoprolol, carteolol, nadolol, and sotalol). Typically, a renally cleared compound begins to accumulate when creatinine clearance values drop below 60 cc/min. An example of this phenomenon can be seen with ACE inhibitors (17), wherein accumulation begins early in the course of renal functional decline. Moreover, ACE inhibitor accumulation in the elderly is poorly studied in the case of many of the ACE inhibitors particularly as relates to the “true level of renal function” when an otherwise healthy elderly subject undergoes formal pharmacokinetic testing. Thus, it has not been uncommon for elderly subjects with serum creatinine values as high as 2.0-mg/dL to be allowed entry into a study whose primary purpose is to determine the difference in drug handling of a renally cleared compound in young versus elderly subjects.

PHARMACODYNAMICS There are numerous physiologic changes with aging that affect pharmacodynamics with alterations in end-organ responsiveness (Table 4.3). Increased peripheral vascular resistance is the cause of systolic and diastolic hypertension in the elderly (18). Inappropriate sodium intake and retention may contribute to increased arteriolar resistance and/or plasma volume. Cardiac output, heart rate, renal blood flow, glomerular filtration rate, and renin levels decline with age. Increased arterial stiffness, resulting from changes in the arterial media and an increase in arterial tonus and arterial impedance, increases

72  Cardiovascular drug therapy in the elderly

Table 4.3  Characteristics of the elderly relative to drug response Physiologic changes Decreased cardiac reserve Decreased LV compliance due to thickened ventricular wall, increased blood viscosity, decreased aortic compliance, increased total and peripheral resistance Decreased baroreceptor sensitivity Diminished cardiac and vascular responsiveness to β agonists and antagonists Suppressed renin-angiotensin-aldosterone system Increased sensitivity to anticoagulant agents Concurrent illnesses Multiple drugs Sinus and AV node dysfunction

Changes in response Potential for heart failure Decrease of cardiac output

Tendency to orthostatic hypotension Decreased sensitivity to β agonists and antagonists Theoretically decreased response to ACE inhibitors, but not observed Increased effects of warfarin Increased drug-disease interactions Increased drug-drug interactions Potential for heart block

Source: The American Geriatrics Society 2015 Beers Criteria Update Expert Panel, J. Am. Geriatr. Soc., 63, 2227–2246, 2015. Abbreviations:  LV, left ventricular; ACE, angiotensin converting enzyme; AV, atrioventricular

systolic blood pressure and contributes to a widened pulse pressure. Maintenance of alpha-adrenergic vasoconstriction with impaired beta-adrenergic-mediated vasodilation may be an additional contributory factor to increased peripheral vascular resistance. The cardiovascular response to catecholamines as well as carotid arterial baroreflex sensitivity are both decreased in the elderly. Left ventricular (LV) mass and left atrial dimension are increased, and there is a reduction in both the LV early diastolic filling rate and volume (18). The pharmacodynamic, chronotropic, and inotropic effects of beta agonists and beta-blockers on beta1-­adrenergic receptors are diminished in the elderly (19–21). The density of beta receptors in the heart is unchanged in the elderly, but there is a decrease in the ability of beta-receptor agonists to stimulate cyclic adenosine monophosphate production (22). There are also age-related changes in the cardiac conduction system, as well as an increase in arrhythmias in the elderly. In the Framingham study, the prevalence of atrial fibrillation was 1.8% in persons 60–69 years old, 4.8% in those 70–79 years old, and 8.8% in those 80–89 years old (23). In a study of 3624 elderly patients (mean age 81 years), the prevalence of atrial fibrillation was 16% (1160) in elderly men and 13% (2464) in elderly women (24). In elderly patients with unexplained syncope, a 24-hour ambulatory electrocardiogram (ECG) should be obtained to rule out the presence of second-degree or third-degree atrioventricular block or sinus node dysfunction with pauses >3 sec not seen on the resting ECG. These phenomena were observed in 21 of 148 patients (14%) with unexplained syncope (25). These 21 patients included 8 with sinus arrest, 7 with advanced second-degree atrioventricular block, and 6 with atrial fibrillation with a slow ventricular rate not drug induced. Unrecognized sinus node or atrioventricular node dysfunction may become evident in elderly persons after drugs such as amiodarone, beta-blockers, digoxin, diltiazem, procainamide, quinidine, or verapamil are administered. Clinical use of these drugs in the elderly, therefore, must be carefully monitored.

USE OF CARDIOVASCULAR DRUGS IN THE ELDERLY Digoxin Digoxin has a narrow toxic-therapeutic ratio, especially in the elderly (26). Decreased renal function and lean body mass may increase serum digoxin levels in this population. Serum creatinine may be normal in elderly persons despite a marked reduction in creatinine clearance, thereby decreasing digoxin clearance and increasing serum digoxin levels. Older persons are also more likely to take drugs that interact with digoxin by interfering with bioavailability and/or elimination. Quinidine, cyclosporin, itraconazole, calcium preparations, verapamil, amiodarone, diltiazem, triamterene, spironolactone, tetracycline, erythromycin, propafenone, and propantheline can increase serum digoxin levels. Hypokalemia, hypomagnesemia, hypercalcemia, hypoxia, acidosis, acute and chronic lung disease, hypothyroidism, and myocardial ischemia may also cause digitalis toxicity despite normal serum digoxin levels. Digoxin may also cause visual disturbances (27), depression, and confusional states in older persons, even with therapeutic blood levels. Indications for using digoxin are slowing a rapid ventricular rate in patients with supraventricular tachyarrhythmias, such as atrial fibrillation, and treating patients with heart failure (HF) in sinus rhythm associated with reduced LV ejection fraction that does not respond to diuretics, ACE inhibitors, and beta-blockers with a class IIa indication (28). Digoxin should not be used to treat patients with HF in sinus rhythm associated with normal LV ejection fraction. By increasing contractility through increasing intracellular calcium ion concentration, digoxin may increase LV stiffness and increase LV filling pressures, adversely affecting LV diastolic dysfunction. Since almost half the elderly patients with HF have normal LV ejection fractions (29,30), LV ejection fraction should be measured

Use of cardiovascular drugs in the elderly  73

in all older patients with HF so that appropriate therapy may be given (31). Many older patients with compensated HF who are in sinus rhythm and are on digoxin may have digoxin withdrawn without decompensation in cardiac function (32,33). A post hoc subgroup analysis of data from women with a LV ejection fraction 100 participants; ≥2 higher-quality trials with some inconsistency; ≥2 consistent, lower-quality trials; or multiple, consistent observational studies with no significant methodological flaws showing at least moderate effects) limit the strength of the evidence. Low—evidence is insufficient to assess harms or risks in health outcomes because of limited number or power of studies, large and unexplained inconsistency between higher-quality studies, important flaws in study design or conduct, gaps in the chain of evidence, or lack of information on important health outcomes. Strength of Recommendations: Strong—benefits clearly outweigh harms, adverse events, and risks, or harms, adverse events, and risks clearly outweigh benefits. Weak—benefits may not outweigh harms, adverse events, and risks.

Table 4.12  Selected cardiovascular or hemostasis medications that should be avoided or have their dosage reduced with varying levels of kidney function in older adults

Medication

Creatinine clearance, mL/min, at which action required

Amiloride