Diastology: Clinical Approach to Heart Failure with Preserved Ejection Fraction [2 ed.] 0323640672, 9780323640671

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EDITION

2

DIASTOLOGY

Clinical Approach to Heart Failure with Preserved Ejection Fraction ALLAN L. KLEIN, MD, FRCP (C), FACC, FAHA, FASE, FESC

Professor of Medicine Cleveland Clinic Lerner College of Medicine of Case Western University Director, Center for the Diagnosis and Treatment of Pericardial Diseases Department of Cardiovascular Medicine Heart, Vascular, and Thoracic Institute Past-President of the American Society of Echocardiography Cleveland Clinic Cleveland, Ohio

MARIO J. GARCIA, MD

Professor of Medicine and Radiology Albert Einstein College of Medicine Chief, Division of Cardiology Co-Director, Montefiore-Einstein Center for Heart and Vascular Care Bronx, New York

1600 John F. Kennedy Blvd. Ste 1800 Philadelphia, PA 19103-2899 DIASTOLOGY: CLINICAL APPROACH TO HEART FAILURE WITH PRESERVED EJECTION FRACTION, SECOND EDITION

ISBN: 978-0-323-64067-1

Copyright © 2021 by Elsevier, Inc. All rights reserved. No part of this publication may be reproduced or transmitted in any form or by any means, electronic or mechanical, including photocopying, recording, or any information storage and retrieval system, without permission in writing from the publisher. Details on how to seek permission, further information about the Publisher’s permissions policies and our arrangements with organizations such as the Copyright Clearance Center and the Copyright Licensing Agency, can be found at our website: www.elsevier.com/permissions. This book and the individual contributions contained in it are protected under copyright by the Publisher (other than as may be noted herein). Notice Practitioners and researchers must always rely on their own experience and knowledge in evaluating and using any information, methods, compounds or experiments described herein. Because of rapid advances in the medical sciences, in particular, independent verification of diagnoses and drug dosages should be made. To the fullest extent of the law, no responsibility is assumed by Elsevier, authors, editors or contributors for any injury and/or damage to persons or property as a matter of products liability, negligence or otherwise, or from any use or operation of any methods, products, instructions, or ideas contained in the material herein. Previous editions copyrighted 2008.

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LIST OF CONTRIBUTORS Øyvind Senstad Andersen, MD

Christopher Michael Bianco, DO

Cardiology Oslo University Hospital Cardiologic Department and Institute of Surgical Research Oslo, Norway

Assistant Professor of Medicine West Virginia University School of Medicine Department of Cardiology Heart and Vascular Institute Morgantown, West Virginia

Bonita A. Anderson, DMU (Cardiac), MAppSc (Med Ultrasound), ACS, FASE, FASA

Barry A. Borlaug, MD

Clinical Fellow Faculty of Health School of Clinical Sciences Queensland University of Technology Advanced Cardiac Scientist Cardiac Sciences Unit The Prince Charles Hospital Brisbane, Queensland, Australia

Christopher P. Appleton, MD, FACC, FASE Professor of Medicine Mayo Clinic School of Medicine Department of Cardiovascular Diseases Mayo Clinic Arizona Phoenix, Arizona

Craig R. Asher, MD, FACC, FASE Department of Cardiology Medical Director Hypertrophic Cardiomyopathy Clinic Cleveland Clinic Florida Weston, Florida

Gerard P. Aurigemma, MD Division of Cardiovascular Medicine Department of Medicine University of Massachusetts Medical School Worcester, Massachusetts

Catalin F. Baicu, PhD Research Associate Professor of Medicine Division of Cardiology Department of Medicine Medical University of South Carolina Charleston, South Carolina

Ruxandra Beyer, MD, PhD Department of Cardiology Heart Institute University of Cluj-Napoca Cluj-Napoca, Romania

Pavan Bhat, MD, FACC Staff Physician Section of Heart Failure and Transplantation Medicine Department of Cardiovascular Medicine Heart, Vascular, and Thoracic Institute Cleveland Clinic Cleveland, Ohio

Professor of Medicine Director of Circulatory Failure Research Department of Cardiovascular Medicine, Mayo Clinic Rochester, Minnesota

Amy D. Bradshaw, PhD Professor Medicine Division of Cardiology Division of Cardiology Medical University of South Carolina Charleston, South Carolina

Darryl J. Burstow, MBBS, FRACP, FCSANZ, FASE Associate Professor Department of Medicine, University of Queensland Eminent Cardiologist Department of Cardiology The Prince Charles Hospital Brisbane, Queensland, Australia

Shemy Carasso, MD, FESC, FASE Clinical Associate Professor of Medicine The Azrieli Faculty of Medicine in the Galilee, Zefat, Israel Head, Non-invasive Cardiac Imaging Unit Cardiovascular Division B Padeh Medical Center, Poriya, Israel

Manuel D. Cerqueira, MD, FACC, MASNC Professor of Medicine and Radiology Cleveland Clinic Lerner College of Medicine of Case Western Reserve University Chairman of Nuclear Medicine Depart Imaging Institute Staff Cardiologist Department of Cardiovascular Medicine Heart, Vascular, and Thoracic Institute Cleveland Clinic Cleveland, Ohio

Michael Chetrit, MD Assistant Professor of Medicine, McGill University Cardiologist, McGill University Health Centre Co-Director, McGill Amyloidosis Project Monteral, Quebec, Canada

Patrick Collier, MD, PhD, FASE, FESC, FACC Associate Professor of Medicine Cleveland Clinic Lerner College of Medicine of Case Western Reserve University Co-Director Cardio-oncology Center Associate Director Echo Lab Department of Cardiovascular Medicine Heart, Vascular, and Thoracic Institute Cleveland Clinic Cleveland, Ohio

Kristine Y. DeLeon-Pennell, PhD Assistant Professor Division of Cardiology Department of Medicine Medical University of South Carolina Charleston, South Carolina

Hisham Dokainish, MD, FRCPC, FACC, FASE Director, Cardiology and Echocardiography Laboratory Circulate Cardiac and Vascular Centre Burlington, Ontario, Canada

Frank A. Flachskampf, MD, FESC, FACC Senior Cardiology Consultant Department of Medical Sciences Uppsala University and Uppsala University Clinic Uppsala, Sweden

Mark K. Friedberg, MD Professor of Pediatrics Labatt Family Heart Centre Department of Pediatrics, The Hospital for Sick Children and University of Toronto Toronto, Ontario, Canada

Andrea C. Furlani, MD Diagnostic Radiology Resident Department of Radiology Montefiore Medical Center Albert Einstein College of Medicine Bronx, New York

Mario J. Garcia, MD Professor of Medicine and Radiology Albert Einstein College of Medicine Chief, Division of Cardiology Co-Director, Montefiore-Einstein Center for Heart and Vascular Care Bronx, New York

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LIST OF CONTRIBUTORS  

Eiran Z. Gorodeski, MD, MPH, FACC, FHFSA Associate Professor of Medicine Case Western Reserve University School of Medicine Department of Medicine Harrington Heart and Vascular Institute University Hospitals Cleveland Medical Center Cleveland, Ohio

Stephen H. Gregory, MD Assistant Professor of Anesthesiology Washington University in St. Louis Department of Anesthesiology St. Louis, Missouri

Richard A. Grimm, DO, FACC, FASE Charles and Loraine Moore Endowed Chair in Cardiovascular Imaging Chief Medical Information Officer Director, Echocardiography Laboratory Department of Cardiovascular Medicine Heart, Vascular, and Thoracic Institute Cleveland Clinic Cleveland, Ohio

Jong-Won Ha, MD, PhD, FESC General Director Severance Hospital Professor of Medicine Department of Cardiology Yonsei University College of Medicine Seoul, Korea

 Cesar J. Herrera, MD, FACC, CEDIMAT Director, Clinical Associate Professor of Medicine (Adjunct) Department of Cardiology CEDIMAT Cardiovascular Center Albert Einstein College of MedicineMontefiore Center for Heart and Vascular Care Santo Domingo, Dominican Republic Albert Einstein College of Medicine Montefiore Center for Heart and Vascular Care Bronx, New York

Allan L. Klein, MD, FRCP (C), FACC, FAHA, FASE, FESC

Professor of Medicine and Physiology and Biophysics Case Western Reserve University Department of Medicine Division of Cardiology University Hospitals Cleveland Medical Center Harrington Heart and Vascular Center Cleveland, Ohio

Massimo Imazio, MD, FESC

Lara C. Kovell, MD

Professor of Cardiology Referral Senior Consultant for Myopericardial Diseases and Cardiovascular Multimodality Imaging University Cardiology, Cardiovascular and Thoracic Department AOU Citta’della Salute e della Scienza di Torino Torino, Italy

Assistant Professor of Medicine Division of Cardiovascular Medicine Department of Medicine University of Massachusetts Medical School Worcester, Massachusetts

Cardiology Department Peter Munk Cardiac Center Toronto General Hospital Toronto, Ontario, Canada

Associate Professor Department of Cardiology, Pulmonology, Hypertension, and Nephrology Ehime University Graduate School of Medicine Toon, Japan

Serge C. Harb, MD, FACC

Wael A. Jaber, MD, FACC, FESC, FASE

Assistant Professor of Medicine Cleveland Clinic Lerner College of Medicine of Case Western Reserve University Staff, Section of Cardiovascular Imaging Department of Cardiovascular Medicine Heart, Vascular, and Thoracic Institute Cleveland Clinic Cleveland, Ohio

Professor of Medicine Mayo Clinic College of Medicine Director, Echocardiography Laboratory & Chair, Division of Cardiovascular Ultrasound Department of Cardiovascular Medicine Mayo Clinic Rochester, Minnesota

Professor of Medicine Cleveland Clinic Lerner College of Medicine of Case Western University Director, Center for the Diagnosis and Treatment of Pericardial Diseases Department of Cardiovascular Medicine Heart, Vascular, and Thoracic Institute Past-President of the American Society of Echocardiography Cleveland Clinic Cleveland, Ohio

Brian D. Hoit, MD

Katsuji Inoue, MD, PhD Manhal Habib, MD, PhD

Garvan C. Kane, MD, PhD, FAHA, FASE

Professor of Medicine Cleveland Clinic Lerner College of Medicine of Case Western Reserve University Director, Nuclear Cardiology and Imaging CoreLab Department of Cardiovascular Medicine Heart, Vascular, and Thoracic Institute Cleveland Clinic Cleveland, Ohio

Deborah H. Kwon, MD, FACC, FSCMR, FASE Associate Professor of Medicine Cleveland Clinic Lerner College of Medicine of Case Western Reserve University Director of Cardiac MRI Co-Director, Center for the Diagnosis & Treatment of Pericardial Diseases Department of Cardiovascular, Medicine and Radiology Heart, Vascular, and Thoracic Institute Cleveland Clinic Cleveland, Ohio

Cameron T. Lambert, MD Fellow Cardiac Electrophysiology and Pacing Department of Cardiovascular Medicine Heart, Vascular, and Thoracic Institute Cleveland Clinic Cleveland, Ohio

LIST OF CONTRIBUTORS

Benjamin D. Levine, MD, FACC, FAHA, FACSM Professor of Medicine and Cardiology Distinguished Professorship in Exercise Science The University of Texas Southwestern Medical Center Director, Institute for Exercise and Environmental Medicine S. Finley Ewing Jr. Chair for Wellness at Texas Health Presbyterian Dallas Harry S. Moss Heart Chair for Cardiovascular Research Dallas, Texas

Martin M. LeWinter, MD Professor of Medicine and Molecular Physiology and Biophysics Emeritus Department of Medicine Larner College of Medicine at the University of Vermont Attending in Cardiology University of Vermont Medical Center Burlington, Vermont

James P. MacNamara, MD Division of Cardiology University of Texas Southwestern Institute of Exercise and Environmental Medicine Dallas, Texas

William R. Miranda, MD Assistant Professor of Medicine Department of Cardiovascular Diseases Mayo Clinic Rochester, Minnesota

Sandhya Murthy, MD Assistant Professor of Medicine Montefiore Medical Center Albert Einstein College of Medicine Department of Medicine The Center for Heart and Vascular Care Director, Pulmonary Hypertension Center Bronx, New York

Sherif F. Nagueh, MD, FACC, FASE, FAHA Professor of Medicine Weill Cornell Medical College Medical Director Echocardiography Laboratory Houston Methodist DeBakey Heart and Vascular Center Houston, Texas

Satoshi Nakatani, MD, PhD, FACC, FESC, FASE (hon) Professor Emeritus, Osaka University Director of Saiseikai Senri Hospital Saiseikai Senri Hospital Suita, Osaka, Japan

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Ileana Piña, MD, MPH, FAHA, FACC, FHFSA Professor of Medicine Senior Staff Fellow, Medical Officer Department of Medicine Wayne State University Detroit, Michigan

Zoran B. Popovic´, MD, PhD Associate Professor of Medicine Cleveland Clinic Lerner College of Medicine of Case Western Reserve University Staff Department of Cardiovascular Medicine Heart, Vascular, and Thoracic Institute Cleveland Clinic Cleveland, Ohio

Miguel A. Quinones, MD, MACC, FASE Winters Family Distinguished Centennial Chair In Cardiovascular Education Professor of Medicine Weil Cornell Medicine Department of Cardiology Houston Methodist Hospital Houston, Texas

Harry Rakowski, MD, FACC, FASE, ED

General Cardiology and Advance Imaging Fellow Department of Cardiology and Hospital Medicine Albert Einstein College of Medicine Bronx, New York

Fellow Weill Cornell Medicine Department of Cardiology New York-Presbyterian Hospital/Weill Cornell Medical Center New York City, New York

Professor of Medicine Department of Medicine University of Toronto Douglas Wigle Research Chair in Hypertrophic Cardiomyopathy Development Director, Peter Munk Cardiac Imaging Centre Division of Cardiology Department of Medicine Toronto General Hospital, University Health Network Toronto, Ontario, Canada

Dimitrios Maragiannis, MD, FESC, FASE, FACC, FAHA

Kazuaki Negishi, MD, PhD

Yogesh NV Reddy, MBBS, MSc

Professor of Medicine Head of Discipline of Medicine Nepean Clinical School Cardiologist Department of Medicine and Health University of Sydney New South Wales, Australia

Assistant Professor of Medicine Department of Cardiovascular Diseases Mayo Clinic Rochester, Minnesota

Mohammed Makkiya, MD

Department of Cardiology 401 General Army Hospital Athens, Greece

Vojtech Melenovsky, MD, PhD Associate Professor of Medicine Department of Cardiology Institute for Clinical and Experimental Medicine – IKEM Charles University, Prague, Czech Republic

Donald R. Menick, PhD, FAHA Professor of Medicine Director of the Gazes Cardiac Research Institute Research Health Scientist Ralph H. Johnson VA Medical Center Department of Medicine/Division of Cardiology Medical University of South Carolina Charleston, South Carolina

Lakshmi Nambiar, MD

Masaru Obokata, MD, PhD Department of Cardiovascular Medicine Mayo Clinic Rochester, Minnesota

Jae K. Oh, MD, FACC, FAHA, FESC, FASE Samsung Professor of Cardiovascular Diseases Director, Echo Core Lab Director, Pericardial Diseases Clinic President, Asian Pacific Association of Echocardiography Department of Cardiovascular Medicine Mayo Clinic Rochester, Minnesota

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

Satyam Sarma, MD Assistant Professor of Medicine Department of Internal Medicine, Division of Cardiology University of Texas Southwestern Medical Dallas, Texas

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LIST OF CONTRIBUTORS  

Aldo L. Schenone, MD Chief Non-invasive Cardiovascular Imaging Fellow Non-invasive Cardiovascular Imaging Department Brigham and Women’s Hospital/Harvard Medical School Boston, Massachusetts

Partho Sengupta, MD Professor of Medicine J.W. Ruby Memorial Hospital Chief, Division of Cardiology Director, Cardiovascular Imaging J.W. Ruby Memorial Hospital WVU Heart and Vascular Institute Morgantown, West Virginia

Otto A. Smiseth, MD, PhD, FESC, FACC, FASE Professor of Medicine Division Head Division of Cardiovascular and Pulmonary Diseases Oslo University Hospital Oslo, Norway

Randall C. Starling, MD, MPH, FACC, FAHA, FESC, FHFSA Professor of Medicine Cleveland Clinic Lerner College of Medicine of Case Western Reserve University Department of Cardiovascular Medicine Heart, Vascular, and Thoracic Institute Cleveland Clinic Cleveland, Ohio

Marie Stugaard, MD, PhD, FESC Doctor of Medicine Department of Health Sciences Osaka University Graduate School of Medicine Suita, Osaka, Japan

 Madhav Swaminathan, MD, MMCi, FASE, FAHA Professor Vice chair, Faculty Development Department of Anesthesiology Duke University Durham, North Carolina

Edlira Tam, DO, MS Division of Cardiology Montefiore-Einstein Heart Center Bronx, New York

W.H. Wilson Tang, MD FACC, FAHA, FHFSA

Lynne Williams, MBBCh, FRCP, PhD Consultant Cardiologist Department of Cardiology Royal Papworth Hospital NHS Foundation Trust Cambridge, United Kingdom

Dmitry M. Yaranov, MD Advanced Heart Failure Failure and Transplant Cardiologist Advanced Heart Failure, Heart Transplant, Mechanical Circulatory Support Baptist Memorial Hospital Memphis, Tennessee

Professor of Medicine Cleveland Clinic Lerner College of Medicine of Case Western Reserve University Research Director Section of Heart Failure and Cardiac Transplantation Medicine Department of Cardiovascular Medicine Heart, Vascular, and Thoracic Institute Cleveland Clinic Cleveland, Ohio

Laura Young, MD

Harsh V. Thakkar, MBBS

Michael R. Zile, MD

Clinical Lecturer School of Medicine University of Tasmania Department of Cardiology The Royal Hobart Hospital Hobart CBD, Tasmania, Australia

James D. Thomas, MD, FACC, FASE Professor of Medicine Feinberg School of Medicine Northwestern University Director, Center for Heart Valve Disease and Co-director Center for Artificial Intelligence in Cardiovascular Disease Division of Cardiology in the Bluhm Cardiovascular Institute Northwestern Medicine Chicago, Illinois

Clinical Instructor of Medicine Cleveland Clinic Lerner College of Medicine of Case Western Reserve University Interventional Cardiology Fellow Department of Cardiovascular Medicine Heart, Vascular, and Thoracic Institute Cleveland Clinic Cleveland, Ohio

Charles Ezra Daniel Professor of Medicine Distinguished University Professor Medical University of South Carolina Chief, Division of Cardiology RHJ Department of Veterans Affairs Medical Center Charleston, South Carolina

F O R E WO R D Diastolic dysfunction and its clinical cousin, heart failure with preserved ejection fraction (HFpEF), are among the most baffling of topics in clinical cardiology. Is it primarily a cardiac condition? Related to comorbidities? A manifestation of poor peripheral muscular oxygen extraction? Maybe a bit of each. And so many cardiac parameters to consider: E wave, A wave, tissue Doppler, LA size, torsion, RV pressure, diastolic strain rate, just to name a few! How to put them together in a unified way is nearly impossible. It is rare to find a resource that addresses all the myriad manifestations of diastolic function: basic principles from cellular physiology to the physics of intracardiac blood flow, multimodality assessment and diagnosis, as well as standard and evolving therapies for this challenging syndrome. In 2008, Drs. Allan Klein and Mario Garcia brought forth their landmark book Diastology, which for the first time brought all aspects of diastolic function, especially the diagnostic aspects, under one cover. It’s hard to believe it’s been 12 years since that initial publication, but the science of diastology has progressed rapidly in that time. Building on the great achievement of the first edition of Diastology, Allan and Mario now bring us their second edition, completely updated with the latest basic and clinical information. In addition to updating all the chapters from the first edition, they bring out four new chapters. These include the diastolic function stress test, the perioperative assessment of diastolic function, and the important entity of pulmonary hypertension in HFpEF. An important new

chapter addresses the ASE/EACVI Diastolic Guidelines (of which there have been two since the first edition), examining the strengths and limitations of these important formulations. On a personal note, I congratulate dear friends Allan and Mario on this great achievement. I have known Allan for over 30 years and well recall planning the first conference on diastolic function in 1992, where we coined for the first time (I think) the word diastology. Soon thereafter, Mario joined us at the Cleveland Clinic, and together the three of us and our colleagues produced some of the landmark research and education in diastolic function. With this book, Allan and Mario continue their masterful scholarship into the science of diastolic function. It is thus with great enthusiasm that I commend the second edition of Diastology to you. James D. Thomas, MD, FASE, FACC, FESC Professor of Medicine Feinberg School of Medicine Northwestern University Director, Center for Heart Valve Disease and Co-director, Center for Artificial Intelligence in Cardiovascular Disease Division of Cardiology in the Bluhm Cardiovascular Institute Northwestern Medicine Chicago, Illinois

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F O R E WO R D I am pleased to say a few words about the 2nd Edition of Diastology edited by Allan Klein and Mario Garcia. I have known both editors for more than 20 years and have followed their careers with great pride. The first edition of this book in 2008 was a magnificent achievement. Diastolic heart failure at that time had evolved substantially to a point where we were beginning to better understand how to define it and manage its various phenotypes. New and improved imaging techniques, including magnetic resonance imaging and use of echo to image strain rate were quickly evolving. The book very much captured our attention regarding the diagnosis and management of this very important clinical syndrome as it emerged from a somewhat obscure clinical entity in the 1970s to a major diagnostic entity with multiple etiologies by 2008. Now it is 2020, and the clinical syndrome of diastolic heart failure is one of the more common diagnoses in cardiology. Heart failure with preserved ejection fraction (HFpEF) is now similar in prevalence to heart failure with reduced ejection fraction (HFrEF) in terms of hospitalization for heart failure in the United States. Hospitalization for HFrEF has steadily declined between 2002 and 2013, while increases in heart failure hospitalizations are now being driven by more cases of HFpEF. Of course, other conditions such as amyloidosis, hypertrophic cardiomyopathy, left ventricular hypertrophy due to long-standing hypertension, chronic renal disease, coronary disease as well as primary

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restrictive, infiltrative and storage cardiomyopathies are also now well recognized as etiologies of diastolic dysfunction leading to the development of heart failure. Valvular heart disease and pericardial disorders are still with us and may also lead to diastolic dysfunction and heart failure. Each of these entities are discussed in great detail by expert contributing authors in the new edition of Diastology. Clinical and laboratory diagnoses are also featured in great detail and treatment options are carefully discussed. Each of the contributing authors brings substantial experience to bear in describing the subtleties of diastolic dysfunction. The book is richly endowed with many tables and figures. This very comprehensive book is the best we have in the field of Diastology. Doctors Klein, Garcia and their contributing authors are to be congratulated for their magnificent contribution. It will be most useful for clinicians, but others will find it to be the definitive text in this complex but important field of cardiac relaxation and filling. Trainees, internists, cardiologists and sonographers will benefit from this wholly updated and outstanding text. Gary S. Francis, M.D. Professor of Medicine University of Minnesota Minneapolis, Minnesota

AC K N OW L E D G M E N T S We would like to especially thank our parents Jean and Sam Klein as well as Marilyn, Jared, Lauren, and Jordan Klein, Anna Kezerashvili and Melinda, and Olivia Garcia for their inspiration and encouragement and unwavering support of our careers. We especially would like to express our thanks to Marie Phillips, who helped and guided us in the journey of putting this book together. Finally, we would like to express our gratitude to the editors of Elsevier including Robin Carter, Sara Watkins and Haritha Dharmarajan for their guidance in making the second edition of this book.

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P R E FA C E A 56-year-old obese woman with exertional dyspnea was referred for evaluation of suspected heart failure with preserved LV ejection fraction. She had a past medical history of Crohn disease, hypothyroidism, and asthma. She had been medically treated for hypertension for several years. Over the last several years, she was hospitalized several times with pneumonia and exacerbations of asthma. Between these admissions, she was experiencing shortness of breath on moderate activity, which was attributed to the combination of moderate asthma and obesity. She was referred to echocardiography to determine if cardiac dysfunction contributed to her dyspnea. Echocardiography revealed normal systolic function, with LV EF of 54%. She had moderate LV hypertrophy with septal wall thickness of 1.3 cm. Peak mitral early diastolic velocity (E) was 73 cm/sec, mitral early diastolic velocity/atrial velocity ratio (E/A) was 0.9 with an E deceleration time (DT) of 222 msec. Septal mitral annulus velocity (e′) was 7 and lateral e′ 8 cm/sec. Previously using the ASE/EACVI 2009 guidelines, this patient would not have met diagnostic criteria for elevated LV filling pressure, since mitral E/A was 0.9. However, in the 2016 ASE/EACVI guidelines by following Algorithm B in the setting of myocardial pathology (LVH), she is in the intermediate diastolic function group where three additional criteria—E/e′ (10), left atrial (LA) volume (35 mL/m2), and peak tricuspid regurgitation (TR) velocity (2.9 cm/sec)—need to be considered to assess for grade 2 diastolic dysfunction and elevated filling pressures (see Chapter 19). Since the first edition of Diastology, published over a decade ago, there have been significant advances in our general understanding of the pathophysiologic mechanisms, epidemiology, and diagnostic approaches to the syndrome of diastolic heart failure, now reclassified as “heart failure with preserved ejection fraction (HFpEF).” Like in the previous edition, this textbook comprehensively discusses the basic molecular and hemodynamic assessment principles, epidemiology, clinical presentation, diagnostic approaches, and treatment of the different cardiovascular diseases that lead to HFpEF. The content of this book is targeted to a broad audience encompassing noninvasive and invasive cardiologists, physiology scientists, cardiology fellows, and cardiac sonographers. Why is the study of diastology relevant? The answer is that a complete understanding of the pathophysiology of diastolic function and a complete characterization through diagnostic imaging are fundamental to the management of all patients with congestive heart failure syndromes, independent of etiology.

HISTORICAL PERSPECTIVE As early as the Renaissance, Leonardo da Vinci described how the lower cardiac chambers of the heart filled with blood by drawing it from the upper chambers. In the 1940s, Carl J. Wiggers proposed the term inherent elasticity to describe the passive properties of the heart. In the 1970s, cardiac physiologists assessed the properties of active ventricular relaxation and passive filling using invasive quantification of intracavity pressure and volume. During the following decade, clinicians recognized that diastolic heart failure was an important cause of congestive heart failure, and Doppler echocardiography emerged as an important noninvasive method to assess the diastolic filling properties of the heart. The term diastology was coined in the early 1990s; imaging modalities, such as Doppler echocardiography and cardiac magnetic resonance imaging (MRI), advanced our understanding of diastolic

function. Over the past decade, newer methods such as myocardial strain imaging, contrast cardiac MRI, and nuclear scintigraphy have been able to enhance our ability to establish the diagnosis of HFpEF and diagnose infiltrative disorders at earlier stages of the disease. Recent results from large-scale clinical trials have now identified targeted treatment for many HFpEF patients, leading to improved outcomes.

ABOUT THE AUTHORS In the late 1980s, Allan Klein started his interest in this field as a Canadian Heart Foundation fellow at the Mayo Clinic studying Doppler assessment of LV filling during acute myocardial infarction and after reperfusion. His first impression was that the quick bedside echocardiographic evaluation, including the mitral E/A ratio and deceleration time, was a simple but powerful measure of LV diastolic filling, relaxation, and prognosis. Also, he was struck by how the grades of diastolic filling related to the clinical exam, including the extra heart sounds (S3 and S4). As a student of the field, he also learned that the study of diastolic function was more complex than the simple analysis of the mitral E/A ratio. During his training, Dr. Klein was very fortunate to have excellent mentors, including Liv Hatle, Jamil Tajik, and James Seward. Dr. Mario Garcia developed his interest in the field while at the Cleveland Clinic in the early days of tissue Doppler echocardiography, color M mode Doppler, and strain rate imaging. His clinical observations and hemodynamic validation of early annular velocities (e′) and the slope of the flow propagation (Vp) as well as the relationship of mitral early filling/annular e-wave (E/e′) and mitral early filling/flow propagation slope (E/Vp) as measures of LV filling pressure were important for the advancement of the field. Their work as well as that of the other leaders who have contributed to the new edition of Diastology makes this textbook an essential read for all cardiovascular specialists.

CONTENTS OF THE BOOK In this second edition, Diastology is organized into five main sections: basic determinants, noninvasive and invasive diagnosis, specific cardiac disease, emerging topics, and treatment. It includes a comprehensive analysis of the major areas of knowledge in the field from the molecular, genetic, and cellular mechanisms to clinical presentation and treatment of HFpEF. The book discusses traditional and newer diagnostic methods, including 2-D and 3-D Doppler echocardiography, LV and LA strain imaging, and nuclear and cardiac MRI techniques. The strengths and weaknesses of the ASE/EACVI 2016 guidelines on diastolic function are analyzed in depth. A review of the prototypical diseases that show diastolic dysfunction, including hypertension, coronary artery disease, hypertrophic cardiomyopathy, restrictive cardiomyopathies, diabetes mellitus, and pericardial disease provide an important clinical perspective. Newer topics, including the effect of pacing, aging, pulmonary hypertension, and perioperative assessment, are also included. General treatment, analyzing the results of clinical trials such as I-PRESERVE, TOPCAT, and PARAGON, and future therapies are reviewed. Of note, the book includes 50 interactive cases and 150 review questions. Finally, it is important to recognize that the field of HFpEF is a fastmoving target. We have made a concerted effort to keep the content current and to avoid overlap between chapters. We surely hope that you enjoy our latest version of the book.

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V I D E O TA B L E O F C O N T E N T S 1. Video 12.1 Supplementary material for Case Study 2. 2. Video 17.1 Supplementary material for Case Study 2. 3. Video 17.2 Supplementary material for Case Study 2. 4. Video 17.3 Supplementary material for Case Study 2. 5. Video 17.4 Supplementary material for Case Study 2. 6. Video 17.5 Supplementary material for Case Study 2. 7. Video 21.1 Supplementary material for Case Study 1. 8. Video 21.2 Supplementary material for Case Study 1. 9. Video 21.3 Supplementary material for Case Study 2. 10. Video 21.4 Supplementary material for Case Study 2. 11. Video 24.1 Supplementary material for Case Study 1. Apical four-chamber view illustrating lateral wall akinesis (arrow); this akinesis was not present on a prior echo obtained 6 months prior to admission. 12. Video 24.2 Supplementary material for Case Study 1. Apical four-chamber view illustrating lateral wall akinesis (arrow); this akinesis was not present on a prior echo obtained 6 months prior to admission. 13. Video 26.1 Supplementary material for Case Study 1. Neck veins in patient with constrictive pericarditis. Note the marked elevation in central venous pressure with distended jugular veins and the prominent x and y descents, typical of constrictive pericarditis. 14. Video 26.2 Supplementary material for Case Study 1. Respirophasic septal shift in a patient with constrictive pericarditis. Apical four-chamber view shows striking respirophasic septal shift; upon inspiration the ventricular septum shifts to toward the left ventricle (left of the screen) with reciprocal changes seen upon expiration. 15. Video 26.3 Coronary angiography in patient with constrictive pericarditis. Left anterior oblique view shows fixation of the acute marginal branches of the right coronary artery in patients with constrictive pericarditis following aortic valve replacement. Calcification of the diaphragm is also present. 16. Video 26.4 Coronary angiography in patient with constrictive pericarditis. Right anterior oblique caudal view shows fixation of the obtuse marginal branches of the left circumflex coronary artery in patients with constrictive pericarditis following aortic valve replacement. 17. Video 33.1 Supplementary material for Case Study 1. Transthoracic echocardiogram 1. 18. Video 33.2 Supplementary material for Case Study 1. Transthoracic echocardiogram 2. 19. Video 33.3 Supplementary material for Case Study 1. Transthoracic echocardiogram 3.

20. Video 33.4 Supplementary material for Case Study 1. Transthoracic echocardiogram 4. 21. Video 35.1 Supplementary material for Case Study 1. A4C. 22. Video 37.1 2-D parasternal long axis, Case Study 1. 23. Video 37.2 2-D parasternal long axis with color Doppler, Case Study 1. 24. Video 37.3 2-D apical four chamber, Case Study 1. 25. Video 37.4 2-D apical two chamber, Case Study 1. 26. Video 37.5 2-D apical three chamber, Case Study 1. 27. Video 37.6 2-D parasternal long axis, Case Study 2. 28. Video 37.7 2-D parasternal long axis with color Doppler, Case Study 2. 29. Video 37.8 2-D apical four chamber, Case Study 2. 30. Video 37.9 2-D apical two chamber, Case Study 2. 31. Video 37.10 2-D apical three chamber, Case Study 2. 32. Video 37.11 2-D parasternal long axis, Case Study 3. 33. Video 37.12 2-D parasternal long axis with color Doppler, Case Study 3. 34. Video 37.13 2-D apical four chamber, Case Study 3. 35. Video 37.14 2-D apical two chamber, Case Study 3. 36. Video 37.15 2-D apical three chamber, Case Study 3. 37. Video 37.16 2-D parasternal long axis, Case Study 4. 38. Video 37.17 2-D parasternal long axis, Case Study 4. 39. Video 37.18 2-D apical four chamber, Case Study 4. 40. Video 37.19 2-D apical two chamber, Case Study 4. 41. Video 37.20 2-D apical three chamber, Case Study 4. 42. Video 37.21 2-D parasternal long axis, Case Study 5. 43. Video 37.22 2-D parasternal long axis, Case Study 5. 44. Video 37.23 2-D apical four chamber, Case Study 5. 45. Video 37.24 2-D apical two chamber, Case Study 5. 46. Video 37.25 2-D apical three chamber, Case Study 5. 47. Video 37.26 2-D parasternal long axis, Case Study 6. 48. Video 37.27 2-D parasternal long axis, Case Study 6. 49. Video 37.28 2-D apical four chamber, Case Study 6. 50. Video 37.-29 2-D apical two chamber, Case Study 6. 51. Video 37.30 2-D apical three chamber, Case Study 6. 52. Video 37.31 2-D parasternal long axis, Case Study 7. 53. Video 37.32 2-D parasternal long axis, Case Study 7. 54. Video 37.33 2-D apical four chamber, Case Study 7. 55. Video 37.34 2-D apical two chamber, Case Study 7. 56. Video 37.35 2-D apical three chamber, Case Study 7. 57. Video 37.36 2-D short axis view, Case Study 7. 58. Video 37.37 2-D subcostal view, Case Study 7. xv

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59. Video 37.38 2-D parasternal long axis, Case Study 8. 60. Video 37.39 2-D parasternal long axis with color, Case Study 8. 61. Video 37.40 2-D apical four chamber, Case Study 8. 62. Video 37.41 2-D apical two chamber, Case Study 8. 63. Video 37.42 2-D apical three chamber, Case Study 8. 64. Video 37.43 2-D apical five chamber of the LVOT, Case Study 8. 65. Video 37.44 2-D parasternal long axis, Case Study 9.

66. Video 37.45 2-D parasternal long axis, Case Study 9. 67. Video 37.46 2-D apical four chamber, Case Study 9. 68. Video 37.47 2-D apical two chamber, Case Study 9. 69. Video 37.48 2-D apical three chamber, Case Study 9. 70. Video 37.49 2-D parasternal long axis, Case Study 10. 71. Video 37.50 2-D parasternal long axis, Case Study 10. 72. Video 37.51 2-D apical four chamber, Case Study 10. 73. Video 37.52 2-D apical two chamber, Case Study 10. 74. Video 37.53 2-D apical three chamber, Case Study 10.

PART I  Basic Determinants of Diastolic Function

1 Molecular, Gene, and Cellular Mechanism Amy D. Bradshaw, Kristine Y. DeLeon-Pennell, and Donald R. Menick

OUTLINE Myocyte Stiffness, 1 Calcium Dysregulation, 1 Posttranslational Modification of Myofibrillar Proteins, 2 Other Posttranslational Modifications, 3 Transthyretin Amyloidosis, 4 Mitochondrial Dysfunction and Age, 4 Myocardial Collagen, 4 Cardiac Fibrillar Collagen, 4 Collagen Deposition in HFpEF, 5 Transcriptional Regulation of Collagen I, 5

Postsynthetic Procollagen Processing and Deposition, 5 ECM Degradation, 5 Tissue Inhibitors of Metalloproteinases, 6 Inflammatory Mediators in HFpEF, 6 Neutrophils, 6 Macrophages, 6 Future Directions, 7 Key Points, 7 Review Questions, 7 References, 7

Although heart failure (HF) has been traditionally affiliated with reduced contractile function and dilation of the left ventricle (LV) resulting in reduced ejection fraction (HFrEF), nearly half of HF patients have an ejection fraction that is normal. These patients present with abnormal LV relaxation, diastolic distensibility, or diastolic stiffness.1 The number of patients hospitalized and the mortality risk for patients with heart failure with preserved ejection fraction (HFpEF) is equivalent to patients with HFrEF (∼50% die within 3 years).2–4 Importantly, whereas HFrEF patients treated with angiotensin-converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), and mineralocorticoid receptor antagonist have improved clinical outcomes,5 no such benefit has been seen in patients with HFpEF.6,7 Therefore determining the signaling pathways and molecular mechanisms that trigger the decline into diastolic HF is one of the major challenges facing cardiovascular medicine. The identification of these pathways will hopefully lead to new therapies for this dramatically growing health problem. Multiple risk factors are associated with HFpEF, including age (>65), hypertension, renal disease, and diabetes mellitus, and HFpEF presents more often in women than in men. But the significance of each risk factor, in terms of molecular mechanisms, remains uncertain in part because access to live human heart tissue at various times during disease progression is limited, and animal models do not fully recapitulate the integrative complexity of human disease. To point, the majority of animal models in use focus on a single defect such as pressure overload (PO), hypertension, obesity, diabetes, renal insufficiency, or age. For technical reasons and efforts to limit confounding variables, rarely are multiple defects combined in animal models. Nonetheless, this chapter will focus on the leading contributors that have been

identified in the research setting, including myocyte stiffness, reactive oxygen species (ROS), age, mitochondrial dysfunction, myocardial interstitial fibrosis, and inflammation.

MYOCYTE STIFFNESS Myocardial stiffness is a hallmark of diastolic heart disease and an important contributor to HFpEF. The contributors of myocardial stiffness and impaired diastolic filling are naturally divided into those specific to the myocyte itself and those factors affecting the extracellular matrix (ECM). We will first discuss myocyte-specific factors identified as determinants of myocyte stiffness, which include calcium dysregulation, mitochondrial energetics, posttranslational modification of titin and other sarcomeric proteins, and infiltration of amyloids.

Calcium Dysregulation Calcium (Ca2+) plays a central role in the excitation-contraction and repolarization-relaxation of the myocardium.8 Hence factors that regulate Ca2+ flux in myocytes are poised to be critical regulators of diastolic function. Depolarization of the sarcolemma results in Ca2+ influx into the cytosol via the voltage-gated L-type channels. This inward Ca2+ current (ICa) promotes the release of Ca2+ from the sarcoplasmic reticulum (SR) by Ca2+–induced Ca2+–release via the ryanodine receptor 2 (RYR). The ICa and SR Ca2+ release raise intracellular free Ca2+ allowing Ca2+ to bind to the myofilament protein troponin C (TnC). When cytosolic Ca2+ is low, the troponin-tropomyosin complex inhibits the formation of the actinomyosin complex. When Ca2+ binds to TnC, it releases the inhibition and allows cross-bridge cycling and

1

2

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Basic Determinants of Diastolic Function

Fig. 1.1  Diagram of cardiomyocyte Ca2+ flux during excitation-contraction coupling. Ca2+ enters via L-type Ca channels, which triggers Ca2+-induced Ca2+ release from the sarcoplasmic reticulum (SR). The increase in cytosolic Ca2+ results in Ca2+ binding to troponin C (TnC) initiating myofilament activation. For relaxation, cytosolic Ca2+ is transported into the SR via SR Ca2+-ATPase (SERCA) and into the extracellular space via sarcolemmal Na/Ca exchanger. β-AR, β-Adrenergic; NCX, Na/Ca exchanger; PKA, protein kinase A; RYR, ryanodine receptor; TnT, troponin T; TnI, troponin I.

contraction of the sarcomeres. In cardiac relaxation, cytosolic free Ca2+ must decline to result in Ca2+ dissociation from TnC. Ca2+ is transported from the cytosol by four pathways: (1) SR Ca2+-ATPase (SERCA), (2) sarcolemmal Na/Ca exchanger (NCX), (3) sarcolemmal Ca2+-ATPase, and (4) mitochondrial Ca2+ uniporter (Fig. 1.1). For Ca2+ homeostasis at each heart beat, the amount of Ca2+ pumped back into the SR by SERCA must equal the amount released through the RYR2 channel, and levels of Ca2+ extruded from the cell must equal the amount that entered via the L-type channel. During relaxation Ca2+ is pumped back into the SR lumen by SERCA, which is regulated by phospholamban (PLN). When PLN is dephosphorylated it binds to SERCA and inhibits its Ca2+ affinity. Phosphorylation of PLN relieves SERCA inhibition and enhances Ca2+ sequestration in the SR increasing the rate of relaxation. PLN is phosphorylated by cyclic adenosine monophosphate (cAMP) activated– protein kinase A (PKA) and Ca-CaM–dependent protein kinase (CaMK) as a result of β-adrenergic stimulation. The major substrates for the cAMP-PKA axis include PLN, L-type Ca channels, RYR, troponin I (TnI), and myosin-binding protein C (cMyBP-C). The relaxant effect of PKA is mediated mainly by phosphorylation of PLN and TnI. PLN phosphorylation (at Ser-16) speeds up SR Ca2+ sequestration, while phosphorylation of TnI speeds up dissociation of Ca2+ from the myofilaments. CaMKII phosphorylation of PLN (at Thr-17) also increases SR Ca2+-ATPase activity. Both PKA and CaMKII are likely to be coactivated during normal sympathetic stimulation (β adrenergic), creating synergy between these important regulatory signaling pathways (see Fig. 1.1). SERCA expression and function is decreased in most HF models. Several studies have also shown reduced SERCA/ PLN ratio with age. In addition, there are data that point to reduced phosphorylation state of PLN in HF.9 This would result in reduced Ca2+ sensitivity of SERCA and lower SR Ca2+ uptake at physiologic

cytoplasmic Ca2+ levels [Ca]I. The reduction of SERCA activity is consistent with the characteristic slowed relaxation and [Ca]I seen in diastolic HF. In animal models when SERCA expression is increased or PLN expression is decreased, myocardial relaxation and [Ca]I decline are accelerated resulting in improved diastolic function.9 Consequently, factors that might target SERCA and other mediators of Ca2+ flux are an active area of research for therapeutic opportunities.

Posttranslational Modification of Myofibrillar Proteins The sarcomeric protein titin is the largest known protein with a length greater than 1 um. It spans half the sarcomere connecting the Z-line to the M-line. It functions as a very large molecular spring contributing to force transmission at the Z-line and resting tension in the I-band region.10 Titin limits the range of sarcomere motion and is a major molecular contributor to myocyte passive stiffness. Titin activity can be modulated both by isoform expression and by phosphorylation. The differences in titin isoforms are correlated with the differences in the mechanical properties of cardiac, skeletal, and smooth muscle and differences of cardiac passive tension across species.11 Importantly, phosphorylation of titin by PKA, PKG, and PKC-α modulates its stiffness.12–15 Consequently, the activity of these kinases in myocytes has a direct influence on diastolic parameters. For example, PKA activated by β-adrenergic stimulation can phosphorylate titin as well as thick and thin filaments of the sarcomere.16 Nitric oxide (NO) and natriuretic peptides initiate signaling pathways activating PKG, which phosphorylates some of the same titin residues in the N2B spring element as PKA. Phosphorylation of the N2B element by either PKA or PKG results in a reduction in passive tension. α-Adrenergic stimulation activates PKC-α in cardiomyocytes, which is known to phosphorylate titin in the proline-valine-glutamate-lysine (PVEK) sequence increasing titinbased passive tension (Fig. 1.2). Therefore phosphorylation of the N2B

CHAPTER 1 

Molecular, Gene, and Cellular Mechanism

3

Fig. 1.2  Diagram of pathways contributing to diastolic dysfunction. Intersitial response: Cardiac connective tissue, composed primarily of collagen types I and III, is maintained by resident cardiac fibroblasts. In response to pressure overload (PO), the recruitment of monocytes through activated endothelium occurs, triggered by increases in cytokine expression, and results in increases in macrophage populations as well as activation of resident fibroblasts. These cell types express extracellular matrix (ECM) components, matricellular proteins, and matrix metalloproteinases (MMPs), which drive remodeling of the myocardium. Sequestered factors in the ECM such as latent TGF-β (LTGF-β), are released through the action of MMPs to further propagate remodeling events. Tissue inhibitors of MMPs (TIMPs), also act to modulate myocardial remodeling by limiting MMP activity on both sequestered cytokines and structural ECM components. Macrophages also contribute fibrotic deposition of collagen in the PO myocardium through matricellular protein and MMP production. Myocyte response: Increased levels of nitric oxide (NO) promote myocyte relaxation through activation of protein kinase G (PKG) and phosphorylation of titin. Increased production of reactive oxygen species (ROS) can foster diastolic dysfunction by reducing the bioavailability of NO. PKA activated by βadrenergic (β-AR) stimulation can phosphorylate titin decreasing passive tension. α-Adrenergic stimulation activates PKC-α in cardiomyocytes, which is known to phosphorylate titin, increasing titin-based passive tension. β-AR stimulated activation of CaMKII and protein kinase (PKA), also results in the phosphorylation of phospholamban (PLN), the ryanodine receptor (RYR), and L-type calcium channels, which increases diastolic cytosolic Ca2+ content consistent with the characteristic slowed relaxation seen in diastolic HF. α-AR, α-Adrenergic; cGMP, cyclic guanosine monophosphate; cMyBP-C, myosin-binding protein C; HDAC2, histone deacetylase 2; NOS, nitric oxide synthase; SERCA, SR Ca2+-ATPase SG2, soluble guanylate cyclase; TGF-β, transforming growth factor-β; TnI, troponin I.

element in titin by PKA or PKG decreases passive tension, whereas phosphorylation of titin’s PEVK element by PKC-α increases passive tension.11 The increased oxidative pressure or ROS in diastolic dysfunction has been proposed to deplete NO reserve, lowering PKG activity and leading to hypophosphorylation of the N2B element and titin stiffing in HFpEF.14,17 Increased ROS can also result in the oxidation of cysteine residues in the N2B element resulting in disulfide bond formation and increased passive tension in mouse models.18,19 In addition to titin, posttranslational modification of thick and thin filaments of myofibrils can affect cardiomyocyte relaxation. As mentioned, TnI and cMyBP-C are targets for phosphorylation by β-adrenergic stimulation. Phosphorylation of cardiac TnI at serine 23/24 by PKA reduces TnC-TnI interaction strength while reducing calcium sensitivity. The weakened C-I interaction may slow thin filament activation and result in faster relaxation kinetics thus increasing early phase relaxation with β-adrenergic stimulation.20 The cardiac cMyBP-C is a thick filament accessory protein that when

unphosphorylated represses both cross-bridge attachment and detachment. It is phosphorylated by multiple kinases, including PKA, PKC, PKD, CaMKII, glycogen synthase kinase 3β, and ribosomal S6 kinase. Phosphorylation of cMyBP-C results in increased rates of cross-bridge cycling.21 Hypophosphorylation of cMyBP-C is associated with diastolic dysfunction in human patients.22 A recent study examined phosphorylation-deficient and phosphomimetic mutants of PKA-targeted cMyBP-C sites. They found that PKA phosphorylation of cMyBP-C threonine 35 results in accelerated cross-bridge detachment of myosin and actin, thereby enhancing relaxation.23

Other Posttranslational Modifications Advanced aging is associated with increased posttranslational modifications and has been associated with a systemic proinflammatory state (inflamm-aging) and development of HFpEF. Inflammation of the coronary microvascular endothelial cells leads to increased production of ROS. Oxidative stress can promote diastolic dysfunction

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Basic Determinants of Diastolic Function

by reducing the bioavailability of NO. Cardiac relaxation is regulated by NO. ROS can affect NO-related signaling at multiple sites. NO is generated by NO synthase (NOS), which requires tetrahydrobiopterin as a cofactor for the reaction. Hypertension and activation of the renin-angiotensin system lead to a depletion of tetrahydrobiopterin. The loss of tetrahydrobiopterin leads to NOS uncoupling, the production of superoxide instead of NO, and diastolic dysfunction.24 Some of the mechanisms of how NO modulates myofilament contractility have been recently revealed. Depletion of tetrahydrobiopterin in hypertension can repress NO synthesis and is associated with S-glutathionylation of MyBP-C, which reduces cross-bridge cycling. S-glutathionylation is an oxidative posttranslation modification of cysteines. Tetrahydrobiopterin supplementation lowers S-glutathionylation of MyBP-C, reduces the changes in actin-myosin cross-bridge cycling, and improves diastolic dysfunction.25 Further, excessive ROS leads to oxidation of guanylate cyclase and affects its responsiveness to NO to synthesize cyclic guanosine monophosphate (cGMP).26 Lower cGMP level decreases PKG activity in cardiomyocytes leading to hypophosphorylation of titin resulting in increased cardiac stiffness. Many cardiac myofibrillar proteins are posttranslationally modified by acetylation in the healthy heart.27–29 Unfortunately, we know very little about the changes in acetylation with cardiac pathologies. One recent study demonstrated that histone deacetylase (HDAC) inhibitors were efficacious in two murine models of diastolic dysfunction. In addition, the investigators showed that HDAC2 copurified with myofibrils. Although the target(s) were not identified, the study showed that ex vivo deacetylation of isolated myofibrils with recombinant HDAC2 significantly increased the rate of myofibril relaxation, whereas acetylation with recombinant p300 decreased myofibril relaxation duration.30 Hence HDAC inhibitors might be a promising avenue for future research into potential HFpEF therapies.

Transthyretin Amyloidosis Cardiac amyloid deposition has also been linked with HFpEF. Over 30 different proteins have been shown to form amyloid fibrils and five (immunoglobulin light chain, immunoglobulin heavy chain, transthyretin, serum amyloid A, and apolipoprotein AI) have been found to infiltrate the heart.31 Autopsy from patients who were diagnosed with HFpEF revealed that transthyretin amyloidosis was present in 32% of those greater than 75 years of age.32 Another study using nuclear scintigraphy to detect amyloids has indicated that 13% of hospitalized patients with HFpEF have transthyretin amyloidosis.33 Interestingly, some HF patients have amyloidosis caused by a mutation in transthyretin. Over 80 transthyretin mutations, with autosomal dominant inheritance, have been associated with tissue amyloid deposition, some within the heart.34 Nearly 25% of African Americans with cardiac transthyretin amyloidosis were heterozygous for a transthyretin V122I mutation.34 Although this condition is rare, interstitial deposition of wild-type and mutant transthyretin is an underrecognized trigger of HF in the elderly.35

Mitochondrial Dysfunction and Age As evidenced in the preceding sections, there are many factors that contribute to cellular changes observed in HFpEF. However, the fact that aging is a critical and overarching factor in the development of HFpEF is clearly noted.36 LV diastolic stiffness increases and LV diastolic filling rate decreases with age.37,38 Kaushik et al. showed that age-related increases in vinculin, a cytoskeletal protein, was linked to cortical stiffening and contractility.39 Vinculin is found localized to integrin-mediated cell–ECM and cadherin-mediated cell–cell adhesions. Vinculin acts as one of several proteins involved in anchoring

F-actin to the membrane. Senescent rats have twofold the ECM content in the myocardium compared to younger rats.40 The senescent myocardium has increased levels of ROS, which can activate transforming growth factor-β (TGF-β), inducing conversion of cardiac fibroblast to myofibroblasts, an activated fibroblast phenotype.41 The aging heart has lower responsiveness to β-adrenergic stimulation. There is lowered PKA and CaMKII phosphorylation of PLN and RYR receptor. Together this results in a lowering of the Ca2+ uptake and relaxation rate.42 The mitochondrial deoxyribonucleic acid (DNA) in aging hearts in both man and mice have up to 16-fold more point mutations and deletions than those of younger animals. Myocardial energetics have been examined as a potential mechanism for reduced systolic reserve in HFpEF with increased age. Patients with HFpEF have been shown to have a reduced phosphocreatine/adenosine triphosphate (ATP) ratio when compared to controls.43 Several studies suggest that abnormal skeletal muscle performance is a contributor to exertional intolerance rather than just limited cardiac reserve.44 One study found that HFpEF patients had reduced type I oxidative muscle fibers, type I/II fiber ratio, and a reduced capillary to fiber ratio in skeletal muscle compared with controls.45 Comorbid diseases, including hypertension and renal failure, are much more common in the elderly. There is increased inflammation with increasing age. Although the cellular mechanisms are not yet clearly defined, myocardial aging is interconnected to molecular events that influence both myocyte contractility and changes in the collagenous ECM (see upcoming discussion) that appear to provide a favorable milieu for the development of HFpEF, particularly when in combination with other comorbitidies such as hypertension and diabetes.

MYOCARDIAL COLLAGEN Cardiac Fibrillar Collagen Fibrillar collagens play a vital role in homeostatic function and pathologic dysfunction in the heart. Collagen types I, III, and V are the most highly represented myocardial fibrillar collagens.46 These three types of collagens form composite fibrils that then form the collagen fibers of the heart. Three categories of collagen fibers in and around myocytes have been described based on their morphologic characteristics: coils, struts, and weaves.47 Presumably each category of collagen fiber has a unique role in providing structural support to myocytes. A perimysial fibrillar collagen weave composed of smaller collagen fibers surrounds each myocyte, whereas the larger collagen fibers present as struts and coils to connect adjacent myocytes and blood vessels. Myocytes are organized in aligned bundles within the myocardium. The bundles are further organized into sheets that slide by one another during each heartbeat to generate the torsional motion to expel blood from the ventricles. Collagen fibers likely also participate in the organization of higher order structures such as bundles and sheets, although these types of structures are more difficult to identify in traditional two-dimensional tissue sections. Recent advances in generating and imaging decellularized hearts have afforded opportunities to visualize cardiac collagenous ECM in three dimensions where these structures can be better appreciated. As imaging technologies advance, the ability to visualize collagen structures in living human hearts in three dimensions will provide critical information for diagnosing and evaluating myocardial fibrosis in patients. Age-related changes in the cardiac ECM have been observed both in man and in animal models.48 In mice, levels of fibrillar collagen were found to be low in neonatal hearts where abundant levels of

CHAPTER 1 

Molecular, Gene, and Cellular Mechanism

fibronectin were detected.49 In adult hearts, fibronectin was significantly decreased, whereas fibrillar collagen levels increased to become the dominant fibrillar ECM component. Interestingly, in aged hearts, levels of fibrillar collagen further increased in comparison to adult ages, and increases were also noted in levels of fibronectin. Increases in fibrillar collagen in aged hearts were associated with increases in tissue stiffness even in the absence of hypertension or PO suggesting a tendency for the development of myocardial fibrosis with age alone.50 Accordingly, age-dependent changes in ECM, coupled with those in myocytes, appear to set the stage for increases in myocardial stiffness that is further exacerbated by comorbid conditions.

Collagen Deposition in HFpEF In patients diagnosed with HFpEF, increases in fibrillar collagen content are significant. In the study by Zile et al., collagen volume fraction was assessed in patient biopsies recovered from three groups: referent control, hypertensive heart disease only, and hypertensive heart disease with HF.51 Collagen content and myocardial stiffness were significantly increased only in biopsies from patients with hypertensive heart disease with HF. Furthermore, collagen-dependent stiffness was measured and shown to make a significant contribution to overall muscle stiffness when the sarcomeric component was removed.51 These results are consistent with increases in collagenous ECM observed in the myocardium of HFpEF patients making a critical contribution to diastolic stiffness. Similarly, animal models of PO that recapitulate many aspects of human fibrotic disease also support a key role for fibrillar collagen in diastolic stiffness. Resident cardiac fibroblasts are the primary cardiac cell type that produces fibrillar collagen both in homeostasis and in hearts subjected to PO.52 Activated fibroblasts, often referred to as myofibroblasts, express elevated levels of contractile cytoskeletal elements and ECM components. Although activated fibroblasts are strongly implicated in cardiac remodeling following infarction, the role of activated fibroblasts in PO is less clear.53 Nonetheless, resident cardiac fibroblasts are the primary producers of fibrillar collagen and, with the assistance of inflammatory cells, are a critical mediator of collagen degradation (see Fig. 1.2). Although imperfect, animal models provide a platform for evaluating cause-and-effect mechanisms of cardiac collagen deposition. Accumulation of ECM derives from (1) increases in transcription, translation, and secretion of ECM proteins; (2) procollagen processing and deposition to insoluble ECM in the extracellular space; and (3) degradation of ECM by myocardial matrix metalloproteinases (MMPs). Evidence that each of these mechanisms might contribute to increases in collagen content in response to PO has been shown in animal models.

Transcriptional Regulation of Collagen I Transcriptional control of messenger ribonucleic acid (mRNA) encoding procollagen I is one mechanism by which levels of secreted procollagen can increase. Measurements of mRNA encoding the subunits of collagen I have been shown to significantly increase as soon as 3 days following the induction of PO.54 The increased levels of mRNA encoding fibrillar collagen subunits coincide with significant increases in MMP expression indicative of extensive ECM remodeling that accompanies hypertrophic growth of the myocardium.55 The expansion of individual myocytes by addition of sarcomeres requires renewed synthesis of basal lamina surrounding each myocyte as well as ECM in and around blood vessels. Likely the interstitial connective tissue also undergoes remodeling in response to hypertrophic growth. Interestingly, the increase in mRNA encoding fibrillar collagens at day

5

3 does not immediately result in an increase in collagen deposition in the extracellular space.54 Significant increases in levels of collagen protein incorporated into collagen fibers is not detected until 1 week after induction of PO. Hence, transcriptional control of fibrillar collagen genes is not the sole mechanism that controls levels of myocardial collagen.

Postsynthetic Procollagen Processing and Deposition Studies from Laurent et al. suggested that deposition of collagen protein into an insoluble ECM is a critical step in controlling the amount of collagen deposited following PO.56 In the heart, ∼50% of newly synthesized collagen is degraded prior to incorporation into the ECM.56 Upon induction of PO, the amount of procollagen degraded decreases accompanied by increases in insoluble collagen deposition. These studies suggest that the efficiency of procollagen processing increases in response to PO and results in increases in collagen content. Procollagen maturation in the extracellular space requires cleavage of both the N-terminal and C-terminal propeptides from the procollagen monomer.57 In addition, modification of amino acids by enzymes that facilitate collagen crosslinking, such as lysyl oxidase, occurs during procollagen processing.58 Other proteins secreted into the extracellular space influence assembly of collagen into insoluble fibrils and include matricellular proteins such as SPARC and periostin as well as other collagen family members and proteoglycans.59 Proteins involved in procollagen processing and assembly are essential factors influencing myocardial collagen content in homeostasis and in response to fibrotic stimuli. For example, the absence of SPARC expression results in reduced amounts of insoluble myocardial collagen deposited in response to PO.60 Likewise, a decrease in insoluble collagen in SPARC-null hearts correlated with a reduction in myocardial stiffness in comparison to wild-type hearts. Hence, like in humans, increases in collagen content in mice is also associated with increases in myocardial stiffness.

ECM Degradation Matrix Metalloproteinases Once collagen has been incorporated into an insoluble ECM, the only known biologic mechanism for reducing collagen content is through enzymatic degradation. MMPs are zinc-dependent endopeptidases primarily responsible for ECM degradation. Of note, HFpEF patients have been found to have elevated levels of circulating MMP-1, MMP-2, MMP-8, and MMP-9.61–64 In addition to ECM degradation, MMPs also perform proteolytic cleavage of inflammatory mediators, matricellular proteins, and other MMPs within the myocardium.65,66 Hence increases in MMP activity are associated with active remodeling of the myocardial ECM that does not necessarily lead directly to reductions in ECM. For example, MMP-dependent cleavage of latent TGF- β, a potent profibrotic cytokine sequestered in the ECM, can lead to increases in ECM production. Of the 25 MMPs described to date, MMP-2 and MMP-9 are the most widely studied (see Refs. 55 and 66). Interestingly, circulating MMP-2 has been shown to be elevated to a higher extent in patients with severe diastolic dysfunction as well as those with diastolic HF.62 Increased MMP-2 activity has also been shown to induce cardiomyocyte hypertrophy and degrade contractile and structural proteins (i.e., TnI, myosin light chain 1, α-actinin, and titin) resulting in decreased cardiac function.67,68 Hence a prominent function of this MMP in cardiac remodeling beyond ECM degradation alone is suggested. In a murine model of LV PO, genetic deletion of MMP-2 actually reduced the degree of myocardial fibrillar collagen accumulation and improved indices of diastolic function.69

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Basic Determinants of Diastolic Function

Neutrophils and monocyte-derived macrophages are a major source of MMP-94. In aged mice, MMP-9 deletion was found to attenuate the age-related decline in diastolic function through a reduction in TGF-β signaling. Reductions in the profibrotic matricellular proteins, periostin and CCN2 (connective tissue growth factor [CTGF]), were detected in the absence of MMP-9.70 MMP-9 is thought to regulate inflammation through its proteolytic activity on both ECM components and cytokine substrates. For example, in a mouse model of myocardial infarction (MI) MMP-9 mediated the post-MI degradation of CD36 leading to a decrease in macrophage phagocytosis of apoptotic neutrophils.71 Although a number of MMP-9 substrates have been identified, including collagens (type I, IV, V, VII, X, and XIV), fibronectin, elastin, interleukin (IL)-8, Cxcl4, and IL-1β, the mechanisms whereby MMP-9 modulates LV remodeling and diastolic dysfunction have not been completely elucidated.72–75 Other MMPs implicated in diastolic dysfunction include MMP-1, which has the highest affinity for fibrillar collagens and preferentially degrades collagens type I and III. Increased MMP-1 activity results in excessive collagen deposition and diastolic dysfunction.76 In addition, MMP-8, a collagenase primarily secreted by neutrophils, negatively correlates with development of HFpEF.64,77 Similarly, MMP-12 inhibition exacerbates cardiac dysfunction by prolonging neutrophil-mediated inflammation highlighting the importance of MMPs in regulation of inflammation and the subsequent development of cardiac dysfunction.78 Taken together, MMPs are critical mediators of myocardial ECM content and might represent a viable target for therapeutic intervention in future applications.

Tissue Inhibitors of Metalloproteinases MMP activity is dependent not only on the concentration of active enzymes but also on the levels of a family of naturally occurring tissue inhibitors of metalloproteinases (TIMPs).79 After chronic stimulation of proinflammatory cytokines, TIMP levels increase leading to decreased MMP/TIMP ratio and increases in fibrillar collagen deposition.80 For example, the interaction between MMP-1 and TIMP-1 is of critical relevance in the maintenance of the integrity of the cardiac collagen network. TIMP-1 colocalizes with MMP-1 in healthy myocardium and is expressed by cardiac fibroblasts and myocytes.81–84 Circulating levels of TIMP-1 closely associate with markers of systemic inflammation, diastolic dysfunction, and HF severity.62,85 In hypertensive subjects with HFpEF, TIMP-1 moderately predicts the presence of HF.86 Using a single MMP to TIMP ratio, however, can be somewhat misleading as there are multiple MMPs and TIMPs present in diseased myocardium. In addition to TIMP-1, TIMP-2 levels correlate with deposition of cardiac ECM.87 In response to angiotensin II infusion, TIMP-2 deleted mice showed enhanced hypertrophy, reduced collagen crosslinking, and suppressed collagen deposition resulting in impaired active relaxation.88 TIMP-3 has cardioprotective functions, as TIMP-3 deletion leads to spontaneous dilated cardiomyopathy,89 whereas TIMP-4 levels increase with hypertrophy and decrease with the onset of HF in spontaneously hypertensive rats.90

Inflammatory Mediators in HFpEF A significant role for inflammatory mediators in the heart following MI has been well established in a number of studies where inflammation has been shown to be a major component contributing to healing and scar formation.91–95 Initiation of the inflammatory response following MI is necessary for adequate wound healing, yet too much or too little inflammation can result in increased dilation and poor cardiac function highlighting the importance of a balanced immune response to

injury.96 Relatively less is known about the role of inflammatory mediators in HFpEF although this actively expanding area of research will certainly lead to new discoveries that are likely to influence treatment strategies. As mentioned, aging is a risk factor for HFpEF and has been linked to increased systemic inflammation termed inflamm-aging. Inflammaging is defined as elevated levels of proinflammatory markers in the blood and other tissues often detected in older individuals. It is hypothesized that this increase in inflammation is the common biologic factor responsible for the decline and the onset of cardiovascular diseases, frailty, multimorbidity, and decline of physical and cognitive function in the elderly. Possible mechanisms potentially underlying inflamm-aging include genomic instability, cell senescence, mitochondria dysfunction, NLRP3 inflammasome activation, and primary dysregulation of immune cells. Obesity is another risk factor for HFpEF that has been linked to an increase in baseline systemic inflammation.97 More than 80% of patients with HFpEF are overweight or obese. Visceral fat produces proinflammatory and chemotactic compounds and is infiltrated by inflammatory cells such as macrophages and lymphocytes.98 Older, obese HFpEF patients that underwent a 20-week caloric restriction diet had significantly improved peak oxygen consumption and quality of life scores. This improvement was found to correlate with reduced body fat mass, increased percent lean body mass, higher thigh muscle/intermuscular fat ratio, and lower biomarkers of inflammation supporting the hypothesis that systemic inflammation due to obesity contributes to exercise intolerance in HFpEF.99 As mentioned, inflammatory cells produce MMPs, which have a significant impact on cardiac remodeling. Studies that support a function for inflammatory cell types in contributing to fibrotic deposition of cardiac collagen are emerging, particularly for neutrophil and macrophage populations.

Neutrophils In response to ischemia, neutrophils are the first cells to respond to the site of injury.100,101 Similarly, neutrophils might also be an important early contributor to PO-induced hypertrophy. In a murine model of PO, the recruitment of neutrophils was characterized as an early event as increases in neutrophil numbers noted at day 1, decreased by day 3.102 Early infiltration of neutrophils was also associated with detection of neutrophil extracellular traps (NETs) in the heart. The release of chromatin by neutrophils in the form of NETs is thought to be an antimicrobial defense mechanism. However, NETs are also thought to lead to further recruitment of platelets and other types of inflammatory cells. In the study by Martinod et al., transgenic mice that were unable to form NETs demonstrated significant reductions in myocardial collagen content in comparison to wild-type mice after 4 weeks of PO.102 Whether neutrophil activity and NET deposition might also contribute to human disease is yet to be established.

Macrophages Similar to neutrophils, increasing evidence that macrophages might also influence fibrotic deposition of collagen after PO is emerging. In a murine model of PO induced by transverse aortic constriction (TAC), cardiac macrophage populations were increased at day 6.103 McDonald et al. also reported increases in macrophage populations at 1 week after TAC.54 Importantly, the time course of collagen accumulation paralleled that of macrophage expansion in the PO myocardium.54 Macrophage expression of the matricellular protein SPARC, a key regulator of myocardial fibrosis, was also found suggesting that

CHAPTER 1 

Molecular, Gene, and Cellular Mechanism

macrophage expression of SPARC might increase procollagen processing and enhance collagen deposition in PO hearts. Evidence that macrophages might also contribute to fibrosis in humans was supported by an increase in macrophages in biopsies from patients diagnosed with HFpEF.104 Tissue samples from referent controls and from those with hypertension in the absence of HFpEF did not demonstrate significant increases in myocardial macrophages. Hulsmans et al. went on to show, in another murine model of diastolic dysfunction, an association with macrophage recruitment and cardiac fibrosis. In mice with macrophage-specific deletion of IL-10, an improvement in diastolic function was found.104 Hence a growing body of evidence suggests that macrophages are a critical inflammatory cell population influencing the development of myocardial fibrosis and diastolic dysfunction.

7

FUTURE DIRECTIONS Cellular mechanisms that influence diastolic function are multivariant in nature. A decrease in cardiomyocyte number, cardiomyocyte hypertrophy, increased collagen deposition, and functional changes at the cellular level can all contribute to LV stiffness and abnormal diastolic function. Determining what factors trigger the decline into HF has never been more important. Clearly, factors that render the aged myocardium more susceptible to diastolic dysfunction include changes in myocyte contractility, age-related ECM remodeling, and inflammation. New strategies that arise from basic research into cellular mechanisms of diastolic dysfunction are highly likely to lead to significant advances for the treatment of patients diagnosed with HFpEF in the coming years.

KEY POINTS • Heart failure with preserved ejection fraction (HFpEF) is characterized by increases in myocardial stiffness contributed by both cellular and molecular mechanisms that arise from alterations in myocytes and in extracellular matrix. • Myocardial energetics are a potential mechanism for reduced systolic reserve in HFpEF with increased age. • A reduction of SERCA activity is consistent with the characteristic slowed relaxation and [Ca]I seen in diastolic HF. In animal models when SERCA expression is increased or PLN expression is decreased, myocardial relaxation and [Ca]I decline are accelerated resulting in improved diastolic function. • Phosphorylation of the N2B element of titin by PKA or PKG decreases passive tension, whereas phosphorylation of titin’s PEVK element by PKC-α increases passive tension. • Cardiac transthyretin amyloid deposition is linked with HFpEF.

• Three primary cellular mechanisms contribute to increases in myocardial collagen accumulation: 1. Increased transcription, translation, and secretion of collagen proteins 2. Increased procollagen processing in the extracellular space 3. Decreases in extracellular matrix degradation • Procollagen processing is influenced by expression of collagenbinding proteins, such as the matricellular protein SPARC, that drives collagen deposition in response to pressure overload. • ECM degradation is controlled by the balance between matrix metalloproteinases (MMPs) and tissue inhibitor of MMPs (TIMPs). • Cardiac fibroblasts are the primary cell type producing fibrillar collagen in the heart; however, expression of collagen-binding proteins, MMPs, and TIMPs by resident and infiltrating immune cells can influence levels of myocardial ECM. • Increases in fibrillar collagen and alterations in ECM assembly, such as differential collagen crosslinking, contribute to fibrotic ECM and myocardial dysfunction in HFpEF.

REVIEW QUESTIONS 1. How does NO regulate cardiac relaxation? a. Generation of NO by NO synthase requires a cofactor, tetrahydrobiopterin, which can reduce actin-myosin cross-bridge cycling b. Through depletion of tetrahydrobiopterin and oxidation of guanylate cyclase c. Through NO synthase uncoupling and production of superoxide 2. What are the important steps for procollagen I production, processing, and deposition (in sequential order)? i. Transcription and translation inside the cell ii. Cleavage by MMPs iii. Incorporation into extracellular matrix enhanced by matricellular proteins

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2 Pathophysiology of Heart Failure With a Preserved Ejection Fraction: Measurements and Mechanisms Causing Abnormal Diastolic Function Michael R. Zile and Catalin F. Baicu

OUTLINE Introduction, 11 Normal Diastolic Function, 12 Measurements of LV Relaxation and Filling, 12 Isovolumic Pressure Decline, 14 LV Filling, 14 Recoil and Suction, 16 Pathophysiologic Determinants of LV Relaxation and Filling, 17 Hemodynamic Load, 17 Heterogeneity, 17 Cardiomyocyte Inactivation, 17 Measurement of LV Diastolic Stiffness, Compliance, Distensibility, and Pressure, 17 Chamber Stiffness, 17 Myocardial Stiffness, 18 Pathophysiologic Determinants of Diastolic Stiffness, 18 Myocardial Versus Extramyocardial Processes Effecting Diastolic Stiffness, 18 Cardiomyocyte, 18

Extracellular Matrix, 19 Abnormal Diastolic Function Limits Exercise in HFpEF, 20 Abnormal Diastolic Function Causes Acute Decompensated HFpEF, 22 Prevalence of Diastolic Dysfunction in HFpEF, 24 Prognostic Value of Abnormal Diastolic Function in HFpEF, 24 Direct Measures of Diastolic Function, 24 Indirect Measures of Diastolic Function, 24 Future Directions, 26 Composite Measures Reflecting Diastolic Function, 26 Direct Measurements of Diastolic Function as a Target for Management of HFpEF, 26 Composite Measurements Reflecting Diastolic Functions as a Target for Management of HFpEF, 26 Key Points, 28 Review Questions, 28 References, 28

INTRODUCTION

have an isolated abnormality in systolic function; rather, from the pathophysiologic point of view, they have abnormalities in systolic properties and eccentric remodeling, with associated or secondary abnormalities in diastolic function and increased diastolic filling pressures. By contrast, patients with HFpEF are characterized by normal LV volume, concentric remodeling, normal LV ejection fraction at rest, but abnormalities in diastolic function.3–16 These patients have abnormalities in diastolic relaxation, filling, and/or distensibility. Clinical manifestations of LV diastolic dysfunction include shortness of breath at rest or with exertion and peripheral edema. However, abnormalities in regional systolic function at rest (such as midwall shortening, longitudinal/circumferential strain, and strain rate) have also been identified in patients with HFpEF. In addition, blunted augmentation in systolic function during exercise has been demonstrated in HFpEF patients. Therefore patients with HFpEF do not have isolated abnormalities in diastolic properties; rather, from the pathophysiologic point of view, they have abnormalities in diastolic properties, concentric remodeling, and diastolic dysfunction-dependent limitations in the ability to augment systolic function during exercise.

Heart failure (HF) can be defined physiologically as an inability of the heart to provide sufficient forward output to meet the perfusion and oxygenation requirements of the tissues at rest and during exercise while maintaining normal diastolic filling pressures. Patients with chronic HF can be divided into two broad groups: heart failure with reduced ejection fraction (HFrEF) and heart failure with preserved ejection fraction (HFpEF). Classifying patients in these two broad categories should be based on characteristic changes in cardiovascular (CV) structure and function (Table 2.1).1,2 Patients with HFrEF are characterized by progressive chamber dilation, eccentric remodeling, and abnormalities in systolic function. Clinical manifestations of left ventricular (LV) systolic dysfunction include decreased cardiac output, increased heart rate, and peripheral vasoconstriction. In addition, patients with HFrEF frequently have symptoms of shortness of breath at rest or with exertion. These symptoms of pulmonary congestion are due, at least in part, to LV diastolic dysfunction and increased diastolic filling pressures. Therefore patients with HFrEF (particularly when they have symptomatic decompensation) do not

11

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Basic Determinants of Diastolic Function

TABLE 2.1  Differences in Structure and Function Differentiate HFrEF Versus HFpEF LV end diastolic volume LV mass Geometry LV ejection fraction LV diastolic pressure

HFrEF

HFpEF

↑ ↑ Eccentric ↓ ↑

↔ ↑ Concentric ↔ ↑

HFpEF, Heart failure with preserved ejection fraction; HFrEF, heart failure with reduced ejection fraction; LV, left ventricular.

TABLE 2.2  Definitions Diastolic Dysfunction: Abnormal diastolic properties of LV (abnormal relaxation, filling dynamics, distensibility). • EF may be normal or low. • Patient may be symptomatic or asymptomatic. Heart Failure With a Preserved Ejection Fraction: Clinical heart failure, preserved EF, abnormal diastolic function. Systolic Dysfunction: Abnormal systolic properties of LV (abnormal performance, function, contractility). • EF is low (and diastolic dysfunction may coexist). • Patient may be symptomatic or asymptomatic. Heart Failure With a Reduced Ejection Fraction: Clinical heart failure, reduced EF, abnormal systolic function.

Diastolic dysfunction and HFpEF are not synonymous terms. Diastolic dysfunction indicates a functional abnormality of diastolic relaxation, filling, or distensibility of the left ventricle—regardless of whether the EF is normal or abnormal and regardless of whether the patient is asymptomatic or has symptoms and signs of HF. Thus diastolic dysfunction refers to abnormal mechanical (diastolic) properties of the ventricle and is present in virtually all patients with HF. HFpEF denotes a patient with the signs and symptoms of clinical heart failure who has a normal EF, normal LV volume, and LV diastolic dysfunction. Similar distinctions apply to the terms systolic dysfunction and HFrEF (Table 2.2). The pathophysiology of HFpEF will be reviewed here, beginning with a discussion of normal diastolic relaxation, filling, and distensibility. Understanding normal diastolic function permits an easier understanding of some of the clinical features of HFpEF. The pathophysiologic mechanisms that cause the development of HFpEF are reflected in changes in LV relaxation and filling; LV and LA structural remodeling and altered geometry; changes in LV, systemic, and pulmonary vascular compliance; skeletal muscle and endothelial function; and proinflammatory and profibrotic signaling (Fig. 2.1).17,18

NORMAL DIASTOLIC FUNCTION Cardiac function is critically dependent upon diastolic physiologic mechanisms to provide adequate LV filling (cardiac input) in parallel with LV ejection (cardiac output) both at rest and during exercise. During diastole, the left ventricle, left atrium, and pulmonary veins form a common chamber, which is continuous with the pulmonary capillary bed. LV diastolic pressure is determined by the volume of blood in the left ventricle during diastole and the diastolic distensibility or compliance of the entire CV system (principally the left ventricle but may also include the left atrium, pulmonary vessels, right ventricle, and systemic arteries). Thus an increase in LV diastolic pressure (whether this occurs at rest or during exercise) will increase pulmonary capillary pressure, which if high enough causes dyspnea, exercise limitation, pulmonary congestion, and edema. Relaxation of the contracted myocardium begins at the onset of diastole. This is a dynamic process that takes place during isovolumic

relaxation (the period between aortic valve closure and mitral valve opening during which LV pressure declines with no change in volume), and then continues during auxotonic relaxation (the period between mitral valve opening and mitral valve closure, during which the left ventricle fills at variable pressure) (Fig. 2.2). The rapid pressure decay and the concomitant untwisting and elastic recoil of the left ventricle produce a suction effect that augments the left atrial (LA)– ventricular pressure gradient, pulling blood into the ventricle thereby promoting diastolic filling (Fig. 2.3). During exercise in normal patients, relaxation rate is increased, and early diastolic pressures decrease, augmenting elastic recoil and diastolic suction and resulting in more rapid filling during a shortened diastolic filling period at increasing heart rates. During the later phases of diastole, the normal left ventricle is composed of completely relaxed cardiomyocytes and is very compliant and easily distensible, offering minimal resistance to LV filling over a normal volume range. Atrial contraction near the end of diastole contributes 20% to 30% to total LV filling volume and increases diastolic pressures by less than 5 mmHg. As a result, LV filling can normally be accomplished by very low filling pressures in the left atrium and pulmonary veins, preserving a low pulmonary capillary pressure (30 msec greater than mitral A wave duration) if LV end-diastolic pressure is elevated. As LV compliance decreases and LA pressure (LAP) increases the proportion of PVs flow decreases. At the same time PVd and E wave velocity increase with PN and RST LV filling being seen. All mitral and their corresponding PV patterns are shown together in Fig. 6. (Bottom left) The relation of pulmonary venous systolic fraction (in % of total forward flow) to pulmonary wedge pressure (PWP). When PVs is less than 40% in a patient with heart disease PWP is elevated. (Bottom right) PW Doppler mitral and pulmonary venous flow velocity in a patient with PN to RST filling who has an enlarged left atrium whose contractile function is failing. PVs is decreased with a systolic fraction less than 40%, PVd is increased, and the velocity and duration of PVa exceed that of the mitral A wave.

The interpretation of mitral versus pulmonary venous A wave duration may not be reliable if the mitral velocity at the start of atrial contraction is greater than 20 cm/sec89 or if atrial contraction occurs when PVd has not fallen to the zero velocity baseline.49 In the first case, the peak mitral A wave velocity, TVI, and A wave duration are longer than normal to accommodate the increased atrial stroke volume that is present, and in the latter the PV A wave duration is shorter because it started above the conventional measuring point of the zero velocity baseline. • With LA contraction, flow duration forward into the left ventricle should be the same or longer than flow backward into the pulmonary vein at all ages. • When flow backward into the pulmonary vein is longer than forward, an abnormal rise in LV pressure occurred shortening the mitral A wave duration, which indicates LV EDP is elevated. • This is the first hemodynamic abnormality that occurs with diastolic dysfunction and can only be diagnosed by comparing the mitral and PV A wave durations. • When PVa is difficult to measure, the ending of mitral and PVa flow referenced to the QRS can be used to obtain the same information.

E/A Wave Ratio The E/A wave ratio has been the single most important variable used to help characterize the overall mitral flow velocity pattern47–49,67,95–98 and define diastolic function patient groups in previous research

studies68,99 (see Figs. 9.7 and 9.9). In patients with systolic HF the E/A ratio is related to filling pressures and prognosis. While this diastolic function evaluation by E/A ratio pattern recognition is quick and has yielded useful data, using it without consideration of the individual variables for mitral velocities described earlier, other 2-D findings, and ancillary Doppler variables may lead to misinterpretation of LV diastolic function and filling pressures. The E/A ratio is most helpful when the mitral DT is linear and pre-A velocity is below 20 cm/sec. If mitral DT is curved, biphasic, or if there is partial fusion of E and A wave velocities, then the LV filling pattern needs a careful assessment in relation to the other echo Doppler findings and variables.

ANCILLARY DATA THAT HELPS THE INTERPRETATION OF MITRAL FLOW VELOCITY PATTERNS M Mode and 2-D Echocardiography There is considerable information about LV diastolic function and filling pressures available from M mode and 2-D cardiac ultrasound recordings to complement Doppler variables.5,100 With practice, the visual interpretation of these anatomic findings will usually suggest what Doppler LV filling patterns are present. From the parasternal long axis view, observing the movement at the atrioventricular groove helps

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Fig. 9.17  (A) Schematic diagram of the relation of PV and mitral flow velocity A wave duration, which relates to the LV pressure rise at atrial contraction (LVa). The graph combines Doppler data from three separate studies and shows that when the reverse duration of PV compared to mitral A wave flow exceeds 30 msec, LV end-diastolic pressure is usually above 15 mmHg (B). (C) PW Doppler mitral and PV flow velocity from a patient with LV hypertrophy and IR filling. The mitral A wave duration is 121 msec and PV A wave duration 200 msec so that flow backwards into the pulmonary vein continues for 80 msec after flow into the LV stops. This indicates LV A wave pressure increases and LV EDP is elevated.

identify the cardiac rhythm, LA size, and contractility. In the parasternal short axis, the normal left atrium appears approximately the same size or slightly larger than the aorta. From apical views the sizes of both atria in relation to their respective ventricles can be made, as well as comparing the size and contractility of each other. Differences are usually obvious. A normal-sized left atrium that appears hypercontractile indicates reduced LV filling in early diastole, increased filling at atrial contraction, and an IR pattern. LA enlargement and reduced contractility are often associated with elevated pressures and pseudonormal or RST mitral filling patterns as long as there have been no recent atrial arrhythmias. At the same time, noting asymmetry in the rate of LV and RV contractility and relaxation, and the excursion of AV longitudinal plane movement, often indicates the abnormalities of ventricular diastolic filling that will be seen on Doppler exam. Left ventricular hypertrophy slows LV relaxation independent of other cardiac abnormalities and results in an impaired relaxation that is often obvious in M mode LV recordings (see Fig. 9.18). In the absence of MR, arrhythmias, or cardiac conduction system disease, LA enlargement usually indicates an elevated mean LA pressure associated with pseudonormal and restrictive mitral flow velocity patterns.93,99,101 Because maximal LA volume is strongly associated with adverse cardiac events such as new onset Afib, congestive HF, and stroke99,101–103 we agree that it should be measured according to American Society of Echocardiography (ASE)/European Society of Cardiology (ESC) guidelines104 in all patients. Conversely, normal LA size suggests mean LA pressure is normal. LA minimum volume is related to pulmonary

wedge pressure with a correlation coefficient equal to that of most other Doppler variables.93 • The M mode of LV wall motion in diastole is an easy way to assess LV relaxation. • An enlarged LA, out of proportion to the other cardiac chambers, may indicate elevated pressure and is associated with increased risk for future Afib and HF.

Tricuspid Flow Velocity Tricuspid and mitral flow velocity patterns are normally qualitatively similar, and with RV pathology the alterations are similar to those seen on the left side of the heart. Tricuspid valve opening normally occurs before mitral valve opening, which is easily assessed visually from the stand apical four-chamber view. If mitral valve opening occurs at the same time, or before tricuspid opening, this is abnormal and reflects altered physiology that needs investigation. Since the tricuspid leaflet orifice is larger, tricuspid velocities are slightly lower. Tricuspid flow velocity increases significantly with respiration; this aspect, which differs from left heart filling, will be discussed in the section on assessing RV diastolic function. Normally, mitral and tricuspid inflow patterns appear similar. Significant differences between the two indicate cardiac pathology is present. Since most cardiac diseases affect the left heart, the more abnormal filling pattern is usually seen in LV filling, although the right heart is also affected through the involvement of the intraventricular septum. For instance, in an individual with an ischemic

CHAPTER 9 

Two-Dimensional and Doppler Evaluation of Left Ventricular Filling

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Fig. 9.18  PW mitral flow velocity together with M mode recordings of the LV cavity in three individuals illustrating how the diastolic wall motion helps in interpreting the LV filling pattern. Compared to the normal subject (left) the patient in the middle panel with LVH has IR filling. Their longer IVRT and reduced E wave velocity matches the slower rate of early diastolic LV filling seen in the LV posterior wall (arrow). The patient on the right has a mitral pattern, which may be difficult to interpret without additional data. However, the M mode recording shows marked LVH, very delayed early diastolic filling with relaxation, and mid-diastolic LV cavity expansion continuing to occur up to the time of atrial contraction. These findings, along with the increased E wave velocity (1m/sec) indicate PN LV filling and moderate diastolic dysfunction.

cardiomyopathy who has a pseudonormal LV filling pattern, the tricuspid filling often lags behind showing an IR pattern.

Tissue Doppler Imaging of Mitral Annular Motion This recently developed ultrasound imaging modality discussed in detail in Chapter 10 has underlying physics and principles similar to those of conventional PW spectral Doppler. From the apical views the velocities are related to LV contraction and relaxation. In interpreting LV filling patterns TDI MAM has its greatest use in distinguishing normal and pseudonormal LV filling. The ratio peak mitral E wave velocity to MAM e′ velocity is used to estimate mean LA pressure.80,105 The normal diastolic velocity pattern of MAM obtained from TDI is similar to that of transmitral flow in patients in sinus rhythm, except inverted.39,104–111 There is positive (above the zero velocity baseline) movement toward the apex with systolic contraction and negative movement back toward the pulmonary veins with LV filling in early (e′) and late diastole (a′). In patients with normal ventricular diastolic function the e′/a′ and mitral E/A flow velocity wave ratios are similar. Patients with IR filling have a MAM e′/a′ ratio less than 1, again mirroring the findings seen with mitral flow velocity. However, in pseudonormal mitral flow velocity patterns, a MAM e′/a′ ratio less than 1, rather than more than 1, is present, reflecting the impaired LV relaxation that separates these patients from true normals. This is similar to the relaxation abnormality seen in the myocardial M mode in Fig. 9.19 despite the normal appearing Doppler LV filling pattern. With RST LV filling the e′/a′ ratio frequently is greater than 1 because the majority of filling occurs in early diastole with little contribution due to atrial contraction. Fig. 9.19 shows a schematic diagram of abnormal LV filling patterns together with TDI MAM and pulmonary venous flow velocity patterns for reference.

The interpretation of TDI MAM is enhanced by an awareness of the factors that influence these annular movements. The e′/a′ ratio is higher in the lateral as compared to the septal annulus because the septal is tethered to the right ventricle and other structures in the middle of the heart. The e′ diastolic annular movement predominates in normals because LV longitudinal movement at the base in both systole and diastole is greater than displacement in a radial direction. In patients with a normal LVEF and pseudonormal filling, a reduced e′ is present because LVH causes an increase in systolic radial movement that is reversed (outward LV motion) in early diastole. The e′/a′ ratio will be less abnormal if there is another reason for the reduced LV compliance than LVH or if the LVEF is decreased. Regardless of LVH a large volume of blood flow across the mitral valve in early diastole due to MR will fill the ventricle and increase upward annular movement and e′ velocity. • DTI MAM is a widely accepted part of modern diastolic function exams that has often replaced other Doppler variables. • Comparing the DTI MAM pattern of e′/a′ to mitral E and A wave pattern helps distinguish pseudonormal from normal LV filling patterns. • The commonly used E/e′ ratio, when elevated, has been found to be a powerful predictor of adverse outcomes in large studies in cardiac patients. • However, the use of E/e′ ratio in individual patients for predicting filling pressures is less useful than commonly believed because of a lack of sensitivity and specificity.

Exercise as a Diastolic Stress Test As shown in Fig. 9.4, impaired relaxation reduces the time available for diastolic filling and myocardial perfusion. With the increase in heart rate with exercise, some individuals with LVH, LV systolic dysfunction

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Fig. 9.19  Schematic diagram showing the correlation of tissue Doppler imaging (TDI) recordings of the mitral annulus with normal and abnormal LV filling patterns. TDI is especially helpful in distinguishing Nl from PN LV filling. Also shown are corresponding LV pressures, abnormal diastolic properties, and PV flow velocity. Note that in Nl filling the mitral and TDI patterns are inverted but similar in terms of early and late diastolic ratios. In contrast, PN filling has a markedly disparate TDI with reduced longitudinal movement in early diastole and increased movement at atrial contraction. In IR filling the arrows in LV pressure and pulmonary venous flow refer to patients with decreased LV compliance in late diastole who have an increase in LV end-diastolic pressure. IR, Impaired relaxation; Irrev RST, irreversibly restrictive; Nl, normal; PN, pseudonormal; RST, restrictive.

of cardiac conduction system disease, and IR filling may have premature fusion of early and late diastolic filling and be unable to increase LV end-diastolic volume normally so that a limitation in cardiac output occurs60,63 (Fig. 9.20). Complaints of a reduced aerobic capacity with exertional dyspnea are common. Patients with pseudonormal and RST filling patterns also have a significant decrease in exercise capacity. However, in these individuals it is the increase in mean LA pressure due to reduced LV compliance that limits exercise rather than a blunted increase in LV end-diastolic volume. In patients presenting with exertional dyspnea, examining changes in the ratio of mitral E wave and TDI e′ velocity at rest and exercise has been proposed as a diastolic stress.112 Using supine bicycle exercise and classifying patients by E/e′ above 10, exercise duration was significantly longer in patients whose E/e′ ratios were 10 or less and did not increase with exercise. These preliminary results suggest the hemodynamic consequences of exercise-induced increase in diastolic filling pressure may be possible noninvasively with exercise Doppler echocardiography, an area that needs further study that includes more diastolic variables.

Pulmonary Artery Pressures The estimation of PA systolic and diastolic pressures is a valuable adjunct to assessing LV filling patterns. Using the modified Bernoulli equation, this can be accomplished in a high percentage of patients with right-sided valvular regurgitation. The velocity of pulmonary regurgitation at end diastole together with an estimate of central venous pressure at the same time (physical exam, inferior vena cava [IVC] size and degree of respiratory collapse, hepatic venous Doppler pattern) is used to estimate PA end-diastolic pressure. In the absence of pulmonary vascular disease this is a surrogate estimate of mean LA pressure. Similarly, peak TR velocity together with central venous pressure at the same time during systole (again best evaluated by the HV = hepatic vein or hepatic venous [HV] Doppler pattern) helps estimate PA systolic pressure.

Patients with IR LV filling are expected to have normal or at worst borderline increases in PA pressure in the absence of pulmonary parenchymal or vascular disease. Pseudonormal filling is associated with elevated mean LA pressure and so PA pressures are passively elevated, usually in the range of 30 to 45 mmHg. With the higher left heart pressures seen in RST filling, PA systolic pressure can be quite elevated, in the range of 50 to 70 mmHg.

PERFORMING AN ECHO DOPPLER EVALUATION OF LV DIASTOLIC FUNCTION The assessment of LV diastolic function requires high-quality 2-D images and Doppler recordings of mitral, pulmonary venous, and TDI flow velocities. Guides for optimizing these recordings and avoiding pitfalls with many examples are available.110 Techniques for optimizing CMM mitral inflow velocity propagation and TDI of the mitral annulus are also covered in chapters in this book on these techniques. Organizing an echo Doppler assessment of LV diastolic function into a standard routine helps both the sonographer and the physician improve their technical and interpretative skills.62,113–115 We recommend starting with M mode and 2-D anatomic imaging to obtain measurements of chamber sizes, maximal LA volume, and LV diastolic and systolic volumes. LV mass, relative wall thickness,116 and LVEF are then calculated. The measurement techniques and normal values are published regularly in ASE standardized guidelines. Variables of special importance include LV absolute mass and relative wall thickness, and maximal LA size (normal  A) may actually be pseudonormalization. In patients with pseudonormal TMF, the duration of the pulmonary A wave will be longer than that of the mitral A wave.10–12 The main advantage of cardiac MRI is that pulmonary venous flow (PVF) can be measured in virtually all cardiac MRI cases as opposed to only 68% of TTE cases due to improved image quality with cardiac MRI.7 Phase velocity cardiac MRI can be used to assess longitudinal myocardial velocities; these are comparable to those obtained by tissue Doppler imaging on TTE, although they are only validated in small sample sizes as of yet.6 Midwall longitudinal fractional shortening has been shown to correlate with LV diastolic function and can also be reliably and easily measured by cardiac MRI.13

MYOCARDIAL STRAIN Fig. 15.4 (A) Mitral inflow pattern using phase contrast MRI in a 24-year-old healthy subject, depicting normal E/A ratio. (B) Severe myocardial relaxation disturbance leading to reversal of the E/A ratio. The early filling velocities are strongly decreased (E), whereas the late-filling velocities are increased (A). (From Bogaert J. Cardiac function. In Bogaert J et al, eds. Clinical Cardiac MRI. New York, NY: Springer-Verlag; 2005:99–141.)

Myocardial strain can be assessed by myocardial tagging, which is unique to cardiac MRI and essentially allows for visualization of myocardial deformation during contraction by use of magnetic labels with a rectangular or radial grid (Fig. 15.6). Tagging of these grids can be obtained every 20 msec, allowing for high temporal resolution. Myocardial tagging may allow for earlier recognition of subclinical diastolic dysfunction, as demonstrated by Edvarsen et al. in a study of 218

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Diagnosis of Heart Failure with Preserved Ejection Fraction function and strain have been recognized as important predictors of cardiovascular morbidity and mortality in patients with diastolic dysfunction.15–17 Myocardial tracking can also be applied to the left atrium as well for quantification of LA function.18,19 Early recognition may allow for aggressive risk factor modification and management to prevent progression of disease, although this has not been well established in clinical practice as of yet.

MAGNETIC RESONANCE SPECTROSCOPY Magnetic resonance spectroscopy utilizes 31P signals as opposed to H1. This thereby allows for definition of regional adenosine triphosphate (ATP) and phosphocreatine (PCr) contents, which can be indirectly suggestive of energy status and viability of the myocardium.20–22 Diastolic function is an active, energy-dependent process and therefore changes in PCr and ATP levels can be quantified by 31P–cardiac MRI; altered highenergy phosphate metabolism has been associated with diastolic dysfunction.23 Currently19 the clinical utility of 31P–cardiac MRI is limited by the low intrinsic signal-to-noise ratio of 31P in humans, thereby making its acquisition technically demanding. Recent data using 7T cardiac MRI allowed for more precise quantification of the spectra when compared to conventional 3T, which may be useful in future practice.24

LATE GADOLINIUM ENHANCEMENT

Fig. 15.5  Pulmonary venous flow assessment by echocardiography and cardiac MRI. (A) Transmitral inflow assessment by echocardiography. (B) Pulmonary venous flow assessment by echo. (C) Pulmonary flow by phase contrast cardiac MRI.

Intravenous gadolinium-chelated contrast agents can be used to detect areas of fibrosis, often defined as late gadolinium enhancement (LGE), as the prolonged washout of the contrast correlates with a reduction in functional capillary density in the irreversibly injured myocardium. Myocardial fibrosis has a well-established role in the development and progression of both systolic and diastolic heart failure. LGE typically represents areas with replacement fibrosis or myocardial infarction, and the pattern of LGE can be useful in regard to identifying the underlying myocardial pathology (Fig. 15.7). Recent studies have indeed shown a correlation between LGE suggestive of fibrosis and diastolic dysfunction in various cardiovascular disease states.25–27 The clinical significance of LGE in patients with diastolic dysfunction is yet to be determined, although hypertrophic cardiomyopathy (HCM) patients with LGE have worse outcomes than counterparts without LGE.28–30

QUANTITATIVE T1 MAPPING AND EXTRACELLULAR VOLUME MEASUREMENTS

Fig. 15.6  Myocardial tagging in a healthy individual demonstrating normal patterns of myocardial deformation between end diastole (A) and end systole (B).

asymptomatic patients with LV hypertrophy (LVH) who were found to have regional diastolic dysfunction despite no clinical cardiovascular disease or LV dysfunction.14 Several other methods for measuring myocardial strain have emerged recently, including strain-encoded imaging (SENC), phase velocity mapping, and deformation encoding with stimulated echoes (DENSE), and feature tracking with cine steady-state free precession (SSFP) imaging. Recently, left atrial (LA)

Deposition of myocardial collagen results in diffuse myocardial fibrosis or myocyte replacement/replacement fibrosis.31 Diffuse myocardial fibrosis can negatively impact diastolic filling and systolic function of the left ventricle. Recently there have been numerous studies demonstrating the utility and accuracy of quantifying myocardial fibrosis with T1 mapping and extracellular measurements in patients with heart failure with preserved ejection fraction (HFpEF), hypertensive heart disease, valvular heart disease, HCM, amyloidosis, and Fabry disease32–38 (Fig. 15.8). T1 times and extracellular volume measurements have been shown to correlate with diastolic dysfunction.37,39,40

DIFFUSION TENSOR IMAGING Cardiac myocytes are organized into sheetlets, which are laminar microstructures that reorganize during cardiac systole from longitudinal to radial planes and thereby are thought to significantly contribute to LV wall thickening.41,42 Although well established within

CHAPTER 15 

Evaluation of Diastolic Function by Cardiac Magnetic Resonance Imaging

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Fig. 15.7  Late Gadolinium Enhancement (LGE) patterns seen in common clinical conditions. If hyperenhancement is present, the endocardium should be involved in patients with ischemic disease. Isolated midwall, epicardial, or global hyperenhancement strongly suggests a nonischemic etiology

Fig. 15.8  Quantification of diffuse fibrosis using T1 mapping with cardiac MRI. (A) Precontrast T1 mapping images; (B) postcontrast T1 mapping images; (C) extracellular volume quantification.

the neuroimaging realm, cardiac diffusion tensor imaging (DTI) is a relatively new technique that allows for in vivo functional assessment of anisotropy and orientation of the sheetlets. Patients with HCM or ischemic heart disease may have altered tissue integrity that can be identified by DT-MRI.43,44 (Fig. 15.9).

MR ELASTOGRAPHY MR elastography is a technique that can measure myocardial shear wave amplitudes (SWA). The development of this technique was based on the principle that myocardial relaxation is related to decreases in the shear modulus, which is determined by the combination of active relaxation and passive stiffness. As such, shear modulus should serve as a marker for diastolic function. Recent data have shown that patients with diastolic dysfunction have significant reductions of SWA within the left ventricle45–47 (Fig. 15.10).

FOUR-DIMENSIONAL FLOW Four-dimensional (4-D) cardiac MRI is a specialized phase contrast cardiac MRI technique that allows for a more comprehensive evaluation of

volumetric flow by enabling multidirectional and multidimensional image acquisition. Intracavitary LV blood flow kinetic energy, a marker of myocardial workload, can be semiautomatically quantified by 4-D cardiac MRI. A recent study demonstrated that kinetic energy parameters derived from 4-D cardiac MRI did indeed correlate with diastolic dysfunction but moreover demonstrated increased correlation with age.48 Further studies are necessary to determine the clinical relevance of these findings (Fig. 15.11).

CLINICAL CORRELATION Left Atrial Morphology and Function Left atrial size and volume remain integral measurements in the evaluation of diastolic dysfunction and can be accurately performed in a reproducible manner with cardiac MRI. As previously discussed, LA pressure is directly affected by LV filling pressure during diastole. Increased LA pressure will result in LA dilation, which thereby serves as a marker of elevated LV filling pressures in patients with chronic diastolic dysfunction. LA enlargement is known to be a poor prognostic factor and thus serves as an important clinical tool in managing patients with diastolic dysfunction.49–51

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Fig. 15.9  High-resolution diffusion tensor imaging (DTI) tractography of the human heart in vivo. The images are of a healthy human volunteer imaged with the velocity-compensated pulse gradient spin echo (PGSE) sequence. (A, B) Coherent tracts with the correct orientation can be resolved in all regions of the myocardium. (Dispersion of hydroxyapatite [HA] over the papillary muscles and trabeculations of the left ventricle is a normal finding.) (C) Magnified view of fibers crossing a region of interest (ROI) in the midlateral wall of the left ventricle reveals the characteristic crossing pattern of myofibers in the subendocardium and subepicardium. A, Apex; S, septum. The higher signal-to-noise ratio (SNR) of the PGSE sequence enabled a resolution of 2 × 2 × 4 mm3 to be achieved, three times better than the resolution obtained with the stimulated echo (STE) approach. (From Mekkaoui C, Reese TG, Jackowski MP, et al. Diffusion MRI in the heart. NMR Biomed. 2017;30(3):e3426.)

or, alternatively, biplane area-length volumetry versus four-chamber planimetry.52 It is important to note that cardiac MRI is considered the gold standard for quantifying LA volume and function, and can be an important tool in identifying the effects of diastolic dysfunction on the left atrium.53–55 LA function can be quantified by various parameters, including left atrial strain; total left atrial emptying fraction (LAEF) [100 × (LAVmax – LAVmin)/LAVmax]; passive LAEF [100 × (LAVmax – LAVpre-a)/LAVmax]; and the active LAEF [100 × (LAVpre-A – LAVmin)/LAVpre-A]. Because several studies have demonstrated the prognostic importance of identifying abnormal LA size and function,55–58 careful attention and dedicated assessment of the left atrium is an important part of evaluating diastolic function and the presence of cardiovascular disease (Fig. 15.12). Fig. 15.10 Steps involved in magnetic resonance elastography (MRE). (A) A mechanical driver is used to introduce shear waves in the sample with soft (bright) and stiff (dark) inclusions. Shear waves are encoded into the phase image (B) obtained using an MRE sequence. Waves in the stiffer areas have longer wavelengths. An inversion algorithm is utilized to compute the stiffness map (C) using the phase image. (Khan S, Fakhouri F, Majeed W, et al. Cardiovascular magnetic resonance elastography: a review. NMR Biomed. 2018;31(10):e3853. doi:10.1002/nbm.3853.)

LV MASS Increased LV mass has been independently associated with diastolic dysfunction and therefore is an important parameter in the evaluation of diastolic dysfunction.59,60 This can be easily calculated using cine short axis views of the left ventricle to define the myocardial contours. Myocardial contouring is usually performed manually to determine LV volume, which is multiplied by myocardial density to yield the LV mass.

HYPERTROPHIC CARDIOMYOPATHY

Fig. 15.11  4-D flow through the pulmonary artery.

Measurement of LA size and volume with cardiac MRI uses the same techniques as with TTE or computed tomography (CT) imaging, including the gold standard technique of Simpson’s volumetric method

Cardiac MRI has taken a much more prominent role in the diagnosis and management of patients with HCM, which is characterized as inappropriate myocardial hypertrophy without an alternative cause. It allows for differentiation of different forms of HCM, determination of obstructive versus nonobstructive disease, and prognostication. In addition, a significant proportion of patients with HCM can present with LV outflow obstruction in the absence of significant LVH. These patients typically have abnormal papillary muscle or mitral valve morphology, which are best identified by cardiac MRI.61 In patients with thickened myocardium, diastolic dysfunction is thought to be one of the initial and most prominent pathophysiologic mechanisms of clinical disease, manifesting as diastolic heart failure. These patients will often have a globally preserved or increased ejection fraction, but regional assessment with myocardial tagging via cardiac MRI has shown regional reduction in systolic wall thickening in hypertrophied areas.62–64

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Fig. 15.12  Left atrial function and strain analysis. (A) Left atrial systole; (B) atrial diastole; (C) left atrial strain analysis.

Approximately 80% of HCM patients will have some degree of abnormal delayed enhancement when gadolinium is administered during cardiac MRI, even in those who are asymptomatic.65,66 LGE usually is present in areas with hypertrophied myocardium and is typically seen in a patchy pattern with multiple foci predominating in the middle third of the ventricular wall and often notable near the insertion points of the RV free walls onto the interventricular septum. The clinical implication of deformation encoding (DE) in HCM patients has been established in numerous retrospective studies, whereby DE has been shown to portend an increased risk of sudden cardiac death or aborted sudden cardiac death.28–30,67 Determining the severity of diastolic dysfunction in patients with HCM is challenging, particularly with cardiac MRI. Recently myocardial elastography was shown to correlate with myocardial stiffness in patients with HCM and may become a clinically useful tool for quantifying diastolic function. The authors demonstrated significant positive correlation between myocardial stiffness by myocardial elastography and early diastolic peak/early diastolic mitral annular velocity, r = 0.783; early diastolic peak/transmitral flow propagation velocity, r = 0.616; LA volume index, r = 0.623; and with fibrosis markers in cardiac magnetic resonance (late gadolinium enhancement, r = 0.804; myocardial T1 precontrast, r = 0.711).68 However, currently quantifying the degree of diastolic function in patients with HCM remains challenging with the clinically available MRI protocols. Morphologic assessment of the extent of LVH and myocardial fibrosis are likely the most useful clinical correlates with the degree of diastolic dysfunction.25,69

Hypertension and Aortic Stenosis Patients with uncontrolled hypertension or significant aortic stenosis develop organized LVH related to chronic LV pressure overload. While sarcomere organization is eccentric in patients with HCM, patients with hypertension and aortic stenosis develop new sarcomeres in parallel in an attempt to normalize wall tension, which results in concentric hypertrophy. This process can also alter the passive elastic properties and myocardial stiffness, resulting in diastolic dysfunction. Altered LV filling can be assessed using GRE sequences to identify early patterns of diastolic dysfunction such as prolonged time to PFR and an early filling percentage. These abnormalities in filling will be evident

before changes in the transmitral flow pattern.70 Reduced LA contractile function as calculated by cardiac MRI has been shown to be a poor prognostic factor in terms of cardiovascular risk in hypertensive patients, even in those without overt diastolic dysfunction.71 In advanced hypertensive heart disease, the classic changes in TMF filling patterns will be evidence on phase contrast cardiac MRI, similar to that seen on TTE.72 31 P-MR spectroscopy can also reveal early changes with a reduced PCr/ATP ratio despite no evidence of LVH.23 The clinical significance of this finding has not yet been established. Myocardial tagging in these patients will often yield a prolonged LV untwisting time and, perhaps more clinically tangible, a reduction in regional strain in asymptomatic patients with LVH.14,73

Coronary Artery Disease Diastolic dysfunction is often the earliest sign of myocardial ischemia and as such may often be underappreciated in patients with ischemic heart disease. Certainly, prior to the advent of cardiac MRI, it was an essentially unrecognized entity of patients with coronary artery disease (CAD). Diastolic filling patterns within this cohort will often be complex, related to the regional heterogeneity of myocardial function in ischemic, scarred, stunned, or hibernating areas. These regional changes in diastolic function can be accurately assessed using threedimensional (3-D) tagging with cardiac MRI, which will typically reveal reduced regional strain most notable in the infarcted regions and delayed, prolonged, and nonuniform LV untwisting in infarcted or hibernating areas of myocardium.74–77 This has been demonstrated in animal models as well, where normal untwisting was restored after reperfusion.74 Phase contrast imaging can also be used to assess for diastolic function in patients with established ischemic heart disease, wherein TMF patterns will be typical of other patients with diastolic dysfunction.8

Constrictive Pericarditis Cardiac MRI provides excellent evaluation of the pericardium due to its excellent tissue characterization, multiplanar imaging, and superior contrast resolution. Cardiac MRI can provide a comprehensive assessment for patients with suspected pericardial disease, including T1-weighted and T2-weighted spin echo, GRE, and tagged cine

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Fig. 15.13  Normal pericardium in a healthy individual, four-chamber view. (A) The pericardium appears as a thin band of low signal intensity (black) on a spin echo image. (B) The pericardium appears as a band of intermediate signal intensity (grey) on a gradient echo (GRE) image.

sequences to assess cardiac function and morphology, pericardial thickening and tethering, and presence of interventricular dependence. Normal pericardial thickness is typically 2 mm and best seen on T1/T2-weighted spin echo images, where the pericardium is seen as a thin rim of tissue between the mediastinal and epicardial fat. A pericardial thickness of 5 to 6 mm has a relatively high specificity for constrictive pericarditis.78,79 Pericardial calcification or fibrosis will have low signal intensity and therefore appear black on spin echo images (Fig. 15.13). Because pericardial calcification is difficult to identify and distinguish from noncalcified thickened pericardium with

cardiac MRI, CT imaging is the recommended imaging modality to identify and quantify the extent of pericardial calcification. T2-weighted fat-suppressed spin echo and delayed enhancement imaging techniques can be used to assess for pericardial inflammation and edema in cases of suspected acute pericarditis (Fig. 15.14). Tissue characterization of the pericardium is of great clinical importance in determining the optimal treatment strategy for patients with constrictive pericarditis. Delayed hyperenhancement of the pericardium distinguished underlying acute pericarditis as the etiology of constrictive physiology versus chronic pericarditis, two entities that are managed differently.80 Cine tagged images can be used to evaluate for tethering or adhesion of the parietal pericardium to the visceral pericardium (Fig. 15.15). Conical deformity of the ventricles, diastolic tethering or restraint of any of the cardiac chambers, and a prominent diastolic bounce can also be seen on cine imaging due to the rapid and then abrupt cessation of filling during diastole, which are classic cardiac MRI findings in the setting of constrictive pericarditis. This respirophasic, interventriculardependent filling can be identified on free-breathing cine sequences.81 Free-breathing cine GRE sequences are used for evaluation of interventricular dependence, whereby the interventricular septum will shift toward the left ventricle during inspiration and toward the right ventricle during expiration due to limited ability to expand in constrictive pericarditis (Fig. 15.16). This technique notably relies on patient cooperation for following instructions regarding adequate inspiratory effort. Similar to echocardiography, respirophasic flow across

Fig. 15.14 Acute pericarditis. (A) Black blood T2 spin echo imaging demonstrating significant pericardial thickening. (B) T2 fat suppressed spin echo imaging demonstrates severe acute edema of the pericardium. (C) Late gadolinium enhancement imaging demonstrates severe inflammation of the pericardium.

Fig. 15.15  Characteristic cardiac MRI findings in a patient with constrictive pericarditis. (A) Four-chamber gradient echo (GRE) image depicting the common tubular-shaped deformity of the ventricles and atrial dilatation. Note the thickened fibrous pericardium over the right ventricular free wall (arrows) and the darker area of calcified pericardium over the lateral wall of the left ventricle (arrowheads). (B, C) Diastolic and systolic still frame from cine tagged four-chamber images shows the characteristic tethering of the pericardium to the epicardial surface during diastole. LA, Left atrium; LV, left ventrical; RA, right atrium; RV, right ventricle.

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31

P-MR spectroscopy. Cardiac MRI can provide additional diagnostic utility in patients with restrictive cardiomyopathy by helping to establish the underlying etiology based on a pattern of functional and morphologic characteristics.

Cardiac Amyloidosis

Fig. 15.16  Free-breathing cine sequence demonstrating septal flattening during inspiration in a patient with constrictive pericarditis. There is significant septal flattening during inspiration.

the mitral valve can also be assessed by real-time phase contrast imaging in spontaneously breathing patients. In a small study, respiratory variation greater than 25% across the mitral was highly sensitive and specific for identifying constrictive pericarditis.82

Restrictive Cardiomyopathy By definition, all patients with restrictive cardiomyopathy will have evidence of diastolic dysfunction and restrictive filling patterns on all imaging modalities. This will be demonstrated on cardiac MRI cine tagged images, phase contrast cardiac MRI, LV filling curves, and

Over 25 unique amyloidogenic proteins have been identified, but the frequency and severity of cardiac involvement can vary significantly among genotypes. Cardiac involvement can carry a significant prognostic and management impact and should therefore be identified as early as possible. LGE on cardiac MRI can identify early cardiac involvement of amyloidosis as demonstrated in one study where 47% of patients with known systemic amyloidosis were found to have cardiac involvement by cardiac MRI despite normal wall thickness on TTE.83 However, typically there is diffuse deposition of the amyloid proteins throughout the cardiac structures, which can result in significant increase in thickness of the myocardium, atrial walls, interatrial septum, and occasionally valvular apparatus. Patients with amyloidosis will typically demonstrate a diffuse pattern of LGE in a noncoronary distribution that is usually limited to subendocardial involvement84 (Fig. 15.17). Additionally, native T1 measurements and electrochemical capacitance voltage (ECV) measurements can identify cardiac amyloidosis at earlier stages (Fig. 15.18) and provide powerful prognostic risk stratification in patients with both transthyretin amyloidosis and primary amyloidosis.85,86 Diastolic dysfunction results with increasing cardiac amyloid deposition, and Maceira et al. demonstrated a significant correlation with postcontrast T1 relaxation times and diastolic function (r = 0.42, p = 0.025).84

Fig. 15.17  A 64-year-old asymptomatic male with increased left ventricular wall thickness. Late gadolinium enhancement demonstrates diffuse gadolinium enhancement in a pattern suspicious for amyloidosis. The patient underwent endomyocardial biopsy and was found to have transthyretin (TTR) amyloidosis. (From Stegman BM, Kwon D, Rodriguez ER, et al. Left ventricular hypertrophy in a runner: things are not always what they seem. Circulation 2014;130(7):590–592. doi:10.1161/CIRCULATIONAHA.114.009362.)

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Fig. 15.18  Precontrast and postcontrast T1 mapping of the myocardium demonstrates markedly abnormal T1 times and expanded extracellular volume. (From Stegman BM, Kwon D, Rodriguez ER, et al. Left ventricular hypertrophy in a runner: things are not always what they seem. Circulation 2014;130(7):590–592. doi:10.1161/CIRCULATIONAHA.114.009362.)

Fig. 15.20  Secondary hemochromatosis in a patient with iron overload due to recurrent blood transfusions for hereditary anemia. (A) Short axis gradient echo (GRE) image demonstrates the characteristic low signal over the liver due to accumulation of iron particles. (B) Axial T2weighted spin echo image demonstrates the abnormally low signal intensity of the myocardium due to iron accumulation within myocardial tissue.

may be more prominent features and most commonly involve the basal anteroseptal wall.

Sarcoidosis

Hemochromatosis

Approximately 5% of patients with systemic sarcoidosis are found to have clinically active cardiac involvement, while a further 20% of patients have evidence of cardiac involvement on autopsy.87,88 Cardiac MRI can help to identify active myocardial inflammation in patients with concern for clinically active disease. This will manifest as focal enhancements on T2-weighted spin echo images due to associated inflammation. Patchy LGE can be seen on delayed enhancement imaging in correlation with areas of caseating granulomas, which will thus be in a pattern of noncoronary distribution89 (Fig. 15.19). LGE has been associated with an increased risk of adverse cardiac events, including death, within cardiac sarcoidosis patients.90 In cases of chronic cardiac sarcoidosis, ventricular wall thinning and aneurysms

Patients with myocardial iron overload are generally asymptomatic until advanced stages where global systolic dysfunction becomes the primary pathophysiologic mechanism. Cardiac MRI findings of hemochromatosis are generally less specific than for other restrictive cardiomyopathies. Restrictive diastolic filling is typically seen when there is cardiac involvement, and it typically precedes the development of systolic dysfunction.91,92 In early stages, cardiac imaging will often demonstrate a dilated cardiomyopathy with increased LV wall thickness and LV end-diastolic volume, which will be evident on GRE sequences. The myocardium will appear dark on T2-weighted spin echo images as a result of loss of signal intensity due to iron accumulation (Fig. 15.20).

Fig. 15.19 Two-chamber (A) and midventricular short axis (B) late gadolinium enhancement images of a patient with cardiac sarcoidosis. Note the typical patchy pattern of hyperenhancement that occurs in a noncoronary distribution. Cine gradient echo (GRE) images (not shown) demonstrated reduced systolic function with regional wall motion abnormalities.

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cardiomyopathy is the primary cause of mortality in patients with FA and is usually a result of end-stage heart failure or fatal arrhythmias.96,97 FA results in HCM, often with preserved systolic function but impaired diastology.98 LV mass in FA patients has been shown to directly correlate with GAA repeat number and age of disease onset.99 Cardiac MRI may demonstrate myocardial fibrosis on LGE, although specific patterns of LGE distribution have not been established to differentiate FA from other hypertrophic cardiomyopathies.100

Glycogen Storage Disorders Glycogen storage disorders (GSDs) are a broad classification of those diseases due to some degree of impairment of the metabolism or synthesis of glycogen. Cardiac involvement is common related to pathologic glycogen accumulation within the myocardium. Characteristic findings include significant LVH and areas of late gadolinium enhancement (Fig. 15.22).

LIMITATIONS AND CONTRAINDICATIONS OF CARDIAC MRI Fig. 15.21 A 27-year-old male with Fabry disease. (A) Steady-state free precession (SSFP) imaging demonstrating diffuse increased left ventricular thickness. (B) Late gadolinium enhancement demonstrating characteristic pattern of enhancement in the lateral wall (arrows).

Fabry Disease Fabry disease is an X-linked inherited disorder that is characterized by α-galactosidase A deficiency, a lysosomal enzyme, which leads to intracellular glycosphingolipid deposition in tissues, including the myocardium. LVH is a common manifestation of Fabry disease and can be difficult to differentiate from alternative etiologies of HCM, with significant implications for treatment options. Fabry disease may result in prolonged T2 relaxation compared to those with HCM.93 Concentric thickening will be evident on black blood imaging and inferolateral basal or midmyocardial fibrosis with subendocardial sparing on LGE94 (Fig. 15.21). Finally, noncontrast T1 mapping can be significantly reduced in patients with Fabry disease when compared to both healthy controls and those with concentric hypertrophy, and this finding can be particularly useful in identifying the presence of Fabry disease.95

Friedreich Ataxia Friedreich ataxia (FA) is an autosomal recessive mitochondrial disorder caused by deoxyribonucleic acid (DNA) triplet repeats of frataxin gene, which results in deficiency of the inner mitochondrial protein frataxin, leading to mitochondrial iron accumulation. Associated

Despite the expanding indications for cardiac MRI, it is important to recognize the limitations and contraindications for this imaging. While pacemakers and defibrillators previously were absolute contraindications, MRI conditional devices are now frequently being implanted. It is important to recognize that while it is safe to perform cardiac MRI in patients with these devices, the image quality and the artifact that arises from the device generator can result in significant image degradation and can significantly limit accurate or complete cardiac evaluation by cardiac MRI. Nonferromagnetic metallic devices include mechanical heart valves and sternal wires, which are safe to image although again may produce significant image artifact. The ability for patients to follow instructions and hold their breath for 10 to 15 seconds is of critical importance to image quality. Furthermore, patients with claustrophobia may have difficulty tolerating the imaging procedure as they must reside within a small and confined space for 30 to 60 minutes. Moderate sedation can be used for patients with significant claustrophobia, but such sedation can alter the patient’s ability to follow instruction and perform adequate breath holds. Arrhythmia will limit accuracy as well due to associated difficulty gating images postprocessing and inability to assess velocity or flow quantification by phase contrast cardiac MRI. Finally, patients should be carefully screened in regard to their renal function. Due to the risk of nephrogenic sclerosing fibrosis, patients with glomerular filtration rate (GFR) less than 30 should not be given gadolinium contrast agents; a decreased gadolinium dose should be given to patients with GFR between 30 and 60. Therefore it is important to carefully review the patient’s clinical context and to determine if adequate imaging can be obtained safely.

Fig. 15.22  A 19-year-old female with Danon disease. Severe concentric left ventricular hypertrophy (LVMi = 204 gm/ m2; basal anteroseptum = 3.0 cm), with relative apical sparing. Severe late gadolinium enhancement in a midmyocardial distribution affecting distal anterior, apical and distal inferior wall segments, basal-to-distal lateral wall and inferoseptal wall segments, and the right ventricular insertion points, compatible with interstitial fibrosis.

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FUTURE DIRECTIONS There have been significant advancements in the role of cardiac MRI for the diagnosis of diastolic dysfunction over the past decades, with further techniques under development for clinical use. The field is

continually expanding, and technology is constantly advancing. Further studies are needed to determine if MR elastography, diffusion tensor imaging, and 4-D flow will demonstrate incremental improvement in diagnostic abilities that will impact clinical management.

KEY POINTS • Cardiac MRI offers excellent spatial and temporal resolution and can be used as an alternative modality to echo in the assessment of LV diastolic function. • Gradient echo sequencing allows for calculation of the peak filling rate (PFR) and time to PFR, both of which will typically be prolonged in diastolic dysfunction. • Phase contrast imaging can be used to measure transvalvular velocities and gradients. Transmitral flow and pulmonary venous

flow can be useful in the identification of patients with diastolic dysfunction. • Late gadolinium enhancement is a well-established marker of interstitial fibrosis and scarring, which plays a significant role in both systolic and diastolic dysfunctions. The pattern of myocardial LGE can be useful in identifying the underlying pathology. • The use of cardiac MRI is contraindicated in patients with internal devices or implants that are ferromagnetic.

REVIEW QUESTIONS The role of artificial intelligence for reproducible and quantitative reconstruction and advanced computation in interpretation and measurements of diastology is also an exciting prospect of this field but yet to be fully established. 1. Which of the following is an absolute contraindication for the patient in the chapter-opening case study to get a cardiac MRI? a. Coronary stents b. Permanent pacemaker c. Cochlear implant d. Mechanical heart valve

3. Intravenous gadolinium is given and the accompanying images are obtained (images showing patchy LGE). These findings are most suggestive of which diagnosis? a. Cardiac sarcoidosis

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2. The case study patient’s transmitral and pulmonary venous flow patterns are shown in Fig. 15.23. Which of the following statements is true? a. Both filling patterns are normal. b. The transmitral flow pattern is abnormal, and the pulmonary venous flow pattern is normal. c. The transmitral flow pattern is uninterpretable due to fused E and A waves, but the pulmonary venous flow pattern is abnormal suggestive of diastolic dysfunction. d. It is impossible to establish whether these patterns are normal with this information alone.

b. Cardiac amyloidosis c. Ischemic cardiomyopathy d. Hypertrophic cardiomyopathy

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Diagnosis of Heart Failure with Preserved Ejection Fraction

50. Tsang TS, Abhayaratna WP, Barnes ME, et al. Prediction of cardiovascular outcomes with left atrial size: is volume superior to area or diameter? J Am Coll Cardiol. 2006;7;47(5):1018–1023. 51. Pritchett AM, Jacobsen SJ, Mahoney DW, et al. Left atrial volume as an index of left atrial size: a population-based study. J Am Coll Cardiol. 2003;41(6):1036–1043. 52. Tops LF, van der Wall EE, Schalij MJ, et al. Multi-modality imaging to assess left atrial size, anatomy and function. Heart. 2007;93(11):1461–1470. 53. Whitlock M, Garg A, Gelow J, et al. Comparison of left and right atrial volume by echocardiography versus cardiac magnetic resonance imaging using the area-length method. Am J Cardiol. 2010;106(9):1345–1350. 54. Madueme PC, Mazur W, Hor KN, et al. Comparison of area-length method by echocardiography versus full-volume quantification by cardiac magnetic resonance imaging for the assessment of left atrial volumes in children, adolescents, and young adults. Pediatr Cardiol. 2014;35(4):645–651. 55. Hof IE, Velthuis BK, Van Driel VJ, et al. Left atrial volume and function assessment by magnetic resonance imaging. J Cardiovasc Electrophysiol. 2010;21(11):1247–1250. 56. Habibi M, Venkatesh BA, Lima JA. Feature tracking cardiac magnetic resonance imaging in the assessment of left atrial function. J Am Coll Cardiol. 2014;63(22):2434–2435. 57. Imai M, Ambale Venkatesh B, Samiei S, et al. Multi-ethnic study of atherosclerosis: association between left atrial function using tissue tracking from cine MR imaging and myocardial fibrosis. Radiology. 2014;273(3):703–713. 58. Markman TM, Habibi M, Venkatesh BA, et al. Association of left atrial structure and function and incident cardiovascular disease in patients with diabetes mellitus: results from multi-ethnic study of atherosclerosis (MESA). Eur Heart J Cardiovasc Imaging. 2017;18(10):1138–1144. 59. Lim YH, Lee JU, Kim KS, et al. Association between inappropriateness of left ventricular mass and left ventricular diastolic dysfunction: a study using the tissue Doppler parameter, e/e’. Korean Circ J. 2009;39(4):138–144. 60. de Simone G, Kitzman DW, Palmieri V, et al. Association of inappropriate left ventricular mass with systolic and diastolic dysfunction: the HyperGEN study. Am J Hypertens. 2004;17(9):828–833. 61. Patel P, Dhillon A, Popovic ZB, et al. Left ventricular outflow tract obstruction in hypertrophic cardiomyopathy patients without severe septal hypertrophy: implications of mitral valve and papillary muscle abnormalities assessed using cardiac magnetic resonance and echocardiography. Circ Cardiovasc Imaging. 2015;8(7):e003132. 62. Arrive L, Assayag P, Russ G, et al. MRI and cine MRI of asymmetric septal hypertrophic cardiomyopathy. J Comput Assist Tomogr. 1994;18(3):376–382. 63. van Dockum WG, Kuijer JP, Gotte MJ, et al. Septal ablation in hypertrophic obstructive cardiomyopathy improves systolic myocardial function in the lateral (free) wall: a follow-up study using CMR tissue tagging and 3D strain analysis. Eur Heart J. 2006;27(23):2833–2839. 64. Soler R, Rodriguez E, Monserrat L, et al. Magnetic resonance imaging of delayed enhancement in hypertrophic cardiomyopathy: relationship with left ventricular perfusion and contractile function. J Comput Assist Tomogr. 2006;30(3):412–420. 65. Moon JC, McKenna WJ, McCrohon JA, et al. Toward clinical risk assessment in hypertrophic cardiomyopathy with gadolinium cardiovascular magnetic resonance. J Am Coll Cardiol. 2003;41(9):1561–1567. 66. Choudhury L, Mahrholdt H, Wagner A, et al. Myocardial scarring in asymptomatic or mildly symptomatic patients with hypertrophic cardiomyopathy. J Am Coll Cardiol. 2002;40(12):2156–2164. 67. He D, Ye M, Zhang L, et al. Prognostic significance of late gadolinium enhancement on cardiac magnetic resonance in patients with hypertrophic cardiomyopathy. Heart Lung. 2018;47(2):122–126. 68. Villemain O, Correia M, Mousseaux E, et al. Myocardial stiffness evaluation using noninvasive shear wave imaging in healthy and hypertrophic cardiomyopathic adults. JACC Cardiovasc Imaging. 2018;00. 69. Finocchiaro G, Haddad F, Pavlovic A, et al. How does morphology impact on diastolic function in hypertrophic cardiomyopathy? A single centre experience. BMJ Open. 2014;4(6):e004814. 70. Hartiala JJ, Foster E, Fujita N, et al. Evaluation of left atrial contribution to left ventricular filling in aortic stenosis by velocity-encoded cine MRI. Am Heart J. 1994;127(3): 593–600.

71. Kaminski M, Steel K, Jerosch-Herold M, et al. Strong cardiovascular prognostic implication of quantitative left atrial contractile function assessed by cardiac magnetic resonance imaging in patients with chronic hypertension. J Cardiovasc Magn Reson. 2011;13:42. 72. Kudelka AM, Turner DA, Liebson PR, et al. Comparison of cine magnetic resonance imaging and Doppler echocardiography for evaluation of left ventricular diastolic function. Am J Cardiol. 1997;80(3):384–386. 73. Nagel E, Stuber M, Burkhard B, et al. Cardiac rotation and relaxation in patients with aortic valve stenosis. Eur Heart J. 2000;21(7):582–589. 74. Kroeker CA, Tyberg JV, Beyar R. Effects of ischemia on left ventricular apex rotation. An experimental study in anesthetized dogs. Circulation. 1995;92(12):3539–3548. 75. Garot J, Pascal O, Diebold B, et al. Alterations of systolic left ventricular twist after acute myocardial infarction. Am J Physiol Heart Circ Physiol. 2002;282(1):H357–H362. 76. Nagel E, Stuber M, Lakatos M, et al. Cardiac rotation and relaxation after anterolateral myocardial infarction. Coron Artery Dis. 2000;11(3):261–267. 77. Bogaert J, Bosmans H, Maes A, et al. Remote myocardial dysfunction after acute anterior myocardial infarction: impact of left ventricular shape on regional function: a magnetic resonance myocardial tagging study. J Am Coll Cardiol. 2000;35(6):1525–1534. 78. Maisch B, Seferovic PM, Ristic AD, et al. Guidelines on the diagnosis and management of pericardial diseases executive summary; the task force on the diagnosis and management of pericardial diseases of the European society of cardiology. Eur Heart J. 2004;25(7):587–610. 79. Soulen RL, Stark DD, Higgins CB. Magnetic resonance imaging of constrictive pericardial disease. Am J Cardiol. 1985;55(4):480–484. 80. Feng D, Glockner J, Kim K, et al. Cardiac magnetic resonance imaging pericardial late gadolinium enhancement and elevated inflammatory markers can predict the reversibility of constrictive pericarditis after antiinflammatory medical therapy: a pilot study. Circulation. 2011;124(17): 1830–1837. 81. Francone M, Dymarkowski S, Kalantzi M, et al. Assessment of ventricular coupling with real-time cine MRI and its value to differentiate constrictive pericarditis from restrictive cardiomyopathy. Eur Radiol. 2006;16(4):944–951. 82. Thavendiranathan P, Verhaert D, Walls MC, et al. Simultaneous right and left heart real-time, free-breathing CMR flow quantification identifies constrictive physiology. JACC Cardiovasc Imag. 2012;5(1):15–24. 83. Syed IS, Glockner JF, Feng D, et al. Role of cardiac magnetic resonance imaging in the detection of cardiac amyloidosis. JACC Cardiovasc Imag. 2010;3(2):155–164. 84. Maceira AM, Joshi J, Prasad SK, et al. Cardiovascular magnetic resonance in cardiac amyloidosis. Circulation. 2005;111(2):186–193. 85. Fontana M, Pica S, Reant P, et al. Prognostic value of late gadolinium enhancement cardiovascular magnetic resonance in cardiac amyloidosis. Circulation. 2015;132(16):1570–1579. 86. Martinez-Naharro A, Treibel TA, Abdel-Gadir A, et al. Magnetic resonance in transthyretin cardiac amyloidosis. J Am Coll Cardiol. 2017;70(4):466–477. 87. Iwai K, Tachibana T, Takemura T, et al. Pathological studies on sarcoidosis autopsy. I. Epidemiological features of 320 cases in Japan. Acta Pathol Jpn. 1993;43(7–8):372–376. 88. Perry A, Vuitch F. Causes of death in patients with sarcoidosis. A morphologic study of 38 autopsies with clinicopathologic correlations. Arch Pathol Lab Med. 1995;119(2):167–172. 89. Ichinose A, Otani H, Oikawa M, et al. MRI of cardiac sarcoidosis: basal and subepicardial localization of myocardial lesions and their effect on left ventricular function. AJR Am J Roentgenol. 2008;191(3):862–869. 90. Greulich S, Deluigi CC, Gloekler S, et al. CMR imaging predicts death and other adverse events in suspected cardiac sarcoidosis. JACC Cardiovasc Imag. 2013;6(4):501–511. 91. Benson LP, Olivieri N, Rose V, et al. Left ventricular function in young adults with thalassemia. Circulation. 1989;80:274. 92. Liu SJ, Collins A, Olivieri N. Is there a predictable relationship between ventricular function and myocardial iron levels in patients with hemochromatosis. Circulation. 1993;88:183. 93. Imbriaco M, Spinelli L, Cuocolo A, et al. MRI characterization of myocardial tissue in patients with Fabry’s disease. AJR Am J Roentgenol. 2007;188(3):850–853.

CHAPTER 15 

Evaluation of Diastolic Function by Cardiac Magnetic Resonance Imaging

94. Deva DP, Hanneman K, Li Q, et al. Cardiovascular magnetic resonance demonstration of the spectrum of morphological phenotypes and patterns of myocardial scarring in Anderson-Fabry disease. J Cardiovasc Magn Reson. 2016;18:14. 95. Thompson RB, Chow K, Khan A, et al. T(1) mapping with cardiovascular MRI is highly sensitive for Fabry disease independent of hypertrophy and sex. Circ Cardiovasc Imag. 2013;6(5):637–645. 96. Bourke T, Keane D. Friedreich’s ataxia: a review from a cardiology perspective. Ir J Med Sci. 2011;180(4):799–805. 97. Tsou AY, Paulsen EK, Lagedrost SJ, et al. Mortality in Friedreich ataxia. J Neurol Sci. 2011;307(1–2):46–49.

205

98. Dutka DP, Donnelly JE, Palka P, et al. Echocardiographic characterization of cardiomyopathy in Friedreich’s ataxia with tissue Doppler echocardiographically derived myocardial velocity gradients. Circulation. 2000;102(11):1276–1282. 99. Rajagopalan B, Francis JM, Cooke F, et al. Analysis of the factors influencing the cardiac phenotype in Friedreich’s ataxia. Mov Disord. 2010;25(7):846–852. 100. Mehta N, Chacko P, Jin J, et al. Serum versus imaging biomarkers in Friedreich ataxia to indicate left ventricular remodeling and outcomes. Tex Heart Inst J. 2016;43(4):305–310.

16 Evaluation of Diastolic Function by Radionuclide Techniques Aldo L. Schenone, Wael A. Jaber, and Manuel D. Cerqueira

OUTLINE Introduction, 206 Basic Principles of Radionuclide Assessment of Diastolic Function, 207 Data Acquisition and Analysis of Diastolic Function by Radionuclide Techniques, 208 Equilibrium Radionuclide Angiocardiography, 208 First-Pass Radionuclide Angiography, 210 ECG-Gated Perfusion Imaging Studies, 210 Data Analysis in the Evaluation of Diastolic Function by Radionuclides Techniques, 211 Clinical Relevance, 211 Coronary Artery Disease, 212

HFpEF and Microvascular Dysfunction, 212 Hypertrophic Cardiomyopathy, 213 Hypertension, 213 Aging, 213 Cardio-Oncology, 213 Constrictive Pericarditis and Restrictive Cardiomyopathy, 213 Limitations, 213 Future Directions, 214 Key Points, 214 Review Questions, 214 References, 214

INTRODUCTION Case Study A 73-year-old man with a history of longstanding hypertension, diabetes mellitus, paroxysmal atrial fibrillation, and coronary artery disease (CAD) presents with progressive shortness of breath and exertional fatigue. Physical examination is notable for prominent apical impulse and a blood pressure of 140/90 mmHg. A transthoracic echocardiogram reported normal systolic function and concentric hypertrophy without significant valvular disease or regional wall motion abnormalities. An ischemic workup performed with a single-photon emission computed tomography (SPECT) stress test revealed ejection fractions of 0.67 at rest and 0.68 at stress without perfusion defects. However, the resting time-activity curve (TAC) showed a profoundly abnormal filling pattern (Fig. 16.1A), with a peak filling rate of 1.67 end-diastolic volume per second (EDV/sec) and a delayed time to maximal rate of 305 msec. Upon comparison to a SPECT perfusion study 1 year prior (see Fig. 16.1B), there is evidence of interval development of diastolic dysfunction with shifting of the diastolic curve to the left from a normal diastolic curve despite preserved systolic function. Based on age and presence of concentric hypertrophy with interval development of diastolic dysfunction in the absence of ischemia on a radionuclide myocardial perfusion study, amyloid was considered in the differential diagnosis. A technetium (99mTc) pyrophosphate scan was performed with results consistent with transthyretin (TTR) cardiac amyloidosis (see Fig. 16.1C). Although the evaluation of diastolic function during perfusion studies is seldom conducted in clinical practice, this case illustrates the potential incremental benefit of such evaluation in selected patients undergoing ischemic evaluation with myocardial perfusion studies.

206

The use of radioactive tracers in nuclear cardiology has been instrumental in the evaluation of patients with known or suspected cardiac disease. The majority of applications have been in the assessment of myocardial perfusion. These tracers can also be used to assess systolic and diastolic ventricular function in the following ways: injected as a bolus and tracked during first pass through the vascular system, attached to red blood cells and measured once in equilibrium within the vascular space, or as myocardial perfusion tracers that define the endocardial borders of the left ventricle.1 Historically equilibrium radionuclide angiocardiography (ERNA) and first-pass radionuclide angiography (FPRNA) were commonly used techniques for the evaluation of systolic and diastolic function both at rest and following exercise. The advantages of these modalities included absolute quantitation, high accuracy and reproducibility, and measurements based on true three-dimensional (3-D) measurements that were free of geometric assumptions. However, these techniques were time consuming, technically challenging, and not practical in most clinical settings. Optimal performance was achieved using singleheaded, small field-of-view gamma cameras that are not currently widely available. The use of dual-headed, large field-of-view systems does not allow optimal, consistent isolation of the left ventricle. Thus they fell in disfavor and were overshadowed by the practicality and lack of radiation exposure of echocardiography in spite of an increase in interobserver variability and lower accuracy.2 Many of the concepts and methods developed for diastolic function analysis with ERNA and FPRNA may be adjunctively applied to electrocardiogram (ECG)–gated radionuclide myocardial perfusion ­

CHAPTER 16 

Evaluation of Diastolic Function by Radionuclide Techniques

207

Fig. 16.1  (A) Resting time-activity curve (TAC) obtained on single-photon emission computed tomography (SPECT) perfusion study revealing a marked ­reduction in the peak filling rate (PFR) of 1.67 end-diastolic volume (EDV)/sec with a delayed time to maximal rate (TPFR) of 305 msec. (B) Resting TAC from a previous SPECT perfusion study 1 year prior exhibiting normal diastolic filling parameter with PFR of 2.98 EDV/sec and TPFR of 139 msec. (C) Technetium (99mTc) pyrophosphate scan ­revealing a cardiac silhouette with an elevated tracer retention exhibiting heart to contralateral chest (H/CL) ratio above 1.5 consistent with the diagnosis of transthyretin (TTR) cardiac amyloidosis.

imaging studies performed with SPECT or positron emission tomography (PET) tracers in the current era.3,4 These may provide incremental and useful clinical data to the assessment of perfusion and systolic function. In some circumstances, diastolic dysfunction may even identify preclinical abnormalities in the absence of alterations of systolic function.5–7 This chapter will describe the concepts and methods of ERNA, FPRNA, and ECG-gated perfusion imaging to obtain diastolic information. It will also describe clinically useful diastolic findings obtained with these techniques resulting from abnormalities of the myocardium and ischemia.

four distinct phases: isovolumic relaxation, early diastolic filling, diastasis, and atrial systole.7 Isovolumic relaxation starts at end systole, is an energy-dependent process, and has a short duration (usually 2.5 end-diastolic volume/sec) 2. Time to peak filling rate (TPFR) (69% during rapid filling) 4. A/E ratio 400 beats are acquired) is summed so that the final TAC is an average rather than information from a single beat or a small number of beats, as is provided by other modalities. For this reason, this technique may be more representative of overall function than are other methods due to the large number of beats averaged.12,13

BOX 16.2  Equilibrium Radionuclide Angiocardiography (ERNA): Methods of Acquisition for Diastolic Function Analysis

Fig. 16.3 Schematic of normal and abnormal diastolic function timeactivity curves. The blue line shows that PFR has a flatter slope and is shifted to the right, indicating a delay in filling in comparison with the normal curve. ED, End diastole; EDV, end-diastolic volume; ES, end systole; IR, isovolumic relaxation; PER, peak ejection rate; PFR, peak filling rate.

1. 20–30 millicuries 99mTc labeled red blood cells 2. Labeling methods a. In vivo: fastest and least expensive but lowest binding efficiency b. Modified in vivo/in vitro: compromise with good labeling efficiency c. In vitro: longest time and expense but best labeling efficiency 3. Planar or single photon emission computed tomography (SPECT) 4. Positioning: best septal separation, left anterior oblique (LAO) 5. Arrhythmia rejection: ±10% of mean R-R interval and drop postpremature beat 6. Temporal resolution:  or = 40% treated with diuretics plus. Am J Cardiol. 1997;80(2):207–209. 89. Zi M, Carmichael N, Lye M. The effect of quinapril on functional status of elderly patients with diastolic heart failure. Cardiovasc drugs Ther. 2003;17(2):133–139.

90. Solomon SD, Anavekar N, Skali H, et al. Influence of ejection fraction on cardiovascular outcomes in a broad spectrum of heart failure patients. Circulation. 2005;112(24):3738–3744. 91. Mentz RJ, Bakris GL, Waeber B, et al. The past, present and future of renin-angiotensin aldosterone system inhibition. Int J Cardiol. 2013;167(5):1677–1687. 92. Redfield MM, Anstrom KJ, Levine JA, et al. Isosorbide mononitrate in heart failure with preserved ejection f­ raction. N Engl J Med. 2015;373(24):2314–2324. 93. Redfield MM, Chen HH, Borlaug BA, et al. Effect of phosphodiesterase-5 inhibition on exercise capacity and clinical status in heart failure with preserved ejection fraction: a r­ andomized clinical trial. JAMA. 2013;309(12):1268–1277. 94. McMurray JJV, Packer M, Desai AS, et al. Angiotensin–neprilysin inhibition versus enalapril in heart failure. N Engl J Med. 2014;371(11): 993–1004. https://doi.org/10.1056/NEJMoa1409077. 95. Solomon SD, McMurray JJV, Anand IS, et al. Angiotensin-Neprilysin Inhibition in Heart Failure with Preserved Ejection Fraction. N Engl J Med. 2019;381(17):1609–1620. doi:10.1056/NEJMoa1908655.

35 Echo-Based Approach to the Management of Heart Failure With Preserved Ejection Fraction Partho Sengupta and Christopher Michael Bianco

OUTLINE Introduction, 473 Pathophysiology, 476 Cellular Dysfunction, 476 Systolic LV Dysfunction, 476 LA Dysfunction, 476 Pulmonary Hypertension and Right Heart Dysfunction, 477 Exercise Limitations, 477 Endothelial Dysfunction, 478 Multisystem Dysfunction, 478

Case Study A 76-year-old female with a history of heart failure with preserved ejection fraction (HFpEF), type 2 diabetes mellitus, obesity, hypertension, and chronic back pain is referred to you from her primary care provider. She was diagnosed with HFpEF approximately 2 years ago and has been hospitalized once in the past year for a presumed HF exacerbation. She reports progressively worse dyspnea on exertion and intermittent lower extremity edema. She denies chest pain, palpitations, or syncope. On physical examination she is afebrile, her pulse is regular at 86 bpm, blood pressure (BP) 158/76 mmHg, respiration rate (RR) 16, and O2 saturation 97%. Her cardiac examination is significant for jugular venous pressure (JVP) of 14 cm H2O, regular rate and rhythm without murmur but with an S4 gallop. Faint rales are heard at both lung bases. Her abdomen is nontender and obese. She has +2 lower extremity pulses and is normothermic; however, she has +1 lower extremity edema bilaterally. Laboratory tests: Na 134 mg/dL, K 3.7 mg/dL, Cl 103 mg/dL, HCO3 24 mg/dL, BUN 19 mg/dL, SCR 0.8 mg/dL, BNP 199 pg/mL, HbA1c 8.4%. Her medications include amlodipine 5 mg once daily, hydrochlorothiazide 12.5 mg once daily, pravastatin 20 mg once daily, metformin 500 mg twice daily, sitagliptin 25 mg once daily, meloxicam 15 mg twice daily as needed, and potassium chloride 20 mEq twice daily. Select echocardiogram images are shown (Video 35.1; Figs. 35.1, 35.2, 35.3, 35.4). Left ventricular (LV) EF by modified biplane Simpson rule method was 58%, and no regional wall motion abnormalities or hemodynamically significant valvular disease were appreciated.

INTRODUCTION Heart failure is a clinical syndrome resulting from structural and functional impairment of ventricular filling or ejection of blood. Patients with HF can be divided into those with reduced ejection fraction (HFrEF) or preserved ejection fraction (HFpEF), and recent literature has also defined an intermediate category of midrange ejection fraction

Clinical Relevance, 478 Stage A: At Risk, 478 Stage B: Preclinical Structural Disease, 478 Stages C and D: Heart Failure Syndrome, 479 Future Directions, 485 Summary, 485 Key Points, 485 Review Questions, 485 References, 485

(HFmrEF).1 Diastolic dysfunction is a central derangement found within all HF patients, regardless of EF. Furthermore, although EF may be preserved, subtle systolic dysfunction is often present in HFpEF as evidenced by deformation imaging.2 In addition to impairment in LV diastolic properties, those with HFpEF may suffer from a multitude of associated conditions, including right heart dysfunction, pulmonary hypertension (PH), ventricular-arterial uncoupling, left atrial (LA) dysfunction, chronotropic incompetence, atrial tachyarrhythmias, and maladaptive peripheral vascular and skeletal abnormalities. Complementary to the diastolic LV assessment, evaluation of several of these associated conditions makes echocardiography an essential tool in the management of HFpEF. Heart failure is not a specific disease entity, instead it is a clinical syndrome that develops as a result of several potentially different forms of underlying cardiovascular (CV) disease. Risk factor acquisition and the subsequent response to risk mitigation strategies, combined with intrinsic individual factors, determine whether structural cardiac abnormalities will develop. Antecedent structural changes lead to the eventual development of symptoms and thus the clinical HF syndrome. With this in mind, the American College of Cardiology/ American Heart Association (ACC/AHA) have developed a HF staging system (Table 35.1). Interventions are aimed at modifying risk factors (stage A), treating structural heart changes (stage B), and reducing morbidity and mortality (stages C and D). Although this conceptual framework has been largely adopted in the HFrEF realm, uptake of this concept into the management and study of HFpEF has been lacking despite widespread agreement that comorbid disease management is imperative in HFpEF treatment. Contrary to common perception, mean survival for patients suffering from HFpEF is similar to those with HFrEF.3 Mode of death in both HFpEF and HFrEF is most commonly related to CV causes, although non-CV causes of death likely represent a more sizable contributor in HFpEF than in HFrEF.4 Comorbid disease states likely

473

474

PART V 

Treatment of HFpEF

Fig. 35.1  Case study: Pulsed-Wave Doppler LV Filling Pattern. Falk RH, Alexander KM, Liao R, Dorbala S. Al (light-chain) cardiac amyloidosis: A review of diagnosis and therapy. J Am Coll Cardiol. 2016;68:1323-1341.

Fig. 35.2 Case study: Lateral Mitral Annulus Tissue Doppler Imaging (TDI). From DOI: 10.1161/ CIR.0000000000000509, ACC/AHA 2017 updated heart failure guidelines.

contribute to both the development and progression of diastolic dysfunction, as well as predict recurrent hospitalizations and clinical deterioration.5 Several echo-derived variables have been associated with increased risk of morbidity and mortality in HFpEF6-9 (Box 35.1). Worsening of diastolic function on serial echocardiographic studies over time is an independent predictor of increased mortality.10

Optimal management strategies for HFpEF remain to be defined. Several large-scale phase III therapeutic clinical trials in HFpEF have been conducted, and all failed to meet their primary end point.11-16 Lack of clear, beneficial evidence-based therapy of HFpEF represents one of the largest unmet needs in CV disease management. Several potential explanations for these neutral results exist, including

CHAPTER 35 

Echo-Based Approach to the Management of Heart Failure

475

Fig. 35.3  Case study: Medial Mitral Annulus Tissue Doppler Imaging (TDI)

Fig. 35.4  Case study: Medial Mitral Annulus Tissue Doppler Imaging (TDI)

BOX 35.1  Prognostic Echocardiographic Features in HFpEF • • • • • •

Reduced LV GLS Restrictive mitral inflow pattern Elevated E/e′ LV hypertrophy LA enlargement Reduced LA strain

• • • • • •

Abnormal pulmonary vein S/D ratio Reduced TAPSE Reduced FAC Reduced RV free wall strain Reduced TAPSE/RVSP ratio Elevated TR peak velocity

Abbreviations: LV, left ventricle; GLS, global longitudinal strain; E/e′, early mitral inflow velocity to mitral annular early diastolic velocity ratio; LA, left atrium; S/D, systole to diastole ratio; TAPSE, Tricuspid annular plane systolic excursion; FAC, fractional area change; RV, right ventricle; RVSP, right ventricular systolic pressure; TR, tricuspid regurgitation.

476

PART V 

Treatment of HFpEF

TABLE 35.1  Progression of HFpEF Through the ACC/AHA Stages Stage A

Stage B

Stages C and D

Pathologic Description

Risk factors (e.g., HTN, DM, Obesity)

DD Without Clinical HF (Preclinical DD)

Clinical Syndrome of HFpEF

Diastolic dysfunction Deposition (collagen, fibrosis) LV dimensions LA dimensions RH dysfunction LV GLS LV GCS LV GRS LA GLS Primary treatment goal(s)

n ↑ n n n n/↓ n n n/↓ Risk factor modification

↑ ↑ n/↓ n/↑ n/↑ n/↓ n/↑ n/↓ n/↓ Comorbid disease management Treating structural heart disease

↑ ↑↑ n/↓ ↑ n/↑ ↓ ↑ ↓ ↓ Reduce filling pressures Phenotype-specific therapy

n/↑/↓, relates to course/characteristic found in most patients; AHA, American Heart Association; ACC, American College of Cardiology; DD, diastolic dysfunction; DM, diabetes mellitus; GLS, global longitudinal strain; GCS, global circumferential strain; GRS, global radial strain; HFpEF, heart failure with preserved ejection fraction; HTN, hypertension; LA, left atrial; LV, left ventricular; RH, right heart.

inconsistent inclusion criteria with respect to the presence and severity of diastolic dysfunction by echocardiography, differing EF and ­circulating natriuretic peptide cutoff values, high representation of confounding comorbid conditions, and an overall heterogeneity of structural abnormalities within study populations.17 The latter recognition of heterogeneity within HFpEF pathogenesis and characterization has led to the concept of phenotyping of distinct HFpEF subtypes.18,19 Although convincing clinical outcomes data are lacking, echocardiographic-derived diastolic function following specific treatment strategies may inform the provider of structural and functional response to therapy.10,20,21 The echocardiographic-based approach to management of HFpEF can broadly be divided into the study of highly load-dependent variables related to real-time volume and pressure status versus relatively load-independent variables related to chronic structural remodeling. Furthermore, LA function, PH, right heart function, and ventricular-arterial coupling can readily be assessed with echocardiography; all are of great importance in HFpEF management.

PATHOPHYSIOLOGY The field’s understanding of HFpEF pathophysiology has exploded in recent years. Once viewed purely as a LV disease of impaired relaxation and increased elastic stiffness, we now know that a multitude of factors influence this condition. Broadly, the pathophysiology of HFpEF can be divided into central and peripheral mechanisms, several of which are readily assessed with echocardiography. Central mechanisms include impaired LV relaxation and progressive stiffness, subclinical LV systolic dysfunction, LA dysfunction, PH, right heart failure, atrial tachyarrhythmias, chronotropic incompetence, atrial dysfunction, coronary microvascular rarefaction, and endothelial dysfunction. Peripheral mechanisms include systemic hypertension, arterial endothelial dysfunction, renal insufficiency, and poor peripheral oxygen extraction by skeletal muscle. Emerging data support systemic inflammation as a principal driver of multiorgan dysfunction that leads to cardiac remodeling and arterial stiffening.

Cellular Dysfunction LV cardiac myocytes from HFpEF patients are more calcium sensitive, the sarcomere protein titin undergoes hypophosphorylation and an isoform shift that leads to increased cell stiffness,22 and maladaptive tinin-actin23 and actomycin24 interactions develop. Although myocardial

fibrosis was previously thought to be a major pathologic mechanism, both in vivo endomyocardial biopsy22 and an autopsy study25 have failed to show impressive fibrosis or collagen volume fraction. However, varying degrees of interstitial fibrosis may be seen, and more extensive hypertrophy and myofibrillar density are common.22 Emerging echocardiographic techniques, including interactive backscatter analysis, can be used to estimate the degree of myocardial fibrosis but currently is largely restricted to the research arena.

Systolic LV Dysfunction Ultrastructural changes also lead to concomitant systolic dysfunction in the presence of normal EF. Necessary restoring forces for normal diastolic function are created during systole and may be impaired with even subtle systolic dysfunction. Depressed global longitudinal strain (GLS) is an early marker of systolic dysfunction and is often present in HFpEF. Although GLS may be depressed, global circumferential strain (GCS) and LV twist remain unchanged or even increase, allowing a preserved LV EF.26 Although LV twist remains preserved, the onset of LV untwist onset is delayed in those with diastolic dysfunction, which compromises the suction function in early diastole.27 Furthermore, even normal resting LV untwist may become markedly compromised with exercise.28 A reduced GLS in HFpEF is independently associated with reduced peak O2 uptake and exercise capacity.29 Therefore subclinical systolic dysfunction also plays a role in exertional symptoms in HFpEF.

LA Dysfunction Abnormal diastolic suction function in HFpEF leads to impaired transmitral diastolic flow patterns apparent in traditional indices such as transmitral Doppler profile, as well as more sophisticated methods, including particle imaging velocimetry and vortex formation analysis.30 Progressive LV diastolic dysfunction leads to impaired LA emptying resulting in LA dysfunction. Chronic LA dysfunction manifests with LA enlargement, thus LA size may be viewed as a potential biomarker of the severity and chronicity of diastolic dysfunction.31 LA function has been divided into three phases: reservoir, conduit, and active contraction.32 During reservoir phase the left atrium stores pulmonary venous return during LV contraction and isovolumetric relaxation. With mitral valve opening, the left atrium acts as a conduit transferring blood passively into the left ventricle. Finally, the left atrium actively contracts contributing to late LV filling. Three-dimensional (3-D) echocardiography allows quantification of LV filling volume resulting from each atrial

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Echo-Based Approach to the Management of Heart Failure

477

Fig. 35.5  Left Atrial Myocardial Mechanics. Figure Abbreviations: AVO, Aortic valve opening; D, diastasis, ECG, electrocardiogram; EF, early filling; ER, early reservoir; ε, strain; LASV, LA stroke volume; LR, late reservoir; Max, maximum; Min, minimum; MVC, mitral valve closure. MVO, mitral valve opening; SR, strain rate; SR ear neg peak, SR early negative peak; SR late neg peak, SR late negative peak; SR pos peak, SR positive peak.

phase, and deformation imaging allows further physiologic assessment of LA function (Fig. 35.5). The degree of decrement in peak LA strain measured during reservoir function has been associated with increasing degrees of diastolic dysfunction.33 Depressed LA contractile function is associated with increased LV filling pressures,34,35 and LA contraction contributes progressively less to LV filling volume with worsening grades of diastolic dysfunction.36 Impaired LA strain response to exercise is associated with right ventricular (RV)–pulmonary artery (PA) uncoupling and exercise ventilation inefficiency.37 Chronic LA hypertension and dysfunction lead to elevated pulmonary capillary wedge pressure (PCWP) and PH.

Pulmonary Hypertension and Right Heart Dysfunction At least two-thirds of HFpEF patients will exhibit evidence of resting pulmonary hypertension (PH-HFpEF),38,39 and pulmonary pressures may increase substantially with exercise, forming the basis of diastolic stress testing. A significant minority (12%) of PH-HFpEF patients will also develop a component of pulmonary vascular remodeling from long-standing pulmonary venous hypertension leading to combined precapillary and postcapillary PH.40 PH-induced RV afterload, reflected by increased end-systolic elastance, eventually leads to RV dysfunction and RV-PA uncoupling. A reduced ratio (41 mm) is present in almost a third of cases.39 RV hypertrophy may be present in up to 45% of patients with PH-HFpEF.43 Pulmonary hypertension and right heart dysfunction may represent important treatment targets that are readily assessed with echocardiography.

Exercise Limitations Chronotropic incompetence is common in HFpEF. During exercise, HFpEF patients display lower peak oxygen uptake (VO2) coupled with blunted increases in heart rate, stroke volume, and EF, often coupled with a hypertensive exercise response.44,45 A stronger relationship exists between exercise capacity and diastolic function than EF.46,47 Abnormal global longitudinal LA and LV stain have both been associated with exercise intolerance.29,37 Compounding central factors, skeletal muscle structural and biochemical changes ensue favoring decreased peripheral O2 extraction, further limiting exercise tolerance.48

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Endothelial Dysfunction Increased arterial stiffness is common in HFpEF. Endothelial dysfunction related to a decrease in NO bioavailability is present in both the peripheral vasculature and the coronary microvasculature. Coronary microvasculature endothelial dysfunction and rarefaction lead to downstream effects, including myocyte hypertrophy and stiffening, as well as promoting inflammatory cell migration into the interstitial space.49 Peripheral arterial endothelial dysfunction leads to decreased compliance and an abnormal vasodilator response to exercise.45 Increased arterial stiffness leads to dramatic changes in BP with relatively small volume changes. Furthermore, reduced central aortic compliance contributes to LV-aortic uncoupling in HFpEF.50 Carotid to femoral pulse wave ­velocity (PWV), a measure of aortic stiffness,51 and pathologic wave reflection, a measure of late systolic wall stress,52 are emerging Doppler echocardiography tools used to evaluate arterial stiffness in HFpEF.

Multisystem Dysfunction Beyond direct central and peripheral CV system changes, an emerging model of HFpEF involves systemic inflammation as a principal disease driver. In this model, systemic inflammation leads to multiorgan dysfunction, including the lungs, kidneys, skeletal muscle, and hematologic system. Extramyocardial organ dysfunction drives cardiac remodeling and arterial stiffening, leading to diastolic dysfunction. This appreciation of the complex pathogenesis combined with vast heterogeneity of remodeling patterns, stages of presentation, and comorbid conditions has led to the recognition of distinct HFpEF phenotypes originally identified by data-driven analytic strategies.18 The phenogroup suffering from PH and right heart failure dysfunction is of particular interest as treatment response can be readily monitoring using serial echocardiographic indices of right heart function and RV-PA interactions. From a clinical perspective, phenotype-specific optimization of myocardial factors (CAD, atrial arrhythmias, chronotropic incompetence) and extramyocardial factors (renal insufficiency, pulmonary dysfunction, hypertension, metabolic disease, anemia, and skeletal muscle deterioration) are important treatment targets. Downstream treatment response can be monitored echocardiographically with assessment of preload-dependent indices reflecting real-time pressure-volume (P-V) relationships and with relatively load-independent variables reflecting longer standing remodeling responses, as well as indices reflecting LA dysfunction and right heart disease.

CLINICAL RELEVANCE Stage A: At Risk Our evolving knowledge of HFpEF implicates extracardiac comorbidities such as hypertension, renal insufficiency, obesity, and metabolic syndrome as central drivers of systemic inflammation and endothelial dysfunction, leading to LV remodeling and diastolic dysfunction. Therefore measures to prevent and adequately treat these implicated comorbidities may ultimately reduce the incidence of HFpEF. LV hypertrophy secondary to hypertension is a known risk factor for the development of diastolic dysfunction and HF.53 Antihypertensive therapy with angiotensin-converting enzyme (ACE) inhibitors more effectively prevents the development of LV hypertrophy than non-ACE inhibitor–based therapy in diabetic patients with hypertension.54 Diuretic therapy may also play a protective role in prevention of symptomatic HF. In a secondary analysis of the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALL-HAT) study, diuretic therapy with chlorthalidone was associated with a decreased incidence of HF compared to lisinopril, amlodipine, or doxazosin.55 Although these data suggest the potential merit of

particular agents, overall BP control is likely the most important factor in preventing the development of LV hypertrophy and progression to structural remodeling.56 Renal insufficiency may contribute to worsening hypertension through volume expansion and promote diastolic dysfunction through several mechanisms, including accumulation of advanced glycation end products, uremic toxins, and systemic inflammation. Even mild chronic kidney disease (CKD), particularly when associated with albuminuria, is associated with endothelial dysfunction and changes in bone mineral handling that have been associated with the development of ventricular hypertrophy and fibrosis.57 Although CKD, hypertension, and subsequent LV hypertrophy play important roles in the development of HF, diastolic dysfunction may actually precede the development of LV hypertrophy in some circumstances.58 Extracellular matrix changes preceding gross hypertrophy and increased wall thickness may lead to increased ventricular stiffness.59 Therefore risk factor modifications beyond hypertension therapy and prevention of LV hypertrophy play an important role in preventing diastolic dysfunction. Metabolic disease, across the diabetic continuum of insulin resistance to frank diabetes mellitus, is strongly associated with the development of adverse remodeling and associated diastolic dysfunction. In most cases, changes in diastolic function are already present before the onset of diabetes and largely associated with the state of insulin resistance.60 A strong association exists between obesity and the development of diastolic dysfunction.61 Obesity leads to mitochondrial dysfunction, hyperinsulinemia with subsequent insulin resistance, and systemic inflammation in keeping with the extramyocardial hypothesis of inflammation driving HFpEF pathogenesis. Also obesity independently increases the risk for incident LV hypertrophy in hypertensive patients.56 In those with established structural changes (stage B), weight loss leads to improved diastolic indices.62 Although data for prevention of diastolic dysfunction are lacking, risk factor modification directed at comorbid conditions in known association with the development of diastolic dysfunction may prove efficacious.

Stage B: Preclinical Structural Disease Approximately one-fourth of the adult US population have evidence of stage B, preclinical diastolic dysfunction.63 Prevalence increases with older age and common cardiovascular comorbidities. Furthermore, even mild, asymptomatic diastolic dysfunction is associated with increased mortality.64 Not surprising, persistent or worsening Doppler pattern of diastolic dysfunction on serial examinations in asymptomatic, stage B individuals increases the likelihood of progression to symptomatic, stage C disease.65 Increasing age, along with the presence of comorbid hypertension, peripheral arterial disease, diabetes, or coronary disease also increases the likelihood of progression from preclinical diastolic dysfunction to symptomatic disease. Therefore treatment strategies addressing these highly prevalent comorbid conditions would seem prudent in preventing the development of clinical HF. Hypertension is one of the strongest risk factors for progression from preclinical disease to clinical HF (stage C).53 Regression of LV hypertrophy can be expected in hypertensive patients once adequate BP control is instituted. Although hypertension treatment with angiotensin receptor blockers (ARBs) has generally shown the highest rates of LV hypertrophy regression,66,67 no particular antihypertensive agent has emerged superior for improvement of diastolic indices.68,69 Diastolic dysfunction worsens across the diabetic continuum, predominantly related to increasing degrees of insulin resistance.60 E′ velocity tends to fall and E/e′ progressively rises as patients evolve from prediabetes to frank diabetes mellitus. In diabetic patients with preclinical diastolic dysfunction, elevated E/e′ ratio is associated with the subsequent development of HFpEF as well as increased mortality

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Fig. 35.6  Diastolic stress testing. Abb: RWMA, regional wall motion abnormalities; LVOTO, left ventricular outflow tract obstruction; MR, mitral regurgitation; SV, stroke volume; CO, cardiac output; SPAP, systolic pulmonary arterial pressure; PH, pulmonary hypertension; TR, tricuspid regurgitation.

independent of hypertension, coronary disease, or other echocardiographic parameters.70 Coronary artery disease (CAD) is present in approximately half of patients with HFpEF.71 Diastolic dysfunction, particularly associated with region wall motion abnormalities, should prompt consideration of underlying CAD. Revascularization of obstructive epicardial coronary disease is associated with improvements in diastolic indices.72 LA size has been described as a biomarker of CV disease and predicts CV risk.31 Progression into symptomatic disease is largely mediated by either resting or effort-induced PH, which implies LA hypertension and dysfunction. Increased LA size is a late manifestation of long-standing LA dysfunction. Furthermore, LA size associated with diastolic dysfunction may be underestimated using standard twodimensional (2-D) imaging, or LA compliance may be decreased despite a relatively normal LA size despite the presence of diastolic dysfunction. Modern echocardiographic techniques, including LA deformation imaging, provide further information regarding LA function. Impaired LA reservoir and conduit function are strongly associated with diastolic dysfunction in preclinical (stage B) disease.73 Importantly, these parameters showed higher diagnostic accuracy in detecting early diastolic dysfunction compared with LA volume index and may serve as a more sensitive marker of diastolic dysfunction than frank LA enlargement.

Stages C and D: Heart Failure Syndrome

diastolic dysfunction, does not necessarily imply a diagnosis of HFpEF. Several diagnostic algorithms are available, the H2FPEF score incorporates both clinical (age >60, obesity, requiring two or more antihypertensive medications) and echocardiographic parameters (RVSP >35 mmHg, E/e′ >9), reflecting the need for an integrative approach to diagnosis.74 Conversely, some patients may have suggestive HF signs and symptoms, yet resting diastolic indices may seem out of proportion to symptoms. Diastolic stress testing may be of value in patients with borderline resting diastolic indices in which the diagnosis of HFpEF is being ­entertained (Fig. 35.6). Normal individuals are able to increase stroke ­volume without significantly increasing filling pressures due to concomitant augmentation of myocardial relaxation and diastolic suction. Increased diastolic suction and relaxation lead to a proportional increase in both the mitral early diastolic E velocity and annular velocity (e′) resulting in a preserved E/e′ relationship in those with a normal exercise response. Exercise-induced elevations in the E/e′ relationship associated with increased tricuspid regurgitation (TR) velocity suggest an abnormal diastolic response. The diastolic stress test (See Chapter 18) is considered definitely abnormal when the following three conditions are met: (1) average E/e′ greater than 14 or septal E/e′ ratio greater than 15 with exercise, (2) peak TR velocity greater than 2.8 m/sec with exercise and (3) septal e′ velocity less than 7 cm/sec if only lateral velocity is acquired, and lateral e′ less than 10 cm/sec at baseline.75

Diagnosis

Differential Diagnosis

The diagnosis of HFpEF may be challenging. At least one-fourth of the US adult population has echocardiographic evidence of diastolic dysfunction, and several etiologies for breathlessness and hypervolemia exist. The presence of nonspecific clinical signs and symptoms, as well as

HFpEF is highly prevalent and associated with significant morbidity and mortality. That said, the clinical diagnosis is challenging, and several other conditions may mimic HFpEF. Echocardiography is a powerful tool in differentiating several states that may present clinically similar. A

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Fig. 35.7 Pulmonary arterial hypertension (PAH) vs pulmonary venous hypertension (PVH).

diagnosis of pulmonary arterial hypertension (PAH) is certainly of concern, particularly when the overall degree of pulmonary hypertension and RV dysfunction appears out of proportion to the degree of left heart diastolic dysfunction. Helpful indices more suggestive of PAH include notching of the right ventricular outflow tract (RVOT) pulsed-wave Doppler profile, a peak TR velocity/RVOT velocity-time integral ratio greater than 0.18, an increased RA-to-LA size ratio, and interatrial or interventricular septal bowing toward the left-sided structures76 (Fig. 35.7). Pericardial constriction should be considered in every patient before making a diagnosis of HFpEF (Fig. 35.8). Useful echocardiographic indices suggestive of constriction include respiration-related ventricular septal shift and variation in mitral and tricuspid inflow E velocity, increased medial mitral annular e′ velocity, annulus reversus, and hepatic vein expiratory diastolic reversal ratio.77 Constriction is associated with constraint primarily of the subepicardial layer, leading to decreased circumferential motion evident by decreased circumferential strain, torsion, and untwisting velocity, while subendocardial longitudinal function is relatively preserved. On the other hand, HFpEF and restrictive cardiomyopathy are associated with reduced longitudinal ­ function, while LV rotational motion is spared.78 Potential hypertrophic cardiomyopathy or restrictive cardiomyopathy, including cardiac amyloidosis, should always be considered prior to making a diagnosis of HFpEF. The echocardiographic and clinical characteristics used in the recognition of these different forms of cardiomyopathy are outside the scope of this chapter; however, one must always consider these forms of cardiomyopathy when assessing for potential HFpEF. Furthermore, disorders such as advanced liver disease, kidney disease, and hypothyroidism may lead to fluid retention, increased filling pressures, and breathlessness and may be initially mistaken for HFpEF or may play a synergistic role in progression from preclinical disease to frank HF.

Fig. 35.8  Constrictive pericarditis (CP) vs restrictive cardiomyopathy (RCM). Diagnostic Algorithm (from reference 75)

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Fig. 35.9  LA strain by diastolic dysfunction (DD) grade. From: Singh et al (ref 33)

Emerging Diagnostic Parameters The complex interrelated myocardial mechanics of systole and diastole in HFpEF can be further appreciated using deformation imaging. Subendocardial dysfunction leading to depressed GLS is often present. GCS and LV twist remain unchanged or may even increase in a compensatory nature allowing for a preserved LV EF.26 However, LV untwist in early diastole is delayed, likely leading to impaired suction function for transmitral filling. With exercise both global longitudinal function and LV untwist may become markedly impaired, which likely further explains exercise intolerance and exercise-induced pulmonary congestion appreciated in the HFpEF population. In the TOPCAT trial, a reduction in GLS was the strongest echocardiographic predictor of CV death or HF.9 Reduced GLS in HFpEF is independently associated with reduced peak O2 uptake and reduced exercise capacity.29 The traditional assessment of diastolic dysfunction has been dominated by the examination of LV relaxation and stiffness properties. Although LA enlargement has long been recognized as a marker of cardiovascular risk and diastolic dysfunction, the assessment of LA function has undergone a renaissance in recent years with currently available imaging techniques. Speckle tracking of the LA walls allows for a physiologic assessment of LA reservoir, conduit, and contractile function. The degree of reduction in peak longitudinal LA strain has been associated with increasing degrees of diastolic dysfunction (Fig. 35.9).33 Furthermore, depressed peak longitudinal strain, as well as LA contractile function, is associated with increased PCWP and may outperform E/e′ ratio in accuracy of estimating LV filling pressures.34,35 The volumetric contribution of each atrial phase to LV filling can be

assessed using 3-D echocardiography. The proportion of LV filling volume during the conduit phase becomes significantly higher with worsening diastolic dysfunction grade. As diastolic dysfunction progresses, conduit phase filling volume increases while filling volume secondary to LA contraction falls.36 LA contraction volume more strongly correlates with E/e′ than other measures of LA volume.79

Echocardiographic-Based Treatment Despite our evolving knowledge of the pathogenesis leading to and perpetuating the HFpEF syndrome, optimal treatment strategies remain to be defined (Table 35.2). Although convincing clinical outcomes data are lacking, echocardiographic-derived parameters (Box 35.2)

BOX 35.2  Potential EchocardiographicBased Treatment Goals • • • • • • •

Improvement in mitral inflow pattern Reduction in TR velocity Reduction in E/e′ ratio Improvement in e′ Reduction in LA size Reduction in RV dimensions Improvement in IVC size and collapsibility

Abbreviations: TR, tricuspid regurgitation; E/e′, ratio of early mitral inflow velocity to mitral annular early diastolic velocity; e′, mitral annular early diastolic velocity; LA, left atrium; RV, right ventricle; IVC, inferior vena cava.

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TABLE 35.2  ACC/AHA Recommendations for the Pharmacologic Treatment of HFpEF COR

LOE

Recommendation

I I IIa

B C C

IIb

B-R

IIb III: No benefit III: No benefit

B B-R C

Systolic and diastolic blood pressure should be controlled in patients with HFpEF in accordance with published clinical practice guidelines. Diuretics should be used for relief of symptoms due to volume overload in patients with HFpEF. The use of beta-blocking agents, ACE inhibitors, and ARBs is patients with HTN is reasonable to control blood pressure in patients with HFpEF. In appropriately selected patients with HFpEF (with LV EF ≥45%, elevated BNP or HF admission within 1 year, estimated GFR >30 mL/min, creatinine 34 mL/m2, E/e′ >14) are abnormal, the diagnostic accuracy of predicting elevated PCWP increases significantly.81 A restrictive patterns of mitral inflow (E/A ≥2) in patients with defined diastolic dysfunction is highly specific for elevated PCWP.81 Likewise, an intermediate mitral inflow pattern associated with multiple abnormal indices of the multiparametric assessment is associated with elevated PCWP. Therapies directed at reduction in LV preload via diuresis or ultrafiltration can improve the mitral inflow pattern in the majority of individuals. Even with therapy, the mitral inflow pattern will never return to normal in most patients. Therefore continued fluid removal until the E/A is less than 1 with improvements in the E/e′ and TR jet velocity may serve as useful echocardiographic targets to define therapeutic success in decongestion.82 In the CHAMPION trial, reduction in HFpEF hospitalizations may have been largely related to significant up-titration of diuretics in the PA pressure-guided treatment group compared to conventional management, highlighting the importance of diuretic therapy in the management of HFpEF.83 An improvement in E/A ratio or TR jet velocity from baseline to follow-up was associated with a lower subsequent risk of first occurrence of HF hospitalization, aborted sudden death, or CV death in the TOPCAT study.84 Abnormal peak atrial longitudinal strain and LA contractile function by LA strain both predict increased PCWP.34,35 Composite indices incorporating both global LA strain and LV strain have also been shown to correlate with filling pressures.85 The change in these variables with therapy has not been well studied but may serve as a future echocardiographic therapeutic target. Right heart dysfunction is present in at least one-fifth of patients with HFpEF.39,42 Assessment of the right-sided filling pressures can inform the clinician regarding right heart function and overall fluid status. Elevated central venous pressure transmits to the renal venous system causing worsening renal function via decreased renal blood flow and renal perfusion pressure, as well as increased tubular pressures and activation of the RAAS and the sympathetic nervous system.86 Renal insufficiency leads to impaired natriuresis further potentiating a vicious cycle of renal dysfunction and volume overload. A distinct phenogroup of older HFpEF patients with right heart dysfunction and

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Fig. 35.10  ASE filling pressure and diastolic dysfunction (DD) grading. from ref 75

renal insufficiency has been identified.87 Significant volume removal in the face of renal insufficiency may be an important treatment strategy in HFpEF, and serial echocardiographic assessments of the inferior vena cava (IVC) may help guide diuresis. Targeting remodeling. LA enlargement is a well-established predictor of adverse outcomes and reflects the cumulative effect of diastolic dysfunction. A regression in LA volume at follow-up was associated with a lower risk of subsequent cardiac events in HFpEF-treated patients from the TOPCAT trial.84 Notably the use of spironolactone in this trial was not associated with improvements in LA volume. Sacubitril-valsartan use in HFpEF was associated with a reduction in LA volume and natriuretic peptide levels in a phase II study88 and is a promising agent being tested in randomized trials currently. Therapies directly addressing LA hypertension and dysfunction represent a potential paradigm shift in treatment, and serial assessment of LA size and function may play an important role in the evolving echocardiographic management of HFpEF. Mitral annular early diastolic tissue velocity (e′) is generally referred to as a load-independent variable reflecting relaxation and restoring forces of the long axis of the left ventricle. However, it is affected by blood pressure, systolic function, and LV minimal pressure, and therefore is not truly load independent. Nonetheless, a reduction in e′ can be viewed as a marker of abnormal LV remodeling. In the absence of acute myocardial infarction or a rapidly progressive myocardial

disorder such as myocarditis, e′ likely represents the cumulative effects of myocyte dysfunction and remodeling over time. Therefore longterm treatment strategies aimed to improve myocardial dysfunction may lead to improvements in diastolic tissue velocity. Improved treatment of hypertension, regardless of the medication used, has been shown to improve e′ in patients with hypertension and diastolic dysfunction.69 Furthermore, the degree of BP reduction correlates with the degree of improvement in e′. However, it must be recognized that the improvement in e′ cannot be clearly attributed to improved diastolic function as afterload reduction is known to impact e′. The impact of mineralocorticoid antagonists on cardiac remodeling and diastolic dysfunction has been inconsistent in the literature. ALDO-DHF, the largest study to investigate the echocardiographic impact of spironolactone on cardiac structure and function in HFpEF, demonstrated significant improvements in e′, E/e′ ratio, LV mass index, and LV size among patients treated with spironolactone.20 Furthermore, the effects of spironolactone on E/e′ ratio remained statistically significant after adjustment for baseline and follow-up BP, suggesting that the reverse remodeling effects of spironolactone were independent of BP reduction. In TOPCAT, the use of spironolactone in HFpEF was associated with a nonsignificant 11% reduction in a combined primary clinical end point. Significant concerns regarding geographic differences in patients and study drug administration in this trial have been raised. On subgroup analysis restricted to the

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Americas, spironolactone was associated with a significant reduction in the primary clinical outcome. TOPCAT failed to demonstrate beneficial effects of spironolactone on e′, E/e′, LV mass index, or LV size; however, less echocardiographic information was available in TOPCAT than ALDO-DHF.84 Therapy with the ARB candesartan was associated with reduction in HF hospitalizations in the CHARM-Preserved trial12; however, use of the irbesartan in the I-PRESERVE trial failed to improve mortality or hospitalization risks in HFpEF patients.16 Although the trial ­evidence supporting ARB therapy in HFpEF is conflicting, there is notably no strong negative outcomes data to date associated with ACE inhibitor or ARB use. Treatment with ARBs and ACE inhibitors has generally shown the highest rates of LV hypertrophy regression in hypertension trials66,67 and, along with other antihypertensive therapy, has been associated with improvements in mitral annular early diastolic tissue velocity (e′).69 The combination of diuretic therapy and either ACE inhibitor or ARB therapy has been shown to improve e′ and natriuretic peptide levels to a greater extent than diuretic therapy alone.89 Furthermore, registry data, which likely reflect more realistic, highly comorbid HFpEF patients, support ARB and ACE inhibitor use.90 Caution must be taken when administering vasodilators to HFpEF patients, as they may experience greater BP reduction, less enhancement in cardiac output, and greater likelihood of stroke volume drop, reflecting a steep end-systolic P-V relationship.91 Judicious use of diuretics, mineralocorticoid antagonists, and ACE inhibitors/ARBs are reasonable first choices to control BP in HFpEF based on the currently available data. Extracellular matrix composition and homeostasis also impact diastolic function. Collagen synthesis, crosslinking, and degradation may play particularly important roles. Increased content of type I myocardial collagen and enhanced collagen crosslinking are associated with impaired e′ and E/e′, and collage overexpression correlates with reduced exercise capacity.92 Furthermore, cardiomyocytes and myocardial extracellular matrix (ECM) are not completely independent compartments, and a close crosstalk exists such that abnormalities in one compartment may be accompanied by changes in the other.93 Diuretic therapy with torsemide more favorably impacts ECM collagen crosslinking than furosemide, and limited clinical data suggest this translates into an improved LV chamber stiffness in patients with hypertensive heart disease.94 Mineralocorticoid antagonist therapy in HFpEF has also been associated with significant improvement in markers of collagen homeostasis.95 Several agents are currently being tested addressing ventricular remodeling and ECM homeostasis, in addition to improved cardiometabolic function on the myocyte level. Targeting right heart function. Right heart dysfunction as measured by traditional echocardiographic indices (RV FAC, TAPSE, RV s′) is present in at least one-fifth and potentially 30% to 50% of patients with HFpEF.39,42 Furthermore, normal resting RV function may deteriorate with exercise if pulmonary pressures rise significantly leading to RV-PA uncoupling. A reduced ratio ( E) mitral inflow patterns and noted a statistically significant improvement toward normalization of the E/A ratio without significant changes in other diastolic indices, including deceleration time, isovolumic relaxation time, and pulmonary vein S/D ratio. Notably no improvements in symptoms resulted from carvedilol use in this small study. Perhaps individualized use of rate control agents may be appropriate in select patients with an E/A ratio of less than 1. In this situation slowing the heart rate may allow for adequate time for LV filling and atrial contraction, which helps to lower the LA pressure and boost cardiac output. However, in patients with a high E/A ratio, the majority of LV filling occurs in early diastole; therefore slowing the heart rate may not help. In fact, slowing the heart rate may actually be harmful in patients with significant ventricular stiffness because stroke volume is often fixed in these patients, and tachycardia may be necessary to maintain cardiac output.102 AFib occurs in approximately two-thirds of HFpEF patients and portends a poorer prognosis.103 Also, AFib independently leads to LA and LV remodeling, as well as greater exertional intolerance.104 Furthermore, AFib is associated with RV dysfunction in HFpEF.6 Management of AFib in HFpEF is outside the scope of this chapter but is an area of active interest. Limited data suggest that maintenance of sinus rhythm following ablation therapy is associated with improvements in LA volume index, LA emptying fraction, E/e′, LV GLS and strain rate, as well as ratios of early mitral inflow (E) and peak strain rate during isovolumetric relaxation period (SRIVR) and early diastole (SRE).105 Given our increasing understanding of the role of LA dysfunction in HFpEF, therapies directed at improvements in LA function will continue to evolve and may include effort at maintenance of sinus rhythm. The study of AFib in HF is an exciting field that will continue to grow and inform the medical community on optimum future treatment strategies.

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SUMMARY HFpEF is responsible for approximately half of all HF hospitalizations. A lack of clearly beneficial evidence-based therapy represents one of the largest unmet needs in CV disease management. Echocardiography remains essential in the diagnosis of HFpEF. Furthermore, echocardiography serves as an ideal tool for the serial evaluations of diastolic parameters in the response to therapeutic interventions. With further study incorporating multiparametric characteristics, we may further refine the phenotypic identification and treatment of HFpEF.

FUTURE DIRECTIONS The echocardiographic assessment of diastolic dysfunction and clinical diagnosis of HFpEF are both complex, multiparametric tasks. Although currently recommended diagnostic algorithms are available, they require a high level of expertise to be effectively used and might still misclassify a significant proportion of cases. Advanced analytic

methods are now available that are well suited for dense, multidimensional data exploration. Machine learning approaches may allow for computer-driven interpretation of diastolic dysfunction and the diagnostic evaluation of HFpEF. Distinct clinical87 and morphofunctional85 phenotypes have already been described using data-driven analytic methods. Clinical phenomapping has identified mutually exclusive phenogroups of individuals with related comorbidities and pathophysiologies that have differential outcomes. The future of HFpEF management likely involves further refinement of HFpEF phenotypes with subsequent phenotype-directed management. Further refinement of phenotyping may include the incorporation of advanced imaging techniques such as deformation imaging and cardiac fluid dynamics, as well as an expanding pool of omics data, including genomics, proteomics, and metabolomics. The field of Big Data analytics utilizing artificial intelligence will allow for precision characterization and study of HFpEF.

KEY POINTS • LA function, pulmonary hypertension, right heart function, and ventricular-arterial coupling can be readily assessed with echocardiography and are of great importance in HFpEF management. • Depressed global longitudinal strain is an early marker of systolic dysfunction and is often present in HFpEF. Global circumferential strain and LV twist remain unchanged or even increase, allowing a preserved LV EF. • Reduced GLS in HFpEF is independently associated with reduced peak O2 uptake and exercise capacity and is a strong echocardiographic predictor of CV death or HF.

• A reduced ratio ( 45%. However, subgroup analysis showed possible benefit in HFpEF patients with low normal ejection fractions and women. Further studies are necessary to further study these subgroups. In this study, sacubitril–valsartan did not result in a significantly lower rate of total hospitalizations for heart failure and death from cardiovascular causes. Moreover, patients assigned to the sacubitril–valsartan group had a higher incidence of hypotension and angioedema.

Phosphodiesterease-5 (PDE5) Inhibitors Many patients with primary pulmonary hypertension also have concomitant HFpEF. Prior studies with patients with HFpEF and pulmonary hypertension showed that treatment with the PDE5 inhibitor sildenafil led to decreased pulmonary arterial pressures and improved functional capacity and improved diastolic dysfunction.12 However, the RELAX study looked at HFpEF patients without pulmonary hypertension and showed no improvement in exercise capacity or clinical status.13 Similarly, the BADDHY study looked at patients with HFpEF and

pulmonary hypertension and looked at bosentan versus placebo therapy and noted no beneficial effects in the bosentan group.14 Further studies are ongoing looking at the combination of phosphodiesterase inhibitors with endothelin antagonists in patients with HFpEF and pulmonary hypertension; however, given the negative results of the BADDHY study and the lack of improvement in exercise capacity in the RELAX study, the future of PDE5 inhibitors in HFpEF remains in question.

Soluble Guanylate Cyclase Stimulators and Activators Insufficient generation of cGMP by soluble guanylase cyclase (sGC) may contribute to the pathophysiology of HFpEF via NO-cGMP-PK signal cascade as described earlier in this chapter. Direct stimulators of sGC differ from the other agents discussed earlier targeting cGMP as they are NO independent in their capacity to increase sGC activity. Vericiguat is a sGC stimulator that was studied in the SOCRATESPRESERVED study. In SOCRATES-PRESERVED, patients with HFpEF received vericiguat or placebo.15 Vericiguat was well tolerated and associated with improvements in quality of life but did not change NT-proBNP. However, preliminary results from the recently completed VITALITY-HFpEF trial which randomized 789 patients in 1:1:1 fashion to either placebo, 10mg vericiguat, or 15mg vericiguat did not show any benefit compared to placebo. Specifically they noted no significant difference in symptoms as assessed by the Kansas City Cardiomyopathy Questionnaire Physical limitation score (KCCQ PLS) and no change in 6 minute walk.16 Looking at other sGC stimulators, in the DILATE-1 study, patients with HFpEF and pulmonary hypertension were randomized to riociguat versus placebo. In that study, riociguat did not significantly effect mean pulmonary arterial pressures, but there was an increase in stroke volume and cardiac index and a decrease in systolic blood pressure (BP) and right ventricular enddiastolic area.17 Further clinic studies are underway; however, all the data for vericiguat and riociguat so far have looked at improvement of indirect hemodynamic variables as opposed to exercise tolerance. At this point, further studies concentrating on HFpEF patients’ exercise capacity are required to demonstrate the clinical utility of vericiguat and riociguat.

Endothelin Receptor Antagonism Endothelin-1 (ET-1) antagonists are elevated and predict mortality in patients with HFrEF. ET-1 as well as both its receptors, ET-A and ET-B, are synthesized and secreted by cardiac myocytes. ET-1 is associated with abnormalities in endothelial function, vascular compliance, pulmonary hypertension, impaired diastolic relaxation, and myocardial fibrosis, which points toward ET-1 being involved in HFpEF pathophysiology. The ET-A antagonist sitaxsentan was examined in a phase II study involving 192 HFpEF patients.18 Treatment with sitaxsentan was associated with increased exercise tolerance but no changes in LV mass or diastolic function in patients with HFpEF. Other studies looking at the dual ET-A/ET-B receptor antagonist macitentan in a murine model of HFpEF showed that macitentan decreased LV hypertrophy and significantly reduced wall thickness measured by echocardiogram.19 In addition, the same study showed macitentan improved adverse cardiac remodeling but reduced the stiffer cardiac collagen-1 and titin N2B expression in the left ventricle. Further human studies are underway looking at the effects of dual ET-A/ET-B receptor antagonism in patients with HFpEF. Given the prior studies showing improvement in echocardiographic parameters, this remains a promising target for future therapies.

Inflammation and Cytokine Inhibition The pathophysiology of HFpEF involves chronic myocardial inflammation. Prior studies that looked at endomyocardial biopsy samples of

CHAPTER 36  patients with HFpEF showed increased cardiac collagen and an increase in inflammatory cells in patients with HFpEF versus normal controls.20 Other studies, using a cardiac fibroblast cell culture system, showed that mechanical stretch mimicking cardiac dilation in HF induces activation of fibroblasts. In addition to activation of fibroblasts, the cell cultures also upregulate chemokine production and trigger typical inflammatory pathways in vitro.21 This points to one general mechanism where mechanical stretch of cardiac tissue leads to inflammation, which can cause permanent remodeling. Specifically, interleukin-1 (IL-1) has been a key proinflammatory cytokine that has been implicated in impaired myocardial relaxation. In the D-HART study, 12 patients with HFpEF were enrolled in a double-blind, randomized, placebo-controlled, crossover trial and assigned to receive anakinra (IL-1 antibody) or placebo. The results showed anakinra led to a statistically significant improvement in peak oxygen consumption and significant reduction in plasma C-reactive protein (CRP) levels. In conclusion, IL-1 blockade with anakinra significantly reduced systemic inflammatory response and improved the aerobic exercise capacity in patients with HFpEF.

Modulators of Intracellular Calcium Homeostasis Chronic HFpEF is associated with increased sympathetic outflow, which through long-term neurohormonal activation induced significant damage to the heart. Specifically, it leads to multiple alterations in the β-adrenergic receptor (β-AR) signaling cascade. Activation of β-ARs increases cyclic adenosine monophosphate (cAMP) production and results in protein kinase A (PKA) phosphorylation of key regulators of contraction coupling such as L-type Ca2+ channels, phospholamban, troponin I, ryanodine receptors (RyR),22 myosin-binding protein Cm, and protein phosphate inhibitor-1.23 There is evidence that alterations in the sarcoplasmic reticulum (SR) Ca2+ cycling are a component of the impaired contractile performance of HFpEF patients. The abnormal intracellular calcium handling includes SR calcium leak through the RyR, decreased SR calcium uptake, and decreased SR content. RyR2 stabilizers such as JTV519 (K201), which stabilizes RYR2s and decreases SR Ca2+ leak, have been shown to improve diastolic function in vitro in murine experimental models.24 Other studies have shown that SEA0400, an Na+/Ca2+ exchanger (NCX) inhibitor, has improved diastolic relaxation in rat animal models with HFpEF. SEA0400 was also associated with improved cardiac remodeling when given chronically to rat models with HFpEF.25 Overall both of these novel substances have only shown improvement in HFpEF in animal models and have not yet been tested in human subjects.

Targeting Extracellular Intrinsic Factors: Noncardiac Mechanisms Glucose-Lowering Drugs Sodium glucose cotransporter-2 (SGLT2) inhibitors. The EMPAREG OUTCOME trial looked at empagliflozin, a SGLT2 inhibitor in patients with type 2 diabetes. The results showed a 38% relative risk reduction, 38% in death from cardiovascular causes, 35% relative risk reduction for hospitalization for HF, and a 32% relative risk reduction for death from any cause.26 This study did not specifically look at patients with HFrEF or HFpEF, but rather patients with type 2 diabetes at increased cardiovascular risk. The mechanism of effect of the cardiovascular benefit of empagliflozin is that the drug induces a mild hyperketonemia. In this state ketones are taken up by the cardiac tissue and oxidized to fatty acids, which would improve the efficiency of oxygen consumption of cardiac mitochondria during work. This hypothesis is known as the “thrifty substrate hypothesis.”27 Given that the prior studies did not specifically look at patients with HFpEF, future studies targeting this population are required to determine the true benefit of this therapy.

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Incretins. Incretins are a group of metabolic hormones that stimulate a decrease in blood glucose levels. Incretins are released after eating and augment the stimulation of insulin from the pancreatic beta islet cells. Glucagon-like peptide-1 (GLP-1) analogues and dipeptidylpeptidase 4 (DDP-4) inhibitors are two classes of medications that have been used to stimulate this metabolic pathway. GLP-1 is a hormone in the incretin family, and GLP receptors have been found in cardiac tissue.28 Stimulation of cardiac GLP receptors leads to increased cardiac glucose intake, which activates myocyte glycolysis.29 Specifically the GLP-1 analogue exenatide has been shown to improve cardiac diastolic function in patients with diabetes.30,31 Similarly, DDP-4 inhibitors are currently being studied in regard to their effect on patients with HFpEF. The DDP-4 inhibitors linagliptin and sitagliptin have been shown to improve diastolic function in patients with diabetes, HFpEF, and chronic kidney disease.32 Future studies are needed to further clarify the role that GLP-1 analogues and DDP-4 have in improving diastolic function in both diabetics and nondiabetics.

Szeto-Schiller (SS) Peptides Therapies to treat HF focus on fixing the mismatch between adenosine triphosphate (ATP) supply and demand. There are multiple reasons why there might be a mismatch: ischemia producing increased workload, hypertension, diastolic dysfunction, and cellular malfunctions. The majority of current therapies on decreased ATP demand by decreasing workload. A different approach targeting mitochondrial function to improve ATP supply might provide new therapies for HFpEF. SS peptides are novel mitochondria-targeted antioxidant peptides that were developed to target the inner mitochondrial membrane with antioxidants. This reduces mitochondrial free radicals and prevents oxidant-induced cell death.33 SS-31 is one such SS peptide, also named MTP-131 or elamipretide, which is currently being studied in phase II clinical trials for HFrEF and HFpEF.

Advanced Glycation End Product Crosslink Breakers Inflammation can lead to oxidative stress, which leads to the formation of advanced glycation end products (AGEs). AGEs are where protein and carbohydrates form an interlinking crosslink with the extracellular matrix.34 Alagebrium chloride is a compound described as a crosslink breaker. In a small study involving patients with HFpEF, 16 weeks of alagebrium chloride resulted in improved diastolic function.35 Another therapeutic target in the AGE pathway is lysl oxidase-like 2 (LOXL2), which is an enzyme involved in the crosslinking of collagen and has been shown to be involved in the fibrosis of HF. Prior studies have shown that using a LOXL2-specific neutralizing monoclonal antibody to inhibit LOXL2 activity in mouse hearts decreases stress-induced fibrosis, ventricular dilation, and systolic and diastolic dysfunction.36 Given the small number of patients recruited in the prior human studies, larger human studies need to be undertaken to determine the utility, but the data from these early studies appear promising.

Micro-RNA Regulation Micro-RNAs (miRNAs) are small noncoding RNA (containing about 22 nucleotides) that function in RNA silencing and posttranscriptional regulation of gene expression. MiRNAs have been reported to regulate genes involved in many essential disease processes as well as HF.37 Additionally, both HFrEF and HFpEF have been found to have different miRNA profiles.38,39 In addition to their usefulness as a biomarker, miRNAs offer a potential therapeutic target for future drug therapy in HF. A prior study looking at the inhibition of miRNA-21 (miR-21) in rat cardiomyocytes in cell culture as a rat model of HFpEF showed that, after injection of a miR-21 antagonist, the cardiac atrophy and cardiac fibrosis typical of HFpEF was reduced.40 Given the limited experience in miRNA therapy in humans overall, further testing

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showing the safety of miRNA therapies in humans needs to be undertaken before the clinical utility of inhibition miR-21 can be investigated.

Novel Device Therapies Interatrial Septal Devices One of the hemodynamic effects of treating HFpEF is reduction in the left atrial (LA) pressure.41 The fundamental concept of interatrial septal devices (IASDs) depends on the Lutembacher syndrome, which is the observation that patients with untreated mitral stenosis and atrial defect with left to right shunt had better survival. A small pilot trial involving 11 patients with HFpEF was undertaken to assess the utility of IASDs. The inclusion criteria included an EF greater than 45%, PCWP greater than 15 mmHg (rest) or greater than 25 mmHg (exercise), and more than one hospitalization for HF within the last 12 months, or New York Heart Association (NYHA) Class III/IV symptoms. In these patients an IASD was implanted using percutaneous transseptal access via the femoral vein. At 30 days, LV pressures were significantly reduced by 5.5 mmHg, and NYHA class was improved by two classes in two patients, one class in five patients, and worsened by one class in one patient.42 A larger study, the REDUCE LAP-HF, looked at 68 HFpEF patients who underwent IASD implantation. After 6 months 52% of patients had reduction in PCWP at rest, 58% had a lower PCWP during exertion, and 39% had both.43 However, REDUCE LAP-HF had not looked if the lower PCWPs translate to improvements in symptoms, which is a concentration of further ongoing studies. The V-wave system is an interatrial shunt system that has been associated with improved clinical and functional status in patients with heart failure. A recent feasibly and safety study looked at 38 patients with HFpEF with NYHA class III symptoms after V-wave implantation. The overall result of the study showed no significant increase in device related adverse events, but a significant improvement in NYHA class, quality of life, and 6-minute walk distance.44 Further larger randomized trials are currently underway to confirm these preliminary results with the V-wave system.

Cardiac Contractility Modulation Cardiac contractility modulation (CCM) therapy is delivered by a pacemaker-like device that applies an electrical signal during the refractory period to the septum. Since the electrical signal is applied during the refractory period there is no cardiac muscle contraction; however, the electrical signals increase the influx of calcium ions in the cardiomyocytes potentially triggering molecular remodeling. This is thought to improve symptoms of HFrEF patients.45 A case series looking at CCM therapy in patients with HFpEF found an improvement in NYHA classification, 6-minute walking distance, quality of life, improvement in diastolic filling parameters, and improvement in EF reserve.46 A phase II trial investing the role of CCM in HFpEF patients is currently ongoing.

Renal Denervation and Baroreflex Activation Therapy One of the underlying mechanisms of HFpEF is increased sympathetic tone. Reduction of sympathetic tone can be achieved by renal denervation. Prior studies looked at the effect of catheter-based renal denervation on LV hypertrophy and diastolic function in patients with resistant hypertension. In that study, 45 patients with resistant hypertension underwent bilateral renal denervation. Compared to controls,

the intervention decreased LV mass and improved diastolic function in addition to improving BP.47 The RDT-PEF study was a prospective trial that further investigated this effect.48 In this trial 25 patients were randomized to renal denervation or medical therapy. There was no difference between intervention and control at 12 months for Minnesota Living with Heart Failure Questionnaire, peak VO2 at exercise, BNP E/e′, or LV mass index. However, more patients in the intervention arm had improved peak VO2, but this was not significant. Future larger studies may show that this is a significant difference and needs additional investigation. Baroreflex activation therapy (BAT) works by stimulating the carotid sinus via an implanted electrode close to the carotid sinus region, which elicits a reflex through the sympathetic and vagal nervous system that reduces BP. Similar to renal denervation, this device has been primarily studied for resistant hypertension. This therapy has been studied in HFrEF in the Barostim HOPE4HF study.49 In this study 146 patients with EF less than 35% and NYHA Class III symptoms were randomized to placebo and BAT in a 1:1 distribution. The results showed that BAT was safe and improved functional status, quality of life, and exercise capacity and reduced NT-proBNP in the intervention group. So far, all the research for BAT has concentrated on HFrEF patients, but dedicated studies concentrating on HFpEF are required to show if this can be a viable therapy in this patient population.

FUTURE DIRECTIONS Drugs and devices developed to treat diastolic HF are thought to hold limited commercial promise because they are primarily add-on therapies in a study population in which treatment goals and treatment outcomes are not well defined. The therapeutic options discussed in this chapter are just some of the examples on which there are published data or that are currently in active clinical development. The fact that there are a limited number of pipeline drugs that specifically target diastolic HF brings home the point that we are in the infancy of understanding the underlying pathophysiology of diastolic HF. Furthermore, the association between improvements of echocardiographic indices of diastolic dysfunction may not relate directly to clinical efficacy. Although LV hypertrophy regression appears to be a good surrogate end point for diastolic HF, definitive proof for this is not yet available. From what we understand now, drugs that affect calcium homeostasis will emerge as important players in this field, although existing neurohormonal antagonists will maintain their presence in the diastolic HF regimen. New targets will emerge, and new drug classes (e.g., AGE crosslink breakers) will be tested as we broaden our understanding of the diversity of diastolic HF. Metabolic modulation has also shown great promise as we begin to understand the close connections between myocardial and vascular metabolic derangements and diastolic dysfunction. Device implantation for treating diastolic HF will need further development to reduce the procedural risks, invasiveness, and expense. Nevertheless, intracardiac hemodynamic monitoring devices will likely play an important role in guiding therapy in this population. The road to clinical development in diastolic HF is tortuous and demanding, but at the same time it is exciting and rewarding as it brings new ideas, new challenges, and new hopes.

KEY POINTS • A proinflammatory state in the endothelium triggers cardiac remodeling, which is specific for HFpEF. Endomyocardial biopsy samples of patients with HFpEF show increased cardiac collagen and an increase in inflammatory cells.

• Inflammation can lead to oxidative stress, which leads to the formation of advanced glycation products. • HFpEF-associated comorbidities lead to endothelial dysfunction through disruption of the intracellular NO-cGMP-PK signal cascade.

CHAPTER 36  • In addition to organic nitrates, inorganic nitrates represent an important route to increase myocardial NO bioavailability in patients with HFpEF. • Insufficient generation of cGMP by sGC may contribute to the pathophysiology of HFpEF. • ET-1 antagonists are elevated and predict mortality in patients with HFrEF. • IL-1 has been a key proinflammatory cytokine that has been implicated in impaired myocardial relaxation. • Increased sympathetic outflow in HFpEF is associated with ­induced myocardial cell injury.

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• SGLT2 inhibitors in patients with type 2 diabetes have shown a ­reduction in death and hospitalization for HF. • Stimulation of cardiac GLP receptors lead to increased cardiac glucose intake, which has shown to improve cardiac diastolic function in patients with diabetes. • Targeting mitochondrial function to improve ATP supply might provide new therapies for HFpEF. • IASDs, to allow left to right shunt, have been shown to decrease LV filling pressures and improve NYHA class in HF patients. • BAT may be helpful in hypertensive-induced HF by eliciting a reflex through the sympathetic and vagal nervous system that reduces BP.

REVIEW QUESTIONS 1. Endothelial dysfunction through disruption of the intracellular NO-cGMP-PK signal cascade results in a. increased myocardial relaxation. b. increased cardiomyocyte stiffness. c. reduced levels of titin. d. decreased generation of NT-proBNP. 2. Which of the following hemodynamic effects is expected during the infusion of sodium nitrite in HFpEP patients? a. Increased capillary wedge pressure b. Increased cardiac output

c. Increased oxygen consumption relative to cardiac output d. Increased LV stiffness 3. Which of the following glucose-lowering drug classes has demonstrated reduction in cardiovascular death and HF hospitalization? a. Sodium glucose cotransporter-2 inhibitors b. Glucagon-like peptide analogues c. Biguanides d. Sulfonylureas

REFERENCES

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1. Tschöpe C, Van Linthout S. New insights in (Inter)cellular mechanisms by heart failure with preserved ejection fraction. Curr Heart Fail Rep. 2014;11(4):436–444. doi:10.1007/s11897-014-0219-3. 2. Van Heerebeek L, Hamdani N, Falcão-Pires I, et al. Low myocardial protein kinase G activity in heart failure with preserved ejection fraction. Circulation. 2012;126(7):830–839. doi:10.1161/CIRCULATIONAHA.111. 3. Redfield MM, Anstrom KJ, Levine JA, et al. Isosorbide mononitrate in heart failure with preserved ejection fraction. N Engl J Med. 2015;373(24):2314–2324. doi:10.1056/NEJMoa1510774. 4. Westermann D, Riad A, Richter U, et al. Enhancement of the endothelial NO synthase attenuates experimental diastolic heart failure. Basic Res Cardiol. 2009;104(5):499–509. doi:10.1007/s00395-009-0014-6. 5. Shah AM, Claggett B, Loehr LR, et al. Heart failure stages among older adults in the community: the atherosclerosis risk in communities study. Circulation. 2017;135(3):224–240. doi:10.1161/CIRCULATIONAHA.116.023361. 6. Borlaug BA, Koepp KE, Melenovsky V. Sodium nitrite improves exercise hemodynamics and ventricular performance in heart failure with preserved ejection fraction. J Am Coll Cardiol. 2015;66(15):1672–1682. doi:10.1016/J.JACC.2015.07.067. 7. Simon MA, Vanderpool RR, Nouraie M, et al. Acute hemodynamic effects of inhaled sodium nitrite in pulmonary hypertension associated with heart failure with preserved ejection fraction. JCI Insight. 2016;1(18):e89620. doi:10.1172/JCI.INSIGHT. 89620. 8. Eggebeen J, Kim-Shapiro DB, Haykowsky M, et al. One week of daily dosing with beetroot juice improves submaximal endurance and blood pressure in older patients with heart failure and preserved ejection fraction. JACC Heart Fail. 2016;4(6):428–437. doi:10.1016/J.JCHF. 2015.12.013. 9. Borlaug BA, Anstrom KJ, Lewis GD, et al. Effect of inorganic nitrite vs placebo on exercise capacity among patients with heart failure with preserved ejection fraction. JAMA. 2018;320(17):1764. doi:10.1001/ jama.2018.14852. 10. Solomon SD, Zile M, Pieske B, et al. The angiotensin receptor neprilysin inhibitor LCZ696 in heart failure with preserved ejection fraction: a phase 2 double-blind randomised controlled trial. Lancet. 2012;380(9851): 1387–1395. doi:10.1016/S0140-6736(12)61227-6. 11. Solomon SD et al. PARAGON-HF Investigators and Committees. Angiotensin-neprilysin inhibition in heart failure with preserved ejection fraction. N Engl J Med. 2019;381:1609–1620. doi:10.1056/NEJMoa1908655.

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22. Currie S, Elliott EB, Smith GL, Loughrey CM. Two candidates at the heart of dysfunction: the ryanodine receptor and calcium/calmodulin protein kinase II as potential targets for therapeutic intervention—an in vivo perspective. Pharm Ther. 2011;131(2):204–220. doi:10.1016/ J.PHARMTHERA. 2011.02.006. 23. Lompré AM, Hajjar RJ, Harding SE, Kranias EG, Lohse MJ, Marks AR. Ca2+ cycling and new therapeutic approaches for heart failure. Circulation. 2010;121(6):822–830. doi:10.1161/CIRCULATIONAHA.109.890954. 24. Sacherer M, Sedej S, Wakuła P, et al. JTV519 (K201) reduces sarcoplasmic reticulum Ca2+ leak and improves diastolic function in vitro in murine and human non-failing myocardium. Br J Pharmacol. 2012;167(3):493–504. doi:10.1111/j.1476-5381.2012.01995.x. 25. Primessnig U, Schönleitner P, Höll A, et al. Novel pathomechanisms of cardiomyocyte dysfunction in a model of heart failure with preserved ejection fraction. Eur J Heart Fail. 2016;18(8):987–997. doi:10.1002/ ejhf.524. 26. Zinman B, Wanner C, Lachin JM, et al. Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes. N Engl J Med. 2015;373(22): 2117–2128. doi:10.1056/NEJMoa1504720. 27. Ferrannini E, Mark M, Mayoux E. CV protection in the EMPA-REG OUTCOME trial: a “thrifty substrate” hypothesis. Diabetes Care. 2016;39(7):1108–1114. doi:10.2337/dci16-0033. 27. Wei Y, Mojsov S. Tissue-specific expression of the human receptor for glucagon-like peptide-I: brain, heart and pancreatic forms have the same deduced amino acid sequences. FEBS Letters. 1995;358(3):219–224. doi:10.1016/0014-5793(94)01430-9. 29. Inzucchi SE, McGuire DK. New drugs for the treatment of diabetes: part II: incretin-based therapy and beyond. Circulation. 2008;117(4):574–584. doi:10.1161/CIRCULATIONAHA.107.735795. 30. Wang X, Han L, Yu YR, et al. Effects of GLP-1 agonist exenatide on cardiac diastolic function and vascular endothelial function in diabetic patients. Sichuan Da Xue Xue Bao. Yi Xue Ban (J Sichuan Univ) Med Sci Ed. 2015;46(4):586–590. http://www.ncbi.nlm.nih.gov/pubmed/26480664. 31. Scalzo RL, Moreau KL, Ozemek C, et al. Exenatide improves diastolic function and attenuates arterial stiffness but does not alter exercise capacity in individuals with type 2 diabetes. J Diabetes Complicat. 2017;31(2):449–455. doi:10.1016/J.JDIACOMP. 2016.10.003. 32. Connelly KA, Bowskill N, Advani S, et al. Dipeptidyl peptidase-4 inhibition improves le ventricular function in chronic kidney disease. Clinical and Investigative Medicine. Medecine Clinique Et Experimentale. 2014;37(3):e172–e185. 33. Nickel AG, von Hardenberg A, Hohl M, et al. Reversal of mitochondrial transhydrogenase causes oxidative stress in heart failure. Cell Metab. 2015;22(3):472–484. doi:10.1016/j.cmet.2015.07.008. 34. Hartog JWL, Voors AA, Bakker SJL, Smit AJ, van Veldhuisen DJ. Advanced glycation end-products (AGEs) and heart failure: pathophysiology and clinical implications. Eur J Heart Fail. 2007;9(12):1146–1155. doi:10.1016/j.ejheart.2007.09.009. 35. Little WC, Zile MR, Kitzman DW, Hundley WG, O’Brien TX, Degroof RC. The effect of alagebrium chloride (ALT-711), a novel glucose crosslink breaker, in the treatment of elderly patients with diastolic heart failure. J Card Fail. 2005;11(3):191–195. doi:10.1016/j.cardfail.2004.09.010.

36. Yang J, Savvatis K, Kang JS, Fan P, Zhong H, Schwartz K, et al. Targeting LOXL2 for cardiac interstitial fibrosis and heart failure treatment. Nat Commun. 2016;7:13710. doi:10.1038/ncomms13710. 37. Ohtani K, Dimmeler S. Control of cardiovascular differentiation by microRNAs. Basic Res Cardiol. 2011;106(1):5–11. doi:10.1007/s00395-0100139-7. 38. Watson CJ, Gupta SK, O’Connell E, et al. MicroRNA signatures differentiate preserved from reduced ejection fraction heart failure. Eur J Heart Fail. 2015;17(4):405–415. doi:10.1002/ejhf.244. 39. Wong LL, Armugam A, Sepramaniam S, et al. Circulating microRNAs in heart failure with reduced and preserved left ventricular ejection fraction. Eur J Heart Fail. 2015;17:393–404. doi:10.1002/ejhf.223. 40. Dong S, Ma W, Hao B, et al. microRNA-21 promotes cardiac fibrosis and development of heart failure with preserved left ventricular ejection fraction by up-regulating Bcl-2. Int J Clin Exp Pathol. 2014;7(2):565–574. http://www.ncbi.nlm.nih.gov/pubmed/24551276. Accessed July 17, 2018. 41. Sinning D, Kasner M, Westermann D, Schulze K, Schultheiss HP, Tschöpe C. Increased left ventricular stiffness impairs exercise capacity in patients with heart failure symptoms despite normal left ventricular ejection fraction. Card Res Pract. 2011;2011:692862. doi:10.4061/2011/692862. 42. Søndergaard L, Reddy V, Kaye D, et al. Transcatheter treatment of heart failure with preserved or mildly reduced ejection fraction using a novel interatrial implant to lower left atrial pressure. Eur J Heart Fail. 2014;16(7):796–801. doi:10.1002/ejhf.111. 43. Hasenfuß G, Hayward C, Burkhoff D, et al. A transcatheter intracardiac shunt device for heart failure with preserved ejection fraction (REDUCE LAP-HF): a multicentre, open-label, single-arm, phase 1 trial. Lancet. 2016;387(10025):1298–1304. doi:10.1016/S0140-6736(16)00704-2. 44. Guimaraes L, et al. Interatrial shunt with the second-generation V-wave system for patients with advanced chronic heart failure. EuroIntervention. 2020;15:1426–1428. doi:10.4244/EIJ-D-19-00291. 45. Borggrefe M, Burkhoff D. Clinical effects of cardiac contractility modulation (CCM) as a treatment for chronic heart failure. Eur J Heart Fail. 2012;14(7):703–712. doi:10.1093/eurjhf/hfs078. 46. Tschöpe C, Van Linthout S, Spillmann F, et al. Cardiac contractility modulation signals improve exercise intolerance and maladaptive regulation of cardiac key proteins for systolic and diastolic function in HFpEF. Int J Cardiol. 2016;203:1061–1066. doi:10.1016/j.ijcard.2015.10.208. 47. Brandt MC, Mahfoud F, Reda S, et al. Renal sympathetic denervation reduces left ventricular hypertrophy and improves cardiac function in patients with resistant hypertension. J Am Coll Cardiol. 2012;59(10): 901–909. doi:10.1016/J.JACC. 2011.11.034. 48. Patel HC, Rosen SD, Hayward C, et al. Renal denervation in heart failure with preserved ejection fraction (RDT-PEF): a randomized controlled trial. Eur J Heart Fail. 2016;18(6):703–712. doi:10.1002/ejhf.502. 49. Abraham WT, Zile MR, Weaver FA, et al. Baroreflex activation therapy for the treatment of heart failure with a reduced ejection fraction. JACC Heart Fail. 2015;3(6):487–496. doi:10.1016/j.jchf.2015.02.006.

PART VI  Cases of Diastolic Heart Failure

KLEIN: 37 Non-Print Items

37

Cases of Diastolic Heart Failure Michael Chetrit, Patrick Collier, and Allan Klein

OUTLINE Case 1: e.1 35-Year-Old African American Man With Suspected Left Ventricular Hypertrophy, e.1 Case 2: e.3 65-Year-Old Caucasian Female Referred for Poorly Controlled Hypertension, e.3 Case 3: e.4 47-Year-Old African American Man With Multiple Myeloma Being Evaluated for Lower Extremity Edema and Dyspnea, e.4 Case 4: e.6 50-Year-Old Caucasian Male Referred for Evaluation of Dyspnea, e.6 Case 5: e.8 50-Year-Old Southeast Asian Female With HFrEF, e.8 Case 6: e.10 71-Year-Old Caucasian Woman With Coronary Artery Disease and Dyspnea, e.10

Case 7: e.12 32-Year-Old Caucasian Male With New Onset Ascites and Pitting Edema, e.12 Case 8: e.14 64-Year-Old Asian Female Presents to the Emergency Room With Acute Dyspnea, e.14 Case 9: e.15 71-Year-Old Caucasian Female With Indeterminate Diastolic Function, e.15 Case 10: e.17 75-Year-Old African American Male During Routine Follow-Up for Known Cardiomyopathy, e.17 References, e.22

CASE 1: 35-Year-Old African American Man With Suspected Left Ventricular Hypertrophy • History: 35-year-old African American athlete referred for evaluation of suspected left ventricular hypertrophy based on an electrocardiogram (ECG) obtained during his annual screening. He is otherwise completely asymptomatic. • Past medical history: None • Past surgical history: Fractured left tibia • Social: Denies any smoking or alcohol consumption • Physical exam: • Pulse: 47 bpm, sinus rhythm • Blood pressure: 120/75 mmHg • Neck: No elevation of jugular venous pressure (JVP), no carotid bruits, no masses • Chest: Lungs are clear to auscultation • Cardiovascular: S1, S2 normal, no murmurs • Abdomen: No tenderness, organomegaly, palpable masses, or bruits, normal bowel sounds • Extremities: No edema

ECG

See Video 37.1: 2-D parasternal long axis. See Video 37.2: 2-D parasternal long axis with color Doppler. See Video 37.3: 2-D apical four chamber. See Video 37.40: 2-D apical two chamber. See Video 37.5: 2-D apical three chamber.

e.1

e.2

PART VI 

Cases of Diastolic Heart Failure

LV-End Diastolic Dimensions M-Mode Parasternal Long-Axis.

Tissue Doppler Septal Mitral Annulus.

Pulsed-wave Doppler LV Inflow.

LA Volume.

Tissue Doppler Lateral Mitral Annulus.

Tricuspid Regurgitation on Continuous Wave Doppler.

CHAPTER 37 

REVIEW QUESTION 1. Which of the following statements is true? a. Diastolic function is normal. b. There is grade 1 diastolic dysfunction.

Cases of Diastolic Heart Failure

c. The E/A ratio of 2.68 is concerning for restrictive physiology. d. Family members should be screened for hypertrophic cardiomyopathy.

CASE 2: 65-Year-Old Caucasian Female Referred for Poorly Controlled Hypertension

LV End-Diastolic Dimensions, M Mode Parasternal Long Axis.

• History: 65-year-old Caucasian female was referred by her primary care physician for poorly controlled essential hypertension. She reports mild exertional dyspnea. She denies chest pain, orthopnea, paroxysmal nocturnal dyspnea, or lower extremity edema. • Past medical history: Normocytic anemia, essential hypertension • Past surgical history: None • Social: Occasional alcohol and social smoker • Physical exam: • Pulse: 75 bpm, sinus rhythm • Blood pressure: 175/92 mmHg • Neck: JVP at the level of the jaw, no carotid bruits, no masses • Chest: Decreased air entry to the bases • Cardiovascular: S1, S2 normal, grade II/VI systolic murmur at the left sternal border • Abdomen: No tenderness, organomegaly, palpable masses or bruits, normal bowel sounds • Extremities: Mild bilateral pitting edema

ECG: Sinus Rhythm. Pulsed-wave Doppler LV Inflow.

See Video 37.6: 2-D parasternal long axis. See Video 37.7: 2-D parasternal long axis with color Doppler. See Video 37.8: 2-D apical four chamber. See Video 37.9: 2-D apical two chamber. See Video 37.10: 2-D apical three chamber.

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Tissue Doppler Lateral Mitral Annulus.

LA Volume.

Tissue Doppler Medial Mitral Annulus.

Tricuspid Regurgitation on Continuous Wave Doppler.

REVIEW QUESTION 2. Which of the following statements is true? a. Diastolic function is normal.

b. There is grade 1 diastolic dysfunction. c. The E/e′ ratio of 17.9 signifies elevated LA pressures. d. There is restrictive filling pattern.

CASE 3: 47-Year-Old African American Man With Multiple Myeloma Being Evaluated for Lower Extremity Edema and Dyspnea • History: 47-year-old African American man was recently diagnosed with multiple myeloma (kappa light chain) when being investigated for anemia. His anemia has since resolved, but he is now complaining of external dyspnea, palpitations, and lower leg edema. An echocardiogram was ordered. • Past medical history: Multiple myeloma, anemia, asthma, dyslipidemia, pleural effusion of unknown etiology, carpel tunnel • Past surgical history: None

• Social: No alcohol or smoking • Current medications: Budesonide, torsemide, eplerenone, bortezomib-dexamethasone • Physical exam: • Pulse: 75 bpm sinus rhythm • Blood pressure: 125/81 mmHg • Neck: JVP at the level of the jaw, no carotid bruits, no masses • Chest: Crackles at the base of the right lung • Cardiovascular: S1, S2 normal, S3, no murmur • Abdomen: No tenderness, organomegaly, palpable masses, or bruits, normal bowel sounds • Extremities: Mild bilateral pitting edema

CHAPTER 37  ECG

Cases of Diastolic Heart Failure

Tissue Doppler Lateral Mitral Annulus.

See Video 37.11: 2-D parasternal long axis. See Video 37.12: 2-D parasternal long axis with color Doppler. See Video 37.13: 2-D apical four chamber. See Video 37.14: 2-D apical two chamber. See Video 37.15: 2-D apical three chamber. LV End-Diastolic Diameter, 2-D Parasternal Long Axis.

Tissue Doppler Medial Mitral Annulus.

Pulsed-wave Doppler LV Inflow.

LA Volume.

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Tricuspid Regurgitation on Continuous Wave Doppler.

REVIEW QUESTIONS 3. Which of the following statements is false? a. There is grade 3 diastolic dysfunction.

Global Longitudinal Strain.

b. There are increased left atrial pressures. c. There is grade 2 diastolic dysfunction. d. Basal to midventricular systolic dysfunction with relative sparing of the apex is a specific sign for cardiac amyloidosis.

CASE 4: 50-Year-Old Caucasian Male Referred for Evaluation of Dyspnea • History: 50-year-old Caucasian male reports mild dyspnea on exertion during his annual checkup. • Past medical history: Type 1 diabetes mellitus, gastroesophageal reflux disease, celiac disease • Past surgical history: None • Social: Occasional alcohol, nonsmoker • Physical exam: • Pulse: 65 bpm, sinus rhythm • Blood pressure: 145/75 mmHg • Neck: No elevation of JVP, no carotid bruits, no masses • Chest: Lungs are clear to auscultation • Cardiovascular: S1, S2 normal, no murmurs • Abdomen: No tenderness, organomegaly, palpable masses or bruits, normal bowel sounds • Extremities: No edema ECG

See Video 37.16: 2-D parasternal long axis. See Video 37.17: 2-D parasternal long axis. See Video 37.18: 2-D apical four chamber. See Video 37.19: 2-D apical two chamber. See Video 37.20: 2-D apical three chamber.

LV End-Diastolic Dimensions, 2-D Parasternal Long Axis.

CHAPTER 37 

Cases of Diastolic Heart Failure

Pulse Wave Doppler LV Inflow.

Tissue Doppler Medial Mitral Annulus.

Tissue Doppler Lateral Mitral Annulus.

LA Volume.

Tricuspid Regurgitation on Continuous Wave Doppler.

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REVIEW QUESTION 5. Which of the following would you recommend next? a. Consider alternative causes and order pulmonary function tests.

b. Consider a stress echocardiogram to assess diastolic function on exertion. c. Initiate treatment for grade 3 diastolic dysfunction. d. No further intervention is necessary.

CASE 5: 50-Year-Old Southeast Asian Female With HFrEF

LV End-Diastolic Dimensions 2-D Parasternal Long.

• History: A 50-year-old Southeast Asian female is referred to a heart failure specialist for management of HFrEF. The patient appears to be well compensated, and an echocardiogram was ordered for follow-up. • Past medical history: Sarcoidosis with cardiac involvement status post PPM-AICD, permanent atrial fibrillation, type 2 diabetes mellitus, vertigo • Past surgical history: Skin biopsy • Social: No alcohol or smoking • Current medications: Spironolactone, atorvastatin, apixaban, carvedilol, hydralazine, isosorbide mononitrate • Physical exam: • Pulse: 60 bpm irregular rhythm • Blood pressure: 105/81 mmHg • Neck: JVP at the level of the jaw, no carotid bruits, no masses • Chest: Lung are clear to auscultation • Cardiovascular: Variable S1, S2 normal, grade 3/6 pansystolic murmur • Abdomen: No tenderness, organomegaly, palpable masses, or bruits, normal bowel sounds • Extremities: 1+ bilateral pitting edema Pulsed-wave Doppler LV Inflow. ECG

See Video 37.21: 2-D parasternal long axis. See Video 37.22: 2-D parasternal long axis. See Video 37.23: 2-D apical four chamber. See Video 37.24: 2-D apical two chamber. See Video 37.25: 2-D apical three chamber.

CHAPTER 37 

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Tissue Doppler Lateral Mitral Annulus.

Tricuspid Regurgitation Continuous Wave Doppler.

Tissue Doppler Medial Mitral Annulus.

Pulsed-wave Doppler Of Pulmonary Vein From Apical Four Chamber.

LA Volume.

Color M Mode of Mitral Inflow From Apical Four Chamber.

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REVIEW QUESTION 6. Which of the following statements is true? a. There is grade 1 diastolic dysfunction. b. There is grade II diastolic dysfunction with increased LA pressures.

c. There is grade III diastolic dysfunction with increased LA pressures. d. Unable to assess diastolic function, suspect normal LA pressures. e. Diastolic function can be assessed using special conditions, suspect elevated LA pressures.

CASE 6: 71-Year-Old Caucasian Woman With Coronary Artery Disease and Dyspnea • History: A 71-year-old Caucasian female with a remote h/o coronary artery bypass surgery reports increased shortness of breath. An echocardiogram was ordered to assess LV function. • Past medical history: Coronary artery disease, hypertension, dyslipidemia, carotid stenosis, aortic stenosis, mild mitral annular calcifications • Past surgical history: Coronary artery bypass surgery (remote), hysterectomy • Social: No alcohol or smoking • Current medications: Atenolol, aspirin, furosemide, omeprazole, atorvastatin • Physical exam: • Pulse: 54 bpm, sinus rhythm • Blood pressure: 147/62 mmHg • Neck: No jugular distention, no carotid bruits, no masses • Chest: Lungs are clear to auscultation • Cardiovascular: S1, S2 normal, Class II/VI systolic ejection murmur • Abdomen: No tenderness, organomegaly, palpable masses, or bruits, normal bowel sounds • Extremities: No edema

ECG

See Video 37.26: 2-D parasternal long axis. See Video 37.27: 2-D parasternal long axis. See Video 37.28: 2-D apical four chamber. See Video 37.29: 2-D apical two chamber. See Video 37.30: 2-D apical three chamber.

LV End-Diastolic Dimensions 2-D Parasternal Long.

Pulsed-wave Doppler LV Inflow.

CHAPTER 37 

Cases of Diastolic Heart Failure

Tissue Doppler Lateral Mitral Annulus.

Tricuspid Regurgitation On Continuous Wave Doppler.

Tissue Doppler Medial Mitral Annulus.

Continuous Wave Doppler Through The Aortic Valve.

LA Volume.

REVIEW QUESTION 7. What is the diastolic profile of this patient? a. Mildly increased LA pressure, normal LV relaxation b. Mildly increased LA pressure, delayed LV relaxation c. Severely increased LA pressure, normal LV relaxation d. Severely increased LA pressure, delayed LV relaxation e. Indeterminate

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CASE 7: 32-Year-Old Caucasian Male With New Onset Ascites and Pitting Edema

Pulsed-wave Doppler LV Inflow.

• History: 32-year-old Caucasian male with a history of viral pericarditis presents 4 years later with new onset ascites and pitting edema. • Past medical history: Viral pericarditis treated with nonsteroidal anti inflammatory drugs, vertigo • Past surgical history: None • Social: Active smoker, one pack per day for 5 years • Current medications: Multivitamins • Physical exam: • Pulse: 87 bpm, sinus rhythm • Blood pressure: 120/78 mmHg • Neck: JVP up to the level of the ear lobes with no change in inspiration, no carotid bruits • Chest: Decreased air entry to right lung with dullness to percussion • Cardiovascular: S1, S2 normal, and an extra heart sound • Abdomen: Distended abdomen with bulging flanks and organomegaly • Extremities: 2+ bilateral pitting edema ECG Tissue Doppler Lateral Mitral Annulus.

See Video 37.31: 2-D parasternal long axis. See Video 37.32: 2-D parasternal long axis. See Video 37.33: 2-D apical four chamber. See Video 37.34: 2-D apical two chamber. See Video 37.35: 2-D apical three chamber. See Video 37.36: 2-D short axis view. See Video 37.37: 2-D subcostal view. LV End-Diastolic Dimensions, 2D Parasternal Long Axis.

Tissue Doppler Medial Mitral Annulus.

CHAPTER 37 

Cases of Diastolic Heart Failure

LA Volume.

Pulsed-wave Doppler RV Inflow With Respiration.

Tricuspid Regurgitation On Continuous Wave Doppler.

Pulsed-wave Doppler Of The Hepatic Veins.

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Pulsed-wave Doppler LV Inflow With Respiration.

REVIEW QUESTION 8. The findings are best explained by: a. normal diastolic function. b. RV dysfunction from arrhythmogenic RV cardiomyopathy. c. constrictive pericarditis. d. idiopathic restrictive cardiomyopathy.

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CASE 8: 64-Year-Old Asian Female Presents to the Emergency Room With Acute Dyspnea

Continuous Wave Doppler of LV Inflow.

• History: 64-year-old Asian female presents to the local emergency department complaining of increasing shortness of breath on exertion without chest pain. The emergency physician hears a systolic ejection murmur and orders an echo. • Past medical history: Sjögren disease, SLE, dyslipidemia • Past surgical history: Cyst removal from the neck • Social: No alcohol or smoking • Current medications: TMP-SMX, azathioprine, folic acid, tacrolimus, cyclosporine, pantoprazole • Physical exam: • Pulse: 82 bpm, sinus rhythm • Blood pressure: 138/70 mmHg • Neck: No jugular distention, no carotid bruits, no masses • Chest: Lungs are clear to auscultation • Cardiovascular: S1, S2 normal, Class III/VI systolic ejection murmur, no S3, no S4 • Abdomen: No tenderness, organomegaly, palpable masses, or bruits, normal bowel sounds • Extremities: No edema ECG

Pulsed-wave Doppler LV Inflow.

See Video 37.38: 2-D parasternal long axis. See Video 37.39: 2-D parasternal long axis with color. See Video 37.40: 2-D apical four chamber. See Video 37.41: 2-D apical two chamber. See Video 37.42: 2-D apical three chamber. See Video 37.43: 2-D apical five chamber of the LVOT. LV End-Diastolic Dimensions, 2D Parasternal Long Axis.

Tissue Doppler Lateral Mitral Annulus.

CHAPTER 37 

Cases of Diastolic Heart Failure

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Tissue Doppler Medial Mitral Annulus.

Tricuspid Regurgitation On Continuous Wave Doppler.

LA Volume.

Continuous Wave Doppler of Aorta From Right Parasternal Long View.

REVIEW QUESTION 9. What is the diastolic profile of this patient who was diagnosed with mild calcific aortic stenosis and has a normal LV systolic ejection fraction?

a.

Diastolic function is normal. b. There is grade I diastolic dysfunction. c. There is grade II diastolic dysfunction. d. There is grade III diastolic dysfunction. e. Unable to assess diastolic function.

CASE 9: 71-Year-Old Caucasian Female With Indeterminate Diastolic Function • History: A previously active 71-year-old Caucasian female presented to her primary care physician endorsing progressive dyspnea on exertion over the last 3 months. She denies any chest pain, orthopnea, or lower leg edema and had already presented to an emergency room where a recent chest x-ray and pulmonary function tests were completed and deemed normal for her age. • Past medical history: Gastroesophageal reflux disease, dyslipidemia • Past surgical history: None

• Social: Denies any smoking or alcohol consumption • Physical exam: • Pulse: 72 bpm, regular rhythm • Blood pressure: 134/84 mmHg • Neck: No elevation of JVP, no carotid bruits, no masses • Chest: Lungs are clear to auscultation • Cardiovascular: S1, S2 normal, systolic ejection murmur at the second intercostal space of the right chest • Abdomen: No tenderness, organomegaly, palpable masses, or bruits • Extremities: No edema

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ECG

Tissue Doppler Lateral Mitral Annulus.

See Video 37.44: 2-D parasternal long axis. See Video 37.45: 2-D parasternal long axis. See Video 37.46: 2-D apical four chamber. See Video 37.47: 2-D apical two chamber. See Video 37.48: 2-D apical three chamber. LV End-Diastolic Dimensions.

Tissue Doppler Septal Mitral Annulus.

Pulsed-wave Doppler LV Inflow.

LA Volume.

CHAPTER 37  See Tricuspid Regurgitation on Continuous Wave Doppler.

Cases of Diastolic Heart Failure

See LA Strain, Two Chamber.

LA Strain, Four Chamber.

REVIEW QUESTIONS 10. Is there diastolic dysfunction? a. There is diastolic dysfunction. b. There is no diastolic dysfunction. c. The diastolic function is indeterminate.

CASE 10: 75-Year-Old African American Male During Routine Follow-Up for Known Cardiomyopathy • History: 75-year-old African American male during routine followup for known nonischemic dilated cardiomyopathy reports mild symptoms and is currently classified as NYHA Class II/IV. • Past medical history: Insulin-dependent diabetes, hypertension, congestive heart failure with a reduced ejection fraction (23%) 6 months prior, and a previous hospitalization more than 1 year ago • Past surgical history: None • Social: No alcohol or smoking • Current medications: Insulin, atorvastatin, metoprolol succinate, isosorbide mononitrate, hydralazine, eplerenone • Physical exam: • Pulse: 60 bpm, sinus rhythm • Blood pressure: 120/65 mmHg • Neck: No jugular distention, no carotid bruits, no masses • Chest: Lungs are clear to auscultation • Cardiovascular: S1, S2 normal, no murmurs, no S3, no S4 • Abdomen: No tenderness, organomegaly, palpable masses, or bruits, normal bowel sounds • Extremities: No edema

ECG

See Video 37.49: 2-D parasternal long axis. See Video 37.50: 2-D parasternal long axis. See Video 37.51: 2-D apical four chamber. See Video 37.52: 2-D apical two chamber. See Video 37.53: 2-D apical three chamber.

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LV End-Diastolic Dimensions, 2D Parasternal Long-Axis.

Tissue Doppler Lateral Mitral Annulus.

Pulsed-wave Doppler LV Inflow.

LA Volume.

Tissue Doppler Medial Mitral Annulus.

Tricuspid Regurgitation on Continuous Wave Doppler.

CHAPTER 37 

REVIEW QUESTIONS 12. Which of the following is true? a. Diastolic function is normal. b. There is grade I diastolic dysfunction. c. There is grade II diastolic dysfunction with increased LA pressures. d. There is grade III diastolic dysfunction with increased LA pressures. e. Unable to assess diastolic function.

ANSWERS 1: A Fig. 37.1 is an algorithm to help determine the presence or absence of diastolic dysfunction in a presumed normal population. In the presence of myocardial pathology, a second algorithm (Fig.  37.2) helps determine the severity of the diastolic dysfunction. The current diastolic profile includes normal tissue doppler image (TDI) e′, E/e′, ­normal indexed left atrial (LA) volumes, and a normal tricuspid regurgitant (TR) jet velocity. Since left ventricular (LV)

Cases of Diastolic Heart Failure

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13. What can be said about the overall prognosis of this patient? a. Any degree of diastolic dysfunction is associated with a poor prognosis. b. A deceleration time greater than 150 msec (this case 290 msec) is associated with a poor prognosis. c. The presence of grade I diastolic dysfunction is more favorable than restrictive filling. d. No correlation can be made between diastolic dysfunction and filling pressures when dealing with dilated cardiomyopathy and reduced ejection fraction. ejection fraction is also normal, criteria for abnormal diastolic function (>50% abnormal parameters) is not met. While an E/A ratio above 2.5 may be indicative of elevated filling pressure in an abnormal heart, in a healthy athletic heart this ratio is driven by a very pronounced early diastolic suction effect from the left ventricle (as confirmed by the elevated septal and lateral e′ values). Increased ECG voltage and increased wall thickness by echocardiography may be normal findings in athlete’s heart and are not associated with myocardial pathology. Other normal findings in

Fig. 37.1  Diagnosis of diastrolic dysfunction in patients with LV EF 50% and above and no LV myocardial disease. (Courtesy of Abhinav Sharma, MD.)

Fig. 37.2  Algorithim for grading diastolic dysfunction in patients with LV myocardial disease or diastolic dysfunction. (Courtesy of Abhinav Sharma, MD.)

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athletes ­include mildly increased LV and LA volumes. These morphologic features are thought to normalize with cessation of exercise. Reduced TDI e′, in contrast, is almost invariably a pathologic finding. Given that this is not a pathologic state, genetic testing is not necessary. 2: C Fig. 37.1 is an algorithm to help determine the presence or absence of diastolic dysfunction in a presumed normal population. In the presence of myocardial pathology, a second algorithm (depicted in Fig. 37.2) helps determine the severity of the diastolic dysfunction and LV filling pressures. The current diastolic profile is demonstrating abnormal annular tissue Dopplers with an average E/e′ above 17 as well as an enlarged left atrium. Given that the ejection fraction is reduced and that there are more than two abnormal components of the diastolic evaluation present, we are dealing with a patient with diastolic dysfunction. Using Fig. 37.2 algorithm, the next step is to assess the E/A relationship. With an E/A ratio of 1.3 and an E velocity of 77 cm/sec we are prompted to evaluate further. Finally, with an increased LAVI, an increased E/e′, and a TR jet of 2.5 m/sec, this patient is diagnosed with grade II diastolic dysfunction and increased LA pressures rather than grade I diastolic dysfunction. Given that the E/A ratio is less than 2, restrictive filling is not yet present. There are a number of ways that have been investigated to estimate LA pressure noninvasively with 2-D and Doppler echocardiography. Ommen et al. demonstrated a correlation with mean LV diastolic pressure and E/e′ ratio. A ratio greater than 15 signified at least 10 to 15 mmHg and as high as 35 mmHg, while an E/e′ less than 8 varied from normal to 17  mmHg at most. In patients with low systolic function this can be further corroborated with an abnormal flow propagation Vp (on color M-mode) and a E/Vp greater than 2.1–3 3:A The current diastolic profile (see Figs.  37.1 and  37.2) is demonstrating abnormal annular tissue Doppler velocitiess with an average E/e′ above 25 as well as a LAVI measured at 56.8  mL/m2. Despite a mildly reduced ejection fraction of 40%, one can clearly identify based on the severely increased LV wall thickness that there is diastolic dysfunction. Using Fig. 37.2 algorithm, the next step is to assess the E/A relationship. With an E/A ratio of 3.5 we can conclude that there is a grade 3/restrictive filling pattern and markedly increased LA pressure. Cardiac amyloidosis is characterized by the progressive infiltration of fibrils causing an increase in wall thickness and LV stiffness and loss of LV compliance. The diastolic filling abnormalities can vary from delayed relaxation to restrictive filling. The progression to restrictive filling is generally associated with a poor prognosis. Cardiac amyloidosis is also characterized by regional variations in longitudinal strain with relative sparing of the apex, which has been found to be a specific echocardiographic sign. Characteristic of a restrictive filling pattern include an E/A ratio more than 2.5, a mitral inflow E wave deceleration time less than 150 msec, and decreased tissue Doppler velocities when interrogating the lateral and septal mitral annulus ( 2.7, deceleration time 130 msec b. e′ > 5 cm/sec c. E/A < 2, deceleration time 170 msec d. LV wall thickness 34 mL/m2), do not exclude the diagnosis of HFpEF due to poor sensitivity. Since this case has multiple typical comorbidities of HFpEF (obesity, hypertension, and atrial fibrillation), further testing should be considered. Invasive right heart catheterization during exercise has emerged as the gold standard to establish or exclude HFpEF and thus should be considered to bring out hemodynamic abnormalities that develop during exercise. Noninvasive diastolic stress echocardiography could be performed to rule out HFpEF. However, a positive exercise echocardiography does not establish HFpEF because of a high rate of false positive. 2. e. Incorrect wedge values can occur if the position of the catheter tip is incorrectly placed or if the balloon occlude is underinflated or overinflated. Intrathoracic pressure is transmitted to the pulmonary venous system. Values can oscillate dramatically and differ from atmospheric pressure in patients with severe dyspnea, air trapping, or receiving positive airway pressure ventilation. High-fidelity micromanometer-tipped catheters respond faster than fluid-filled catheters to rapid changes in pressure. These are not routinely used due to their much higher cost. Simultaneous recording of LV and capillary wedge pressure is required in some instances to establish the diagnosis of

497

mitral stenosis or severe mitral regurgitation as the etiology of HF. 3. e. Even though by definition HFpEF patients have normal or near-normal EF, contractility is commonly impaired as demonstrated when using advanced quantitative imaging methods such as strain imaging. Pulmonary hypertension can occur not only secondary to increase LA pressure but as a result of chronic pulmonary vascular remodeling. This often leads to impaired RV function. Ventricular interdependence imposed by the pericardium can lead to elevation of LV filling pressures secondary to acute RV failure in conditions such as RV infarction, hypoventilation, and pulmonary embolism.

CHAPTER 9 1. b. The patient is young and has abnormal loading conditions with a very high cardiac output. The LVEDP is elevated as pulmonary venous A wave duration exceeds mitral A wave duration by 30 msec. 2. a. The evidence that LV filling is a normal pattern is the concordance of the E/A wave velocity ratio with the TDI MAM e′/a′ velocity ratio. Although the left atrium is enlarged because of the high cardiac output, there is no evidence of increased LA pressure by either LV IVRT or reduced pulmonary venous systolic flow. 3. a. A Valsalva maneuver that showed a decrease in both mitral E and A wave velocities with LA pressure reduction would have been confirmatory evidence of the normal LV relaxation present. 4. a. The patient is middle aged and has normal loading conditions at the time of his echo. There is no evidence of increased filling pressures. 5. b. Mitral filling pattern is abnormal with a long IVRT, reduced mitral E wave, and increased A wave, indicating impaired relaxation. His TDI MAM e′ and a′ also have a ratio consistent with decreased longitudinal function, which suggests LV hypertrophy from either HT or obesity. 6. b. As in the previous answer, this patient represents the large group of patients with early diastolic dysfunction due to impaired LV relaxation who have no increase in filling pressures. However, in long-term studies, they are at increased risk for progression of disease and future adverse CV events. 7. d. This elderly male has multiple risk factors for cardiac disease and systolic and diastolic dysfunction. He has moderate LV hypertrophy with stage III–IV chronic kidney disease and is significantly volume overloaded, as seen by his dilated IVC. 8. c. His increased LA volume, short LV IVRT, increased mitral E/A wave ratio, and short DT and A wave duration are all consistent with pseudonormal filling. His TDI e′ and a′ MAM also has a pattern (ratio  A may actually be pseudonormalization. In patients with pseudonormal TMF, the duration of the pulmonary venous atrial reversal (AR) wave will be longer than that of the mitral A wave.10–12 However, pulmonary venous flow by echocardiography can sometimes yield suboptimal results, as illustrated in this case. PVF by cardiac MRI can be measured in the majority of cardiac MRI cases, as opposed to only 68% of TTE cases due to improved image quality with cardiac MRI.7 3. b. The global diffuse hyperenhancement is most consistent with a diagnosis of cardiac amyloidosis. Patients with amyloidosis will typically demonstrate a diffuse pattern of LGE in a noncoronary distribution that can also extend into the right ventricle, interatrial septum, and atrial walls. Additionally, native T1 measurements and ECV measurements can identify cardiac amyloidosis at earlier stages and provide powerful prognostic risk stratification

500

REVIEW QUESTION ANSWERS  



in patients with both transthyretin amyloidosis and primary amyloidosis.

CHAPTER 16 1. d. The radionuclide assessment of the diastolic LV function is attained plotting the changes in radioactivity over time, which is proportional to changes in LV volume over time. This allows the calculation of ventricular filling rates, maximum filling timing, as well as time to peak filling rates. An adequate temporal sampling of the LV volume is crucial to capture the subtle alterations in diastolic filling requiring at least 16 to 32 frames per heart cycle. The presence of arrhythmias during the data acquisition reduces the quality and fidelity of the diastolic assessment. As any change in the R-R interval invariably introduces changes in the diastolic filling, beats with R-R interval that vary by more than ±10% from the mean R-R must be rejected, as well as the beat following the rejected beat. Finally, the evaluation of diastolic function using radionuclides techniques was initially conducted using the equilibrium and first-pass radionuclide angiocardiogram; however, myocardial perfusion studies are also able to adjunctively assess the diastolic function assuming an optimized data acquisition for this purpose as presented in this chapter. 2. b. The rate of volume change over time during early diastole provides the most important measurements of ventricular diastolic function. These measurements include the peak ventricular filling rate (PFR) and the time to peak filling rate (TPFR). Under normal conditions, the PFR is greater than 2.5 EDV/sec attained in less than 180 msec, otherwise an impaired diastolic dysfunction is suggested. Alterations in these parameters are highly sensitive but lack specificity, as they can be altered in the absence of pathology due to age, heart rate, systolic function, enddiastolic volume, adrenergic state, medications, and even changes in methods of acquisition and processing. 3. d. The high sensitivity of radionuclide techniques in the detection of diastolic dysfunction may allow the identification of certain clinical conditions such as hypertensive heart disease, chemotherapy-induced cardiotoxicity, or even microvascular dysfunction before the onset of symptoms. For instance, those patients with hypertensive heart disease present with diastolic impairments that appear to be dependent on myocardial mass rather than age or severity of hypertension. The presence of an impaired diastolic function despite a normal LV systolic function can suggest the presence of HFpEF in the right clinical context. Nevertheless, radionuclides techniques only detect diastolic dysfunction in less than 60% of patients with suspected HFpEF. This highlights the wide heterogeneity of pathology within these groups of patients. Finally, the adjunctive analysis of diastolic function during myocardial perfusion studies might be of help to ascertain the underlying pathology in patients presenting with cardiorespiratory symptoms with normal myocardial perfusion, as illustrated in the case study.

CHAPTER 17 1. d. This is a case example of cardiac amyloid. Classic features include marked LV and RV wall thickening, a small pericardial effusion, marked biatrial dilatation, and apical sparing on the GLS bull’s eye plot. LV systolic function is normal with an LV EF of 60%. For LV diastolic function, in the setting of a normal LV EF, the assessment normally begins with algorithm A in Fig. 17.1. However, there is a significant increase in LV wall thickness, as well as abnormal GLS (−9.4%), indicating the presence of underlying myocardial disease. Therefore in this instance, analysis of LV diastolic grading begins with algorithm B. The transmitral inflow profile shows that the E/A ratio is greater than 2; this is consistent with grade III diastolic dysfunction and elevated LAP. To support this further, there is a marked reduction in both the septal and lateral e′ velocities (2.7 cm/sec and 4.1 cm/sec, respectively), an elevated average E/e′ ratio of 37, and a dilated left atrium (indexed LA volume 53 mL/m2). 2. c. In this case, there is evidence of grade III diastolic dysfunction with an elevated LAP. When there is diastolic dysfunction, impaired relaxation is in most patients present across all grades. Both the IVRT and Vp are indices that reflect LV relaxation; hence it would be expected that both of these indices would be prolonged. However, while the Vp is relatively preload independent, the IVRT is preload dependent. This means that the IVRT is influenced by the LAP. Therefore in this case example, the Vp would be prolonged, but the IVRT would be shortened by the increased LAP. Remember that while LV relaxation is prolonged, because of the coexistent marked elevation in the LAP, the crossover between the LA and LV pressures occurs earlier and thus the mitral valve opens earlier than normal. This results in the shortening of the IVRT. 3. c. Grade III diastolic dysfunction is consistent with restrictive LV filling and a marked elevation in LAP. In these cases, the Valsalva maneuver may be performed to differentiate between reversible restrictive LV filling and irreversible restrictive LV filling. When there is reversible restrictive LV filling, following preload reduction, the profile is reversed to either a pseudonormal profile or even to an abnormal relaxation profile. When there is irreversible restrictive LV filling, following preload reduction, the profile remains unchanged, the E/A ratio remains high, and the DT remains short. An adequate Valsalva attempt is a 10% reduction in the peak transmitral E velocity from the baseline value. In the example shown, the peak transmitral E velocity decrease by just 3% (resting E velocity 1.26 m/ sec and 1.22 m/sec with Valsalva); therefore this was a suboptimal Valsalva attempt. 4. a. This pulmonary venous trace was acquired at high PRF. This is identified by the appearance of a second sample volume along the Doppler beam (see figure). Therefore the displayed signal shows the pulmonary venous inflow signal from sample volume 1 (SV1) plus the transmitral inflow signal from sample volume 2 (SV2) superimposed

REVIEW QUESTION ANSWERS

on the pulmonary venous trace; the pulmonary venous S velocity is seen below the zero baseline, while a combination of the transmitral E and the pulmonary venous D velocities are seen above and below the zero baseline. This occurs when the velocity scale is set too high and the high PRF mode is activated. Recall that in the low PRF mode, the transducer emits a pulse, and then waits for the returning signal before sending out the next pulse; this limits the maximum velocity that can be displayed. To increase the velocity scale further, the number of sample volumes can be increased by going into high PRF mode. In high PRF mode, the transducer does not wait for the first pulse to return to the transducer before sending out a second pulse, and this then increases the maximum displayed velocity. Decreasing the velocity scale will remove the second sample volume and eliminate contamination of the pulmonary venous signal by transmitral inflow.

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gathering data regarding stress-induced elevation of LV filling pressure. These features may make exercise Doppler echocardiography during supine bicycle exercise the optimal approach to demonstrate the increase in LV filling pressures with exercise. 2. c. Diastolic stress echocardiography is indicated when resting echocardiography does not explain the symptoms of heart failure or exertional dyspnea. Patients with completely normal hearts and diastolic function at rest with preserved e′ velocity need not undergo stress testing, as it is highly unlikely that they will develop diastolic dysfunction and elevated filling pressures with exercise. Likewise, patients with abnormal findings at baseline consistent with elevated LV filling pressures should not be referred for stress testing, as the cardiac etiology for dyspnea has already been established and their filling pressures will almost certainly increase further with exercise. The most appropriate patient population for diastolic stress echocardiography is the group of patients with grade I diastolic dysfunction, which indicates delayed myocardial relaxation and normal LA mean pressure at rest. 3. d. Diastolic stress echocardiography is definitively normal if the septal E/e′ is less than 10 at rest and with exercise, and the peak tricuspid regurgitation (TR) velocity is less than 2.8 m/sec at rest and with stress. A study is definitively abnormal when the septal E/e′ ratio is above 15, peak TR velocity is greater than 2.8 m/sec with exercise, and the septal e′ velocity is less than 8 cm/sec at baseline.

CHAPTER 19

CHAPTER 18 1. c. Atrial pacing is a feasible and easy way of stressing the heart, especially in patients in whom physical exercise is not possible. However, it must be noted that the hemodynamic changes associated with atrial pacing are different from those associated with physical exercise. The main hemodynamic change with atrial pacing is a decrease in LV stroke volume due to a decrease in LV filling time that is not accompanied by an adequate compensatory increase in systemic venous return. Therefore to demonstrate an increase in LV filling pressure with stress, pacing is not a suitable technique. Dobutamine has been frequently used to pharmacologically stress the cardiovascular system. Similar to atrial pacing, dobutamine may not be a suitable technique to demonstrate an increase in LV filling pressure with stress. However, dobutamine administration may be helpful to evaluate myocardial longitudinal functional reserve in subjects with an inability to exercise. Physical exercise is the most physiologic means of

1. c. Algorithm 1 should be used from the ASE/EACVI 2016 guidelines. Of the four parameters used to evaluate LV diastolic function, three are positive: septal e′ less than 7 and lateral e′ less than 10, TR velocity greater than 2.8 m/ sec, and LA volume greater than 34 mL/m2. As more than 50% of the parameters are positive, there is reason to suspect diastolic dysfunction. 2. c. Algorithm 2 should be used since the patient has a cardiac history and myocardial disease. The first step in the evaluation of LV filling pressure is estimation of mitral flow velocities. This patient has a mitral E velocity of 65 cm/sec and an E/A ratio of 0.9, which places the patient in the intermediate group, where three additional parameters need to be evaluated. Two of these three additional parameters, TR velocity and E/e′, are below their respective cutoff values (2.8 m/sec and 14), whereas LA volume is above the cutoff value. Thus the majority of parameters are negative, the patient is considered to have grade I diastolic dysfunction, and LV filling pressure is assumed to be normal. 3. a, d. In patients with atrial fibrillation, there is normally dilatation of the left atrium, and thus elevated LA volume cannot be used to estimate LV filling pressure. As there is no atrial contraction, the E/A ratio cannot be estimated. E/e′ and TR velocity, on the other hand, correlate well with LV filling pressure also in patients with atrial

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fibrillation, and these two parameters can thus be used in the evaluation of LV filling pressure. 4. b. In the guidelines from 2009, grade I diastolic dysfunction was defined as patients with echocardiographic evidence of diastolic function but normal LV filling pressure. In the updated version, four criteria are used to decide whether diastolic dysfunction is present or not in patients with normal systolic function. Only if three or four of these parameters are positive, the patient is said to have diastolic dysfunction. Three of these parameters are also used to decide whether LV filling pressure is elevated or not. Thus to be defined as having diastolic dysfunction, LV filling pressure is elevated. This is a more restrictive definition, defining fewer patients as having diastolic dysfunction than with the 2009 guidelines. Thus sensitivity (the ability of the test to be positive in patients with diastolic dysfunction) was reduced, whereas the specificity (the ability of the test to be negative in patients without the disease) was increased. 5. c. In the early stages of diastolic dysfunction, patients may have completely normal echocardiography at rest or evidence of delayed relaxation only. When heart rate increases with activity in healthy individuals, LV relaxation rate also increases. Patients with diastolic dysfunction may not be able to increase relaxation rate with exercise. This results in impairment of diastolic function with exercise. Thus in patients presenting mainly with symptoms of diastolic dysfunction with exercise but normal echocardiography at rest, a diastolic stress test is recommended.

CHAPTER 20 1. c. At the myocardial level, LV diastolic dysfunction is caused by incomplete and/or slowed relaxation and increased passive stiffness. Titin, along with extracellular matrix collagen, is responsible for the passive stiffness of the myocardium. In hypertensive patients with HFpEF, reduced phosphorylation of PKA/PKG sites on titin has been reported14,15 and serves to increase titin’s stiffness, and in turn reduce diastolic LV chamber compliance. Increased, not decreased, collagen has been reported in these patients and also contributes to diastolic dysfunction. Reduced SERCA2 activity and reduced troponin I phosphorylation have not been reported. 2. c. The development of HFpEF has been attributed to multiple comorbidities, including, but not limited to, hypertension, obesity, diabetes, and chronic kidney disease.4 Of all of these, hypertension is thought to be present in at least 90% of HFpEF patients,5 and is thus the most common. 3. c.  ACC/AHA guidelines recommend chlorthalidone as a first-line agent for blood pressure lowering in HFpEF patients.17,19 This is based in part on the results of the ALL-HAT trial, which showed that chlorthalidone reduced the risk of cardiovascular events, including heart failure in hypertensive patients. The guidelines also

support inhibition of the renin-angiotensin system (RAS) with ACE inhibitors or ARBs as first-line treatment for hypertension management, particularly in patients with T2DM. Beta blockers are not guideline-recommended first-line blood pressure–lowering agents in patients with HFpEF and may possibly contribute to diastolic dysfunction and adverse outcomes.20,21 Hydralazine and nitrates are also not first-line treatments.

CHAPTER 21 1. e. The patient is clearly in heart failure (shortness of breath, pulmonary rales, peripheral edema, increased NT-proBNP). His LV EF is calculated at 45%, which is only mildly reduced, but his GLS is 9% (normal, 20%), which is severely reduced. GLS is a marker of both systolic and diastolic LV function. Since there are clear signs of diastolic dysfunction, this may explain some of the reduction in GLS, but GLS is also more sensitive to milder forms of systolic LV dysfunction than ejection fraction, in particular in patients with LV hypertrophy (as in this case). Degenerative mitral stenosis is mild with transmitral velocities not exceeding 1.4 m/sec; the mean gradient of 5 mmHg confirms mild stenosis. Such a stenosis can explain neither the considerable pulmonary hypertension nor the heart failure symptoms. Regarding the right ventricle, size and function are described as normal, although given the high right-sided pressures, there may still be silent RV dysfunction, which may manifest with physical exertion. 2. c. Several studies6,7 have suggested in aortic stenosis patients that baseline LV diastolic function before valve intervention (surgical or transcatheter) affects postinterventional survival and quality of life, independently of LV systolic function. Of course, ejection fraction and, even more so, global longitudinal strain, as well as increased pulmonary pressures, are also strong predictors of prognosis. 3. b. Mitral regurgitation, due to the additional regurgitant volume passing through the mitral valve in diastole, increases E wave velocity. This in turn also leads to higher E/A and E/e′ ratios independently of myocardial diastolic function, although e′ may be commensurately elevated if the left ventricle contracts and relaxes more vigorously due to the extra volume load. RV pressures tend to increase due to backward propagation of high LA pressures caused by mitral regurgitation. Finally, systolic pulmonary venous flow is pushed back by the regurgitant blood entering the left atrium in systole, leading to a decreased S/D ratio. All of these parameters also change in the same direction in the presence of diastolic dysfunction (without mitral regurgitation). LV wall thickness, however, is not affected by mitral regurgitation.

CHAPTER 22 1. b. Based on the results of the CHAMPION trial in 2014 the FDA approved use of the CardioMEMS sensor in both patients with HFpEF and HFrEF, who had symptomatic

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HF (NYHA Class III) and were on optimal medical therapy with a history of HF hospitalization within the last year. 2. c. The most recent ACC/AHA guidelines state that in select patients with HFpEF, the use of spironolactone may be considered to reduce hospitalizations (COR IIb, LOA B-R). No other pharmacologic interventions have been proven to improve mortality or readmissions in HFpEF. 3. d. The major concern with LVAD implantation in patients with HFpEF is obstruction of flow into the LV inflow cannula due to the smaller cavity size and thickness of the LV walls. Patients with HFpEF in the studies experience more frequent and difficult-to-manage suction events. The investigators suggested the need for technical modifications in the surgical procedure. An echocardiographic analysis of a cohort of HFpEF patients found that larger LVEDD is a marker of better outcome. LVEDD of 4.6 cm and below was associated with increased mortality post LVAD implantation. 4. b. The ACC/AHA guideline for the management of heart failure classifies disease progression into four stages: stage A includes patients with risk factors for HF but without structural heart disease, stage B includes those with structural heart disease without HF symptoms, stage C represents symptomatic HF associated with underlying structural heart disease, and stage D reflects refractory symptoms despite guideline-directed medical therapy (GDMT). 5. d. According to ACC/AHA guidelines, HFpEF is defined as the presence of the HF syndrome in an individual with a LV EF of 50% and above. Patients suffering from HFpEF where LV diastolic dysfunction predominates usually also exhibit LV systolic dysfunction as evident by abnormalities of longitudinal strain, LV end-systolic (Ees) stiffness (elastance), ventricular-arterial coupling (Ea/Ees ratio), and vasculoventricular coupling. In addition, chronotropic incompetence, abnormal vasorelaxation, right heart dysfunction, and abnormalities in the periphery are present in patients with HFpEF. 6. c. Compared to patients with HFrEF, those with HFpEF are older and more likely to be female. The incidence and prevalence of HFpEF increase sharply with age. The prevalence of HFpEF is increasing relative to HFrEF at a rate of 1% per year, suggesting that HFpEF may become the most common type of HF in the near future. The proportion of patients hospitalized with acute HF who had HFpEF increased from 33% in 2005 to 39% in 2010. At the same time, the proportion of HF hospitalizations due to HFrEF decreased from 52% to 47% in the United States. 7. c. COMPASS-HF, a randomized clinical trial testing the efficacy of Chronicle, enrolled 301 patients with NYHA Class III–IV symptoms regardless of LV EF but failed to show any significant effect on hospitalizations, as compared to the control group. LAPTOP-HF, a large randomized trial designed to test the safety and effectiveness of LA pressure-guided HF therapy, was terminated early by

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the study’s data and safety monitoring board after randomization of only 486 patients because of a high number of implant-related complications. The CHAMPION trial found a 37% reduction in the primary end point of HF-related hospitalization compared to the control group. 8. c.  Patients with HFpEF presenting with acute HF have higher systolic blood pressure values than those with HFrEF. Treatment with intravenous nitroprusside results in greater blood pressure reduction in HFpEF, less enhancement in cardiac output, and greater likelihood of stroke volume drop in HFpEF, as compared to HFrEF. 9. b. Based on the results of the CHAMPION trial in 2014, the FDA approved the use of the CardioMEMS sensor in both patients with HFpEF and HFrEF, who had symptomatic HF (NYHA Class III) and were on optimal medical therapy with a history of HF hospitalization within the last year. 10. c. The most recent ACC/AHA guidelines state that in select patients with HFpEF, the use of spironolactone may be considered to reduce hospitalizations (COR IIb, LOA B-R). No other pharmacologic interventions have been proven to improve mortality or readmissions in HFpEF. 11. d. The major concern with LVAD implantation in patients with HFpEF is obstruction of flow into the LV inflow cannula due to the smaller cavity size and thickness of the LV walls. Patients with HFpEF in the studies experienced more frequent and difficult-to-manage suction events. The investigators suggested the need for technical modifications in the surgical procedure. An echocardiographic analysis of a cohort of HFpEF patients found that larger LVEDD is a marker of better outcome. LVEDD less than or equal to 4.6 cm was associated with increased mortality postLVAD implantation.

CHAPTER 23 1. e. Recent studies suggest that ∼1% of patients diagnosed with HCM actually have Fabry disease. Mimics of HCM are referred to as phenocopies and include many other infiltrative or storage diseases, such as Fabry disease, amyloidosis, and glycogen storage diseases. Fabry disease is an X-linked disease caused by a deficiency in the lysosomal enzyme α-galactosidase A, leading to accumulation of glycosphingolipids in various tissues, including the heart. Fabry disease should be suspected in patients diagnosed with HCM when there are systemic symptoms or signs, a family history of Fabry disease or cardiomyopathy with male predominance in severity, or suggestive echocardiographic or cardiac MRI findings. Systemic symptoms and signs include cornea verticillata, hypohidrosis, acroparasthesias, premature transient ischemic attack/stroke, kidney disease with proteinuria, and angiokeratoma. On echocardiography, patients are more often nonobstructers, with symmetric hypertrophy, and may have hypokinesis or thinning of the inferolateral basal wall. On cardiac MRI, the hallmark finding is low native T1 values.

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2. d. The presence of extreme LV hypertrophy in a young male with the presence of ventricular preexcitation suggests alternative diagnoses other than HCM. The rare glycogen storage diseases (PRKAG2, Danon disease, and LAMP2 mutations) should be suspected with this clinical history. Danon disease is an X-linked dominant gene affecting primarily young males under the age of 20 years old. Noncardiac manifestations include skeletal myopathy, mental retardation or behavioral abnormalities, and ocular changes. Echocardiography may show massive hypertrophy, and electrocardiography may show preexcitation. Laboratory testing is notable for elevated CPK, LFTs, and troponin levels. Patients with Danon disease usually have a malignant clinical course, and if undetected are at risk of premature sudden death. 3. e.  The clinical history, physical examination, laboratory testing, and echocardiogram are all consistent with idiopathic restrictive cardiomyopathy (IRCM). The clinical findings are consistent with biventricular diastolic heart failure. The echocardiogram is virtually diagnostic in this case. The ventricular wall thickness with IRCM is generally normal or at most mildly increased due to extensive fibrosis. There is severe diastolic dysfunction (grade III or restrictive filling pattern), with an elevated LA pressure (elevated E/e′ ratio, LA enlargement, and pulmonary hypertension). The slow color M mode propagation velocity, absence of respiratory variability, and prominence of atrial reversal in the hepatic veins with inspiration are consistent with a restrictive cardiomyopathy, not constrictive pericarditis. Cardiac catheterization hemodynamics, cardiac MRI, cardiac biopsy, and genetic testing may be helpful for confirming the diagnosis. The prognosis, particularly in the pediatric population, is poor and cardiac transplantation should be considered.

CHAPTER 24 1. b. The patient is presenting in the setting of a myocardial infarction with abnormal baseline echo, so likely has some degree of diastolic dysfunction. After using the recommended variables to evaluate LV diastolic function in the setting of preserved LV EF with structural disease, we next rely on E/A ratio and velocities. With septal E/e′ ratio less than 14, LA maximum volume index greater than 34 mL/m2, and peak TR velocity less than 2.8 m/sec, she falls into the grade I diastolic dysfunction category with normal LV filling pressures. 2. c. Though pulmonary venous flow analysis was deemphasized in the 2016 ASE/ESE diastolic guideline document, valuable pathophysiologic insight is provided by these data. What is shown here is the absence of a pulmonary vein S wave and a remarkably D-dominant pattern. The differential diagnosis for this finding includes choices a through c; however, with the data furnished thus far, the most reasonable choice is c. The ECG described and the rhythm strip on the echo shows sinus rhythm. DT less than 140 msec is an independent predictor for in-hospital

heart failure and cardiac death. E/e′ is another independent predictor of in-hospital events and follow-up LV EF. Option a is not correct because high LA pressure alone can blunt the S wave. Option b is an incorrect choice because the ECG tracing clearly shows a P wave. It is true, however, that the pulmonary vein S wave will be blunted in patients with atrial fibrillation because the first component of a pulmonary vein S wave depends on atrial relaxation. Option d is incorrect. While it is very likely that this patient has a high LVEDP, the A reversal duration on which this judgement depends is not clearly shown in this real-world example.

3. e. There is still evidence for elevated filling pressures by virtue of an elevated E/e′ ratio. According to the ASE guidelines, using the second grading algorithm (invoked here because of manifest LV dysfunction), this individual has grade II diastolic function. Even if one were to eschew the grade nomenclature, this patient has evidence of elevated filling pressures. Option a is an incorrect choice because the E/e′ ratio is elevated, denoting elevated mean LA pressure. Option b is incorrect because the presence of three of three abnormal criteria for the second algorithm denotes grade II or pseudonormal diastolic function. Options c and d are incorrect choices because of the marked reduction in E/A ratio, which is no longer greater than 2.

CHAPTER 25 1. c. Mutations related to HCM result in the production of abnormal myocardial sarcomeric proteins that have altered contraction and relaxation. Myosin heavy chain mutations in this region enhance contractility at the expense of impaired relaxation. 2. b. Coronary blood flow reserve is compromised in HCM through increased myocardial oxygen demand secondary to increased myocardial mass, myocyte disarray, the presence of interstitial fibrosis, and decreased oxygen supply due to abnormalities of the coronary microvasculature. 3. a. Peak myocardial systolic velocities, strain, and diastolic function parameters are preserved in an athlete’s heart,

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when compared to HCM. LV mass and LA volumes are often increased in both conditions. Concentric LV hypertrophy is more common in HCM.

CHAPTER 26 1. c. Prominent x and y descents are the classic venous wave morphology seen in patients with constrictive pericarditis (W sign). These are negative deflections (i.e., descents), in contrast to the large v wave seen in patients with severe tricuspid regurgitation. Cannon a waves are typically seen in patients with complete heart block or atrioventricular dissociation. The presence of markedly elevated venous pressure and blunted y descents is consistent with cardiac tamponade and reflects the impaired ventricular diastolic filling associated with increased intrapericardial pressures. 2. b. The Doppler signal shown illustrates the typical increased diastolic flow reversals during expiration seen in constrictive pericarditis. The proper timing in the respiratory cycle is identified by the simultaneous respirometer (upward deflections mark the beginning of inspiration, whereas the downward deflections mark the onset of expiratory) and the peak systolic forward flow velocities (highest at peak inspiration and lowest at peak expiration). Increased inspiratory flow reversals are seen in restrictive cardiomyopathy, whereas systolic flow reversals are typical for severe tricuspid regurgitation (note the preserved systolic forward flow in this patient; only trivial tricuspid regurgitation was present). 3. d. The presence of respirophasic septal shift is shown in the video; during inspiration, the ventricular septum moves toward the LV cavity with reciprocal changes occurring during expiration. This reflects the reciprocal changes in RV and LV preload due to the presence of pericardial restraint/constrictive pericardium. The inspiratory decrease in mitral E velocities reflects the presence of dissociation of intrathoracic-intracardiac pressures, where filling of the left heart decreases during inspiration. Signs of elevated filling pressures are demonstrated by the dilated inferior vena cava and the restrictive mitral inflow seen in constrictive pericarditis. Lastly, pulsus paradoxus is a consequence of the decreased inspiratory stroke volume of the left ventricle, due to a combination of both ventricular interdependence and dissociation of intrathoracic-intracardiac pressures. 4. b. His cardiac magnetic resonance demonstrates significant late gadolinium enhancement, consistent with ongoing pericardial inflammation. Although surgical pericardiectomy remains the definite therapy for patients with refractory or chronic constrictive pericarditis, anti inflammatory therapy should always be attempted initially in patients presenting with evidence of ongoing inflammation (elevated inflammatory markers or late gadolinium enhancement on cardiac MRI). Surgical pericardiectomy should be reserved for those presenting subacutely, who have failed medical therapy or in those where anti

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inflammatory therapy is felt to have low yield. Given the diagnostic bedside, echocardiographic, and crosssectional findings, the diagnosis of constrictive pericarditis can be established, foregoing the need for cardiac catheterization.

CHAPTER 27 1. d. In aortic stenosis and other left obstructive lesions, development of endocardial fibroelastosis in fetal life contributes to a noncompliant left ventricle over and above myocardial fibrosis. A merged mitral inflow E and A wave is common in this scenario, when infants are tachycardic and complicate assessment of diastolic function using mitral inflow parameters. The left atrium may not be dilated due to unloading of the left atrium through the patent foramen ovale in fetal life and postnatally. LV systolic function may be significantly reduced in critical AS, but good systolic function does not preclude the presence of diastolic dysfunction. 2. c. The diastolic parameters are consistent with signs of delayed relaxation and decreased compliance (pseudonormal), with some parameters intermediate because of the opposed effects of impaired relaxation versus increased filling pressures. The presence of a mid-diastolic L wave is consistent with both delayed relaxation and increased filling pressures, especially the latter. While it is difficult to classify the diastolic function of this adolescent using adult criteria, he has abnormal diastolic function affecting both early and late diastole. 3. b. As the previous case demonstrates for the left ventricle, this case displays features of RV delayed relaxation and decreased compliance. While the clinical implications of antegrade end-diastolic flow in the main pulmonary artery are not totally clear, it is thought to reflect decreased RV compliance and not delayed relaxation. The E/e′ ratio does not accurately predict filling pressures in children, including those with congenital heart disease. Pulmonary regurgitation duration shortens with restrictive physiology.

CHAPTER 28 1. e. Diabetes mellitus dramatically increases HF. Data from the Framingham population demonstrated twofold to fivefold excess risk for developing new HF in individuals with diabetes mellitus.5 If they are young, the excess risk is fourfold to eightfold.5 The effect has a greater impact on women as compared to men,5 which is also the case in patients with HFpEF. 2. b. Data are from Australian heart disease statistics, published by the National Heart Foundation of Australia.6 A recent cohort study of 1.9 million persons found that heart failure and peripheral arterial disease are the initial cardiovascular presentations of diabetes7 (see Introduction in Chapter 28). 3. d. See Table 28.1. From more than 8%, there is a significant increase in HF incidence. Of note, each 1% elevation in

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HbA1c leads to an 8% to 15% increase in the frequency of HF independent of other risk factors.9,10 Conversely, a 1% reduction of HbA1c levels is associated with a 16% reduced risk of developing HF and worsening outcome.11 4. b. See Imaging for Systolic Function section in Chapter 28. The myocardial strain imaging is a relatively new technique to determine the degree of myocardial deformation (strain and strain rate). In current practice, most are derived from two-dimensional speckle tracking echocardiography (2D STE) but can be derived from threedimensional images (3D STE). Myocardial strain is defined as the change in the length of a segment divided by the original length of the segment, whereas the strain rate is the rate at which this deformation occurs during a cardiac cycle. GLS is calculated by averaging the strains of three apical views. Reduced GLS is a sensitive marker of systolic dysfunction, identifying diminished longitudinal deformation even while EF is preserved. A decrease in GLS was independently associated with all-cause death and hospitalization after adjusting for age, systolic BP, exercise capacity, and HbA1c (HR 1.12 [1.00–1.21]), as well as provided incremental prognostic value up to 10 years.64 5.  a,  e. See Management section in Chapter 28 and Table 28.2. Multiple studies have looked at the CV benefits of the antidiabetic medications. Metformin120 and SGLT2i14,130–132 being the only classes showing positive signals. Metformin and SGLT2i have protective effects, whereas thiazolidinediones increase HF. Insulin has similar HF incidence with placebo but more HF compared with other glucose-lowering drugs. Sulfonylureas are less favorable to metformin. Further trials are ongoing, which will shed more light on this area.

CHAPTER 29 1. b. In the normal heart, the complex process of LV myocardial deformation results from the oblique orientation of myocardial fibers, whereby endocardial ones are aligned more parallel to the long axis and relate primarily to longitudinal mechanics, versus epicardial fibers, responsible primarily for circumferential mechanics. Both layers contribute to LV rotation, and the sum of their deformation represents radial deformation. ASE guidelines do not strictly define normal ranges of GLS as the result of the wide heterogeneity of published data; however, values above −20% with a SD of ± 2% are suggested as normal reference. Both technical (clip selection, timing, vendor, image quality, etc.) and clinical (age, gender, volume status, hemodynamics, etc.) factors constitute potential sources of variability in the clinical application of speckle tracking strain. Limitations of tissue Doppler imaging in strain imaging include noise, angle dependency, and measurement of deformation between time points as opposed to deformation between original and measured

length, factors not applicable to speckle tracking strain analysis. 2. c. Dyspnea is a rather complex complaint associated with a multiplicity of potential mechanisms and etiologies ranging from cardiac and musculoskeletal, to respiratory disorders. As such, a single parameter of LV performance cannot assess all these factors, particularly if measured in resting conditions. Remodeling processes in the ailing heart lead to impaired myocardial relaxation and contractility causing either systolic or diastolic dysfunction regardless of the LV EF or the underlying disease mechanism. Hypertrophic cardiomyopathy encroaches the LV cavity during diastolic filling, thereby reducing end-diastolic volume and increasing the EF; changes in stroke volume and contractility in this setting do not necessarily impact EF. Since EF is influenced by preload and afterload (markers of pressure/volume interactions), it cannot be used as a reliable reproducible marker of contractility. 3. a. Despite absent or subtle LV mechanics abnormalities at rest, many patients with HFpEF exercise testing may unmask abnormal LV untwisting and longitudinal strain indices (in addition to reduced mitral annular motion) that are invariably correlated with peak VO2 max and elevated filling pressures. 4. d. Patients with HFpEF have a normal EF despite reduced longitudinal strain. Increased LV volume, reflecting remodeling, is the main difference between HFpEF and HFrEF; in the former, there is LV stiffness that largely depends on volume, which explains why the pressurevolume loop is shifted up and to the left. The reason patients with HFpEF have a normal EF despite reduced longitudinal strain is the presence of preserved circumferential strain and twist that compensates for the reduced shortening of subendocardial fibers.

CHAPTER 30 1. d. This patient’s HR of 64 is indicative of chronotropic incompetence in the setting of cardiogenic shock. ECMO cannulation, while indicated for refractory cardiogenic shock, is not the correct answer for this patient given his partial response to pharmacologic therapies and several less invasive/morbid additive therapies still available. Option b is a reasonable answer if the patient remains in cardiogenic shock after his chronotropic incompetence is corrected and if his peripheral artery disease permits insertion. Option c is incorrect because while an echocardiogram should be performed urgently, the patient should be stabilized first. Additionally, there are no signs on the physical exam of aortic valve incompetence. 2. c. Doppler echo-guided AV optimization studies are designed to optimize the diastolic filling period of the cardiac cycle. Typically this is done by programming an inappropriately short AV delay, and then progressively

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prolonging the AV delay until the A wave fully emerges in the diastolic interval. The A wave should terminate just after the onset of the QRS (within 40 msec) most closely approximating normal electrical-mechanical delay. These characteristics allow the atria to contribute to ventricular filling, thereby maximizing cardiac output. Abbreviation of the E wave by the A wave is representative of the passive filling stage of diastole being cut short by a premature atrial contraction. 3. a. Available series show up to 6.7% of HBP leads will require revision after implant due to loss of capture or increasing thresholds. This failure rate is improving with improved equipment but still prevents the widespread adoption of this technology. The HBP does not lead to increased rates of TV disruption, and in most cases can be affixed to the atrial side of the TV. The initial success rates for HBP implant are over 90% in modern series and will likely continue to improve as delivery sheaths and the leads themselves are improved. There are many series demonstrating the restoration of AV/VV synchrony and downstream improvements in EF and LVESV/LVEDV in patients utilizing HBP compared to those with a traditional RVA pacing system.

CHAPTER 31 1. c. The patient has TTE findings indicative of diastolic dysfunction but no objective evidence of volume overload or lung congestion by exam. The clinical definition of HFpEF requires additional confirmatory findings such as lung congestion on chest x-ray and/or elevated BNP. 2. b. The TTE findings at rest are consistent with grade I diastolic dysfunction. One may, however, consider an exercise study to determine if the symptoms of dyspnea are related to worsened hemodynamics during exercise. 3. b. The cardiopulmonary exercise can determine the degree of exercise intolerance as well as to differentiate cardiac versus ventilatory failure as the etiology of symptoms. 4. d.  ASE diastolic function set cutoffs for e′ velocities of 10 cm/sec for lateral annulus and 8 cm/sec for septal annulus. In Amil Shah’s 2016 analysis of ARIC, 82% of subjects ages 67 to 90 years had an abnormal septal e′ and 91% had an abnormal lateral e′. As expected, subjects below this cutoff did not have an increased risk of heart hospitalization or death. 5. b. Aging in itself appears to prolong LV relaxation. Markers of relaxation in lifelong exercisers, such as e′ velocities or isovolumetric relaxation time, are more similar to their sedentary peers than young controls. On the other hand, compliance curves in lifelong exercisers are superimposable with the young controls, and sedentary seniors are shifted to the left. While compliance declines with sedentary aging, this appears to be primarily related to fitness and lifestyle and is preventable. Systolic function does not decline with age, though more data on systolic mechanics are needed.

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6. c. Aging results in an expected sarcopenia that can result in deconditioning and fatigue on exertion. Other changes that occur include a decrease in oxygen carrying capacity (VO2max), decrease in lung function, and alterations of diastolic function. Ejection fraction and elevated resting cardiac filling pressures are not expected to change with healthy age. 7. c. HFpEF is highly prevalent in the elderly population and often presents later in life. In 2008, Tribouilloy et al. demonstrated that the incidence of HFpEF overtakes HFrEF in the seventh decade of life. 8. b. With aging, the heart undergoes alterations that may compromise longitudinal function, such as myocardial remodeling and becoming more spheroid. A recent study using speckle tracking echocardiography found reduced longitudinal strain in sedentary seniors compared to sedentary young participants, but this difference was ameliorated in seniors with a committed level of lifelong exercise.

CHAPTER 32 1. c. Tricuspid regurgitation does not significantly affect the assessment of LV filling pressures. With mitral annular calcification, the restriction of the mitral annulus by calcification renders tissue Doppler imaging of the mitral annulus inaccurate in reflecting LV filling dynamics. Additionally, transmitral flow (E/A ratio, Vp) is more reflective of valvular pathology than the intrinsic relaxation of the left ventricle. Similarly, increased LA pressures in patients with severe primary mitral regurgitation will result in an increase in the transmitral E wave velocity and blunting or reversal of the S wave during assessment of pulmonary vein flow. Similarly, the E/e′ ratio has not been shown to reliably predict LV filling pressures in patients with primary mitral regurgitation. Finally, studies of diastolic assessment in patients with hypertrophic cardiomyopathy have not been shown to reliably predict LV filling pressures. 2. b. Diastolic dysfunction has been demonstrated to be most strongly predictive of death and atrial fibrillation following coronary artery bypass grafting. This patient with grade III diastolic dysfunction would have an approximately 28-fold increase in his risk for postoperative atrial fibrillation. The proposed mechanism of this increased risk is a decrease in LV compliance, resulting in increased LA pressure, which promotes stretch, fibrosis, and the development of atrial arrhythmias. 3. a. Ventricular pacing has a variable effect on indices of diastolic function, depending on the specific site of pacing. In general, studies assessing the effect of ventricular pacing on diastolic function show a mostly deleterious effect. Patients receiving DDD, DOO, and VVI pacing will all typically receive ventricular pacing. In contrast, patients paced in AAI mode will only receive atrial pacing, which has not been shown to dramatically alter indices of diastolic function.

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CHAPTER 33

CHAPTER 35

1. d. Echocardiography demonstrates findings consistent with HFpEF physiology. The parasternal long and short axis views demonstrate a normal LV EF. There is Doppler and 2-D evidence of pulmonary hypertension. The estimated RA pressure is in excess of 15 mmHg, given the markedly dilated inferior vena cava without collapse on inspiration. The peak tricuspid regurgitant velocity of 3.7 m/sec suggests the pulmonary artery systolic pressure is in excess of 70 mmHg. Despite the significant elevation in the RA pressure, there appears to be relative equivalence of atrial pressures as the intraatrial septum swings to the left and to the right throughout the cardiac cycle. This elevation in LA pressure is supported by the mitral inflow pattern that has a short deceleration time and a high lateral E/e′ ratio. 2. d. The hemodynamics are consistent with postcapillary PH with a markedly elevated pulmonary capillary wedge pressure; however, there are also features of a precapillary component with an elevated pulmonary vascular resistance at 5 WU. 3. a. In the setting of marked volume overload in a patient not responding to loop diuretics, the addition of metolazone would be the next logical step. Metoprolol is not indicated in the absence of myocardial ischemia or systemic hypertension. Sildenafil is not recommended in the management of any patients with HFpEF, including those with PH. Ultrafiltration will only be indicated for volume management if the patient is unresponsive to diuretics.

1. d. Current guidelines recommend control of hypertension in patients with HFpEF in accordance with published clinical practice guidelines. Both spironolactone and candesartan are associated with antihypertensive effects. Furthermore, each has also been associated with a reduction in HFpEF hospitalizations and both carry a IIb recommendation in the updated 2017 ACC/AHA/HFSA guidelines. The use of NSAIDs and DDP-4 inhibitors in heart failure patients should be discouraged and are associated with fluid retention and increased heart failure hospitalizations. 2. a. In the TOPCAT trial, a reduction in LA volume at followup was associated with a lower risk of subsequent occurrence of the primary composite outcome (CV death, HF hospitalization, or aborted cardiac arrest).84 3. b. A large systematic review and meta-analysis, including 38 studies of HFpEF, published in the European Heart Journal in 2016 reported the prevalence of echocardiographic RV dysfunction by TAPSE was 28%, by FAC was 18%, and by RV S′ was 21%.39 4. d. In HFpEF, an impaired LA strain response is a key hemodynamic trigger for RV-to-PC uncoupling and exercise ventilation inefficiency.37 LV GLS correlates independently to peak VO2 in patients with preserved EF and was found to be superior to other echocardiographic parameters in identifying patients with reduced exercise capacity.29 LVH has not been found to correlate with exercise intolerance in HFpEF patients. 5. d. In 2017, a focused update of the 2013 ACC/AHA/HFSA guidelines was released. Based on the CHARM-Preserved Trial, the use of ARBs continued to receive a IIb LOE B recommendation to decrease hospitalization for patients with HFpEF. Based on a post hoc analysis of the TOPCAT trial, the use of aldosterone receptor antagonists received a IIb LOE B-R recommendation for appropriately selected individuals with HFpEF to decrease hospitalizations. It was found that in patients studied in the Americas, rates of the primary end point were fourfold higher than those in Russia/Georgia; in the Americas population, treatment with spironolactone was efficacious in reducing the trial’s primary end point. The routine use of nitrates or phosphodiesterase-5 inhibitors to increase activity or quality of life received a Class III (no benefit) recommendation based on the results of the NEATHFpEF trial and RELAX, respectively.

CHAPTER 34 b. False. AF appears to be more prevalent in patients with HFpEF than in the other HF phenotypes. In 41,446 patients from the Swedish Heart Failure Registry, there was an AF prevalence of 65% in patients with HFpEF, 60% in HF with midrange EF (HFmrEF), and 53% in patients with HFrEF, despite similar age, sex, prior myocardial infarction, and history of stroke among the three groups.70 a. True. In the CHARM-Preserved trial, which randomized 3023 HF patients with HF and LV EF greater than 40% to candesartan or placebo, there was no overall difference in the primary outcome of all-cause death between the two groups; however, HF hospitalizations were significantly lower in the candesartan compared to the placebo group. More patients in the candesartan group developed hypotension, hyperkalemia, or renal insufficiency.6 b. False. The TOPCAT study evaluated spironolactone versus placebo in patients with HF with preserved EF (>45%). While it did not show a significant difference in the primary end point (a composite of death from cardiovascular causes, aborted cardiac arrest, or hospitalization for the management of HF) in patients randomized to spironolactone or placebo, hospitalizations for the management of HF were significantly reduced in the spironolactone arm.12

CHAPTER 36 1. b. The endothelium plays an important role in cardiovascular homeostasis by regulating cardiac function, vasomotor tone, and vascular permeability. The HFpEF-associated comorbidities lead to endothelial dysfunction through disruption of the intracellular NO-cGMP-PK signal cascade. A disorder in this signal cascade contributes to the development of remodeling, including increased cardiomyocyte stiffness that is characteristic of HFpEF. The disruption of the NO-cGMP-PK signal cascade has been

REVIEW QUESTION ANSWERS

shown to lead to disturbances in the regulation of titin and an increase in fibrosis. 2. b. In a study of patients with HFpEF undergoing invasive cardiac catheterization at rest and during exercise, the infusion of sodium nitrite resulted in significant reduction in exercise pulmonary capillary wedge pressure, improvement of cardiac output with exercise, and normalization in the increase of cardiac output relative to oxygen consumption.

509

3. a.  The EMPA-REG OUTCOME Trial looked at empagliflozin, a SGLT2 inhibitor in patients with type 2 diabetes. The results showed a 38% relative risk reduction, 38% in death from cardiovascular causes, 35% relative risk reduction for hospitalization for heart failure, and a 32% relative risk reduction for death from any cause. More recently, other SGLT2 inhibitors have demonstrated similar results.

INDEX Page numbers followed by b denote boxes, those followed by f denote figures, and those followed by t denote tables. A Ablation, 466 Abnormal diastolic dysfunction, 20 Abnormal diastolic function, 71 heart failure with preserved ejection fraction (HFpEF) limits exercise in, 20 prognostic value of, 24 Abnormal myocardial deformation, in HFpEF, 143 Abnormal relaxation, 14 Abnormal ventricles, 152 Abnormal ventricular-arterial stiffening, 71, 79 Activated fibroblasts, 5 Acute decompensated heart failure (ADHF), 22 Acute heart failure (AHF), 279 Acute ischemia, 78f transmitral inflow in, 313t Acute myocardial infarction, Doppler filling profiles in, 315f, 315, 316f, 317f Adenosine triphosphate (ATP), 491 Advanced aging, 3 Advanced glycation end products (AGEs), 90, 491 AFib. See Atrial fibrillation Afterload, 73f, 75, 78 Age, 4 heart failure with preserved ejection fraction (HFpEF), 89 AGEs. See Advanced glycation end products Aging, 71, 143, 425 left ventricular filling and, 111, 213 left ventricular relaxation affected by, 213 mitral flow velocity and, 111t pulmonary venous flow velocity and, 120 Akt activation, 78 Allograft rejection, 284 Altered coronary microcirculation, diabetes mellitus, 378 American College of Cardiology/American Heart Association (ACC/AHA), 473, 476t American Society of Echocardiography (ASE), 160 adult diastolic guidelines, 353 American Society of Echocardiography and European Association of Cardiovascular Imaging guideline, 162 American Society of Echocardiography Consensus Statement, 143 American Society of Echocardiography/ European Association of Cardiovascular Imaging (ASE/EACVI) guidelines, 97, 99 diastolic dysfunction, 249 HFpEF, diagnosing of, 252 LV filling pressure, 252

510

misinterpretation of, 254 American Society of Echocardiography guidelines, 147 Amyloidosis, 268, 293 Amyloidosis. See Cardiac amyloidosis Anesthetic agents, 444 Angiotensin-converting enzyme (ACE) inhibitor, 385, 386t, 478 therapy, heart failure with preserved ejection fraction (HFpEF), 468 Angiotensin II receptor blockers (ARBs), 264 Angiotensin neprilysin receptor inhibitors, heart failure with preserved ejection fraction (HFpEF), 469 Angiotensin receptor, 490 Angiotensin receptor blockers (ARBs), heart failure with preserved ejection fraction (HFpEF), 468 Annular velocities, intracardiac filling pressures, 173 Antidiabetic medications, diabetes mellitus management, 383 Antihypertensive therapy, HFpEF, 465 Aortic regurgitation, 271 Aortic stenosis (AS), 268, 362 magnetic resonance imaging, 197 Applanation tonometry, 74 Arterial hypertension, 329 Asymptomatic LV dysfunction, abnormal myocardial deformation in, 408 Atherosclerosis process, 378 Athlete, left ventricular hypertrophy, e.1 Athlete’s heart, 329 Atrial based pacing (AAI), 418 Atrial booster pump function, 44 Atrial conduit function, 46 Atrial fibrillation (AFib), 90, 160, 162, 255, 414b, 445, 477 description of, 130 heart failure with preserved ejection fraction (HFpEF), 466 intracardiac filling pressures, 175, 176f with low EF, e.8 Atrial flutter, 130 Atrial interstitium, 41 Atrial myocardium, 41 Atrial P-V loops, 44 Atrial reservoir function, 42, 45f, 46f Atrial septal defect (ASD), 352, 361 Atrial stunning, 40 Atrial systole, 208 Atrial systolic failure, 47 model of, 48 Atrioventricular (AV) delay, optimization of, 420 Atrioventricular synchrony, loss of, 368 Atrium, pressure-volume relations of, 43, 44f

Autologous stem cell transplantation (ASCT), 282 Automated cardiac chamber quantification technique, 158f Average pulmonary capillary wedge pressure, 96 B Balloon dilatation of aortic stenosis, 363 Baroreflex activation therapy (BAT), 492 Baseline impedance, prognostic value of, 27f Baseline in predicting mortality, change from, 27f Bernoulli equation, 54, 126 β-adrenergic activation, 78 Beta blockers heart failure with preserved ejection fraction (HFpEF), 468 hypertrophic cardiomyopathy treated with, 329 Biplane method of disks, 402 Biventricular (BiV) pacing, 416, 417t, 418, 419 Blood pressure pulsatility, 72 B mode echocardiography, 158 Brain natriuretic peptide (BNP), 153, 455 Buffered beat acquisition, 210, 211 Bundle branch block (BBB), 416 C Calcium ATPase, 241 Calcium channel blockers, 329 Calcium dysregulation, 1 Calcium homeostasis, diabetes mellitus, 377 Calcium infusion, 43 Canadian Trial of Physiologic Pacing (CTOPP), 418 Cancer therapeutics-related cardiac dysfunction (CTRCD), 406 Candesartan in Heart Failure: Assessment of Reduction in Mortality and Morbidity (CHARM)-Preserved trial, 464 Canine model, 152 Cardiac amyloid deposition, 4 Cardiac amyloidosis, e.4 case study of, 292b classification of, 293 clinical presentation of, 294 diagnostic algorithm, 298f echocardiography of, 295 etiology of, 293 familial, 293 flow diagram of, 300f forms of, 294t laboratory testing and biopsy, 296 orthostatic hypotension in, 294 secondary, 294 senile systemic, 294

Index

Cardiac autonomic dysfunction, 382 Cardiac cachexia, 294 Cardiac catheterization, 93, 292 pericardial diseases, 341, 343f Cardiac connective tissue, 3f Cardiac contractility modulation (CCM) therapy, 492 Cardiac cycle, 107, 400 Cardiac electromechanical activation, 143 Cardiac extracellular matrix, 4 Cardiac fibrillar collagen, 4 Cardiac filling pressure, respiratory variation in, 96f Cardiac function, 12 pacing, adverse effects of duration of pacing, 419 pacing mode, 418 pacing site, 418 underlying cardiac status, 419 pacing impact, 416, 417t Cardiac imaging in diabetes mellitus, 379 diastolic function, imaging for, 379 imaging techniques for, 382 myocardial characterization, 381 screening, 379, 379t systolic function, imaging for, 379 Cardiac index, 22f Cardiac magnetic resonance imaging pericardial diseases, 341, 342f pericardium, 34f, 34 Cardiac myofibrillar proteins, 4 Cardiac resynchronization therapy (CRT), 416 multisite pacing in, 420 Cardiac status, 419 Cardiac strain analysis, 400 Cardiac tamponade, 36 pericardial diseases, 343 right atrial tracings in, 336f CardioMEMS Heart Sensor Allows Monitoring of Pressure to Improve Outcomes in NYHA Class III Heart Failure Patients (CHAMPION), 278, 464 Cardiomyocyte, 18. See also Myocytes Ca2+ flux, 2f, 2 inactivation, 17 Cardiomyopathy. See also Diabetic cardiomyopathy; Dilated cardiomyopathy; Hypertrophic cardiomyopathy characteristics, 290 hypertrophic and dilated cardiomyopathies in children, 363, 365f infiltrative cardiomyopathies, 292 MRI, 297 nuclear imaging, 297 pathophysiology, 290 primary restrictive cardiomyopathies, 291 storage cardiomyopathies, 299

Cardio-oncology, radionuclide techniques in, 213 Cardioprotective agents, diabetes mellitus, 385 Cardiorenal syndrome (CRS), 466 Cardiovascular aging heart failure with preserved ejection fraction, 428 LV compliance, 432, 433f LV filling pressure, 434, 436f LV relaxation, 430, 431f mitral inflow, 433, 435f systolic function, 429, 430f Cardiovascular (CV) disease, 375, 394 Cardiovascular reserve function, Ees on, 77f Catheter Ablation for Atrial Fibrillation and Heart Failure (CASTLE AF) trial, 466 Cellular dysfunction, 476 Cellular insulin signaling, 377 Cellular mechanisms, 7 Central aortic pressure, 74 Chamber stiffness, 17, 53 Chest radiography, pericardial diseases (PD), 336, 337f Chronic atrial and ventricular dysfunction, 48 Chronic hypertension, 406 Chronic kidney disease (CKD), 478 Chronic resynchronization therapy (CRT), 143, 414b Chronotropic incompetence, 416 in diastolic heart failure, 416 Circulation, lumped parameter model of, 59 Circumferential strain (CS), 400 Cluster analysis diabetes, cardiac phenotypes, 383f CMM. See Color M mode Collagen deposition in HFpEF, 5 Collagen I, transcriptional regulation of, 5 Color-coded 3-D LV display, 144f Color-encoded tissue Doppler velocities, 138f Color M mode (CMM) in clinical settings, 153 flow propagation, 151 indices, limitations, 154 intraventricular pressure gradients, 152 Vp slope, 151f Color M mode Doppler, 150 background of, 150 clinical relevance, 153 and diastolic function, 152 vector flow mapping, 154 Color M mode propagation velocity, diastolic echocardiographic examination, 221 Comorbid diseases, 4 Compliance left ventricle (LV) heart failure with preserved ejection fraction (HFpEF), 432, 433f mechanisms, 400 measurement of, 17 Composite measures reflecting diastolic function, 26

511

Computational fluid models, 62 Computerized tomography, pericardial diseases, 341f, 341 Computer modeling, of vortices during left ventricular filling, 62, 64f Concentric remodeling (CR), 258, 260 Conduit function, 42 left atrial, 46 Congenital heart disease (CHD), 349 adult guidelines, applicability of, 353 assessing diastolic function, difficulties in, 353 children with diastolic function, right ventricle, 364 dilated atria, 350f E/A ratio, 350f echocardiographic evaluation of, 355 filling pressures, E/e’ ratio and measures of, 357 isovolumic relaxation time, 351f mitral inflow Doppler, 352f, 355, 356f pathophysiology of diastolic dysfunction in children with, 352 pulmonary a-wave reversal duration, 350f pulmonary venous Doppler, 356f, 356 tissue Doppler velocities, 357, 358f, 359t, 360t diastolic Doppler variables, influences of age and heart rate on, 354t diastolic dysfunction in LV pressure loading, 362 ventricular volume overload, 359 Constrictive pericarditis (CP), 37, 228, 335f coronary angiography, 342 echocardiographic diagnosis, diagnostic algorithm for, 340f, 340 hepatic vein Doppler in, 338, 339f Mayo Clinic echocardiographic criteria, diagnosis of, 340t mitral inflow and annular tissue Doppler in, 338f, 338 radionuclide evaluation, 213 radionuclide techniques for, 213 respirophasic septal in, 336, 337f versus restrictive cardiomyopathy (RCM), 480f, 505 right atrial tracings in, 336f Continuous positive airway pressure (CPAP), 258b Contractility, 73f Coronary angiography, constrictive pericarditis, 342 Coronary artery disease (CAD), 90, 171, 378, 479 acute ischemia, transmitral inflow in, 313t as distinct HFpEF phenotype, 318 Doppler echocardiography, acute myocardial infarction, 315f, 315, 316f, 317f ECG, 309f echo Doppler data, 309t

512

Index

Coronary artery disease (CAD) (Cont.) heart failure with preserved ejection fraction (HFpEF), 465 left ventricular and pulmonary capillary wedge, 310f M mode echo, 309f post-infarction left ventricular remodeling, 310 prevalence of, 308 pulmonary venous flow velocities, 309f radionuclide diastolic function analysis, 212 radionuclide techniques for, 212 septal and lateral tissue Doppler velocities, 309f sex differences, in CAD and diastolic function, 317 transmitral flow pattern, 309f Coronary flow reserved (CFR), 212 Coronary microvascular dysfunction (CMD), 89, 212 CRT. See Chronic resynchronization therapy Cytokine inhibition, 490 D Danon disease, 300 Deformation, 138 analysis, 392f Deformation indices, 160 clinical utility of, 147 Delayed hyperenhancement, 198, 200f Diabetes mellitus, 375 altered coronary microcirculation, 378 cardiac imaging in, 379 diastolic function, imaging for, 379 imaging techniques for, 382 myocardial characterization, 381 screening, 379, 379t systolic function, imaging for, 379 coronary artery disease and, 378 diabetic cardiomyopathy, mechanisms and predictive factors of, 376 heart failure with preserved ejection fraction (HFpEF), 465 HFpEF, 90 insulin resistance and altered insulin signaling in, 376 interaction with hypertension, 378 management, 382 antidiabetic medications, 383 cardioprotective agents, 385 dipeptidylpeptidase 4, 384 GLP1-recepter agonist, 384 lifestyle modifications, 383 metformin, 383 sodium glucose cotransporter-2 inhibitor, 385, 385t metabolic changes, detection of, 385 metabolic factors, 377 calcium homeostasis, 377 free fatty acid metabolism, 377 myocardial fibrosis, 378

neurohormones, inappropriate activation of, 378 serologic markers, 385 Diabetic cardiomyopathy, 465 development and progression of, 377f of diabetes mellitus, 385 mechanisms and predictive factors of, 376 Diastasis, 109, 208 Diastole, 12, 14f, 14, 17, 22, 89, 94 left ventricular chamber, 53 phases of, 207 Diastolic assessment, in functionally single ventricle, 367 Diastolic blood flow, 186 Diastolic dysfunction, 3f, 269 acute/recurrent pericarditis, 36 algorithm recommended by the ASE guidelines for detection of, 171f, 171 ASE, 483f cardiac tamponade, 36 constrictive pericarditis, 37 definition of, 12t, 249, 253f diastolic flow patterns in, 352f diastolic heart failure algorithm for, e.14f diagnosis, e.14f in HFrEF, 511 L WAVE, 504 disease-specific assessment atrial fibrillation, 445 hypertrophic cardiomyopathy, 445 left ventricular assist device, 445 mitral valve disease, 445 effusive constrictive pericarditis, 37 epidemiology of, 107 grading of, 112, 113f, 115f, 249, 447f heart failure with preserved ejection fraction, 416, 428 LV compliance, 432, 433f LV filling pressure, 434, 436f LV relaxation, 430, 431f mitral inflow, 433, 435f systolic function, 429, 430f heart transplantation, 283 in HFpEF, 24, 89 in hypertension and HFpEF, 260 hypertension-associated concentric remodeling, myocardial determinants of LV diastolic properties, 261f, 261, 263f intact left ventricle, hypertensionassociated concentric remodeling and diastolic properties of, 260 in hypertrophic cardiomyopathy, 196, 325 LA strain, 473, 481f pathophysiology of, 352 pericardial effusion, 36 sarcomere mutations and calcium handling myosin-binding protein C (MYBPC3) mutations, 322 α-tropomyosin mutation, 323

troponin T (TNNT) mutations, 323 treatment of, 274 Diastolic echocardiographic examination acquisition and measurement, echocardiographic variables, 222, 223t, 224t indexed LA volume, 225 mitral annular velocities, 222, 226f transmitral inflow, 222, 223t, 224t tricuspid regurgitant velocity, 222, 227f complementary echocardiographic parameters color M mode propagation velocity, 221 isovolumic relaxation time, 221, 221t LV and LA strain, 222 LV wall thickness and mass, 221 pulmonary venous inflow, 221 complementary echocardiographic parameters, acquisition and measurement of, 225 isovolumic relaxation time, 227, 228f LV and LA strain, 228, 229f LV wall thickness and LV mass, 225 pulmonary venous inflow, 227 complementary measurements, 218 diastolic function in, 217b diastolic stress testing, 231 echocardiographic parameters indexed LA volume, 221 left ventricular diastolic dysfunction, algorithm for diagnosis of, 218, 219f mitral annular velocities, 219, 220t transmitral inflow, 218, 220f tricuspid regurgitant velocity, 220 LV filling pressures, 218 respiratory monitoring and special maneuvers, 228 postural maneuvers, 231 respiratory monitoring, 229, 230f Valsalva maneuver, 230, 231f right ventricular diastolic function, 232 technical aspects, 232t tricuspid annular velocities, 233, 234f tricuspid inflow, 232, 233f Diastolic filling, 334, 415 pressures, 24 Diastolic filling time (DFT), 109f Diastolic function, 270, 284 assessment of, 442, 444f guidelines for, 442 perioperative period, 447, 448f postoperative cardiac surgery patient, 447 in children echocardiographic evaluation of, 355 filling pressures, E/e’ ratio and measures of, 357 mitral inflow Doppler, 352f, 355, 356f pulmonary venous Doppler, 356f, 356 tissue Doppler velocities, 357, 358f, 359t, 360t in children and developmental, 349

Index

color M mode Doppler and, 152 for diabetes mellitus, 379 direct measures of, 24 evaluation of, 249, 254 in hypertrophic cardiomyopathy, 322 indirect measures of, 24 invasive assessment of, 94 left ventricular. See Left ventricular diastolic function measurements and cutoff values, 442, 443t noninvasive evaluation of, 349 pacing impact on, 416, 418t right ventricle, conditions predominantly affecting, 364 pediatric pulmonary hypertension, 366 tetralogy of Fallot, 364, 365f, 366f right ventricular, 130 sex differences, in, 317 in special populations, 255 transthoracic echocardiography, 325, 326f Diastolic heart failure (DHF), 86, 308, 392, 394 atrial fibrillation with low EF, e.8 cardiac amyloidosis, e.4 characteristics of, 308 chronotropic incompetence in, 416 constrictive pericarditis versus restrictive cardiomyopathy, 505 in diabetes mellitus. See Diabetes mellitus diastolic dysfunction algorithm for, e.14f diagnosis, e.14f in HFrEF, 511 L WAVE, 504 hypertension, e.3, e.6 indeterminate, 509 LVH in an athlete, e.1 mortality rates, 308 severe MAC, 507 Diastolic LV function, 270 Diastolic mitral regurgitation, 130 Diastolic pressure elevation, mechanisms, 169 versus volume relationships in chronic heart failure patients, 18f Diastolic pressure-volume relationships, 55f Diastolic reserve, 231 Diastolic stiffening, 75 Diastolic stiffness, pathophysiologic determinants of, 18 Diastolic stress echocardiogram abnormal echo data, 244f, 244 echo data, 243, 244f guidelines, 245 Diastolic stress testing, 125, 231, 479f, 479 Diastolic tissue Doppler signals, 186 Diastolic tricuspid regurgitation, 130 Diastology stress test epidemiology, 240 invasive diastology stress test, 242 myocardial relaxation, 241 noninvasive diastology stress test, 242

passive pressure-volume relation, 241 pathophysiology, 240 restoring forces, 241 studies, 245 technical challenges, 245 Diffusion tensor (DT)-cardiac MRI, 328 Diffusion tensor imaging (DTI), 194, 196f Digital filtering, 211 harmonic analysis, 211 Digitalis, heart failure with preserved ejection fraction (HFpEF), 468 Dilated cardiomyopathy (DCM), 280, 328, 353 in children, 363, 365f Dipeptidylpeptidase 4 (DPP-4) diabetes mellitus, 384 inhibitor, 491 Direct measures of diastolic function, 24 Disopyramide, 329 Distensibility, measurement of, 17 Diuretics, 299 heart failure with preserved ejection fraction (HFpEF), 467 Dobutamine stress echocardiography (DSE), 154 Doppler beam, 139 Doppler echo assessment of LV filling, 14 Doppler echocardiogram, 14 Doppler echocardiographic indices, 137 Doppler echocardiography, 100, 187, 243 acute myocardial infarction, 315f, 315, 316f, 317f diastolic function assessments, 126 limitations of, 131 tissue. See Tissue Doppler Doppler indices, 159 Doppler techniques, 187 Doppler versus B mode methods, 141 +dP/dt, 401, 403 DSE. See Dobutamine stress echocardiography Dual-chamber pacemakers, 415 Dysfunction, 143 Dyspnea, 240, 258b Dyssynchrony, 17, 47 assessment, STE in, 142f diagnostic evaluation and optimization of, 419 AV delay, optimization of, 420 VV delay, optimization of, 420 E Ea. See Effective arterial elastance E/A wave ratio, 123 ECG-gated perfusion imaging, 210 Echo, 150 Echo-based HFpEF clinical relevance heart failure syndrome, 479 preclinical structural disease, 478 risk, 478 pathophysiology

513

cellular dysfunction, 476 endothelial dysfunction, 478 exercise limitations, 477 left atrial dysfunction, 476, 477f multisystem dysfunction, 478 pulmonary hypertension and right heart dysfunction, 477 systolic LV dysfunction, 476 prognostic features, 475b progression, 476t Echocardiograph, diastolic stress, 241f, 242 Echocardiographic-based treatment electromechanical function, 484 filling pressures, 482, 483f remodeling, 483 right heart function, 484 Echocardiographic indices, 181b Echocardiographic parameters, 254 Echocardiographic predictors diastolic function, 446 systolic function, 446 Echocardiography, 99, 145, 181 amyloidosis evaluations, 295 diastolic function, in children, 355 Doppler. See Doppler echocardiography left ventricle (LV), 393 pericardium, 33 pulmonary hypertension exercise testing, 457 laboratory testing, 455 12-lead electrocardiogram, 456, 456t transthoracic echocardiography, 456, 456t speckle tracking, 326 for vortex visualization, 152f ECM. See Extracellular matrix E/e’ intracardiac filling pressures, 173 ratio, 357 Ees. See End-systolic elastance Effective arterial elastance (Ea), 72, 73f, 74, 77f, 81f Effusive constrictive pericarditis, 37, 344 Ejection fraction (EF), 87f, 93 left ventricle (LV), 393 controversies on, 394 global longitudinal speckle tracking strain versus, 399 HFpEF phenotypes, 395 historical views of, 393 normal and impaired contractility, 394 use of, 396 Ejection phase, 43 Elastance, left ventricle, 402 Eleclazine, 330 Electrocardiography, pericardial diseases (PD), 336, 337f Electromechanical activation, 143 Empagliflozin, 469 Empagliflozin Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients (EMPA-REG) trial, 464

514

Index

End-diastolic pressure (EDP), 352 volume, 312f Endomyocardial biopsy (EMB), 283 Endothelial dysfunction, 478 Endothelial NO-synthase (eNOS) activators, 489 Endothelin-1 (ET-1) antagonists, 490 Endothelin receptor antagonism, 490 End-systolic elastance (Ees), 73f, 75, 76f End-systolic P-V relationship (ESPVR), 94f End-systolic strain (ESS), 140f End-systolic volume (ESV), 241 Enhanced mechanical deformation, 396 Equilibrium radionuclide angiocardiography (ERNA), 209f acquisition methods, 208b buffered beat acquisition, 210 description of, 206 diastolic function analysis using, 208 frame mode, 209 left anterior oblique, 208, 209f list mode acquisition, 209 ESPVR. See End-systolic P-V relationship ESS. See End-systolic strain Euro-Filling study, 97 European Association of Cardiovascular Imaging, 160 European Society of Cardiology (ESC) guidelines, 97 European System for Cardiac Operative Risk Evaluation (EuroSCORE), 446 e’ velocity, 357 E/Vp ratio, 153 E-wave velocity description of, 56, 116 in mitral regurgitation and stenosis, 128 Exercise capacity, 78 Exercise, heart failure with preserved ejection fraction, 436, 438f Exercise-induced pulmonary hypertension (EiPH), 245f, 245 Exercise reserve versus ventricular-arterial stiffening, 78 Exercise stress testing, 98 Exertional dyspnea, 240 Extracellular matrix (ECM), 1, 3f, 19, 20f, 400 degradation, 5 Extracellular volume fraction (ECV), 362 Extramyocardial processes effecting diastolic stiffness versus myocardial stiffness, 18 F Fabry disease, 201f, 201, 299, 300f Familial amyloidosis, 293 Fatty acid translocase (FAT)/cluster of differentiation 36 (CD36), 377 Female gender, HFpEF, 90 F-fluorodeoxyglucose (FDG), 35 Fibrillar collagens, 4 Fibrosis, 268

Filling. See Left ventricular filling Filling pressures, E/e’ ratio and measures, 357 First pass radionuclide angiography, 206, 210 basic requirements, 210b of diastolic function, 210 Flow propagation, 150 obtaining and measuring, 151 Flow velocity propagation, 152f Fluid-structure interaction (FSI) models, 62 18-Fluorodeoxyglucose (18-FDG) positron emission tomography (PET) study, 377 Four-dimensional (4-D) cardiac MRI, 195, 196f Frailty, heart failure with preserved ejection fraction (HFpEF), 466 Frame mode acquisition, 209 Frank-Starling mechanism, 401 Frank-Starling relationship, 100, 107 Free fatty acid metabolism, diabetes mellitus, 377 Friedreich ataxia (FA), 201 Functionally single ventricle, diastolic assessment in, 367 G GCS. See Global circumferential strain Get With the Guidelines-Heart Failure (GWTG-HF), 87 Global circumferential strain (GCS), 143, 147 Global longitudinal speckle tracking strain versus EF, left ventricle, 399 Global longitudinal strain (GLS), 139f, 139, 145, 147, 222, 269, 379, 394, 446, 476 Global radial strain (GRS), 143 GLP1-recepter agonist (GLP1-RA), diabetes mellitus, 384 GLS. See Global longitudinal strain Glucagon-like peptide-1 (GLP-1), 384, 491 Glucose transporter 4 (GULT4), 377 Glycogen storage disorders (GSD), 300 magnetic resonance imaging, 201f, 201 Gold standard measure, 74 Gradient echo sequences, 192, 193f Grading system, 250 GRS. See Global radial strain Guanosine monophosphate (GMP), 378 Guideline-directed medical therapy (GDMT), 276 H HCM. See Hypertrophic cardiomyopathy Heart failure (HF), 1, 11, 375 burden of, 88f diastolic. See Diastolic heart failure glucose-lowering drugs on, 384t multiple phenotypes of, 392 Heart failure, invasive hemodynamic assessment in, 93 diastolic function, 94

HFpEF diagnosis of, 97 pathophysiology of, 97 left heart, beyond, 100 systolic function, 93 Heart failure midrange ejection fraction (HFmrEF) Heart failure syndrome diagnosis, 479f, 479 differential diagnosis, 479, 480f echocardiographic-based treatment, 481b, 481, 482t emerging diagnostic parameters, 481f, 481 Heart failure with a preserved LV ejection fraction (HFpEF), 258 epidemiology of hypertension, 260 five modern RCTs in, 264t hypertension epidemiology of, 260 pathophysiology, diastolic dysfunction in, 260 treatment, 264 pathophysiology of diastolic dysfunction, 260 hypertension-associated concentric remodeling, myocardial determinants of LV diastolic properties, 261f, 261, 263f intact left ventricle, hypertensionassociated concentric remodeling and diastolic properties of, 260 prevention of, 265 treatment, 264 Heart failure with preserved ejection fraction (HFpEF), 11, 12t, 73f, 75f, 76f, 86, 169, 170, 212b, 212, 414, 425, 463 abnormal diastolic function in, 24 abnormal diastolic function limits exercise in, 20 abnormal myocardial deformation in, 143 abnormal ventricular-arterial stiffening, 79 ACE inhibitor therapy, 468 versus age/gender referent control, 22f angiotensin receptor blockers, 468 beta blockers, 468 cardiac function, adverse effects of pacing duration of pacing, 419 pacing mode, 418 pacing site, 418 underlying cardiac status, 419 cardiovascular aging, diastolic dysfunction and, 428 LV compliance, 432, 433f LV filling pressure, 434, 436f LV relaxation, 430, 431f mitral inflow, 433, 435f systolic function, 429, 430f collagen deposition in, 5 comorbid conditions, 89 composite measurements reflecting diastolic functions, 26 definitions of, 12t development of, 13f

Index

diagnosis of, 97, 147, 252 diastolic dysfunction and, 12, 24, 89, 416 diastolic heart failure, chronotropic incompetence in, 416 digitalis, 468 direct measurements reflecting diastolic functions, 26 diuretics, 467 Doppler findings in, 16f and elderly clinical course of, 426 comorbidities, role of, 426 diagnosis of, 427 epidemiology of, 425 exercise for prevention, 436, 438f guidelines for diagnosis of, 97 versus HFrEF, 86 increased vascular stiffness impairs metabolic exercise performance in, 79f inflammatory mediators in, 6 invasive hemodynamic assessment in, 97 left ventricle EF, 395 left ventricular (LV) diastolic pressures in, 23f long-acting nitrates, 469 mineralocorticoid receptor antagonists, 468 new normal, 434 noninvasive echocardiographic predictors of, 25f NT-proBNP and clinical outcomes in, 26f pathophysiology, 464 cardiac function, pacing impact on, 416, 417t diastolic function, pacing impact on, 416, 418t pathophysiology of, 97 permanent cardiac pacemakers, function of, 415 phase III, placebo-controlled trials of medical therapy, 467t phase III RCTs angiotensin neprilysin receptor inhibitors, 469 SGLT2 inhibitor, 469 phenotype, CAD as, 318 phosphodiesterase inhibitors, 469 placebo-controlled randomized controlled trials, 464 prevalence and economic burden, 87f, 87, 88f problem aging/sedentary aging, 434 prognostic echocardiographic features, 475b pulmonary hypertension epidemiology, 453, 454f exercise testing, 457 laboratory testing, 455 12-lead electrocardiogram, 456, 456t management, 457, 458t, 459t pathophysiology, 454, 455f prognosis, 454

right heart hemodynamic assessment, 457, 458f transthoracic echocardiography, 456, 456t radionuclide diastolic function analysis, 212 stage D heart failure acute heart failure, 279 classification systems, 277, 278f implantable hemodynamic monitoring, 278 interatrial shunt devices, 279 phenotypes, 276 systolic dysfunction in, 404 treatment guidelines, 464 treatment of comorbidities atrial fibrillation, 466 coronary artery disease, 465 diabetes mellitus, 465 frailty, 466 hypertension, 465 obesity, 465 renal disease, 466 sleep apnea, 466 Heart failure with preserved systolic function (HFpEF) metabolic modulation angiotensin receptor and neprilysin inhibition, 490 endothelin receptor antagonism, 490 eNOS activators, 489 inflammation and cytokine inhibition, 490 inorganic nitrates, nitrites, and beetroot juice, 490 intracellular calcium homeostasis, 491 NO-cGMP-PK activators, 489 organic nitrates, 489 phosphodiesterease-5 (PDE5) inhibitors, 490 soluble guanylate cyclase stimulators and activators, 490 noncardiac mechanisms advanced glycation end product crosslink breakers, 491 glucose-lowering drugs, 491 micro-RNA regulation, 491 Szeto-Schiller peptides, 491 novel device therapies cardiac contractility modulation, 492 interatrial septal devices, 492 renal denervation and baroreflex activation therapy, 492 Heart failure with reduced ejection fraction (HFrEF), 11, 12t, 86, 252 comorbid conditions, 89 definitions of, 12t versus HFpEF, 86 prevalence and economic burden, 87f, 87, 88f systolic dysfunction and, 12 Heart, lumped parameter model of, 59

515

Heart rate recovery (HRR), 416 Heart transplantation stage D heart failure diastolic dysfunction, 283 hypertrophic cardiomyopathy, 281 physiology of, 283 RCM, 282 Heart transplants, 256 Helical ventricular myocardial band (HVMB) model, 141 Hemochromatosis, 200f, 200, 300 Hemodynamic load, 17 Hemoglobin A1c (HbA1c), 375 Hepatic vein flow, 184, 185f Hepatic venous (HV) flow, 185 inflow, 233, 234f Hepatic venous systolic filling fraction, 185 Heterogeneity, 17 HF. See Heart failure HFpEF. See Heart failure with preserved ejection fraction HFrEF. See Heart failure with reduced ejection fraction HF with preserved EF, systolic dysfunction in left ventricle, 404 M mode echocardiography, TDI and strain analysis, 404, 405f preclinical diastolic dysfunction, 406f, 406, 407f, 408f High basal Ees, 76 High cardiac output, intracardiac filling pressures, 176 His bundle pacing (HBP), 420 HVMB model. See Helical ventricular myocardial band model Hyperglycemia, 378 Hyperinsulinemia, 378 Hypertension (HTN), 171, 258, 362 description of, 213 diabetes mellitus, 378 diastolic heart failure, e.3, e.6 heart failure with a preserved LV ejection fraction (HFpEF) epidemiology of, 260 pathophysiology, diastolic dysfunction in, 260 treatment, 264 heart failure with preserved ejection fraction (HFpEF), 465 magnetic resonance imaging, 197 and obesity, 258b radionuclide diastolic function analysis, 213 Hypertension-associated concentric remodeling and diastolic properties, intact left ventricle, 260 myocardial determinants of LV diastolic properties, 261f, 261, 263f Hypertension, HFpEF, 90 Hypertensive heart disease (HHD), 221, 329

516

Index

Hypertrophic cardiomyopathy (HCM), 145, 164f, 353 versus athlete’s heart, 329 beta blockers for, 329 calcium channel blockers for, 329 calcium, diastolic levels in children, 363, 365f clinical presentation of, 324 definition of, 322 diastolic dysfunction in, 196, 325 diastolic function in, 322 diffusion tensor (DT)-cardiac MRI, 328 speckle tracking echocardiography, 326 differential diagnosis, 329 Doppler of mitral valve inflow in, 356f genotype/phenotype relations, 324 heart transplantation, 281 versus hypertensive heart disease, 329 hypertrophy associated with, 196 left ventricular outflow tract obstruction, 322 magnetic resonance imaging of, 196 mitral and pulmonary venous (PV) flow velocities, 325 obstructive, 324 pathology of, 322, 323f perioperative diastolic assessment, 445 phenotypic heterogeneity of, 324 prognosis of, 325 radionuclide techniques for, 213 sarcomeric gene mutations, 322, 323f subclinical disease, 329 symptoms of, 324 tissue Doppler velocities, 325 treatment of, 329 Hypertrophic obstructive cardiomyopathy, 192, 193f Hypertrophy, 145, 269 Hypoxia, 466 I Idealized pressure-volume loop, 73f Idiopathic HFpEF, 212 Idiopathic restrictive cardiomyopathy (RCM), 291 IHD. See Ischemic heart disease Impaired global longitudinal strain, 143 Impedance, 72 Implantable cardioverter defibrillator (ICD) therapy, 419 Implantable hemodynamic monitor (IHM), 23f, 24 Increased diastolic filling pressures, 26 Incretins, 491 Indexed LA volume, diastolic echocardiographic examination, 225 Indirect measures of diastolic function, 24 Industry Task Force, 160 Inferior vena cava (IVC), 234, 235f diameter, 183, 184f Infiltrative cardiomyopathies, 292 Infiltrative heart disease, 90

Inflammaging, 6 Inflammatory mediators in HFpEF, 6 Initial isovolumic contraction, 140 Inorganic nitrates, 490 Inorganic nitrite, 81 Inorganic Nitrite Delivery to Improve Exercise Capacity in HFpEF (INDIE) trial, 464 Inotropic therapy, 447 Insulin resistance, 378 in diabetes mellitus, 376 Intact left ventricle, hypertension-associated concentric remodeling and diastolic properties of, 260 Interatrial septal devices (IASDs), 492 Interatrial shunt devices (IASD), 279f, 279 Internal linear dimensions, 157 Interstitial fibrosis, 145 Interventricular (VV) dyssynchrony, 416 Intracardiac blood flow determinants, 54 Intracardiac filling pressures AFib and rhythm disorders, 175, 176f algorithm to estimate LVFP, applying an, 174f, 174 annular velocities and E/e’, 173 clinically meaningful report preparation, 177 definition of, 169 diastolic pressure elevation, mechanisms of, 169 high cardiac output, 176 incorporating parameters, 174, 175f LA strain, 177 LV relaxation, evaluation, 171 mitral annular calcification, 176 mitral regurgitation, 176 peak TR velocity, 174 pulmonary vein velocities, 173f, 173 in sinus rhythm, 172f, 172 strain by speckle tracking, 177 TE-e’ time interval, 176 transmitral velocity, 172 Intracellular calcium homeostasis, 491 Intraoperative diastolic function assessment, 442 Intravascular volume status, 444 Intraventricular flow description of, 62 fluid-mechanical computer modeling of, 62 Intraventricular pressure gradients (IVPG), 150 color M-mode Doppler echocardiography of, 66f, 66 description of, 63f, 63 Invasive assessment of RV diastolic function, 181 Invasive diastology stress test, 242, 243f Invasive hemodynamic assessment left ventricle +dP/dt, 401 elastance, 402 stroke work, 401, 402f

Invasive hemodynamic assessment in heart failure, 93 diastolic function, 94 HFpEF diagnosis of, 97 pathophysiology of, 97 left heart, beyond, 100 systolic function, 93 In vitro modeling, 150 I-PRESERVE echocardiographic substudy, 162 Irbesartan in Heart Failure with Preserved Ejection Fraction Study (I-PRESERVE) trial, 464 Ischemia acute. See Acute ischemia Doppler inflow patterns affected by, 311 experimental studies of, 66 Ischemic heart disease (IHD), 145 Isovolumic pressure decline, 14 Isovolumic relaxation (IVR), 94, 143 duration of, 207 rate of, 12 Isovolumic relaxation time (IVRT), 14, 292, 352, 444 diastolic echocardiographic examination, 221, 221t complementary echocardiographic parameters, acquisition and measurement of, 227, 228f flow, 115, 116f left ventricular intervals, 113, 115f in mid-left ventricular cavity, 117f IVPG. See Intraventricular pressure gradients IVR. See Isovolumic relaxation K Kaiser Permanente Northern California (KPNC), 378 Kaplan-Meier curves, 153f Kaplan-Meier estimate, 27f Kirchoff ’s first law, 59 L Lagrangian formula, 139 Lagrangian strain, 139f LAP. See Left atrial pressure Laplace’s law, 260, 403 Late (A wave) CMM flow propagation, 152 Late gadolinium enhancement (LGE), magnetic resonance imaging, 194, 195f 12-Lead electrocardiogram, 456, 456t Left atrial (LA) appendage, 160 description of, 41f, 44 flow, 40b, 41f booster pump function, 42f, 42, 162 conduit function, 46 dysfunction, 162, 476, 477f enlargement, 162 pressure-volume loops, 45f, 48f

Index

reservoir dysfunction, 163 reservoir function, 44 stiffness, 163 strain, 255 intracardiac filling pressures, 177 volume, 327, 327t Left atrial function anatomic and histologic considerations, 40 assessment of deformation indices, 160 Doppler indices, 159 pressure-volume and pressure-strain loops, estimation of, 161 volumetric changes, 159 diastolic left ventricular dysfunction and, 48 in disease, 47 and diastolic LV dysfunction, 48f, 48 and interplay in LV systolic dysfunction, 48 in model of atrial systolic failure, 48 and systolic LV dysfunction, 47, 48f left ventricular systolic dysfunction and, 47 pathophysiology and dyssynchrony, 47 in health, 42 left atrial booster pump function, 42f, 42 left atrial conduit function, 46 left atrial reservoir function, 42, 45f, 46f phases of, 327, 328f risk stratification and prognostic prediction with, 162 Left atrial pressure (LAP), 153, 242 diastolic filling rates affected by, 311 relaxation, 120 Left atrial size measurement of three-dimensional echocardiography, 158 two-dimensional echocardiography, 157 risk stratification and prognostic prediction with, 162 Left atrium, 157, 158f, 159, 165 booster pump function, 42 enlargement of, 324 function of, 40 pressure-volume loops, 48f pressure-volume relations of, 43 Left heart, beyond, 100 Left ventricle (LV), 391 assessment, echocardiographic parameters in, 397f, 398f central measure of, 393 chronic hemodynamic loading adaptation, 47 diastolic pressure, 245, 246f diastolic stress testing, 396 echocardiographic assessment +dP/dt, 403 LV ejection fraction, 402

LV ejection fraction, by 3-D echocardiography, 402 2-D echocardiographic assessment of EF, 402 wall stress, 403 ejection fraction (EF) controversies on, 394 global longitudinal speckle tracking strain versus, 399 HFpEF phenotypes, 395 historical views of, 393 normal and impaired contractility, 394 use of, 396 etiology and/or pathophysiology, 395 filling pressure, 245 flow propagation inside, 62 HF with preserved EF, systolic dysfunction in, 404 M mode echocardiography, TDI and strain analysis, 404, 405f preclinical diastolic dysfunction, 406f, 406, 407f, 408f invasive hemodynamic assessment +dP/dt, 401 elastance, 402 stroke work, 401, 402f mechanisms, 400 cellular to LV chamber mechanics, 400 LV strain/deformation, 400 recoil, stiffness, relaxation and compliance, 400 regional versus global contractility, 401 torsion, twist/untwisting, restoring forces, and early diastolic load, 400 myocardial deformation echocardiographic tools, 396 myocardial performance (Tei) index, 403 myocardial strain and torsion, 403 passive diastolic properties of, 57, 58f pressure propagation inside, 63 pressure-volume relationship, 241 pulse wave (PW) Doppler, 393f relaxation, 53 tissue Doppler systolic velocities, 403 Left ventricular anatomic structure, 141 Left ventricular apex, 17 Left ventricular-arterial coupling, pathophysiology of, 72 Left ventricular assist device (LVAD), 280, 281t, 282f, 445 Left ventricular chamber diastole, 53 Left ventricular compliance, 110 heart failure with preserved ejection fraction (HFpEF), 432, 433f Left ventricular contractility, 93 Left ventricular diastolic myocardial determinants, hypertensionassociated concentric remodeling, 261f, 261, 263f Left ventricular diastolic dysfunction, 97. See also Diastolic dysfunction algorithm for diagnosis of, 218, 219f

517

grading of, 112, 113f, 115f left atrial function and, 48 perioperative period effect on assessment anesthetic agents, 444 intravascular volume status, 444 mechanical ventilation and patient position, 444 Left ventricular diastolic filling properties, 258 Left ventricular diastolic function assessment algorithm for, 442, 443f measurements for, 448, 448t Doppler echocardiography assessments description of, 126 equilibrium radionuclide angiocardiography assessment of, 208 hypertension effects on, 213 impaired LV relaxation, 109f radionuclide assessments of, 207, 208b time-activity curve, 208f, 208 Left ventricular diastolic pressure, 19f, 24 Left ventricular diastolic stiffness, measurement of, 17 Left ventricular diastolic time constant, 143 Left ventricular dilation, 63, 64f Left ventricular ejection fraction, 402 by 3-D echocardiography, 402 Left ventricular end-diastolic pressure (EDP), 252 Left ventricular end-diastolic pressure (LVEDP), 95f, 95, 169, 170f, 221 versus pulmonary capillary wedge pressure (PCWP), 95 Left ventricular end diastolic pressurevolume relationship, 312f Left ventricular filling, 14 age-related changes in, 213 cardiac loading conditions effect on, 112 contribution, vorticeal flow to, 67, 68f determinants of, 108f Doppler mitral flow velocity patterns, 108 dynamics, 14f, 15f historical perspectives of, 107 major determinants of, 109f pathophysiologic determinants of, 17 relaxation during, 58, 125 sinus tachycardia effects on, 128 variations in, 128 velocity of, 56 Left ventricular filling patterns age-related changes in, 111 baseline, 63, 65f diastolic properties, 109 natural history of, 110f normal and abnormal, 109, 110f patient management uses of, 131 Left ventricular filling pressure, 250 estimation of, 153, 252 evaluation of, 251f heart failure with preserved ejection fraction, 434, 436f

518

Index

Left ventricular filling pressure (LVFP), 95, 169, 170f Left ventricular geometry, 66f, 66 Left ventricular global diastolic strain rate (GDSR), 222 Left ventricular global longitudinal strain (GLS), 255 Left ventricular hemodynamics, 143 Left ventricular hypertrophy (LVH), 171 an athlete, e.1 in hypertrophic cardiomyopathy, 196 ventricular time-volume curves in, 199f, 199 Left ventricular isovolumic relaxation, 15f Left ventricular isovolumic relaxation time. See Isovolumic relaxation time Left ventricular mass, magnetic resonance imaging, 196 Left ventricular outflflow tract time-velocity integral, 115 verapamil effects on, 329 Left ventricular preatrial contraction (pre-A) pressure, 252 Left ventricular pressure loading congenital heart disease, diastolic dysfunction in, 362 Left ventricular pressure relaxation time (IVRT), 392f Left ventricular relaxation, 94 aging effects on, 213 and filling, measurements, 12 heart failure with preserved ejection fraction, 430, 431f invasive markers of, 431, 432f noninvasive markers of, 431, 432f intracardiac filling pressures, 171 isovolumic period of, 66 pathophysiologic determinants of, 17 Left ventricular remodeling definition of, 310 post-infarction, 310 Left ventricular strain/deformation, 400 Left ventricular stroke volume, 44 Left ventricular systolic dysfunction, left atrial function and, 47 Left ventricular systolic function, 40b, 41f Left ventricular torsion, 140 Left ventricular untwisting, 67f, 67, 327f, 327 Left ventricular wall thickness and mass diastolic echocardiographic examination, 221 Lifestyle modifications, diabetes mellitus, management, 383 List mode acquisition, 209 Load-altering maneuvers, 229 Long-acting nitrates, heart failure with preserved ejection fraction (HFpEF), 469 Longitudinal axis tissue Doppler velocities, 138f Loop diuretic therapy, 464

Low ejection fraction, atrial fibrillation, e.8 Lumped parameter model, 59 LVEDP. See Left ventricular end-diastolic pressure (LVEDP) Lysl oxidase-like 2 (LOXL2), 491 Lysosomal-associated membrane protein-2 (LAMP2), 299 M Macrophages, 6 Magnetic resonance imaging amyloidosis, 199f, 199 artifacts, 201 clinical correlation, 195 constrictive pericarditis, 197 contraindications, 201 coronary artery disease evaluations, 197 delayed hyperenhancement, 198, 200f description of, 191 diffusion tensor imaging, 194, 196f dilated cardiomyopathy evaluations, 200 Fabry disease, 201f, 201 four-dimensional (4-D) cardiac MRI, 195, 196f Friedreich ataxia, 201 glycogen storage disorders, 201f, 201 gradient echo sequences, 192, 193f hemochromatosis, 200f, 200 hypertension and aortic stenosis, 197 imaging sequences of, 192 late gadolinium enhancement, 194, 195f left atrial morphology and function, 195 limitations of, 201 LV mass, 196 MR elastography, 195, 196f myocardial strain, 193, 194f pericardium, 197 phase contrast, 192, 193f, 194f phase velocity, 192, 193f, 194f physics of, 191 quantitative T1 mapping and extracellular volume measurements, 194, 195f restrictive cardiomyopathy, 199 sarcoidosis, 200f, 200 spin-echo sequence, 192, 193f Magnetic resonance spectroscopy, 194 Major adverse cardiovascular events (MACE), 407 Mammalian cardiovascular system, 71 Mathematical curve fitting, 211 Matrix metalloproteinases (MMPs), 5, 385 Mayo Clinic hemodynamic laboratory, 96 Mean right atrial pressure, noninvasive estimation of, 183 Metabolic modulation, HFpEF angiotensin receptor and neprilysin inhibition, 490 endothelin receptor antagonism, 490 eNOS activators, 489 inflammation and cytokine inhibition, 490 inorganic nitrates, nitrites, and beetroot juice, 490

intracellular calcium homeostasis, 491 NO-cGMP-PK activators, 489 organic nitrates, 489 phosphodiesterease-5 (PDE5) inhibitors, 490 soluble guanylate cyclase stimulators and activators, 490 Metaiodobenzylguanidine (MIBG), 379 Metalloproteinases, tissue inhibitors of, 6 Metformin, 383 diabetes mellitus, 383 Micromanometers, 93, 96 Micro-RNAs (miRNAs), 491 Microvascular dysfunction, radionuclide technique, 212 Mineralocorticoid receptor antagonists, heart failure with preserved ejection fraction (HFpEF), 468 Mitochondrial deoxyribonucleic acid (DNA), 4 Mitochondrial dysfunction, 4 Mitogen-activated protein (MAP) kinase, 377 Mitral annular calcification (MAC), 255, 274 intracardiac filling pressures, 176 Mitral annular motion, tissue Doppler imaging of, 125 Mitral annular velocities, diastolic echocardiographic examination, 219, 220t, 222, 226f Mitral A-wave duration of, 119f, 120, 121f velocity of, 120 Mitral deceleration time, 108f, 118 Mitral E/A ratio, 127 Mitral flow acceleration of, 56 deceleration of, 56 modeling of, 57 preload effects on, 59 relaxation effects on, 57, 58f Mitral flow velocity age-related changes in, 111t Doppler measurement of, 118f in hypertrophic cardiomyopathy, 325 left ventricular diastolic dysfunction graded by, 112 patterns abnormal, 128 interpretation of, 127 M-mode echocardiography of, 123 tricuspid flow velocity patterns versus, 124 two-dimensional echocardiography of, 123 uncommon, 128 at start of atrial contraction, 119 variables of, 108f description of, 109f left ventricular isovolumic relaxation time, 113 Mitral inertance, 56, 57, 59f

Index

Mitral inflow, 150, 151f heart failure with preserved ejection fraction, 433, 435f ischemia effects on, 313t, 314 left ventricular dilation effects on, 63 resistant hypertension at baseline, 67, 68f Mitral inflow Doppler diastolic function, in children, 352f, 355, 356f pattern, 153 Mitral inflow flow propagation, 150 Mitral regurgitation (MR), 272, 445 diastolic, 130 E-wave velocities in, 117, 127 intracardiac filling pressures, 176 Mitral respiratory flow velocity, 128 Mitral stenosis, 274 E-wave velocities in, 117, 128 Mitral time-velocity integral, 115 Mitral to pulmonary venous A-wave duration, 122 Mitral valve flow variables, 353t regurgitation, 59 Mitral valve disease, 445 M mode cursor, 151 M-mode echocardiography, 404, 405f mitral flow velocity patterns evaluated with, 123 M-mode echocardiography (internal linear dimensions), 157 Modern STE techniques, 141 Modified Bernoulli equation, 187 Monocyte-derived macrophages, 6 MR elastography, 195, 196f MR spectroscopy (MRS), 382 of diabetes mellitus, 385 Multibeat EDPVR, 95 Multiple noninvasive techniques, 139 Multiple risk factors, 1 Multisensor-based composite risk score, 27f Multisite pacing, in cardiac resynchronization therapy, 420 Multisite Stimulation in Cardiomyopathies (MUSTIC), 419 Multisystem dysfunction, 478 Myocardial blood flow (MBF), 212 Myocardial characterization diabetes mellitus, cardiac imaging in, 381 Myocardial collagen, 4, 261 Myocardial contractility, 394 Myocardial deformation, 143, 160 versus clinical variables in hypertension risk assessment, 407f, 407 imaging, 396 measurements of, 137 Myocardial diastolic strain rate, 188 Myocardial disease, 244 Myocardial energetics, 4 Myocardial fiber orientation, 141 Myocardial fibrosis, 145 diabetes mellitus, 378

Myocardial hypertrophy, 362 Myocardial ischemia, 145, 324 Myocardial performance, 391 Myocardial performance (Tei) index, left ventricle, 403 Myocardial relaxation, 94, 241 causes of, 53 magnetic resonance spectroscopy of, 194 mitral flow affected by, 53 pressure decrease during, 53 ventricular compliance and, 57 Myocardial stiffness, 1, 18 versus extramyocardial processes effecting diastolic stiffness, 18 Myocardial strain imaging, systolic function, 379 Myocardial tagging, 193, 194f Myocardial velocities, 137 Myocardium atrial, 41 Myocytes, 4. See also Cardiomyocyte in atrial myocardium, 41 fibers, 141 hypertrophy of, 311 stiffness, 1 Myofiber inactivation, 17 Myofibrillar proteins, posttranslational modification of, 2 Myosin-binding protein C (MYBPC3), 322 Myosin heavy chain, 47 mutations, 322 N Navier-Stokes equations, 54 Neprilysin inhibition, 490 Neurohormones, inappropriate activation of, 378 Neutrophils, 6 New York Heart Association (NYHA), 22 NO-cGMP-PK activators, 489 Noninvasive diastolic stress test, 99 Noninvasive echocardiographic predictors of HFpEF, 25f Noninvasive estimation of mean right atrial pressure, 183 Noninvasive imaging, 93 pericardium cardiac magnetic resonance imaging, 34f, 34 echocardiography, 33 nuclear scintigraphy, 35f, 35, 36t x-ray, 32f, 33, 34f x-ray computed tomography, 34, 35f Nonischemic cardiomyopathy (NICM), 414b Non-ST elevation myocardial infraction (NSTEMI), 145 Normal aging, 154 Normal diastolic function, 12 Normal electromechanical activation, 143 Normal physiology, 141 NO synthase (NOS), 3 NSTEMI. See Non-ST elevation myocardial infraction

519

N-terminal proBNP (NT-proBNP), 271b, 455 Nuclear imaging, pericardial diseases, 342 Nuclear scintigraphy, pericardium, 35f, 35, 36t O Obesity, 6 constrictive pericarditis, 343, 345f heart failure with preserved ejection fraction (HFpEF), 465 HFpEF, 90 Obesity-induced myocardial dysfunction, 407 Oblique sinus, 31 Obstructive hypertrophic cardiomyopathy, 324 Obstructive lung disease, constrictive pericarditis, 343 Obstructive sleep apnea (OSA), 258b Ongoing Cardiovascular Outcome Trials, in type 2 diabetes mellitus, 385t Optimal filling pressures, 464 Organic nitrates, 489 Orthotopic heart transplant (OHT), 283, 284 Oxidative stress, 3 P Pacing adverse effects, cardiac function duration of pacing, 419 pacing mode, 418 pacing site, 418 underlying cardiac status, 419 Parameters, in evaluation of diastolic function, 254 Passive behavior, 74 Passive chamber stiffness, 95 Passive diastolic pressure-volume relationship (DPVR), 17 Passive leg raise, 231 Passive myocardial stiffness, 263f Passive ventricular stiffness, 95 Patent ductus arteriosus (PDA), 359 Patient education, 464 PCWP. See Pulmonary capillary wedge pressure Peak acceleration rate, of mitral E velocity, 175 Peak filling rate (PFR), 192, 207 Peak forward flow velocity in early systole, 120 Peak mitral A-wave velocity, 120 Peak mitral E-wave velocity, 56, 116, 117f, 125 Peak positive strain (PPS), 140f Peak systolic pulmonary artery pressure (PASP), 174 Peak tricuspid E velocity, 187 Peak TR velocity, intracardiac filling pressures, 174 Pediatric pulmonary hypertension, 366

520

Index

Percutaneous coronary interventions, 311 Percutaneous transluminal coronary angioplasty, 313t Perhexiline, 329 Pericardial calcification, 335f Pericardial diseases (PD), 31 cardiac catheterization, 341, 343f cardiac MRI, 341, 342f cardiac tamponade, 343 computerized tomography, 341f, 341 and cardiac magnetic resonance imaging, 335f diagnostic evaluation chest radiography and electrocardiography, 336, 337f clinical presentation and physical exam findings, 336 laboratory evaluation, 336 transthoracic echocardiography, 336, 337f, 338f, 339f differential diagnosis, 342 tricuspid regurgitation and restrictive cardiomyopathy, 342 epidemiology, 334 nuclear imaging, 342 pathophysiology, 334 pericardiectomy, 345 prevalence of, 334 speckle tracking imaging, 339f, 339 treatment medical therapy, 344 Pericardial effusion, 36 Pericardial pressure, 101 Pericardiectomy, pericardial diseases, 345 Pericardium, 31 anatomy, 31, 32f diastolic dysfunction acute/recurrent pericarditis, 36 cardiac tamponade, 36 constrictive pericarditis, 37 effusive constrictive pericarditis, 37 pericardial effusion, 36 magnetic resonance imaging, 197 noninvasive imaging cardiac magnetic resonance imaging, 34f, 34 echocardiography, 33 nuclear scintigraphy, 35f, 35, 36t x-ray, 32f, 33, 34f x-ray computed tomography, 34, 35f pathophysiology, 36 physiology, 31, 32f, 33b pressure/volume curve of, 33f Pericardium and ventricular interaction, 101 Perioperative diastolic assessment, 443, 447, 448f Perioperative diastolic dysfunction, grading, 446, 447f Permanent pacemakers (PPM), 415 PH. See Pulmonary hypertension (PH) Phase contrast imaging, 192, 193f, 194f

Phosphodiesterase inhibitors, heart failure with preserved ejection fraction (HFpEF), 469 Phosphodiesterease-5 (PDE5) inhibitors, 490 Phospholamban (PLN), 2 Physical activity, 436 PLN. See Phospholamban Positive end-expiratory pressure (PEEP), 444 Positron emission tomography (PET), pericardial diseases, 342 Post-infarction left ventricular remodeling, 310 Postoperative diastolic assessment, 447 Postsynthetic procollagen processing and deposition, 5 Posttranslational modification, 3 of myofibrillar proteins, 2 Postural maneuvers, 231 P-P gating, 160 PPS. See Peak positive strain Pre-A velocity, 118f, 119 Preclinical diastolic dysfunction (PDD), 406f, 406, 407f, 408f HF with preserved EF, systolic dysfunction in, 406f, 406, 407f, 408f Preclinical structural disease, 478 Preload augmentation, 231 description of, 59 during Valsalva maneuver, 112 Preoperative systolic function, 446 Pressure measurement of, 17 overload, 145 Pressure-strain loops, estimation of, 161 Pressure-volume, estimation of, 161 Pressure-volume relations description of, 43 diastolic, 55f Pressure-volume relationship (PVR), 240 of ventricle, 241, 242f Primary restrictive cardiomyopathies, 291, 293f P-R interval, 120 Procollagen maturation, 5 Prognosis, 147 Prognostic value of baseline impedance, 27f of multisensor-based risk score, 27f Prosthetic valves, 274 Pseudonormal filling pattern, 153 Pulmonary arterial hypertension (PAH) echocardiographic features, 456t versus pulmonary venous hypertension (PVH), 480f Pulmonary artery pressures, 126 Pulmonary artery systolic pressure (PASP), 220, 325 Pulmonary capillary wedge pressure (PCWP), 95, 98f, 242, 252, 261, 279, 434, 436f, 445, 452. See also Pulmonary hypertension (PH)

estimation of, 445, 446f versus left ventricular end-diastolic pressure (LVEDP), 95 measurements, pitfalls, 96 Pulmonary hypertension (PH), 100, 244, 361 classification of, 452 clinical assessment and diagnosis exercise testing, 457 laboratory testing, 455 12-lead electrocardiogram, 456, 456t transthoracic echocardiography, 456, 456t composite scores, 457 definition of, 452 epidemiology, 453, 454t HFpEF, 454f, 454 management, 457, 458t, 459t pathophysiology, 454, 455f patient’s course, 458 prognosis of, 454 and right heart dysfunction, 477 right heart hemodynamic assessment, 457, 458f right heart imaging, 457 types of, 452, 453f Pulmonary regurgitation signal, 187f Pulmonary vascular disease, 100 Pulmonary vascular resistance (PVR), 452 Pulmonary vein(s) description of, 40 flow, 58 flow variables, 353t modeling of, 61f sensitivity analysis for, 62t velocities, intracardiac filling pressures, 173f, 173 Pulmonary vein–left atrial pressure gradient, 62 Pulmonary venous Doppler diastolic function, 356f, 356 in children, 356f, 356 Pulmonary venous flow, 160 velocity age-related changes in, 120 mitral to pulmonary venous A-wave duration, 122 Pulmonary venous flow velocity, 120, 309f Pulmonary venous hypertension (PVH) versus pulmonary arterial hypertension, 480f Pulmonary venous inflow diastolic echocardiographic examination, 221 complementary echocardiographic parameters, acquisition and measurement of, 227 Pulsatile load, 72–74, 79 Pulsed Doppler echocardiography, 159 Pulsed tissue Doppler imaging, 186 Pulse wave (PW) analysis, 74 Pulse wave (PW) Doppler, 393f echocardiography, 352 imaging, 185

Index

left ventricle, 393f velocities, 150 Pulse wave tissue Doppler echocardiography, 160 Pulsus paradoxus, 36 Pure vasodilators, 80 Purkinje cells, 143 Q Quantitative T1 mapping, magnetic resonance imaging, 194, 195f R RAAS activation, 378 Radial artery pressure, 96f Radionuclide diastolic function analysis in cardio-oncology, 213 clinical patient populations, 212b constrictive pericarditis, 213 coronary artery disease, 212 coronary microvascular dysfunction (CMD), 212 data analysis, 211f, 211 HFpEF, 212 hypertension and, 213 Radionuclide techniques advantages of, 206 cardio-oncology evaluation, 213 constrictive pericarditis evaluation, 213 coronary artery disease applications, 212 diastolic function assessment, 207, 208b ECG-gated perfusion imaging, 210 first pass radionuclide angiography, 206, 210 hypertension evaluations, 213 hypertrophic cardiomyopathy evaluations, 213 limitations, 213 restrictive cardiomyopathy evaluation, 213 Randomized controlled trials (RCTs), 31 Ranolazine, 330 RAP. See Right atrial pressure Rapid flow propagation, 151f Recesses, 31 Recoil, 16 left ventricle (LV), mechanisms, 400 Recurrent pericarditis, 36 Regional right ventricular outflow tract (RVOT), 364 Relaxation, 12 Relaxation, left ventricle (LV) heart failure with preserved ejection fraction, 430, 431f invasive markers of, 431, 432f noninvasive markers of, 431, 432f mechanisms, 400 Remifentanil, 444 Remodeling. See Left ventricular remodeling Renal denervation, 492 Renal disease, heart failure with preserved ejection fraction (HFpEF), 466 Renin-angiotensin-aldosterone system (RAAS), 264, 265

Repetitive arousals, 466 Reservoir function, 44 Resident cardiac fibroblasts, 5 Respiratory collapse, 183 Respirometer, 230 Restoring forces, ventricle contracts, 241 Restrictive cardiomyopathy (RCM), 90, 290, 335f, 335 characteristics of, 291 versus constrictive pericarditis, 480f, 505 heart transplantation, 282 hepatic vein Doppler in, 338, 339f magnetic resonance imaging, 199 pericardial diseases, 342 radionuclide evaluation, 213 radionuclide techniques for, 213 Right atrial appendage, 40 function, 182f, 182 size, 181f, 181 strain, 182f Right atrial pressure (RAP), 184f Right atrium, 182f, 185 Right heart, 100 Right heart catheterization (RHC), 93, 97 pulmonary hypertension, 457 Right ventricular diastolic function. See also Diastolic dysfunction description of, 130 evaluation of, 180b, 181 invasive assessment of, 181 noninvasive estimation of mean right atrial pressure, 183 right atrial function, 182f, 182 right atrial size, 181f, 181 RV morphology, 183 RV systolic function parameters, 183 Right ventricular outflow tract (RVOT) obstruction, 220 Right ventricular (RV), pressure-volume relationship, 241 Right ventricular-pulmonary artery coupling, 100 R-R gating, 160 RV apical (RVA) pacing, 418 RV diastolic pressure (RVDP), 278 RV-focused apical four-chamber, 183 RV morphology, 183 RV systolic dysfunction, 100 RV systolic function parameters, 183 RV systolic pressure (RVSP), 278 S Sarcoidosis, 200f, 200 Sarcomeric protein titin, 2 Sarcoplasmic reticulum (SR), 89, 241 SBP. See Systolic blood pressure Secondary amyloidosis, 294 Senile systemic amyloidosis, 294 Sensor-based metrics, 26 Sensor-based technologies, 26 Septal ablation, 330

521

SERCA, 2 Sex differences, in CAD and diastolic function, 317 SGLT2i, 383 SGLT2 inhibitor, heart failure with preserved ejection fraction (HFpEF), 469 Short-tau inversion-recovery (STIR), 34 Simpson biplane method, 392f Simultaneous echocardiography, invasive exercise hemodynamic assessment with, 99f, 99 Single photon emission computed tomography (SPECT), 207f, 208, 209 Sinuses, 31 Sinus rhythm intracardiac filling pressures in, 172f, 172 algorithm to estimate LVFP, applying, 174 annular velocities and E/e’, 173 incorporating parameters, 174 peak TR velocity, 174 pulmonary vein velocities, 173 transmitral velocity, 172 Sinus tachycardia, 128 Sleep apnea, heart failure with preserved ejection fraction (HFpEF), 466 Society of Thoracic Surgeons (STS), 446 Sodium glucose cotransporter-2 inhibitor (SGLT2i), diabetes mellitus, 385 Sodium glucose cotransporter-2 (SGLT2) inhibitors, 376, 491 Soluble guanylase cyclase (sGC), 490 Speckles, 141 Speckle tracking echocardiography (STE), 141, 142f, 143, 147, 296 in dyssynchrony assessment, 143 fractional early apical reverse rotation, 327 left ventricular strain rate analysis, 326f, 326 left ventricular untwisting, 327f, 327 phasic left atrial volumes and function, 327, 327t, 328f Speckle tracking imaging, 141, 145f, 146f, 339f, 339 Speckle tracking, intracardiac filling pressures, 177 Spin-echo sequence, 192, 193f SR. See Strain rate Stage D heart failure acute and chronic, 279 allograft rejection, 284 definition of, 276 durable mechanical circulatory support, 280 epidemiology, 277 etiology of, 278 heart transplantation diastolic function after, 283 physiology of, 283 trends and national outcomes, 281 implantable hemodynamic monitoring, 278 interatrial shunt devices, 279 phenotypes, 276

522

Index

STE. See Speckle tracking echocardiography Stiff LA syndrome, 47 Stiffness, left ventricle (LV), mechanisms, 400 Storage cardiomyopathies Fabry disease, 299 glycogen storage disorders, 300 Strain, 138, 139f, 140f, 160 Strain rate (SR), 139, 140f Strain rate calcium ATPase (SERCA2), 241 Stress-strain relationship, 18 Stroke work (SW), left ventricle, 401, 402f Study of the Effects of Nebivolol Intervention on Outcomes and Rehospitalization in Seniors with Heart Failure (SENIORS) trial, 464 Subepicardial fibers, 141 Suction, 16 Sudden cardiac arrest, 349b Superior vena cava (SVC) inflow, 233, 234f SVR. See Systemic vascular resistance Synchrony, 17 Systemic vascular resistance (SVR), 72 Systole, apical four-chamber color Doppler images in, 269f Systolic anterior motion (SAM), 297 Systolic blood pressure (SBP), 76f Systolic dysfunction definitions of, 12t left atrial function and, 47 Systolic filling fraction, 185 Systolic function for diabetes mellitus, 379 echocardiographic predictors, 446 heart failure with preserved ejection fraction, 429, 430f invasive assessment of, 93 Systolic left ventricular dysfunction, 476 Systolic longitudinal function, TDI, 401 Systolic torsion, 66 Systolic ventricular stiffness, 74 Szeto-Schiller peptides, 491 T TAC. See Total arterial compliance Tachycardia, 22, 128 TAPSE. See Tricuspid annular plane systolic excursion 99m Tc radiolabeled agents, 210 TDE. See Tissue Doppler echocardiography TDI. See Tissue Doppler imaging TEE. See Transesophageal echocardiography TE-e’ time interval, intracardiac filling pressures, 176 Tetralogy of Fallot (TOF), 364, 365f, 366f Therapeutic strategies targeting stiffness, 79 Therapy for Adults with Heart Failure and Preserved Systolic Function (TOPCAT) trial, 464 Thermodilution catheter, 317 3-D diastolic strain assessment, 448

Three-dimensional echocardiography, 158, 159, 165, 182f, 183 LV ejection fraction by, 402 Three-element Windkessel model, 74 Time to peak filling rate (TPFR), 207 Time velocity integral (TVI), 115, 185 TIMPs. See Tissue inhibitors of metalloproteinases Tissue Doppler echocardiography (TDE), 138, 160, 292 Tissue Doppler imaging, 170 derived strain, 141 HCM versus hypertensive heart disease, 329 left ventricle, global and regional systolic function of, 401 mitral annular motion, 125 systolic longitudinal function, 401 transmitral velocity, 169b, 170f Tissue Doppler imaging (TDI), 137, 141, 186, 284 Tissue Doppler systolic velocities, left ventricle, 403 Tissue Doppler tricuspid systolic lateral annular velocity, 183 Tissue Doppler velocities, 325 diastolic function, in children, 357, 358f, 359t, 360t Tissue inhibitors of metalloproteinases (TIMPs), 6 Titin, 2, 3, 261, 262 Torrent-Guasp’s model of a helical heart, 400 Torsion, 140 Total arterial compliance (TAC), 74 Transaortic flow, continuous wave Doppler tracing of, 269f Transcatheter aortic valve replacement (TAVR), 250 Transcriptional regulation of collagen I, 5 Transesophageal echocardiogram (TEE), 442 Transesophageal echocardiography (TEE), 157, 160 Translational motion, 138 Transmitral Doppler flow patterns, 16 Transmitral E/A ratio, 448 Transmitral flow (TMF), 61f, 62t, 193, 309f Transmitral gradient, 57 Transmitral inflow, 159 diastolic echocardiographic examination, 222, 223t, 224t pulsed wave Doppler of, 269f pulse wave Doppler of, 271b, 273f Transmitral pressure gradient (TMPG), 109f, 109 Transmitral pulse wave Doppler analysis, 444f Transmitral velocity (MV) Doppler recording of, 169b, 170f intracardiac filling pressures, 172 Transthoracic echocardiography (TTE), 157, 182, 325, 326f

pericardial diseases, 336, 337f, 338f, 339f systolic function, imaging for, 379 Transthyretin (TTR), 283, 292 amyloidosis, 4 Transverse sinus, 31 Treatment of Preserved Cardiac Function Heart Failure with an Aldosterone Antagonist (TOPCAT), 86 Treppe effect, 110 Tricuspid annular plane systolic excursion (TAPSE), 183, 457 Tricuspid annular velocities diastolic echocardiographic examination, right ventricular diastolic function, 233, 234f Tricuspid annulus velocities, 186 Tricuspid E/é ratio, 187 Tricuspid flow velocity, 124 Tricuspid inflow, 186 diastolic echocardiographic examination, right ventricular diastolic function, 232, 233f Tricuspid regurgitant velocity, 169b, 170f diastolic echocardiographic examination, 220, 222, 227f Tricuspid regurgitation (TR), 126 diastolic, 130 pericardial diseases, 342 velocity, 244 α-Tropomyosin, 323 Troponin T (TNNT), 323 TTE. See Transthoracic echocardiography TVI. See Time velocity integral Twist, 140 2-D echocardiographic assessment of EF, 402 Two-dimensional echocardiography, 157, 159, 165, 182 Fabry disease, 302f mitral flow velocity patterns evaluated with, 123 2-D speckle tracking-derived strain, 141 2-D STE-derived strain, 141 2-D transthoracic echocardiography LA size and volume, 325 mitral and pulmonary venous (PV) flow velocities, 325 myocardial tissue Doppler velocities, 325 pulmonary artery systolic pressure, 325 Type 2 diabetes mellitus (T2DM), 375 Ongoing Cardiovascular Outcome Trials in, 385t Typical spectral display, 137 U Ultrafiltration in Decompensated Heart Failure with Cardiorenal Syndrome (CARRESS HF) trial, 466 Ultrasound-based strain measurements, 139 V Valsalva maneuver, 112, 230, 231f, 379

Index

Valve disease aortic regurgitation, 271 aortic stenosis, 268 mitral annular calcification, 274 mitral regurgitation, 272 mitral stenosis, 274 prosthetic valves, 274 treatment, 274 valvular heart disease, epidemiology of, 268 Valvular heart disease, 268 Vector flow mapping (VFM), 154 Ventricular afterload, 72 Ventricular-arterial stiffening versus exercise reserve, 78 in heart failure, 74 pathophysiology of, 75, 77t Ventricular-based pacing (VVI), 418 Ventricular compliance, 57

Ventricular contractility, 394 Ventricular end-systolic chamber stiffness, 72 Ventricular filling, 367, 368 Ventricular function, 349, 394 Ventricular myocardium, 324 Ventricular performance, 394 Ventricular remodeling. See Left ventricular remodeling Ventricular septal defect (VSD), 359, 361 Ventricular stiffening, 74 Ventricular systolic stiffness, 75f Ventricular-vascular stiffening, 74, 79 Ventricular volume overload congenital heart disease, diastolic dysfunction in, 359 Verapamil, 329 VFM. See Vector flow mapping

523

Vinculin, 4 Volumetric changes, 159 Vortex formation, 152 Vortex visualization, echocardiographic techniques for, 152f VV delay, optimization of, 420 W Wall motion score index (WMSI), 399 Wall stress, left ventricle, 403 Wave separation analysis, 74 Worsening augmentation index, 82f X X-ray computed tomography, pericardium, 34, 35f X-ray, pericardium, 32f, 33, 34f