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B R A U N WA L D ’ S

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HEART

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DISEASE

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MEDICINE
CARDIOVASCULAR
A TEXTBOOK OF

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ELEVENTH EDITION

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B R AU N WA LD’S
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HEART
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DISEASE

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A TEXTBOOK OF
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CARDIOVASCULAR
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MEDICINE
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Edited by
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DOUGLAS P. ZIPES, MD DOUGLAS L. MANN, MD
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Distinguished Professor Lewin Chair and Professor of Medicine, Cell Biology,
Division of Cardiology and the Krannert Institute of Cardiology and Physiology
Indiana University School of Medicine Chief, Division of Cardiology
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Indianapolis, Indiana Washington University School of Medicine in St. Louis
Cardiologist-in-Chief
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PETER LIBBY, MD Barnes-Jewish Hospital
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Mallinckrodt Professor of Medicine St. Louis, Missouri
Harvard Medical School
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Brigham and Women’s Hospital GORDON F. TOMASELLI, MD fre


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Boston, Massachusetts Michel Mirowski MD Professor of Cardiology
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Professor of Medicine
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ROBERT O. BONOW, MD Chief, Division of Cardiology


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Johns Hopkins School of Medicine


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Max and Lilly Goldberg Distinguished Professor of Cardiology


Vice Chairman, Department of Medicine Baltimore, Maryland
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Director, Center for Cardiac Innovation


Northwestern University Feinberg School of Medicine Editor and Online Editor
Chicago, Illinois
EUGENE BRAUNWALD,
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MD, MD(Hon), ScD(Hon), FRCP


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Distinguished Hersey Professor of Medicine


Harvard Medical School
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Founding Chairman, TIMI Study Group


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Brigham and Women’s Hospital


Boston, Massachusetts
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1600 John F. Kennedy Blvd.
Ste. 1800
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Philadelphia, PA 19103-2899
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Braunwald’s
Heart Disease: A Textbook of Two-Volume Set ISBN: 978-0-323-46342-3
Cardiovascular Medicine, Eleventh Edition Single Volume ISBN: 978-0-323-46299-0
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International Edition ISBN: 978-0-323-55592-0

Copyright © 2019 by Elsevier Inc.


Previous editions copyrighted 2015, 2012, 2008, 2005, 2001, 1997, 1992, 1988, 1984, 1980 by Saunders,
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an imprint of Elsevier Inc.
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All rights reserved. No part of this publication may be reproduced or transmitted in any form or by
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any means, electronic or mechanical, including photocopying, recording, or any information storage
and retrieval system, without permission in writing from the publisher. Permissions may be sought
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directly from Elsevier’s Rights Department: phone: (+1) 215 239 3804 (US) or (+44) 1865 843830 (UK);
fax: (+44) 1865 853333; e-mail: healthpermissions@elsevier.com. You may also complete your request

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online via the Elsevier website at http://www.elsevier.com/permissions.
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Notice
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Knowledge and best practice in this field are constantly changing. As new research and
experience broaden our knowledge, changes in practice, treatment, and drug therapy may
become necessary or appropriate. Readers are advised to check the most current information
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provided (i) on procedures featured or (ii) by the manufacturer of each product to be
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administered, to verify the recommended dose or formula, the method and duration of
administration, and contraindications. It is the responsibility of the practitioner, relying on their
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own experience and knowledge of the patient, to make diagnoses, to determine dosages and the
best treatment for each individual patient, and to take all appropriate safety precautions. To the
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fullest extent of the law, neither the Publisher nor the Authors assume any liability for any injury
and/or damage to persons or property arising out of or related to any use of the material
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contained in this book.
  The Publisher
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International Standard Book Number: 978-0-323-46342-3
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Executive Content Strategist: Dolores Meloni


Senior Content Development Specialist: Anne Snyder fre
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Publishing Services Manager: Patricia Tannian
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Senior Project Manager: John Casey


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Design Direction: Renee Duenow


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Cover image courtesy Kelly Jarvis, PhD, and Michael Markl, PhD
Northwestern University Feinberg School of Medicine, Chicago, Illinois
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Printed in Canada
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9 8 7 6 5 4 3 2 1
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To

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Pat, Rob, and Sam
Beryl, Oliver, and Brigitte

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Joan, Debra, Jeffrey, and David

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Charlene, Sarah, Emily, and Matthew

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Laura, Erica, Jonathan, and Stephanie

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f Acknowledgments
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Creating a 2000-page textbook is a herculean task requiring input from many dedicated and skilled
individuals. In addition to thanking the enthusiastic contributors who have written the chapters, at
Elsevier we would like to thank Dolores Meloni, executive content strategist, for her resolve in keeping
five independently thinking editors on the same path; Anne Snyder, senior content development strategist,
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for organizing us to make things happen on time; and John Casey, senior project manager. Many others,
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including copyeditors, artists, and production staff helped make this textbook what it is. Finally, as
stated in the preface, we owe an inestimable debt of gratitude to Dr. Braunwald for his vision, integrity,
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and high standards, which we have tried to emulate.
We would also like to thank our many colleagues from all over the world who have written to us
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with suggestions on how to improve Heart Disease. We consider each recommendation carefully and

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welcome such input. In particular, we acknowledge the comments on multiple chapters from the
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following:
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Azin Alizadehasl, MD, Rajaie Cardiovascular Medical and Research Center, Tehran, Iran
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Arash Hashemi, MD, Erfan General Hospital, Tehran, Iran
Anita Sadeghpour, MD, Rajaie Cardiovascular Medical and Research Center, Tehran, Iran
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Leili Pourafkari, MD, Razi Hospital, Tabriz, Iran
Mehran Khoshfetrat, MD, Tehran, Iran
Babak Geraiely, MD, Tehran University of Medical Sciences
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Shabnam Madadi, MD, Cardiac Imaging Center, Shahid Rajaei Heart Center, Tehran, Iran
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Banasiak Waldemar, MD, Centre for Heart Disease, Military Hospital, Wroclaw, Poland
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Carlos Benjamín Alvarez, MD, PhD, Sacré Coeur Institute, Buenos Aires, Argentina
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Elias B. Hanna, MD, Division of Cardiology, Louisiana State University, New Orleans, Louisiana
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f Contributors
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Keith D. Aaronson, MD, MS Elliott M. Antman, MD
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Bertram Pitt MD Collegiate Professor of Cardiovascular Medicine Professor of Medicine
Professor of Internal Medicine Associate Dean for Clinical/Translational Research
Division of Cardiovascular Medicine Harvard Medical School
University of Michigan Senior Investigator
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Ann Arbor, Michigan TIMI Study Group
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Mechanical Circulatory Support Brigham and Women’s Hospital
Boston, Massachusetts
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William T. Abraham, MD Critical Evaluation of Clinical Trials
Professor of Internal Medicine, Physiology, and Cell Biology
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Chair of Excellence in Cardiovascular Medicine Pavan Atluri, MD

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Director, Division of Cardiovascular Medicine Assistant Professor of Surgery
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Associate Dean for Clinical Research Director, Cardiac Transplantation and Mechanical Circulatory Assist
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Director, Clinical Trials Management Organization Program
Deputy Director, Davis Heart and Lung Research Institute Director, Minimally Invasive and Robotic Cardiac Surgery Program
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The Ohio State University Division of Cardiovascular Surgery
Columbus, Ohio Department of Surgery
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Devices for Monitoring and Managing Heart Failure University of Pennsylvania
Philadelphia, Pennsylvania
Michael A. Acker, MD Surgical Management of Heart Failure
Chief, Division of Cardiovascular Surgery
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Director, Penn Medicine Heart and Vascular Center Larry M. Baddour, MD
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University of Pennsylvania Health System Professor of Medicine
Philadelphia, Pennsylvania Mayo Clinic College of Medicine
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Surgical Management of Heart Failure Rochester, Minnesota
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Cardiovascular Infections
Michael J. Ackerman, MD, PhD
Aaron L. Baggish, MD
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Windland Smith Rice Cardiovascular Genomics Research Professor
Professor of Medicine, Pediatrics, and Pharmacology Associate Professor of Medicine
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Mayo Clinic College of Medicine and Science Harvard Medical School
Director, Long QT Syndrome/Genetic Heart Rhythm Clinic Director, Cardiovascular Performance Program
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Director, Mayo Clinic Windland Smith Rice Sudden Death Massachusetts General Hospital
Genomics Laboratory Boston, Massachusetts
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Mayo Clinic Exercise and Sports Cardiology
Rochester, Minnesota
Genetics of Cardiac Arrhythmias C. Noel Bairey Merz, MD
Director, Barbra Streisand Women’s Heart Center
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Philip A. Ades, MD Director, Linda Joy Pollin Women’s Heart Health Program
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Professor of Medicine Director, Preventive Cardiac Center
University of Vermont College of Medicine Professor of Medicine
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Burlington, Vermont Cedars-Sinai Medical Center
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Exercise-Based, Comprehensive Cardiac Rehabilitation Los Angeles, California
Cardiovascular Disease in Women
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Michelle A. Albert, MD, MPH
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Professor of Medicine Gary J. Balady, MD


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Director, CeNter for the StUdy of AdveRsiTy and CardiovascUlaR Professor of Medicine
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DiseasE (NURTURE Center) Boston University School of Medicine


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University of California at San Francisco Director, Non-Invasive Cardiovascular Laboratories


San Francisco, California Boston Medical Center
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Cardiovascular Disease in Heterogeneous Populations Boston, Massachusetts


Exercise Electrocardiographic Testing
Larry A. Allen, MD, MHS
Associate Professor of Medicine David T. Balzer, MD
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Division of Cardiology Professor


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University of Colorado School of Medicine Division of Pediatric Cardiology


Aurora, Colorado Washington University School of Medicine
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Management of Patients with Cardiovascular Disease Approaching St. Louis, Missouri


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End of Life Catheter-Based Treatment of Congenital Heart Disease


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Joshua A. Beckman, MD Marc P. Bonaca, MD, MPH

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Professor of Medicine Associate Physician
Division of Cardiovascular Medicine Division of Cardiovascular Medicine

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eContributors

Director, Vanderbilt Translational and Clinical Cardiovascular


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Research Center Assistant Professor, Harvard Medical School

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Vanderbilt University School of Medicine Investigator, TIMI Study Group

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Nashville, Tennessee Boston, Massachusetts
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Anesthesia and Noncardiac Surgery in Patients with Heart Disease Approach to the Patient with Chest Pain

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Peripheral Artery Diseases
Donald M. Bers, PhD
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Silva Chair for Cardiovascular Research Robert O. Bonow, MD, MS
Distinguished Professor and Chair Max and Lilly Goldberg Distinguished Professor of Cardiology
Department of Pharmacology Vice Chairman, Department of Medicine
University of California, Davis Director, Center for Cardiac Innovation
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Davis, California Northwestern University Feinberg School of Medicine
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Mechanisms of Cardiac Contraction and Relaxation Chicago, Illinois
Nuclear Cardiology
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Sanjeev Bhalla, MD Approach to the Patient with Valvular Heart Disease
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Professor Appropriate Use Criteria: Echocardiography
Mallinckrodt Institute of Radiology Appropriate Use Criteria: Multimodality Imaging in Stable Ischemic

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Washington University in St. Louis Heart Disease and Heart Failure
Department of Diagnostic Radiology Aortic Valve Disease
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Section of Cardiothoracic Imaging Mitral Valve Disease
St. Louis, Missouri Guidelines: Management of Valvular Heart Disease
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The Chest Radiograph in Cardiovascular Disease
Barry A. Borlaug, MD
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Aruni Bhatnagar, PhD Associate Professor of Medicine
Professor of Medicine Mayo Medical School
Division of Cardiovascular Medicine Consultant, Cardiovascular Diseases
Department of Medicine Mayo Clinic
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University of Louisville Rochester, Minnesota
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Louisville, Kentucky Mechanisms of Cardiac Contraction and Relaxation
Air Pollution and Cardiovascular Disease
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Eugene Braunwald, MD, MD(Hon), ScD(Hon), FRCP
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Deepak L. Bhatt, MD, MPH Distinguished Hersey Professor of Medicine
Senior Investigator, TIMI Study Group Harvard Medical School;
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Executive Director, Interventional Cardiovascular Programs Founding Chairman, TIMI Study Group
Heart and Vascular Center Brigham and Women’s Hospital
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Brigham and Women’s Hospital Boston, Massachusetts
Professor of Medicine Non–ST Elevation Acute Coronary Syndromes
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Harvard Medical School
Boston, Massachusetts Alan C. Braverman, MD
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Percutaneous Coronary Intervention Alumni Endowed Professor in Cardiovascular Diseases
Treatment of Noncoronary Obstructive Vascular Disease Professor of Medicine
Washington University School of Medicine
Surya P. Bhatt, MD Director, Marfan Syndrome Clinic
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Assistant Professor of Medicine Director, Inpatient Cardiology Firm


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UAB Lung Health Center St. Louis, Missouri
Division of Pulmonary, Allergy, and Critical Care Medicine Diseases of the Aorta
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University of Alabama at Birmingham
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Birmingham, Alabama J. Douglas Bremner, MD
Chronic Lung Diseases and Cardiovascular Disease Professor of Psychiatry and Radiology
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Emory University School of Medicine
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Bernadette Biondi, MD and Atlanta Veterans Affairs Medical Center


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Professor Atlanta, Georgia


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Department of Clinical Medicine and Surgery Psychiatric and Behavioral Aspects of Cardiovascular Disease
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University of Naples Federico II


Naples, Italy John E. Brush Jr, MD
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Endocrine Disorders and Cardiovascular Disease Professor of Medicine


Cardiology Division
Erin A. Bohula, MD, DPhil Eastern Virginia Medical School and Sentara Healthcare
TIMI Study Group and Division of Cardiology Norfolk, Virginia
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Brigham and Women’s Hospital Clinical Decision Making in Cardiology


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Harvard Medical School


Boston, Massachusetts
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ST-Elevation Myocardial Infarction: Management


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Julie E. Buring, MD Jean-Pierre Després, PhD

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Professor of Medicine Scientific Director
Brigham and Women’s Hospital International Chair on Cardiometabolic Risk

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Contributors
Professor of Epidemiology Professor, Department of Kinesiology
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Harvard Medical School Faculty of Medicine
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Harvard School of Public Health Université Laval
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Boston, Massachusetts Director of Research, Cardiology

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Risk Markers and the Primary Prevention of Cardiovascular Disease Québec Heart and Lung Institute
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Québec, Canada
Hugh Calkins, MD Obesity and Cardiometabolic Disease
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Nicholas J. Fortuin Professor of Cardiology
Director, Cardiac Arrhythmia Service Stephen Devries, MD
Director, Electrophysiology Laboratory and Arrhythmia Service Executive Director
The Johns Hopkins Hospital Gaples Institute for Integrative Cardiology
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Baltimore, Maryland Deerfield, Illinois;
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Hypotension and Syncope Associate Professor
Division of Cardiology
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John M. Canty Jr., MD Northwestern University Feinberg School of Medicine
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SUNY Distinguished and Albert and Elizabeth Rekate Professor Chicago, Illinois
Chief, Division of Cardiovascular Medicine Integrative Approaches to the Management of Patients with Heart

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Jacobs School of Medicine and Biomedical Sciences Disease
University at Buffalo
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Buffalo, New York Vasken Dilsizian, MD
Coronary Blood Flow and Myocardial Ischemia Professor of Medicine and Radiology
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University of Maryland School of Medicine
Mercedes R. Carnethon, PhD Chief, Division of Nuclear Medicine
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Associate Professor and Vice Chair University of Maryland Medical Center
Department of Preventive Medicine Baltimore, Maryland
Feinberg School of Medicine Nuclear Cardiology
Northwestern University Appropriate Use Criteria: Multimodality Imaging in Stable Ischemic
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Chicago, Illinois Heart Disease and Heart Failure
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Cardiovascular Disease in Heterogeneous Populations
Mark T. Dransfield, MD
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Leslie T. Cooper Jr., MD Professor of Medicine
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Professor of Medicine UAB Lung Health Center
Chair, Cardiovascular Department Division of Pulmonary, Allergy, and Critical Care Medicine
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Mayo Clinic University of Alabama at Birmingham
Jacksonville, Florida Birmingham VA Medical Center
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Myocarditis Birmingham, Alabama
Chronic Lung Diseases and Cardiovascular Disease
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Mark A. Creager, MD
Professor of Medicine and Surgery Dirk J. Duncker, MD, PhD
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Geisel School of Medicine at Dartmouth Professor of Experimental Cardiology
Hanover, New Hampshire Department of Cardiology
Director, Heart and Vascular Center Erasmus University Medical Center
Dartmouth-Hitchcock Medical Center Rotterdam, The Netherlands
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Lebanon, New Hampshire Coronary Blood Flow and Myocardial Ischemia


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Peripheral Artery Diseases
Rodney H. Falk, MD
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George D. Dangas, MD, PhD Director, Cardiac Amyloidosis Program
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Professor of Medicine (Cardiology) Brigham and Women’s Hospital
Zena and Michael A. Wiener Cardiovascular Institute Associate Clinical Professor of Medicine
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Icahn School of Medicine at Mount Sinai Harvard Medical School
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New York, New York Boston, Massachusetts


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Coronary Angiography and Intravascular Imaging The Dilated, Restrictive, and Infiltrative Cardiomyopathies
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James A. de Lemos, MD James C. Fang, MD


Professor of Internal Medicine Professor of Medicine
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Division of Cardiology Chief, Division of Cardiovascular Medicine


UT Southwestern Medical Center Executive Director
Dallas, Texas Cardiovascular Service Line
Stable Ischemic Heart Disease University of Utah Health Sciences Center
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Percutaneous Coronary Intervention Salt Lake City, Utah


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History and Physical Examination: An Evidence-Based Approach


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Savitri E. Fedson, MD Jacques Genest, MD

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Associate Professor Professor, Faculty of Medicine
Center for Medical Ethics and Health Policy McGill University

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eContributors

Baylor College of Medicine


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Houston, Texas Montreal, Quebec, Canada

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Ethics in Cardiovascular Medicine Lipoprotein Disorders and Cardiovascular Disease

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G. Michael Felker, MD, MHS Robert E. Gerszten, MD

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Professor of Medicine Herman Dana Professor of Medicine
Division of Cardiology Harvard Medical School
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Chief, Heart Failure Section Chief, Division of Cardiovascular Medicine
Duke University School of Medicine Beth Israel Deaconess Medical Center
Durham, North Carolina Boston, Massachusetts
Diagnosis and Management of Acute Heart Failure Biomarkers and Use in Precision Medicine
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Jerome L. Fleg, MD Linda Gillam, MD, MPH
Medical Officer Chairperson
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Division of Cardiovascular Sciences Department of Cardiovascular Medicine
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National Heart, Lung, and Blood Institute Morristown Medical Center
Bethesda, Maryland Atlantic Health System

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Cardiovascular Disease in the Elderly Morristown, New Jersey
Echocardiography
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Lee A. Fleisher, MD
Robert D. Dripps Professor and Chair Robert P. Giugliano, MD, SM
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Anesthesiology and Critical Care Physician, Cardiovascular Medicine Division
Professor of Medicine Brigham and Women’s Hospital
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Perelman School of Medicine at the University of Pennsylvania Associate Professor of Medicine
Philadelphia, Pennsylvania Harvard Medical School
Anesthesia and Noncardiac Surgery in Patients with Heart Disease Boston, Massachusetts
Non–ST Elevation Acute Coronary Syndromes
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Daniel E. Forman, MD
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Professor of Medicine Ary L. Goldberger, MD
University of Pittsburgh Professor of Medicine
e.

e.

e.

e.
Section of Geriatric Cardiology Harvard Medical School
fre

fre

fre

fre
Divisions of Geriatrics and Cardiology Director
University of Pittsburgh Medical Center Margret and H.A. Rey Institute for Nonlinear Dynamics in Medicine
ks

ks

ks

ks
VA Pittsburgh Healthcare System Associate Chief
Pittsburgh, Pennsylvania Interdisciplinary Medicine and Biotechnology
oo

oo

oo

oo
Cardiovascular Disease in the Elderly Beth Israel Deaconess Medical Center
Boston, Massachusetts
eb

eb

eb

eb
William K. Freeman, MD Electrocardiography
Professor of Medicine
m

m
Mayo Clinic College of Medicine Jeffrey J. Goldberger, MD, MBA
Scottsdale, Arizona Professor of Medicine and Biomedical Engineering
Cardiovascular Infections Chief of the Cardiovascular Division
University of Miami Miller School of Medicine
m

J. Michael Gaziano, MD, MPH Miami, Florida


co

co

co

co
Chief, Division of Aging Cardiac Arrest and Sudden Cardiac Death
Brigham and Women’s Hospital
e.

e.

e.

e.
Scientific Director Samuel Z. Goldhaber, MD
re

fre

fre

fre
Massachusetts Veterans Epidemiology Research and Information Professor of Medicine
Center Harvard Medical School
f
ks

ks

ks
Veterans Administration Director, Thrombosis Research Group
ok

Boston Healthcare System Senior Staff Physician, Cardiovascular Medicine Division


oo

oo

oo

Professor of Medicine Brigham and Women’s Hospital


o

Harvard Medical School Boston, Massachusetts


eb

eb

eb

eb

Boston, Massachusetts Pulmonary Embolism


Global Burden of Cardiovascular Disease
m

Larry B. Goldstein, MD
Thomas A. Gaziano, MD, MSc Ruth L. Works Professor and Chairman
Assistant Professor Department of Neurology
Harvard Medical School Co-Director, Kentucky Neuroscience Institute
m

Cardiovascular Medicine Division University of Kentucky College of Medicine


co

co

co

co

Brigham and Women’s Hospital Lexington, Kentucky


Boston, Massachusetts Prevention and Management of Ischemic Stroke
e.

e.

e.

e.

Global Burden of Cardiovascular Disease


fre

fre

re

fre
sf
ks

ks

ks
ok
oo

oo

oo
o
eb

eb

eb

eb
m

om

m
xi

co

co

co
c
William J. Groh, MD, MPH Marc Humbert, MD, PhD

e.

e.

e.

e.
Clinical Professor of Medicine Professor of Respiratory Medicine
Medical University of South Carolina Service de Pneumologie

re

fre

fre

fre
Contributors
Chief of Medicine, Ralph H. Johnson VAMC Hôpital Bicêtre
f
Charleston, South Carolina Assistance, Publique Hôpitaux de Paris
ks

ks

ks
ok
Neurologic Disorders and Cardiovascular Disease Université Paris-Sud
oo

oo

oo
Paris, France

o
Martha Gulati, MD Pulmonary Hypertension
eb

eb

eb

eb
Division Chief of Cardiology
University of Arizona, Phoenix Massimo Imazio, MD
m

m
Professor of Medicine Contract Professor of Physiology
Physician Executive Director Department of Public Health and Pediatrics
Banner University Medical Center Cardiovascular Institute University of Torino
Phoenix, Arizona Attending Cardiologist
m

m
Cardiovascular Disease in Women University Cardiology Division
co

co

co

co
Department of Medical Sciences
Gerd Hasenfuss, MD AOU Città della Salute e della Scienza di Torino
e.

e.

e.

e.
Professor of Medicine Torino, Italy
fre

fre

fre

re
Chair, Department of Cardiology and Pneumology Pericardial Diseases
Chair, Heart Center

f
Silvio E. Inzucchi, MD
ks

ks

ks

ks
University of Goettingen
Chair, Heart Research Center Professor
oo

oo

oo

oo
DZHK (German Center of Cardiovascular Research) Department of Medicine, Section of Endocrinology
Goettingen, Germany Yale University School of Medicine
eb

eb

eb

eb
Pathophysiology of Heart Failure New Haven, Connecticut
Diabetes and the Cardiovascular System
m

m
Howard C. Herrmann, MD
John W. Bryfogle Professor of Cardiovascular Medicine and Surgery James L. Januzzi Jr, MD
Perelman School of Medicine at the University of Pennsylvania Physician
Health System Director for Interventional Cardiology Cardiology Division
m

m
Director, Cardiac Catheterization Labs Massachusetts General Hospital
co

co

co

co
Hospital of the University of Pennsylvania Hutter Family Professor of Medicine
Philadelphia, Pennsylvania Harvard Medical School
e.

e.

e.

e.
Transcatheter Therapies for Valvular Heart Disease Boston, Massachusetts
fre

fre

fre

fre
Approach to the Patient with Heart Failure
Joerg Herrmann, MD
ks

ks

ks

ks
Associate Professor of Medicine Cylen Javidan-Nejad, MD
Department of Cardiovascular Diseases Associate Professor
oo

oo

oo

oo
Mayo Clinic Mallinckrodt Institute of Radiology
Rochester, Minnesota Washington University in St. Louis
eb

eb

eb

eb
Cardiac Catheterization Department of Diagnostic Radiology
Section of Cardiothoracic Imaging
m

m
Ray E. Hershberger, MD St. Louis, Missouri
Professor of Medicine The Chest Radiograph in Cardiovascular Disease
Director, Division of Human Genetics
Division of Cardiovascular Medicine Mariell Jessup, MD
m

Section of Heart Failure and Cardiac Transplantation Professor Emeritus of Medicine


co

co

co

co
The Ohio State University Wexner Medical Center University of Pennsylvania
Columbus, Ohio Philadelphia, Pennsylvania;
e.

e.

e.

e.
The Dilated, Restrictive, and Infiltrative Cardiomyopathies Chief Scientific Officer
re

fre

fre

fre
Fondation Leducq
L. David Hillis, MD Paris, France
f
ks

ks

ks
Professor Emeritus and Former Chair Surgical Management of Heart Failure
ok

Department of Internal Medicine


oo

oo

oo

The University of Texas Health Science Center Sekar Kathiresan, MD


o

San Antonio, Texas Associate Professor of Medicine


eb

eb

eb

eb

Drug and Toxin-Induced Cardiomyopathies Harvard Medical School


Director, Center for Genomic Medicine
m

Priscilla Y. Hsue, MD Massachusetts General Hospital


Professor Boston, Massachusetts
Department of Medicine Principles of Cardiovascular Genetics
University of California
m

Division of Cardiology Scott Kinlay, MBBS, PhD


co

co

co

co

San Francisco General Hospital Associate Chief, Cardiovascular Medicine


San Francisco, California Director, Cardiac Catheterization Laboratory and Vascular Medicine
e.

e.

e.

e.

Cardiovascular Abnormalities in HIV-Infected Individuals Physician, Brigham and Women’s Hospital


fre

fre

re

fre

West Roxbury, Massachusetts;


Associate Professor in Medicine
sf
ks

ks

ks

Harvard Medical School


ok

Boston, Massachusetts
oo

oo

oo

Treatment of Noncoronary Obstructive Vascular Disease


o
eb

eb

eb

eb
m

om

m
xii

co

co

co
c
Irwin Klein, MD Daniel J. Lenihan, MD

e.

e.

e.

e.
Professor of Medicine Professor of Medicine
New York University School of Medicine Director, Cardio-Oncology Center of Excellence

re

fre

fre

fre
eContributors

New York, New York


sf Advanced Heart Failure
Endocrine Disorders and Cardiovascular Disease Clinical Research

ks

ks
ok

ok
Cardiovascular Division

oo

oo
Kirk U. Knowlton, MD Washington University in St. Louis
bo

o
Professor of Medicine St. Louis, Missouri

eb

eb

eb
Chief, Division of Cardiology Tumors Affecting the Cardiovascular System
Department of Medicine
m

m
University of California San Diego Martin M. LeWinter, MD
La Jolla, California Professor of Medicine and Molecular Physiology and Biophysics
Myocarditis University of Vermont Larrner College of Medicine
Attending Cardiologist and Director
m

m
Harlan M. Krumholz, MD, SM Heart Failure and Cardiomyopathy Program
co

co

co

co
Section of Cardiovascular Medicine University of Vermont Medical Center
Department of Internal Medicine Burlington, Vermont
e.

e.

e.

e.
Yale School of Medicine Pericardial Diseases
fre

fre

fre

re
Department of Health Policy and Management
Yale School of Public Health Peter Libby, MD

f
ks

ks

ks

ks
Center for Outcomes Research and Evaluation Mallinckrodt Professor of Medicine
Yale–New Haven Hospital Harvard Medical School
oo

oo

oo

oo
New Haven, Connecticut Brigham and Women’s Hospital
Clinical Decision Making in Cardiology Boston, Massachusetts
eb

eb

eb

eb
Biomarkers and Use in Precision Medicine
Raymond Y. Kwong, MD, MPH The Vascular Biology of Atherosclerosis
m

m
Associate Professor of Medicine Risk Markers and the Primary Prevention of Cardiovascular Disease
Harvard Medical School Systemic Hypertension: Management
Director of Cardiac Magnetic Resonance Imaging Lipoprotein Disorders and Cardiovascular Disease
Cardiovascular Medicine Division ST-Elevation Myocardial Infarction: Pathophysiology and Clinical
m

m
Brigham and Women’s Hospital Evolution
co

co

co

co
Boston, Massachusetts
Cardiovascular Magnetic Resonance Imaging Brian R. Lindman, MD, MSci
e.

e.

e.

e.
Associate Professor of Medicine
fre

fre

fre

fre
Bonnie Ky, MD, MSCE Medical Director, Structural Heart and Valve Center
Assistant Professor of Medicine and Epidemiology Vanderbilt University Medical Center
ks

ks

ks

ks
Division of Cardiovascular Medicine Nashville, Tennessee
University of Pennsylvania School of Medicine Aortic Valve Disease
oo

oo

oo

oo
Senior Scholar
Center for Clinical Epidemiology and Biostatistics Sheldon E. Litwin, MD
eb

eb

eb

eb
University of Pennsylvania School of Medicine Countess Alicia Spaulding-Paolozzi SmartState Endowed Chair in
Philadelphia, Pennsylvania Cardiovascular Imaging
m

m
Cardio-Oncology Professor of Medicine
Division of Cardiology
Richard A. Lange, MD, MBA Medical University of South Carolina
President and Dean, Paul L. Foster School of Medicine Ralph H. Johnson Veterans Affairs Medical Center
m

Rick and Ginger Francis Endowed Chair Charleston, South Carolina


co

co

co

co
Professor, Department of Internal Medicine Heart Failure with a Preserved Ejection Fraction
Texas Tech University Health Sciences Center at El Paso
e.

e.

e.

e.
El Paso, Texas Michael J. Mack, MD
re

fre

fre

fre
Drug and Toxin-Induced Cardiomyopathies Medical Director, Cardiovascular Surgery
Baylor Scott & White Health
f
ks

ks

ks
Eric Larose, DVM, MD Plano, Texas
ok

Associate Professor, Department of Medicine Transcatheter Therapies for Valvular Heart Disease
oo

oo

oo

Faculty of Medicine
o

Québec Heart and Lung Institute Calum A. MacRae, MB, ChB, PhD
eb

eb

eb

eb

Université Laval Associate Professor of Medicine


Québec, Canada Chief, Cardiovascular Medicine
m

Obesity and Cardiometabolic Disease Brigham and Women’s Hospital and Harvard Medical School
Broad Institute of Harvard and MIT
John M. Lasala, MD Harvard Stem Cell Institute
Professor of Medicine Boston, Massachusetts
m

Cardiology Division Personalized and Precision Cardiovascular Medicine


co

co

co

co

Washington University School of Medicine


St. Louis, Missouri
e.

e.

e.

e.

Catheter-Based Treatment of Congenital Heart Disease


fre

fre

re

fre
sf
ks

ks

ks
ok
oo

oo

oo
o
eb

eb

eb

eb
m

om

m
xiii

co

co

co
c
Douglas L. Mann, MD Peter A. McCullough, MD, MPH

e.

e.

e.

e.
Lewin Chair and Professor of Medicine, Cell Biology, and Vice Chief of Internal Medicine
Physiology Baylor University Medical Center

re

fre

fre

fre
Contributors
Chief, Division of Cardiology Consultant Cardiologist
f
Washington University School of Medicine in St. Louis Baylor Heart and Vascular Hospital
ks

ks

ks
ok
Cardiologist-in-Chief Dallas, Texas
oo

oo

oo
Barnes-Jewish Hospital Interface Between Renal Disease and Cardiovascular Illness

o
St. Louis, Missouri
eb

eb

eb

eb
Approach to the Patient with Heart Failure Darren K. McGuire, MD, MHSc
Pathophysiology of Heart Failure Professor of Internal Medicine
m

m
Management of Heart Failure Patients with Reduced Ejection Division of Cardiology
Fraction Department of Internal Medicine
University of Texas Southwestern Medical Center
Barry J. Maron, MD Dallas, Texas
m

m
Hypertrophic Cardiomyopathy Institute Diabetes and the Cardiovascular System
co

co

co

co
Tufts Medical Center
Boston, Massachusetts Vallerie V. McLaughlin, MD
e.

e.

e.

e.
Hypertrophic Cardiomyopathy Professor of Medicine
fre

fre

fre

re
Division of Cardiovascular Medicine
Martin S. Maron, MD Director, Pulmonary Hypertension Program

f
ks

ks

ks

ks
Director, Hypertrophic Cardiomyopathy Institute University of Michigan Health System
Tufts Medical Center Ann Arbor, Michigan
oo

oo

oo

oo
Boston, Massachusetts Pulmonary Hypertension
Hypertrophic Cardiomyopathy
eb

eb

eb

eb
Roxana Mehran, MD
Nikolaus Marx, MD Professor of Medicine (Cardiology)
m

m
Professor of Medicine/Cardiology Director of Interventional Cardiovascular Research and Clinical
Department of Internal Medicine I Trials
University Hospital Aachen Zena and Michael A. Wiener Cardiovascular Institute
Aachen, Germany Icahn School of Medicine at Mount Sinai
m

m
Diabetes and the Cardiovascular System New York, New York
co

co

co

co
Coronary Angiography and Intravascular Imaging
Justin C. Mason, PhD
e.

e.

e.

e.
Professor of Vascular Rheumatology John M. Miller, MD
fre

fre

fre

fre
National Heart and Lung Institute Professor of Medicine
Imperial College London Indiana University School of Medicine
ks

ks

ks

ks
London, United Kingdom Director, Cardiac Electrophysiology Services
Rheumatic Diseases and the Cardiovascular System Indiana University Health
oo

oo

oo

oo
Indianapolis, Indiana
Frederick A. Masoudi, MD, MSPH Diagnosis of Cardiac Arrhythmias
eb

eb

eb

eb
Professor of Medicine Therapy for Cardiac Arrhythmias
University of Colorado Anschutz Medical Campus
m

m
Aurora, Colorado; James K. Min, MD
Chief Science Officer Professor of Radiology and Medicine
National Cardiovascular Data Registry Programs Director, Dalio Institute of Cardiovascular Imaging
Washington, DC Weill Cornell Medicine, NewYork–Presbyterian
m

Measuring and Improving Quality of Care: Relevance to New York, New York
co

co

co

co
Cardiovascular Clinical Practice Cardiac Computed Tomography
e.

e.

e.

e.
Laura Mauri, MD, MSc David M. Mirvis, MD
re

fre

fre

fre
Professor of Medicine Professor Emeritus
Harvard Medical School University of Tennessee College of Medicine
f
ks

ks

ks
Director of Clinical Biometrics Memphis, Tennessee
ok

Division of Cardiovascular Medicine Division Electrocardiography


oo

oo

oo

Brigham and Women’s Hospital


o

Boston, Massachusetts Fred Morady, MD


eb

eb

eb

eb

Percutaneous Coronary Intervention McKay Professor of Cardiovascular Disease


Professor of Medicine
m

Bongani M. Mayosi, MBChB, DPhil University of Michigan Health System


Professor of Medicine Ann Arbor, Michigan
Dean, Faculty of Heath Sciences Atrial Fibrillation: Clinical Features, Mechanisms, and Management
University of Cape Town
m

Cape Town, South Africa Anthony P. Morise, MD


co

co

co

co

Rheumatic Fever Professor of Medicine


West Virginia University School of Medicine
e.

e.

e.

e.

Laurence B. McCullough, PhD Director, Stress Cardiovascular Laboratory


fre

fre

re

fre

Distinguished Professor Emeritus West Virginia University Heart and Vascular Institute
Center for Medical Ethics and Health Policy Morgantown, West Virginia
sf
ks

ks

ks

Baylor College of Medicine Exercise Electrocardiographic Testing


ok

Houston, Texas
oo

oo

oo

Ethics in Cardiovascular Medicine


o
eb

eb

eb

eb
m

om

m
xiv

co

co

co
c
David A. Morrow, MD, MPH Francis D. Pagani, MD, PhD

e.

e.

e.

e.
Professor of Medicine Otto Gago MD Professor of Cardiac Surgery
Harvard Medical School Department of Cardiac Surgery

re

fre

fre

fre
eContributors

Director, Levine Cardiac Intensive Care Unit


sf University of Michigan Hospital
Cardiovascular Division Ann Arbor, Michigan

ks

ks
ok

ok
Brigham and Women’s Hospital Mechanical Circulatory Support

oo

oo
Director, TIMI Biomarker Program
bo

o
Senior Investigator, TIMI Study Group Patricia A. Pellikka, MD

eb

eb

eb
Boston, Massachusetts Chair, Division of Cardiovascular Ultrasound
ST-Elevation Myocardial Infarction: Pathophysiology and Clinical Professor of Medicine
m

m
Evolution Consultant, Department of Cardiovascular Medicine
ST-Elevation Myocardial Infarction: Management Mayo Clinic
Stable Ischemic Heart Disease Rochester, Minnesota
Tricuspid, Pulmonic, and Multivalvular Disease
m

m
Dariush Mozaffarian, MD, DrPh
co

co

co

co
Dean, Friedman School of Nutrition Science & Policy Philippe Pibarot, DVM, PhD
Jean Mayer Professor of Nutrition and Medicine Professor
e.

e.

e.

e.
Tufts University Québec Heart & Lung Institute
fre

fre

fre

re
Boston, Massachusetts Université Laval
Nutrition and Cardiovascular and Metabolic Diseases Québec, Canada

f
ks

ks

ks

ks
Prosthetic Heart Valves
Kiran Musunuru, MD, PhD, MPH
oo

oo

oo

oo
Associate Professor of Cardiovascular Medicine and Genetics Paul Poirier, MD, PhD
Perelman School of Medicine at the University of Pennsylvania Professor, Faculty of Pharmacy
eb

eb

eb

eb
Philadelphia, Pennsylvania Québec Heart and Lung Institute
Principles of Cardiovascular Genetics Université Laval
m

m
Cardiovascular Regeneration and Repair Québec, Canada
Obesity and Cardiometabolic Disease
Robert J. Myerburg, MD
Professor of Medicine and Physiology Dorairaj Prabhakaran, MD, DM (Cardiology), MSc
m

m
Department of Medicine Director, Centre for Control of Chronic Conditions
co

co

co

co
University of Miami Miller School of Medicine Vice President (Research and Policy)
Miami, Florida Public Health Foundation of India
e.

e.

e.

e.
Cardiac Arrest and Sudden Cardiac Death Gurgaon, India;
fre

fre

fre

fre
Professor (Epidemiology)
Patrick T. O’Gara, MD London School of Hygiene and Tropical Medicine
ks

ks

ks

ks
Professor of Medicine London, United Kingdom
Harvard Medical School Global Burden of Cardiovascular Disease
oo

oo

oo

oo
Senior Physician
Brigham and Women’s Hospital Andrew N. Redington, MD
eb

eb

eb

eb
Boston, Massachusetts Chief, Pediatric Oncology
History and Physical Examination: An Evidence-Based Approach Heart Institute
m

m
Prosthetic Heart Valves Cincinnati Children’s Hospital Medical Center
Cincinnati, Ohio
Jeffrey E. Olgin, MD Congenital Heart Disease in the Adult and Pediatric Patient
Chief of Cardiology
m

Gallo-Chatterjee Distinguished Professor of Medicine Susan Redline, MD, MPH


co

co

co

co
Co-Director of the UCSF Heart and Vascular Center Peter C. Farrell Professor of Sleep Medicine
University of California, San Francisco Harvard Medical School
e.

e.

e.

e.
San Francisco, California Senior Physician, Division of Sleep and Circadian Disorders
re

fre

fre

fre
Supraventricular Arrhythmias Departments of Medicine and Neurology
Ventricular Arrhythmias Brigham and Women’s Hospital
f
ks

ks

ks
Bradyarrhythmias and Atrioventricular Block Physician, Division of Pulmonary Medicine
ok

Department of Medicine
oo

oo

oo

Iacopo Olivotto, MD Beth Israel Deaconess Medical Center


o

Referral Center for Cardiomyopathies Boston, Massachusetts


eb

eb

eb

eb

Azienda Ospedaliera Universitaria Careggi Sleep-Disordered Breathing and Cardiac Disease


Florence, Italy
m

Hypertrophic Cardiomyopathy Paul M. Ridker, MD


Eugene Braunwald Professor of Medicine
Catherine M. Otto, MD Harvard Medical School
J. Ward Kennedy-Hamilton Endowed Chair in Cardiology Director, Center for Cardiovascular Disease Prevention
m

Professor of Medicine Division of Preventive Medicine


co

co

co

co

Director, Heart Valve Clinic Brigham and Women’s Hospital


University of Washington School of Medicine Boston, Massachusetts
e.

e.

e.

e.

Seattle, Washington Biomarkers and Use in Precision Medicine


fre

fre

re

fre

Approach to the Patient with Valvular Heart Disease Risk Markers and the Primary Prevention of Cardiovascular Disease
Aortic Valve Disease
sf
ks

ks

ks

Guidelines: Management of Valvular Heart Disease


ok
oo

oo

oo
o
eb

eb

eb

eb
m

om

m
xv

co

co

co
c
David Robertson, MD Ashish Shah, MD

e.

e.

e.

e.
Professor of Medicine, Pharmacology and Neurology Professor of Medicine
Vanderbilt University Medical Center Department of Cardiac Surgery

re

fre

fre

fre
Contributors
Nashville, Tennessee Vanderbilt University Medical Center
f
Cardiovascular Manifestations of Autonomic Disorders Nashville, Tennessee
ks

ks

ks
ok
Tumors Affecting the Cardiovascular System
oo

oo

oo
Rose Marie Robertson, MD

o
Chief Science and Medical Officer Candice K. Silversides, MD
eb

eb

eb

eb
American Heart Association Associate Professor of Medicine
Dallas, Texas Mount Sinai Hospital
m

m
Cardiovascular Manifestations of Autonomic Disorders Toronto, Ontario, Canada
Pregnancy and Heart Disease
Dan M. Roden, MD
Professor of Medicine, Pharmacology, and Biomedical Informatics Jeffrey F. Smallhorn, MBBS
m

m
Director, Oates Institute for Experimental Therapeutics Professor Emeritus of Pediatrics
co

co

co

co
Senior Vice-President for Personalized Medicine University of Alberta
Vanderbilt University Medical Center Edmonton, Alberta, Canada
e.

e.

e.

e.
Nashville, Tennessee Congenital Heart Disease in the Adult and Pediatric Patient
fre

fre

fre

re
Drug Therapeutics and Personalized Medicine
Scott D. Solomon, MD

f
Michael Rubart, MD
ks

ks

ks

ks
Professor of Medicine
Assistant Professor of Pediatrics Harvard Medical School
oo

oo

oo

oo
Department of Pediatrics Director, Noninvasive Cardiology
Indiana University School of Medicine Brigham and Women’s Hospital
eb

eb

eb

eb
Indianapolis, Indiana Boston, Massachusetts
Mechanisms of Cardiac Arrhythmias Echocardiography
m

m
John S. Rumsfeld, MD, PhD Lynne Warner Stevenson, MD
Professor of Medicine Director of Cardiomyopathy and Lisa Jacobson Professor of
University of Colorado School of Medicine Medicine
m

m
Anschutz Medical Campus Vanderbilt Heart and Vascular Institute
co

co

co

co
Aurora, Colorado; Vanderbilt University Medical Center
Chief Innovation Officer Nashville, Tennessee
e.

e.

e.

e.
American College of Cardiology Management of Patients with Cardiovascular Disease Approaching
fre

fre

fre

fre
Washington, DC End of Life
Measuring and Improving Quality of Care: Relevance to
ks

ks

ks

ks
Cardiovascular Clinical Practice Rakesh M. Suri, MD, DPhil
Professor of Surgery
oo

oo

oo

oo
Marc S. Sabatine, MD, MPH Cleveland Clinic Abu Dhabi
Chairman, TIMI Study Group Abu Dhabi, United Arab Emirates
eb

eb

eb

eb
Lewis Dexter MD Distinguished Chair in Cardiovascular Medicine Cardiovascular Infections
Brigham and Women’s Hospital
m

m
Professor of Medicine Charles D. Swerdlow, MD
Harvard Medical School Clinical Professor of Medicine
Boston, Massachusetts Cedars-Sinai Medical Center
Approach to the Patient with Chest Pain University of California Los Angeles
m

Los Angeles, California


co

co

co

co
Marc Schermerhorn, MD Pacemakers and Implantable Cardioverter-Defibrillators
Associate Professor of Surgery
e.

e.

e.

e.
Harvard Medical School John R. Teerlink, MD
re

fre

fre

fre
Chief, Division of Vascular and Endovascular Surgery Professor of Medicine
Beth Israel Deaconess Medical Center School of Medicine
f
ks

ks

ks
Boston, Massachusetts University of California, San Francisco
ok

Diseases of the Aorta Director, Heart Failure


oo

oo

oo

Director, Echocardiography
o

Benjamin M. Scirica, MD, MPH San Francisco Veterans Affairs Medical Center
eb

eb

eb

eb

Associate Professor of Medicine San Francisco, California


Harvard Medical School Diagnosis and Management of Acute Heart Failure
m

Associate Physician, Cardiovascular Division


Senior Investigator, TIMI Study Group David J. Tester, BS
Brigham and Women’s Hospital Associate Professor of Medicine
Boston, Massachusetts Mayo Clinic College of Medicine and Science
m

ST-Elevation Myocardial Infarction: Pathophysiology and Clinical Senior Research Technologist II-Supervisor,
co

co

co

co

Evolution Windland Smith Rice Sudden Death Genomics Laboratory


Mayo Clinic
e.

e.

e.

e.

Rochester, Minnesota
fre

fre

re

fre

Genetics of Cardiac Arrhythmias


sf
ks

ks

ks
ok
oo

oo

oo
o
eb

eb

eb

eb
m

om

m
xvi

co

co

co
c
Judith Therrien, MD Paul J. Wang, MD

e.

e.

e.

e.
Associate Professor Professor of Medicine
Department of Medicine Director, Arrhythmia Service

re

fre

fre

fre
eContributors

McGill University
sf Stanford University
Montreal, Quebec, Canada Stanford, California

ks

ks
ok

ok
Congenital Heart Disease in the Adult and Pediatric Patient Pacemakers and Implantable Cardioverter-Defibrillators

oo

oo
bo

o
James D. Thomas, MD Carole A. Warnes, MD

eb

eb

eb
Director, Center for Heart Valve Disease Professor of Medicine
Director, Academic Affairs Consultant in Cardiovascular Diseases and Internal Medicine
m

m
Bluhm Cardiovascular Institute Pediatric Cardiology
Northwestern Memorial Hospital Director of Adult Congenital Heart Disease Clinic
Professor of Medicine Mayo Clinic
Northwestern University Feinberg School of Medicine Rochester, Minnesota
m

m
Chicago, Illinois Pregnancy and Heart Disease
co

co

co

co
Mitral Valve Disease
David D. Waters, MD
e.

e.

e.

e.
Paul D. Thompson, MD Professor Emeritus
fre

fre

fre

re
Chief of Cardiology Division of Cardiology
Hartford Hospital San Francisco General Hospital

f
ks

ks

ks

ks
Hartford, Connecticut Department of Medicine
Exercise and Sports Cardiology University of California, San Francisco
oo

oo

oo

oo
Exercise-Based, Comprehensive Cardiac Rehabilitation San Francisco, California
Cardiovascular Abnormalities in HIV-Infected Individuals
eb

eb

eb

eb
Gordon F. Tomaselli, MD
Michel Mirowski MD Professor of Cardiology Gary D. Webb, MDCM
m

m
Professor of Medicine Consultant to the Cincinnati Adult Congenital Heart Program
Chief, Division of Cardiology Cincinnati, Ohio
Johns Hopkins School of Medicine Congenital Heart Disease in the Adult and Pediatric Patient
Baltimore, Maryland
m

m
Approach to the Patient with Cardiac Arrhythmias Jeffrey I. Weitz, MD
co

co

co

co
Mechanisms of Cardiac Arrhythmias Professor of Medicine and Biochemistry
Diagnosis of Cardiac Arrhythmias McMaster University
e.

e.

e.

e.
Therapy for Cardiac Arrhythmias Canada Research Chair in Thrombosis
fre

fre

fre

fre
Ventricular Arrhythmias Executive Director, Thrombosis and Atherosclerosis Research
Neurologic Disorders and Cardiovascular Disease Institute
ks

ks

ks

ks
Hamilton, Ontario, Canada
James E. Udelson, MD Hemostasis, Thrombosis, Fibrinolysis, and Cardiovascular Disease
oo

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Professor of Medicine and Radiology
Tufts University School of Medicine Nanette Kass Wenger, MD
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Chief, Division of Cardiology Professor of Medicine (Cardiology) Emeritus
The CardioVascular Center Emory University School of Medicine
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Tufts Medical Center Consultant, Emory Heart and Vascular Center
Boston, Massachusetts Atlanta, Georgia
Nuclear Cardiology Cardiovascular Disease in the Elderly
Appropriate Use Criteria: Multimodality Imaging in Stable Ischemic
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Heart Disease and Heart Failure Walter R. Wilson, MD


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Professor of Medicine
Viola Vaccarino, MD, PhD Mayo Clinic College of Medicine
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Wilton Looney Chair of Cardiovascular Research Rochester, Minnesota
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Professor and Chair, Department of Epidemiology Cardiovascular Infections
Rollins School of Public Health
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Professor, Department of Medicine Stephen D. Wiviott, MD
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Emory University Investigator, TIMI Study Group


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Atlanta, Georgia Cardiovascular Medicine Division


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Psychiatric and Behavioral Aspects of Cardiovascular Disease Brigham and Women’s Hospital
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Associate Professor
Ronald G. Victor, MD Cardiovascular Medicine
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Burns and Allen Chair in Cardiology Research Harvard Medical School


Director, Hypertension Center of Excellence Boston, Massachusetts
Associate Director, Cedars-Sinai Heart Institute Guidelines: Management of Patients with ST-Elevation Myocardial
Cedars-Sinai Medical Center Infarction
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Los Angeles, California


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Systemic Hypertension: Mechanisms and Diagnosis Joseph C. Wu, MD, PhD


Systemic Hypertension: Management Director, Stanford Cardiovascular Institute
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Simon H. Stertzer Professor of Medicine and Radiology


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Stanford University School of Medicine


Stanford, California
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Cardiovascular Regeneration and Repair


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Justina C. Wu, MD, PhD Douglas P. Zipes, MD

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Assistant Professor of Medicine Distinguished Professor
Harvard Medical School Division of Cardiology and the Krannert Institute of Cardiology

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Contributors
Associate Director, Noninvasive Cardiology Indiana University School of Medicine
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Brigham and Women’s Hospital Indianapolis, Indiana
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Boston, Massachusetts Approach to the Patient with Cardiac Arrhythmias
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Echocardiography Mechanisms of Cardiac Arrhythmias

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Diagnosis of Cardiac Arrhythmias
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Syed Wamique Yusuf, MD Therapy for Cardiac Arrhythmias
Associate Professor of Medicine Supraventricular Arrhythmias
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Department of Cardiology Atrial Fibrillation: Clinical Features, Mechanisms, and Management
University of Texas MD Anderson Cancer Center Ventricular Arrhythmias
Houston, Texas Bradyarrhythmias and Atrioventricular Block
Tumors Affecting the Cardiovascular System Pacemakers and Implantable Cardioverter-Defibrillators
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Hypotension and Syncope
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Michael R. Zile, MD Neurologic Disorders and Cardiovascular Disease
Charles Ezra Daniel Professor of Medicine
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Division of Cardiology
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Medical University of South Carolina
Chief, Division of Cardiology

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Ralph H. Johnson Veterans Affairs Medical Center
Charleston, South Carolina
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Heart Failure with a Preserved Ejection Fraction
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f Preface
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This is the 11th edition of the classic textbook, Heart Disease: A Textbook We have continued the tradition of including practice guidelines, and
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Of Cardiovascular Medicine, that Dr. Eugene Braunwald began almost have written the text for all levels of learners and for all specialties in
40 years ago. The editors are pleased and honored to dedicate this cardiology. As before, information not directly relevant to practicing
edition to him for his extraordinary contributions to the discipline of clinicians is presented in smaller font. More detailed information on
cardiology, especially this textbook and its companions, and for his many topics can be found in the companions to this book:
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unique concept of creating a “living textbook.”
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In the past several decades, cardiology has advanced at a breakneck Cardiovascular Intervention by Deepak L. Bhatt
pace on many fronts. Knowledge of the diagnosis and management Cardiovascular Therapeutics by Elliott Antman and Marc Sabatine
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of patients with heart disease, as well as understanding of responsible Chronic Coronary Artery Disease by James DeLemos and Torbjorn
mechanisms and preventive approaches, advance daily. Genetics, Omland
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molecular biology and pharmacology, imaging, catheter-based therapy, Clinical Arrhythmology and Electrophysiology by Ziad Issa, John Miller,

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and cardiac repair are only a sampling of what we encounter daily. and Douglas Zipes
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This constant flow of innovative research has generated a prolifera- Clinical Lipidology by Christie Ballantyne
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tion of new cardiovascular journals, cumulatively publishing an Diabetes in Cardiovascular Medicine by Darren McGuire and Nikolaus
unprecedented amount of information. With the rapidly changing Marx
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cardiovascular knowledge base, an authoritative textbook like Heart Heart Failure by Michael Felker and Douglas Mann
Disease to which readers can turn, confident that the statements are Hypertension by George Bakris and Matthew Sorrentino
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as accurate and up-to-date as possible, offers even greater value. Mechanical Circulatory Support by Robert Kormos and Leslie Miller
As with each edition of this reference work, international experts Myocardial Infarction by David Morrow
— household names to many readers — have totally revised every Preventive Cardiology by Roger Blumenthal, JoAnn Foody, and Nathan
chapter. In addition, 14 new chapters have been added to recognize Wong
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the ever-expanding role of cardiology into areas such as oncology, Valvular Heart Disease by Catherine Otto and Robert Bonow
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chronic lung disease, environmental toxins, catheter-based treatments Vascular Medicine by Marc Creager, Joshua Beckman, and Joseph
of congenital heart disease, and other topics. Some sections have Loscalzo
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been revised for clarity, such as arrhythmias; some have been expanded, Braunwald’s Heart Disease Review and Assessment by Leonard Lilly
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such as diseases of heart valves; others have had a shift of emphasis, Atlas of Cardiovascular CT by Allen Taylor
such as congenital heart disease in the adult. Finally, to maintain Atlas of Cardiovascular MR by Christopher Kramer and W Greg Hundley
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vitality of standard topics, new authors have replaced more than a Atlas of Nuclear Cardiology by Amil Iskandrian and Ernest Garcia
third of those who have tirelessly written for previous editions, in
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chapters on ethics, personalized and precision medicine, imaging, In keeping with the revitalization theme noted above, one of us
obesity, diabetes, sleep-disordered breathing, autonomic nervous (DPZ) will be leaving after this edition. Beginning with the 2nd edition
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system, and other areas. of Heart Disease in 1984, Dr. Zipes has written the arrhythmia section
In the preface for the 10th edition of Heart Disease, we emphasized and, in more recent editions, with co-authors, and has co-edited Heart
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that the online version contained audio, video, and written information Disease since the 6th edition. Gordon F. Tomaselli will be his very
not available in the print edition. We have continued and expanded capable replacement.
this practice. To put this 11th edition in perspective, it contains more The editors and authors, along with the Elsevier staff, have endeav-
than 2700 illustrations and 565 tables, while maintaining the number ored to make Heart Disease the go-to source for current cardiology
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of printed pages near 2000. The eBook includes an additional 400 knowledge, maintaining the high standards Dr. Braunwald set many
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illustrations, 60 tables, and 300 videos. years ago. We hope readers will enjoy reading this edition and learn
We have divided the book into 11 sections, including fundamentals from it, as we all strive to improve patient care, our ultimate goal.
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of cardiovascular disease; genetics and personalized medicine; evalu-
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ation of the patient; heart failure; arrhythmias, sudden death, and Douglas P. Zipes
syncope; preventive cardiology; atherosclerotic cardiovascular disease; Peter Libby
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diseases of heart valves; diseases of the myocardium, pericardium, Robert O. Bonow
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and pulmonary vasculature bed; cardiovascular disease in special Douglas L. Mann


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populations; and cardiovascular disease and disorders of other organs. Gordon F. Tomaselli
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f Preface to the First Edition
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Cardiovascular disease is the greatest scourge affecting the industrial- disease by medical and surgical means. Indeed, in the United States,
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ized nations. As with previous scourges — bubonic plague, yellow a steady reduction in mortality from cardiovascular disease during the
fever, and small pox — cardiovascular disease not only strikes down past decade suggests that the effective application of this increased
a significant fraction of the population without warning but also causes knowledge is beginning to prolong human life span, the most valued
prolonged suffering and disability in an even larger number. In the resource on earth.
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United States alone, despite recent encouraging declines, cardiovascular To provide a comprehensive, authoritative text in a field that has
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disease is still responsible for almost 1 million fatalities each year and become as broad and deep as cardiovascular medicine, I enlisted
more than half of all deaths; almost 5 million persons afflicted with the aid of a number of able colleagues. However, I hoped that my
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cardiovascular disease are hospitalized each year. The cost of these personal involvement in the writing of about half of the book would
diseases in terms of human suffering and material resources is almost make it possible to minimize the fragmentation, gaps, inconsistencies,
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incalculable. organizational difficulties, and impersonal tone that sometimes plague

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Fortunately, research focusing on the prevention, causes, diagnosis, multiauthored texts. Although Heart Disease: A Textbook of Cardio-
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and treatment of heart disease is moving ahead rapidly. Since the vascular Medicine is primarily a clinical treatise and not a textbook
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early part of the twentieth century, clinical cardiology has had a of fundamental cardiovascular science, an effort has been made to
particularly strong foundation in the basic sciences of physiology and explain, in some detail, the scientific bases of cardiovascular diseases.
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pharmacology. More recently, the disciplines of molecular biology, To the extent that this book proves useful to those who wish to
genetics, developmental biology, biophysics, biochemistry, experimental broaden their knowledge of cardiovascular medicine and thereby
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pathology and bioengineering have also begun to provide critically aids in the care of patients afflicted with heart disease, credit must
important information about cardiac function and malfunction. be given to the many talented and dedicated persons involved in its
In the past 25 years, in particular, we have witnessed an explosive preparation. I offer my deepest appreciation to my fellow contributors
expansion of our understanding of the structure and function of the for their professional expertise, knowledge, and devoted scholarship,
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cardiovascular system—both normal and abnormal—and of our ability which has so enriched this book. I am deeply indebted to them for
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to evaluate these parameters in the living patient, sometimes by means their cooperation and willingness to deal with a demanding editor.
of techniques that require penetration of the skin but also with increas-
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ing accuracy, by noninvasive methods. Simultaneously, remarkable Eugene Braunwald
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progress has been made in preventing and treating cardiovascular 1980
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f Video Contents
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10 History and Physical Examination: An 14.33 Quadricuspid aortic valve
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Evidence-Based Approach, 83 14.34 Tricuspid stenosis
10.1 V wave 14.35 Carcinoid tricuspid valve
10.2 Kussmaul sign 14.36 Pulmonic stenosis
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10.3 Precordial diastolic gallop 14.37 Normal bileaflet mechanical mitral prosthesis, by
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4D transesophageal echocardiography
14 Echocardiography, 174 14.38 Rocking aortic valve bioprosthesis
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14.1 Mirror artifact 14.39 Thrombosed bileaflet mechanical mitral prosthesis
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14.2 Four-dimensional transesophageal echocardiogram 14.40 Tamponade with right atrial inversion

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of aortic and mitral valves 14.41 Tamponade with right ventricular outflow tract
14.3 Echo contrast demonstrating pseudoaneurysm at inversion
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left ventricular apex 14.42 Constriction with respirophasic septal shift
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14.4 Left anterior descending artery infarct 14.43 Aortic dissection in a Marfan patient
14.5 Right ventricle and inferior myocardial infarction 14.44 Aortic dissection and severe aortic regurgitation in
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14.6 Flail anterior mitral valve a Marfan patient
14.7 Flail anterior mitral valve with color Doppler 14.45 Aortic dissection with flap prolapsing back through
showing severe mitral regurgitation aortic valve on transesophageal echocardiography
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14.8 Anteroseptal ventricular septal defect 14.46 Aortic dissection showing site of perforation on
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transesophageal echocardiography
14.9 Inferoseptal ventricular septal defect
14.47 Deep venous thrombus in transit through right
14.10 Left ventricular pseudoaneurysm
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atrium
14.11 Hemopericardium
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14.48 McConnell sign of pulmonary embolus
14.12 Giant left ventricular aneurysm
14.49 Vegetation on a rheumatic mitral valve
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14.13 Takotsubo cardiomyopathy with left ventricular
14.50 Abscess around a bicuspid aortic valve
thrombus
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14.51 Left atrial myxoma
14.14 Sarcoidosis
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14.52 Papillary fibroelastoma on aortic valve
14.15 Ischemic cardiomyopathy with mitral regurgitation
14.53 Spontaneous echo contrast ("smoke") in left atrial
14.16 Functional mitral regurgitation as shown from the
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appendage on transesophageal echocardiography
left atrial aspect
14.54 Left atrial thrombus and spontaneous echo
14.17 Hypertrophic obstructive cardiomyopathy
contrast s/p MV repair
14.18 Hypertrophic obstructive cardiomyopathy
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14.55 Patent foramen ovale bubble study and interatrial


14.19 Apical hypertrophic cardiomyopathy with apical septal aneurysm
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aneurysm
14.56 MitraClip, as viewed on 4D transesophageal
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14.20 Left ventricular noncompaction echocardiography
14.21 Arrhythmogenic cardiomyopathy
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14.22 Amyloid heart


16 Nuclear Cardiology, 261 fre
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14.23 Löffler endocarditis
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16.1 Rubidium PET imaging


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14.24 Positive stress echocardiogram for left anterior


16.2 FDG PET imaging
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descending artery ischemia


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14.25 Positive stress echocardiogram for inferior ischemia


and ischemic mitral regurgitation 17 Cardiovascular Magnetic Resonance
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14.26 Normal mitral valve, by 4D transesophageal Imaging, 301


echocardiography 17.1 Cine CMR imaging of myocardial infarction
14.27 Rheumatic mitral stenosis complications
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14.28 Rheumatic mitral stenosis viewed from left 17.2 CMR imaging of ischemia and infarct extent
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ventricular aspect, by 3D transesophageal 17.3 Quantitation of myocardial iron content


echocardiography
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17.4 Myocardial rupture after acute inferior myocardial


14.29 Bileaflet mitral valve prolapse infarction
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14.30 Bicuspid aortic valve, short-axis view 17.5 Severe left anterior descending arterial stenosis
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14.31 Bicuspid aortic valve, long-axis view 17.6 Mitral valve anomaly in hypertrophic
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14.32 Unicuspid aortic valve cardiomyopathy


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17.7 Microvascular dysfunction in a patient with 63.4 Transthoracic echocardiogram of the root

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hypertrophic cardiomyopathy phenotype of a bicuspid aortic valve

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17.8 Ventricular tachycardia and syncope 63.5 Transesophageal echocardiogram of dilated aortic
Video Contents

f 17.9 Takotsubo cardiomyopathy root


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17.10 Chronic constrictive pericarditis with pericardial 63.6 Acute type A aortic dissection complicated by

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severe aortic regurgitation
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adhesions post radiation

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17.11 Atrial septal defect 63.7 Transesophageal echocardiogram of acute type A
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aortic dissection
17.12 Vector flow lines in the normal aorta
63.8 Color flow Doppler of acute type A aortic
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17.13 Abnormal flow patterns dissection
17.14 Cine imaging of large mass attached to mitral valve 63.9 Transesophageal echocardiogram of acute type A
17.15 Myocardial infarction and coronary stenosis aortic dissection with prolapse of dissection flap
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63.10 Color flow transesophageal echocardiogram of
19 Cardiac Catheterization, 348 severe aortic regurgitation due to acute type A aortic
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19.1 Radial artery catheterization using Seldinger dissection
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technique 63.11 Color flow transesophageal echocardiogram of
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19.2 Right heart catheterization via 7F sheath in right severe aortic regurgitation due to massive aortic root
internal jugular vein aneurysm

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19.3 Left ventriculogram of extensive regional wall 63.12 Transthoracic echocardiogram of type A aortic
motion abnormalities dissection
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19.4 Left ventriculogram of mild-moderate mitral 63.13 Transthoracic echocardiogram of patient presenting
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regurgitation (grade I-II) with severe chest pain and near syncope
19.5 Left ventriculogram of ventricular septal defect 63.14 Transthoracic echocardiogram (subcostal view) of
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patient with chest pain demonstrating acute aortic
19.6 Aortogram of moderate aortic regurgitation,
dissection
Sellers grade II
63.15 Transesophageal echocardiogram of highly mobile
19.7 Aortogram of De Bakey type II dissection of the
dissection flap
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ascending aorta
63.16 Transesophageal echocardiogram of acute type A
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19.8 Right ventriculogram of patient with pulmonary
aortic dissection
valve stenosis
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63.17 Transesophageal echocardiogram of acute type A
aortic dissection
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34 Mechanisms of Cardiac Arrhythmias, 619
63.18 Acute type A aortic dissection
34.1 Simulation of anterograde conduction through the
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atrioventricular node 63.19 Type A aortic dissection with dissection flap
originating in the aortic root
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34.2 Simulation of fast-slow reentry using an
electroanatomical model 63.20 Transesophageal echocardiogram of type A
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intramural hematoma of the aorta
34.3 Posterior left atrial activation during atrial fibrillation
63.21 Transesophageal echocardiogram of an intramural
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34.4 Ventricular fibrillation spiral wave activity hematoma of the aorta

35 Diagnosis of Cardiac Arrhythmias, 648 66 Treatment of Noncoronary Obstructive


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35.1 Focal atrial tachycardia Vascular Disease, 1365


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35.2 Macroreentrant right atrial tachycardia following 66.1 Diagnostic angiography
atriotomy for repair of atrial septal defect
66.2 Distal superficial femoral artery
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66.3 Wire advancement through superficial femoral
36 Therapy for Cardiac Arrhythmias, 670
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artery
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36.1 Macroreentrant left atrial tachycardia after


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66.4 Percutaneous transluminal angioplasty of the
pulmonary vein isolation
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superficial femoral artery


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36.2 Macroreentrant left atrial tachycardia after


66.5 Angiography following percutaneous transluminal
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pulmonary vein isolation


angioplasty
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66.6 Angiography following first stent insertion


62 Percutaneous Coronary Intervention, 1271
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66.7 Angiography of the more proximal lesion


62.1 Air injected down the right coronary artery
66.8 Angiography following second stent insertion
62.2 Three coronary arteries off the right coronary cusp
66.9 Post-stent dilation angiography
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66.10 Post-stent angiography


63 Diseases of the Aorta, 1295
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63.1 Echocardiogram of a patient with Marfan


68 Aortic Valve Disease, 1389
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syndrome
68.1 Level of outflow obstruction
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63.2 Transesophageal echocardiogram of bicuspid aortic


valve and dissection flap 68.2 Left ventricular dilation and increased sphericity
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63.3 Acute type A aortic dissection complicating a with chronic severe aortic regurgitation
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massive aortic root aneurysm 68.3 Mild aortic regurgitation


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68.4 Vena contracta measurements 75.3 Anomalous left coronary artery originating from

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68.5 Imaging findings in severe aortic regurgitation right pulmonary artery

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68.6 Severe aortic regurgitation 75.4 Scimitar syndrome

Video Contents
f68.7 Transesophageal echocardiography of a stenotic 75.5 Scimitar syndrome
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bicuspid aortic valve

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75.6 Parachute mitral valve
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68.8 Bicuspid aortic valve 75.7 Tricuspid atresia and dextrocardia

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75.8 Normal heart
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69 Mitral Valve Disease, 1415
75.9 Atrioventricular discordance
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69.1 Mild rheumatic mitral stenosis
75.10 Atrioventricular and ventriculoarterial discordance
69.2 Planimetry of mitral valve area
75.11 Double-inlet left ventricle
69.3 Mitral stenosis jet on color-flow Doppler imaging
75.12 Double-inlet left ventricle
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69.4 Three-dimensional transesophageal
echocardiography of mitral stenosis 75.13 Double-inlet left ventricle
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69.5 Three-dimensional visualization of rheumatic mitral 75.14 Double-inlet left ventricle
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stenosis 75.15 Double-inlet left ventricle
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69.6 Spontaneous left atrial contrast 75.16 Double-inlet left ventricle
69.7 Transesophageal echocardiography-guided balloon

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75.17 Double-inlet left ventricle
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mitral commissurotomy
75.18 Double-inlet ventricle with common atrium and
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69.8 Mitral valve morphology common atrioventricular valve
69.9 Normal degree of mitral regurgitation 75.19 Hypoplastic posterior left ventricle
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69.10 Mitral valve prolapse
75.20 Superior-inferior ventricles and crisscross heart
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69.11 Flail mitral valve leaflet
75.21 Ventricular inversion with common atrioventricular
69.12 Mitral leaflet flail valve and ostium prima defect
69.13 Functional mitral regurgitation 75.22 Tricuspid atresia
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69.14 Anteriorly directed mitral regurgitation on 75.23 Tricuspid atresia
transesophageal echocardiography
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75.24 Hypoplastic right ventricle
69.15 Posteriorly directed mitral regurgitation on
75.25 Hypoplastic left heart syndrome
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transesophageal echocardiography
75.26 Repaired common atrioventricular valve
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69.16 Bileaflet prolapse and late systolic mitral regurgitation
69.17 Multiple mitral regurgitation jets on 75.27 Repaired common atrioventricular valve
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transesophageal echocardiography 75.28 Three-dimensional echocardiography of tricuspid
valve, with a hypoplastic mitral valve
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69.18 Three-dimensional image of a mitral valve
69.19 Radiation-induced aortic and mitral stenosis 75.29 Coronary sinus defect
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69.20 Secondary mitral regurgitation 75.30 Coronary sinus defect
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69.21 Proximal isovelocity surface area imaging 75.31 Anomalous pulmonary venous drainage
75.32 Sinus venosus defect
70 Tricuspid, Pulmonic, and Multivalvular 75.33 Sinus venosus defect
Disease, 1445
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75.34 Amplatzer closure of secundum atrial septal defect


70.1 Cafergot-induced tricuspid valve disease
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75.35 Cause and treatment of platypnea/orthodeoxia
70.2 Tricuspid stenosis syndrome
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75.36 Three-dimensional echocardiography of cleft mitral
71 Prosthetic Heart Valves, 1455
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71.1 Transesophageal echocardiographic view of


leaflet
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75.37 Primum atrial defect


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obstructed mitral bileaflet mechanical valve
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75.38 Primum atrial defect


71.2 Transthoracic echocardiographic parasternal
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75.39 Regurgitant left atrioventricular valve in a primum


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long-axis view of stented bioprosthetic valve


atrial defect
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71.3 Transthoracic color Doppler-echocardiographic


parasternal long-axis view of obstructive valve thrombosis 75.40 Unbalanced atrioventricular septal defect
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in balloon transcatheter aortic valve 75.41 Unbalanced atrioventricular septal defect


71.4 Transthoracic color Doppler echocardiographic 75.42 Unbalanced atrioventricular septal defect
apical three-chamber view of two paravalvular regurgitant
75.43 Doubly committed subarterial ventricular septal
jets in a transcatheter aortic valve
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defect
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75 Congenital Heart Disease in the Adult and 75.44 Doubly committed subarterial ventricular septal
defect
Pediatric Patient, 1519
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75.45 Doubly committed subarterial ventricular septal


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75.1 Anomalous origin of left coronary artery from


pulmonary artery defect
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75.46 Perimembranous inlet ventricular septal defect


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75.2 Anomalous origin of left coronary artery from


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pulmonary artery 75.47 Perimembranous inlet ventricular septal defect


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75.48 Perimembranous ventricular septal defect with 75.79 Three-dimensional echocardiography of abnormal

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right ventricular muscle bundles and a small subaortic tricuspid valve in congenitally corrected transposition of
ridge the great arteries

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Video Contents

f75.49 Perimembranous ventricular septal defect with 75.80 Three-dimensional echocardiography of tricuspid
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right ventricular muscle bundles and small subaortic ridge regurgitation in congenitally corrected transposition of the

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75.50 Perimembranous ventricular septal defect with great arteries
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right ventricular muscle bundles and small subarterial 75.81 Stent management of hypoplastic aortic arch

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ridge
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75.82 Stent management of adult aortic coarctation
75.51 Perimembranous ventricular septal defect with 75.83 Stent management of complex coarctation repair
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right ventricular muscle bundles
75.84 Stent management of aortic coarctation
75.52 Perimembranous ventricular septal defect with
75.85 Balloon dilation of critical neonatal aortic stenosis
right ventricular muscle bundles and small subaortic
ridge 75.86 Fibromuscular subaortic stenosis
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75.53 Stenotic homograft conduit with stent therapy 75.87 Tunnel subaortic stenosis
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75.54 Radiofrequency-assisted balloon dilation of atretic 75.88 Three-dimensional echocardiography of
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pulmonary valve fibromuscular subaortic stenosis
75.89 Transesophageal echocardiography of congenital
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75.55 Calcified homograft conduit with potential
coronary compression mitral stenosis

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75.56 Melody valve placement in stenotic homograft 75.90 Transesophageal echocardiography of congenital
conduit mitral stenosis and fibromuscular subaortic stenosis
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75.57 Catheter management of troubled Fontan 75.91 Isolated cleft of the mitral valve
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circulation 75.92 Isolated cleft of the mitral valve
75.58 Interventional and thrombolytic management of 75.93 Three-dimensional echocardiography of isolated
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thrombosis in Fontan patient mitral cleft
75.59 Catheter management of stenotic left pulmonary 75.94 Muscular inlet ventricular septal defect
artery in Fontan patient 75.95 Double-orifice mitral valve
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75.60 Stent management of kinked Fontan connection 75.96 Three-dimensional echocardiography of double-
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75.61 Postoperative view of a palliative Senning orifice mitral valve
procedure 75.97 Severe tricuspid regurgitation in congenitally
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75.62 Postoperative view of palliative Senning procedure corrected transposition of the great arteries
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75.63 Postoperative view of palliative Senning procedure 75.98 Ebstein malformation of tricuspid valve
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75.64 Postoperative view of palliative Senning procedure 75.99 Ebstein malformation of tricuspid valve
75.65 Systemic tricuspid valve coaptation after Senning 75.100 Ebstein malformation of tricuspid valve
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procedure 75.101 Valvular pulmonary stenosis
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75.66 Postoperative view of Rastelli procedure 75.102 Valvular pulmonary stenosis
75.67 Postoperative view of Rastelli procedure 75.103 Dysplastic pulmonary valve stenosis
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75.68 Rastelli repair of tricuspid valve regurgitation 75.104 Catheter management of neonatal pulmonary
shows moderate tricuspid regurgitation atresia with intact ventricular septum
75.69 Moderate systemic tricuspid regurgitation after 75.105 Cor triatriatum
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Senning procedure 75.106 Cor triatriatum


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75.70 Systemic tricuspid regurgitation after Senning 75.107 Cor triatriatum
procedure
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75.108 Catheter management of large circumflex artery
75.71 Three-dimensional echocardiography of systemic fistula to left ventricle
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tricuspid valve after Senning procedure


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75.72 Interventional therapy of Mustard baffle stenosis 83 Pericardial Diseases, 1662


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and leakage
83.1 Cine loops of two-dimensional echocardiogram
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75.73 Poor tricuspid leaflet coaptation from a patient with cardiac tamponade
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75.74 Three-dimensional echocardiography of tricuspid


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83.2 Cine MR images in a patient with pericardial


regurgitation effusion and underlying pulmonary hypertension
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75.75 Transesophageal echocardiography of tricuspid 83.3 Cine MR images in a patient with both pericardial
regurgitation and pleural effusions
75.76 Abnormal systemic tricuspid valve in congenitally 83.4 Cine MR images illustrating septal “bounce” in a
corrected transposition of the great arteries patient with constrictive pericarditis
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75.77 Abnormal tricuspid valve in congenitally corrected 83.5 Cine MR images of a patient with constrictive
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transposition of the great arteries pericarditis before pericardiectomy


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75.78 Three-dimensional echocardiography of abnormal 83.6 Cine MR images of a patient with constrictive
tricuspid valve in congenitally corrected transposition of pericarditis after pericardiectomy illustrating relief of
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the great arteries exaggerated ventricular interaction


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PART  I FUNDAMENTALS OF

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CARDIOVASCULAR DISEASE
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1  Global Burden of Cardiovascular Disease
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THOMAS A. GAZIANO, DORAIRAJ PRABHAKARAN, AND J. MICHAEL GAZIANO
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SHIFTING BURDEN, 1 Latin America and the Caribbean, 7 Aging Populations, 14
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North Africa and the Middle East, 7 Fetal Influences, 14
EPIDEMIOLOGIC TRANSITIONS, 1
South Asia, 7 Environmental Exposures, 14
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Age of Inactivity and Obesity: a Fifth
Sub-Saharan Africa, 7
Phase?, 3 ECONOMIC BURDEN, 15
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Different Patterns of Epidemiologic RISK FACTORS, 8
COST-EFFECTIVE SOLUTIONS, 15
Transition, 3 Tobacco, 8
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Established Cardiovascular Disease
Hypertension, 8
CURRENT VARIATIONS IN THE GLOBAL Management, 15

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Lipids, 9
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BURDEN, 3 Risk Assessment, 15
Diabetes, 10
High-Income Countries, 5 Policy and Community Interventions, 16
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Obesity, 12
East Asia and Pacific, 6
Diet, 13 SUMMARY AND CONCLUSION, 17
Central and Eastern Europe and Central
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Physical Inactivity, 14
Asia, 6 REFERENCES, 17
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Over the last decade, cardiovascular disease (CVD) has become the EPIDEMIOLOGIC TRANSITIONS
leading cause of death worldwide. In 2013, CVD caused an estimated
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17.3 million deaths and led to 330 million disability-adjusted life-years The overall increase in the global burden of CVD and the distinct
(DALYs) lost1—about 32% of all deaths and 13% of all DALYs lost that regional patterns result in part from the “epidemiologic transition,”
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year. Overall, these data represent increases in both absolute numbers which includes four basic stages (Table 1.1): Pestilence and Famine,
and percentages of deaths and DALYs compared with 2010 estimates. Receding Pandemics, Degenerative and Man-Made Diseases, and
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As with many high-income countries during the last century, low- and Delayed Degenerative Diseases.2,3 Movement through these stages
middle-income countries are now experiencing an alarming and has dramatically shifted the causes of death over the last two centuries,
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accelerating increase in CVD. from infectious diseases and malnutrition in the first stage to CVD
This chapter reviews the features of the epidemiologic transitions and cancer in the third and fourth stages. Although the transition
underlying this shift in CVD morbidity and mortality and evaluates through the age of Pestilence and Famine has occurred much later
the transition in different regions of the world. A survey of the current in LMICs, it has also occurred more rapidly, driven largely by the
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burden of risk factors and behaviors associated with CVD includes transfer of low-cost agricultural technologies, the overall globalization
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regional variations and trends. A review of the economic impact of of world economies, and public health advances.
CVD highlights the cost-effectiveness of various strategies to reduce Humans evolved during the age of Pestilence and Famine and
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it. The chapter ends with a discussion of the diverse challenges that have lived with epidemics and hunger for most of recorded history.
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the increasing burden of CVD poses for various regions of the world, Before 1900, infectious diseases and malnutrition constituted the most
along with potential solutions to this global problem. common causes of death in virtually every part of the world, with
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tuberculosis, pneumonia, and diarrheal diseases accounting for a
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majority of deaths. These conditions, along with high infant and child
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SHIFTING BURDEN mortality rates, resulted in a mean life expectancy of approximately


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30 years.
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Between 1990 and 2013, deaths from CVD increased from 26% to Per capita income and life expectancy increase during the age of
32% of all deaths globally, a reflection of the rapid epidemiologic Receding Pandemics as the emergence of public health systems,
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transition, particularly in low- and middle-income countries (LMICs). cleaner water supplies, and improved food production and distribution
Although the net percentage of deaths caused by CVD overall has combine to reduce deaths from infectious disease and malnutrition.
increased, this results from an increase in LMICs and a decline in Improvements in medical education follow, and along with other
high-income countries (HICs) (Fig. 1.1). CVD now causes the most public health changes, contribute to dramatic declines in infectious
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deaths in all low- and middle-income regions, with the exception of disease mortality rates. Rheumatic valvular disease, hypertension, and
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sub-Saharan Africa, where it is the leading cause of death in those older cerebrovascular accident (stroke) cause most CVD. Coronary heart
than 45 years. In absolute numbers, CVD causes four to five times as disease (CHD) often occurs at a lower prevalence rate than stroke,
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many deaths in LMICs as in HICs. Within the six World Bank–defined and CVD accounts for 10% to 35% of deaths.
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low- and middle-income regions, the CVD burden differs vastly (Fig. During the stage of Degenerative and Man-Made Diseases,
1.2), with CVD death rates as high as 59% in Eastern Europe and continued improvements in economic circumstances, combined with
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as low as 12% in sub-Saharan Africa. The CVD mortality rate is 38% urbanization and radical changes in the nature of work-related activities,
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in HICs. led to dramatic changes in diet, activity levels, and behaviors such
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1
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LOW- AND LOW- AND as smoking. For example, in the United States, deaths from infectious

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I MIDDLE-INCOME 1990 MIDDLE-INCOME 2013 diseases decreased to fewer than 50 per 100,000 people per year, and
life expectancy increased to almost 70 years. The increased availability
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9.5% 9.3%
of foods high in calories, coupled with decreased physical activity,
21.2% contributes to an increase in atherosclerosis. In this stage, CHD and
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29.8% stroke predominate, and between 35% and 65% of all deaths are related
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to CVD. Typically, the ratio of CHD to stroke is 2 : 1 to 3 : 1.
25.9%

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In the age of Delayed Degenerative Diseases, CVD and cancer

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41.6% remain the major causes of morbidity and mortality, but CVD age-
27.8% adjusted mortality rates decline by almost half, accounting for 25% to
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34.9% 40% of all deaths. Two significant advances have contributed to the
decline in CVD mortality rates: new therapeutic approaches and
prevention measures targeted at people with or at risk for CVD.4
Treatments once considered advanced—including the establish-
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HIGH-INCOME 1990 HIGH-INCOME 2013 ment of emergency medical systems, coronary care units, and the
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6.5% widespread use of new diagnostic and therapeutic technologies such
7.8% as echocardiography, cardiac catheterization, percutaneous coronary
5.8%
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6.2% intervention (PCI), bypass surgery, and implantation of pacemakers
and defibrillators—have now become the standard of care. Advances
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37.5%
43.1% in drug development have also yielded major benefits on both acute

f
and chronic outcomes. Efforts to improve the acute management
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43.0% of myocardial infarction (MI) led to the application of lifesaving
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50.1% interventions such as beta-adrenergic blocking agents (beta block-
ers), PCI, thrombolytics, statins, and angiotensin-converting enzyme
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(ACE) inhibitors (see Chapters 58 and 59). The widespread use of
an “old” drug, aspirin, has also reduced the risk of dying of acute
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CVD ONC CMNN INJ or secondary coronary events. Low-cost pharmacologic treatment
for hypertension (see Chapter 47) and the development of highly
FIGURE 1.1  Changing pattern of mortality, 1990 to 2013. CVD, Cardiovascular effective cholesterol-lowering drugs such as statins have also made
disease; ONC, other noncommunicable diseases; CMNN, communicable, maternal, major contributions to both primary and secondary prevention by
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neonatal, and nutritional diseases; INJ, injury. (From Global Burden of Disease Study
2013. Age-sex specific all-cause and cause-specific mortality, 1990–2013, Seattle:
reducing CVD deaths (see Chapter 48).
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Institute for Health Metrics and Evaluation; 2014.)
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55.7%
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(409 million)
High-income
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37.5%
(984 million)
38.0%
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37.7% (2033 million)
(471 million)
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11.5%
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(937 million)
27.4%
28.5%
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(1698 million)
(636 million)
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East Asia and Pacific Middle East and North Africa High-Income
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Eastern Europe and Central Asia South Asia


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Latin America and the Caribbean Sub-Saharan Africa


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FIGURE 1.2  Cardiovascular disease deaths as a percentage of all deaths in each region and total regional population, 2013. (From Global Burden of Disease Study 2013:
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Age-sex specific all-cause and cause-specific mortality, 1990–2013. Seattle: Institute for Health Metrics and Evaluation; 2014; and World Health Organization. Global Health
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Observatory Data Repository. Demographic and socioeconomic statistics: population data by country. http://apps.who.int/gho/data/view.main.POP2040?lang=en.)
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TABLE 1.1  Five Typical Stages of Epidemiologic Transition in CVD Mortality and Types

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TYPICAL PROPORTION 1

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OF DEATHS CAUSED PREDOMINANT TYPES

Global Burden of Cardiovascular Disease


f STAGE DESCRIPTION BY CVD (%) OF CVD
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Pestilence and Predominance of malnutrition and infectious diseases as causes of death; <10 Rheumatic heart disease,

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Famine high rates of infant and child mortality; low mean life expectancy. cardiomyopathies caused by
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infection and malnutrition

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Receding Pandemics Improvements in nutrition and public health lead to decrease in rates of 10-35 Rheumatic valvular disease,
deaths caused by malnutrition and infection; precipitous decline in hypertension, CHD, stroke
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infant and child mortality rates.
Degenerative and Increased fat and caloric intake and decreased physical activity lead to 35-65 CHD, stroke
Man-Made emergency of hypertension and atherosclerosis; with increased life
Diseases expectancy, mortality from chronic, noncommunicable diseases exceeds
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mortality from malnutrition and infectious diseases.
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Delayed CVDs and cancer are the major causes of morbidity and mortality; better 40-50 CHD, stroke, congestive heart
Degenerative treatment and prevention efforts help avoid deaths among those with failure
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Diseases disease and delay primary events. Age-adjusted CVD mortality declines;
CVD affects older and older individuals.
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Inactivity and Increasing prevalence of obesity and diabetes; some slowing of CVD 38

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Obesity mortality rates in women.
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CVD, Cardiovascular disease; CHD, coronary heart disease.
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Modified from Omran AR. The epidemiologic transition: a theory of the epidemiology of population change. Milbank Mem Fund Q 1981;49:509; and Olshanksy SJ, Ault
AB. The fourth stage of the epidemiologic transition: the age of delayed degenerative diseases. Milbank Q 1986;64:355.
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In concert with these advances, public health campaigns have
conveyed that certain behaviors increase the risk of CVD and that Different Patterns of
lifestyle modifications can reduce risk. In this regard, smoking cessation Epidemiologic Transition
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furnishes a model of success. In the United States, for example, 57% The HICs have followed different patterns of the CVD transition, which
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of men smoked cigarettes in 1955; in 2012, 20.5% of men smoked. The differ in both peak death rate from CHD and time of transition. Three
prevalence of smoking among U.S. women has fallen from 34% in patterns emerge that rely on data from countries with an established
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1965 to 15.8% in 2012.5 Campaigns beginning in the 1970s dramatically death certification system11 (Fig. 1.3). One pattern, followed by the
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improved the detection and treatment of hypertension in the United United States and Canada, showed a rapid rise and peak in the 1960s
States. This intervention likely had an immediate and profound effect and 1970s, followed by a relatively rapid decline through the end of
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on stroke rates and a subtler effect on CHD rates. Public health messages the 2000s. The peak was 300 to 700 CHD deaths per 100,000 population,
concerning saturated fat and cholesterol had a similar impact on fat with current rates between 100 and 200 per 100,000. This pattern also
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consumption and cholesterol levels. Population mean cholesterol occurred in the Scandinavian countries, the United Kingdom, Ireland,
levels also declined, from 220 mg/dL in the early 1960s to 192 mg/dL Australia, and New Zealand. A second pattern showed a peak in the
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by 2014,6 with a simultaneous decrease in the prevalence of elevated same period but a peak CHD death rate of only 100 to 300 per 100,000.
low-density lipoprotein (LDL) cholesterol. Countries such as Portugal, Spain, Italy, France, Greece, and Japan
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followed this pattern. Some countries did not have the same rapid
rate of decline, with slower rates in central European countries (Austria,
Age of Inactivity and Obesity: Belgium, Germany) compared to northern European countries (Finland,
a Fifth Phase? Sweden, Denmark, Norway), but with lower peaks of 300 to 350 per
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Troubling trends in certain risk behaviors and risk factors may fore- 100,000 in the 1960s and 1970s. Some countries appear to display a
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shadow a new phase of epidemiologic transition, the age of Inactivity third pattern of continued rise (particularly many components of the
and Obesity7 (see Chapters 49 and 50). In many parts of the former Soviet Union), and others have yet to see any significant increase,
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industrialized world, physical activity continues to decline while total such as many countries in sub-Saharan Africa (excluding South Africa).
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caloric intake increases at alarming rates, resulting in an epidemic Latin America has less longitudinal data, but limited data suggest that
of overweight and obesity. Consequently, rates of type 2 diabetes, many of the countries follow the pattern of either Mediterranean or
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hypertension, and lipid abnormalities associated with obesity are Southern European countries, with peaks between 50 and 300 deaths
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rising—a particularly evident trend in children.6 These changes are per 100,000. Whether other LMICs will follow a “classic” pattern of
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occurring while measurable improvements in other risk behaviors significant increases then rapidly declining rates (as happened in
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and risk factors, such as smoking, have slowed. If these trends continue, North America, Australia, and northwestern European HICs), a more
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age-adjusted CVD mortality rates, which have declined over the past gradual rise and fall (as in the southern and central European countries),
several decades in HICs, could plateau, as they have for young women or some other pattern will depend in part on cultural differences,
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in the United States, or even increase in the coming years. This trend secular trends, and responses at the country level with regard to both
pertains particularly to age-adjusted stroke death rates. This concerning public health and treatment infrastructures.
increase in obesity also applies to LMICs.8
Fortunately, recent trends in the first decade of this century suggest
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a tapering in the increases in obesity among adults, although the rates CURRENT VARIATIONS IN
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remain alarmingly high at almost 34%.9 Furthermore, continued progress THE GLOBAL BURDEN
in the development and application of therapeutic advances and other
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secular changes appear to have offset the effects from the changes Three phenomena impact the various metrics for disease burden. First,
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in obesity and diabetes; cholesterol levels, for example, continue to population growth increases the overall number of deaths caused
decline. Overall, in this decade, age-adjusted mortality has continued by CVD globally. Second, a trend in general aging of the population
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to decline at about 3% per year, from a rate of 341 per 100,000 population has shifted the proportion of deaths caused by CVD in most regions
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in 2000 to 223 per 100,000 in 2013.10 as a result of better control of many communicable diseases that
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4

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800 Global

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I World Bank high income
700
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World Bank upper middle income
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DEATH RATE/100,000

600 World Bank lower middle income


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World Bank lower income
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500

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450
eb Fundamentals of Cardiovascular

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400
400
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CVD DEATH RATES
300

PER 100,000
200 350
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100 Canada United States
300
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0
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A 250
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TIME (year)

f
200
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800 1990 1995 2000 2005 2010 2013
Greece
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Spain YEAR
700 Portugal
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DEATH RATE/100,000

FIGURE 1.4  Cardiovascular disease death rates per 100,000 population from 1990
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600 to 2013, by World Bank income categories. (From Global Burden of Disease Study
2013. Age-sex specific all-cause and cause-specific mortality, 1990–2013. Seattle:
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Institute for Health Metrics and Evaluation; 2014.)
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400
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300 x of death, especially in LMICs without standardized protocols, are
xx x x xxxx
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xxx xx x uncertain.
200 xxxxxxxxx xxxxxx Globally, CVD deaths increased by 46% between 1990 and 2013.
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xxx x xx The increase in overall CVD deaths results from both increases in
xxxxx
100 xx
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CHD and stroke-related deaths. In 2013, CHD accounted for 15% of all
deaths worldwide. The second-ranking cause of death was stroke, at
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12% (equally split between ischemic stroke and hemorrhagic stroke).
B An estimated 14.5 million people died from CHD and stroke, which
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together accounted for almost a quarter of all deaths worldwide in


TIME (year) 2013.1
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800 xx Although still substantial, deaths from communicable, neonatal,
and maternal diseases are decreasing worldwide,1,12 with a 27% decrease
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700 between 1990 and 2013. Deaths from noncommunicable diseases
x increased in the same period. In 2013, CHD accounted for the largest
x xx
DEATH RATE/100,000

600 x xx portion of global years of life lost (YLLs) and DALYs. Stroke was the
x xx third-ranking contributor to global YLLs and DALYs. On the other
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xx
500 hand, in 1990, communicable diseases accounted for the largest portion
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of both YLLs and DALYs.
400 Despite the increase in overall CVD deaths, age-adjusted death rates
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decreased by 21.9% in the same period, from 374 to 292 per 100,000
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300 population, suggesting significant delays in age of occurrence and/or
improvements in case-fatality rates. Unfortunately, not all countries
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200 Russia (USSR before 1991) appear to share in the reductions. Examination of regional trends is
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Belarus helpful in estimating global trends in the burden of disease, particularly


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Ukraine CVD. Because 85% of the world’s population lives in LMICs, these
100
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Russian Federation
x Lithuania–Latvia countries largely drive global CVD rates. These estimates depend on
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0 modeling mortality rates in areas where established death certification–


C based vital registration systems do not cover an entire country. Even
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50
55
60
65
70
75
80
85
90
95
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as age-adjusted rates have been falling globally, the pattern is different


19
19
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20

when assessed by income (Fig. 1.4) or by region (Fig. 1.5).


TIME (year)
The magnitude of the peak of the CVD epidemic, and whether the
FIGURE 1.3  Differing coronary heart disease mortality patterns. A, Rapid rise and peak has arrived at all, has a great range. Here we describe and
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decline. B, Mild rise and decline. C, Continuing rapid rise. (From Mirzaei M, Truswell
highlight trends in the seven regions of the world as defined by the
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A, Taylor R, Leeder SR: Coronary heart disease epidemics: not all the same. Heart
2009;95(9):740-6.) GBD project, which includes HICs as one grouping and divides the
remaining LMICs into six geographic regions with a variety of subre-
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e.

gions. The East Asia and Pacific, Europe and Central Asia, Latin America
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strike those at early ages. Third, prevention of CVD and treatment and Caribbean, and Middle East and North Africa Regions all saw
for those with CVD have both improved, which reduces age-adjusted declines in age-adjusted CVD mortality from 1990 to 2013. Sub-Saharan
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mortality rates. We rely on data from the Global Burden of Disease Africa had little change in its age-adjusted CVD mortality rates. South
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(GBD) study data from 2013. Although extensive, data from GBD Asia was the only region that experienced a significant increase in
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2013 has limitations. The availability and reliability of data on cause the age-adjusted mortality rates.
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5

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East Asia and Pacific
Southeast Asia

Asia Asia and Pacific


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e.
Europe and Central Asia 1

Southeast
East and
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Latin America and Caribbean East Asia

Global Burden of Cardiovascular Disease


f Sub-Saharan Africa
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Middle East and North Africa Oceania

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South
South Asia
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South Asia

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World Bank high income
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500 Central Asia
CVD DEATH RATE PER 100,000

Central Asia
Central and

Europe and
Eastern
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450 Central Europe

400 Eastern Europe

350
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Middle
North Africa and

Africa
North

East
and
Middle East
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300
Central Sub-Saharan
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e.
Sub-Saharan Africa
250 Africa
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Eastern Sub-Saharan
200 Africa

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Southern Sub-Saharan
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150
Africa
1990 1995 2000 2005 2010 2013
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Western Sub-Saharan
YEAR Africa
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FIGURE 1.5  Cardiovascular disease death rates per 100,000 population from 1990 Andean Latin America
to 2013 in low- and middle-income countries by region, compared to World Bank
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high-income countries. (From Global Burden of Disease Study 2013. Age-sex specific Central Latin America

Latin America
and Caribbean
all-cause and cause-specific mortality, 1990–2013. Seattle: Institute for Health Metrics
and Evaluation; 2014.)
Southern Latin America
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Tropical Latin America
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Much of the variation appears to relate to income, which is one
Caribbean
proxy for the stages of the epidemiologic transition. Looking at age-
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adjusted CVD death rates by income reveals the different trends over
High-income regions

Australasia
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the last two decades. In lower-income regions the death rates have
increased from 340 per 100,000 in 1990 to 390 per 100,000 in 2013. Western Europe
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Lower middle-income countries saw a small increase (416 to 432 per
100,000 deaths), followed by a decline to 400 per 100,000 population. Asia Pacific 1990
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Upper middle-income countries saw a 25% decline, from 392 per 100,000 2013
in 1990 to 296 per 100,000. High-income countries had a nearly 37% North America
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decline, from 330 to 202 CVD deaths per 100,000.
The LMICs have a high degree of heterogeneity with respect to the 0 100 200 300 400 500 600 700
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phase of the epidemiologic transition. First, LMIC subregions differ CVD AGE-ADJUSTED DEATH RATES PER 100,000
by age-adjusted CVD death rates, as well as by trends over the last 20
years (Fig. 1.6). CVD mortality rates are increasing in most LMICs FIGURE 1.6  Age-adjusted death rates per 100,000 population for cardiovascular
but are decreasing in HICs. Next, low- and middle-income subregions disease, 1990 and 2013. (From Global Burden of Disease Study 2013. Age-sex specific
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all-cause and cause-specific mortality, 1990–2013. Seattle: Institute for Health Metrics
are unique, as illustrated by the different CVD disease rates by cause and Evaluation; 2014.)
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in each region (Fig. 1.7). Lastly, in the East Asia and Pacific and
sub-Saharan Africa regions, stroke still exceeds CHD as a cause of
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CVD death. Hypertensive heart disease is the largest single contributor
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among remaining causes of CVD morbidity and mortality.
Variability in disease prevalence among various regions likely results High-Income Countries
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from multiple factors. First, the countries are in various phases of the In 2013, CVD accounted for almost 38% of all deaths in high-income
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epidemiologic transition described earlier. Second, the regions may regions, and CHD caused more than half of these deaths (see Fig.
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have cultural and genetic differences that lead to varying levels of 1.7). The movement of most HICs through the epidemiologic transition,
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CVD risk. For example, per capita consumption of dairy products with rising levels of risk factors and CVD death rates until the 1970s
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(and thus consumption of saturated fat) is much higher in India than and then declines in both over the next 40 years, resembles what
in China, although it is rising in both countries. Third, certain additional occurred in the United States. CHD is the dominant form, with rates
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competing pressures exist in some regions, such as war or infectious that tend to be twofold to fivefold higher than stroke rates. Two notable
diseases (HIV/AIDS) in sub-Saharan Africa. exceptions are Portugal, where stroke rates for both men and women
Because CHD affects a younger population in LMICs, the number exceed CHD rates, and Japan, where stroke causes many more fatalities
of deaths is increased in the working population. For some LMICs, than CHD. In both these countries, however, the pattern seems to be
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the severity of the epidemiologic transition has appeared to follow a moving toward that seen in other HICs, with more rapid declines in
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reverse social gradient, with members of lower socioeconomic groups stroke rates than in CHD rates.
having the greatest rates of CHD and the highest levels of various risk Age-adjusted mortality for CVD declined in all HICs. This age-adjusted
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factors. Unfortunately, reductions in risk factors do not follow the decline results largely from preventive interventions that allow people
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same trend. Compared with people in the upper and middle socio- to avert disease, treatments to prevent death during an acute manifesta-
economic strata, those in the lowest stratum are less likely to acquire tion of disease (particularly stroke or MI), and interventions that prolong
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and apply information on risk factors and behavior modifications or survival once CVD is manifest. Thus the average age at death from
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to have access to advanced treatment. Consequently, CVD mortality CVD continues to climb, and as a result, CVD affects a larger retired
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rates decline later among those of lower socioeconomic status. population.


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East Asia South Asia per 100,000 and 88 per 100,000, respectively. Mortality rates and number

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I and Pacific of deaths attributable to stroke and CHD increased in this region
between 1990 and 2010; stroke rates increased by approximately 18%,
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1% 2% 2%
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3% whereas CHD rates increased by almost 40%.12 Japan is unique among


2% HICs; as its communicable disease rates fell in the early 20th century,
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6% 3%

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9% its stroke rates increased dramatically. CHD rates, however, did not
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rise as sharply in Japan as in other industrialized nations and have

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37% remained lower than in any other industrialized country. Overall, CVD

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rates have fallen 60% in Japan since the 1960s, largely because of a
54% decrease in age-adjusted stroke rates. Japanese men and women
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30% currently have the highest life expectancy in the world: 86.4 years for
women and 79.6 years for men. The difference between Japan and
51% other industrialized countries may stem in part from genetic factors,
although the traditional Japanese fish- and plant-based, low-fat diet
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and resultant low cholesterol levels may have also contributed. Neverthe-
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less, as in many other countries, dietary habits in Japan are undergoing
Europe and North Africa and substantial changes. Since the late 1950s, cholesterol levels have
Central Asia Middle East
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4% progressively increased in both urban and rural populations. Although
4% 3% the prevalence of CVD risk factors is increasing in the Japanese popula-
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6% 8%
1% tion, the incidence of coronary artery disease remains low and even

f
declined.13 This situation could change, however, because there seems
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1% 7%
to be a long lag phase before dietary changes manifest as CHD events.
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54% 49%
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31% East Asia and Pacific
32% Demographic and Social Indices
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The East Asia and Pacific (EAP) region is the most populated low-
income and middle-income region in the world, with almost 2 billion
people; approximately 49% of the region is urban. The gross national
income (GNI) per capita is $4243, ranging from $4420 in Thailand to
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Sub-Saharan Latin America and $1130 in Laos. In 2004, total health expenditure was 4.8% of total gross
Africa Caribbean
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domestic product (GDP), or $183 per capita.14 The region is divided
3% into three distinct subregions: Southeast Asia, East Asia, and Oceania.
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8% China is by far the most populated country, representing almost 70%
13%
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1% 6% of the region. Life expectancy has risen quickly across the EAP region
5% in past decades, up to an average of 72 years. In China the increase
29%
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9% has been dramatic: from 37 years in the mid-1950s to 73 years in 2010.14
50% This increase associates with a large rural to urban migration pattern,
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2% rapid urban modernization, aging of the population, decreased birth
42% 32% rates, major dietary changes, increasing tobacco use, and a transition
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to work requiring low levels of physical activity.
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Burden of Disease
CVD caused more than 5.2 million deaths in the EAP region in 2013,
High-income accounting for 38% of all deaths in the region. More than half of these
Regions
deaths resulted from stroke, whereas only 31% were caused by CHD
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4% (see Fig. 1.7). CVD death rates differed significantly between subre-
CHD
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4% 9% gions, most notably in Oceania. Age-adjusted mortality rates were
1% Stroke highest in Oceania, at 439 per 100,000 in 2010, even though overall
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mortality for CVD was 205 per 100,000, suggesting that many premature
RHD
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deaths from CVD are occurring in Oceania.
52%
HHD Stroke and CHD lead as causes of death in the East Asia and
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30%
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Southeast Asia subregions. In Oceania, however, lower respiratory
Cardiomyopathy
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and myocarditis infections and diabetes account for the largest proportion of deaths.
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Whereas stroke and CHD rates increased in both East Asia and
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Other
Southeast Asia, stroke rates decreased slightly in Oceania, from 40 to
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36 per 100,000.12 China appears to be straddling the second and third


FIGURE 1.7  Cardiovascular disease death by specific cause and region. CHD,
stages of a Japanese-like epidemiologic transition. Men in China age
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Coronary heart disease; RHD, rheumatic heart disease; HHD, hypertensive heart disease.
(From Global Burden of Disease Study 2013. Age-sex specific all-cause and cause-specific 50 to 69 have stroke death rates of 190 per 100,000, versus CHD death
mortality, 1990–2013. Seattle: Institute for Health Metrics and Evaluation; 2014.) rates of 123 per 100,000.1
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Central and Eastern Europe and


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Western Europe, with an overall CVD mortality rate of 344 per Central Asia
100,000 in 2013 and an age-standardized rate of 163 per 100,000, had Demographic and Social Indices
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the highest mortality rates, whereas Australasia had the lowest overall Of the three subregions that constitute this region—Central Asia, Central
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(234/100,000) rate, and Japan had the lowest age-adjusted rate Europe, and Eastern Europe—Eastern Europe is the most populated.
(110/100,000). As mentioned, high-income regions have higher mortality Russia alone accounts for more than 30% of the region’s 404 million
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rates for CHD than for stroke. The exception is the East Asia and inhabitants. Sixty-five percent of the population in the region is urban,
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Pacific region, where overall death rates for stroke and CHD are 132 with an average life expectancy of 71 years. The average GNI per
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capita for the region ranges from $870 in Tajikistan to $23,610 in Slovenia.
North Africa and the Middle East

e.

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Russia has a GNI of $10,400. On average, the region spends more than 1
6% of total GDP on public and private health care. Health expenditure Demographic and Social Indices

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Global Burden of Cardiovascular Disease
per capita ranges from $49 per capita in Tajikistan to $2154 in Hungary. The 19 countries of the North Africa and Middle East region represent
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Russia spends about $525 per capita, or 5.1% of its GDP.14 approximately 5% of the world’s population (337 million people). Egypt
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and Iran are the two most populous countries in the region, with
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Burden of Disease Egypt representing 24% of total inhabitants and Iran, 22%. Approximately

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The highest rates of CVD mortality occur in this region. Overall CVD 59% of the population is urban, with an average life expectancy of 72
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mortality rates are 793 per 100,000 in Eastern Europe and 547 per years. The average GNI per capita for the region is $3869, ranging
100,000 in Central Europe. Overall rates resemble or exceed those from $1070 in Yemen to $48,900 in Kuwait. Approximately 5.3% of the
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seen in the United States in the 1960s, when CVD peaked. CHD is GDP, or approximately $203 per capita, is expended for health in the
generally more common than stroke, which suggests that the countries region. The per capita health expenditure ranges from $63 in Yemen
that constitute Eastern Europe and Central Asia remain largely in to $1450 in the United Arab Emirates.14
the third phase of the epidemiologic transition. As expected in this
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phase, people who develop and die of CVD have a lower average Burden of Disease
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age than that in HICs. In 2013, CVD accounted for almost 60% of all Forty-two percent of all deaths in the North Africa and Middle East
deaths in the region, 55% of which resulted from CHD and 33% from region result from CVD: 9% from CHD and 32% from stroke. The region
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stroke. has lower CVD mortality rates than global averages. In 2013 the overall
A country-level analysis reveals important differences in CHD profiles death rate per 100,000 for CHD, stroke, and overall CVD were 89, 57,
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within the Central and Eastern Europe and Central Asia region (see and 180, respectively. The mortality rate for CHD only declined margin-

f
Fig. 1.3). Since the dissolution of the Soviet Union, CVD rates have ally in the region since 1990, when the rates were 88, 62, and 192
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increased surprisingly in some of these countries, with the highest deaths per 100,000 population, respectively. However, age-adjusted
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rates (almost 800 per 100,000 for men) in Ukraine, Bulgaria, Belarus, mortality rates for CVD declined by almost 25% across the region. In
and Russia.11 By 2013, this region had the highest CVD mortality rates 2013, CVD accounted for 20 million DALYs lost, or 21% of all DALYs
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in the world. Of note, deaths resulting from CHD in these countries lost in the region. The DALYs lost were split differently between CHD
affect not only older adults; the GBD study estimates that working-age and stroke, at 9.7 million and 5.7 million, respectively.12
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populations (15 to 69 years) have a significant CHD burden. Almost
one third of all deaths in persons age 45 to 49, for example, result
from CVD. For people age 60 to 64, CVD accounts for half of all deaths, South Asia
27% of which are caused by CHD.12 Demographic and Social Indices
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The South Asia region (SAR), one of the world’s most densely populated
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regions, accounts for about 24% of the world’s population, with more
Latin America and the Caribbean than 1.6 billion residents. India, home to almost 75% of the region’s
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Demographic and Social Indices inhabitants, is the largest country in the region. Only 31% of the region
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The Latin America and Caribbean (LAM) region comprises Andean is urban, and life expectancy is approximately 65 years. Average GNI
Latin America, Central Latin America, Southern Latin America, Tropical per capita for the region is $1299, ranging from $540 in Nepal to $6530
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Latin America, and the Caribbean. The region has a total population in Maldives. India’s GNI per capita of $1410 sits near the regional
of 589 million, 79% of which is urban.14 Brazil, the region’s most populous average. Countries in the SAR spend an average of 3.9% of their total
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country, represents one third of the population, with Argentina, GDP, or $47 per capita, on health care. Maldives spends the most per
Colombia, Mexico, Peru, and Venezuela making up another third. The capita at $208, and India spends $31, or 5% of its GDP. The lowest
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Caribbean nations, including the Dominican Republic, Jamaica, and expenditures for health care are $22 per capita in Pakistan and $23 in
Haiti, account for less than 10% of the population in the region. Life Bangladesh.14
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expectancy in the LAM region is approximately 74 years but varies
greatly. In 2010, for example, Haiti and Cuba had life expectancies of Burden of Disease
64 years and 79 years, respectively. Average GNI per capita in the CVD accounts for 27% of all deaths in the SAR. CHD led causes of
region is about $8544 (purchasing power parity [PPP] of $11,587). The mortality in 2013—responsible for 15% of total reported fatalities, or
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region spends an average of 7.7% of its GDP on health care. This level 2 million deaths, and more than half of CVD mortality. Cerebrovascular
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of spending translates into health care expenditures that range from disease accounted for 6.8% of all deaths and 30% of CVD deaths. The
$46 per capita in Haiti to $1003 per capita in Barbados.14 region loses almost 60.5 million DALYs from CVD, accounting for 10%
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of the total. CHD contributes 4.6% of the DALYs lost because of CVD,
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Burden of Disease nearly twice as high as for stroke.12 Mortality rates for CVD are increasing
The LAM region bears a substantial CVD burden. In 2013, CVD caused in the region.
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29% of all deaths in the region. As in HICs, CHD dominates among CVD probably represents 31% of all deaths in India, the largest
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circulatory diseases (see Fig. 1.7). Mortality rates vary significantly country in the SAR. Studies also show a higher CHD prevalence in
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by subregion. The Caribbean has the highest age-standardized mortality men and in urban residents. The rise in CHD mortality contributes to
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rates for CHD and stroke: 150 deaths per 100,000 and 110 per 100,000, the economic burden in the Indian subcontinent. Data indicate that
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respectively. As with other global trends, overall mortality increased symptoms of CHD arise 5 to 10 years earlier in this region than in
between 1990 and 2013, but age-adjusted mortality declined for this Western European and Latin American countries.15
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region. Death rates also increased in Central Latin America and Andean
Latin America; similar increases in mortality occurred in Tropical
Latin America. Together, CHD (14%), stroke (6.9%), and hypertensive Sub-Saharan Africa
heart disease (2.1%) accounted for almost one quarter of all deaths Demographic and Social Indices
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in Central Latin America in 2010. Southern Latin America, which The GBD study divides sub-Saharan Africa into four subregions: Central
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includes Argentina, Chile, and Uruguay, was the only subregion to Africa, East Africa, Southern Africa, and Western Africa. Approximately
have declines in both overall and age-adjusted CVD mortality rates. 875 million people live in these four regions, with Nigeria being the
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Overall CVD, CHD, and stroke mortality rates decreased in this subregion most populous (163 million) and Cape Verde being the least populous
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between 1990 and 2010, but to a lesser extent than for global changes.12 (500,600). Only 36% of the population in the region is urban. The
The lower reductions in the LAM region may result from rapid lifestyle average GNI per capita is $1255, ranging from $250 in Burundi to $7480
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changes: unfavorable dietary changes, increased smoking, increased in Botswana. Overall, the region also has the lowest average life
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obesity, and less exercise. expectancy—54 years.14 Average public and private health care
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expenditures for the region are 6.5% of the total GDP, or $84 per capita. in sub-Saharan Africa. Tobacco use is generally less than 1% in women

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I The range of health care expenditures per capita for sub-Saharan in these regions but is much higher in men.
Africa is similar to the GDP range for this region, from $3 in Burundi Other forms of tobacco use increase risk for CHD. Bidis (hand-rolled
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to $511 in Seychelles. Nigeria spends $23 per capita, or 4.6% of the cigarettes common in South Asia), kreteks (clove and tobacco ciga-
total GDP.14 rettes), hookah pipes (water pipes used for smoking flavored tobacco),
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and smokeless tobacco all link to increased CHD risk.17 The combined
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Burden of Disease use of different forms of tobacco associates with a higher risk of MI

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eb Fundamentals of Cardiovascular

In Western Africa, CVD accounts for 7.5% of all deaths. The highest than using one type.

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portion of CVD-caused deaths occurred in Southern Africa, where Secondhand smoke also contributes to CHD risk. In 2011, approxi-
13% of all deaths were caused by CVD. Mortality rates in the region mately 600,000 nonsmokers died as a consequence of exposure to
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are lower than global averages and are decreasing, in line with global secondhand smoke. A retrospective analysis of 192 countries found
trends. The exception is Southern Africa, where rates increased from that the largest portion of secondhand smoke–related deaths in 2004
129 to 136 per 100,000. Communicable, neonatal, and maternal disorders resulted from ischemic heart disease.18 Smoking bans have both
still dominate causes of death in sub-Saharan Africa. Malaria and HIV/ immediate and long-term effects in reducing admissions for acute
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AIDS lead as causes of death, accounting for almost half of all deaths coronary syndrome (ACS). In Ireland, implementation of a country-wide
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in the region.12 smoking ban in workplaces decreased ACS-related hospital admissions
promptly by 12%, and after 2 years, such admissions decreased by an
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additional 13%.19
RISK FACTORS
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Worldwide, CVD is largely driven by modifiable risk factors, such as Hypertension
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smoking, lack of physical activity, and diets high in fat and salt (see Elevated BP is an early indicator of epidemiologic transition. Rising
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also Chapters 45 to 47 and 49 and 50). Elevated levels of blood mean population BP occurs as populations industrialize and move
pressure (BP) and cholesterol remain the leading causes of CHD; from rural to urban settings. Worldwide, approximately 62% of strokes
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tobacco, obesity, and physical inactivity remain important contributors and 49% of CHD cases are attributable to suboptimal (>115 mm Hg
as well. The GBD project estimated that the population-attributable systolic) BP, a factor thought to account for more than 7 million deaths
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fraction (PAF) for individual risk factors for CHD in LMICs in 2013 annually. The GBD project estimates that 19% of deaths and 9% of
were as follows: high BP, 54%; high cholesterol, 32%; overweight and DALYs lost globally result from nonoptimal levels of BP.20 The high
obesity, 18%; dietary intake, 67%; and smoking, 18%. Because factors rate of undetected, and therefore untreated, hypertension presents a
may contribute to similar disease mechanisms, the sum exceeds major concern in LMICs. The high prevalence of undetected and
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100%. Unique features regarding some CHD risk factors in LMICs are untreated hypertension probably drives the elevated rates of hemor-
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described next. rhagic stroke throughout Asia.
The most recent update of the GBD study analyzed mean systolic
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BP between 1980 and 2008 using multiple published and unpublished
Tobacco
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health surveys and epidemiologic studies. The analysis, which applied
By many accounts, tobacco use is the most preventable cause of death a bayesian hierarchical model to each sex by age, country, and year,
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in the world. More than 1.3 billion people use tobacco worldwide, found a global decrease in mean systolic BP between 1980 and 2008
with 5.8 trillion cigarettes smoked globally in 2014.16 More than in both men and women.21 Worldwide, the age-standardized prevalence
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80% of tobacco use occurs in LMICs, and if current trends continue of uncontrolled hypertension has decreased from 33% to 29% in men
unabated, tobacco will cause more than 1 billion deaths during the 21st and from 29% to 25% in women. However, the number of people with
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century. uncontrolled hypertension (systolic BP ≥140 mm Hg) has increased;
Tobacco use varies greatly across the world, as do deaths attributable in 1980, 605 million had uncontrolled hypertension, and by 2008, the
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to smoking in both sexes (Fig. 1.8). Although historically greatest in number increased to 978 million. The trend results largely from popula-
HICs, tobacco consumption has shifted dramatically to LMICs in recent tion growth and aging. Globally, mean systolic BP has decreased by
decades; some of the highest tobacco use now occurs in the EAP 0.8 mm Hg per decade among men and by 1.0 mm Hg per decade
region. Kiribati has the highest prevalence of age-adjusted tobacco among women. In 2008, age-standardized mean systolic BP values
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use in the world: 71.0% in men and 42.9% in women. Indonesia has worldwide were 128.1 mm Hg in men and 124.4 mm Hg in women.
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similarly high rates (>60% prevalence in men). China is the largest The proportion of CVD deaths attributable to BP by country in 2013
consumer of tobacco in the world, with an estimated 301 million varied by gender (Fig. 1.9). The highest mean systolic BP in 2013
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smokers in 2010 (>50% prevalence in men). Smoking rates have occurred in East and West African countries, where both men and
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increased in China by 50% since 1980. Several countries in the Central women had systolic BP levels that were significantly higher than global
and Eastern Europe regions also have alarmingly high prevalence averages. In Mozambique and in São Tomé and Príncipe, for example,
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rates, including Russia (approximately 60.0% in men and 24.3% in mean systolic BP in women was 135.4 mm Hg and 136.3 mm Hg,
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women), Ukraine (>50% prevalence in men), and Albania (60% preva- respectively. In men, mean systolic BP was as high as 137.5 mm Hg
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lence in men). Latin America, the Middle East, and North Africa have in Mozambique and 139.4 mm Hg in Niger. Men in Eastern Europe
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high rates as well, although smoking is not as common among women had mean systolic BP levels comparable to those in East and West
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in these regions as it is in the Pacific region. Countries in sub-Saharan Africa. Mean systolic BP was lowest in high-income regions such as
Africa have some of the lowest prevalence rates; Niger and Ethiopia, Australasia (117.4 mm Hg in Australian women) and North America
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for example, have less than 10% and 1% prevalence in men and women, (123.3 mm Hg in U.S. men).
respectively. The most significant decreases occurred in high-income regions,
Women also have a high—and increasing— smoking prevalence where mean systolic BP decreased by 2.4 mm Hg per decade in men
in several countries, including Kiribati (42.9%), Austria (45.1%), Nauru and 3.1 mm Hg per decade in women. The decrease in men ranged
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(50%), and Greece (41.4%). In general, however, considerably more from 1.7 to 2.8 mm Hg per decade, with the greatest decrease occurring
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men than women smoke. Exceptions to this pattern include Nauru in the North America subregion. The decrease in mean systolic BP
and Greece, which have comparable tobacco use prevalence in men in women ranged from 2.3 mm Hg per decade in North America to
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and in women. Where they do occur, variations by sex can be sub- 3.9 mm Hg per decade in Australasia.
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stantial. In China, for example, tobacco use prevalence is 50% in men Mean systolic BP increased in several regions. In South Asia, systolic
but only 2.2% in women. Indonesia has similarly diverging trends: BP increased by 0.8 mm Hg per decade in men and 1.0 mm Hg per
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prevalence in men is 61.3% and only 5.1% in women. Significant varia- decade in women. Southeast Asia saw similar increases: 0.9 mm Hg
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tions also occur in North Africa, the Middle East, and some countries per decade in men and 1.3 mm Hg per decade in women. In East
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Global Burden of Cardiovascular Disease
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1% 5% 10% 15% 20% 25% 30% 35% 40%
41%
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Females
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1% 5% 10% 15% 20% 25% 30% 35% 40%41%
CVD DEATHS ATTRIBUTABLE TO TOBACCO SMOKE, 2013 (% total deaths)
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FIGURE 1.8  Cardiovascular disease mortality attributable to tobacco smoke in 2013, percentage of total deaths, males versus females. (From Institute for Health Metrics
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and Evaluation (IHME). GBD Compare. Seattle: IHME, University of Washington; 2015. http://vizhub.healthdata.org/gbd-compare.)
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Africa, mean systolic BP increased by 1.6 mm Hg per decade in men (often only total cholesterol). In HICs, mean population cholesterol
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and 2.5 mm Hg per decade in women. The most significant increases levels are generally decreasing, but in LMICs, these levels vary widely.
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in men occurred in East Africa (1.6 mm Hg per decade). In women, As countries move through epidemiologic transition, mean population
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mean systolic BP increased the most in Oceania (2.7 mm Hg per plasma cholesterol levels typically rise. Changes accompanying
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decade). urbanization clearly play a role, because urban residents tend to have
Notable sex differences occurred in Oceania and West Africa. In higher plasma cholesterol levels than rural residents. This shift results
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Oceania, mean systolic BP in women increased by 2.7 mm Hg per largely from greater consumption of dietary fats, primarily from animal
decade, the largest increase in any female cohort in the world. In products and processed vegetable oils, and decreased physical
men in this region, however, mean systolic BP increased by only 1.2 mm activity.
Hg per decade. Data from West Africa show diverging trends in men Globally, mean serum total cholesterol levels have decreased.22
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and women: although mean systolic BP in men decreased by 0.4 mm The GBD study analyzed data between 1980 and 2008 using a bayesian
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Hg per decade, it decreased in women by 2.5 mm Hg. model to estimate mean total cholesterol by age, country, and year.
Age-standardized mean total cholesterol was 4.64 mmol/L (179.6 mg/
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dL) in men and 4.76 mmol/L in women in 2008 (184.2 mg/dL). CVD


Lipids
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death rates attributable to cholesterol have changed between 1990 to


Worldwide, high cholesterol causes about 56% of ischemic heart disease 2013, with most of the larger LMICs (China, India, Brazil) worsening
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and 18% of strokes, accounting for 4.4 million deaths annually. and most HICs improving (Fig. 1.10). In 2008 the combined regions
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Unfortunately, most LMICs have limited data on cholesterol levels of Australasia, North America, and Western Europe had a mean total
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Males
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37% 40% 45% 50% 55% 60% 65% 70%71%
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Females
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37% 40% 45% 50% 55% 60% 65%


m70%71%
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CVD DEATHS ATTRIBUTABLE TO HIGH SYSTOLIC


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BLOOD PRESSURE, 2013 (% total deaths)
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FIGURE 1.9  Cardiovascular disease mortality attributable to high systolic blood pressure in 2013, percentage of total deaths, males versus females. (From Institute for Health
Metrics and Evaluation (IHME). GBD Compare. Seattle: IHME, University of Washington; 2015. http://vizhub.healthdata.org/gbd-compare.)
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cholesterol of 5.24 mmol/L in men and 5.23 mmol/L in women. In per decade in men and by 0.09 mmol/L per decade in women. The
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Greenland, mean total cholesterol was as high as 5.7 mmol/L for both high-income Asia-Pacific subregion showed a similar trend, but the
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sexes. Sub-Saharan Africa had the lowest levels for both sexes. Some increase was more moderate (≤0.1 mmol/L per decade). South Korea
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cohorts, primarily men in Southern African countries such as Liberia, demonstrated no change in cholesterol levels. Singapore data were
Nigeria, and Burkina Faso, had levels less than 4.0 mmol/L. also notable: In the 1980s, cholesterol levels decreased for both men
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Between 1980 and 2008, mean total cholesterol levels decreased and women, but beginning in 2000, the downward trend ended in
by 0.08 mmol/L per decade in men and by 0.07 mmol/L per decade men. In women the trend reversed, increasing from 4.7 mmol/L in
in women. The most significant decreases in cholesterol levels occurred 2000 to 5.3 mmol/L in 2008. Several regions, including North Africa
in the Central Europe, Eastern Europe, and Central Asia regions: and Middle East, sub-Saharan Africa, and South Asia, showed no
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0.23 mmol/L per decade in men and 0.24 mmol/L per decade in women. notable change in cholesterol levels, in part because of a lack of
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The high-income regions of Australasia, North America, and Western available historical data. In general, women in LMIC subregions had
Europe had similarly large decreases in cholesterol levels: 0.19 mmol/L higher total cholesterol than their counterparts in HICs.
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per decade in men and 0.21 mmol/L per decade in women. Countries


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such as Finland and Sweden had notably faster decreases in cholesterol


levels than other Western European countries. Diabetes
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Several exceptions to the worldwide downward trend in cholesterol Diabetes prevalence has grown rapidly worldwide in the past 30 years.
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levels occurred. In the EAP region, levels increased by 0.08 mmol/L As a result, death rates for CVD attributable to diabetes have increased
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to 25.4%. Future growth will be

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concentrated in LMICs, especially 1
in regions such as sub-Saharan

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Global Burden of Cardiovascular Disease
Africa, Middle East and North
f Africa, and Southeast Asia.24 In
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addition, a majority of cases will
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remain within those age 45 to 64

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in LMICs, whereas those older
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than 65 are most affected in HICs.
Rising rates of obesity, aging, and
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urbanization of the population
are likely related to the diabetes
epidemic. Almost 90% of type
2 diabetes cases are associated
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with obesity, and diabetes and
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its related complications are the
costliest consequence of obesity.
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Mortality from diabetes is also
increasing, with approximately
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1990 4.6 million deaths in 2011.

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Asian countries face a relatively
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larger burden of diabetes com-
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2 20 40 60 80 100 120 140 160 180 200 220 230 pared with the Europe and
Central Asia or Latin America and
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Caribbean regions. India and
China, for example, have the
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largest numbers of people with
diabetes in the world: 61.3 million
and 90 million, respectively. Asian
populations may have a higher
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risk for developing diabetes even
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at a lower body mass index (BMI),
because of a greater tendency
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toward visceral obesity. In addi-
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tion, this population may experi-
ence both undernutrition (during
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the perinatal period) and rapid
weight gain (during childhood),
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a combination that increases the
risk for insulin resistance.25
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The most recent GBD study
found a global increase in mean
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2013 FPG. The study analyzed multiple
published and unpublished health
surveys and epidemiologic studies
by applying a bayesian hierarchi-
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2 20 40 60 80 100 120 140 160 180 200 220 230


cal model for each sex by age,
CVD DEATHS, PER 100,000, ATTRIBUTABLE TO
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country, and year. Between 1980
HIGH TOTAL CHOLESTEROL, 1990 vs. 2013 and 2008, mean FPG increased
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FIGURE 1.10  Cardiovascular disease mortality attributable to high total cholesterol, deaths per 100,000, 1990 versus 2013. by 0.07 mmol/L (1.26 mg/dL) per
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(From Institute for Health Metrics and Evaluation (IHME). GBD Compare. Seattle: IHME, University of Washington; 2015. http:// decade in men and 0.08 mmol/L
vizhub.healthdata.org/gbd-compare.)
(1.44  mg/dL) per decade in
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women. The upward trend in FPG
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was nearly universal.23 In almost


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for many LMICs, particularly in East Asia, South Asia, and Eastern every region worldwide, mean FPG increased or remained unchanged;
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Europe and Central Asia (Fig. 1.11). According to the GBD study, an regions that displayed apparent decreases (e.g., men in the East Asia
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estimated 346 million people worldwide have diabetes.23 The more and Southeast Asia region) were not statistically different from flat
expansive International Diabetes Foundation (IDF) definition—which, trends (posterior probabilities ≤0.80).
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in addition to fasting plasma glucose (FPG) as in the GBD study, Although some regions had unchanging mean FPG levels, other
includes oral glucose tolerance and hemoglobin A1c tests—found that regions, including southern and tropical Latin America, Oceania, and
366 million people had diabetes in 2011. Almost 50% of these cases high-income regions, experienced significant increases. The most
were undiagnosed. By 2030 the number of people with diabetes is notable region is Oceania; between 1980 and 2008, mean FPG increased
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expected to increase to 522 million. This rise is estimated to occur at by 0.22 mmol/L per decade in men and 0.32 mmol/L per decade in
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2.7% annually, a higher growth rate than that of the total world adult women. By 2008, Oceania had the highest mean FPG for both sexes
population. (6.09 mmol/L for men, 6.09 mmol/L for women) and the highest
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Eighty percent of people with diabetes live in LMICs. The highest prevalence of diabetes (15.5% in men, 15.9% in women) in the world.
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regional prevalence for diabetes occurs in the Middle East and North In addition to Oceania, the Caribbean and North Africa and the
Africa, where an estimated 12.5% of the adult population (20 to 79 years Middle East have the highest mean FPG levels worldwide: 21% to 25%
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of age) has diabetes. Pacific island and Middle Eastern countries have of men and 21% to 32% of women in these countries have diabetes.
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the highest prevalence, with age-adjusted prevalence ranging from 18.8% By contrast, men in sub-Saharan Africa and women in Asia-Pacific
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m2).26 Explanations for this rapid rise

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I include changes in dietary patterns,
physical activity, and urbanization.
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eb Disease

Popkin and colleagues27 report that the


use of edible oils, caloric sweeteners,
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and animal-source foods is increasing.
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Annual animal food consumption

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eb Fundamentals of Cardiovascular

tripled in China from the 1950s to

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1990s. Physical activity declines as
urbanization leads to increased use
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of motorized vehicles and a change
to more sedentary occupations.
Unlike data from the 1980s, which
showed that obesity affected predomi-
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nantly the higher-income group in
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LMICs, a recent analysis shows a shift
to the poor in the burden of overweight
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and obesity. Although higher-income
1990 groups still have the highest prevalence
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of overweight and obesity, rates are

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increasing faster in lower-income
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groups.28 The poor are relatively more
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1 10 20 30 40 50 60 70 80 90 100 110 120 130 susceptible to obesity as a developing
country’s GNP approaches the middle-
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income range.28,29 Higher GDP is also
associated with faster rates of increase
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in the prevalence of overweight and
obesity in lower-income groups.28
Women are more affected than
men, with overweight women generally
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outnumbering underweight women, as
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indicated by data from LMICs.26 In the
same survey, prevalence of overweight
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women exceeded 20% in more than
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90% of surveyed countries. Even rural
areas in half the countries surveyed
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exhibited such rates. Adolescents are at
particular risk: 19% of U.S. adolescents
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are obese.30 The number of overweight
children is increasing in countries as
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diverse as China, Brazil, India, Mexico,
2013 and Nigeria. According to the most
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recent World Health Organization
(WHO) estimates, 40 million children
younger than 5 years are overweight.
Brazil saw an alarming rise, from 4% to
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1 10 20 30 40 50 60 70 80 90 100 110 120 130


14% over a two-decade period. In 1980
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CVD DEATHS, PER 100,000, ATTRIBUTABLE TO the worldwide obesity prevalence rate
HIGH FASTING PLASMA GLUCOSE, 1990 vs. 2013 was 4.8% in men and 7.9% in women.
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FIGURE 1.11  Cardiovascular disease mortality attributable to high fasting plasma glucose, deaths per 100,000, 1990 By 2008, prevalence rates had almost
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versus 2013. (From Institute for Health Metrics and Evaluation (IHME). GBD Compare. Seattle: IHME, University of Washington; doubled, to 9.8% in men and 13.8% in
2015. http://vizhub.healthdata.org/gbd-compare.) women.
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Globally, BMI rose in both men and
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women. The GBD study analyzed


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HICs had the lowest mean FPG in 2008: 5.27 mmol/L and 5.17 mmol/L, published and unpublished health examination surveys and epide-
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respectively. The only significant decrease in mean FPG occurred in miologic studies (linear regressions were developed to estimate mean
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women in Singapore, where levels fell by 0.21 mmol/L per decade. BMI from overweight or obesity prevalence, when available) and found
Trends in mean FPG also varied by sex. In sub-Saharan Africa, for that between 1980 and 2008, global BMI rose by 0.4 kg/m2 per decade
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example, mean FPG increased by 0.05 mmol/L per decade in men, in men and 0.5 kg/m2 per decade in women.
but by 0.13 mmol/L per decade in women. The Central Asia, North BMI varied substantially between regions and by sex and over time.
Africa, and Middle East region had similar differences in sex: mean In more than two thirds of the countries, the contribution of obesity
FPG increased by 0.06 mmol/L per decade in men and by 0.16 mmol/L to attributable burden of CVD death rates worsened. The majority of
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per decade in women. countries that improved were from HICs, although some were from
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each of the LMICs that saw improvements except from South Asia
(Fig. 1.12). In 2008 the age-standardized mean BMI in the United
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Obesity States was 28.5 kg/m2 in men and 28.3 kg/m2 in women. In contrast


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Obesity is increasing throughout the world and particularly in LMICs, with the United States and other HICs with similarly high BMIs, the
which have steeper trajectories than in HICs. According to the latest sub-Saharan Africa and Asia regions have some of the lowest mean
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GBD study, almost 1.46 billion adults were overweight (BMI ≥25 kg/m2) BMIs. Men in Ethiopia, for example, have a mean BMI of 20.2 kg/m2,
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in 2008; of these, approximately 502 million were obese (BMI ≥30 kg/ and women in Bangladesh have a mean BMI of 20.5 kg/m2.
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rate close to the global average,

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0.4 kg/m2 per decade. The most 1
significant discrepancy in sex trends

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Global Burden of Cardiovascular Disease
occurred in Central Africa. BMI in
f men in Central Africa decreased
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by 0.2 kg/m2 per decade, the only
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significant decrease in any male

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population in the world. In women
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in Central Africa, however, mean
BMI increased by 0.7 kg/m2 per
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decade, a rate greater than the
world average.
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Diet
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As humans have evolved, selec-
tive pressures have favored the
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ability to conserve and store fat
1990 as a defense against famine. This
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adaptive mechanism has become

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unfavorable in light of the larger
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portion sizes, processed foods, and
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4 20 40 60 80 100 120 140 160 180 200 220230 sugary drinks that many people now
regularly consume. Between 1970
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and 2010, the average daily per
capita caloric intake in the United
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States increased from 2076 to 2534
calories.31 As per capita income
increases, so does consumption
of fats and simple carbohydrates,
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whereas intake of plant-based
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foods decreases. A key element of
this dietary change is an increased
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intake of saturated animal fats and
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inexpensive hydrogenated vegetable
fats, which contain atherogenic
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trans fatty acids. New evidence
suggests that high intake of trans
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fats may also lead to abdominal
obesity, another risk factor for
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CVD. (See Chapters 49 and 50 for
further discussion of diet, obesity,
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2013 and CVD.)
China provides a good example
of such a “nutritional transition”—
rapid shifts in diet linked to socio-
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4 20 40 60 80 100 120 140 160 180 200 220230 economic changes. The China
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CVD DEATHS, PER 100,000, ATTRIBUTABLE TO Nationwide Health Survey found
HIGH BODY MASS INDEX, 1990 vs. 2013 that between 1982 and 2002, calo-
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FIGURE 1.12  Cardiovascular disease mortality attributable to high body-mass index, deaths per 100,000, 1990 versus 2013. ries from fat increased from 25% to
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(From Institute for Health Metrics and Evaluation (IHME). GBD Compare. Seattle: IHME, University of Washington; 2015. http:// 35% in urban areas and from 14% to
vizhub.healthdata.org/gbd-compare.) 28% in rural areas, as calories from
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carbohydrates fell from 70% to 47%.
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As recently as 1980, the average BMI


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for Chinese adults was about 20 kg/


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The largest increase in BMI occurred in Oceania. Between 1980 m2, and less than 1% had a BMI of 30 kg/m2 or greater. From 1992 to
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and 2008, mean BMI rose by 1.3 kg/m2 per decade in men and 1.8 kg/ 2002, the number of overweight adults increased by 41%, and the
m2 per decade in women. Of the islands in the Oceania region, Nauru number of obese adults increased by 97%.
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had the largest BMI increase of more than 2 kg/m2. BMI trends were China and other countries in transition have the opportunity to
similar in the North American high-income region (1.1 kg/m2 per decade spare their populations from the high levels of trans fats that North
in men and 1.2 kg/m2 per decade in women). In Latin America and Americans and Europeans have consumed over the past 50 years by
the Caribbean, mean BMI for women increased 0.6 to 1.4 kg/m2 per avoiding government policies that can contribute to the CVD burden.
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decade. By contrast, mean BMI decreased in Central African men An estimated 30,000 CVD deaths could be averted over 10 years in
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by 0.2 kg/m2 per decade and remained unchanged in South Asian the United Kingdom with elimination of trans fats, reductions in
men. In women, mean BMI remained static, with changes less than saturated-fat consumption, reduced salt intake, and increased fruit
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0.2 kg/m2 per decade in Central Asia, Central Europe, and Eastern and vegetable consumption.32 Another facet of the nutritional transition
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Europe. for countries adopting a Western diet is the introduction of high-sugar


Although regional trends generally showed concordance between beverages associated with weight gain and increased risk for type 2
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sexes, some exceptions occurred. There was no change in mean diabetes. A meta-analysis suggests up to a 16% relative risk increase
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BMI in South Asian men, but mean BMI in women increased at a in CHD per unit of sugar-sweetened beverages consumed daily.33
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14

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mothers demonstrated favorable cardiovascular risk profiles among
I Physical Inactivity

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the children of mothers who received such supplementation.39,40
In HICs the widespread prevalence of physical inactivity produces a The mechanisms of increased risk appear to be both biologic
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high population-attributable risk of cardiovascular consequences. (alterations in fetal tissues and postnatal epigenetic modifications)
Physical inactivity is also increasing in low- and middle-income regions and social (cognitive impairment, low productivity, and higher preva-
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of the world, witnessing a shift from physically demanding, agriculture- lence of cardiovascular risk factors among those with lower birth
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based work to largely sedentary, service industry–based and office- weight and early-life adverse influences), and childhood obesity and

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based work. A switch to mechanized transportation accompanies this sedentary habits aggravate this risk. Thus the prevention of adverse

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work shift. fetal exposures and subsequent long-term consequences require a
Current guidelines call for moderate exercise for at least 30 minutes holistic approach. An understanding of prenatal risk factors and their
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5 or more days a week, or vigorous exercise for 20 minutes 3 days a early childhood modifiers will provide an opportunity for interventions
week. Gallup’s November 2011 Health and Healthcare poll found that before the development of risk factors. Remedies include improved
51.6% of U.S. adults say they exercise three or more times a week. maternal nutrition during pregnancy and lactation, emphasis on
These numbers have remained essentially unchanged since 2008. breastfeeding through early infancy, and ensuring adequate balanced
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Physical inactivity levels are similarly high in other regions of the nutrition to infants. On the basis of current understanding, policymakers
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world. In the Middle East and North Africa region, for example, physical and health care professionals should design and develop preventive
inactivity is fairly common, with a prevalence ranging from 32.9% in strategies that effectively influence these very early determinants of
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Syria to 56.7% in Iraq. In urban China the proportion of adults who CVD development.41
participate in moderate- and high-level activity has decreased signifi-
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cantly, whereas participation in low-level activity has increased. The

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study of about 500,000 adults in China found that a lack of physical Environmental Exposures
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activity and an increase in sedentary leisure time were independently Environmental pollution, especially both indoor and outdoor air
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associated with greater adiposity.34 pollution, has emerged as a major cause of death and disease burden42
The Cuban economic crisis that began in 1989, when Cuba lost (see Chapter 52). Exposure to particulate-matter (PM) air pollution,43
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the Soviet Union as a trading partner, and the resultant hardship for heavy metals (e.g., cadmium, arsenic, lead, mercury),44 and polyaromatic
its people improved their overall cardiovascular health. The crisis hydrocarbons 45 is associated with increased risk of mortality and
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worsened for the next 5 years, and complete recovery did not take morbidity from CVD. The GBD comparative risk assessments of 2010
place until 2000. Sustained food rationing led to a reduction in per and 2013 have shown that more than 30% of all DALYs from ischemic
capita food intake, and the lack of public transportation resulting heart disease and about 40% of DALYs from strokes result from
from fuel shortages meant that more people were walking and environmental risk factors,46,47 approximately the same as those
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riding bikes. During the crisis period, the proportion of physically attributable to tobacco smoke. Of these exposures, air pollution
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active adults increased from 30% to 67%, and a 1.5-unit shift in BMI (household and ambient) is the most prominent risk factor, contributing
distribution was observed; CHD declined up to 1995. However, a to approximately 7 million premature deaths annually, with a majority
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rebound in population weight mirrored a reduction in physical activity occurring in LMICs such as India and China.
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and resulted in the cessation of CHD mortality decline from 2000 In many developing countries, populations experience a continuum
to 2010.35 of exposure to ambient air pollution (from vehicles, industry, etc.)
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and household air pollution (from cooking, heating, and lighting),
resulting in significant contributions to the health burden, as in India,
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Aging Populations where it is the second most important risk factor for poor health. More
Average life expectancy will reach 83 years in developed regions and than half of all deaths associated with air pollution exposure are
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75 years in less developed regions by 2025, according to WHO.36 This through cardiovascular and cerebrovascular pathways, involving
increase is associated with a decline in overall infant mortality and ischemic heart disease,48 heart failure,49 stroke,50 and hypertension.51
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fertility rates. Although older adults will constitute a greater percentage Three pathways, listed below in order of the strength of the evidence
of the population in HICs—more than 65 million Americans will be base, may contribute to the mechanisms that link PM exposure to
older than 65 by 2025—low- and middle-income regions will see the CVD and cerebrovascular disease:
population over 60 more than double from 1995 to 2025. 1. Particle transport into the lungs provoking inflammatory responses
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The time of transition to an older population is sharply shorter in and promoting systemic oxidative stress. This leads to increased
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LMICs. For example, whereas it took the United States and Canada more risk of thrombosis, endothelial dysfunction, atherosclerosis progres-
than 65 years to double their over-65 population, LMICs will do so every sion, and dyslipidemia.
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25 years for the next 50 years. Such acute changes in the population 2. Particle transport into the lungs promoting autonomous nervous
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structure leave less time to expand an already overburdened health system imbalances. This leads to pathologic alterations in hyperten-
infrastructure to address the chronic diseases of older adults, which sion, endothelial dysfunction, vasoconstriction, and atherosclerosis.
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prominently include cardiovascular conditions (see Chapter 88). 3. Absorption of particles through the lungs into the bloodstream
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causing tissue-level interactions. This results in platelet aggregation,


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vasoconstriction, and endothelial dysfunction.


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Fetal Influences The epidemiologic evidence base suggests that exposure to arsenic,52
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Adverse influences such as undernutrition during fetal life (fetal cadmium,53 and lead54 follows the common physiologic pathways
“programming”) and early postnatal life appear to affect the prevalence observed with air pollution. In addition, the mechanistic evidence
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of adult CVD and contribute to its risk factors. Barker,37 in his “devel- from animal and human studies indicates that arsenic exposure is
opmental origins of adult disease” hypothesis, suggested that adverse associated with carotid intima media thickness, a marker for athero-
influences early in development, particularly during intrauterine life, sclerosis, with links to diabetes also observed.55
could result in permanent changes in the physiology and metabolism Regardless of the primary route and the pathophysiology involved,
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of the pancreas, kidney, muscle, and vascular endothelium, resulting short- or long-term exposure to various environmental pollutants is
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in adult insulin resistance, metabolic syndrome, hypertension, and associated with an increased risk of ischemic heart disease, stroke,
CHD. Recent evidence indicates that the first 2 years of postnatal life heart failure, and preclinical conditions such as endothelial dysfunction,
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are a sensitive or “critical” period of development, and any stimulus thrombosis, atherosclerosis, and hypertension. Although epidemiologic
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or insult during this period appears to have lasting or lifelong signifi- evidence has been well documented for single pollutants, the synergistic
cance for adult-onset CVD.38 Several epidemiologic studies have impacts are understudied. From a physician’s perspective, informing
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demonstrated these associations, and two randomized trials from patients on how to avoid exposure and protect themselves should be
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Guatemala and India on nutritional supplementation for pregnant part of primary prevention.
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ECONOMIC BURDEN

HEALTHCARE EXPENDITURES
25

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1

(%) DUE TO HIGH BLOOD


Despite some overlap, at least three approaches can measure the

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20

Global Burden of Cardiovascular Disease


economic burden associated with CHD. The first source of financial
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PRESSURE
burden reflects the costs incurred in the health care system itself and
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reported in “cost-of-illness” studies. In these studies, the cost of CHD
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includes the costs of hospitalizations for angina and MI, as well as
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heart failure attributable to CHD. The cost of specific treatments or
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procedures related to CVD (e.g., thrombolytics, catheterization, PCI)
and the cost associated with outpatient management and secondary 5
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prevention (e.g., office visits, pharmaceutical costs) are also included.
In addition, nursing home, rehabilitation (inpatient and outpatient), 0
and home nursing costs require consideration. EAP ECA LAM MNA SAR SSA HIGH-
The second economic assessment is derived from microeconomic INCOME
ECONOMY
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studies that assess the household impact of catastrophic health events
FIGURE 1.13  Percentage of health care expenditures attributed to high blood
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such as MI. These studies look at out-of-pocket expenses incurred by
pressure. EAP, East Asia and Pacific; ECA, Europe and Central Asia; LAM, Latin America
the individual patient or family that might have other, downstream and the Caribbean; MNA, Middle East and North Africa; SAR, South Asia region;
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economic impacts, such as loss of savings or sale of property to cover SSA, sub-Saharan Africa.
medical costs. Many LMICs lack an extensive insurance scheme, and
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health care costs are almost entirely borne by individuals; 150 million

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people experience financial catastrophe each year because of medical trend could have profound economic effects over the next 25 years,
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expenditures.56 Furthermore, the limited data do not confirm the as workers in their prime succumb to CVD.
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causality between chronic disease and individual or household poverty.
However, expenditures for CHD or its addictive risk factors (e.g.,
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tobacco) could lead to substantial and even impoverishing costs. COST-EFFECTIVE SOLUTIONS
The third method of determining financial burden from CHD is
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based on a macroeconomic analysis. These assessments examine The large reductions in age-adjusted CVD mortality rates that have
lost worker productivity, or the economic growth lost as a result of occurred in HICs result from three complementary types of interven-
adults with CHD or their caregivers being partially or completely out tions. One strategy targets those with acute or established CVD. A
of the workforce because of illness. The data for the impact of chronic second entails risk assessment and targeting persons at high risk
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diseases on labor supply and productivity are more robust. An additional because of multiple risk factors for intervention before their first CVD
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cost usually not accounted for is the intangible loss of welfare associated event. The third strategy uses mass education or policy interventions
with pain, disability, or suffering by the affected person. These indirect directed at the entire population to reduce the overall level of risk
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costs are often addressed by “willingness-to-pay” analyses, asking factors. This section reviews various cost-effective interventions (see
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generally how much would an individual pay to avert suffering or Chapter 45). Much work remains undone in LMICs to determine the
dying prematurely from CHD. The gains are not merely improved work best strategies given limited resources, but if implemented, these
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performance, but also enjoying activities beyond productivity. U.S. interventions could help significantly in reducing the burden. Table
studies suggest that as much as 1% to 3% of GDP is attributable to the 1.2 lists the cost-effectiveness ratios for many high-yield interventions
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cost of care for CVD, with almost half of that related to CHD.57 In that could be or have been adopted in low- and middle-income regions.
China, annual direct costs of CVD are estimated at more than $40
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billion (U.S.), or about 4% of GNI. In South Africa, 2% to 3% of GNI is
devoted to the direct treatment of CVD, which equates to about 25% Established Cardiovascular
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of South African health care expenditures. The indirect costs are Disease Management
estimated at more than double that of the direct costs. Although few People at highest risk are those having an MI or stroke; as many as
cost-of-illness studies for CHD have been performed in other regions, half die before they ever receive medical attention. For those who do
such studies have reported on the financial burdens attributed to risk reach a hospital, many cost-effective strategies exist.60 Four incremental
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factors for CHD. For example, the direct costs caused by diabetes in strategies were evaluated for the treatment of MI and compared with
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the Latin American and Caribbean countries were estimated at $10 a strategy of “no treatment” as a control for the six World Bank low- and
billion (U.S.). Indirect costs were estimated at more than $50 billion middle-income regions. The four strategies compared were (1) aspirin;
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in 2000. The limited studies available suggest that obesity-related (2) aspirin and atenolol (beta blocker); (3) aspirin, atenolol, and
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diseases account for 2% to 8% of all health care expenditures in HICs. streptokinase; and (4) aspirin, atenolol, and tissue plasminogen activator
In India and China the costs for obesity are about 1.1% and 2.1% of (t-PA). The incremental cost per quality-adjusted life-year (QALY) gained
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GDP, respectively. for the aspirin and beta-blocker interventions was less than $25 for
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Recently, the costs attributable to nonoptimal BP levels as mediated all six regions. Costs per QALY gained for streptokinase were between
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through stroke and MI were evaluated for all regions of the world. $630 and $730 across the regions. Incremental cost-effectiveness ratios
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Globally, the health care costs of elevated BP were estimated at $370 for t-PA were about $16,000/QALY gained, compared with streptokinase.
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billion (U.S.) for 2001; this amount represented approximately 10% of Minor variations occurred between regions as a result of small differ-
all global health care expenditures for that year. Regional variations ences in follow-up care based on regional costs.
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do exist, with hypertension being responsible for up to 25% of health Secondary prevention strategies have equal cost-effectiveness in
care costs in the Eastern Europe region (Fig. 1.13). Over a 10-year LMICs. A combination of aspirin, an ACE inhibitor, a beta blocker,
period, BP-related health care costs could equal $1 trillion (U.S.) and a statin for secondary prevention can lead to acceptable cost-
globally, and indirect health care costs attributed to BP could be effectiveness ratios in all low- and middle-income regions. Use of
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nearly four times as much.58,59 currently available generic agents, even in the absence of the “polypill,”
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The high proportion of CVD burden that occurs earlier among could be highly cost-effective, on the order of $300 to $400 per person
adults of working age augments its macroeconomic impact in LMICs. per QALY gained.
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Under current projections, in LMICs such as South Africa, CVD will


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strike 40% of adults between ages 35 and 64, compared with 10% in
the United States. India and China will have death rates in the same Risk Assessment
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age-group that are two and three times that for most HICs. In view of Primary prevention is paramount for the large number of people who
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the large populations in these two rapidly growing economies, this have high risk for acquiring CVD. In view of limited resources, finding
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TABLE 1.2  Cost-Effectiveness for a Selection of Coronary different regions of the world, with and without cholesterol data. A

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I Heart Disease (CHD) Interventions in Developing Regions study based on the U.S. National Health and Nutrition Examination
Survey (NHANES) follow-up cohort demonstrated that a non–laboratory-
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COST-EFFECTIVENESS RATIO
eb Disease

INTERVENTION ($US/DALY)*
based risk tool that uses information obtained in a single encounter
(age, systolic BP, BMI, diabetes status, and smoking status) can predict
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Drug Treatments

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CVD outcomes as effectively as one that requires laboratory testing,
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Acute Myocardial Infarction with C-statistics of 0.79 for men and 0.83 for women that were no

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ASA, BB (global) 11-22 different from those obtained using the Framingham-based risk tool,

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and has been shown to correlate with other scores in other countries.66
ASA, BB, SK (global) 634-734 Furthermore, the results of “goodness-of-fit” tests suggest that the
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ASA, BB, t-PA (global) 15,860-18,893 non–laboratory-based model is well calibrated across a wide range
Prehospital thrombolysis (Brazil) 457/LY of absolute risk levels and without changes in risk classification. The
ankle-brachial index (ABI) also appears to add to risk discrimination
Secondary Treatment (CHD)
and improve the NRI as an alternative noninvasive tool.65 Furthermore,
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Multidrug regimen (ASA, BB, ACEI, statin) 1686-2026 community health workers can use the simple risk score effectively,
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(global) decreasing the cost of screening significantly.67,68
Coronary artery bypass graft (global) 24,040-72,345
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Primary Prevention
Policy and Community Interventions
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Cholesterol lowering (Brazil) 441/LY Education and public policy interventions that have reduced smoking

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rates, lowered mean BP levels, and improved lipid profiles contribute
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Multidrug regimen (AR > 20%-25%) 771-1195
(global) to reduction in CHD rates.4 Education and policy efforts directed at
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Policy Interventions tobacco consumption have contributed substantially to the reductions
in CVD. In addition, salt and cholesterol reduction has been evaluated
Tobacco
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as a cost-effective strategy to reduce stroke and MI in HICs.69 Community
Price increase of 33% 2-85 interventions70 have reduced levels of multiple risk factors and, in
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Nonpolicy Interventions 33-1432 some cases, CHD mortality.
Salt Reduction‡
Tobacco Use
2-8 mm Hg reduction Cost-saving: 250 Tobacco control can be conceptualized in terms of strategies that
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Fat-Related Interventions§ reduce the supply of or the demand for tobacco. Most public health
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Reduced saturated-fat intake Cost-saving: 2900 and clinical strategies to date focus on reducing demand through
economic disincentives (taxes), health promotion (media and packaging
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Trans fat replacement: 7% reduction in 50-1500
efforts), restricted access (to advertising and tobacco), or clinical
CHD
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assistance for cessation. The WHO effort to catalyze the creation of
Devices a global treaty against tobacco use was a key milestone. In May 2003
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Cardioverter-defibrillators: primary 50,345 (US$PPP/QALY) the WHO World Health Assembly unanimously adopted the WHO
prevention (Brazil) Framework Convention in Tobacco Control (FCTC), the first global
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tobacco treaty. The FCTC had been ratified by 168 countries as of
ASA, Acetylsalicylic acid (aspirin); BB, beta blocker; SK, streptokinase; ACEI,
angiotensin-converting enzyme inhibitor; t-PA, tissue plasminogen activator; AR, 2016, making it one of the most widely embraced treaties in the United
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absolute risk. Nations. The FCTC has spurred efforts for tobacco control across the
*Across six World Bank regions; DALY, disability-adjusted life-year; PPP, purchasing globe by providing both rich and poor nations with a common
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power parity; QALY, quality-adjusted life-year. framework of evidence-based legislation and implementation strategies

Range includes different estimates of cost of interventions, as well as blood pressure
reduction (<$0.50-$1.00). known to reduce tobacco use.
§
Range includes estimates of cost of interventions (<$0.50-$6.00). Jha and colleagues71 presented a landmark analysis of the cost-
Data from Gaziano TA. Cardiovascular disease in the developing world and its effectiveness of tobacco control in 2006, and the findings have led
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cost-effective management. Circulation 2005;112:3547; and Gaziano TA, Galea G, it to be a major focus on noncommunicable diseases.72 With tax,
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Reddy KS. Chronic diseases 2—scaling up interventions for chronic disease prevention:
the evidence. Lancet 2007;370:1939. treatment, and nonprice interventions, a 33% price increase would
result in a reduction of 19.7 to 56.8 million (5.4% to 15.9% of total)
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