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Perfect for residents, generalists, anesthesiologists, emergency department physicians, medical students, nurses, and other healthcare professionals who need a practical, working knowledge of cardiology, Netter's Cardiology, 3rd Edition, provides a concise overview of cardiovascular disease highlighted by unique, memorable Netter illustrations. This superb visual resource showcases the well-known work of Frank H. Netter, MD, and his successor, Carlos Machado, MD, a cardiologist who has created clear, full-color illustrations in the Netter tradition. New features and all-new chapters keep you up to date with the latest information in the field.
3rd Edition
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George A. Stouffer, MD

Frank H. Netter, MD

Ernest and Hazel Craige Distinguished Professor of Medicine
Chief, Division of Cardiology
Physician in Chief, UNC Heart and Vascular Service Line
University of North Carolina at Chapel Hill
Chapel Hill, North Carolina


Marschall S. Runge, MD, Ph @
Professor of Internal Medicine
Dean, University of Michigan Medical Schoo\
Executive Vice President for Medical Affairs
Chief Executive Officer, Michigan Medicine
Ann Arbor, Michigan

Cam Patterson, MD, MBA
University of Arkansas for Medical Sciences
Little Rock, Arkansas

Joseph S. Rossi, MD
Associate Professor of Medicine
Director, Cardiac Catheterization Laboratory
University of North Carolina at Chapel Hill
Chapel Hill, North Carolina


Carlos A.G. Machado, MD
John A. Craig, MD
David J. Mascaro, MS
Enid Hatton
Steven Moon, MA
Kip Carter, MS, CMI
Tiffany S. Davanzo, MA, CMI

1600 John F. Kennedy Blvd.
Ste 1600
Philadelphia, PA 19103-2899

ISBN: 978-0-323-54726-0

Copyright © 2019 by Elsevier, Inc. All rights reserved.
No part of this publication may be reproduced or transmitted in any form or by any means, electronic or
mechanical, including photocopying, recording, or any information storage and retrieval system, without
permission in writing from the publisher. Details on how to seek permission, further information about the
Publisher’s permissions policies and our arrangements with organizations such as the Copyright Clearance
Center and the Copyright Licensing Agency, can be found at our website:
This book and the individual contributions contained in it are protected under copyright by the Publisher
(other than as may be noted herein).

Knowledge and best practice in this field are constantly changing. As new research and experience broaden
our understanding, changes in research methods, professional practices, or medical treatment may become; 
Practitioners and researchers must always rely on their own experience and knowledge in evaluating and
using any information, methods, compounds, or experiments described herein. In using such information
or methods they should be mindful of their own safety and the safety of others, including parties for
whom they have a professional responsibility.
With respect to any drug or pharmaceutical products identified, readers are advised to check the most
current information provided (i) on procedures featured or (ii) by the manufacturer of each product to be
administered, to verify the recommended dose or formula, the method and duration of administration,
and contraindications. It is the responsibility of practitioners, relying on their own experience and
knowledge of their patients, to make diagnoses, to determine dosages and the best treatment for each
individual patient, and to take all appropriate safety precautions.
To the fullest extent of the law, neither the Publisher nor the authors, contributors, or editors, assume
any liability for any injury and/or damage to persons or property as a matter of products liability,
negligence or otherwise, or from any use or operation of any methods, products, instructions, or ideas
contained in the material herein.
Previous editions copyrighted 2010 and 2004.
Library of Congress Cataloging-in-Publication Data
Names: Stouffer, George A., editor. | Runge, Marschall Stevens, 1954- editor. | Patterson, Cam, editor. |
Rossi, Joseph S., editor. | Netter, Frank H. (Frank Henry), 1906-1991, illustrator.
Title: Netter’s cardiology / edited by George A. Stouffer, Marschall S. Runge, Cam Patterson, Joseph S. Rossi ;
illustrations by Frank H. Netter ; contributing illustrations, Carlos A. G. Machado [and 6 others].
Other titles: Cardiology
Description: 3rd edition. | Philadelphia, PA : Elsevier, [2019] | Includes bibliographical references and index.
Identifiers: LCCN 2018013552 | ISBN 9780323547260 (hardcover : alk. paper)
Subjects: | MESH: Cardiovascular Diseases | Diagnostic Techniques, Cardiovascular
Classification: LCC RC667 | NLM WG 120 | DDC 616.1/2—dc23 LC record available at https://lccn.loc.

Content Strategist: Marybeth Thiel
Publishing Services Manager: Catherine Albright Jackson
Senior Project Manager: Claire Kramer
Design Direction: Patrick Ferguson

Printed in China
Last digit is the print number: 9





4 3



George A. Stouffer, MD, was born in Indiana, Pennsylvania, and
was graduated from Bucknell University and the University of
Maryland, School of Medicine. He completed his internal medicine
residency, cardiology fellowship, and interventional cardiology fellowship at the University of Virginia. During his cardiology fellowship, he completed a 2-year National Institutes of Health research
fellowship in the laboratory of Gary Owens at the University of
Virginia. He was on the faculty at the University of Texas Medical
Branch from 1995 to 2000, where he became an associate professor
and served as Co-Director of Clinical Trials in the Cardiology
Division and as Associate Director of the Cardiac Catheterization
Laboratory. He joined the faculty at the University of North Carolina in 2000 and currently serves as the Henry A. Foscue Distinguished Professor of Medicine and Chief of Cardiology. Dr. Stouffer’s
main focus is clinical cardiology with an emphasis on interventional
cardiology, but he is also involved in clinical and basic science
research. His basic science research is in the areas of regulation of
smooth muscle cell growth, the role of the smooth muscle cytoskeleton in regulating signaling pathways, thrombin generation,
and renal artery stenosis.
Marschall S. Runge, MD, PhD, was born in Austin, Texas, and
was graduated from Vanderbilt University with a BA in general
biology and a PhD in molecular biology. He received his medical
degree from the Johns Hopkins School of Medicine and trained in
internal medicine at Johns Hopkins Hospital. He was a cardiology
fellow and junior faculty member at Massachusetts General Hospital.
Dr. Runge’s next position was at Emory University, where he directed
the Cardiology Fellowship Training Program. He then moved to
the University of Texas Medical Branch in Galveston, where he
was Chief of Cardiology and Director of the Sealy Center for
Molecular Cardiology. He was at the University of North Carolina
from 2000 to 2015, where he served as Charles Addison and Elizabeth Ann Sanders Distinguished Professor of Medicine, Chair of
the Department of Medicine, President of UNC Physicians, and
Vice Dean for Clinical Affairs. He is currently Dean of the Medical
School at the University of Michigan, Executive Vice President for
Medical Affairs, and Chief Executive Officer of Michigan Medicine.
Dr. Runge is board-certified in internal medicine and cardiovascular
diseases and has spoken and published widely on topics in clinical
cardiology and vascular medicine.

Cam Patterson, MD, MBA, was born in Mobile, Alabama. He
was a Harold Sterling Vanderbilt Scholar and studied psychology
and English at Vanderbilt University, graduating summa cum laude.
Dr. Patterson attended Emory University School of Medicine,
graduating with induction in the Alpha Omega Alpha Honor Society,
and completed a residency in Internal Medicine at Emory University
Hospitals and Chief Residency at Grady Memorial Hospital. He
completed 3 years of research fellowship under the guidance of
Edgar Haber at the Harvard School of Public Health, developing
an independent research program in vascular biology and angiogenesis that was supported by a National Institutes of Health fellowship. He did a cardiology fellowship and was on the faculty at
the University of Texas Medical Branch from 1996 to 2000. Dr.
Patterson was at the University of North Carolina at Chapel Hill
from 2000 to 2014 where he served as founding director of the
UNC McAllister Heart Institute, Chief of Cardiology, and the
Ernest and Hazel Craige Distinguished Professor of Cardiovascular
Medicine. He received his MBA from the UNC Kenan-Flagler
School of Business in 2008. He is an elected member of the American
Society of Clinical Investigation and the Association of University
Cardiologists. Until recently he was Senior Vice President and
Chief Operating Officer at New York Presbyterian–Weill Cornell
Medical Center and currently serves as Chancellor of the University
of Arkansas for Medical Sciences.
Joseph S. Rossi, MD, was born in Hopedale, Illinois. He completed
his undergraduate studies at the University of Illinois and then
completed his medical education at the University of Illinois–Chicago,
graduating with induction into the Alpha Omega Alpha Honor
Society. He completed residency and fellowships in internal medicine, cardiovascular disease, and interventional cardiology at Northwestern University, where he also obtained a master’s degree in
clinical investigation. Dr. Rossi is currently the Director of the
Cardiac Catheterization Lab at the University of North Carolina.
He is actively involved in multiple clinical trials and has received
research grants to support his interest in the pharmacogenomics
of dual antiplatelet therapy and complex coronary artery revascularization among Medicare beneficiaries. Dr. Rossi is particularly
interested in pairing clinical and administrative data to enhance
our knowledge of trends and resource utilization for patients with
advanced vascular disease.


Our goal for the third edition of Netter’s Cardiology was to provide
a concise and practical overview of cardiovascular medicine that has
been updated to include new information and important clinical
areas that were not well covered in the previous editions or in other
cardiology texts. To accomplish this expansion while maintaining a
focused text that could be used as a ready reference, we again avoided
exhaustive treatment of topics. We also have made every effort to
present the essential information in a reader-friendly format that
increases the reader’s ability to learn the key facts without getting
lost in details that can obfuscate the learning process.
The first two editions of Netter’s Cardiology were an effort to
present in a concise and highly visual format the ever-increasing
amount of medical information on cardiovascular disease. The
challenge that clinicians face in “keeping up” with the medical
literature has continued to grow in the 14 years since the first
edition of Netter’s Cardiology. This need to process the ever-expanding
medical information base and apply new findings to the optimal
care of patients is acute in all areas of medicine, but perhaps it
is most challenging in disciplines that require practitioners to
understand a broad spectrum of evidence-based medicine, such
as the field of cardiovascular diseases. The explosion of medical
knowledge is also a real educational challenge for learners at all
levels—students, residents, and practicing physicians—who must
rapidly determine what is and is not important, organize the key
information, and then apply these principles effectively in clinical
The third edition includes substantial changes. All the chapters
have been updated, there is a new section on Structural Heart
Disease, and new chapters have been added on Basic Anatomy and
Embryology of the Heart, Stem Cell Therapies for Cardiovascular
Disease, Diabetes and Cardiovascular Events, Coronary Hemodynamics and Fractional Flow Reserve, Epidemiology of Heart Failure:
Heart Failure with Preserved Ejection Fraction and Heart Failure
with Reduced Ejection Fraction, Management of Acute Heart Failure,
Cardiac Transplantation and Mechanical Circulatory Support
Devices, Cardiovascular Manifestations of Rheumatic Fever, Clinical
Presentation of Adults with Congenital Heart Disease, Transcatheter
Aortic Valve Replacement, Transcatheter Mitral Valve Repair, Tricuspid and Pulmonic Valve Disease, Deep Vein Thrombosis and
Pulmonary Embolism, Cardiac Tumors and Cardio-oncology, and
Cardiovascular Disease in the Elderly.
As in the first two editions, the contributing authors have taken
advantage of the genius of Frank Netter by carefully selecting the
best of his artwork to illustrate the most important clinical concepts
covered in each chapter. When Netter artwork was unavailable or
difficult to apply to illustrate modern clinical concepts, we again
used the great artistic talents of Carlos A. G. Machado, MD, to
create new artwork or to skillfully edit and update some of Frank
Netter’s drawings. The combination of Dr. Machado’s outstanding
skills as a medical artist and his knowledge of the medical concepts
being illustrated was an invaluable asset.
As in the first two editions, we chose to use authors from the
University of North Carolina School of Medicine at Chapel Hill
or those with close ties to the university. This allowed us to select
authors who are clinical authorities, many of whom are also well
known for their national and international contributions. All have
active clinical practices that require daily use of the information
covered in their chapters, and all are well aware of the approach
to patient management used by their peers at other institutions and
in other practice settings. Many of the contributing authors for this
edition also contributed to prior editions of this textbook. Each
author, whether a previous contributor or not, was given clearly
defined guidelines that emphasized the need to distill the large
amount of complex information in his or her field and to present
it concisely in a carefully prescribed format maintained across all


chapters. The result is a text that is truly clinically useful and less
of a compendium than is commonly the case in many medical texts.
We believe that the changes we have made in the third edition
substantially improve Netter’s Cardiology and ensure that it will continue to be a highly useful resource for all physicians, both generalists
and subspecialists, who need to remain current in cardiology—from
trainees to experienced practitioners. Whether we have succeeded
will obviously be determined by our readers. We welcome the comments, suggestions, and criticisms of readers that will help us improve
future editions of this work.
George A. Stouffer, MD
Ernest and Hazel Craige Distinguished Professor of Medicine
Chief, Division of Cardiology
Physician in Chief, UNC Heart and Vascular Service Line
University of North Carolina at Chapel Hill
Chapel Hill, North Carolina
Marschall S. Runge, MD, PhD
Professor of Internal Medicine
Dean, University of Michigan Medical School
Executive Vice President for Medical Affairs
Chief Executive Officer, Michigan Medicine
Ann Arbor, Michigan
Cam Patterson, MD, MBA
University of Arkansas for Medical Sciences
Little Rock, Arkansas
Joseph S. Rossi, MD
Associate Professor of Medicine
Director, Cardiac Catheterization Laboratory
University of North Carolina at Chapel Hill
Chapel Hill, North Carolina


Algorithms have been color coded for quick reference.

Algorithm for Evaluating Patients in Whom
Renal Artery Stenosis Is Suspected
Clinical findings associated with renal artery stenosis



Noninvasive evaluation
(duplex ultrasonography of renal
arteries, magnetic resonance
angiography, or computed
tomographic angiography)

Follow clinically
Treat risk factors

Renal artery stenosis present

Renal artery stenosis absent

Nuclear imaging
to estimate fractional
flow to each kidney

Follow clinically
Treat risk factors

Unilateral renal artery
stenosis and asymmetric
perfusion present

Unilateral renal artery
stenosis and symmetric
perfusion present

Follow clinically
Treat risk factors
Consider revascularization

Orange  test

Blue  all other

Bilateral renal artery
stenosis present

Green  treatment options


Frank H. Netter, MD

Frank H. Netter was born in 1906 in New York City. He studied
art at the Art Student’s League and the National Academy of Design
before entering medical school at New York University, where he
received his medical degree in 1931. During his student years, Dr.
Netter’s notebook sketches attracted the attention of the medical
faculty and other physicians, allowing him to augment his income
by illustrating articles and textbooks. He continued illustrating as
a sideline after establishing a surgical practice in 1933, but he ultimately opted to give up his practice in favor of a full-time commitment to art. After service in the United States Army during
World War II, Dr. Netter began his long collaboration with the
CIBA Pharmaceutical Company (now Novartis Pharmaceuticals).
This 45-year partnership resulted in the production of the extraordinary collection of medical art so familiar to physicians and other
medical professionals worldwide.
In 2005, Elsevier, Inc., purchased the Netter Collection and all
publications from Icon Learning Systems. There are now more
than 50 publications featuring the art of Dr. Netter available through
Elsevier, Inc. (
Dr. Netter’s works are among the finest examples of the use of
illustration in the teaching of medical concepts. The 13-book Netter
Collection of Medical Illustrations, which includes the greater part of
the more than 20,000 paintings created by Dr. Netter, became and
remains one of the most famous medical works ever published. The
Netter Atlas of Human Anatomy, first published in 1989, presents
the anatomic paintings from the Netter Collection. Now translated
into 16 languages, it is the anatomy atlas of choice among medical
and health professions students the world over.
The Netter illustrations are appreciated not only for their aesthetic qualities, but also, more important, for their intellectual
content. As Dr. Netter wrote in 1949, “. . . clarification of a subject
is the aim and goal of illustration. No matter how beautifully painted,
how delicately and subtly rendered a subject may be, it is of little
value as a medical illustration if it does not serve to make clear some
medical point.” Dr. Netter’s planning, conception, point of view,
and approach are what inform his paintings and what makes them
so intellectually valuable.
Frank H. Netter, MD, physician and artist, died in 1991.
Learn more about the physician-artist whose work has inspired
the Netter Reference collection at


Carlos A. G. Machado, MD

Carlos Machado was chosen by Novartis to be Dr. Netter’s successor. He continues to be the main artist who contributes to the
Netter collection of medical illustrations.
Self-taught in medical illustration, cardiologist Carlos Machado
has contributed meticulous updates to some of Dr. Netter’s original
plates and has created many paintings of his own in the style of
Netter as an extension of the Netter collection. Dr. Machado’s
photorealistic expertise and his keen insight into the physician/
patient relationship inform his vivid and unforgettable visual style.
His dedication to researching each topic and subject he paints places
him among the premier medical illustrators at work today.
Learn more about his background and see more of his art at

This third edition of Netter’s Cardiology benefited enormously from
the hard work and talent of many dedicated individuals.
First, we thank the contributing authors. All are current or former
faculty members at the University of North Carolina School of
Medicine, Chapel Hill, or have close ties to the institution. Without
their intellect, dedication, and drive for excellence, Netter’s Cardiology, third edition, could not have been published. We had a solid
foundation on which to build the third edition, thanks to the hard
work of the contributing authors of the second edition, many of
whom we were fortunate to have continue on to this edition. We
are also grateful for the invaluable editorial contribution that Dr.
E. Magnus Ohman made to the first edition.
Special recognition goes to John A. Craig, MD, and Carlos A.
G. Machado, MD. They are uniquely talented physician-artists
who, through their work, brought to life important concepts in
medicine in the new and updated figures included in this text.
Marybeth Thiel at Elsevier was invaluable in bringing the third
edition to fruition.
We would especially like to acknowledge our families: our wives—
Susan Runge, Meg Stouffer, Emma Rossi, and Kristine Patterson—
whose constant support, encouragement, and understanding made
completion of this text possible; our children—Thomas, Elizabeth,
William, John, and Mason Runge; Mark, Jeanie, Joy, and Anna
Stouffer; Paul, Samuel, and James Rossi; and Celia, Anna Alyse,
and Graham Patterson—who inspire us and remind us that there
is life beyond the computer; and, finally, our parents—whose persistence, commitment, and work ethic got us started on this road
many, many years ago.


Cam Patterson, MD, MBA
University of Arkansas for Medical Sciences
Little Rock, Arkansas
Joseph S. Rossi, MD
Associate Professor of Medicine
Director, Cardiac Catheterization Laboratory
University of North Carolina at Chapel Hill
Chapel Hill, North Carolina
Marschall S. Runge, MD, PhD
Professor of Internal Medicine
Dean, University of Michigan Medical School
Executive Vice President for Medical Affairs
Chief Executive Officer, Michigan Medicine
Ann Arbor, Michigan
George A. Stouffer, MD
Ernest and Hazel Craige Distinguished Professor of Medicine
Chief, Division of Cardiology
Physician in Chief, UNC Heart and Vascular Service Line
University of North Carolina at Chapel Hill
Chapel Hill, North Carolina
Basil Abu-el-Haija, MD
Clinical Cardiac Electrophysiology
Staff Physician, Kaweah Delta Hospital
Visalia, California
Tiffanie Aiken, BS
MD Candidate 2019
University of South Carolina School of Medicine Greenville
Greenville, South Carolina
Sameer Arora, MD
Cardiovascular Disease Fellow
University of North Carolina at Chapel Hill
Chapel Hill, North Carolina
Matthew S. Baker, MD
Assistant Professor of Medicine
Division of Cardiology
University of North Carolina School of Medicine
Chapel Hill, North Carolina
Charles Baggett, MD
The Harbin Clinic
Rome, Georgia
Thomas M. Bashore, MD
Professor of Medicine
Senior Vice Chief, Division of Cardiology
Duke University Medical Center
Durham, North Carolina


Sharon Ben-Or, MD
Assistant Professor
Department of Surgery
University of South Carolina at Greenville
Greenville, South Carolina
Hannah Bensimhon, MD
Cardiology Fellow
Department of Medicine
University of North Carolina at Chapel Hill
School of Medicine
Chapel Hill, North Carolina
Christoph Bode, MD, PhD
Chairman of Internal Medicine
Medical Director, Department of Cardiology and Angiology
Albert-Ludwigs-Universität Freiburg
Freiburg, Germany
Michael Bode, MD
Cardiovascular Disease Fellow
Department of Medicine
Division of Cardiology
University of North Carolina at Chapel Hill
Chapel Hill, North Carolina
Weeranun D. Bode, MD
Assistant Professor
Department of Medicine
Division of Cardiology
University of North Carolina at Chapel Hill
Chapel Hill, North Carolina
Mark E. Boulware, MD
Interventional Cardiologist
University of Colorado Health Heart and Vascular Center
Colorado Springs, Colorado
Michael E. Bowdish, MD
Director, Mechanical Circulatory Support
Assistant Professor of Surgery
Keck School of Medicine of University of Southern California
Los Angeles, California
Timothy Brand, MD
Cardiothoraic Surgery Resident
University of North Carolina Hospitals
Chapel Hill, North Carolina
Bruce R. Brodie, MD, FACC
Past President, LeBauer Cardiovascular Research Foundation
Cone Health Heart and Vascular Center
Greensboro, North Carolina
Adam W. Caldwell, MD
Cardiovascular Disease Fellow
Division of Cardiology
University of North Carolina School of Medicine
Chapel Hill, North Carolina
Eric P. Cantey, MD
Department of Medicine
Feinberg School of Medicine at Northwestern University
Chicago, Illinois


Thomas G. Caranasos, MD
Assistant Professor
Department of Surgery
University of North Carolina at Chapel Hill
Chapel Hill, North Carolina

Frank L. Conlon, PhD
Departments of Biology and Genetics
University of North Carolina at Chapel Hill
Chapel Hill, North Carolina

Wayne E. Cascio, MD
Environmental Public Health Division
National Health and Environmental Effects Research Laboratory
Office of Research and Development
U.S. Environmental Protection Agency
Chapel Hill, North Carolina

Jason Crowner, MD
Assistant Professor of Surgery
Division of Vascular Surgery
University of North Carolina School of Medicine
Chapel Hill, North Carolina

Matthew A. Cavender, MD, MPH
Assistant Professor of Medicine
Department of Medicine
Division of Cardiology
University of North Carolina at Chapel Hill
Chapel Hill, North Carolina
Patricia P. Chang, MD, MHS
Associate Professor of Medicine
Director of Heart Failure and Transplant Program
Division of Cardiology
University of North Carolina at Chapel Hill
Chapel Hill, North Carolina
Christopher Chien, MD FACC
Clinical Assistant Professor
Division of Cardiology
University of North Carolina
Chapel Hill, North Carolina
Medical Director, Heart Failure Clinic
UNC-Rex Hospital
Raleigh, North Carolina
Christopher D. Chiles, MD
Clinical Assistant Professor of Medicine
Texas A&M Health Science Center
Program Director, Cardiovascular Disease Fellowship
Baylor Scott & White Health/Texas A&M
Temple, Texas
Eugene H. Chung, MD
Associate Professor
Cardiac Electrophysiology Service
Department of Internal Medicine
Michigan Medicine
University of Michigan
Ann Arbor, Michigan
David R. Clemmons, MD
Kenan Professor of Medicine
Division of Internal Medicine
University of North Carolina School of Medicine
Chapel Hill, North Carolina
Romulo E. Colindres, MD, MSPH, FACP
Clinical Professor of Medicine
Division of Nephrology and Hypertension
Department of Medicine
University of North Carolina at Chapel Hill
Chapel Hill, North Carolina

Xuming Dai, MD, PhD
Assistant Professor of Medicine
Division of Cardiology
University of North Carolina at Chapel Hill
Chapel Hill, North Carolina
Arjun Deb, MD
Associate Professor
Department of Medicine (Cardiology) and Molecular, Cell, and
Developmental Biology
Broad Stem Cell Research Center
University of California, Los Angeles
Los Angeles, California
Cody S. Deen, MD
Assistant Professor of Medicine
Division of Internal Medicine/Cardiology
University of North Carolina at Chapel Hill
Chapel Hill, North Carolina
Gregory J. Dehmer, MD, MACC, MSCAI
Vice President, Medical Director Cardiovascular Services
Baylor Scott & White Health
Central Texas Division
Temple, Texas
Professor of Medicine
Department of Internal Medicine
Division of Cardiology
Texas A&M College of Medicine
Bryan, Texas
John S. Douglas, Jr., MD
Professor of Medicine
Director of Interventional Cardiology Fellowship Program
Emory University School of Medicine
Atlanta, Georgia
Allison G. Dupont, MD
Interventional Cardiologist
The Heart Center of Northeast George Medical Center
Gainesville, Georgia
Fredy H. El Sakr, MD
Fellow in Cardiovascular Medicine
University of Michigan Hospital
Ann Arbor, Michigan
Joseph J. Eron, MD
Professor of Medicine
Director, Clinical Core
University of North Carolina Center for AIDS Research
Division of Infectious Disease
University of North Carolina School of Medicine
Chapel Hill, North Carolina




Mark A. Farber, MD, FACS
Professor of Radiology and Surgery
Division of Vascular Surgery
Director, Aortic Center
University of North Carolina School of Medicine
Chapel Hill, North Carolina

Anna Griffith, MD
Clinical Fellow
Division of Hematology and Oncology
Department of Internal Medicine
University of North Carolina Hospitals
Chapel Hill, North Carolina

Sunita Juliana Ferns, MD, MRCPCH(UK), FHRS
Assistant Professor of Pediatrics
Director, Pediatric Invasive Electrophysiology
University of North Carolina at Chapel Hill
Chapel Hill, North Carolina

Thomas R. Griggs, MD
Professor Emeritus
Medicine, Pathology, and Laboratory Medicine
University of North Carolina School of Medicine
Chapel Hill, North Carolina

Michelle A. Floris-Moore, MD, MS
Associate Professor
Department of Medicine
Division of Infectious Diseases
University of North Carolina School of Medicine
Chapel Hill, North Carolina

Benjamin Haithcock, MD
Associate Professor of Surgery and Anesthesiology
University of North Carolina Hospitals
Chapel Hill, North Carolina

H. James Ford, MD
University of North Carolina
Division of Pulmonary and Critical Care
Chapel Hill, North Carolina
Elizabeth Boger Foreman, MD, FAASM
Sleep Medicine Specialist
Sentara Martha Jefferson Medical and Surgical Associates
Charlottesville, Virginia

Eileen M. Handberg, PhD
Professor of Medicine
Department of Medicine
University of Florida
Gainesville, Florida
Alan L. Hinderliter, MD
Associate Professor of Medicine
Division of Cardiology
University of North Carolina at Chapel Hill
Chapel Hill, North Carolina

Elman G. Frantz, MD
Professor of Pediatrics
Division of Cardiology
University of North Carolina School of Medicine
Director, Pediatric Cardiac Catheterization Laboratory
North Carolina Children’s Hospital
Co-Director, Adult Congenital Heart Disease Program
University of North Carolina Heart and Vascular Center
Chapel Hill, North Carolina

Lucius Howell, MD
Asheville Cardiology Associates/Mission Health
Asheville, North Carolina

Anil K. Gehi, MD
Associate Professor of Medicine
Director, Clinical Cardiac Electrophysiology Service
Division of Cardiology
University of North Carolina School of Medicine
Chapel Hill, North Carolina

Thomas S. Ivester, MD, MPH
Professor of Maternal Fetal Medicine
Department of Obstetrics and Gynecology
University of North Carolina School of Medicine
Chief Medical Officer and Vice President for Medical Affairs
UNC Health Care
Chapel Hill, North Carolina

Leonard S. Gettes, MD
Professor Emeritus
Department of Medicine
Division of Cardiology
University of North Carolina at Chapel Hill
Chapel Hill, North Carolina
Olivia N. Gilbert, MD
Advanced Heart Failure and Transplant Cardiologist
Novant Health Forsyth Heart and Wellness
Winston-Salem, North Carolina
Allie E. Goins, MD
Department of Medicine
Emory University
Atlanta, Georgia

James P. Hummel, MD
Visiting Associate Professor of Medicine
Division of Cardiovascular Medicine
University of Wisconsin School of Medicine and Public Health
Madison, Wisconsin

Brian C. Jensen, MD
Associate Professor of Medicine and Pharmacology
Department of Medicine
Division of Cardiology
University of North Carolina School of Medicine
UNC McAllister Heart Institute
Chapel Hill, North Carolina
Beth L. Jonas, MD
Reeves Foundation Distinguished Professor of Medicine
Division of Rheumatology, Allergy, and Immunology
University of North Carolina at Chapel Hill
Chapel Hill, North Carolina


Golsa Joodi, MD, MPH
Post-Doctoral Research Fellow
Department of Medicine
Division of Cardiology
University of North Carolina at Chapel Hill
Chapel Hill, North Carolina

Phil Mendys, PharmD
Co-Director, Lipid and Prevention Clinic
Department of Medicine
Division of Cardiology
University of North Carolina Healthcare
Chapel Hill, North Carolina

Jason N. Katz, MD, MHS
Associate Professor of Medicine
Department of Internal Medicine
University of North Carolina
Chapel Hill, North Carolina

Venu Menon, MD, FACC, FAHA
Director, Cardiac Intensive Care Unit
Director, Cardiovascular Fellowship
Associate Director, C5 Research
Professor of Medicine
Cleveland Clinic Lerner College of Medicine
Case Western Reserve University
Cleveland, Ohio

Audrey Khoury, BS, AB
Medical Student
University of North Carolina School of Medicine
Chapel Hill, North Carolina
J. Larry Klein, MD
Professor of Medicine and Radiology
Department of Cardiology and Radiology
University of North Carolina at Chapel Hill
Chapel Hill, North Carolina
Martyn Knowles, MD, FACS
Adjunct Assistant Professor of Surgery
Division of Vascular Surgery
University of North Carolina at Chapel Hill
Chapel Hill, North Carolina
David W. Lee, MD
Chief Cardiology Fellow
Division of Cardiology
University of North Carolina School of Medicine
Chapel Hill, North Carolina
Daniel J. Lenihan, MD, FACC
Professor of Medicine
Director, Cardio-Oncology Center of Excellence
Advanced Heart Failure
Clinical Research
Cardiovascular Division
Washington University
St. Louis, Missouri
Fong T. Leong, MBChB, PhD, FRCP, FHRS
Consultant, Cardiac Electrophysiologist
University Hospital of Wales
Cardiff, United Kingdom
Gentian Lluri, MD, PhD
Assistant Professor
Department of Medicine
Division of Cardiology
University of California, Los Angeles
Los Angeles, California
Robert Mendes, MD, FACS
Adjunct Assistant Professor
Division of Vascular of Surgery
University of North Carolina School of Medicine
Chapel Hill, North Carolina

Michael R. Mill, MD
Professor of Surgery and Pediatrics
University of North Carolina at Chapel Hill
Chapel Hill, North Carolina
Paula Miller, MD
Clinical Associate Professor of Medicine and Cardiology
Department of Medicine
Division of Cardiology
University of North Carolina School of Medicine
Chapel Hill, North Carolina
Timothy A. Mixon, MD, FACC, FSCAI
Interventional Cardiologist
Baylor Scott & White Health
Temple, Texas
Associate Professor of Medicine
Department of Internal Medicine
Division of Cardiology
Texas A&M College of Medicine
Bryan, Texas
J. Paul Mounsey, PhD, BSc, BM, BCh
Chief of Electrophysiology, East Carolina Heart Institute
Professor of Medicine
Brody School of Medicine
East Carolina University
Greenville, North Carolina
E. Magnus Ohman, MD, FRCPI
Professor of Medicine
Associate Director, Duke Heart Center—Cardiology Clinics
Director, Program for Advanced Coronary Disease
Duke Clinical Research Institute
Duke University Medical Center
Durham, North Carolina
Rikin Patel, DO
Cardiovascular Disease Fellow
Baylor Scott & White Health/Texas A&M
Temple, Texas
Kristine B. Patterson, MD
Associate Professor of Medicine
Division of Infectious Disease
Columbia University Medical Center
New York, New York




Eric D. Pauley, MD
Cardiovascular Disease Fellow
University of North Carolina Hospitals
Chapel Hill, North Carolina
Pamela S. Ro, MD
Associate Professor
Department of Pediatrics
University of North Carolina at Chapel Hill
Chapel Hill, North Carolina
Rachel D. Romero, MD
Division of Rheumatology, Allergy, and Immunology
University of North Carolina at Chapel Hill
Chapel Hill, North Carolina
Lisa J. Rose-Jones, MD
Assistant Professor of Medicine
Division of Cardiology
University of North Carolina at Chapel Hill
UNC Center for Heart and Vascular Care
Chapel Hill, North Carolina
Richard S. Schofield, MD
Professor of Medicine
Division of Cardiovascular Medicine
University of Florida College of Medicine
Department of Veterans Affairs Medical Center
Gainesville, Florida
Kristen A. Sell-Dottin, MD
Assistant Professor
University of Louisville
Louisville, Kentucky
Jay D. Sengupta, MD
Clinical Cardiac Electrophysiologist
Minneapolis Heart Institute at Abbott Northwestern Hospital
Minneapolis, Minnesota
Faiq Shaikh, MD
Molecular Imaging Physician Consultant
Cellsight Technologies, Inc.
San Francisco, California
Arif Sheikh, MD
Associate Professor
Department of Radiology
Columbia University
New York, New York
David S. Sheps, MD, MSPH
Department of Epidemiology
University of Florida
Gainesville, Florida
Brett C. Sheridan, MD
San Francisco Cardiology
San Francisco, California
Ross J. Simpson, Jr., MD, PhD
Director of the Lipid and Prevention Clinic at University of
North Carolina
Professor of Medicine and Adjuvant Professor of Epidemiology
University of North Carolina at Chapel Hill
Chapel Hill, North Carolina

Christopher E. Slagle, PhD
Postdoctoral Fellow
Departments of Biology and Genetics
University of North Carolina at Chapel Hill
Chapel Hill, North Carolina
Sidney C. Smith, Jr., MD, FAHA, FESC, FACP, MACC
Professor of Medicine
Department of Medicine/Division of Cardiology
University of North Carolina at Chapel Hill
Chapel Hill, North Carolina
Mark A. Socinski, MD
Professor of Medicine
Division of Hematology and Oncology
Multidisciplinary Thoracic Oncology Program
Lineberger Comprehensive Cancer Center
University of North Carolina School of Medicine
Chapel Hill, North Carolina
Robert D. Stewart, MD, MPH
Staff, Pediatric and Congenital Heart Surgery
Heart and Vascular Institute
Cleveland Clinic
Cleveland, Ohio
Thomas D. Stuckey, MD, FACC
Medical Director, LeBauer Cardiovascular Research and
Cone Health Heart and Vascular Center
Greensboro, North Carolina
Carla A. Sueta, MD, PhD
Professor of Medicine Emerita
Division of Cardiology
University of North Carolina School of Medicine
Chapel Hill, North Carolina
Khola S. Tahir, MD
Cardiovascular Disease Fellow
University of North Carolina at Chapel Hill
Chapel Hill, North Carolina
Walter A. Tan, MD, MS
Associate Professor of Medicine
Director, Cardiac Catheterization Laboratories
Wake Forest—Baptist Health
Winston-Salem, North Carolina
David A. Tate, MD
Associate Professor of Medicine Emeritus
Division of Cardiology
University of North Carolina School of Medicine
Chapel Hill, North Carolina
Rebecca E. Traub, MD
Assistant Professor
Department of Neurology
University of North Carolina at Chapel Hill
Chapel Hill, North Carolina
Bradley V. Vaughn, MD
Professor of Neurology
University of North Carolina School of Medicine
Chapel Hill, North Carolina


John P. Vavalle, MD, MHS, FACC
Assistant Professor of Medicine
Director of Structural Heart Disease
University of North Carolina at Chapel Hill
Chapel Hill, North Carolina
Anirudh Vinnakota, MS
Case Western Reserve University School of Medicine
Department of Thoracic and Cardiovascular Surgery
Cleveland, Ohio
Raven A. Voora, MD
Assistant Professor of Medicine
Division of Nephrology
University of North Carolina at Chapel Hill
Chapel Hill, North Carolina
Thelsa Thomas Weickert, MD
Assistant Professor
Department of Medicine
Division of Cardiology
University of North Carolina at Chapel Hill
Chapel Hill, North Carolina
Andy Wessels, PhD
Professor and Vice-Chair, Department of Regenerative Medicine
and Cell Biology
Co-Director, Cardiovascular Developmental Biology Center
Medical University of South Carolina
Charleston, South Carolina
John T. Wilkins, MD, MS
Assistant Professor of Medicine (Cardiology) and Preventive
Northwestern University Feinberg School of Medicine
Chicago, Illinois


Park W. Willis IV, MD
Sarah Graham Kenan Distinguished Professor of Medicine and
Pediatrics Emeritus
Director, Cardiac Ultrasound Laboratories
Division of Cardiology
University of North Carolina School of Medicine
Chapel Hill, North Carolina
Eric H. Yang, MD, MBA
Director of Interventional Cardiology and Cardiac
Catheterization Laboratories
Department of Cardiovascular Disease
Mayo Clinic Arizona
Phoenix, Arizona
Michael Yeung, MD
Assistant Professor of Medicine
University of North Carolina School of Medicine
Chapel Hill, North Carolina
Andrew O. Zurick III, MD, MSEd, FACC, FASE
Director of Advanced Cardiovascular Imaging
Cardiovascular Medicine
St. Thomas Heart
Nashville, Tennessee
Affiliated Assistant Professor
Division of Internal Medicine in the Department of Clinical
Medical Education
University of Tennessee Health Science Center, College of
Knoxville, Tennessee

Visit for the following:

Chapter 52 Catheter-Based Therapies for Adult Congenital
Heart Disease
Video 52-1 Bedside echo-guided balloon atrial septostomy
Video 52-2 Free pulmonary regurgitation after tetralogy of Fallot repair, stepwise
Melody valve implantation after prestenting, and competent Melody valve
Video 52-3 Stepwise transcatheter closure of a patent ductus arteriosus with the
Amplatzer Duct Occluder
Video 52-4 Stepwise transcatheter closure of a secundum atrial septal defect with
the Amplatzer Septal Occluder
Video 52-5 Stepwise transcatheter closure of a patent foramen ovale with an
Amplatzer Occluder



Basic Anatomy and Embryology of the Heart
Frank L. Conlon, Christopher E. Slagle, Andy Wessels

Heart development begins as the primary germ layers—ectoderm, mesoderm, and endoderm—are induced and progressively changed to various
cell types during the morphogenetic process of gastrulation. Combinatorial networks of intercellular signaling events cooperate with massive
tissue migrations and internalizations to lay out the basic body plan of
the vertebrate embryo. Mesoderm-derived cardiac precursors are among
the first cell populations to internalize, coalescing into 2 bilateral populations toward the anterior end of the embryo between 13 and 15 days of
human development. The identity of these progenitor pools as cardiac
precursors is defined and maintained by expression of a core cohort of
developmental gene regulators or transcription factors. These cardiac
transcription factors function cooperatively and hierarchically to induce
expression of appropriate structural proteins, including components of
the specialized cardiomyocyte contractile apparatus and ion channels.
Many cardiac transcription factors function not only in the initial specification of cardiac precursors, but also in later aspects of heart morphogenesis, such as establishing chamber identity, chamber-vessel alignment,
and conduction system development. Therefore proper spatial and
temporal functions of cardiac transcription factors dictate development
of a healthy and functional heart. This requirement of correct genetic
regulation is exemplified by the numerous congenital heart defects associated with or caused by mutations in cardiac transcription factors.
Even at such early stages of embryonic development, the cardiac
precursor pools have been subdivided into two distinct sources of progenitors according to expression of different subsets of cardiac transcription factors. The first, designated as the first heart field, will form
the primitive linear heart tube, which will give rise to the left ventricle
and most of the atrial tissues. The second heart field, incorporated into
the primitive embryonic heart at various stages of development, contributes to the right ventricle and outflow tract. The developing heart
receives further contributions from the cardiac neural crest and the
mesothelium. The cardiac neural crest is made of ectodermal cells arising
outside the heart fields at the lateral borders of the neural plate and
because of neural induction from the midline ectoderm. The cardiac
neural crest migrates to the heart-forming region, where it contributes
to septation of the outflow tract into the arterial and pulmonary vessels.
The mesothelium is the embryonic cell source that gives rise to the
epicardium, an epithelium that covers the surface of the heart and that
plays a role in a number of processes, such as the development of the
coronary system and the formation of the annulus fibrosis.

Even before gastrulation has completed, the internalized bilateral cardiac
precursor pools continue to migrate in response to signaling cues from
neighboring tissues. Remaining as cohesive epithelia, the heart fields


move anteriorly and ventrally between 15 and 20 days of development,
fusing at the embryonic midline to form the transient cardiac crescent
(Fig. 1.1). Proper midline fusion of the bilateral cardiac primordia is
essential for development of the heart. Several cardiac transcription
factors are required for this process, and loss of function of any one of
them causes extensive defects in further morphogenesis, including cardia
bifida in severe cases.
Newly united as the cardiac crescent, the multipotent cardiac progenitors coalesce further to form a linear tube by 3 weeks of development, segregating into the future endocardial lining and myocardial
walls (Fig. 1.2). The linear heart tube consists exclusively of differentiated
first heart field cells; the second heart field persists as a mesenchymal
population, which is a loose association of rapidly dividing precursor
cells adjacent to the heart tube. Although no specialized electrical conduction system has yet arisen, the myocardium of the linear heart tube
already exhibits autonomous contractions. Compared with those of a
mature heart, these contractions are slow and weak, driven only by the
intrinsic depolarizing activity and conductivity of the still-maturing
cardiomyocytes. Once the conduction system develops and connects
to the mature working myocardium, it will serve as an extrinsic regulator of the electrical impulses within the myocardium. Sufficient contractile force will, in turn, allow the heart to beat at the strength required
to circulate blood throughout the body.

As a consequence of its formation, differentiation, and rudimentary
functionality, the linear heart tube is mostly postmitotic. During the
fourth week of human gestation, growth and elongation of the linear
heart tube occur by means of contribution and division of second heart
field cells at both the sinus venosus and truncus arteriosus (posterior
and anterior poles, respectively). Concurrently, an embryo-wide genetic
program breaks the final axis of symmetry—the left-right axis. Asymmetrical intercellular signaling on the left side of the embryo governs
the migration and division of second heart field cells in the lengthening
heart tube, leading to two major morphological cardiac asymmetries.
First, the entire linear heart tube displaces to the right and rotates
90 degrees about its anterior-posterior axis, so that the original
ventral surface of the linear tube is now the left side of a C-shaped tube
(Fig. 1.3). Second, asymmetrical mitotic expansion of the second heart
field contributions leads to localized “ballooning” of the primitive atrial
and ventricular regions of the heart tube, transforming the C-shaped
tube into an S-shaped heart (Fig. 1.3).
Further gross morphogenetic movements of the embryo bring the
two poles in close apposition, anterior to the primitive chambers. This
repositioning prepares the inflow and outflow tracts for appropriate
connections to the developing vasculature, thereby contributing to
proper segregation of oxygenated and deoxygenated blood flow among
the heart, lungs, and body. By 30 days of gestation, the prospective atria

Approximately 20 days postconception

Ventral view

Sagittal view

Approximately 21 days postconception


Ventral view

Sagittal view

FIG 1.1 Formation of the heart<-tu?e.

Approximately 22 days postoonception


Ventral view

Sagittal view

Approximately 23 days postconception


~ - -1:--- -fu'-t- - Endocardi um - ---ll~a-i'+J-.


Ventral view

Sagittal view

FIG 1.2 Formation of the heart tube (continued).


SECTION I Introduction
Approximately 23 days postconception


Ventral view

Dorsal aorta
Sagittal view

Approximately 24 days postconception




Dorsal aorta


Ventral view

Sagittal view

FIG 1.3 Formation of the heart loop.

are repositioned anterior to the ventricular region, marking the first
resemblance of the embryonic heart to its future adult structure.
Formation of the S-looped heart overlaps with the beginnings of
ventricular and outflow tract septation and valve development as endocardial cushions emerge within the atrioventricular junction and the
outflow tract.

During the time of cardiac looping, at approximately 3 weeks of development, the arterial and venous poles of the heart decrease or cease
cell division. At the same time, cardiomyocytes at two distinct locations
within the intervening tissue reinitiate cell proliferation. This localized
expansion of cardiomyocytes gives rise anteriorly to the atria and posteriorly to the left ventricle, with the area separating the two regions
giving rise to the atrioventricular canal. Studies in chickens and mice
demonstrated that the atria grow not only through proliferation but
also by the recruitment of cells to the venous pole of the heart. The
left ventricle and the atria are largely derived from a common pool of
progenitors termed the first heart field (Fig. 1.4). In contrast, the second
heart field gives rise to the dorsal mesenchymal protrusion and primary
atrial septum, which are tissues that are critically important for atrioventricular septation, the outflow tract, and the right ventricle. A conserved role for the second heart field is supported by the observations
that abnormalities that affect the expansion of the second heart field
are associated with congenital heart disease in mouse models and humans,
including atrial and atrioventricular defects, as well as outflow tract

Contribution of cells from the second heart field to the heart is
complete by the fifth week of human development. At this stage, chamber
identity can be established by inspecting anatomic features and/or by
the expression of left or right ventricular chamber-specific genes. As
the cardiovascular system develops to support postnatal systemic and
pulmonary circulations, the heart goes through a series of complex
remodeling events. Critical steps in this process are the formation of
the septa between individual components of the heart, with the purpose
of separating the respective blood flows within the heart, and the formation of valves facilitating unidirectional flow among the respective
components. Together, these two events are commonly referred to as
valvuloseptal morphogenesis.

Atrial septation is initiated when the second heart field–derived dorsal
mesenchymal protrusion and the myocardial primary atrial septum
(or septum primum) extend ventrally into the, yet undivided, common
atrium. In the mouse, this process takes place between embryonic day
(ED) 9.5 to 10.5; in humans the process occurs around day 30. The
space between the leading edge of the atrial septum and the fusing
atrioventricular cushions in the atrioventricular canal is the primary
atrial foramen. As the primary atrial septum grows toward the mesenchymal atrioventricular cushions, thereby closing the primary interatrial
foramen, perforations appear in the upper part of the primary atrial
septum. These perforations will eventually coalesce and form the secondary interatrial foramen. As this part of atrial septation process nears
completion, the secondary atrial septum (or septum secundum) appears


Basic Anatomy and Embryology of the Heart


Heart tube derivatives

Heart tube primordia
Aortic arches (AA)

Truncus arteriosus (TA)
Bulbus cordis (BC)
Ventricle (V)
Atrium (A)

Sinus venosus (SV)

Ascending aorta
Pulmonary trunk

Aortic vestibule of left ventricle
Conus arteriosus of right ventricle

Trabecular walls of left and right ventricles

Adult heart, anterior view

Auricles/pectinate muscle walls of left
and right atria (smooth wall of left
atrium from pulmonary veins)

Coronary sinus
Smooth wall of right atrium

Adult heart, posterior view

FIG 1.4 Summary of heart tube derivatives.

in the space between the primary atrial septum and the left venous
valve in the roof of the right atrium. Eventually, the upper part of the
primary atrial septum will fuse with the secondary atrial septum, thereby
closing off the secondary atrial foramen and completing the atrial septation process. Failure of fusion of the two atrial septa will lead to the
congenital defect patent foramen ovale.
Compared with atrial septation, the creation of the ventricular septum
is a rather straightforward process. As the tubular heart expands, undergoes looping, and remodels, distinctive left and right ventricular
components appear. During this process, a myocardial ridge, the interventricular septum, emerges between the left and right ventricle. Subsequent outward expansion of the ventricles, a process sometimes referred
to as “ballooning,” in combination with upward growth of the interventricular septum and eventual fusion of crest of the septum with the
atrioventricular cushions, completes the process of ventricular septation.
Cell lineage tracing experiments in the mouse demonstrated that, like
the right ventricle, the interventricular septum is largely derived from
the second heart field.
The third septal structure that is required for separating the respective blood flows in the heart is found in the outflow tract. After completion of cardiac looping, a single outflow tract can be found connected
to the right ventricular component of the yet unseptated heart. Septation
of this outflow tract is required for the formation of an aorta, which
eventually connects to the left ventricle, and a pulmonary trunk that
comes from the right ventricle. Two sets of endocardial ridges are located
within the outflow tract, and as a result of their fusion, these will separate
the common outflow tract into an aorta and a pulmonary trunk. Failure
of fusion can lead to congenital defects, including a double outlet right

ventricle. The cardiac neural crest is also important in the septation
process that separates aorta and pulmonary trunk. Abnormal development of the cardiac neural crest specifically affects the formation of
the aorticopulmonary septum downstream of the semilunar valves (Fig.
1.5). This can result in the congenital defect common arterial trunk
(or truncus arteriosus) or in aorticopulmonary window.

The fully formed heart contains two sets of one-way valves. In the
atrioventricular junction, the atrioventricular valves facilitate unidirectional flow through the left and right atrioventricular orifices, whereas
at the ventriculoarterial junction, the semilunar valves serve the same
function at the junction of the left ventricle and the aorta, and at the
junction of the right ventricle and the pulmonary trunk.
Atrioventricular valve formation is initiated at the atrioventricular
junction of the looping heart (see previous description); two atrioventricular cushions appear as a result of local accumulation of extracellular
matrix between the atrioventricular endocardium and myocardium. A
process of endothelial-to-mesenchymal transformation leads to the
generation of a population of mesenchymal cells that colonize the cushions. As the heart grows, and these major atrioventricular cushions
become bigger, they eventually fuse, thereby separating the common
atrioventricular junction into the left and right atrioventricular orifices.
As this process takes place, on the lateral walls of these respective orifices,
two additional atrioventricular cushions form. These are known as the
left and right lateral atrioventricular cushions. These lateral cushions
also become populated with endocardially derived mesenchyme. Recent


SECTION I Introduction

Neural crest
neural folds
1st occipital
Level of

1st cervical

Neural tube
1st thoracic

Sulcus limitans


Embryo at 24 days
(dorsal view)
Neural crest

Embryo at 4 weeks
(transverse view)

Neural tube
(spinal cord)

FIG 1.5 Nervous tissue of embryo at 24 days and 4 weeks.

cell fate studies in mice showed that epicardially derived cells migrate
into these lateral cushions. Epicardially derived cells do not populate
the major cushions. Further remodeling of the cushion-derived tissues
eventually leads to the formation of the mitral valve leaflets in the left
atrioventricular orifice and the tricuspid valve leaflets in the right atrioventricular orifice.
In many respects, the development of the semilunar valves is similar
to that of the atrioventricular valves. It involves the fusion of two mesenchymal tissues, the parietal and septal endocardial ridges, which result
in the separation of the left and right ventricular outflows. The emergence of a set of smaller endocardial ridges, the intercalated ridges at
the opposite sides of the formed septum, resembles the process of formation of the lateral cushions in the atrioventricular junction. The
remodeling of these two sets of mesenchymal ridges will eventually
lead to the formation of the semilunar valves.

The neural crest is a transient population of cells that form from the
dorsal ectoderm at the time of neural tube closure (Fig. 1.5). The neural
crest population arises through a series of inductive interactions with
surrounding tissues around the fourth week of development. Once
formed, the cells undergo an epithelial-to-mesenchymal transition,
migrating ventrally and laterally to contribute to a wide array of tissue
types, including the epinephrine-producing cells of the adrenal gland,
the parasympathetic neurons, cartilage, bone, connective tissue, and
pigment cells. The neural crests themselves are multipotential at the

time of their formation; their ultimate fate is a reflection of their relative position along the anterior-to-posterior axis of the embryo. In the
cranial portions of the embryo, classic fate mapping studies showed
that a subpopulation of neural crest cells enter the arterial pole or the
venous pole of the heart to give rise to all of the parasympathetic
innervation of the heart, the smooth muscle layer of the great vessels,
and portions of the outflow tract. This population is termed the cardiac
neural crest. Ablation studies in chicks and genetic studies in mammals
demonstrated not only that the cardiac neural crest cells contribute to
these regions of the heart but also that they are also essential for the
proper formation of each of these structures.

The walls of the developed heart essentially consist of three cell layers:
the endocardium, the myocardium, and the epicardium. The endocardium and myocardium are generated early in development during the
formation of the primitive linear heart tube (see previous description).
However, the epicardium, a layer of epithelial cells covering the heart,
is like the cardiac neural crest, a late addition to the developing heart.
The source of the epicardium is the proepicardium, a local proliferation
of the mesothelium found in association with the sinus venosus at the
venous pole. In the mouse, the proepicardium can be seen around ED
9.5; in humans, this happens around day 30. Shortly after its generation,
the proepicardium attaches to the myocardial surface in the atrioventricular junction. From there, the cells spread out as an epicardial sheet
and eventually cover nearly the entire heart. Cell fate studies in animal


Basic Anatomy and Embryology of the Heart

models indicated that the epicardial-like cells covering the distal part
of the outflow tract are not derived from the proepicardium proper
but instead come from the pericardial mesothelium associated with the
aortic sac.
After formation of the epicardium, epithelial-to-mesenchymal transformation of a subpopulation of epicardial cells leads to the formation
of epicardially derived cells that migrate into the space between the
epicardium and the myocardium. This process is most pronounced at
the junction between the atria and ventricles, where it leads to the
formation of the atrioventricular sulcus. Furthermore, cell fate studies
in animal model systems demonstrated that epicardially derived cells
also migrate into the ventricular myocardial walls where they differentiate into interstitial fibroblasts and coronary smooth muscle cells. In
addition, these animal studies also revealed that epicardially derived
cells contribute significantly to the leaflets of the atrioventricular valves
that are derived from the lateral atrioventricular cushions.

Bruneau BG. Signaling and transcriptional networks in heart development
and regeneration. Cold Spring Harb Perspect Biol. 2013;5:a008292.


A comprehensive review of primary literature on the genetic and molecular underpinnings of cardiac morphogenesis.
De la Cruz M, Markwald RR, eds. Living Morphogenesis of the Heart.
An excellent detailed summary of the original studies in cardiac development.
Kirby ML. Cardiac Development. Oxford University Press; 2007.
An outstanding comprehensive text on vertebrate heart development.
Männer J. Cardiac looping in the chick embryo: a morphological review with
special reference to terminological and biomechanical aspects of the
looping process. Anat Record. 2000;259:248–262.
An in-depth review of primary literature documenting looping of the linear heart
tube, illustrated with electron micrographs of the morphological process in chicken
Rana MS, Christoffels VM, Moorman AFM. A molecular and genetic outline
of cardiac morphogenesis. Acta Physiol. 2013;207:588–615.
A synthesis of literature detailing contributions of various cardiac progenitor sources
to development of the mature vertebrate heart.

The History and Physical Examination
Marschall S. Runge, Fredy H. El Sakr, E. Magnus Ohman, George A. Stouffer

The ability to determine whether disease is present or absent—and
how that patient should be treated—is the ultimate goal for clinicians
who evaluate patients with suspected heart disease. Despite the number
of diagnostic tests available, the importance of a careful history and
physical examination has never been greater. Opportunities for errors
in judgment are abundant, and screening patients for coronary risk
using a broad and unfocused panel of laboratory and noninvasive tests
can lead to incorrect diagnoses and unnecessary testing. Selection of
the most appropriate test and therapeutic approach for each patient is
based on a skillfully performed history and physical examination. Furthermore, interpretation of any test results is based on the previous
probability of disease, which again is based on the history and physical.
Although entire texts have been written on cardiac history and physical
examination, this chapter specifically focuses on features of the cardiac
history and the cardiovascular physical examination that help discern
the presence or absence of heart disease.

The history and physical examination should allow the clinician to
establish the previous probability of heart disease, that is, the likelihood
that the symptoms reported by the patient result from heart disease. A
reasonable goal is to establish the risk of heart disease in a patient as
“low,” “intermediate,” or “high.” One demonstration of this principle
in clinical medicine is the assessment of patients with chest pain, in
which exercise stress testing to accurately diagnose coronary heart disease
(CHD) depends on the previous probability of disease. In patients with
a low risk of CHD based on clinical findings, exercise stress testing
results in a large number of false-positive test results. Because up to
15% of exercise stress tests produce positive results in individuals without
CHD, use of this test in a low-risk population can result in an adverse
ratio of false-positive to true-positive test results and unnecessary cardiac
catheterizations. Conversely, in patients with a high risk of CHD based
on clinical findings, exercise stress testing can result in false-negative
test results, which is an equally undesirable outcome, because patients
with significant coronary artery disease (CAD) and their physicians
may be falsely reassured that no further evaluation or treatment is
Emphasis is increasing on quantifying previous probability to an
even greater degree with various mathematical models. This is a useful
approach in teaching and may be clinically feasible in some diseases.
However, for most patients with suspected heart disease, categorizing
risk as low, intermediate, and high is appropriate, reproducible, and
feasible in a busy clinical practice. Therefore obtaining the history and
physical examination represents a key step before any testing, to minimize use of inappropriate diagnostic procedures.


A wealth of information is available to clinicians who carefully assess
the history of the patient. Key components are assessment of the chief
complaint; careful questioning for related, often subtle symptoms that
may further define the chief complaint; and determination of other
factors that help categorize the likelihood of disease. Major symptoms
of heart patients include chest discomfort, dyspnea, palpitations, and
syncope or presyncope.

Chest Discomfort
Determining whether chest discomfort results from a cardiac cause is
often a challenge. The most common cause of chest discomfort is myocardial ischemia, which produces angina pectoris. Many causes of angina
exist, and the differential diagnosis for chest discomfort is extensive
(Box 2.1). Angina that is reproducible and constant in frequency and
severity is often referred to as stable angina. For the purposes of this
chapter, stable angina is a condition that occurs when CAD is present,
and coronary blood flow cannot be increased to accommodate for
increased myocardial demand. However, as discussed in Chapters 12
through 14, there are many causes of myocardial ischemia, including
fixed coronary artery stenoses and endothelial dysfunction, which lead
to reduced vasodilatory capacity.
A description of chest discomfort can help establish whether the
pain is angina or of another origin. First, characterization of the quality
and location of the discomfort is essential (Fig. 2.1). Chest discomfort
because of myocardial ischemia may be described as pain, a tightness,
a heaviness, or simply an uncomfortable and difficult-to-describe feeling.
The discomfort can be localized to the mid-chest or epigastric area, or
may be characterized as pain in related areas, including the left arm,
both arms, the jaw, or the back. The radiation of chest discomfort to
any of these areas increases the likelihood of the discomfort being angina.
Second, the duration of discomfort is important because chest discomfort due to cardiac causes generally lasts minutes. Therefore pain of
short duration (“seconds” or “moments”), regardless of how typical it
may be of angina, is less likely to be of cardiac origin. Likewise, pain
that lasts for hours, on many occasions, in the absence of objective
evidence of myocardial infarction (MI), is not likely to be of coronary
origin. Third, the presence of accompanying symptoms should be considered. Chest discomfort may be accompanied by other symptoms
(including dyspnea, diaphoresis, or nausea), any of which increase the
likelihood that the pain is cardiac in origin. However, the presence of
accompanying symptoms is not needed to define the discomfort as
angina. Fourth, factors that precipitate or relieve the discomfort should
be evaluated. Angina typically occurs during physical exertion, during
emotional stress, or in other circumstances of increased myocardial


The History and Physical Examination



This chapter reviews the role of the physical examination in cardiovascular medicine, as well as typical findings in common cardiovascular

heart failure
heart sounds
hemodynamic maneuvers



The History and Physical Examination

BOX 2.1 Differential Diagnosis of
Chest Discomfort

BOX 2.2

• Hyperthyroidism
• Tachycardia (e.g., atrial fibrillation)
• Coronary spasm
• Coronary atherosclerosis (angina pectoris)
• Acute coronary syndrome
• Aortic stenosis
• Hypertrophic cardiomyopathy
• Aortic regurgitation
• Mitral regurgitation
• Severe systemic hypertension
• Severe right ventricular/pulmonary hypertension
• Severe anemia/hypoxia


• Aortic dissection
• Pericarditis
• Mitral valve prolapse syndrome: autonomic dysfunction
• Gastroesophageal reflux disease
• Esophageal spasm
• Esophageal rupture
• Hiatal hernia
• Cholecystitis
• Pulmonary embolus
• Pneumothorax
• Pneumonia
• Chronic obstructive pulmonary disease
• Pleurisy
• Thoracic outlet syndrome
• Degenerative joint disease of the cervical or thoracic spine
• Costochondritis
• Herpes zoster
• Anxiety
• Depression
• Cardiac psychosis
• Self-gain

oxygen demand. When exercise precipitates chest discomfort, relief after
cessation of exercise substantiates the diagnosis of angina. Sublingual
nitroglycerin also relieves angina, generally over a period of minutes.
Instant relief or relief after longer periods lessens the likelihood that
the chest discomfort was angina.
Although the presence of symptoms during exertion is important
in assessing CHD risk, individuals, especially sedentary ones, may have
angina-like symptoms that are not related to exertion. These include
postprandial and nocturnal angina, or angina that occurs while the
individual is at rest. As described herein, “rest-induced angina,” or the
new onset of angina, connotes a pathophysiology different from effortinduced angina. Angina can also occur in persons with fixed CAD and


Conditions That Cause Increased
Myocardial Oxygen Demand
Tachycardia of various etiologies
Pulmonary embolism
Central nervous system stimulants
Psychological stress

increased myocardial oxygen demand due to anemia, hyperthyroidism,
or similar conditions (Box 2.2). Angina occurring at rest, or with minimal
exertion, may denote a different pathophysiology, one that involves
platelet aggregation, which is clinically termed “unstable angina” or
“acute coronary syndrome” (see Chapters 20 and 21).
Patients with heart disease need not present with chest pain at all.
Anginal equivalents include dyspnea during exertion, abdominal discomfort, fatigue, or decreased exercise tolerance. Clinicians must be
alert to and specifically ask about these symptoms. Often, a patient’s
family member or spouse notices subtle changes in the endurance of
the patient or that the individual no longer performs functions that
require substantial physical effort. Sometimes, patients may be unable
to exert themselves due to comorbidities. For instance, the symptoms
of myocardial ischemia may be absent in patients with severe peripheral
vascular disease who have limiting claudication. One should also be
attuned to subtle or absent symptoms in individuals with diabetes mellitus (including type 1 and type 2 diabetes), which is a coronary risk
equivalent as defined by the Framingham Risk Calculator.
When the likelihood that CHD accounts for a patient presenting
with chest discomfort or any of the aforementioned variants is considered, assessment of the cardiac risk factor profile is important. The
Framingham Study first codified the concept of cardiac risk factors,
and over time, quantification of risk using these factors has become an
increasingly useful tool in clinical medicine. Cardiac risk factors determined by the Framingham Study include a history of cigarette smoking,
diabetes mellitus, hypertension, or hypercholesterolemia; a family history
of CHD (including MI, sudden cardiac death, and first-degree relatives
having undergone coronary revascularization); age; and sex (male).
Although an attempt has been made to rank these risk factors, all are
important, with a history of diabetes mellitus being perhaps the single
most important factor. Subsequently, a much longer list of potential
predictors of cardiac risk has been made (Box 2.3). Multiple risk calculators have since been created, such as the atherosclerotic cardiovascular
disease algorithm used by the American College of Cardiology, the
American Heart Association cholesterol guidelines, and the Multi-Ethnic
Study of Atherosclerosis (MESA), which uses classic risk factors with
the addition of a coronary artery calcium score to predict a 10-year
risk of CHD.
Symptoms suggestive of vascular disease require special attention.
Peripheral vascular disease may mask CHD because the individual may
not be able to exercise sufficiently to provoke angina. A history of stroke,
transient ischemic attack, or atheroembolism in any vascular distribution is usually evidence of significant vascular disease. Sexual dysfunction
in men is not an uncommon presentation of peripheral vascular disease.
The presence of Raynaud-type symptoms should also be elicited because
such symptoms suggest abnormal vascular tone and function, and
increase the risk that CHD is present.


SECTION I Introduction
Most commonly radiates to
left shoulder and/or ulnar
aspect of left arm and hand
May also radiate to neck,
jaw, teeth, back, abdomen,
or right arm
of pain

of myocardial

of breath


Crushing weight
and/or pressure



Weakness, collapse, coma

Chiefly retrosternal and intense

FIG 2.1 Pain of myocardial ischemia.

BOX 2.3

Cardiac Risk Factors


High cholesterol
Sedentary lifestyle
High-fat diet
Metabolic syndrome
Family history of CHD (including history of MI, sudden cardiac death, and
first-degree relatives who underwent coronary revascularization)
• Age
• Male sex
• Obesity
CHD, Coronary heart disease; MI, myocardial infarction.

Determining whether the patient has stable or unstable angina is
as important as making the diagnosis of angina. Stable angina is important to evaluate and treat but does not necessitate emergent intervention.
However, unstable angina or acute coronary syndrome carries a significant risk of MI or death in the immediate future. The types of
symptoms reported by patients with stable and unstable angina differ
little, and the risk factors for both are identical. The severity of symptoms is not necessarily greater in patients with unstable angina, just as
a lack of chest discomfort does not rule out significant CHD. The
important distinction between stable and unstable coronary syndromes
is whether the onset is new or recent, and/or progressive (e.g., occurring

more frequently or with less exertion). The initial presentation of angina
is, by definition, unstable angina, although for a high percentage of
individuals this may merely represent the first recognizable episode of
angina. For those with unstable angina, the risk of MI in the near future
is markedly increased. Likewise, when the patient experiences angina
in response to decreased levels of exertion or when exertional angina
has begun to occur at rest, these urgent circumstances require immediate therapy. The treatment of stable angina and acute coronary syndrome
is discussed in Chapters 19 to 21.
The Canadian Cardiovascular Society Functional Classification of
Angina Pectoris is a useful guide for everyday patient assessment
(Box 2.4). Categorizing patients according to their class of symptoms
is rapid and precise and can be used in follow-up. Class IV describes
the typical patient with acute coronary syndrome.
Finally, it is important to distinguish those patients who have noncoronary causes of chest discomfort from those with CHD. Patients
with gastroesophageal reflux disease (GERD) often present with symptoms that are impossible to distinguish from angina. In numerous studies,
GERD was the most common diagnosis in patients who underwent
diagnostic testing for angina and were found not to have CHD. The
characteristics of the pain can be identical. Because exercise can increase
intraabdominal pressure, GERD may be exacerbated with exercise,
especially after meals. Symptoms from GERD can also be relieved with
use of sublingual nitroglycerin. GERD can also result in early morning
awakening (as can unstable angina) but tends to awaken individuals 2
to 4 hours after going to sleep, rather than 1 to 2 hours before arising,
as is the case with unstable angina. Other causes (see Box 2.1) of anginalike pain can be benign or suggestive of other high-risk syndromes,
such as aortic dissection or pulmonary embolus. Many of these “coronary
mimics” can be ruled out by patient history, but others, such as valvular
aortic stenosis, can be confirmed or excluded by physical examination.

BOX 2.4 Canadian Cardiovascular Society
Classification of Angina Pectoris
Ordinary physical activity, for example, walking or climbing stairs, does
not cause angina; angina occurs with strenuous, rapid, or prolonged exertion at work or recreation.
IL Slight limitation of ordinary activity; for example, angina occurs when
walking or stair climbing after meals, in cold, in wind, under emotional
stress, or only during the few hours after awakening, when walking more
than two blocks on the level, or when climbing more than one flight of
ordinary stairs at a normal pace and during normal conditions.
Ill. Marked limitation of ordinary activity; for example, angina occurs when
walking one or two blocks on the level or when climbing one flight of stairs
during normal conditions and at a normal pace.
IV. Inability to carry on any physical activity without discomfort; angina syndrome may be present at rest

The History and Physical Examination
Left-Sided Cardiac Heart Failure

Cardiac auscultation for third heart sounds
(S3 ) and murmurs should be performed in
stand ard positions, including th at with the
patient sitting forward.
S1 Systolic


Chest auscultation reveals bilateral
rales and pleural effusions (when
CHF is chronic).

From Campeau L. Grading of angina pectoris [letter]. Circulation.

The goal of taking the history is to alert the clinician to entities that
can be confirmed or excluded by physical examination or that necessitate further diagnostic testing.
Cyanosis of lips
and nail beds
may be present
if the patient
is hypoxic.

Dyspnea, Edema, and Ascites
Dyspnea can accompany angina pectoris or it can be an angina! equivalent. Dyspnea can also reflect congestive heart failure (CHF) or occur
because of noncardiac causes. The key to understanding the etiology
of dyspnea is a clear patient history, which is then confirmed by a
targeted physical examination.
Dyspnea during exertion that quickly resolves at rest or with use of
nitroglycerin may be a result of myocardial ischemia. It is important
to establish the amount of activity necessary to provoke dyspnea, tfi
reproducibility of these symptoms, and the duration of reco erx. As
with angina, dyspnea, as an angina! equivalent or an acoom anying
symptom, tends to occur at a given workload or stress level; dyspnea
that occurs one day at low levels of exertion bu~
pro pted by
vigorous exertion on another day is less likely; to be an angina!
In patients with CHF, dyspnea generally eflects increased left ventricular (LV) filling pressures (Fig. 2.2). Altl\.ough V systolic dysfunction
is the most common cause of the dyspnea, dyspnea also occurs in
individuals with preserved LV systolic function and severe diastolic
dysfunction. However, these two entities present differently, and physical
examination can distinguish them. With LV systolic dysfunction, dyspnea
tends to gradually worsen, and its exacerbation is more variable than
that of exertional dyspnea resulting from myocardial ischemia, although
both are due to fluctuations in pulmonary arterial volume and left
atrial filling pressures. Typically, patients with LV systolic dysfunction
do not recover immediately after exercise cessation or use of sublingual
nitroglycerin, and the dyspnea may linger for longer periods. Orthopnea,
the occurrence of dyspnea when recumbent, or paroxysmal nocturnal
edema provides further support for a presumptive diagnosis of LV
systolic dysfunction. Patients with LV diastolic dysfunction tend to
present abruptly with severe dyspnea that resolves more rapidly in
response to diuretic therapy than does dyspnea caused by LV systolic
dysfunction. The New York Heart Association (NYHA) functional classification for CHF (Table 2. 1) is extremely useful in following patients
with CHF and provides a simple and rapid means for longitudinal
assessment. The NYHA functional classification also correlates well
with prognosis. Patients who are in NYHA functional class I have a low

Patients with left-sided
CHF may be uncomfortable
lying down.
FIG 2.2 Physical examination. CHF, Congestive heart failure.

risk of death or hospital admission witliin tlie following year. In contrast,
the annual mortality rate of those with NYHA functional class IV symptoms exceeds 30%.
As with chest discomfort, the differential diagnosis of dyspnea is
broad, encompassing many cardiac and noncardiac causes (Box 2.5).
Congenital heart disease, with or without pulmonary hypertension,
can cause exertional dyspnea. Patients with significant intracardiac or
extracardiac shunts and irreversible pulmonary hypertension (Eisenmenger syndrome) are dyspneic during minimal exertion and often at
rest. It is also possible to have dyspnea because of acquired valvular
heart disease, usually from aortic or mitral valve stenosis or regurgitation. All of these causes should be easily distinguished from CHD or
CHF by physical examination. Primary pulmonary causes of dyspnea
must be considered, with chronic obstructive pulmonary disease and
reactive airways disease (asthma) being the most common causes. Again,
a careful history for risk factors ( e.g., cigarette smoking, industrial
exposure, allergens) associated witli tliese entities and an accurate physical
examination should distinguish primary pulmonary causes from dyspnea
due to CHD or CHF.


SECTION I Introduction


Comparison of the ACC/AHA and the NYHA Classifications of Heart Failure


At high risk for HF but without structural
heart disease or symptoms of heart failure
Structural heart disease but without signs
or symptoms of heart failure
Structural heart disease with previous or
current symptoms of heart failure



I (mild)

No limitation of physical activity. Ordinary physical activity does not cause undue
fatigue, palpitation, or dyspnea.
No limitation of physical activity. Ordinary physical activity does not cause undue
fatigue, palpitation, or dyspnea.
Slight limitation of physical activity. Comfortable at rest, but ordinary physical
activity results in fatigue, palpitation, or dyspnea.
Marked limitation of physical activity. Comfortable at rest, but less than ordinary
activity causes fatigue, palpitation, or dyspnea.
Unable to carry out any physical activity without discomfort. Symptoms of cardiac
insufficiency at rest. If any physical activity is undertaken, discomfort is increased.

1 (mild)
2 (mild)
III (moderate)


Refractory heart failure requiring specialized

IV (severe)

ACC/AHA, American College of Cardiology/American Heart Association; HF, heart failure; NYHA, New York Heart Association.
NYHA data from the Criteria Committee of the New York Heart Association. Diseases of the Heart and Blood Vessels: Nomenclature and
Criteria for Diagnosis. Boston: Brown; 1964.
ACC/AHA data from Yancy CW, Jessup M, Bozkurt B, et al. 2013 ACCF/AHA guideline for the management of heart failure: a report
of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol.

BOX 2.5

Differential Diagnosis of Dyspnea

• Reactive airways disease (asthma)
• Chronic obstructive pulmonary disease
• Emphysema
• Pulmonary edema
• Pulmonary hypertension
• Lung transplant rejection
• Infection
• Interstitial lung disease
• Pleural disease
• Pulmonary embolism
• Respiratory muscle failure
• Exercise intolerance
• Ischemic heart disease/angina pectoris
• Right-sided heart failure
• Aortic stenosis or regurgitation
• Arrhythmias
• Dilated cardiomyopathy
• Hypertrophic cardiomyopathy
• Congestive heart failure
• Mitral regurgitation or stenosis
• Mediastinal abnormalities
• Pericardial tuberculosis
• Transposition of the great arteries
• Blood transfusion reaction
• Measles

Peripheral edema and ascites are physical examination findings
consistent with pulmonary hypertension and/or right ventricular (RV)
failure. These findings are included in the history because they may be
part of the presentation. Although patients often comment on peripheral
edema, with careful questioning, they may also identify increasing
abdominal girth consistent with ascites. Important questions on lower
extremity edema include determination of whether the edema is symmetrical (unilateral edema suggests alternate diagnoses) and whether
the edema improves or resolves with elevation of the lower extremities.
The finding of “no resolution overnight” argues against RV failure as
an etiology. In addition, for peripheral edema and ascites, it is important
to ask questions directed toward determining the presence of anemia,
hypoproteinemia, or other causes. The differential diagnosis of edema
is broad and beyond the scope of this chapter.

Palpitations and Syncope
It is normal to be aware of the sensation of the heart beating, particularly
during or immediately after exertion or emotional stress. Palpitations
refer to an increased awareness of the heart beating. Patients use many
different descriptions, including a “pounding or racing of the heart,”
the feeling that their heart is “jumping” or “thumping” in their chest,
the feeling that the heart “skips beats” or “races,” or countless other
descriptions. A history that shows that palpitations began to occur
during or immediately after exertion, and not at other times, raises the
concern that these sensations reflect ventricular ectopy associated with
myocardial ischemia. It is more difficult to assess the significance of
palpitations occurring at other times. Supraventricular and ventricular
ectopy may occur at any time and may be benign or morbid. As discussed in Chapters 41 and 42, ventricular ectopy is worrisome in patients
with a history of MI or cardiomyopathy. Lacking this information,
clinicians should be most concerned if lightheadedness or presyncope
accompanies palpitations.
Syncope generally indicates an increased risk for sudden cardiac
death and is usually a result of cardiovascular disease and arrhythmias.

BOX 2.6

Differential Diagnosis for Syncope

• Mechanical
Outflow tract obstruction
Pulmonary hypertension
Congenital heart disease
Myocardial disease: low-output states
• Electrical
• Neurocardiogenic
Vasovagal (vasodepression)
Orthostatic hypotension
• Peripheral neuropathy
Primary autonomic insufficiency
Intravascular volume depletion
Acute pain states
Carotid sinus hypersensitivity

If a syncopal episode is a presenting complaint, the patient should be
admitted for further assessment. In approximately 85% of patients, the
cause of syncope is cardiovascular. In patients with syncope, assessment
for CHD, cardiomyopathy, and congenital or valvular heart disease
should be performed. In addition, neurocardiogenic causes represent
a relatively common and important possible etiology for syncope.
Box 2.6 shows the differential diagnosis for syncope. It is critical to
determine whether syncope really occurred. A witness to the episode
and documentation of an intervening period are helpful. In addition,
with true syncope, injuries related to the sudden loss of consciousness
are common. However, individuals who report recurrent syncope
(witnessed or unwitnessed) but has never injured themselves may
not be experiencing syncope. This is not to lessen the concern that a
serious underlying medical condition exists but, instead, to reaffirm
that the symptoms fall short of syncope, with its need for immediate

There are several advantages to obtaining the history of the patient before
the physical examination. First, the information gained in the history
directs the clinician to pay special attention to aspects of the physical
examination. For instance, a history consistent with CHD necessitates
careful inspection for signs of vascular disease; a history suggestive of
CHF should make the clinician pay particular attention to the presence
of a third heart sound. Second, the history allows the clinician to establish
a rapport with patients and to assure patients that the clinician is interested in their well-being; clinicians are then allowed to perform a complete
physical examination, which is imperative in a complete evaluation. In
this light, the therapeutic value of the physical examination to the patient
should not be underestimated. Despite the emphasis on technology today,
even the most sophisticated patients expect to be examined, to have their
hearts listened to, and to be told whether worrisome findings exist or
whether the examination results were normal.

The History and Physical Examination


General Inspection and Vital Signs
Much useful information can be gained by an initial “head-to-toe”
inspection and assessment of vital signs. For instance, truncal obesity
may signal the presence of type 2 diabetes or metabolic syndrome.
Cyanosis of the lips and nail beds may indicate underlying cyanotic
heart disease. Hairless, dry-skinned lower extremities or distal ulceration
may indicate peripheral vascular disease. Other findings are more specific
(Fig. 2.3). Abnormalities of the digits are found in atrial septal defect;
typical findings of Down syndrome indicate an increased incidence of
ventricular septal defect or more complex congenital heart disease;
hyperextensible skin and lax joints are suggestive of Ehlers-Danlos syndrome; and tall individuals with arachnodactyly, lax joints, pectus
excavatum, and an increased arm length-to-height ratio may have Marfan
syndrome. These represent some of the more common morphological
phenotypes in individuals with heart disease. Vital signs can also be
helpful. Although normal vital signs do not rule out CHD, marked
hypertension may signal cardiac risk, whereas tachycardia, tachypnea,
and/or hypotension at rest suggest CHF.

Important Components of the
Cardiovascular Examination
The clinician should focus efforts on those sites that offer a window
into the heart and vasculature. Palpation and careful inspection of the
skin for secondary changes because of vascular disease or diabetes is
important. Lips, nail beds, and fingertips should be examined for cyanosis (including clubbing of the fingernails) and, when indicated, for
signs of embolism. Examination of the retina using an ophthalmoscope
can reveal evidence of long-standing hypertension, diabetes, or atheroembolism, denoting underlying vascular disease. Careful examination
of the chest, including auscultation, can help to differentiate causes of
dyspnea. The presence of dependent rales is consistent with left-sided
heart failure. Pleural effusions can result from long-standing LV dysfunction or noncardiac causes and can be present with predominantly
right-sided heart failure, representing transudation of ascites into the
pleural space. Hyperexpansion with or without wheezing suggests a
primary pulmonary cause of dyspnea, such as chronic obstructive pulmonary disease or reactive airways disease. The presence of wheezing
rather than rales does not rule out left-sided heart failure. It is not
uncommon to hear wheezing with left-sided CHF. Wheezing from leftsided CHF is most commonly primarily expiratory. Inspiratory and
expiratory wheezing, particularly with a prolonged inspiratory-toexpiratory ratio, is more likely to be caused by intrinsic lung disease.
The vascular examination is an important component of a complete
evaluation. The quality of the pulses, in particular, the carotid and the
femoral pulses, can identify underlying disease (Fig. 2.4). Diminished
or absent distal pulses indicate peripheral vascular disease. The examiner
should also auscultate for bruits over both carotids, over the femoral
arteries, and in the abdomen. Abdominal auscultation should be performed, carefully listening for aortic or renal bruits, in the mid-abdominal
area before abdominal palpation, which can stimulate increased bowel
sounds. Distinguishing bruits from transmitted murmurs in the carotid
and abdominal areas can be challenging. When this is a concern, carefully marching out from the heart using the stethoscope can be helpful.
If the intensity of the murmur or bruit continually diminishes farther
from the heart, it becomes more likely that this sound originates from
the heart, rather than from a stenosis in the peripheral vasculature.
Much information is available about the peripheral vascular examination, but by following the simple steps outlined herein, the examiner
can gather most of the accessible clinical information.
Examination of the jugular venous pulsations is a commonly forgotten step. Jugular venous pressure, which correlates with right atrial


SECTION I Introduction
Marfan syndrome

Ehlers-Danlos syndrome

Upper body segment

Hyperextensibility of
thumbs and fingers

of elbows

Lower body segment

Easy splitting of the
skin (so-called cigarette
paper scars) over
bony prominences,
hyperelastic auricles

of skin

Down syndrome
Typical facies seen in Down syndrome
Upward slanting
eyes contrasting
with ethnic group
Small mouth with
protruding tongue

Walker-Murdoch wrist sign.
Because of long fingers
and thin forearm, thumb
and little finger overlap
when patient grasps wrist.

Wide gap between the
first and second toes

“Simian“ crease
on the palm

FIG 2.3 Physical examination: general inspection.

pressure and RV diastolic pressure, should be estimated initially with
the patient lying with the upper trunk elevated 30 to 45 degrees. In this
position, at normal jugular venous pressure, no pulsations are visible.
This correlates roughly to a jugular venous pressure of <6 to 10 cm.
The absence of jugular vein pulsations with the patient in this position
can be confirmed by occluding venous return by placing a fingertip
parallel to the clavicle in the area of the sternocleidomastoid muscle.
The internal and external jugular veins should partially fill. Although
normal jugular venous pressure examination of the waveforms is less
important, the head of the examination table can be lowered until the
jugular venous pulsations are evident. When the jugular venous pulsations are visible at 30 degrees, the examiner should note the waveforms.
It is possible to observe and time the a and v waves by simultaneously
timing the cardiac apical impulse or the carotid impulse on the contralateral side. An exaggerated a wave is consistent with increased atrial
filling pressures because of tricuspid valve stenosis or increased RV
diastolic pressure. A large v wave generally indicates tricuspid valve
regurgitation, a finding easily confirmed by auscultation.
Finally, it is important to palpate the precordium before cardiac
auscultation. This is the easiest way to identify dextrocardia. Characteristics of the cardiac impulse can also yield important clues about
underlying disease. Palpation of the precordium is best performed from
the patient’s right side with the patient lying flat. The cardiac apical
impulse is normally located in the fifth intercostal space along the midclavicular line. Most examiners use the fingertips to palpate the apical
impulse. It is often possible to palpate motion corresponding to a third
or fourth heart sound. Use of the fingertips offers fine detail on the

size and character of the apical impulse. A diffuse and sustained apical
impulse is consistent with LV systolic dysfunction. In contrast, patients
with hypertrophic cardiomyopathy often have a hyperdynamic apical
impulse. Thrills, palpable vibrations from loud murmurs or bruits, can
also be palpated.
The RV impulse, if identifiable, is located along the left sternal border.
Many clinicians prefer to palpate the RV impulse with the base of the
hand, lifting the fingertips off the chest wall. In RV hypertrophy, a
sustained impulse can be palpated, and the fingertips then can be placed
at the LV impulse to confirm that the two are distinct. In patients with
a sustained RV impulse, the examiner should again look for prominent
a and v waves in the jugular venous pulsations.

Cardiac Auscultation
Hearing and accurately describing heart sounds is arguably the most
difficult part of the physical examination. For this reason and because
of the commonplace use of echocardiography, many clinicians perform
a cursory examination. The strongest arguments for performing cardiac
auscultation carefully are to determine whether further diagnostic testing
is necessary and to correlate findings of echocardiography with the
clinical examination so that in longitudinal follow-up, the clinician can
determine the progression of disease without repeating echocardiography
at each visit. In addition, as clinicians make more of these correlations,
their skills in auscultation will become better, and their patients will
be better served. With normal general cardiac physical examination
results, the absence of abnormal heart sounds, and a normal electrocardiogram, the use of echocardiography for evaluation of valvular or

Examples of carotid pulses and the
entities with which they are associated

S1 S2



The History and Physical Examination
Examples of venous pulses and the
entities with which they are associated





S1 S2
a c


Hypertrophic cardiomyopathy
(Bisferiens pulse)
S1 S2


S1SM S2 S1 SM S2


Aortic regurgitation
(Corrigan pulse)
S1 S2

v S3 v S3


Pulmonary hypertension
secondary to mitral stenosis


v h
x y

Tricuspid regurgitation

Jugular a




a S S
c v

Careful auscultation of the abdomen can reveal
bruits from vessels such as aorta and renal arteries.
Dilatation of the abdominal portion of
the aorta can be recognized by palpation.
Diminished or absent peripheral pulses
indicate peripheral vascular disease.

Cardiac apical impulse (palpation of the precordium)
S1 S2
S1 S2
S1 S2
Diffuse and
(left ventricular

FIG 2.4 Important components of cardiac examination.

congenital heart disease is not indicated. Furthermore, if there are no
symptoms of CHF or evidence of hemodynamic compromise, echocardiography is not indicated for assessment of LV function. Practice
guidelines from cardiologists and generalists agree on this point, as do
third-party insurers. It is neither appropriate nor feasible to replace a
careful cardiovascular examination using auscultation with more expensive testing.
The major impact of echocardiography has been in the quantitative
assessment of cardiovascular hemodynamics, that is, the severity of
valvular and congenital heart disease. It is no longer necessary for the
clinician to make an absolute judgment on whether an invasive assessment (cardiac catheterization) is needed to further define hemodynamic
status or whether the condition is too advanced to allow surgical intervention based on history and physical examination. Instead of diminishing the role of cardiac auscultation, the advent of echocardiography
has redefined it. Auscultation remains important as a screening technique
for significant hemodynamic abnormalities, as an independent technique
to focus and verify the echocardiographic study, and as an important
means by which the physician can longitudinally follow patients with
known disease.
There are several keys to excellence in auscultation. Foremost is the
ability to perform a complete general cardiac physical examination, as
described. The findings help the examiner focus on certain auscultatory
features. Second, it is important to use a high-quality stethoscope. Largely
dictated by individual preference, clinicians should select a stethoscope
that has both bell and diaphragm capacity (for optimal appreciation
of low-frequency and high-frequency sounds, respectively), fits the ears

comfortably, and is well insulated so that external sounds are minimized.
Third, it is important to perform auscultation in a quiet environment.
When skills in auscultation are developing, trying to hone these in the
hall of a busy emergency department or on rounds while others are
speaking is time poorly spent. In addition, taking the time to return to
see a patient with interesting findings detected during auscultation,
and repetition, are keys to becoming competent in auscultation.
The patient should