HANDBOOK of CARDIAC Anatomyp Physiologyp AND

HANDBOOK OF CARDIACANATOMYp PHYSIOLOGYpAND DEVICES HANDBOOK OF CARDIAC ANATOMY t PHYSIOLOGY t AND DEVICES

Edited by PAUL A. IAIZZO, PhD Department of Surgery University of Minnesota Minneapolis, MN

For additional copies, pricing for bulk purchases, and/or information about other Humana titles, contact Humana at the above address or at any of the following numbers: Tel: 973-256-1699; Fax: 973-256-8341; E-maih [email protected] or visit our website at http://humanapr.com

All rights reserved. No part of this book may be reproduced, stored in a retrieval system, or transmitted in any form or by any means, electronic, mechanical, photocopying, microfilming, recording, or otherwise without written permission from the Publisher.

All articles, comments, opinions, conclusions, or recommendations are those of the author(s), and do not necessarily reflect the views of the publisher.

Due diligence has been taken by the publishers, editors, and authors of this book to assure the accuracy of the information published and to describe generally accepted practices. The contributors herein have carefully checked to ensure that the drug selections and dosages set forth in this text are accurate and in accord with the standards accepted at the time of publication. Notwithstanding, as new research, changes in government regulations, and knowledge from clinical experience relating to drug therapy and drug reactions constantly occurs, the reader is advised to check the product information provided by the manufacturer of each drug for any change in dosages or for additional warnings and contraindications. This is of utmost importance when the recommended drug herein is a new or infrequently used drug. It is the responsibility of the treating physician to determine dosages and treatment strategies for individual patients. Further it is the responsibility of the health care provider to ascertain the Food and Drug Administration status of each drug or device used in their clinical practice. The publisher, editors, and authors are not responsible for errors or omissions or for any consequences from the application of the information presented in this book and make no warranty, express or implied, with respect to the contents in this publication.

This publication is printed on acid-free paper.@

ANSI Z39.48-1984 (American National Standards Institute) Permanence of Paper for Printed Library Materials.

Cover design by Patricia F. Cleary.

Cover illustrations: Images were created in the Visible Heart ® Laboratory of Professor Iaizzo. (Upper left) An external view of an isolated human heart reanimated in vitro. (The heart was obtained via LifeSource as a research gift from an organ donor whose heart was deemed not viable for transplantation.) (Upper right) An internal view of the apex of the left ventricle of a human heart; note the high degree of trabeculations. (Lower right) Serial endoscopic images showing movements, top-to-bottom, of a tricuspid valve, a pulmonary valve, a mitral valve, and an implanted mechanical aortic valve (left to right, respectively) from within functioning human hearts. (Lower left) Images obtained from an in vitro electrical mapping study of an isolated human heart: an EnSite ® 3000 catheter is deployed in the left ventricle and a mapping catheter touches the endocardium. To the right is shown an anatomical isopotential map of excitation (voltage changes) and below it two views of constructed isochronal maps (time sequences of depolarization, anterior and posterior views).

Photocopy Authorization Policy: Authorization to photocopy items for internal or personal use, or the internal or personal use of specific clients, is granted by Humana Press Inc., provided that the base fee of US $30.00 is paid directly to the Copyright Clearance Center at 222 Rosewood Drive, Danvers, MA 01923. For those organizations that have been granted a photocopy license from the CCC, a separate system of payment has been arranged and is acceptable to Humana Press Inc. The fee code for users of the Transactional Reporting Service is: [1-58829-443-9/05 $30.00].

Printed inChina. 10 9 8 7 6 5 4 3 2 1

E-ISBN 1-59259-835-8

Library of Congress Cataloging-in-Publication Data

Handbook of cardiac anatomy, physiology, and devices / edited by Paul A. Iaizzo. p. cm. -- (Current clinical oncology) Includes bibliographical references and index. ISBN 1-58829-443-9 (alk. paper) 1. Heart--Anatomy--Handbooks, manuals, etc. 2. Heart--Physiology--Handbooks, manuals, etc. 3. Heart--Diseases--Treatment--Handbooks, manuals, etc. I. Iaizzo, Paul A. II. Series: Current clinical oncology (Totowa, N.J.) QMI81.H36 2005 616.1'2--dc22 2004010861 PREFACE

The medical device industry in the US is growing at reference materials. In addition, many of the numerous Medtronic an incredibly rapid pace; in fact, today it is as large as employees who have visited the Visible Heart ® laboratory the automobile industry in terms of revenues. Not only has (over 500 individuals, with many repeat visits, in the past seven our overall understanding of the molecular basis of disease years) have routinely emphasized the need for advanced training dramatically increased, but so has the number of available opportunities in systems physiology, specifically for the seasoned devices to treat specific health problems. This is particularly biomedical employee. One last historical note of interest: my true in the field of cardiac care. Advances in our understanding current laboratory (Visible Heart® laboratory), where isolated heart of disease processes are being made daily, and novel means to studies are performed weekly, is the same laboratory where C. treat cardiac diseases are concomitantly being developed. With Walton Lillehei and his many esteemed colleagues conducted a this rapid growth rate, the biomedical engineer has been majority of their cardiovascular research studies in the late 1950s challenged to either retool or continue to seek out sources of and early 1960s. concise information. An added feature of this book that I hope will enhance its utility The major impetus for developing the Handbook of Cardiac is a CD containing the Visible Heart ®Viewer, which was developed Anatomy, Physiology, and Devices was the need for a major as a joint venture between my laboratory at the University of resource textbook for students, residents, and practicing Minnesota and the Cardiac Rhythm Management Division biomedical engineers. Another motivation was to promote the at Medtronic, Inc. An second Companion CD also contains various expertise, past and present, in the area of cardiovascular science additional color images and movies that were provided by the at the University of Minnesota. As Director of Education for authors to supplement their chapters. The Lillehei Heart Institute at the University of Minnesota, I Importantly, the accompanying media includes functional believe that this book also represents an outreach opportunity to images of human hearts. These images were obtained from hearts carry on the Lillehei legacy through the 21 st century. made available via LifeSource, and more specifically through the It may be of interest to note that there are several direct generosity of families and individuals who made the final gift and indirect historical connections with C. Walton Lillehei. of organ donation (their hearts were not deemed viable for First, several of the individuals who contributed chapters had transplantation). the privilege to work with him. Second, there is the connection with Medtronic, Inc.; founder Earl Bakken was one of the first Acknowledgments true biomedical engineers, and he worked directly with I would like to thank Medtronic, Inc. for their continued Lillehei to develop implantable pacemakers at the University of support of this collaborative project over the past seven years, Minnesota. In accordance with this latter collaboration, it turns and I especially acknowledge the commitment, partnership, out that there are numerous individuals currently working at and friendship of Tim Laske and Dale Wahlstrom, which has Medtronic Inc. who strongly encouraged the University of made our research possible. In addition, I would like to thank Minnesota to develop outreach materials such as the Handbook Jilean Dagenais and Mike Leners for their creative efforts in of Cardiac Anatomy, Physiology, and Devices, as well as other producing many of the movie and animation clips found on the educational programs. Companion CD. More specifically, it was through my collaborations with Tim It is also my pleasure to thank the past and present graduate Laske, Mark Hjelle (my brother-in-law), and Dale Wahlstrom, all students who have worked in my laboratory and have also been from the Cardiac Rhythm Management Division at Medtronic, contributors to this text, including: Edward Chinchoy, James Inc., who influenced the inception of this book in numerous ways Coles, Anthony Dupre, Kevin Fitzgerald, Alexander Hill, Ryan including: (1) the development of the Visible Heart® media project Lahm, Timothy Laske, Anna Legreid, Michael Loushin, Daniel in 1997, which is an ongoing effort to visualize functional cardiac Sigg, Nicholas Skadsberg, and Sarah Vincent. I feel extremely anatomy and to make such images available for instruction; (2) the fortunate to have had the opportunity to work with such talented creation of the Physiology Industrial Advisory Board, which scientists and engineers. I have learned a great deal from each evaluated and subsequently created outreach programs to serve the of them. greater local biomedical industry; and (3) the creation of the week- I would like to acknowledge the exceptional efforts of our long short course, Advanced Cardiac Physiology and Anatomy, Lab Coordinator, Monica Mahre, who: (1) assisted me in which was designed specifically for the biomedical engineer coordinating the efforts of the contributing authors; (2) skillfully working in industry. Importantly, this course has been taught at the incorporated my editorial changes; (3) verified the readability University of Minnesota for the past four years and is the basis of and formatting of each chapter; (4) pursued requested additions this textbook (the senior authors of most chapters present lectures or missing materials for each chapter; (5) contributed as a in the course). Over the years, I have fielded numerous requests by coauthor; and (6) kept a positive outlook throughout. I would engineers who have taken this course to develop more formal also like to thank Dee McManus for coordinating the support of VI PREFACE the Lillehei Heart Institute in their funding of illustrator Martin Finally, I would like to thank my family and friends for their Finch, who prepared several of the original figures; Gary support of my career and their assistance over the years. Without Williams for his computer expertise and assistance with such encouragement, I would not have even dreamed of taking on numerous figures; William Gallagher and Charles Soule, who such an ambitious project. Specifically, I would like to thank my made sure the laboratory kept running smoothly while many of wife Marge, my three daughters, Maria, Jenna, and Hanna, my us were busy writing or editing; Dick Bianco for his support of morn Irene, and siblings, Mike, Chris, Mark, and Susan, for always our lab and this book project; the Chairman of the Department being there for me. On a personal note, some of my motivation for of Surgery, Dr. David Dunn, for his support and encouragement; working on this project comes from the memory of my father and the Biomedical Engineering Institute at the University of Anthony, who succumbed to sudden cardiac death at too early an Minnesota, headed by Dr. Jeffrey McCullough, who supported age, and from the positive encouragement of my uncle Tom Halicki, this project by funding the Cardiovascular Physiology Interest who is doing well seven years after a heart transplant. Group (most of whose members contributed chapters). Paul A. laizzo, PhD CONTENTS

Preface ...... V 14 Blood Pressure, Heart Tones, and Diagnoses Contributors ...... ix George Bojanov ...... 181 Companion CD ...... xi 15 Basic ECG Theory, Recordings, The Visible Heart® ...... xiii and Interpretation Part I. Introduction Anthony Dupre, Sarah Vincent, l General Features of the Cardiovascular System and Paul A. laizzo ...... 191 Paul A. laizzo ...... 3 16 Mechanical Aspects of Cardiac Performance Part II. Anatomy Michael K. Loushin and Paul A. laizzo ...... 203 2 Cardiac Development 17 Energy Metabolism in the Normal Brad J. Martinsen and Jamie L. Lohr ...... 15 and Diseased Heart 3 Anatomy of the Thoracic Wall, Pulmonary Arthur H. L. From and Robert J. Bache ...... 223 Cavities, and Mediastinum 18 Introduction to Echocardiography Kenneth P. Roberts Jamie L. Lohr...... 241 and Anthony J. Weinhaus ...... 25 19 Cardiac Magnetic Resonance Imaging 4 Anatomy of the Human Heart Michael Jerosch-Herold, Ravi Teja Anthony J. Weinhaus Seethamraju, and Carsten Rickers ...... 249 and Kenneth P. Roberts ...... 51 Part IV. Devices and Therapies 5 Comparative Cardiac Anatomy 20 Historical Perspective of Cardiovascular Alexander J. Hill and Paul A. laizzo ...... 81 Devices and Techniques 6 The Coronary System and Associated Dee M. McManus, Monica A. Mahre, Medical Devices and Paul A. laizzo ...... 273 Ryan Lahm and Paul A. laizzo ...... 93 21 Animal Models for Cardiac Research 7 The Pericardium Robert P. Gallegos, Andrew L. Rivard, Edward Chinchoy, Michael R. Ujhelyi, and Richard W. Bianco ...... 287 Alexander J. Hill, Nicholas D. Skadsberg, 22 Cardiac Arrhythmias and Transcatheter Ablation and Paul A. Iaizzo ...... 101 Fei Lii, Scott Sakaguchi, Part III. Physiology and Assessment and David G. Benditt ...... 303 8 Cardiac Myocytes 23 Pacing and Defibrillation Vincent A. Barnett ...... 113 Timothy G. Laske, Anna M. Legreid, 9 The Cardiac Conduction System and Paul A. laizzo ...... 323 Timothy G. Laske and Paul A. laizzo ...... 123 24 Biventricular Pacing for Congestive 10 Autonomic Nervous System Heart Failure Kevin Fitzgerald, Robert F. Wilson, Fei Lii and Leslie W. Miller ...... 349 and Paul A. laizzo ...... 137 25 Cardiac Mapping Systems 11 Cardiac and Vascular Receptors and Signal Nicholas D. Skadsberg, Transduction: Physiological Timothy G. Laske, and Paul A. laizzo ...... 361 and Pathophysiological Roles of lmportant 26 Cardiopulmonary Bypass and Cardioplegia Cardiac and Vascular Receptors J. Ernesto Molina ...... 371 Daniel C. Sigg ...... 149 27 Heart Valve Disease 12 Reversible and Irreversible Damage Robert P. Gallegos of the Myocardium: New Ischemic Syndromes, and R. Morton Bolman III ...... 385 Ischemia/Reperfusion Injuly, and Cardioprotection 28 Less-Invasive Cardiac Surgery James A. Coles, Jr., Daniel C. Sigg, Kenneth K. Liao ...... 405 and Paul A. laizzo ...... 161 29 Treatment of Cardiac Septal Defects: 13 The Effects of Anesthetic Agents The Evolution of the Amplatzer ® Family on Cardiac Function of Devices Michael K. Loushin ...... 171 John L. Bass ...... 413

VII VIII CONTENTS

30 End-Stage Cardiomyopathy: 32 Genomics-Based Tools and Technology Ventricular Assist Devices Jennifer L. Hall ...... 439 Soon J. Park ...... 421 33 Emerging Cardiac Devices 31 Experimental Cell Transplantation and Technologies for Myocardial Repair Paul A. laizzo ...... 445 Joseph Lee, Atsushi Asakura, Index ...... 459 and Jianyi Zhang ...... 427 CONTRIBUTORS

ATSUSHI ASAKURA, PhD " Cardiovascular Division, JAMIE L. LOHR, MD • Division of Cardiology, Department Department of Medicine, University of Minnesota, of Pediatrics, University of Minnesota, Minneapolis, MN Minneapolis, MN MICHAEL K. LOUSHIN, MD ° Department of Anesthesiology, ROBERT J. BACHE, MD ° Cardiovascular Division, Department University of Minnesota, Minneapolis, MN of Medicine, and Center for Magnetic Resonance FEI LO, MD, PhD ° Cardiovascular Division, Department Research, University of Minnesota, Minneapolis, MN of Medicine, University of Minnesota, Minneapolis, MN VINCENT A. BARNETT, PhD o Department of Physiology, MONICA A. MAHRE, BS ° Department of Surgery, University University of Minnesota, Minneapolis, MN of Minnesota, Minneapolis, MN JOHN L. BASS, MD ° Department of Pediatrics, Division BRAD J. MARTINSEN, PhD ° Division of Cardiology, of Cardiology, University of Minnesota, Minneapolis, MN Department of Pediatrics, University of Minnesota, DAVID G. BENDITT, MD * Cardiovascular Division, Minneapolis, MN Department of Medicine, University of Minnesota, DEE M. MCMANUS, BS • Lillehei Heart Institute, University Minneapolis, MN of Minnesota, Minneapolis, MN RICHARD W. BIANCO • Experimental Surgical Services, LESLIE W. MILLER, MD ° Cardiovascular Division, Department of Surgery, University of Minnesota, Department of Medicine, University of Minnesota, Minneapolis, MN Minneapolis, MN GEORGE BOJANOV, MD • Department of Anesthesiology, J. ERNESTO MOLINA, MD, PhO • Division of Cardiovascular University of Minnesota, Minneapolis, MN and Thoracic Surgery, Department of Surgery, University R. MORTON BOLMAN III, MD ° Division of Cardiovascular and of Minnesota, Minneapolis, MN Thoracic Surgery, Department of Surget~y, University SOON J. PARK, MD ° Department of Cardiovascular and of Minnesota, Minneapolis, MN Thoracic Surgery, California Pacific Medical Center, EDWARD CHINCHOY, PhD ° Medtronic, Inc., Minneapolis, MN San Francisco, CA JAMES A. COLES, JR., PhD ° Medtronic, Inc., Minneapolis, MN CARSTEN RICKERS, MD ° Department of Pediatric Cardiology, ANTHONY DUPRE, MS ° Department of Surgery, University University Hospital Hamburg-Eppendorf, Hamburg, of Minnesota, Minneapolis, MN Germany KEVIN FITZGERALD, MS ° Department of Surgery, University ANDREW L. RIVARD, MD ° Department of Physiology, of Minnesota, Minneapolis, MN University of Minnesota, MN ARTHUR H. L. FROM, MD ° Cardiovascular Division, KENNETH P. ROBERTS, PhD ° Department of Urologic Surgery, Department of Medicine, and Center for Magnetic University of Minnesota, Minneapolis, MN Resonance Research, University of Minnesota, SCOTT SAKAGUCHI, MD ° Department of Medicine, University Minneapolis, MN of Minnesota, Minneapolis, MN ROBERT P. GALLEGOS, MD * Division of Cardiac and Thoracic RAVI TEJA SEETHAMRAJU, PhD ° Siemens Medical Solutions USA, Surgery, Department of Surgery, University of Minnesota, Inc.; Visiting Assistant Professor, Radiology, Harvard Minneapolis, MN Medical School, Charlestown, MA JENNIFER L. HALL, PhD ° Cardiovascular Division, DANIEL C. SI~, Mb, PhD • Medtronic, Inc., Minneapolis, MN Department of Medicine, University of Minnesota, NICHOLAS D. SKADSBERG, PhD ° Departments of Biomedical Minneapolis, MN Enginee14ng and Surge17, University of Minnesota, ALEXANDER J. HILL, PhD o Medtronic, Inc., Minneapolis, MN Minneapolis, MN PAUL A. IAIZZO, PhD ° Departments of Surgery, Physiology, MICHAEL R. UJHELYI, PharmD. FCCP * Medtronic, Inc., and Anesthesiology, Director of Education for the Lillehei Minneapolis, MN Heart Institute, University of Minnesota, Minneapolis MN SARAH VINCENT, Ms ° Department of Surgery, University MICHAEL JEROSCH-HEROLD, PhD ° Cardiac MRI Section, of Minnesota, Minneapolis, MN University of Minnesota, Minneapolis, MN ANTHONY J. WEINHAUS, PhD ° Departments of Physiology RYAN LAHM, MS * Medtronic, Inc., Minneapolis, MN and Genetics, Cell Biology, and Development, University TIMOTHY G. LASKE, PhD • Medtronic, Inc., Minneapolis, MN of Minnesota, Minneapolis, MN JosEprt LEE, BS ° Department of Biomedical Engineering, ROBERT F. WILSON, MD ° Division of Cardiology, University University of Minnesota, Minneapolis, MN of Minnesota, Minneapolis, MN ANNA M. LEGREID, PharmD ° Medtronic, Inc., Minneapolis, MN JIANYI ZHANG, MD, PhD ° Division of Cardiology, Department KENNETH K. LIAO, MD ° Division of Thoracic and of Medicine, University of Minnesota, Minneapolis, MN Cardiovascular Surgery, Department of Surgery, University of Minnesota, Minneapolis, MN

IX COMPANION CD for Handbook of Cardiac Anatomy, Physiology, and Devices

The Companion CD serves to complement the text by Fig. 21 Atrial septal defect. including additional figures and/or short video clips to support Fig. 22 Ventricular septal defect. the various chapters. The opening screen provides access to this material. Throughout the text, a cross reference to the Fig. 23 Vascular supply to the heart. Companion CD alerts the reader to the availability of this Fig. 24 Atrial branch of right coronary. additional material. The Companion CD is compatible with any XP Windows or Fig. 25 Arterial supply to the septum. Apple Macintosh operating system. Fig. 26 Venous drainage of the heart. Fig. 27 The great cardiac vein. CONTENTS Fig. 28 The middle cardiac vein. Fig. 29 Anterior cardiac veins. CHAPTER 4 ANATOMY OF THE HUMAN HEART

Fig. 1 Position of the heart in the thorax. CHAPTER 6 THE CORONARY SYSTEM AND ASSOCIATED Fig. 2 Cadaveric dissection. MEDICAL DEVICES

Fig. 3 Anterior surface of the heart. Fig. 1 CoronaryVeins.mpg Fig. 4 The pericardium. Fig. 5 PlaceLateral.mpg Fig. 5 Cardiac tamponade. CHAPTER 7 THE PERICARDIUM Fig. 6 Pericardial sinuses. jpegl Fig. 7 Posterior portion of the pericardial sac in a swine Internal anatomy of the heart. from which the heart was removed. Fig. 8 Cardiopulmonary circulation. mpeg 1 The effect of removing the pericardium from an Fig. 9 Cardiac circulation. isolated swine heart. Fig. 10 Embryonic origin of the heart. CHAPTER 9 THE CARDIAC CONDUCTIONSYSTEM Fig. 11 Internal anatomy of the right atrium. internodaltracts.jpg Fig. 12 Koch's triangle. mpeg7-1 The conduction system Fig. 13 The location of the SA node. Fig. 14 Internal anatomy of the right ventricle. CHAPTER 13 THE EFFECTS OF ANESTHETICAGENTS ON CARDIAC FUCNTION Fig. 15 Valves of the heart. jpegl. An anesthesiologist administering intravenous Fig. 16 Internal anatomy of the left atrium and ventricle. medications to a patient for induction of general anesthesia. Fig. 17 Mitral valve. jpeg2. An anesthesia machine and ventilator. Fig. 18 The cardiac skeleton. jpeg3. An anesthesiologist titrating the dose of an Fig. 19 Fetal circulation. inhalational anesthetic to maintain anesthesia and Fig. 20 Chiari network. cardiovascular stability.

XI XII COMPANION CD

CHAPTER 16 MECHANICALASPECTS OF CARDIAC SECTION 3. PERFORMANCE styletNew.mpg jpeg 1 Monitor display of electrocardiogram, xray 1.jpg blood pressures, and SvO> xray2.jpg jpeg 2 Cannulation of a peripheral artery. xray3.jpg jpeg 3 Cannulation of a peripheral artery. xray4.jpg jpeg 4 Pressure transducer for monitoring blood pressures. xray5.jpg jpeg 5 Central venous access kit. xray6.jpg jpeg 6 Cannulation of right internal jugular vein. SECTION 4.8. jpeg 7 Pulmonary artery catheter. resyncl.mpg

jpeg 8 Inflated balloon at the distal tip of SECTION 5.10. pulmonary artery catheter. fluoro.avi jpeg 9. Pulmonary artery catheter for continuous monitoring of cardiac output styletNew.mpg and mixed venous saturation. 5076huma.mpg jpeg 10 Millar catheter. AApendFL.mpg jpeg 11 Sensors on a Millar catheter. rva4074.mpg 5076humv.mpg CHAPTER 23 PACINGAND DEFIBRILLATION RV Apex.mpg SECTION 2.2. 6944DEFl.mpg normal.mpg 6932humf.mpg SECTION 2.4. FIG. 1 1 CONNECTORPLUGIN.MPG AT.mpg FIG. 33 ENERGYVECTORDUAL.MPG AF.mpg VT.mpg CHAPTER 28 LESS-INvASIVECARDIAC SURGERY VF.mpg Fig. 1 Fig. 3 Fig. 5 Fig. 2 Fig. 4 Fig. 6 THE VISIBLE HEART ®

CONTENTS

1. HEARTANATOMY 1.1. COMPARATIVEANATOMY 1.2. TOPOGRAPHICANATOMY 1.3. SURFACE ANATOMY 1.4. CORONARY ANATOMY 1.5. Four CHAMBERS 1.6. VALVES 1.7 PRESSURES AND FLOWS 1.8. CONDUCTIONSYSTEM 2. DISEASESAND TREATMENTS 2.1. CORONARY ARTERY DISEASE 2.2. VALVULARDISEASE 2.3. CARDIOMYOPATHIESAND HEART FAILURE 2.4. CONGENITALDEFECTS 2.5. PERICARDIALPATHOLOGY 2.6. POsT-SURGICALHEART 2.7. BRADYARRHYTHMIAS 2.8. TACHYARRHYTHMIAS 3. DEVICECHOICES AND INTERVENTIONSITES 3.1. TRADITIONALSITES 3.2. EMERGING SITES 3.3. PACING LEAD SYSTEMS 3.4. DEFIBRILLATIONLEAD SYSTEMS 3.5. MAPPING AND ABLATION 3.6. OTHER DEVICES 4. VISIBLEHEART LAB 4.1. APPARATUS 4.2. REFERENCES

The Visible Heart ®, a CD accompanying Handbook of All images and videos on The Visible Heart ® were Cardiac Anatomy, Physiology, and Devices, is designed to captured in the laboratory of Dr. Iaizzo, utilizing the Visible be a self-contained electronic textbook, developed via a Heart ® technologies that are subject to pending US Patent collaboration between the University of Minnesota Medical Application No. 09/419,271 filed October 15, 1999 and PCT School and Medtronic, Inc. It utilizes Visible Heart ® Application No. US99/24791, filed October 22, 1999 by the technologies, a significant advancement in the modeling of University of Minnesota and Medtronic, Inc. the isolated heart that allows display of full-motion images captured from inside the endocardium of the functioning large mammalian heart. With the support of LifeSource, The Visible Heart ® presents images obtained from human hearts donated by generous individuals, whose final acts continue to enhance our understanding of the inner workings of the human heart and to contribute to lifesaving advances in cardiac medicine.

XIII INTRODUCTION I 1 General Features of the Cardiovascular System

PAUL A. IAIZZO, PhD

CONTENTS

INTRODUCTION COMPONENTS OF THE CARDIOVASCULAR SYSTEM SOURCES

1. INTRODUCTION 2.1. Blood Currently, approx 60 million individuals in the United Blood is composed of formed elements (cells and cell frag- States alone have some form of cardiovascular disease. More ments) suspended in the liquid (plasma) fraction. Blood, con- specifically, heart attacks continue to be an increasing prob- sidered the only liquid connective tissue in the body, has three lem in our society. Coronary bypass surgery, angioplasty, general functions: (1) transportation (e.g., 02, CO2, nutrients, stenting, the implantation of pacemakers/defibrillators, and wastes, hormones); (2) regulation (e.g., pH, temperature, valve replacement are currently routine treatment procedures, osmotic pressures); and (3) protection (e.g., against foreign with growing numbers of such procedures performed each molecules and diseases, as well as for clotting to prevent year. However, such treatments often provide only temporary excessive loss of blood). Dissolved within the plasma are many relief of the progressive symptoms of cardiac disease. Optimi- proteins, nutrients, metabolic waste products, and various zation of therapies and the development of new ones (e.g., other molecules traveling between the organ systems. coated vascular or coronary stents, left ventricular assist The formed elements in blood include red blood cells devices, and biventricular pacing) continue to dominate the (erythrocytes), white blood cells (leukocytes), and the cell cardiovascular biomedical industry. fragments known as platelets. All are formed in bone marrow The purpose of this chapter is to provide a general over- from a common stem cell. In a healthy individual, the majority view of the cardiovascular system as a quick reference as to (~99%) of blood cells are red cells, which have a primary role the underlying physiological composition of this system. More in 02 exchange. Hemoglobin, the iron-containing heme pro- details concerning the pathophysiology of the cardiovascular tein that binds oxygen, is concentrated within the red cells; system and state-of-the-art treatments can be found in subse- hemoglobin allows blood to transport 40 to 50 times the quent chapters. In addition, note that a list of sources and amount of oxygen that plasma alone could carry. references is provided at the end of this chapter. The white cells are required for the immune process to 2. COMPONENTS protect against infections and cancers. The platelets play a primary role in blood clotting. In a healthy cardiovascular OF THE CARDIOVASCULAR SYSTEM system, the constant movement of blood helps keep these cells The principal components considered to make up the cardio- well dispersed throughout the plasma of the larger diameter vascular system include the blood, blood vessels, heart, and vessels. lymphatic system. The hematocrit is defined as the percentage of blood volume occupied by the red cells (erythrocytes). It can be easily mea- sured by centrifuging (spinning at high speed) a sample of blood, which forces these cells to the bottom of the centrifuge tube. From: Handbook of Cardiac Anatomy, Physiology, and Devices Edited by: P. A. Iaizzo © Humana Press Inc., Totowa, NJ The leukocytes remain on the top, and the platelets form a very 4 PART I: INTRODUCTION / IAIZZO thin layer between the cell fractions (other, more sophisticated Pulmonary trunk methods are also available to do such analyses). Normal hema- ! tocrit is approx 45% in men and 42% in women. Pulmonary arteries The total volume of blood in an average-size individual (70 kg) is approx 5.5 L; hence, the average red cell volume Cal~~ of lungs would be roughly 2.5 L. Because the fraction containing both t Pulmonary veins leukocytes and platelets is normally relatively small or negli- ...... q gible, in such an individual the plasma volume can be estimated as 3.0 L. Approximately 90% of plasma is water, which acts: (1) as a solvent, (2) to suspend the components of blood, (3) in absorption of molecules and their transport, and (4) in the transport of thermal energy. Proteins make up 7% of the plasma (by weight) and exert a colloid osmotic pressure. Protein types include albumins, globulins (antibodies and immunoglobulins), and fibrinogen. To date, more than 100 dis- tinct plasma proteins have been identified, and each presum- ably serves a specific function. The other main solutes in plasma include electrolytes, nutrients, gases (some 02, large amounts of CO2 and N2), regulatory substances (enzymes and hormones), and waste products (urea, uric acid, creatine, creatinine, biliru- bin, and ammonia). Arteries 2.2. Blood Vessels Blood flows throughout the body tissues in blood vessels via Arterioles bulk flow (i.e., all constituents together and in one direction). An Capillaries extraordinary degree of branching of blood vessels exists within the human body, which ensures that nearly every cell in the body Venules lies within a short distance from at least one of the smallest branches of this system--a capillary. Nutrients and metabolic Veins end products move between the capillary vessels and the sur- roundings of the cell through the interstitial fluid by diffusion. mmm Yenae ¢a~ae Subsequent movement of these molecules into a cell is accomplished by both diffusion and mediated transport. Nevertheless, blood flow through all organs can be considered as passive and Fig. 1. The major paths of blood flow through pulmonary and systemic occurs only because arterial pressure is kept higher than venous circulatory systems. AV, atrioventricular. pressure via the pumping action of the heart. In an individual at rest at a given moment, approx 5% of the total circulating blood is actually in capillaries. Yet, this volume of blood can be considered to perform the primary func- systemic circulation branch from the aorta (this is the largest tions of the entire cardiovascular system, specifically the supply artery of the body, with a diameter of 2-3 cm) and divide into of nutrients and removal of metabolic end products. The cardio- progressively smaller vessels. The aorta's four principal divi- vascular system, as reported by the British physiologist Will- sions are: the ascending aorta (begins at the aortic valve, where, iam Harvey in 1628, is a closed-loop system, such that blood is close by, the two coronary artery branches have their origin), pumped out of the heart through one set of vessels (arteries) and the arch of the aorta, the thoracic aorta, and the abdominal aorta. then returns to the heart in another (veins). The smallest of the arteries eventually branch into arterioles. More specifically, it can be considered that there are two They, in turn, branchinto an extremely large number (estimated closed-loop systems that both originate and return to the at 10 billion in the average human body) of vessels with the heart--the pulmonary and systemic circulations (Fig. 1). The smallest diameter, the capillaries. Next, blood exits the capillar- pulmonary circulation is composed of the right heart pump ies and begins its return to the heart via the venules. Microcir- and the lungs, whereas the systemic circulation includes the culation is a term coined to describe collectively the flow of left heart pump, which supplies blood to the systemic organs blood through arterioles, capillaries, and venules (Fig. 2). (i.e., all tissues and organs except the gas exchange portion of Importantly, blood flow through an individual vascular the lungs). Because the right and left heart pumps function in bed is profoundly regulated by changes in activity of the sym- a series arrangement, both will circulate an identical volume pathetic nerves innervating the arterioles. In addition, arteri- of blood in a given minute (cardiac output, normally expressed olar smooth muscle is very responsive to changes in local in liters per minute). chemical conditions (i.e., those changes associated with In the systemic circuit, blood is ejected out of the left ven- increases or decreases in the metabolic rate of that given organ) tricle via a single large artery--the aorta. All arteries of the within an organ. CHAPTER 1 / CARDIOVASCULAR SYSTEM FEATURES 5

From Heart L

Fig. 2. The microcirculation, including arterioles, capillaries, and venules. The capillaries lie between, or connect, the arterioles and venules. They are found in almost every tissue layer of the body, but their distribution varies. Capillaries form extensive branching networks that dramatically increase the surface areas available for the rapid exchange of molecules. A metarteriole is a vessel that emerges from an arteriole and supplies a group of 10 to 100 capillaries. Both the arteriole and the proximal portion of the metarterioles are surrounded by smooth muscle fibers, which elicit contractions and relaxations so as to regulate blood flow through the capillary bed. Typically, blood flows intermittently through a capillary bed as a result of the periodic contractions of the smooth muscles (5-10 times per min: vasomotion), which are regulated both locally (metabolically) and by sympathetic control. (Figure modified from Tortora and Grabowski, 2000.)

Capillaries, which are the smallest and most numerous blood materials across capillary walls, e.g., kidneys, liver, intes- vessels in the human body (ranging from 5-10 ~tm in diameter tines, and bone marrow. and numbering around 10 billion), are also the vessels with the If a molecule cannot pass between capillary endothelial thinnest walls; an inner diameter of 5 ~tm is just wide enough for cells, then it must be transported across the cell membrane. an erythrocyte to squeeze through. Further, it is estimated that The mechanisms available for transport across a capillary wall there are 25,000 miles of capillaries in an adult; each capillary differ for various substances depending on their molecular has an individual length of about 1 mm. sizes and degree of lipid solubility. For example, certain pro- Most capillaries are little more than a single-cell-layer thick, teins are selectively transported across endothelial cells by a consisting of a layer of endothelial cells and a basement mem- slow, energy-requiring process known as transcytosis. In this brane. This minimal wall thickness facilitates the capillary's process, the endothelial cells initially engulf the proteins in primary function: to permit the exchange of materials between the plasma within capillaries by endocytosis. The molecules cells in tissues and the blood. As mentioned, small molecules are then ferried across the cells by vesicular transport and (e.g., O2, CO2, sugars, amino acids, and water) are relatively released by exocytosis into the interstitial fluid on the other free to enter and leave capillaries readily, promoting efficient side. Endothelial cells generally contain large numbers of material exchange. Nevertheless, the relative permeability of endocytotic and exocytotic vesicles, and sometimes these fuse capillaries varies from region to region in the body with regard to form continuous vesicular channels across the cell. to the physical properties of their formed walls. The capillaries within the heart normally prevent excessive Based on such differences, capillaries are commonly movement of fluids and molecules across their walls, but clini- grouped into two major classes: continuous and fenestrated. cal situations have been noted in which they may become In the continuous capillaries, which are more common, the "leaky." For example, "capillary leak syndrome," possibly endothelial cells are joined such that the spaces between them induced following cardiopulmonary bypass, may last from are relatively narrow (i.e., narrow intercellular gaps). These hours to days. More specifically, in such cases, the inflamma- capillaries are permeable to substances having small molecu- tory response in the vascular endothelium can disrupt the lar sizes and/or high lipid solubilities (e.g., OR, CO2, and ste- "gatekeeper" function of capillaries; their increased perme- roid hormones) and are somewhat less permeable to small ability will result in myocardial edema. water-soluble substances (e.g., Na ÷, K ÷, glucose, and amino From capillaries, blood throughout the body then flows into acids). In fenestrated capillaries, the endothelial cells possess the venous system. It first enters the venules, which then coa- relatively large pores that are wide enough to allow proteins lesce to form larger vessels, the veins (Fig. 2). Then veins from and other large molecules to pass through. In some such cap- the various systemic tissues and organs (minus the gas exchange illaries, the gaps between the endothelial cells are even wider portion of the lungs) unite to produce two major veins: the than usual, enabling quite large proteins (or even small cells) inferior vena cava (lower body) and superior vena cava (above to pass through. Fenestrated capillaries are primarily located the heart). By way of these two great vessels, blood is returned in organs whose functions depend on the rapid movement of to the right heart pump, specifically into the right atrium. 6 PART I: INTRODUCTION / IAIZZO

To heart

Relaxed skeletal muscles Contracted skeletal muscles

Fig. 3. Contractions of the skeletal muscles aid in returning blood to the heart; this is termed the skeletal muscle pump. While standing at rest, the relaxed vein acts as a reservoir for blood; contractions of limb muscles not only decrease this reservoir size (venous diameter), but also actively force the return of more blood to the heart. Note that the resulting increase in blood flow caused by the contractions is only toward the heart because of the valves in the veins.

Like capillaries, the walls of the smallest venules are very that empty into the left atrium. As blood flows through the lung porous and are the sites from which many phagocytic white capillaries, it picks up oxygen supplied to the lungs by breathing blood cells emigrate from the blood into inflamed or infected air; hemoglobin within the red blood cells becomes loaded with tissues. Venules and veins are also richly innervated by sympa- oxygen (oxygenated blood). thetic nerves and smooth muscles that constrict when these nerves are activated. Thus, increased sympathetic nerve activ- 2.3. Blood Flow ity is associated with decreased venous volume, which results The task of maintaining an adequate interstitial homeosta- in increased cardiac filling and therefore increased cardiac sis (the nutritional environment surrounding cells) requires output (via Starling's law of the heart). that blood flows almost continuously through each of the Many veins, especially those in the limbs, also feature millions of capillaries in the body. The following is a brief abundant valves (which are notably also found in the cardiac description of the parameters that govern flow through a given venous system), thin folds of the intervessel lining that form vessel. All bloods vessels have certain lengths L and internal flaplike cusps. The valves project into the vessel lumen and radii r through which blood flows when the pressure in the are directed toward the heart (promoting unidirectional flow inlet and outlet (Pi and Po, respectively) are unequal; in other of blood). Because blood pressure is normally low in veins, words, there is a pressure difference (AP) between the vessel these valves are important in aiding venous return by prevent- ends that supplies the driving force for flow. Because friction ing the backflow of blood (which is especially true in the develops between moving blood and the stationary vessel upright individual). In addition, contractions of skeletal walls, this fluid movement has a given resistance (vascular) muscles (e.g., in the legs) also play a role in decreasing the size that is the measure of how difficult it is to create blood flow of the venous reservoir and thus the return of blood volume to through a vessel. Then, a relative relationship among vascular the heart (Fig. 3). flow, the pressure difference, and resistance (i.e., the basic The pulmonary circulation is composed of a similar circuit. flow equation) can be described: Blood leaves the right ventricle in a single great vessel, the pulmonary artery (trunk), which within a short distance (centi- Flow pressure difference AP = or Q = -- meters) divides into the two main pulmonary arteries, one sup- resistance R plying the right lung and another the left. Once within the lung proper, the arteries continue to branch down to arterioles and where Q is the flow rate (volume/time), zSa° is the pressure then ultimately form capillaries. From there, the blood flows difference (mmHg), and R is the resistance to flow (mmHg into venules, eventually forming four main pulmonary veins × time/volume). CHAPTER 1 / CARDIOVASCULAR SYSTEM FEATURES 7

This equation may be applied not only to a single vessel, but Aorta also to describe flow through a network of vessels (i.e., the vascular bed of an organ or the entire systemic circulatory system). It is known that the resistance to flow through a cylindrical tube or vessel depends on several factors (described by Poiseuille), including (1) radius, (2) length, (3) viscosity of the fluid (blood), and (4) inherent resistance to flow, as follows:

R = 8Lq ~r 4 where r is the inside radius of the vessel, L is the vessel length, and t 1 is the blood viscosity. It is important to note that a small change in vessel radius will have a very large influence (fourth power) on its resistance to flow; for instance, decreasing the vessel diameter by 50% will increase its resistance to flow approx 16-fold. If the preceding two equations are combined into one expression, which is commonly known as the Poiseuille equation, it can be used to approximate better the factors that influence flow Fig. 4. Pathway of blood flow through the heart and lungs. Note that though a cylindrical vessel: the pulmonary artery (trunk) branches into left and right pulmonary arteries. There are commonly four main pulmonary veins that return j~ / -4 blood from the lungs to the left atrium. (Modified from Tortora and Q=AP-- 8Lq Grabowski, 2000.) Nevertheless, flow will only occur when a pressure difference exists. Hence, it is not surprising that arterial blood pressure is perhaps the most regulated cardiovascular variable in the human body; this is principally accomplished by regulat- venae cavae. It next passes through the tricuspid valve into the ing the radii of vessels (e.g., arterioles and metarterioles) right ventricles, and from there is pumped through the pulmo- within a given tissue or organ system. Whereas vessel length nary valve into the pulmonary artery. After passing through the and blood viscosity are factors that influence vascular resis- pulmonary capillary beds, the oxygenated pulmonary venous tance, they are not considered variables that can be easily blood returns to the left atrium through the pulmonary veins. regulated for the purpose of the moment-to-moment control of The flow of blood then passes through the mitral valve into the blood flow. Regardless, the primary function of the heart is to left ventricle and is pumped through the aortic valve into the keep pressure within arteries higher than those in veins, hence aorta. creating a pressure gradient to induce flow. Normally, the In general, the gross anatomy of the right heart pump is con- average pressure in systemic arteries is approx 100 mmHg, siderably different from that of the left heart pump; yet, the and it decreases to nearly 0 mmHg in the great caval veins. pumping principles of each are primarily the same. The ven- The volume of blood that flows through any tissue in a given tricles are closed chambers surrounded by muscular walls, and period of time (normally expressed in milliliters/minute) is the valves are structurally designed to allow flow in only called the local bloodflow. The velocity (speed) of blood flow one direction. The cardiac valves passively open and close in (expressed in centimeters/second) can generally be considered response to the direction of the pressure gradient across them. inversely related to the vascular cross-sectional area such that The myocytes of the ventricles are organized primarily in a velocity is slowest when the total cross-sectional area is largest. circumferential orientation; hence, when they contract, the ten- sion generated within the ventricular walls causes the pressure 2.4. Heart within the chamber to increase. As soon as the ventricular pres- The heart lies in the center of the thoracic cavity and is sus- sure exceeds the pressure in the pulmonary artery (right) and/or pended by its attachment to the great vessels within a fibrous aorta (left), blood is forced out of the given ventricular cham- sac known as the pericardium; note that humans have relatively ber. This active contractile phase of the cardiac cycle is known thick-walled pericardia compared to those of the commonly as systole. The pressures are higher in the ventricles than the studied large mammalian cardiovascular models (i.e., canine, atria during systole; hence, the tricuspid and mitral (atrio- porcine, or ovine; see also Chapter 7). A small amount of fluid ventricular) valves are closed. When the ventricular myocytes is present within the sac (pericardial fluid); it lubricates the relax, the pressures in the ventricles fall below those in the atria, surface of the heart and allows it to move freely during func- and the atrioventricular valves open; the ventricles refill, and tion (contraction and relaxation). The pericardial sac extends this phase is known as diastole. The aortic and pulmonary (semi- upward, enclosing the great vessels (see also Chapters 3 and 4). lunar or outlet) valves are closed during diastole because the The pathway of blood flow through the chambers of the heart arterial pressures (in the aorta and pulmonary artery) are greater is indicated in Fig. 4. Recall that venous blood returns from the than the intraventricular pressures. For more details on the car- systemic organs to the right atrium via the superior and inferior diac cycle, see Chapter 16. 8 PART I: INTRODUCTION / IAIZZO

The effective pumping action of the heart requires that there for how effective the modulation of the heart by this innerva- be a precise coordination of the myocardial contractions (mil- tion is, it has been reported that the cardiac output often can be lions of cells); this is accomplished via the conduction system increased by more than 100% by sympathetic stimulation; in of the heart. Contractions of each cell are normally initiated contrast, output can be nearly terminated by parasympathetic when electrical excitatory impulses (action potentials) propa- (vagal) stimulation. gate along their surface membranes. The myocardium can be Cardiovascular function is also modulated through reflex viewed as a functional syncytium; action potentials from one mechanisms that involve baroreceptors, the chemical composi- cell conduct to the next cell via the gap junctions. In the healthy tion of the blood, and/or via the release of various hormones. heart, the normal site for initiation of a heartbeat is within the More specifically, baroreceptors, which are located in the walls sinoatrial node, located in the right atrium. For more details on of some arteries and veins, exist to monitor their relative blood this internal electrical system, refer to Chapter 9. pressure. Those specifically located in the carotid sinus help to The heart normally functions in a very efficient fashion; the maintain normal blood pressure reflexively in the brain, whereas following properties are needed to maintain this effectiveness: those located in the area of the ascending arch of the aorta help (1) the contractions of the individual myocytes must occur at to govern general systemic blood pressure (for more details, see regular intervals and be synchronized (not arrhythmic); (2) the Chapter 10). valves must fully open (not be stenotic); (3) the valves must not Chemoreceptors that monitor the chemical composition of leak (not be insufficient or regurgitant); (4) the ventricular con- blood are located close to the baroreceptors of the carotid sinus tractions must be forceful (not failing or lost because of an and arch of the aorta in small structures known as the carotid and ischemic event); and (5) the ventricles must fill adequately aortic bodies. The chemoreceptors within these bodies detect during diastole (no arrhythmias or delayed relaxation). The changes in blood levels of 02, CO2, and H ÷. Hypoxia (a low subsequent chapters in this book cover normal and abnormal availability of O2), acidosis (increased blood concentrations of performance of the heart and various clinical treatments to H+), and/or hypercapnia (high concentrations of CO2) stimulate the chemoreceptors to increase their action potential firing fre- enhance function. quencies to the brain cardiovascular control centers. In response 2.5. Regulation of Cardiovascular Function to this increased signaling, the central nervous system control centers (hypothalamus) in turn cause an increased sympathetic Cardiac output in a normal individual at rest ranges between stimulation to arterioles and veins, producing vasoconstriction 4 and 6 L/min, but during severe exercise the heart may be and a subsequent increase in blood pressure. In addition, the required to pump four to seven times this amount. There are two chemoreceptors simultaneously send neural input to the respi- primary modes by which the blood volume pumped by the heart ratory control centers in the brain to induce the appropriate at any given moment is regulated: (1) intrinsic cardiac regula- control of respiratory function (e.g., increased 02 supply and tion in response to changes in the volume of blood flowing into reduced CO2 levels). It is beyond the scope of this book to the heart and (2) control of heart rate and cardiac contractility discuss the details of the hormonal regulatory system, which by the autonomic nervous system. The intrinsic ability of the include: (1) the renin-angiotensin-aldosterone system, (2) the heart to adapt to changing volumes of inflowing blood is known release of epinephrine and norepinephrine, (3) antidiuretic hor- as the Frank-Starling mechanism (law) of the heart, named mones, and (4) atrial natriuretic peptides (released from the after the two great pioneering physiologists of a century ago. atrial heart cells). In general, the Frank-Starling response can be described The overall functional arrangement of the blood circulatory simply: The more the heart is stretched (increased blood vol- system is shown in Fig. 5. The role of the heart needs to be ume), the greater will be the subsequent force of ventricular considered in three different ways: as the right pump, as the left contraction and thus the amount of blood ejected through the pump, and as the heart muscle tissue with its own metabolic and semilunar valves (aortic and pulmonary). In other words, within flow requirements. As described here, the pulmonary (right its physiological limits, the heart will pump out all the blood heart) and systemic (left heart) circulations are arranged in a that enters it without allowing excessive damming of blood in series. Thus, cardiac output increases in each at the same rate; veins. The underlying basis for this phenomenon is related to hence, an increased systemic need for a greater cardiac output the optimization of the lengths of sarcomeres (the functional will automatically lead to a greater flow of blood through the subunits of striate muscle); there is optimization in the potential lungs (inducing a greater potential for 02 delivery). for the contractile proteins (actin and myosin) to form In contrast, the systemic organs are functionally in a parallel crossbridges. It should also be noted that "stretch" of the right arrangement; hence, (1) nearly all systemic organs receive blood atrial wall (e.g., because of increased venous return) can directly with an identical composition (arterial blood), and (2) the flow increase the rate of the sinoatrial node by 10-20%; this also aids through each organ can be and is controlled independently. For in the amount of blood that will ultimately be pumped per minute example, during exercise the circulatory response is an increase by the heart. For more details on the contractile function of in blood flow through some organs (e.g., heart, skeletal muscle, heart, refer to Chapter 8. and brain), but not others (e.g., kidney and gastrointestinal sys- The pumping effectiveness of the heart is also effectively tem). The brain, heart, and skeletal muscles typify organs in controlled by both the sympathetic and parasympathetic which blood flows solely to supply the metabolic needs of the components of the autonomic nervous system. There is tissue; they do not recondition the blood. extensive innervation of the myocardium by such nerves (for The blood flow to the heart and brain is normally only slightly more details of this innervation, see Chapter 10). To get a feel greater than that required for their metabolism; hence, small CHAPTER 1 / CARDIOVASCULAR SYSTEM FEATURES 9

Lungs ,oo. jftb

• Heart

I Bram ~= 3% I

SkeletalMuscle 15Vo I A 11 Bone " ] r v. o It

n System,Spleen ~ - I e r

I Skin ~, 6%

_ I I 8% I OTHER I Fig. 5. A functional representation of the blood circulatory system at a given moment in time. The percentages indicate the approximate relative percentages of the cardiac output that is delivered to the major organ systems within the body of a healthy subject at rest.

interruptions in flow are not well tolerated. For example, if ture). Blood-conditioning organs can often withstand, for short coronary flow to the heart is interrupted, electrical and/or func- periods of time, significant reductions of blood flow without tional (pumping ability) activities will be altered noticeably subsequent compromise. within a few beats. Likewise, stoppage of flow to the brain will lead to unconsciousness within a few seconds, and permanent 2.6. Coronary Circulation brain damage can occur in as little as 4 min without flow. The To sustain viability, it is not possible for nutrients to diffuse flow to skeletal muscles can dramatically change (flow can from the chambers of the heart through all the layers of cells increase from 20-70% of total cardiac output) depending on that make up the heart tissue. Thus, the coronary circulation is use, and thus their metabolic demand. responsible for delivering blood to the heart tissue itself (the Many organs in the body perform the task of continually myocardium). The normal heart functions almost exclusively reconditioning the circulating blood. Primary organs perform- as an aerobic organ with little capacity for anaerobic metabo- ing such tasks include (1) the lungs (02 and CO 2 exchange); lism to produce energy. Even during resting conditions, 70- (2) the kidneys (blood volume and electrolyte composition, Na ÷, 80% of the oxygen available in the blood circulating through K ÷, Ca 2+, C1- and phosphate ions); and (3) the skin (tempera- the coronary vessels is extracted by the myocardium. 10 PART I: INTRODUCTION / IAIZZO

Lymp.h node inducing either arteriolar smooth muscle constriction or dila- tion). It is also common to consider that some of these feedback loops are in opposition. Interestingly, coronary arteriolar vasodilation from a resting state to one of intense exercise can result in an increase of mean coronary blood flow of approx 0.5-4.0 mL/min/g. As with all systemic circulatory vascular beds, the aortic or arterial pressure (perfusion pressure) is vital for driving blood through the coronaries and thus needs to be considered another important determinant of coronary flow. More specifically, coronary blood flow varies directly with the pressure across the coronary microcirculation, which can be considered essen- tially as the aortic pressure because coronary venous pressure is typically near zero. However, because the coronary circulation perfuses the heart, some very unique determinants for flow through these capillary beds may also occur; e.g., during systole, myocardial extravascular compression causes coronary flow to be near zero, yet it is relatively high during diastole (note that this is the opposite of all other vascular beds in the body). Fig. 6. Schematic diagram showing the relationship between the lymphatic system and the cardiopulmonary system. The lymphatic system 2.7. lymphatic System is unidirectional, with fluid flowing from interstitial space back to the The lymphatic system represents an accessory pathway by general circulatory system. The sequence of flow is from blood capillaries (systemic and pulmonary) to the interstitial space, to the lym- which large molecules (e.g., proteins and long-chain fatty acids) phatic capillaries (lymph), to the lymphatic vessels, to the thoracic can reenter the general circulation and thus not accumulate in duct, into the subclavian veins (back to the right atrium). (Modified the interstitial space. If such particles accumulate in the inter- from Tortora and Grabowski, 2000.) stitial space, then filtration forces exceed reabsorptive forces, and edema occurs. Almost all tissues in the body have lymph channels that drain excessive fluids from the interstitial space (exceptions include portions of skin, the central nervous system, the endomysium of muscles, and bones with prelymphatic It then follows that, because of the limited ability of the heart channels). to increase oxygen availability by further increasing oxygen The lymphatic system begins in various tissues with blind- extraction, increases in myocardial demand for oxygen (e.g., end specialized lymphatic capillaries that are roughly the size during exercise or stress) must be met by equivalent increases of regular circulatory capillaries, but they are less numerous in coronary blood flow. Myocardial ischemia results when the (Fig. 6). However, the lymphatic capillaries are very porous arterial blood supply fails to meet the needs of the heart muscle and thus can easily collect the large particles within the inter- for oxygen and/or metabolic substrates. Even mild cardiac is- stitial fluid known as lymph. This fluid moves through the chemia can result in anginal pain, electrical changes (detected converging lymphatic vessels and is filtered through lymph on an electrocardiogram), and the cessation of regional cardiac nodes, in which bacteria and particulate matter are removed. contractile function. Sustained ischemia within a given myo- Foreign particles that are trapped in the lymph nodes are cardial region will most likely result in an infarction. destroyed (phagocytized) by tissue macrophages lining an As noted, as in any microcirculatory bed, the greatest resis- inner meshwork of sinuses. Lymph nodes also contain T and B tance to coronary blood flow occurs in the arterioles. Blood lymphocytes, which can destroy foreign substances by a vari- flow through such vessels varies approximately with the fourth ety of immune responses. There are approx 600 lymph nodes power of the radii of these vessels; hence, the key regulated located along the lymphatic vessels; they are 1-25 mm long variable for the control of coronary blood flow is the degree of (bean shaped) and covered by a capsule of dense connective constriction or dilatation of coronary arteriolar vascular smooth tissue. Lymph flow is unidirectional through the nodes (Fig. 6). muscle. As with all systemic vascular beds, the degree of coro- The lymphatic system is also one of the major routes for nary arteriolar smooth muscle tone is normally controlled by absorption of nutrients from the gastrointestinal tract (particu- multiple independent negative-feedback loops. These mecha- larly for the absorption of fat and lipid-soluble vitamins A, D, nisms include various neural, hormonal, and local nonmetabolic E, and K). For example, after a fatty meal, lymph in the thoracic and local metabolic regulators. duct may contain as much as 1-2% fat. It should be noted that the local metabolic regulators of The majority of lymph then reenters the circulatory system arteriolar tone are usually the most important for coronary flow in the thoracic duct, which empties into the venous system at the regulation; these feedback systems involve oxygen demands juncture of the internal jugular and subclavian veins (which of the local cardiac myocytes. In general, at any point in time, then enters into the right atrium; see Chapters 3 and 4). The flow coronary blood flow is determined by integrating all the differ- of lymph from tissues toward the entry point into the circulatory ent controlling feedback loops into a single response (i.e., system is induced by two main factors: (1) higher tissue inter- CHAPTER 1 / CARDIOVASCULAR SYSTEM FEATURES 11 stitial pressures and (2) the activity of the lymphatic pumps such flow will quickly cause serious edema. Therefore, the lym- (contractions within the lymphatic vessels themselves, contrac- phatic circulation plays a critical role in keeping the interstitial tions of surrounding muscles, movement of parts of the body, protein concentration low and in removing excess Capillary fil- and/or pulsations of adjacent arteries). In the largest lymphatic trate from tissues throughout the body. vessels (e.g., thoracic duct), the pumping action can generate SOURCES pressures as high as 50-100 mm Hg. Valves located in the lymphatic vessel, like in veins, aid in the prevention of the backflow Alexander, R.W., Schlant, R.C., and Fuster, V. (eds.) (1998) Hurst's the Heart, Arteries and Veins, 9th Ed. McGraw-Hill, New York, NY. of lymph. Germann, W.J. and Stanfield,C.L. (eds.) (2002) Principles ofHuman Physi- Approximately 2.5 L of lymphatic fluid enter the general ology. Pearson Education/Benjamin Cummings, San Francisco, CA. blood circulation (cardiopulmonary system) each day. In the Guyton, A.C. and Hall, J.E. (eds.) (2000) Textbook of Medical Physiology, steady state, this indicates a total body net transcapillary fluid 10th Ed. Saunders, Philadelphia, PA. Mohrman, D.E. and Heller, L.J. (eds.) (2003) Cardiovascular Physiology, filtration rate of 2.5 L per day. When compared with the total 5th Ed. McGraw-Hill, New York, NY. amount of blood that circulates each day (approx 7000 L per Tortora, G.J. and Grabowski, S.R. (eds.) (2000) Principles of Anatomy day), this seems almost insignificant; however, blockage of and Physiology, 9th Ed. Wiley, New York, NY. ANATOMY II 2 Cardiac Development

BRAD J. MARTINSEN, PhD AND JAMIE L. LOHR, MD

CONTENTS

INTRODUCTION TO HUMAN HEART EMBRYOLOGY AND DEVELOPMENT PRIMARY HEART FIELD AND LINEAR HEART TUBE FORMATION SECONDARY HEART FIELD, OUTFLOWTRACT FORMATION, AND CARDIAC LOOPING CARDIAC NEURAL CREST AND OUTFLOWTRACT AND ATRIAL AND VENTRICULARSEPTATION PROEPICARDIUM AND CORONARY ARTERY DEVELOPMENT CARDIAC MATURATION SUMMARY OF EMBRYONIC CONTRIBUTIONTO HEART DEVELOPMENT REFERENCES

1. INTRODUCTION TO HUMAN HEART human congenital heart disease (5). In addition, great strides EMBRYOLOGY AND DEVELOPMENT have also been made in our knowledge of the contribution of the cardiac neural crest and the epicardium to overall heart devel- The primary heart field, secondary heart field, cardiac neural opment. crest, and proepicardium are the four major embryonic regions involved in the process of vertebrate heart develop- 2. PRIMARY HEART FIELD ment (Fig. 1). They each make an important contribution to AND LINEAR HEART TUBE FORMATION overall cardiac development, which occurs with complex developmental timing and regulation. This chapter describes The cells that will become the heart are among the first cell how these regions interact to form the final structure of the heart lineages formed in the vertebrate embryo (6,7). By day 15 of in relationship to the generalized developmental timeline of human development, the primitive streak has formed (8), and human embryology (Table 1). the first mesodermal cells to migrate (gastrulate) through the The heart is the first organ to fully form and function during primitive streak are cells fated to become the heart (9,10) vertebrate development, and many of the underlying mecha- (Fig. 2). These mesodermal cells migrate to an anterior and nisms are considered molecularly and developmentally con- lateral position where they form bilateral primary heart fields served (1). The description presented here is based on heart (Fig. 1A) (11). Studies of chick development have not sup- development research from the chick, mouse, frog, and human ported the previously held notion of a medial cardiac crescent model systems. Importantly, numerous research findings have that bridges the two bilateral primary heart fields (12). Com- redefined the understanding of the primary heart field, which plete comparative molecular and developmental studies gives rise to the main structure of the heart (atria and ventricles) between the chick and mouse are required to confirm these and have led to exciting discoveries of the secondary heart field, results. The posterior border of the bilateral primary heart field which gives rise to the outflow tracts of the mature heart (2-4). reaches to the first somite in the lateral mesoderm on both sides These discoveries were a critical step in advancing our under- of the midline (Fig. 1A) (3,12). standing of how the outflow tracts of the heart form, an area in At day 18 of human development, the lateral plate meso- which many congenital heart defects arise, and thus have had derm is split into two layers: somatopleuric and splanchno- important implications for the understanding and prevention of pleuric (8). It is the splanchnopleuric mesoderm layer that From: Handbook of Cardiac Anatomy, Physiology, and Devices contains the myocardial and endocardial cardiogenic precur- Edited by: P. A. Iaizzo © Humana Press Inc., Totowa, NJ sors in the region of the primary heart fields as defined above.

15 16 PART I1: ANATOMY / MARTINSEN AND I.OHR

Fig. 1. The four major contributors to heart development illustrated in the chick model system: primary heart field, secondary heart field, cardiac neural crest, and proepicardium. (A) Day 1 chick embryo (equivalent to day 20 of human development). Red denotes primary heart field cells. (B) Day 2.5 chick embryo (equivalent to -5 wk of human development). Green denotes cardiac neural crest cells; yellow denotes secondary heart field cells; blue denotes proepicardial cells. (C) Day 8 chick heart (equivalent to -9 wk of human development). Green dots represent derivatives of the cardiac neural crest; yellow dots represent derivatives of the secondary heart field; red dots represent derivatives of the primary heart fields; blue dots represent the derivatives of the proepicardium. Ao, aorta; APP, anterior parasympathetic plexis; Co, coronary vessels; E, eye; H, heart; IFT, inflow tract; LA, left atrium; LV, left ventricle; Mb, midbrain; NF, neural folds; OFT, outflow tract; Otc, otic placode; P, pulmonary artery; RA, right atrium; RV, right ventricle; T, trunk. CHAPTER 2 / C'ARDIAC DEVELOPMENT 17

Table 1 Developmental Timeline of Human Heart Embryology Days of human Developmental development process 0 Fertilization. 1-4 Cleavage and movement down the oviduct to the uterus. 5-12 Implantation of the embryo into the uterus. 13-14 Primitive streak formation (midstreak level contains precardiac cells). 15-17 Formation of the three primary germ layers (gastrulation): ectoderm, mesoderm, and endoderm. Midlevel primitive streak cells that migrate to an anterior and lateral position form the bilateral primary heart field. 17-18 Lateral plate mesoderm splits into the somatopleuric mesoderm and splanchnopleuric mesoderm. Splanchnopleuric mesoderm contains the myocardial and endocardial cardiogenic precursors in the region of the primary heart field. 18-26 Neurulation (formation of the neural tube) 20 Cephalocaudal and lateral folding brings the bilateral endocardial tubes into the ventral midline of the embryo. 21-22 Heart tube fusion. 22 Heart tube begins to beat. 22-28 (3-4 wk) Heart looping and the accretion of cells from the primary and secondary heart fields. 22-28 (3-4 wk) Proepicardial cells invest the outer layer of the heart tube and eventually form the epicardium and coronary vasculature. 22-28 (3-4 wk) Neural crest migration starts. 32-37 (5-6 wk) Cardiac neural crest migrates through the aortic arches and enters the outflow tract of the heart. 57+ (9 wk) Outflow tract and ventricular septation complete. Birth Functional septation of the atrial chambers as well as the pulmonary and systemic circulatory systems. Most of the human developmental timing information is from ref. 8, except for the human staging of the secondary heart field and proepicardium, which was correlated from other model systems (2~l,14).

Neural fold Dorsal aorta Presumptive endocardial cells delaminate from the splanch- Somatopleuric nopleuric mesoderm and coalesce via vasculogenesis to form planchnopleuric two lateral endocardial tubes (Fig. 2A) (13). igrating During the third week of human development, two bilateral hnopleuric cells layers of myocardium surrounding the endocardial tubes are A Endocardial tube brought into the ventral midline during closure of the ventral foregut via cephalic and lateral folding of the embryo (Fig. 2A) (8). The lateral borders of the myocardial mesoderm layers are the first heart structures to fuse, followed by the fusion of the two endocardial tubes to form one endocardial tube surrounded by splanchnopleuric-derived myocardium (Fig. 2B,C). The medial borders of the myocardial mesoderm layers are the last g lateral to fuse (14). Thus, the early heart is continuous with noncardiac ardium splanchnopleuric mesoderm across the dorsal mesocardium (Fig. 2C). This will eventually partially break down to form the ventral aspect of the linear heart tube with a posterior inflow (venous pole) and anterior outflow (arterial pole), as well as the dorsal wall of the pericardial cavity (5,14). During the fusion of ~rest cells the endocardial tubes, the myocardium secretes an acellular y heart field matrix, forming the cardiac jelly layer that separates the myocardium and endocardium. 'sal By day 22 of human development, the linear heart tube ;ocardium begins to beat. As the human heart begins to fold and loop from days 22-28 (described in the next section), epicardial cells will endocardial invest the outer layer of the heart tube (Fig. 1B and Fig. 3A), resulting in a heart tube with four primary layers: endocardium, nyocardium cardiac jelly, myocardium, and epicardium (Fig. 3B) (8).

3. SECONDARY HEART FIELD, OUTFLOW TRACT Fig. 2. Cross-sectional view of human heart tube fusion: (A) Day 20, FORMATION, AND CARDIAC LOOPING cephalocaudal and lateral folding brings bilateral endocardial tubes into the ventral midline of the embryo. (B) Day 21, start of heart tube A cascade of signals identifying the left and right sides of the fusion. (C) Day 22, complete fusion, resulting in the beating primitive embryo are thought to initiate the process of primary linear heart tube. Ectoderm, dark gray; mesoderm, gray; endoderm, white. 18 PART I1: ANATOMY / MARTINSEN AND LOHR

Mvocardium.

Er pican

rating Lrdial \

'enosl

Jm ~rsum

A Fig. 3. Origin and migration of proepicardial cells. (A) Whole mount view of the looping human heart within the pericardial cavity at day 28. Proepicardial cells (dark gray dots, mesoderm origin) emigrate from the sinus venosus and possibly the septum transversum and then migrate out over the outer surface of the ventricles, eventually surrounding the entire heart. (B) Cross-sectional view of the looping heart showing the four layers of the heart: epicardium, myocardium, cardiac jelly, and endocardium. LV, left ventricle; RV, right ventricle.

Linear heart Looping & Septation tube Accretion Day 22 Day 28 9 weeks

Fig. 4. Looping and septation of the human primary linear heart tube. Dark gray and white regions represent tissue added during the looping process from the primary and secondary heart field, respectively. Ao, aorta; AV, atrioventricular region; LA, left atrium; LV, left ventricle; P, pulmonary artery; RA, right atrium; RV, right ventricle.

heart tube looping (15). The primary heart tube loops to the flow tract (conus) and distal outflow tract (truncus) are added to right of the embryo and bends, to allow convergence of the the arterial pole from the secondary heart field (2-4). inflow (venous) and outflow (arterial) ends, from days 22-28 of The secondary heart field (Fig. 1B and Fig. 2C) is located human development (Fig. 4). This process occurs prior to the along the splanchnopleuric mesoderm (beneath the floor of the division of the heart tube into four chambers and is required for foregut) at the attachment site of the dorsal mesocardium (2- proper alignment and septation of the mature cardiac chambers. 4,14). During looping, the secondary heart field cells undergo During the looping process, the primary heart tube increases epithelial-to-myocardial transformation at the outflow (arte- dramatically in length (four- to fivefold), and this process dis- rial) pole and add additional myocardial cells onto the develop- places atrial myocardium posteriorly and superiorly dorsal to ing outflow tract. This lengthening of the primary heart tube the forming ventricular chambers (5,8,15). During the looping appears to be an important process for the proper alignment of process, the inflow (venous) pole, atria, and atrioventricular the inflow and outflow tracts prior to septation. If this process region are added to, or accreted from, the posterior region of the does not occur normally, ventricular septal defects and paired primary heart fields; the myocardium of proximal out- malpositioning of the aorta may occur (14). CHAPTER 2 / CARDIAC DEVELOPMENT 19

Thus, by day 28 of human development, the chambers of the heart are in position and are demarcated by visible con- strictions and expansions that denote the sinus venosus, common atrial chamber, atrioventricular sulcus, ventricular chamber, and conotruncus (proximal and distal outflow tract) (Fig. 4) (8,14). 4. CARDIAC NEURAL CREST AND OUTFLOW TRACT AND ATRIAL AND VENTRICULAR SEPTATION Once the chambers are in their correct positions after looping, extensive remodeling of the primitive vasculature and septation of the heart can occur. The cardiac neural crest is an extracardiac (from outside the primary or secondary heart fields) population of cells that arises from the neural tube in the region of the first three somites up to the midotic placode level (rhombomeres 6-8) (Fig. 5). Cardiac neural crest cells leave the neural tube during weeks 3-4 of human development and migrate through aortic arches 3, 4, and 6 (Fig. 1B) and then eventually move into the developing outflow tract of the heart during weeks 5 and 6. These cells are necessary for complete septation of the outflow tract and ventricles (which is completed by week 9 of human development), as well as for the formation of the anterior parasympathetic plexis, which contributes to cardiac innervation and the regulation of heart rate (8,16-18). The primitive vasculature of the heart is bilaterally symmetrical, but during weeks 4 to 8 of human development, there is remodeling of the inflow end of the heart so that all systemic blood will flow into the future right atrium (8). In addition, there is extensive remodeling of the initially bilaterally symmetrical aortic arch arteries into the great arteries (septation of the aortic and pulmonary vessels) that is dependent on the presence of the cardiac neural crest (14,19). The distal outflow tract (truncus) Fig. 5. Origin of the cardiac neural crest within a 34-h chick embryo. septates into the aorta and pulmonary trunk via the fusion of two Green dots represent cardiac neural crest cells in the neural folds of streams or prongs of cardiac neural crest that migrate into the hindbrain rhombomeres 6-8 (the region of the first three somites up distal outflow tract. In contrast, the proximal outflow tract to the midotic placode level). Fb, forebrain; Mb, midbrain. septates by fusion of the endocardial cushions and eventually joins proximally with the atrioventricular endocardial cushion tissue and the ventricular septum (20,2 l). The endocardial cushions are formed by both atrioventricular canal and outflow tract endocardial cells that migrate into the cardiac jelly, forming fuse with the atrioventricular cushions, which also divide the bulges or cushions. left and right atrioventricular canals and serve as the source of Despite its clinical importance, to date almost nothing is cells for the atrioventricular valves. Prior to septation, the known about the molecular pathways that determine cell lin- right atrioventricular canal and right ventricle expand to the eages in the cardiac neural crest or that regulate outflow tract right, causing a realignment of the atria and ventricles so that septation (14). However, it is known that if the cardiac neural they are directly over each other. This allows venous blood crest is removed before it begins to migrate, the conotruncal entering from the sinus venosus to flow directly from the right septa completely fails to develop, and blood leaves both the atrium to the presumptive right ventricle without flowing ventricles through what is termed a persistent truncus arterio- through the presumptive left atrium and ventricle (8,14). The sus, a rare congenital heart anomaly in humans. Failure of out- new alignment also simultaneously provides the left ventricle flow tract septation may also be responsible for other forms of with a direct outflow path to the truncus arteriosus and subse- congenital heart disease, including transposition of the great quently to the aorta. vessels, high ventricular septal defects, and tetralogy of Fallot Between weeks 4 and 7 of human development, the left and (8,16,18). right atria undergo extensive remodeling and are eventually The septation of the outflow tract (conotruncus) is tightly septated. However, during the septation process, a right-to-left coordinated with the septation of both the ventricles and atria shunting of oxygenated blood (oxygenated by the placenta) is to produce a functional heart. All of these septa eventually created via shunts, ducts, and foramens (Fig. 6). Prior to birth, 20 PART I1: ANATOMY / MARTINSEN AND LOHR

Fora OV

Fig. 6. Transition from fetal dependence on the placenta for oxygenated blood to self-oxygenation via the lungs. (A) Circulation in the fetal heart before birth. Pink arrows show right-to-left shunting of placentally oxygenated blood through the foramen ovale and ostium secundum. (B) Circulation in the infant heart after birth. The first breath of the infant and cessation of blood flow from the placenta cause final septation of the heart chambers (closure of the foramen ovale and ostium secundum) and thus separation of the pulmonary and systemic circulatory systems. Blue arrows show the pulmonary circulation, and the red arrows show the systemic circulation within the heart. AV, atrioventricular; LA, left atrium; LV, left ventricle; RA, right atrium; RV, right ventricle.

the use of the pulmonary system is not necessary, but eventually in the circulatory system occur because of the transition from a complete separation of the systemic and pulmonary circula- fetal dependence on the placenta for oxygenated blood to self- tory systems will be necessary for normal cardiac and systemic oxygenation via the lungs. During fetal life, only small function (8). Initially, the right sinus horn is incorporated into amounts of blood are flowing through the pulmonary system the right posterior wall of the primitive atrium, and the trunk of because the fluid-filled lungs create high resistance, resulting the pulmonary venous system is incorporated into the posterior in low-pressure and low-volume flow into the left atrium from wall of the left atrium via a process called intussusception. the pulmonary veins. This allows the high-volume blood flow At day 26 of human development, a crescent-shaped wedge coming from the placenta to pass through the inferior vena of tissue, called the septum primum, begins to extend into the cava into the right atrium, where it is then directed across the atrium from the mesenchyme of the dorsal mesocardium. As it foramen ovale into the left atrium. The oxygenated blood then grows, it diminishes the ostium primum, a foramen that allows flows into the left ventricle and directly out to the body via the shunting of blood from the right to the left atrium. However, aorta. At birth, the umbilical blood flow is interrupted, stop- programmed cell death near the superior edge of the septum ping the high-volume flow from the placenta. In addition, the primum creates a new foramen, the ostium secundum, which alveoli and pulmonary vessels open when the infant takes its continues the right-to-left shunting of oxygenated blood. An first breath, dropping the resistance in the lungs and allowing incomplete, ridged septum secundum with a foramen ovale near more flow into the left atrium from the lungs. This reverse in the floor of the right atrium forms next to the septum primum; pressure difference between the atria pushes the flexible sep- both fuse with the septum intermedium of the atrioventricular tum primum against the ridged septum secundum and closes cushions (8). the foramen ovale and ostium secundum, resulting in the com- At the same time as atrial septation is beginning, at about the plete septation of the heart chambers (Fig. 6) (8). end of the fourth week of human development, the muscular 5. PROEPICARDIUM AND CORONARY ventricular septum begins to grow toward the septum intermedium (created by the fusion of the atrioventricular cush- ARTERY DEVELOPMENT ions), creating a partial ventricular septum. By the end of the The last major contributor to vertebrate heart development ninth week of human development, the outflow tract septum has discussed in this chapter is the proepicardium. Prior to heart grown down onto the upper ridge of this muscular ventricular looping, the primary heart tube consists of endocardium, car- septum and onto the inferior endocardial cushion, which com- diac jelly, and myocardium. It is not until the start of heart pletely separates the right and left ventricular chambers. looping that the epicardium surrounds the myocardium, form- Not until after birth, however, does the heart become func- ing the fourth layer of the primary heart tube (Fig. 3) (22). This tionally septated in the atrial region. At birth, dramatic changes population of cells will eventually give rise to the coronary CHAPTER 2 / CARDIAC DEVELOPMENT 21 vasculature. A neural crest origin of the coronary vessels was myocardium has less muscle mass and less cellular organiza- originally hypothesized, but lineage tracing studies have shown tion than the mature myocardium. The newborn myocardium that the neural crest gives rise to cells of the tunica media of the consists of 30% contractile proteins and 70% noncontractile aortic and pulmonary trunks, but not to the coronary arteries mass (membranes, connective tissues, and organelles), in con- (13,23). These investigators also concluded that the coronary trast to the adult myocardium, which is 60% contractile mass vasculature is derived from the proepicardial organ, a nest of (30). The myocardial cells of the fetus are rounded, and both the cells in the dorsal mesocardium of the sinus venosus or septum myocardial cells and myofibrils within them are oriented ran- transversum. These cells, which are derived from an indepen- domly. As the fetal heart matures, these myofibrils increase in dent population of splanchnopleuric mesoderm cells, migrate size and number and orient to the long axis of the cell, which onto the primary heart tube between day 22 and day 28 of further contributes to improved myocardial function (28). The human development (Fig. 3),just as the heart begins its looping fetal myocardial cell contains higher amounts of glycogen than (8,14). Prior to migration, these cells are collectively called the the mature myocardium, suggesting a higher dependence on proepicardium or the proepicardial organ. glucose for energy production; in experiments in nonprimate Interestingly, three lineages of the coronary vessel cells model systems, the fetal myocardium is able to meet its meta- (smooth muscle, endothelial, and connective tissue cells) are bolic needs with lactate and glucose as the only fuels (33). In segregated in the proepicardium prior to migration into the heart contrast, the preferred substrate for energy metabolism in the tube (13,24). These cells will coalesce to form coronary vessels adult heart is long-chain fatty acids, although the adult heart is de novo via the process of vasculogenesis (25). It has also been able to utilize carbohydrates as well (33,34). This change is shown that the epicardium provides an intrinsic factor needed considered to be triggered in the first few days or weeks of life for normal myocardial development and is a source of cells by an increase in serum long-chain fatty acids with feeding, but needed for forming the interstitial myocardium and cushion the timing and clinical impact of this transition relative to an ill mesenchyme (14,26). It should be noted that an understanding or nonfeeding neonate with cardiovascular disease is currently of the embryological origin of the vascular system and its unknown. molecular regulation is thought to be important in helping to In addition, the maturing myocardial cells undergo changes explain the varying susceptibility of different components of in the expression of their contractile proteins, which may be the vascular system to atherosclerosis (13,27). responsible for some of the maturational differences in cardiovascular function. Changes in expression of contractile proteins 6. CARDIAC MATURATION that may be important in humans include a gradual increase in Although the embryonic heart is fully formed and func- the expression of myosin light chain 2 (MLC 2) in the ventricle tional by the 1 lth week of pregnancy, the fetal and neonatal from the neonatal period through adolescence. In the fetal heart continue to grow and mature rapidly, with many clini- ventricle, two forms of myosin light chain, MLC 1 and MLC 2, cally relevant changes taking place after birth. During fetal are expressed in equal amounts (30,35). Increased MLC 1 development, or from the time after the embryo is completely expression is associated with increased contractility; for formed in the first trimester of pregnancy until birth, the heart example, it has been documented in isolated muscle from grows primarily by the process of cell division (28-31). Within patients with tetralogy of Fallot that both MLC 1 expression and a few weeks after birth, the predominant mechanism of car- contractility are increased (36). After birth, there is a gradual diac growth is cell hypertrophy; in other words, existing car- increase in the amount of MLC 2, or the "regulatory" myosin diac cells become larger rather than increasing significantly in light chain, which has a slower rate of force development but number (28-30). can be phosphorylated to increase calcium-dependent force The exact timing of this process and the mechanisms regu- development in mature cardiac muscle (30,37). lating these changes are not yet completely elucidated. In the There is also variability in actin isoform expression during classic explanation, mature cardiac cells lose the ability to cardiac development. The human fetal heart predominantly divide; however, more recent work suggests that a limited expresses cardiac ct-actin; the more mature human heart amount of cell division can occur in adult human hearts dam- expresses skeletal c~-actin (28,38). Actin is responsible for aged by ischemia (32). This finding has led to a renewed inter- interacting with myosin cross bridges and regulating adenos- est in understanding the regulation of cell division during ine triphosphatase (ATPase) activity, and work done in the cardiac maturation. Additional maturational changes in both mouse model system suggests that the change to skeletal actin the fetal and neonatal heart include alterations in the compo- may be an additional mechanism of enhanced contractility in sition of cardiac muscle, differences in energy production, and the mature heart (28,39,40). maturation of the contractile function. These changes, along There are also developmental changes of potential functional with associated physiological changes in the transitional cir- significance within the regulatory proteins of the sarcomere. culation, as discussed in Section 4, affect the treatments of More specifically, the fetal heart expresses both ~- and [3-tro- newborns with congenital heart disease, particularly those pomyosin, a regulatory filament, in nearly equal amounts; after requiring interventional procedures or cardiac surgery. birth, the proportion of [3-tropomyosin decreases, and c~-tro- The hemodynamic changes associated with birth include a pomyosin increases, potentially to optimize diastolic relaxation significant increase in left ventricular cardiac output to meet the (28,41,42). Interestingly, an expression of high levels of 13-tro- increased metabolic needs of the newborn infant. This improve- pomyosin in the neonatal heart has been linked to early death ment in cardiac output occurs despite the fact that the neonatal caused by myocardial dysfunction (43). 22 PART I1: ANATOMY / MARTINSEN AND LOHR

Last, the isoform of the inhibitory troponin, troponin I, also the complexity of human heart development. Each of these changes after birth. The fetal myocardium contains mostly the regions makes a unique contribution to the heart, but they skeletal isoform of troponin I (28,44); after birth, the myocar- ultimately depend on each other for the creation of a fully dium begins to express cardiac troponin I, and by approx 9 mo functional organ. of age, only cardiac troponin I is present (28,45,46). It should An understanding of the mechanisms of human heart devel- also be noted that cardiac troponin I can be phosphorylated to opment provides clues to the etiology of congenital heart dis- improve calcium responsivity and contractility, which may ease. Nevertheless, to date, the genetic regulatory mechanisms improve function in the more mature heart; it is thought that the of these developmental processes are just starting to be charac- skeletal form of troponin I may serve to protect the fetal and terized. A molecular review of heart development is outside the neonatal myocardium from acidosis (30,39,47). scope of this chapter, but several interesting molecular heart In summary, the full impact of these developmental changes reviews have been published (14,52,53). A better understand- in contractile proteins and their effect on cardiac function ing of the embryological origins of the heart combined with the or perioperative treatment of the newborn with heart disease characterization of the genes that control heart development remains unclear at the present time. However, such insights (54) may lead to many new clinical applications to treat con- may provide future modes for optimizing therapy in children. genital and adult heart disease. Two of the most clinically relevant features of the immature REFERENCES myocardium are its requirement for high levels of extracellular calcium and a decreased sensitivity to [3-adrenergic inotropic 1. Srivastava, D. and Olson, E.N. (2000) A genetic blueprint for cardiac development. Nature. 407,221-226. agents. The neonatal heart has a decrease in both volume and 2. Kelly, R.G., Brown, N.A., and Buckingham, M.E. (2001) The arte- functional maturity of the sarcoplasmic reticulum, which stores rial pole of the mouse heart forms from Fgfl0-expressing cells in intracellular calcium (28). The paucity of intracellular calcium pharyngeal mesoderm. Dev Cell. 1,435-440. storage and subsequent release via the sarcoplasmic reticulum 3. Mjaatvedt, C.H., Nakaoka, T., Moreno-Rodriguez,R., et al. (2001) in the fetal and neonatal myocardium increases the require- The outflow tract of the heart is recruited from a novel heart-forming ments of these myocardia for extracellular calcium, so that field. Dev Biol. 238, 97-109. 4. Waldo, K.L., Kumiski, D.H., Wallis, K.T., et al. (2001) Conotruncal exogenous administration of calcium can be used to augment myocardium arises from a secondaryheart field. Development. 128, cardiac contractility in the appropriate clinical setting. In addi- 3179-3188. tion, neonates and infants are significantly more sensitive to 5. Kelly, R.G. and Buckingham, M.E. (2002) The anterior heart-form- calcium channel blocking drugs than older children and adults ing field: voyage to the arterial pole of the heart. Trends Genet. 18, and thus are at a higher risk for severe depression of myocardial 210-216. 6. Hatada, Y. and Stern, C.D. (1994) A fate map of the epiblast of the contractility with the administration of these agents (28,30,48). early chick embryo. Development. 120, 2879-2889. Last, although data in humans are limited, there appears to 7. Yutzey, K.E. and Kirby, M.L. (2002) Wherefore heart thou? Embry- be significantly decreased sensitivity to [3-agonist agents in onic origins of cardiogenic mesoderm. Dev Dyn. 223, 307-320. the immature myocardium and in older children with congeni- 8. Sherman, L.S., Potter, S.S., and Scott, W.J. (eds.) (2001) Human tal heart disease (30,49-51). This may be attributable to a Embryology, 3rd Ed. Churchill Livingstone, New York, NY. 9. Garcia-Martinez, V. and Schoenwolf, G.C. (1993) Primitive-streak paucity of receptors, sensitization to endogenous catechola- origin of the cardiovascular system in avian embryos. Dev Biol. 159, mines at birth or with heart failure, or a combination of these 706-719. and/or additional factors. Because of this decreased respon- 10. Psychoyos, D. and Stern, C.D. (1996) Fates and migratory routes siveness to [3-agonists, there is a common requirement clini- of primitive streak cells in the chick embryo. Development. 122, cally for administrating higher doses of [3-agonist inotropic 1523-1534. 11. DeHaan, R.L. (1963) Organization of the cardiogenic plate in the agents in newborns and infants. Importantly, alternative medi- early chick embryo. Acta Embryol Morphol Exp. 6, 26-38. cations, including phosphodiesterase inhibitors, are often use- 12. Ehrman, L.A. and Yutzey, K.E. (1999) Lack of regulation in the heart ful adjuncts to improve contractility in newborns with forming region of avian embryos. Dev Biol. 207, 163-175. myocardial dysfunction (30). 13. Harvey, R.P. and Rosenthal, N. (eds.) (1998) Heart Development. Although the structure of the heart is complete in the first Academic Press, New York, NY. 14. Kirby, M.L. (2002) Molecular embryogenesis of the heart. Pediatr trimester of pregnancy, cardiac growth and maturation occur Dev Pathol. 5,516-543. in the fetus, newborn, and child. Many of these developmental 15. Lohr, J.L. and Yost, J.H. (2000) Vertebrate model systems in the changes, particularly decreased intracellular calcium stores study of early heart development: xenopus and zebrafish. Am J Med in the immature sarcoplasmic reticulum and a decreased Genet. 97,248-257. responsiveness to [3-agonist inotropic agents, have a significant 16. Kirby, M.L., Gale, T.F., and Stewart, D.E. (1983) Neural crest cells contribute to normal aorticopulmonary septation. Science. 220, impact on the care of newborns, infants, and children with con- 1059-1061. genital heart disease, particularly those requiring surgical inter- 17. Kirby, M.L. and Stewart, D.E. (1983) Neural crest origin of cardiac vention early in life. ganglion cells in the chick embryo: identification and extirpation. Dev Biol. 97,433-443. 7. SUMMARY OF EMBRYONIC 18. Kirby, M.L., Turnage, K.L., 3rd, and Hays, B.M. (1985) Character- CONTRIBUTION TO HEART DEVELOPMENT ization of conotruncal malformations following ablation of "cardiac" neural crest. Anat Rec. 213, 87-93. The contribution of the four major embryonic regions (pri- 19. Bockman,D.E., Redmond, M.E., and Kirby, M.L. (1989) Alteration mary heart field, secondary heart field, cardiac neural crest, of early vascular development after ablation of cranial neural crest. and proepicardium; Fig. 1) to heart development illustrates Anat Rec. 225,209-217.