Handbook of Cardiac Anatomy, Physiology, and Devices [3 ed.] 9783319194646, 331919464X

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Paul A. Iaizzo Editor

Handbook of Cardiac Anatomy, Physiology, and Devices Third Edition

Handbook of Cardiac Anatomy, Physiology, and Devices

Paul A. Iaizzo Editor

Handbook of Cardiac Anatomy, Physiology, and Devices Third Edition

Editor Paul A. Iaizzo University of Minnesota Department of Surgery Minneapolis, MN, USA

Additional material to this book can be downloaded from http://extras.springer.com ISBN 978-3-319-19463-9 ISBN 978-3-319-19464-6 DOI 10.1007/978-3-319-19464-6

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Library of Congress Control Number: 2015950854 Springer Cham Heidelberg New York Dordrecht London 1st edition: © 2005 Humana Press Inc. 2nd edition: © 2009 Springer Science+Business Media, LLC © Springer International Publishing Switzerland 2015 This work is subject to copyright. All rights are reserved by the Publisher, whether the whole or part of the material is concerned, specifically the rights of translation, reprinting, reuse of illustrations, recitation, broadcasting, reproduction on microfilms or in any other physical way, and transmission or information storage and retrieval, electronic adaptation, computer software, or by similar or dissimilar methodology now known or hereafter developed. The use of general descriptive names, registered names, trademarks, service marks, etc. in this publication does not imply, even in the absence of a specific statement, that such names are exempt from the relevant protective laws and regulations and therefore free for general use. The publisher, the authors and the editors are safe to assume that the advice and information in this book are believed to be true and accurate at the date of publication. Neither the publisher nor the authors or the editors give a warranty, express or implied, with respect to the material contained herein or for any errors or omissions that may have been made. Printed on acid-free paper Springer International Publishing AG Switzerland is part of Springer Science+Business Media (www.springer.com)

Foreword

In the course of one’s professional life, you may be fortunate to encounter an opportunity that brings new clarity to your approach to business. I had such an experience in 1997, when three people—Dr. Paul A. Iaizzo, Tim Laske, and Mark Hjelle—walked into my office and started talking about reanimating porcine hearts on the bench, as a training tool for engineers and scientists working on medical devices. I had no idea what they were talking about, and I did not really know Dr. Paul A. Iaizzo, a professor at the University of Minnesota. But I did know Tim Laske and Mark Hjelle, who are two of the most creative engineers I have ever met. I trust their judgment and their skills. The trio’s story, vision, and declaration of what could be achieved were compelling. I was cautious, however, because, to that point in time, our ability to work effectively in partnership with universities was nothing to write home about…except to complain. Nonetheless, we were always looking for better ways to educate our employees engaged in research, design, or manufacturing of medical products. Clinical applicability is the name of the game for any medical product, but it is very easy for scientists and engineers to design without fully understanding the environment in which their products are being used. This is true in all industries. Lack of understanding of the specific application creates mediocrity in performance. Because of the increasing complexity of the products required to support the rapidly growing tachycardia and resynchronization therapies, we were feeling the pressure to “up our game.” If Tim and Mark believed that Dr. Iaizzo could do what he was proposing, I had no choice but to say yes, and we provided the seed money to get the Visible Heart® laboratory off the ground. Little did I realize at the time what “the trio” and the University of Minnesota team were about to accomplish. Throughout this book, you will see many images and videos of what the heart prep at the University of Minnesota’s Visible Heart Lab can produce. The results of Professor Iaizzo and his research team exceeded my most optimistic projections of the value of the investment. The Visible Heart Lab brings a new depth of understanding to what actually is going on inside beating animal and human hearts. It has helped to reshape how the industry designs and evaluates products. It changed how we made decisions on products to fund or not fund and impacted how we ran our business. In advocating for the investment, Tim Laske, Mark Hjelle, and I made one mistake—we underestimated what Dr. Iaizzo and his team were capable of accomplishing. We would not make that mistake again. I do not believe failure is ever considered as an option by his team. However, as fantastic as the Visible Heart prep is by itself, it is not the most valuable product of the Visible Heart Lab. I am in awe of Dr. Iaizzo, his team, and industry partners who worked so hard to master the reanimation of hearts. The quality and educational value of the videos and images that they produce are amazing and unbelievably impactful. But the real “gems” of the Visible Heart Lab are the students who graduate every year and go out into the world. The heart prep experience is the core of their training. It is where the students get a chance to “put it all together” in their minds. The training they receive along the way in physiology, biochemistry, instrumentation, tissue engineering, genetics, core biology, and many other related disciplines is unparalleled in my experience. You will see both the basic and applied nature of their education and research as you read this book. v

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It was clear to me the first time we brought one of these students into our company that they were not the “normal” new graduates. Within weeks after graduating and coming to work at Medtronic, they were providing advice on cardiac anatomy and function to seasoned scientists and engineers who had been designing complex products and bringing them to market for years. These graduates had an uncanny ability to visualize products in the final application and judge how they would perform. They quickly became integrated and valuable contributors to our team, months to years ahead of our expectations. Once we experienced the quality of these graduates, we hired as many as we could. At one time we had hired all but one of the fourteen Ph.D. students; we would have hired that one too, if there had been an opening. Unfortunately, one of our competitors hired this individual. Years later, these graduates are still breaking new ground and raising the bar for others. They are establishing incubators in New York and computer modeling centers in California, running clinical study departments, managing product development for Fortune 500 companies, starting new companies, and providing leadership in many notable organizations. Most significantly, some of them are teaching, and all of them are both teachers and students. That is because Dr. Iaizzo ingrained in them the value and importance of continual learning and passing on knowledge to others. As a result, they are collaborators by nature, and they make a difference. Finally, I have to give credit to Dr. Iaizzo and his academic partners for the role they played in creating a new environment between the University of Minnesota and the medical device industry. Their response to the educational needs of the industry over the past 20 years has been more than notable—it is remarkable!! My experience with this dynamic group started with a casual comment made to Dr. Iaizzo in a hallway conversation almost 20 years ago regarding the need for training of industry scientists and engineers on anatomy and physiology. That hallway conversation sparked the annual “Advanced Cardiac Physiology and Anatomy” course, creating what has become the gold standard for training on the basics of anatomy and physiology for medical device professionals. Additionally, Dr. Iaizzo participates in the “New Product Design and Business Development” course, which was developed to pair business people with students to work in partnership with companies to solve real-world new product issues. Importantly, he created the Visible Heart Lab which represents the first major collaborative breakthrough in several years that initiated a change in the dynamic between the industry and the University. Subsequently, the University approved the establishment of the Medical Devices Center that has broken new ground in working in close partnering relationships with the industry. Building upon such work, the team of Professors Art Erdman, Will Durfee, and Paul Iaizzo founded the Design of Medical Devices Conference that is already a large and globally recognized annual conference. Last year the University announced a new policy governing intellectual property, which makes it easier for companies to license technology and enhances the University’s ability to capitalize on its research. This year a master’s degree in medical devices was offered for the first time. For years the University of Minnesota and the device industry did not partner well. Today they have set the standard for what collaborations between industry and academia can be, and it gets better every year. I am amazed and in admiration of what a team of creative people can do when they decide to do what most think is impossible. Enjoy the book; it gives you a sense of the quality of the people involved. LifeScience Alley and the BioBusiness Alliance of Minnesota Minneapolis, MN, USA

Dale Wahlstrom

Preface

Personalized medicine, clinical imaging, and the medical device industry continue to grow at an incredibly rapid pace. Further, our overall understanding of the molecular basis of diseases steadily increases, as does the number of available therapies to treat specific health problems. This remains particularly true in the field of cardiovascular care. With this rapid growth rate in cardiac medicine, clinicians and biomedical engineers alike have been challenged to either retool or continue to seek out sources of concise information. The major impetus for this third edition was to update this resource textbook for interested students, residents, clinicians, and/or practicing biomedical engineers. A secondary motivation was to promote the expertise, past and present, in the areas of cardiovascular science at the University of Minnesota. As Director of Education for the Lillehei Heart Institute and Associate Director for Education of the Institute for Engineering in Medicine at the University of Minnesota, I feel that this book also represents a unique outreach opportunity to carry on the legacy of Drs. C. Walton Lillehei, M.D., Ph.D., and Earl Bakken, M.D., Ph.D. (Hon.) through the twenty-first century. Interestingly, the completion of this textbook coincides with two recent important anniversaries in cardiovascular medicine and engineering at the University of Minnesota. First, it was 61 years ago, in 1954, that Dr. C. Walton Lillehei performed the first cross-circulation procedures at the University. One year ago in January, Earl Bakken (the cofounder of Medtronic) turned 90 years old; Dr. Bakken has five implanted Medtronic devices and continues to be an inspiration to those working in this field. For the past 15 years, the University of Minnesota has presented the week-long short course Advanced Cardiac Physiology and Anatomy, which was designed specifically for the biomedical engineer working in the industry; this serves as the course textbook. Thus there was a need to update the textbook to include state-of-the-art information on a variety of topics related to cardiac anatomy, physiology, and devices. For example, six new chapters were added to this third edition, and all other chapters were carefully updated and/or greatly expanded. One last historical note that I feel is interesting to mention once again is that my current laboratory, where isolated heart studies are performed weekly (the Visible Heart® laboratory), is the same laboratory in which C. Walton Lillehei and his many esteemed colleagues conducted the majority of their cardiovascular research studies in the late 1950s and early 1960s. It is also the laboratory where Earl Bakken, along with Drs. Vincent Gott and Lillehei, first tested the wearable battery-powered pacemaker on an animal with an induced heart block. After being tested on an animal, the prototype pacemaker was very quickly (later the same day) used by Dr. Lillehei on one of his cardiac surgical patients. With this new edition, complimentary materials (e.g., movies and images) that will enhance this textbook’s utility can be accessed online. Additionally, my laboratory continues to support the online, free access website The Atlas of Human Cardiac Anatomy (www.vhlab.umn.edu/ atlas) which also contains many tutorials and unique movie clips of functional cardiac anatomy. These images were obtained from human hearts made available via LifeSource (St. Paul, MN, USA), through the generosity of families and individuals who made the final gift of organ donation for research (their hearts were not deemed viable for transplantation).

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I would especially like to acknowledge the exceptional efforts of our Lab Coordinator, Monica Mahre, who for a third time (1) assisted me in coordinating the efforts of contributing authors, (2) skillfully incorporated my editorial changes, (3) verified the readability and formatting of each chapter, (4) pursued additions or missing materials for each chapter, (5) contributed as a coauthor, and (6) kept a positive outlook throughout. I would also like to thank Gary Williams for his computer expertise and assistance with numerous figures; Tinen Iles and Charles Soule who made sure the laboratory kept running smoothly while many of us were busy writing or editing; the Chairman of the Department of Surgery, Dr. David Rothenberger, for his support and encouragement; the Institute for Engineering in Medicine at the University of Minnesota, headed by Prof. Bin He, who helped support this project via educational funds; and the Lillehei Heart Institute at the University of Minnesota, headed by Dr. Daniel Garry, who also generously supported educational outreach efforts. I would like to thank Medtronic, Inc., for their continued support of the Visible Heart® laboratory for the past 18 years, and I especially acknowledge the commitment, partnership, and friendship of Tim Laske, Mark Hjelle, Alex Hill, Michael Eggen, Nick Skadsberg, Mark Borash, Rick McVenes, and Dale Wahlstrom for making our collaborative research possible. It is also my pleasure to thank the past and present graduate students or residents who have worked in my laboratory and who were contributors to this third edition including Sara Anderson, Michael Bateman, James Coles, Michael Eggen, Kevin Fitzgerald, Alexander Hill, Brian Howard, Stephen Howard, Tinen Iles, Jason Johnson, Ryan Lahm, Timothy Laske, Anna Legreid Dopp, Michael Loushin, Lars Mattison, Jason Quill, Maneesh Shrivastav, Daniel Sigg, Julianne Spencer, Eric Richardson, Nicholas Skadsberg, and Sarah Vieau. I feel extremely fortunate to have the opportunity to work with such a talented group of scientists and engineers, and I continue to learn a great deal from each of them. Finally, I would like to thank my family and friends for their continued support of my career and their assistance over the years. Specifically, I would like to thank my wife, Marge; my three daughters, Maria, Jenna, and Hanna; my mom Irene; and my sisters Chris and Susan, for always being there for me. On a personal note, it has been a difficult couple of years as both of my brothers passed away, as well as my longtime laboratory scientist Bill Gallagher. Furthermore, I myself dealt with some health issues that provided me with a much greater appreciation for cardiac medicine, medical advances, and what is feels like to be a patient. I am truly inspired by all individuals who dedicate their lives to all aspects of cardiovascular science and technology. Minneapolis, MN, USA

Paul A. Iaizzo

Contents

Part I 1

Introduction

General Features of the Cardiovascular System ................................................... Paul A. Iaizzo

3

Part II Anatomy 2

Attitudinally Correct Cardiac Anatomy ................................................................ Alexander J. Hill

15

3

Cardiac Development .............................................................................................. Brad J. Martinsen and Jamie L. Lohr

23

4

Anatomy of the Thoracic Wall, Pulmonary Cavities, and Mediastinum ............ Mark S. Cook and Anthony J. Weinhaus

35

5

Anatomy of the Human Heart ................................................................................ Anthony J. Weinhaus

61

6

Comparative Cardiac Anatomy .............................................................................. Alexander J. Hill and Paul A. Iaizzo

89

7

Detailed Anatomical and Functional Features of the Cardiac Valves ................. 115 Michael G. Bateman, Jason L. Quill, Alexander J. Hill, and Paul A. Iaizzo

8

The Coronary Vascular System and Associated Medical Devices ....................... 137 Julianne H. Spencer, Sara E. Anderson, Ryan Lahm, and Paul A. Iaizzo

9

The Pericardium ...................................................................................................... 163 Eric S. Richardson, Alexander J. Hill, Nicholas D. Skadsberg, Michael Ujhelyi, Yong-Fu Xiao, and Paul A. Iaizzo

10

Congenital Cardiac Anatomy and Operative Correction .................................... 175 Charles Shepard, Robroy McIver, and James D. St. Louis

11

Mechanical Circulatory Support Devices in Pediatric Patients .......................... 187 Mark D. Plunkett and James D. St. Louis

Part III

Physiology and Assessment

12

Cellular Myocytes .................................................................................................... 201 Vincent A. Barnett

13

The Cardiac Conduction System ............................................................................ 215 Timothy G. Laske, Maneesh Shrivastav, and Paul A. Iaizzo

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Contents

14

Autonomic Nervous System .................................................................................... 235 Paul A. Iaizzo and Kevin Fitzgerald

15

Cardiac and Vascular Receptors and Signal Transduction.................................. 251 Daniel C. Sigg and Ayala Hezi-Yamit

16

Reversible and Irreversible Damage of the Myocardium: Ischemia/Reperfusion Injury and Cardioprotection ............................................ 279 Brian T. Howard, Tinen L. Iles, James A. Coles Jr., Daniel C. Sigg, and Paul A. Iaizzo

17

The Effects of Anesthetic Agents on Cardiac Function ........................................ 295 Jason S. Johnson and Michael K. Loushin

18

Blood Pressure, Heart Tones, and Diagnoses ........................................................ 307 Jacob Hutchins

19

Basic ECG Theory, 12-Lead Recordings, and Their Interpretation ................... 321 Sarah Vieau and Paul A. Iaizzo

20

Mechanical Aspects of Cardiac Performance........................................................ 335 Michael K. Loushin, Jason L. Quill, and Paul A. Iaizzo

21

Fueling Normal and Diseased Hearts: Myocardial Bioenergetics ....................... 361 Arthur H.L. From and Robert J. Bache

22

Introduction to Echocardiography ......................................................................... 385 Jamie L. Lohr and Shanthi Sivanandam

23

Monitoring and Managing the Critically Ill Patient in the Intensive Care Unit ....................................................................................... 399 Fahd O. Arafat and Gregory J. Beilman

24

Cardiovascular Magnetic Resonance Imaging and MR-Conditional Cardiac Devices ........................................................................................................ 411 Michael D. Eggen and Cory M. Swingen

Part IV Devices and Therapies 25

Historical Perspective of Cardiovascular Devices and Techniques Associated with the University of Minnesota ........................................................ 439 Paul A. Iaizzo and Monica A. Mahre

26

Pharmacotherapy for Cardiac Diseases................................................................. 457 Anna Legreid Dopp and Katie Willenborg

27

Animal Models for Cardiac Research .................................................................... 469 Nicholas Robinson, Laura Souslian, Robert P. Gallegos, Andrew L. Rivard, Agustin P. Dalmasso, and Richard W. Bianco

28

Catheter Ablation of Cardiac Arrhythmias ........................................................... 493 Henri Roukoz, Fei Lü, and Scott Sakaguchi

29

Cardiac Ablative Technologies ................................................................................ 521 Boaz Avitall and Arthur Kalinski

30

Pacing and Defibrillation ........................................................................................ 543 Timothy G. Laske, Anna Legreid Dopp, Michael D. Eggen, and Paul A. Iaizzo

Contents

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31

Cardiac Resynchronization Therapy ..................................................................... 577 Nathan A. Grenz and Zhongping Yang

32

Cardiac Mapping Technology ................................................................................. 599 Nicholas D. Skadsberg, Bin He, Timothy G. Laske, Charu Ramanathan, and Paul A. Iaizzo

33

Cardiopulmonary Bypass and Cardioplegia ......................................................... 615 Gabriel Loor and J. Ernesto Molina

34

Heart Valve Disease.................................................................................................. 635 Laura Harvey, Kenneth K. Liao, and Ranjit John

35

Less Invasive Cardiac Surgery ............................................................................... 659 Kenneth K. Liao

36

Transcatheter Valve Repair and Replacement ...................................................... 671 Lars M. Mattison, Timothy G. Laske, and Paul A. Iaizzo

37

Cardiac Septal Defects: Treatment via the Amplatzer® Family of Devices ........ 685 John L. Bass

38

Harnessing Cardiopulmonary Interactions to Improve Circulation and Outcomes After Cardiac Arrest and Other States of Low Blood Pressure ............................................................................................. 699 Anja Metzger and Keith Lurie

39

End-Stage Congestive Heart Failure in the Adult Population: Ventricular Assist Devices ....................................................................................... 725 Kenneth K. Liao and Ranjit John

40

Cell Transplantation for Ischemic Heart Disease ................................................. 733 Jianyi Zhang and Daniel J. Garry

41

The Use of Isolated Heart Models and Anatomical Specimens as Means to Enhance the Design and Testing of Cardiac Devices ....................... 751 Michael G. Bateman, Michael D. Eggen, Julianne H. Spencer, Tinen L. Iles, and Paul A. Iaizzo

42

Current Status of Development and Regulatory Approval of Cardiac Devices.................................................................................................... 765 Stephen A. Howard, Michael G. Bateman, Timothy G. Laske, and Paul A. Iaizzo

43

Clinical Trial Requirements for Cardiac Devices ................................................. 777 Jenna C. Iaizzo

44

Cardiac Devices and Technologies: Continued Rapid Rates of Development .............................................................................................. 787 Paul A. Iaizzo

Index .................................................................................................................................. 795

Part I Introduction

1

General Features of the Cardiovascular System Paul A. Iaizzo

Abstract

The purpose of this chapter is to provide a general overview of the human cardiovascular system, to serve as a quick reference on its underlying physiological composition. The rapid transport of molecules over long distances between internal cells, the body surface, and/or various specialized tissues organs is the primary function of the cardiovascular system. This body-wide transport system is composed of several major components: blood, the blood vessels, the heart, and the lymphatic system. When functioning normally, this system adequately provides for the wide-ranging activities that a human can accomplish. Failure in any of these components can lead to pathological or even grave consequences. Subsequent chapters will cover, in greater detail, the anatomical, physiological, and pathophysiological features of the cardiovascular system. Keywords

Cardiovascular system • Blood • Blood vessels • Blood flow • Heart • Coronary circulation • Lymphatic system

1.1

Introduction

Currently, more than 85 million individuals in the United States have some form of cardiovascular disease. More specifically, heart failure continues to be an increasing problem in our society. Coronary bypass surgery, angioplasty, stenting, the implantation of pacemakers and/or defibrillators, and valve replacement are currently routine treatment procedures, with growing numbers of these procedures being performed worldwide each year. However, such treatments often provide only temporary relief of the progressive symptoms of cardiovascular disease. Nevertheless, optimizing therapies and/or the development of new treatments continue

to dominate the cardiovascular biomedical industry (e.g., coated or biodegradable vascular or coronary stents, left ventricular assist devices, biventricular pacing, implantable monitors, and transcatheter-delivered valves). The purpose of this chapter is to provide a general overview of the cardiovascular system, so to serve as a quick reference relative to its underlying physiological mechanisms. More details concerning the pathophysiology of the cardiovascular system and state-of-the-art treatments can be found in subsequent chapters. In addition, the reader should note that a list of source references is provided at the end of this chapter.

1.2 P.A. Iaizzo, PhD (*) Department of Surgery, University of Minnesota, 420 Delaware St. SE, B172 Mayo, MMC 195, Minneapolis, MN 55455, USA e-mail: [email protected]

Components of the Cardiovascular System

The principle components considered to make up the cardiovascular system include: blood, blood vessels, the heart, and the lymphatic system (Fig. 1.1).

© Springer International Publishing Switzerland 2015 P.A. Iaizzo (ed.), Handbook of Cardiac Anatomy, Physiology, and Devices, DOI 10.1007/978-3-319-19464-6_1

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P.A. Iaizzo

Fig. 1.1 The major components of the cardiovascular system: circulating blood, the blood vessels, the heart, and the lymphatic system. (Left) Major vessels that return deoxygenated blood to the heart (blue) and

major arteries carrying oxygenated blood that leave the heart (red). (Right) Shown is the relative extent of the lymphatic system within the human body

1.2.1

immune process, e.g., to protect against infections and also cancers. Platelets play a primary role in blood clotting. In a healthy cardiovascular system, the constant movement of blood helps keep these various cells and plasma constituents well dispersed throughout the larger-diameter vessels. The hematocrit is defined as the percentage of blood volume that is occupied by the red cells (erythrocytes). It can be easily measured by centrifuging (spinning at high speed) a sample of blood, which forces these cells to the bottom of the centrifuge tube. The leukocytes remain on the top and the platelets form a very thin layer between the cell fractions (other more sophisticated methods are also available for such analyses). Normal hematocrit is approximately 45 % in men and 42 % in women. The total volume of blood in an average-sized individual (70 kg) is approximately 5.5 L; hence, the average red cell volume would be roughly 2.5 L. Since the fraction containing both leukocytes and platelets is normally relatively small or negligible, in such an individual, the plasma volume can be estimated to be 3.0 L. Approximately 90 % of plasma is water which acts: (1) as a solvent, (2) to suspend the components of blood, (3) in the absorption of molecules and their transport, and (4) in the transport of thermal energy. Proteins make up 7 % of

Blood

Blood is composed of formed elements (cells and cell fragments) which are suspended in the liquid fraction known as plasma. Blood, often considered as the only liquid connective tissue in the body, has three general functions: (1) transportation (e.g., O2, CO2, nutrients, waste, hormones), (2) regulation (e.g., pH, temperature, osmotic pressures), and (3) protection (e.g., against foreign molecules and diseases, as well as for clotting to prevent excessive loss of blood). Dissolved within the plasma are many proteins, nutrients, metabolic waste products, and various other molecules being transported between multiple organ systems. The formed elements in blood include red blood cells (erythrocytes), white blood cells (leukocytes), and the cell fragments known as platelets. These are all formed in bone marrow from a common stem cell. In a healthy individual, the majority of bloods cells are red blood cells (~99 %) which have a primary role in O2 exchange. Hemoglobin, the iron-containing heme protein which binds oxygen, is concentrated within the red cells; hemoglobin allows blood to transport 40–50 times the amount of oxygen that plasma alone could carry. The white cells are required for the

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Cardiovascular System Features

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the plasma (by weight) and exert a colloidc osmotic pressure. Protein types include albumins, globulins (antibodies and immunoglobulins), and fibrinogen. To date, more than 100 distinct plasma proteins have been identified, and each presumably serves a specific physiologic function. The other main solutes in plasma include: electrolytes, nutrients, gases (some O2, large amounts of CO2 and N2), regulatory substances (enzymes and hormones), and waste products (urea, uric acid, creatine, creatinine, bilirubin, and ammonia).

1.2.2

Blood Vessels

Blood flows throughout the body’s tissues within blood vessels via bulk flow (i.e., all constituents together and in one direction). An extraordinary degree of vascular branching exists within the human body, which ensures that nearly every cell in the body lies within a short distance from at least one of the smallest branches of this system—a capillary. Nutrients and metabolic end products move between the capillary vessels and the surroundings of the cell through the interstitial fluid by diffusion. 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 somewhat passive and occurs only because arterial pressure is kept higher than venous pressure via the pumping action of the heart. In an individual at rest at any given moment, approximately 5 % of the total circulating blood is actually within the capillaries. Yet, this volume of blood can be considered to perform the primary functions of the entire cardiovascular system, specifically the supply of nutrients and removal of metabolic end products. The cardiovascular system, as reported by the British physiologist William Harvey in 1628, is a closed-loop system, such that blood is pumped out of the heart through one set of vessels (arteries) and then returns to the heart in another (veins). More specifically, one can consider that there are two closed-loop systems which both originate and return blood to the heart—the pulmonary and systemic circulations (Fig. 1.2). The pulmonary circulation is composed of the right heart pump and the lungs, whereas the systemic circulation includes the left heart pump which supplies blood to the systemic organs (i.e., all tissues and organs except the gas exchange portion of the lungs). Because the right and left heart pumps function in a series arrangement, both will circulate an identical volume of blood in a given minute (one’s cardiac output, normally expressed in liters per minute). In the systemic circuit, blood is ejected out of the left ventricle via a single large artery—the aorta. All arteries of the systemic circulation branch from the aorta (this is the largest artery of the body, with a diameter ranging from 2 to 4 cm) and divide into progressively smaller vessels. The aorta’s four principle divisions are the ascending aorta (begins at the

Fig. 1.2 The major paths of blood flow through pulmonary and systemic circulatory systems. AV atrioventricular

aortic valve where, close by, the two coronary artery branches have their origin), the arch of the aorta, the thoracic aorta, and the abdominal aorta. The smallest of the arteries eventually branch into arterioles. They, in turn, branch into an extremely large number of the smallest diameter vessels—the capillaries (with an estimated

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Fig. 1.3 The microcirculation including arterioles, capillaries, and venules. The capillaries lie between, or connect, the arterioles to the 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 10–100 capillaries. Both the arteriole and the proximal portion of the metarterioles are surrounded by smooth muscle fibers whose contractions and relaxations regulate blood flow through the capillary bed. Typically, blood flows intermittently through a capillary bed due to the periodic contractions of the smooth muscles (5–10 times per minute, vasomotion), which is regulated both locally (metabolically) and by autonomic control (Figure modified from [5])

ten billion in the average human body). Next, blood exits the capillaries and begins its return to the heart via the venules. Microcirculation is a term coined to collectively describe the flow of blood through arterioles, capillaries, and the venules (Fig. 1.3). Importantly, blood flow through an individual vascular bed is profoundly regulated by changes in activity of the sympathetic nerves innervating the arterioles. In addition, arteriolar smooth muscle is very responsive to changes in local chemical conditions within an organ (i.e., those changes associated with increases or decreases in the metabolic rate of that given organ). Capillaries, which are the smallest and most numerous blood vessels in the human body (ranging from 5 to 10 μm in diameter and again numbering around ten billion), are also the thinnest walled vessels; an inner diameter of 5 μm is just wide enough for an erythrocyte to squeeze through. Further, it is estimated that there are 25,000 miles of capillaries in an adult, each with an individual length of about 1 mm. Most capillaries are little more than a single cell layer thick, consisting of a layer of endothelial cells and a basement membrane. This minimal wall thickness facilitates the capillary’s primary function, which is to permit the exchange of materials between cells in tissues and the blood within. As mentioned above, small molecules (e.g., O2, CO2, sugars, amino acids, and water) are relatively free to enter and leave capillaries readily, promoting efficient material exchange. Nevertheless, the relative permeability of capillaries varies from body region to body region, with regard to the physical properties of their formed walls.

P.A. Iaizzo

Based on such differences, capillaries are commonly grouped into two major classes: continuous and fenestrated capillaries. In the continuous capillaries, which are more common, the endothelial cells are joined together such that the spaces between them are relatively narrow (i.e., narrow intercellular gaps). These capillaries are permeable to substances having small molecular sizes and/or high lipid solubilities (e.g., O2, CO2, and steroid hormones) and are somewhat less permeable to small water-soluble substances (e.g., Na+, K+, glucose, and amino acids). In fenestrated capillaries, the endothelial cells possess relatively large pores that are wide enough to allow proteins and other large molecules to pass through. In some such capillaries, the gaps between the endothelial cells are even wider than usual, enabling quite large proteins (or even small cells) to pass through. Fenestrated capillaries are primarily located in organs whose functions depend on the rapid movement of materials across capillary walls, e.g., kidneys, liver, intestines, and bone marrow. If a molecule cannot pass between capillary endothelial cells, then it must be transported across the cell membrane. The mechanisms available for transport across a capillary wall differ for various substances depending on their molecular size and degree of lipid solubility. For example, certain proteins are selectively transported across endothelial cells by a slow, energy-requiring process known as transcytosis. In this process, the endothelial cells initially engulf the proteins in the plasma within capillaries by endocytosis. The molecules are then ferried across the cells by vesicular transport and released by exocytosis into the interstitial fluid on the other side. Endothelial cells generally contain large numbers of endocytotic and exocytotic vesicles, and sometimes these fuse to form continuous vesicular channels across the cell. The capillaries within the heart normally prevent excessive movement of fluids and molecules across their walls, but clinical situations have been noted where they may become “leaky.” For example, capillary leak syndrome may be induced following cardiopulmonary bypass and might last from hours up to days. More specifically, in such cases, the inflammatory response in the vascular endothelium can disrupt the “gatekeeper” function of capillaries; their increased permeability will result in myocardial edema. From capillaries, blood throughout the body then flows into the venous system. It first enters the venules which then coalesce to form larger vessels—the veins (Fig. 1.3). Then veins from the various systemic tissues and organs (minus the gas exchange portion of the lungs) unite to form two major veins—the inferior vena cava (lower body) and superior vena cava (above the heart). By way of these two great vessels, blood is returned to the right heart pump, specifically into the right atrium. Like capillaries, the walls of the smallest venules are very porous and represent the sites where many phagocytic white blood cells emigrate from the blood into inflamed or infected tissues. Venules and veins are also richly

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1.2.3

Fig. 1.4 Contractions of the skeletal muscles aid in returning blood to the heart—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 due to the contractions is only toward the heart due to the valves that are present within the veins

innervated by sympathetic nerves and thus the smooth muscles within constrict when these nerves are activated. Therefore, increased sympathetic nerve activity is associated with a decreased venous volume, which results in increased venous return and hence cardiac filling and ultimately an increased cardiac output (via Starling’s law of the heart). Many veins, especially those in the limbs, also feature abundant valves (which are notably also found in the cardiac venous system) which are thin folds of the intervessel lining that form flap-like cusps. The valves project into the vessel lumens and are directed toward the heart, thus promoting unidirectional flow of blood. Because blood pressure is normally low in veins, these valves are important for aiding venous return, by preventing the backflow of blood (which is especially true in the upright individual). In addition, contractions of skeletal muscles (e.g., in the legs) also play a role in decreasing the size of the venous reservoir and thus the return of blood volume to the heart (Fig. 1.4). The pulmonary circulation is comprised of a similar circuit. Blood leaves the right ventricle in a single great vessel, the pulmonary artery (trunk), which, within a short distance (centimeters), divides into the two main pulmonary arteries, one supplying the right lung and another the left. Once within the lung proper, the arteries continue to branch down to arterioles and then ultimately form capillaries. From there, the blood flows into venules, eventually forming four main pulmonary veins which empty into the left atrium. As blood flows through the lung capillaries, it picks up oxygen supplied to the lungs by breathing air; hemoglobin within the red blood cells is loaded up with oxygen (oxygenated blood).

Blood Flow

The task of maintaining an adequate interstitial homeostasis (the nutritional environment surrounding cells) requires that blood flows almost continuously through each of the millions of capillaries within the human body. The following is a brief description of the parameters that govern flow through a given vessel. All blood vessels have certain lengths (L) and internal radii (r) through which blood flows when the pressure in the inlet and outlet are unequal (Pi and Po, respectively); in other words, there is a pressure difference (ΔP) between the vessel ends, which supplies the driving force for flow. Because friction develops between moving blood and the stationary vessel walls, this fluid movement has a given resistance (vascular), which is the measure of how difficult it is to create blood flow through a vessel. One can then describe a relative relationship between vascular flow, the pressure difference, and resistance (i.e., the basic flow equation): Flow = pressure difference or Q = D P resistance

R

where Q = flow rate (volume/time), ΔP = pressure difference (mmHg), and R = resistance to flow (mmHg × time/volume). This equation may be applied not only to a single vessel but can also be used 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 = 8 Lh p r4 where r = inside radius of the vessel, L = vessel length, and η = blood viscosity. It is important to note that a small change in vessel radius will have a very large influence (4th power) on its resistance to flow; e.g., decreasing vessel diameter by 50 % will increase its resistance to flow by approximately 16-fold. If one combines the preceding two equations into one expression, which is commonly known as the Poiseuille equation, it can be used to better approximate the factors that influence flow though a cylindrical vessel: Q = DP p r 4 8Lh 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, and this is principally accomplished

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by regulating the radii of vessels (e.g., arterioles and metarterioles) within a given tissue or organ system. Whereas vessel length and blood viscosity are factors that influence vascular resistance, they are not considered variables that can be easily regulated for the purpose of the momentto-moment control of blood flow. Regardless, the primary function of the heart is to keep pressure within arteries higher than those in veins, hence a pressure gradient to induce flow. Normally, the average pressure in systemic arteries is approximately 100 mmHg and decreases to near 0 mmHg in the great caval veins. The volume of blood that flows through any tissue in a given period of time (normally expressed as mL/min) is called the local blood flow. The velocity (speed) of blood flow (expressed as cm/s) can generally be considered to be inversely related to the vascular cross-sectional area, such that velocity is slowest where the total cross-sectional area is largest. Shown in Fig. 1.5 are the relative pressure drops one can detect through the vasculature; the pressure varies in a given vessel also relative to the active and relaxation phases of the heart function (see below).

1.2.4

Fig. 1.5 Relative pressure changes one could record in the various branches of the human vascular system due to contractions and relaxation of the heart (pulsatile pressure changes). Note that pressure may be slightly higher in the large arteries than that leaving the heart into the aorta due to their relative compliance and diameter properties. The largest drops in pressures occur within the arterioles which are known as the active regulatory vessels. The pressures in the large veins that return blood to the heart are near zero

The Heart

The heart lies in the center region of the thoracic cavity and is suspended by its attachment to the great vessels within a fibrous sac known as the pericardium; note that humans have relatively thick-walled pericardiums compared to those of the commonly studied large mammalian cardiovascular models (i.e., canine, porcine, or ovine; see also Chap. 9). A small amount of fluid is present within the sac, pericardial fluid, which lubricates the surface of the heart and allows it to move freely during functioning (i.e., cycles of contractions and relaxations). The pericardial sac extends upward enclosing the great vessels (see also Chaps. 4 and 5). The pathway of blood flow through the chambers of the heart is indicated in Fig. 1.6. Recall that venous blood returns from the systemic organs to the right atrium via the superior and inferior venae cavae. It next passes through the tricuspid valve into the right ventricles and from there is pumped through the pulmonary valve into the pulmonary artery. After eventually passing through the pulmonary capillary beds, the oxygenated pulmonary venous blood returns to the left atrium through the pulmonary veins. The flow of blood then passes through the mitral valve into the left ventricle and is pumped through the aortic valve into the aorta. In general, the gross anatomy of the right heart pump is considerably different from that of the left heart pump, yet the pumping principles of each are primarily the same. The ventricles are closed chambers surrounded by muscular walls, and the valves are structurally designed to allow flow in only one direction. The cardiac valves passively open and close in response to the direction of the pressure gradient across them.

Fig. 1.6 The pathway of blood flow through the heart and lungs. Note that the pulmonary artery (trunk) branches, within a few centimeters, into left and right pulmonary arteries. There are commonly four main pulmonary veins that return blood from the lungs to the left atrium (Modified from [5])

The myocytes of the ventricles are organized primarily in a circumferential orientation; hence, when they contract, the tension generated within the ventricular walls causes the pressure within the chamber to increase. As soon as the ventricular pressure exceeds the pressure in the pulmonary artery (right) and/or aorta (left), blood is forced out of the given ventricular chamber. This active contractile phase of the cardiac cycle is known as systole. The generated pres-

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Cardiovascular System Features

9

The heart normally functions in a very efficient fashion and the following properties are needed to maintain this effectiveness: (1) the contractions of the individual myocytes must occur at regular intervals and be synchronized (not arrhythmic), (2) the valves must fully open (not stenotic), (3) the valves must not leak when closed (not insufficient or regurgitant), (4) the ventricular contractions must be forceful (not failing or lost due to an ischemic event), and (5) the ventricles must fill adequately during diastole (no arrhythmias or delayed relaxation).

1.2.5

Fig. 1.7 Average relative pressures within the various chambers and great vessels of the heart. During filling of the ventricles, the pressures are much lower and, upon active contraction, they will increase dramatically. Relative pressure ranges that are normally elicited during systole (active contraction; ranges noted above lines) and during diastole (relaxation; ranges noted below lines) are shown for the right and left ventricles, right and left atria, pulmonary artery and pulmonary capillary wedge, and aorta. Shown at the bottom of this figure are the relative pressure changes one can detect in a normal healthy heart as one moves from the right heart through the left heart and into the aorta; this flow pattern is the series arrangement of the two-pump system

sures are higher in the ventricles than the atrium during systole; hence, the tricuspid and mitral (atrioventricular) valves are closed. When the ventricular myocytes relax, the pressures in the ventricles fall below those in the atria, and the atrioventricular valves open; the ventricles refill and this phase is known as diastole. The aortic and pulmonary (semilunar or outlet) valves are closed during diastole because the arterial pressures (in the aorta and pulmonary artery) are greater than the intraventricular pressures. Shown in Fig. 1.7 are the average pressures within the various chambers and great vessels of the heart. For more details on the cardiac cycle, see Chap. 20. The effective pumping action of the heart requires that there be a precise coordination of the myocardial contractions (millions of cells), and this is accomplished via the conduction system of the heart. Contractions of each cell are normally initiated when electrical excitatory impulses (action potentials) propagate along their surface membranes. The myocardium can be viewed as a functional syncytium; action potentials from one cell conduct to the next cell via the gap junctions. In the healthy heart, the normal site for initiation of a heartbeat is within the sinoatrial node, located in the right atrium. For more details on this internal electrical system, refer to Chap. 13.

Regulation of Cardiovascular Function

Cardiac output in a normal individual at rest ranges between 4 and 6 L/min, but during severe exercise, the heart may be required to pump three to five times this amount. There are two primary modes by which the blood volume pumped by the heart, at any given moment, is regulated: (1) by the intrinsic cardiac regulation, in response to changes in the volume of blood flowing into the heart, and (2) by the control of heart rate and cardiac contractility via the autonomic nervous system. The intrinsic ability of the heart to adapt to changing volumes of inflowing blood is known as the Frank–Starling mechanism (law) of the heart, named after two great physiologists of a century ago. In general, the Frank–Starling response can simply be described—the more the heart or myocytes are stretched (e.g., via an increased blood volume), the greater will be the subsequent force of ventricular contraction and, thus, the amount of blood ejected through the aortic valve. In other words, within its physiological limits, the heart will pump out all the blood that enters it without allowing excessive damming of blood in veins. The underlying basis for this phenomenon is related to the optimization of the lengths of sarcomeres, the functional subunits of striated muscle; in other words, there is optimization in the potential for the contractile proteins (actin and myosin) to form crossbridges. It should also be noted that “stretch” of the right atrial wall (e.g., due to increased venous return) can directly increase the rate of the sinoatrial node by 10–20 %; this also aids in the amount of blood that will ultimately be pumped per minute by the heart. For more details on the contractile function of heart, refer to Chap. 12. The pumping effectiveness of the heart is also effectively controlled by the sympathetic and parasympathetic components of the autonomic nervous system. There is extensive innervation of the myocardium by such nerves (for more details on innervation, see Chap. 14). To understand how effective the modulation of the heart by this innervation is, investigators have reported that cardiac output often can be increased by more than 100 % by sympathetic stimulation and, by contrast, output can be nearly terminated by parasympathetic (vagal) stimulation.

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Cardiovascular function is also modulated through reflex mechanisms that involve baroreceptors and the chemical composition of the blood and via the release of various hormones. More specifically, baroreceptors, which are located in the walls of some arteries and veins, exist to monitor one’s relative blood pressure. Those specifically located in the carotid sinus help to reflexively maintain normal blood pressure in the brain, whereas those located in the area of the ascending arch of the aorta help to govern general systemic blood pressure (for more details, see Chaps. 14, 18, and 20). Chemoreceptors that monitor the chemical composition of blood are located close to the baroreceptors of the carotid sinus and arch of the aorta, in small structures known as the carotid and aortic bodies. The chemoreceptors within these bodies detect changes in blood levels of O2, CO2, and H+. Hypoxia (low availability of O2), acidosis (increased blood concentrations of H+), and/or hypercapnia (high concentrations of CO2) can all stimulate the chemoreceptors to increase their action potential firing frequencies to the brain’s cardiovascular control centers. In response to this increased signaling, the central nervous system control centers (hypothalamus), in turn, cause an increased sympathetic stimulation to arterioles and veins, producing vasoconstriction and a subsequent increase in blood pressure. In addition, the chemoreceptors simultaneously send neural input to the respiratory control centers in the brain, to induce the appropriate control of respiratory function (e.g., increase O2 supply and reduce CO2 levels). Features of this hormonal regulatory system include: (1) the renin-angiotensin-aldosterone system, (2) the release of epinephrine and norepinephrine, (3) antidiuretic hormones, and (4) atrial natriuretic peptides (released from the atrial heart cells). For details on this complex regulation, refer to Chap. 15. The overall functional arrangement of the blood circulatory system is shown in Fig. 1.8. The role of the heart needs be considered in three different ways: as the right pump, as the left pump, and as the heart muscle tissue which has its own metabolic and flow requirements. As described above, the pulmonary (right heart) and system (left heart) circulations are arranged in a series (see also Fig. 1.7). Thus, cardiac output increases in each at the same rate; hence, an increased systemic need for a greater cardiac output will automatically lead to a greater flow of blood through the lungs (greater potential for O2 delivery). In contrast, the systemic organs are functionally arranged in a parallel arrangement; hence, (1) nearly all systemic organs receive blood with an identical composition (arterial blood), and (2) the flow through each organ can be and is controlled independently. For example, during exercise, a typical circulatory response is to increase blood flow through some organs (e.g., heart, skeletal muscle, brain) but not others (e.g., kidney and gastrointestinal system). The brain,

P.A. Iaizzo

Fig. 1.8 A functional representation of the human circulatory system. The numbers indicate the approximate relative percentages of the cardiac output that is delivered, at a given moment in time, to the major organ systems within the body

heart, and skeletal muscles typify organs in which blood flows solely to supply the metabolic needs of the tissue; they do not recondition the blood. The blood flow to the heart and brain is normally only slightly greater than that required for their metabolism; hence, small interruptions in flow are not well tolerated. For example, if coronary flow to the heart is interrupted, electrical and/or functional (pumping ability) activities will noticeably be altered within a few heartbeats (as can be detected by a 12-lead electrocardiogram or ECG; see Chap. 19. Likewise, stoppage of flow to the brain will lead to unconsciousness within a few seconds, and permanent brain damage can occur in as little as 4 min without flow. The flow to skeletal muscles can dramatically change (flow can increase from 20 to 70 % of total cardiac output) depending on use and thus their metabolic demand. Many organs in the body perform the task of continually reconditioning the circulating blood. Primary organs that perform such tasks include the (1) lungs (O2 and CO2 exchange), (2) kidneys (blood volume and electrolyte composition, Na+, K+, Ca2+, Cl−, and phosphate ions), and

1

Cardiovascular System Features

(3) skin (temperature). Blood-conditioning organs can often withstand, for short periods of time, significant reductions of blood flow without subsequent compromise.

1.2.6

The Coronary Circulation

In order to sustain viability, it is not possible for nutrients to diffuse from the internal wall chambers of the heart (endocardium) through all the layers of cells that make up the heart tissue. Thus, the coronary circulation is responsible for delivering blood to the heart tissue itself (the myocardium). The normal heart functions almost exclusively as an aerobic organ with little capacity for anaerobic metabolism to produce energy. Even during resting conditions, 70–80 % of the oxygen available within the blood circulating through the coronary vessels is extracted by the myocardium. It then follows that because of the limited ability of the heart to increase oxygen availability by further increasing oxygen extraction, increases in myocardial demand for oxygen (e.g., during exercise or stress) must be met by equivalent increases in coronary blood flow. Myocardial ischemia results when the arterial blood supply fails to meet the needs of the heart muscle for oxygen and/or metabolic substrates. Even mild cardiac ischemia can result in anginal pain, focal electrical changes, and the cessation of regional cardiac contractile function. Sustained ischemia within a given myocardial region will most likely result in an infarction (cell death). As noted above, as in any microcirculatory bed, the greatest resistance to coronary blood flow occurs in the arterioles. Blood flow through such vessels varies approximately with the fourth power of these vessels’ radii; hence, the key regulated variable for the control of coronary blood flow is the degree of constriction or dilatation of coronary arteriolar vascular smooth muscle. As with all systemic vascular beds, the degree of coronary arteriolar smooth muscle tone is normally controlled by multiple independent negative feedback loops. These mechanisms include various neural, hormonal, local non-metabolic, and/or local metabolic regulators. It should be noted that the local metabolic regulators of arteriolar tone are usually the most important for coronary flow regulation; these feedback systems involve oxygen demands of the local cardiac myocytes. In general, at any point in time, coronary blood flow is determined by integrating all the different controlling feedback loops into a single response (i.e., inducing either arteriolar smooth muscle constriction or dilation). It is also common to consider that some of these feedback loops are in opposition to one another. Interestingly, coronary arteriolar vasodilation from a resting state to one of intense exercise can result in an increase of mean coronary blood flow from approximately 0.5–4.0 mL/ min/g. For more details on metabolic control of flow, see Chaps. 15 and 21.

11

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 as another important determinant of coronary flow. More specifically, coronary blood flow varies directly with the pressure across the coronary microcirculation, which can be essentially considered as the aortic pressure since coronary venous pressure is typically near zero. However, since the coronary circulation perfuses the heart, some very unique determinants for flow through these capillary beds may also occur; 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). For more details on the coronary vasculature and its function, refer to Chap. 8.

1.2.7

Lymphatic System

The lymphatic system represents an accessory pathway by which large molecules (proteins, long-chain fatty acids, bacteria, etc.) can reenter the general circulation and thus not accumulate in the interstitial space. If such particles do accumulate within the interstitial spaces, 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 which have pre-lymphatic channels). The lymphatic system begins in various tissues with blind-end specialized lymphatic capillaries that are roughly the size of regular circulatory capillaries, but they are less numerous (Fig. 1.9). However, the lymphatic capillaries are very porous and thus can easily collect the large particles within the interstitial fluid known as lymph. This fluid moves through the converging lymphatic vessels and is filtered through lymph nodes where bacteria and particulate matter are removed. Foreign particles that are trapped in the lymph nodes are destroyed (phagocytized) by tissue macrophages which line a meshwork of sinuses that lie within. Lymph nodes also contain T and B lymphocytes which can destroy foreign substances by a variety of immune responses. There are approximately 600 lymph nodes located along the lymphatic vessels; they are 1–25 mm long (bean shaped) and covered by a capsule of dense connective tissue. Note that lymph flow is unidirectional through the nodes (Fig. 1.9). The lymphatic system is also one of the major routes for absorption of nutrients from the gastrointestinal tract (particularly for the absorption of fat and lipid-soluble vitamins A, D, E, and K). For example, after a fatty meal, lymph in the thoracic duct may contain as much as 1–2 % fat.

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the steady state, this indicates a total body net transcapillary fluid filtration rate of 2.5 L/day. When compared with the total amount of blood that circulates each day (approximately 7000 L/day), this seems almost insignificant; however, blockage of such flow will quickly cause serious tissue edema. Therefore, the lymphatic circulation plays a critical role in keeping the interstitial protein concentrations low and also in removing excess capillary filtrate from tissues throughout the body.

1.3

Fig. 1.9 A schematic diagram showing the relative relationship between the lymphatic system and the cardiopulmonary system. The lymphatic system is unidirectional, with fluid flowing from interstitial space back to the general circulatory system. The sequence of flow is from blood capillaries (systemic and pulmonary) to the interstitial space, to the lymphatic capillaries (lymph), to the lymphatic vessels, to the thoracic duct, and into the subclavian veins (back to the right atrium) (Modified from [5])

The majority of lymph reenters the circulatory system via the thoracic duct which empties into the venous system at the juncture of the left internal jugular and subclavian veins (which then enters into the right atrium; see Chaps. 4 and 5). The flow of lymph from tissues toward the entry point into the circulatory system is induced by two main factors: (1) higher tissue interstitial pressures and (2) the activity of the lymphatic pumps (contractions within the lymphatic vessels themselves, contractions of surrounding muscles, movement of parts of the body, and/or pulsations of adjacent arteries). In the largest lymphatic vessels (e.g., thoracic duct), the pumping action can generate pressures as high as 50–100 mmHg. Valves located in the lymphatic vessel, like in veins, aid in the prevention of the backflow of lymph. Approximately 2.5 L of lymphatic fluid reenters the general blood circulation (cardiopulmonary system) each day. In

Summary

The primary function of the cardiovascular system is rapid transport of molecules over long distances between internal cells, the body surface, various specialized tissue and/or organs. This body-wide transport system is composed of several major components: blood, the blood vessels (arteries and veins), the heart, and the lymphatic system. When functioning normally, this system adequately provides for the wide-ranging activities that a human can accomplish. Failure in any of these components can lead to grave consequence. Many of the subsequent chapters in this book will cover, in greater detail, the anatomical, physiological, and pathophysiological features of the various components of the cardiovascular system. The normal and abnormal performance of the heart and various clinical treatments to enhance function will also be discussed within the following chapters.

References 1. Alexander RW, Schlant RC, Fuster V (eds) (1998) Hurst’s the heart, arteries and veins, 9th edn. McGraw-Hill, New York 2. Germann WJ, Stanfield CL (eds) (2002) Principles of human physiology. Pearson Education, Inc./Benjamin Cummings, San Francisco 3. Guyton AC, Hall JE (eds) (2000) Textbook of medical physiology, 10th edn. W.B. Saunders Co., Philadelphia 4. Mohrman DE, Heller LJ (eds) (2003) Cardiovascular physiology, 5th edn. McGraw-Hill, New York 5. Tortora GJ, Grabowski SR (eds) (2000) Principles of anatomy and physiology, 9th edn. Wiley, New York. http://www.vhlab.umn.edu/ atlas

Part II Anatomy

Attitudinally Correct Cardiac Anatomy

2

Alexander J. Hill

Abstract

Anatomy is one of the oldest branches of medicine, dating back as far as the third century Throughout time, the discipline has been served well by a universal system for describing structures based on the anatomic position. Unfortunately, cardiac anatomy has been a detractor from this long-standing tradition and has commonly been incorrectly described using confusing and inappropriate nomenclature. This is most likely due to the examination of the heart in the Valentine position, in which the heart stands on its apex, as opposed to how it is actually oriented in the body. The description of the major coronary arteries, such as the anterior descending and posterior descending, is attitudinally incorrect; as the heart is oriented in the body, the surfaces are actually superior and inferior. An overview of attitudinally correct human anatomy, the problem areas, and the comparative aspects of attitudinally correct anatomy will be presented in this chapter. BC.

Keywords

Cardiac anatomy • Attitudinally correct nomenclature • Comparative anatomy

2.1

Introduction

Anatomy is one of the oldest branches of medicine, with historical records dating back at least as far as the third century BC. Cardiac anatomy has been a continually explored topic throughout this time, and there are still publications on new facets of cardiac anatomy being researched and reported today. One of the fundamental tenets of the study of anatomy has been the description of the structure based on the universal orientation, otherwise termed the anatomic position (Fig. 2.1). The anatomic position depicts the subject facing the observer and is then divided into three orthogonal planes. Each plane divides the body or individual structure within A.J. Hill, PhD (*) Medtronic, 8200 Coral Sea Street NE, Mounds View, MN 55112, USA Department of Surgery, University of Minnesota, Minneapolis, MN 55432, USA e-mail: [email protected]

the body (such as the heart) into two portions. Thus, using all three planes, each portion of the anatomy can be localized precisely within the body. These three planes are called (1) the sagittal plane, which divides the body into right and left portions; (2) the coronal plane, which divides the body into anterior and posterior portions; and (3) the transverse plane, which divides the body into superior and inferior portions. Each plane can then be viewed as a slice through a body or organ and will also have specific terms that can be used to define the structures within. If one is looking at a sagittal cut through a body, the observer would describe structures as being anterior or posterior and superior or inferior. On a coronal cut, the structures would be described as superior or inferior and right or left. Finally, on a transverse cut, anterior or posterior and right or left would be used to describe the structures. This terminology should be used regardless of the actual position of the body. For example, assume an observer is looking down at a table and does not move. If a body is lying on its back on this table, the anterior surface would be facing upward toward the observer. Now, if the body is lying on its left side, the right surface of the body would be facing

© Springer International Publishing Switzerland 2015 P.A. Iaizzo (ed.), Handbook of Cardiac Anatomy, Physiology, and Devices, DOI 10.1007/978-3-319-19464-6_2

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A.J. Hill

Fig. 2.1 Illustration showing the anatomic position. Regardless of the position of the body or organ upon examination, the anatomy of an organ or the whole should be described as if observed from this vantage point. The anatomic position can be divided by three separate orthogonal planes: (1) the sagittal plane, which divides the body into right and left portions; (2) the coronal plane, which divides the body into anterior and posterior portions; and (3) the transverse plane, which divides the body into superior and inferior portions

upward toward the observer, and the anterior surface would be facing toward the right. Regardless of how the body is moved, the orthogonal planes used to describe it move with the body and do not stay fixed in space. The use of this position and universal terms to describe structure have served anatomists well and have led to easier discussion and translation of findings among different investigators. It continues to be emphasized that there remains a strong need in the fields of cardiovascular science and medicine to promote the use of attitudinally correct cardiac anatomic nomenclature [1, 2].

2.2

The Problem: Cardiac Anatomy Does Not Play by the Rules

As described above, the use of the anatomic position has stood the test of time and is still used to describe the position of structures within the body. However, within approximately

the last 50 years, descriptions of cardiac anatomy have not adhered to the proper use of these terms; rather they have been replaced with inappropriate descriptors. There are two major reasons for this: (1) many descriptions of heart anatomy have been made with the heart removed from the body and incorrectly positioned during examination, and (2) a heart-centric orientation has been preferred to describe the structures. These two reasons are interrelated and negatively affect the proper description of cardiac anatomy. Typically, when the heart is examined outside the body, it has been placed on its apex into the so-called Valentine position, which causes the heart to appear similar to the common illustration of the heart used routinely in everything from greeting cards to instant messenger icons (Fig. 2.2). It is the author’s opinion that this problem has been confounded by the comparative positional differences seen between humans and large mammalian cardiac models used to help understand human cardiac anatomy and physiology. As you will see in the following

2

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Attitudinal Anatomy

Fig. 2.2 A human heart viewed from the so-called anterior position, demonstrating the Valentine heart orientation used by many to incorrectly describe anatomy. The red line surrounding the heart is the characteristic symbol, which was theoretically derived from observing the heart in the orientation

sections, the position of the heart within a sheep thorax is very similar to the Valentine position used to examine human hearts. I will point out that I have been guilty of describing structures in such a manner, as is evidenced by some of the images available in the Visible Heart® Viewer CD (Fig. 2.2), as have countless others as seen in the scientific literature and many textbooks (even including this one). Regardless, it is a practice I have since given up and have reverted to the timehonored method using the anatomic position. Further impacting the incorrect description of cardiac anatomy is the structure of the heart itself. A common practice in examining the heart is to cut the ventricular chambers in the short axis, which is perpendicular to the long axis of the heart which runs from the base to the apex. This practice is useful in the examination of the ventricular chambers, but the cut plane is typically confused as actually being transverse to the body when it is, in most cases, an oblique plane. The recent explosion of tomographic imaging techniques, such as magnetic resonance imaging (MRI) and computed tomography (CT), in which cuts such as the one just described are commonly made, has further fueled the confusion. Nevertheless, this incorrect use of terminology to describe the heart can be considered to impact a large and diverse group of individuals. Practitioners of medicine, such as interventional cardiologists and electrophysiologists, are affected, as are scientists investigating the heart and engineers designing medical devices. It is considered here that describing

terms in a more consistent manner, and thus using the appropriate terminology, would greatly increase the efficiency of interactions between these groups. It should be noted that there have been a few exceptions to this rule, in that attempts have been made to promote proper use of anatomic terminology. Most notable are the works of Professor Robert Anderson [3–6], although he will also admit that he has been guilty of using incorrect terminology in the past. Other exceptions to this rule are Wallace McAlpine’s landmark cardiac anatomy textbook [7] and an excellent textbook by Walmsley and Watson [8]. In addition to these exceptions, a small group of scientists and physicians has begun to correct the many misnomers that have been used to describe the heart in the recent past; this is the major goal of this chapter. A description of the correct position of the heart within the body will be presented along with specific problem areas, such as the coronary arteries, where terms such as left anterior descending artery are most obviously incorrect and misleading.

2.3

The Attitudinally Correct Position of the Human Heart

The following set of figures used to describe the correct position of the heart within the body was created from 3D volumetric reconstructions of magnetic resonance images of

18

Fig. 2.3 Volumetric reconstructions from magnetic resonance imaging showing the anterior surfaces of two human hearts. The major structures visible are the right atrium and right ventricle. The apex of the heart is positioned to the left and is not inferior as in the Valentine position. The so-called anterior interventricular sulcus (shown with a red star) in fact begins superiorly and travels to the left and only slightly anteriorly. I inferior, L left, LV left ventricle, R right, RV right ventricle, S superior

healthy humans with normal cardiac anatomy. In Fig. 2.3, the anterior surfaces of two human hearts are shown. Note that in this view of the heart, the major structures visible are the right atrium and right ventricle. In reality, the right ventricle is positioned anteriorly and to the right of the left ventricle. Also, note that the apex of the heart is positioned to the left and is not inferior, as in the Valentine position. Furthermore, note that the so-called anterior interventricular sulcus (shown with a red star), in fact, begins superiorly and

A.J. Hill

Fig. 2.4 Volumetric reconstructions from magnetic resonance imaging showing the posterior surfaces of two human hearts. The major structures visible are the right and left atrium and the descending aorta (top image only). The apex of the heart is positioned to the left and is not inferior as in the Valentine position. I inferior, L left, LA left atrium, LV left ventricle, R right, RV right ventricle, S superior

travels to the left and only slightly anteriorly. Figure 2.4 shows the posterior surfaces of two human hearts, in which the first visible structure is the descending aorta. Anterior to that are the right and left atria. Figure 2.5 shows the inferior or diaphragmatic surfaces of two human hearts, commonly referred to as the posterior surface, based on Valentine positioning. The inferior caval vein and descending aorta are cut in the short axis; in this region of the thorax, they tend to travel parallel to the long axis of the body. Note that the socalled posterior interventricular sulcus is actually positioned inferiorly (shown with a red star). Figure 2.6 shows a superior view of two human hearts. In this view, the following

2

Attitudinal Anatomy

Fig. 2.5 Volumetric reconstructions from magnetic resonance imaging showing the inferior or diaphragmatic surfaces of two human hearts. This surface is commonly, and incorrectly, referred to as the posterior surface, based on Valentine positioning. The inferior caval vein (IVC) and descending aorta are cut in the short axis; in this region of the thorax, they tend to travel parallel to the long axis of the body. The socalled posterior interventricular sulcus is actually positioned inferiorly and is denoted by a red star. A anterior, L left, LV left ventricle, P posterior, R right, RV right ventricle

structures are visible: (1) the superior caval vein, (2) the aortic arch and the major arteries arising from it, (3) the free portion of the right atrial appendage, and (4) the pulmonary trunk which, after arising from the right ventricle, runs in the transverse plane before bifurcating into the right and left pulmonary arteries. Also, note that the position of the anterior interventricular sulcus (shown with a red star) is more correctly termed superior.

2.4

Commonly Used Incorrect Terms

This section will specifically describe a few obvious problem areas in which attitudinally incorrect nomenclature is commonly used: the coronary arteries, myocardial segmentation for depiction of infarction, and cardiac valve nomenclature.

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Fig. 2.6 Volumetric reconstructions from magnetic resonance imaging showing the superior surfaces of two human hearts. In this view, the following structures are visible: the superior caval vein (SVC), the aortic arch (AoArch), and the major arteries arising from it, the free portion of the right atrial appendage, and the pulmonary trunk (PA) which, after arising from the right ventricle, runs in the transverse plane before bifurcating into the right and left pulmonary arteries. Also, note that the position of the “anterior” interventricular sulcus (shown with a red star) is more correctly termed superior. A anterior, AA ascending aorta, L left, LV left ventricle, P posterior, R right, RV right ventricle

In the normal case, there are two coronary arteries which arise from the aortic root, specifically from two of the three sinuses of Valsalva. These two coronary arteries supply the right and left halves of the heart, although there is considerable overlap in supply, especially in the interventricular septum. Nevertheless, the artery which supplies the right side of the heart is aptly termed the right coronary artery, and the corresponding artery which supplies the left side of the heart is termed the left coronary artery. Therefore, the sinuses in which these arteries arise can be similarly named the right coronary sinus and left coronary sinus, and for the sinus with no coronary artery, the noncoronary sinus; this convention is commonly used. These arteries then branch as they continue their path along

20

the heart, with the major arteries commonly following either the atrioventricular or interventricular grooves, with smaller branches extending from them. It is beyond the scope of this chapter to fully engage in a description of the nomenclature for the entire coronary arterial system. However, there are two glaring problems which persist in the nomenclature used to describe the coronary arteries, both which involve the interventricular grooves. First, shortly after the left coronary artery arises from the left coronary sinus, it bifurcates into the left anterior descending and the left circumflex arteries. The left anterior descending artery follows the so-called “anterior” interventricular groove, which was described previously as being positioned superiorly and to the left and only slightly anteriorly (Fig. 2.3). Second, depending on the individual, either the right coronary artery (80–90 %) or the left circumflex artery supplies the opposite side of the interventricular septum as the left “anterior” descending. Regardless of the parent artery, this artery is commonly called the “posterior” descending artery. However, similar to the socalled “anterior” descending artery, the position of this artery is not posterior but rather inferior (Fig. 2.5). Now that the courses of the two main coronary arteries are clear, the description of myocardial segmentation needs to be addressed. It is rather interesting that, although clinicians typically call the inferior interventricular artery the posterior descending artery, they often correctly term an infarction caused by blockage in this artery as an inferior infarct. Current techniques used to assess the location and severity of myocardial infarctions include MRI, CT, and 2D, 3D, or 4D cardiac ultrasound. These techniques allow for the clinician to view the heart in any plane or orientation; due to this, a similar confusion in terminology arises. Recently, an American Heart Association working group issued a statement in an attempt to standardize nomenclature for use with these techniques [9]. Upon close examination, this publication correctly terms areas supplied by the inferior interventricular artery as inferior but incorrectly terms the opposite aspect of the heart as anterior. Finally, nomenclatures commonly used to describe the leaflets of the atrioventricular valves—the tricuspid and mitral valves—are typically not attitudinally correct. For example, the tricuspid valve is situated between the right atrium and right ventricle and is so named because, in the majority of cases, there are three major leaflets or cusps. These are currently referred to as the anterior, posterior, and septal leaflets and were most likely termed in this manner due to examination of the heart in the Valentine position. Figure 2.7 shows an anterior view of a human heart in an attitudinally correct orientation, with the tricuspid annulus shown in orange. The theorized locations of the

A.J. Hill

Fig. 2.7 Volumetric reconstruction from magnetic resonance imaging (MRI) showing the anterior surfaces of the right ventricle and atrium of a human heart. The tricuspid annulus is highlighted in orange and was traced on the MRI images. The theorized positions of the commissures between the leaflets are drawn in red, and the leaflets are labeled appropriately. AS anterosuperior, I inferior, L left, R right, RA right atrium, RV right ventricle, S superior, Sp septal

commissures between the leaflets are shown in red. In order for the “anterior” leaflet to be truly anterior, the tricuspid annulus would need to be orthogonal to the image. However, the actual location of the annulus is in an oblique plane as shown in the figure, and therefore the leaflets would be more correctly termed anterosuperior, inferior, and septal. The same is true for the mitral valve, although the terms used to describe it are a bit closer to reality than the tricuspid valve. The mitral valve has two leaflets, commonly referred to as the anterior and posterior. However, Fig. 2.8 shows that the leaflets are not strictly anterior or posterior, or else the plane of the annulus (shown in orange) would be perpendicular to the screen. Therefore, based on attitudinal terms, one would prefer to define these leaflets as anterosuperior and posteroinferior. It should be noted that these leaflets have also been described as aortic and mural, which is less dependent on orientational terms and also technically correct.

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Attitudinal Anatomy

rior (dorsal) aspect of the sternum. Further confounding the differences is varying nomenclature. The terms inferior and superior are rarely used and rather are replaced by cranial and caudal. Likewise, the terms anterior and posterior are commonly replaced with ventral and dorsal. Also see Figs. 6.10 and 6.11 in Chap. 6 for more information on the relative position of a sheep heart compared to a human heart.

2.6

Summary

As the field of cardiac anatomy continues to play an important role in the practice of medicine and the development of medical devices, it benefits all involved to adopt commonly used terminology to describe the heart and its proper location in the body. Furthermore, it may be of great utility to describe the cardiac anatomy of major animal models using the same terminology as that of humans, at least when comparisons are being made between species. Finally, due to advances in 3D and 4D imaging and their growing use in the cardiac arena, a sound foundation of attitudinally correct terms will benefit everyone involved.

References

Fig. 2.8 Volumetric reconstruction from magnetic resonance imaging (MRI) showing the anterior surfaces of the left ventricle and atrium of a human heart. The mitral annulus is highlighted in orange and was traced on the MRI images. The theorized positions of the commissures between the leaflets are drawn in red, and the leaflets are labeled appropriately. AS anterosuperior, I inferior, L left, LA left atrium, LV left ventricle, PI posteroinferior, R right, S superior

2.5

Comparative Aspects of Attitudinally Correct Cardiac Anatomy

In addition to the incorrect terminology used to describe the human heart, translation of cardiac anatomy between human and other species is often further complicated due to differences in the orientation of the heart within the thorax. Compared to the human heart, the commonly used large mammalian heart is rotated so that the apex is aligned with the long axis of the body. Furthermore, the apex of the heart is oriented anteriorly and is commonly attached to the poste-

1. Iaizzo PA, Anderson RH, Hill AJ (2013) The importance of human cardiac anatomy for translational research. J Cardiovasc Transl Res 6:105–106 2. Anderson RH, Spicer DE, Hlavacek AJ, Hill AJ, Loukas M (2013) Describing the cardiac components–attitudinally appropriate nomenclature. J Cardiovasc Transl Res 6:118–123 3. Anderson RH, Becker AE, Allwork SP et al (eds) (1980) Cardiac anatomy: an integrated text and colour atlas. Churchill Livingston, New York 4. Anderson RH, Razavi R, Taylor AM (2004) Cardiac anatomy revisited. J Anat 205:159–177 5. Cook AC, Anderson RH (2002) Attitudinally correct nomenclature. Heart 87:503–506 6. Cosio FG, Anderson RH, Kuck KH et al (1999) Living anatomy of the atrioventricular junctions. A guide to electrophysiologic mapping. Circulation 100:e31–e37 7. McAlpine WA (1975) Heart and coronary arteries: an anatomical atlas for clinical diagnosis, radiological investigation, and surgical treatment. Springer, New York 8. Walmsley R, Watson H (1978) Clinical anatomy of the heart. Churchill Livingstone, New York 9. Cerqueira MD, Weissman NJ, Dilsizian V et al (2002) Standardized myocardial segmentation and nomenclature for tomographic imaging of the heart: a statement for healthcare professionals from the Cardiac Imaging Committee of the Council on Clinical Cardiology of the American Heart Association. Circulation 105:539–542

Cardiac Development

3

Brad J. Martinsen and Jamie L. Lohr

Abstract

The first heart field (FHF), second heart field (SHF), cardiac neural crest (CNC), and proepicardial organ (PEO) are the four major embryonic regions involved in vertebrate heart development. They each make an important contribution to overall cardiac development with complex developmental timing and regulation. This chapter describes how these regions interact to form the final structure of the heart in relationship to the developmental timeline of human embryology. Keywords

Human heart embryology • First heart field • Second heart field • Cardiac neural crest • Proepicardial organ • Cardiac development

3.1

Introduction to Human Heart Embryology and Development

The first heart field (FHF), second heart field (SHF), cardiac neural crest (CNC), and the proepicardial organ (PEO) are the four major embryonic regions involved in the process of vertebrate heart development (Fig. 3.1). They each make an important contribution to cardiac development with their own complex developmental timing and regulation (Table 3.1) [1, 2]. The heart is the first internal organ to form and function during vertebrate development, and many of the mechanisms of heart formation are molecularly and developmentally conserved [3–6]. The description presented here is based on development research from the chick, mouse, frog, and human model systems. Research conducted in the last decade has redefined the FHF which gives rise to the left ventricle and parts of the atria; furthermore, it has led

B.J. Martinsen, PhD (*) • J.L. Lohr, MD Division of Pediatric Cardiology, Department of Pediatrics, University of Minnesota School of Medicine, East Building, MB 560, 2450 Riverside Avenue, Minneapolis, MN 55454, USA e-mail: [email protected]

to the exciting discovery of the SHF which gives rise to the outflow tract, right ventricle, and parts of the atria of the mature heart [7–18]. These discoveries were critical steps in helping us understand how the outflow tract of the heart forms, a cardiac structure where many congenital heart defects arise, and thus has important implications for the understanding and prevention of congenital heart disease [6, 15–19]. Great strides have also been made in understanding the contributions of both the CNC [20] and the PEO [15, 21, 22] to overall heart development.

3.2

First Heart Field Contribution to the Linear Heart Tube, Left Ventricle, and Atria

The cells that will become the heart are among the first cell lineages formed in the vertebrate embryo [23, 24]. By day 15 of human development, the primitive streak has formed [1] and the first mesodermal cells to migrate (gastrulate) through the primitive streak are also the cells fated to become myocytes or heart cells [25, 26] (Fig. 3.2). These mesodermal cells dedicated for heart development migrate to an anterior and lateral position where they initially form a bilateral FHF and a more medially located SHF [10, 11, 15, 16, 27]

© Springer International Publishing Switzerland 2015 P.A. Iaizzo (ed.), Handbook of Cardiac Anatomy, Physiology, and Devices, DOI 10.1007/978-3-319-19464-6_3

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Fig. 3.1 The four major contributors to heart development illustrated in the chick model system: first heart field, second heart field, cardiac neural crest, and the proepicardial organ. (A) Day 1 chick embryo (equivalent to day 20 of human development). Red denotes first heart field cells and yellow denotes second heart field cells. (B) Day 2.5 chick embryo (equivalent to approximately 5 weeks of human development). Color code: green = cardiac neural crest cells; red = first heart field cells; yellow = second heart field cells; blue = proepicardial cells. (C) Day 8 chick heart (equivalent to approximately 9 weeks of human development). Color code: green = derivatives of the cardiac neural crest; yel-

low = derivatives of the second heart field; red = derivatives of the first heart field; blue = derivatives of the proepicardial organ. Ao aorta, APP anterior parasympathetic plexus, APS aorticopulmonary septum, BA branchial arch, Co coronary vessels, E eye, H heart, IFT inflow tract, IVS interventricular septum, LA left atrium, LV left ventricle, LVAB left ventral arterial branch of the Xth (vagal) cranial nerve, Mb midbrain, NF neural folds, OFT outflow tract, Otc otic placode, P pulmonary artery, RA right atrium, RDAB right dorsal arterial branch of the Xth (vagal) cranial nerve, RV right ventricle, SMC smooth muscles cells, T trunk

(Fig. 3.1A). Specifically, the posterior border of the bilateral FHF reaches down to the first somite in the lateral mesoderm on both sides of the midline [8, 28] (Fig. 3.1A). At day 18 of human development, the lateral plate mesoderm is split into two layers—somatopleuric and splanchnopleuric [1]. It is the splanchnopleuric mesoderm layer that contains the myo-

cardial, smooth muscle, and endocardial cardiogenic precursors in the region of the FHF and SHF, as defined above. Presumptive endocardial cells delaminate from the splanchnopleuric mesoderm in the FHF and coalesce via vasculogenesis to form two lateral endocardial tubes [29]. During the third week of human development, two bilateral layers of

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Table 3.1 Developmental timeline of human heart embryology Human development (days) 0 1–4 5–12 13–14 15–17

17–18

18–26 20

21–22 22 22–28

32–37 57+ Birth

Developmental process Fertilization Cleavage and movement down the oviduct to the uterus Implantation of the embryo into the uterus Primitive streak formation (midstreak level contains precardiac cells) 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 first heart field and a more medially located the second heart field 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 first heart field and second heart field Neurulation (formation of the neural tube) Cephalocaudal and lateral folding brings the bilateral endocardial tubes into the ventral midline of the embryo Heart tube fusion Heart tube begins to beat Heart looping and the accretion of cells from the first and second heart fields; proepicardial cells invest the outer layer of the heart tube and eventually form the epicardium and coronary vasculature; neural crest migration starts Cardiac neural crest migrates through the aortic arches and enters the outflow tract of the heart Outflow tract and ventricular septation complete Functional septation of the atrial chambers, as well as the pulmonary and systemic circulatory systems

Most of the human developmental timing information is from Larsen’s Human Embryology [1], except for the human staging of the second heart field and proepicardium which was correlated from other model systems [7–9, 30]

myocardium surrounding the endocardial tubes are brought into the ventral midline during closure of the ventral foregut via cephalic and lateral folding of the embryo [1] (Fig. 3.2A). The lateral borders of the myocardial mesoderm layers are the first heart structures to fuse, followed by the fusion of the two endocardial tubes which then form one endocardial tube surrounded by splanchnopleuric-derived myocardium (Fig. 3.2B, C). The medial borders of the myocardial mesoderm layers are the last to fuse [30]. Thus, the early heart is continuous with splanchnopleuric mesoderm across the dorsal mesocardium (Fig. 3.2C). 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

Fig. 3.2 Cross-sectional view of human heart tube fusion. (A) Day 20, cephalocaudal and lateral folding brings bilateral endocardial tubes into the ventral midline of the embryo. (B) Day 21, start of heart tube fusion. (C) Day 22, complete fusion, resulting in the beating primitive heart tube. Color code of the embryonic primary germ layer origin: blue/ purple = ectoderm; red = mesoderm; orange = endoderm; yellow = second heart field. FHF first heart field, SHF second heart field

cavity [18, 30]. During the fusion of the endocardial tubes, the myocardium secretes an extracellular (acellular) matrix (enriched in chondroitin sulfate, versican, heparan sulfate, hyaluronic acid, hyaluronan, and proteoglycans), forming the cardiac jelly layer separating the myocardium and endocardium [31]. By day 22 of human development, the linear heart tube begins to beat. As the human heart begins to fold and loop from day 22 to day 28 (described below), epicardial cells from the PEO will invest the outer layer of the heart tube (Figs. 3.1B and 3.3A), resulting in a heart tube with four primary layers: endocardium, cardiac jelly, myocardium, and epicardium [1] (Fig. 3.3B).

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Fig. 3.3 Origin and migration of proepicardial cells. (A) Whole mount view of the looping human heart within the pericardial cavity at day 28. Proepicardial cells (blue dots) 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. Color code: yellow = second heart field (SHF)-derived cells; red (within heart) = first heart field (FHF)derived cells. LV left ventricle, RV right ventricle

3.3

Second Heart Field Contribution to the Outflow Tract, Right Ventricle, and Atria

A cascade of signals identifying the left and right sides of the embryo is thought to initiate the process of primary linear heart tube looping [32]. The primary heart tube loops to the right of the embryo and bends to allow convergence of the inflow (venous) and outflow (arterial) ends between day 22 and day 28 of human development (Fig. 3.4). This process occurs prior to the division of the heart tube into four chambers and is required for proper alignment and septation of the mature cardiac chambers. During the looping process, the primary heart tube increases dramatically in length (by fourto fivefold) on both the outflow and inflow poles via the addition of progenitor cells originating from the SHF (pharyngeal mesoderm) [7–18]. These multipotent progenitor cells within the developing heart give rise to myocardium, smooth muscle, and endothelial cells [12]. Previous experiments in the 1970s already revealed that the distal right ventricle and outflow tract (OFT) are added later to the looping heart by addition of cells lying outside the early heart [12, 33]. Researchers at that time, however, still assumed that the primary linear heart tube already contained all the cell lineages to build the adult heart. It was not until the rediscovery of these progenitor cells in 2001 (at the time termed anterior heart field or secondary heart field) that the clinical relevance of congenital heart defects was correlated to cells in this heart field—a big step in truly understanding heart development [7–9, 12]. The terms anterior heart field and secondary heart field are now considered to be a subpopulation of the SHF, a larger field of progenitor cells in pharyngeal mesoderm [12, 34].

The SHF is then contained within a larger field of multipotent cranial mesoderm (cardiocraniofacial field) that plays a critical role in development of both the arterial pole of the heart and craniofacial morphogenesis [12]. Specifically, the SHF (Figs. 3.1b and 3.2c) is located along the splanchnopleuric mesoderm (beneath the floor of the foregut) at the attachment site of the dorsal mesocardium [7–18]. During looping, the anterior SHF (previously termed anterior heart field or secondary heart field) cells undergo epithelial-tomyocardial transformation at the outflow (arterial) pole and add additional myocardial cells onto the then developing outflow tract, creating the great vessels (aorta and pulmonary trunk) and the right ventricle. This lengthening of the primary heart tube appears to be an important process for the proper alignment of the inflow and outflow tracts prior to septation. If this process does not occur normally, ventricular septal defects and malpositioning of the aorta may occur [30]. Recent evidence also indicates that the posterior SHF contributes to the inflow tract, creating parts of the left and right atria. Thus, the SHF contains two primary regions: (1) an anterior region or compartment that contributes to the outflow tract and (2) a posterior region or compartment that contributes to the inflow tract, as well as possibly the PEO [10, 15, 17, 35–37]. Defects in posterior SHF development result in conotruncal, atrial, and atrioventricular septal defects, major forms of congenital heart defects in humans [12]. By day 28 of human development, the chambers of the heart are in position and are demarcated by visible constrictions and expansions which denote the sinus venosus, common atrial chamber, atrioventricular sulcus, ventricular chamber, and conotruncus (proximal and distal outflow tract) [1, 30] (Fig. 3.4).

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Fig. 3.4 Looping, accretion, and septation of the human primary linear heart tube. Blue (first heart field- and second heart fieldderived cells) and yellow (second heart field-derived cells) regions represent tissue added during looping; red = first heart fieldderived cells. Ao aorta, AV atrioventricular, LA left atrium, LV left ventricle, P pulmonary trunk, RA right atrium, RV right ventricle

3.4

Cardiac Neural Crest Contribution and Septation of the Outflow Tract and Ventricles

Once the chambers are in the correct position after looping, extensive remodeling of the primitive vasculature and septation of the heart can occur. The CNC is an extracardiac population of cells (from outside of the first or SHFs) that arise from the neural tube in the region of the first three somites up to the midotic placode level (rhombomeres 6, 7, and 8) (Fig. 3.5) [2, 38, 39]. CNC cells leave the neural tube during weeks 3–4 of human development and then migrate through aortic arches 3, 4, and 6 (Fig. 3.1b) and eventually into the developing outflow tract of the heart (during weeks 5–6). These cells are necessary for complete septation of the outflow tract and ventricles (completed by week 8 of human development), as well as the formation of the anterior parasympathetic plexus which contributes to cardiac innervation and regulation of heart rate [1, 2, 20, 38–42]. Recent evidence shows that CNC cells migrate to the venous pole of the heart as well and that their role is in the development of the parasympathetic innervation, the leaflets of the atrioventricular valves, and possibly the cardiac conduction system [43– 45]. The primitive vasculature of the heart is bilaterally symmetrical but, during weeks 4–8 of human development, there is remodeling of the inflow end of the heart so that all systemic blood flows into the future right atrium [1]. In addition, there is also 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 CNC [30, 46]. The distal outflow tract (truncus) septates into the aorta and pulmonary trunk via the fusion of two streams or prongs of CNC that migrate into the distal outflow tract. In contrast, the proximal outflow

Fig. 3.5 Origin of the cardiac neural crest within a 34-h chick embryo. Green dots represent cardiac neural crest cells in the neural folds of hindbrain rhombomeres 6, 7, and 8 (the region of the first three somites up to the midotic placode level). Fb forebrain, Mb midbrain

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B.J. Martinsen and J.L. Lohr

tract septates by fusion of the endocardial cushions and eventually joins proximally with the atrioventricular endocardial cushion tissue and the ventricular septum [47, 48]. The endocardial cushions are formed by both atrioventricular canal and outflow tract endocardial cells that migrate into the cardiac jelly, forming bulges or cushions. Despite its clinical importance, to this date, almost nothing is known about the molecular pathways that determine cell lineages in the CNC or regulate outflow tract septation [30, 49, 50]. However, it is known that if the CNC is removed before it begins to migrate, conotruncal septa completely fail to develop, and blood leaves both the ventricles through what is termed a persistent truncus arteriosus, a rare congenital heart anomaly that can be seen in humans [20, 40]. Failure of outflow tract septation may also be responsible for other forms of congenital heart disease including transposition of the great vessels, high ventricular septal defects, and tetralogy of Fallot [1, 20, 38, 40]. Additional information on these congenital defects can be found in Chap. 10. The septation of the outflow tract (conotruncus) is tightly coordinated with the septation of the ventricles and atria to produce a functional heart [1, 51, 52]. All of these septa eventually fuse with the atrioventricular (AV) cushions that also divide the left and right AV canals and serve as a source of cells for the AV valves. Prior to septation, the right atrioventricular canal and right ventricle expand to the right, causing a realignment of the atria and ventricles so that they

are directly over each other. This allows venous blood entering from the sinus venosus to flow directly from the right atrium to the presumptive right ventricle without flowing through the presumptive left atrium and ventricle [1, 30]. The new alignment also simultaneously provides the left ventricle with a direct outflow path to the truncus arteriosus and subsequently to the aorta. Between weeks 4 and 7 of human development, the left and right atria undergo extensive remodeling and are eventually septated. Yet, during the septation process, a right-to-left shunting of oxygenated blood (oxygenated by the placenta) is created via a series of shunts, ducts, and foramens (Fig. 3.6). Prior to birth, the use of the pulmonary system is not necessary, but eventually a complete separation of the systemic and pulmonary circulatory systems will be required for normal cardiac and systemic function [1]. Initially, the right sinus horn is incorporated into the right posterior wall of the primitive atrium, and the trunk of the pulmonary venous system is incorporated into the posterior wall of the left atrium via a process called intussusception. At day 26 of human development, a crescent-shaped wedge of tissue called the septum primum begins to extend into the atrium from the mesenchyme of the dorsal mesocardium. As it grows, the septum primum diminishes the ostium primum, a foramen allowing the shunting of blood from the right to left atrium. However, programmed cell death near the superior edge of the septum primum creates a new foramen, the ostium secundum, which continues the right-to-left shunting

Fig. 3.6 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 red arrows show the systemic circulation within the heart. Color code: Blue (first heart field- and second heart field-derived cells), red (first heart field-derived cells), and yellow (second heart field-derived cells). AV atrioventricular, LA left atrium, LV left ventricle, RA right atrium, RV right ventricle

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Cardiac Development

of oxygenated blood. An incomplete, ridged septum secundum with a foramen ovale near the floor of the right atrium forms next to the septum primum, both of which fuse with the septum intermedium of the AV cushions [1]. At the same time as atrial septation is beginning, about the end of the fourth week of human development, the muscular ventricular septum begins to grow toward the septum intermedium (created by the fusion of the atrioventricular cushions), creating a partial ventricular septum. By the end of the ninth week of human development, the outflow tract septum has grown down onto the upper ridge of this muscular ventricular septum and onto the inferior endocardial cushion, completely separating the right and left ventricular chambers. It is not until after birth, however, that the heart is functionally septated within the atrial region. At birth, dramatic changes in the circulatory system occur due to the transition from fetal dependence on the placenta for oxygenated blood to self-oxygenation via the lungs. More specifically, during fetal life, only small amounts of blood (about 5 % of the cardiac output) are flowing through the pulmonary system because the fluid-filled lungs create high flow resistance, resulting in low-volume flow into the left atrium from the pulmonary veins. This allows the high-volume blood flow coming from the placenta to pass through the inferior vena cava into the right atrium, where it is then directed across the foramen ovale into the left atrium. The oxygenated blood then flows into the left ventricle and directly out to the body of the fetus via the aorta. At birth, the umbilical blood flow is interrupted, stopping the high-volume flow from the placenta. In addition, the alveoli and pulmonary vessels open when the infant takes its first breath, dropping the resistance in the lungs and allowing more flow into the left atrium from the lungs. This reverse in pressure difference between the atria pushes the flexible septum primum against the ridged septum secundum and closes off the foramen ovale and ostium secundum, resulting in the complete septation of the heart chambers [1] (Fig. 3.6). For more information on defects and repairs of the foramen ovale, see Chap. 37.

3.5

Proepicardial Organ and Coronary Artery Development

The last major contributor to vertebrate heart development discussed in this chapter is the PEO [15, 21, 22]. Prior to heart looping, the primary heart tube consists of endocardium, cardiac jelly, and myocardium. It is not until the start of heart looping that epicardial cells from the PEO surround the myocardium, forming the fourth layer of the primary heart tube called the epicardium [15, 53] (Fig. 3.3). This population of cells will eventually give rise to the coronary vasculature. A neural crest origin of the coronary vessels was originally hypothesized, but recent lineage tracing studies have shown that the neural crest gives rise

to cells of the tunica media of the aortic and pulmonary trunks but not the coronary arteries [29, 54]. These experiments eventually showed that the coronary vasculature is derived from the PEO, a nest of cells in the dorsal mesocardium of the sinus venosus or septum transversum. These cells, which are derived from an independent population of splanchnopleuric mesoderm cells, migrate onto the primary heart tube (Fig. 3.3) between days 22 and 28 of human development, just as the heart initiates looping [1, 30]. Prior to migration, these cells are collectively called the PEO (or proepicardium). Interestingly, three lineages of the coronary vessel cells (smooth muscle, endothelial, and connective tissue cells) are segregated in the PEO prior to migration into the heart tube [29, 55]. These cells will coalesce to form coronary vessels de novo via the process of vasculogenesis [56]. Recently, it has also been shown that the epicardium provides a factor needed for normal myocardial development and is a source of cells forming the interstitial myocardium and cushion mesenchyme [30, 36]. It is considered that understanding the embryological origin of the vascular system and its molecular regulation may help to explain the varying susceptibility of different components of the vascular system to atherosclerosis [29, 57]. Recently, it has also been suggested that epicardiumderived cells may provide a source of cells for myocardial regeneration after a myocardial infarction [22]. Lastly, among the different stem cell populations identified in the later heart, Isl1-positive cells may be a population of resident cardiovascular stem cells derived from residual SHF cells [12, 58, 59]. Thus, approaches aimed at cardiac repair by manipulation of cardiac progenitor cells will depend on properly understanding how lineage choices are regulated in the SHF and PEO [12, 60].

3.6

Cardiac Maturation

Although the embryonic heart is fully formed and functional by the 11th week of pregnancy, the fetal and neonatal heart continues to grow and mature rapidly, with many clinically relevant changes taking place after birth. During fetal development or from the time after the embryo is completely formed in the first trimester of pregnancy until birth, the heart grows primarily by the process of cell division [61– 64]. Within a few weeks after birth, the predominant mechanism of cardiac growth is cell hypertrophy, so that most existing cardiac cells become larger, rather than increasing significantly in number [61–63]. The exact timing of this process and the mechanisms regulating this change are not yet completely elucidated. It has classically been thought that mature cardiac cells lose their ability to divide; however, recent work suggests that limited amounts of cell division do occur in adult hearts that have been damaged by ischemia [65–67].

30

This finding has led to a renewed interest in understanding the regulation of cell division during cardiac maturation. Additional maturational changes in the fetal and neonatal heart include (1) alterations in the composition of the cardiac myocytes, (2) differences in energy production, and/or (3) maturation of the contractile function. These changes, along with physiologic changes in the transitional circulation, as discussed earlier, significantly affect the treatment of newborns with congenital heart disease, particularly those requiring interventional procedures or cardiac surgery. The hemodynamic changes associated with birth include significant increases in left ventricular cardiac output to meet the increased metabolic needs of the newborn infant. This improvement in cardiac output occurs despite the fact that the neonatal myocardium has less muscle mass and less cellular organization than the mature myocardium. The newborn myocardium consists of 30 % contractile proteins (mass) and 70 % noncontractile mass (membranes, connective tissues, and organelles). This is in contrast to the adult myocardium which is 60 % contractile mass [63]. The myocardial cells of the fetus are rounded, and both the myocardial cells and myofibrils within them are oriented randomly. As the fetal heart matures, these myofibrils increase in size and number and also orient themselves to the long axis of the rows of cells, which will likely contribute to improved myocardial function [61]. In general, the fetal myocardial cell contains higher amounts of glycogen than the mature myocardium, suggesting an increased dependence on glucose for energy production. In experiments using nonprimate model systems, the fetal myocardium is able to meet metabolic needs with lactate and glucose as the primary fuels [68]. In contrast, the preferred substrate for energy metabolism in the adult heart is long-chain fatty acids, although the adult heart is able to utilize carbohydrates as well [68, 69]. This change is presumably triggered in the first few days or weeks of life by an increase in serum long-chain fatty acids with feeding, yet the timing and clinical impact of this change in ill or nonfeeding neonates with cardiovascular disease remain unknown. In addition to the changes described above, maturing myocardial cells undergo changes in their expression of many innate contractile proteins, which may be responsible for some of the maturational differences in cardiovascular function. For example, the gradual increase in expression of myosin light chain 2 (MLC 2) in the ventricle from the neonatal period through adolescence is considered to be important in humans. In the fetal ventricle, two myosin light chain forms, MLC 1 and MLC 2, are expressed in equal amounts [63, 70]; MLC 1 is associated with increased contractility and has been documented to increase contractility in isolated muscle from patients with tetralogy of Fallot [71]. After birth, there is a gradual increase in the amount of MLC 2 or the “regulatory” myosin light chain, which has a slower rate

B.J. Martinsen and J.L. Lohr

of force development, but can be phosphorylated to increase calcium-dependent force development in mature cardiac muscle [63, 72]. There is also variability in actin isoform expression during cardiac development. More specifically, the human fetal heart predominantly expresses cardiac alphaactin, while the more mature human heart expresses skeletal alpha-actin [61, 73]. Furthermore, actin is responsible for interacting with myosin crossbridges and regulating ATPase activity; work done in the mouse model system suggests that the change to skeletal actin may be one of the mechanisms of enhanced contractility in the mature heart [61, 74, 75]. There are also developmental changes of potential functional significance in the regulatory proteins of the sarcomere. Initially, the fetal heart expresses both alpha- and beta-tropomyosin, a regulatory filament, in nearly equal amounts. After birth, the proportion of beta-tropomyosin decreases and alphatropomyosin increases, possibly optimizing diastolic relaxation [61, 76, 77]. In contrast, expression of high levels of beta-tropomyosin in the neonatal heart is associated with early death due to myocardial dysfunction [78]. Lastly, the isoform of the inhibitory troponin, troponin I, changes after birth. The fetal myocardium contains mostly the skeletal isoform of troponin I [61, 79]. After birth, the myocardium begins to express cardiac troponin I, and by approximately 9 months of age, only cardiac troponin I is present [61, 80, 81]. Importantly, cardiac troponin I can be phosphorylated to improve calcium-binding dynamics and contractility, which correlates with improved function in the more mature heart. It is thought that the skeletal form of troponin I may serve to protect the fetal and neonatal myocardium from acidosis [63, 74, 82]. The full impact of these developmental changes in contractile proteins and their effect on cardiac function or perioperative treatment of newborns with heart disease remain unclear at the present time. Two of the most clinically relevant features of the immature myocardium are its requirement for high levels of extracellular calcium and a decreased sensitivity to beta-adrenergic inotropic agents. The neonatal heart has a decrease in both volume and amount of functionally mature sarcoplasmic reticulum, which is the intercellular storage site for calcium [61]. This paucity of intracellular calcium storage and release via the sarcoplasmic reticulum in the fetal and neonatal myocardium increases the requirement of the fetal myocardium for extracellular calcium, so that exogenous administration of calcium can be used to augment cardiac contractility in the appropriate clinical setting. In addition, neonates and infants are significantly more sensitive to calcium channelblocking drugs than older children or adults and thus may be at risk for severe depression of myocardial contractility with the administration of these agents [61, 63, 83]. Lastly, although data in humans are limited, there appears to be significantly decreased sensitivity to beta-agonist agents in the immature myocardium and also in older children with con-

3

Cardiac Development

genital heart disease [63, 84–86]. This altered sensitivity may be due to: (1) a paucity of receptors, (2) sensitization to endogenous catecholamines at birth or with heart failure, or (3) some combination of these or additional factors. Due to this decreased responsiveness to beta-agonists, there are common requirements for higher doses of beta-agonist inotropic agents in newborns and infants. Note that alternative medications, including phosphodiesterase inhibitors, are often useful adjuncts to improve contractility in newborns with myocardial dysfunction [63]. Although the structure of the heart is complete in the first trimester of pregnancy, cardiac growth and maturation continue to occur in the fetus, newborn, and child. Many of these developmental changes, particularly decreased intracellular calcium stores in the immature sarcoplasmic reticulum and a decreased responsiveness to beta-agonist inotropic agents, significantly impact the care of newborns, infants, and children with congenital heart disease, particularly those requiring surgical intervention early in life.

3.7

Summary of Embryonic Contribution to Heart Development

The contribution of the four major embryonic regions to heart development—FHF, SHF, CNC, and PEO—illustrates the complexity of human heart development. Each of these regions has a unique contribution to the heart, but they ultimately depend on each other for the creation of a fully functional organ. Furthermore, a better understanding of the mechanisms of human heart development will provide clues to the etiology of congenital heart disease. The genetic regulatory mechanisms of these developmental processes are just beginning to be characterized. A molecular review of heart development is outside the scope of this chapter, but several informative molecular heart reviews have been recently published [6, 16, 30, 87, 88]. A better understanding of the embryological origins of the heart, combined with the characterization of the genes that control heart development, will likely lead to many new clinical applications to treat congenital and/or adult heart disease.

References 1. Schoenwolf GC, Bleyl BB, Brauer PR, Francis-West PH (eds) (2009) Larsen’s human embryology, 4th edn. Churchill Livingstone Elsevier, Philadelphia 2. Martinsen BJ (2005) Reference guide to the stages of chick heart embryology. Dev Dyn 233:1217–1237 3. Srivastava D, Olson EN (2000) A genetic blueprint for cardiac development. Nature 407:221–226 4. Jensen B, Wang T, Christoffels VM, Moorman AFM (2013) Evolution and development of the building plan of the vertebrate heart. Biochim Biophys Acta 1833:783–794

31 5. Sperling SR (2011) Systems biology approaches to heart development and congenital heart disease. Cardiovasc Res 91:269–278 6. Fahed AC, Gelb BD, Seidman JG, Seidman CE (2013) Genetics of congenital heart disease: the glass half empty. Circ Res 112:707–720 7. Kelly RG, Brown NA, Buckingham ME (2001) The arterial pole of the mouse heart forms from Fgf10-expressing cells in pharyngeal mesoderm. Dev Cell 1:435–440 8. Mjaatvedt CH, Nakaoka T, Moreno-Rodriguez R et al (2001) The outflow tract of the heart is recruited from a novel heart-forming field. Dev Biol 238:97–109 9. Waldo KL, Kumiski DH, Wallis KT et al (2001) Conotruncal myocardium arises from a secondary heart field. Development 128:3179–3188 10. Xin M, Olson EN, Bassel-Duby R (2013) Mending broken hearts: cardiac development as a basis for adult heart regeneration and repair. Nat Rev Mol Cell Biol 14:529–541 11. Kodo K, Yamagishi H (2011) A decade of advances in the molecular embryology and genetics underlying congenital heart defects. Circ J 75:2296–2304 12. Kelly RG (2012) The second heart field. Curr Top Dev Biol 100:33–65 13. Van den Berg G, Abu-Issa R, de Boer BA et al (2009) A caudal proliferating growth center contributes to both poles of the forming heart tube. Circ Res 104:179–188 14. De Boer BA, van den Berg G, de Boer PAJ et al (2012) Growth of the developing mouse heart: an interactive qualitative and quantitative 3D atlas. Dev Biol 368:203–213 15. Brade T, Pane LS, Moretti A et al (2013) Embryonic heart progenitors and cardiogenesis. Cold Spring Harb Perspect Med 3:a013847 16. Lin CJ, Lin CY, Chen CH et al (2012) Partitioning the heart: mechanisms of cardiac septation and valve development. Development 139:3277–3299 17. Francou A, Saint-Michel E, Mesbah K et al (2013) Second heart field cardiac progenitor cells in the early mouse embryo. Biochim Biophys Acta 1833:795–798 18. Kelly RG, Buckingham ME (2002) The anterior heart-forming field: voyage to the arterial pole of the heart. Trends Genet 18:210–216 19. Degenhardt K, Singh MK, Epstein JA (2013) New approaches under development: cardiovascular embryology applied to heart disease. J Clin Invest 123:71–74 20. Keyte A, Hutson MR (2012) The neural crest in cardiac congenital anomalies. Differentiation 84:25–40 21. Pérez-Pomares JM, de la Pompa JL (2011) Signaling during epicardium and coronary vessel development. Circ Res 109:1429–1442 22. Smart N, Riley PR (2012) The epicardium as a candidate for heart regeneration. Future Cardiol 8:53–69 23. Hatada Y, Stern CD (1994) A fate map of the epiblast of the early chick embryo. Development 120:2879–2889 24. Yutzey KE, Kirby ML (2002) Wherefore heart thou? Embryonic origins of cardiogenic mesoderm. Dev Dyn 223:307–320 25. Garcia-Martinez V, Schoenwolf GC (1993) Primitive-streak origin of the cardiovascular system in avian embryos. Dev Biol 159:706–719 26. Psychoyos D, Stern CD (1996) Fates and migratory routes of primitive streak cells in the chick embryo. Development 122:1523–1534 27. DeHaan RL (1963) Organization of the cardiogenic plate in the early chick embryo. Acta Embryol Moprhol Exp 6:26–38 28. Ehrman LA, Yutzey KE (1999) Lack of regulation in the heart forming region of avian embryos. Dev Biol 207:163–175 29. Harvey RP, Rosenthal N (eds) (1999) Heart development, 1st edn. Academic, San Diego 30. Kirby ML (2002) Molecular embryogenesis of the heart. Pediatr Dev Pathol 23:537–544

32 31. Nandadasa S, Foulcer S, Apte SS (2014) The multiple, complex roles of versican and its proteolytic turnover by ADAMTS proteases during embryogenesis. Matrix Biol 35:34–41 32. Lohr JL, Yost HJ (2000) Vertebrate model systems in the study of early heart development: Xenopus and zebrafish. Am J Med Genet 97:248–257 33. De la Cruz MV, Sánchez Gómez C, Arteaga MM, Argüello C (1977) Experimental study of the development of the truncus and the conus in the chick embryo. J Anat 123:661–686 34. Dyer LA, Kirby ML (2009) The role of secondary heart field in cardiac development. Dev Biol 336:137–144 35. Kelly RG (2005) Molecular inroads into the anterior heart field. Trends Cardiovasc Med 15:51–56 36. Gittenberger-de Groot AC, Vrancken Peeters MP, Bergwerff M et al (2000) Epicardial outgrowth inhibition leads to compensatory mesothelial outflow tract collar and abnormal cardiac septation and coronary formation. Circ Res 87:969–971 37. Lie-Venema H, van den Akker NMS, Bax NAM et al (2007) Origin, fate, and function of epicardium-derived cells (EPDCs) in normal and abnormal cardiac development. Scientific World Journal 7:1777–1798 38. Kirby ML, Gale TF, Stewart DE (1983) Neural crest cells contribute to normal aorticopulmonary septation. Science 220:1059–1061 39. Kirby ML, Stewart DE (1983) Neural crest origin of cardiac ganglion cells in the chick embryo: identification and extirpation. Dev Biol 97:433–443 40. Kirby ML, Turnage KL, Hays BM (1985) Characterization of conotruncal malformations following ablation of “cardiac” neural crest. Anat Rec 213:87–93 41. O’Rahilly R, Müller F (2007) The development of the neural crest in the human. J Anat 211:335–351 42. Porras D, Brown CB (2008) Temporal-spatial ablation of neural crest in the mouse results in cardiovascular defects. Dev Dyn 237:153–162 43. Hildreth V, Webb S, Bradshaw L et al (2008) Cells migrating from the neural crest contribute to the innervation of the venous pole of the heart. J Anat 212:1–11 44. Poelmann RE, Jongbloed MRM, Molin DGM et al (2004) The neural crest is contiguous with the cardiac conduction system in the mouse embryo: a role in induction? Anat Embryol (Berl) 208:389–393 45. Poelmann RE, Gittenberger-de Groot AC (1999) A subpopulation of apoptosis-prone cardiac neural crest cells targets to the venous pole: multiple functions in heart development? Dev Biol 207:271–286 46. Bockman DE, Redmond ME, Kirby ML (1989) Alteration of early vascular development after ablation of cranial neural crest. Anat Rec 225:209–217 47. Waldo K, Miyagawa-Tomita S, Kumiski D, Kirby ML (1998) Cardiac neural crest cells provide new insight into septation of the cardiac outflow tract: aortic sac to ventricular septal closure. Dev Biol 196:129–144 48. Waldo KL, Lo CW, Kirby ML (1999) Connexin 43 expression reflects neural crest patterns during cardiovascular development. Dev Biol 208:307–323 49. Martinsen BJ, Groebner NJ, Frasier AJ, Lohr JL (2003) Expression of cardiac neural crest and heart genes isolated by modified differential display. Gene Expr Patterns 3:407–411 50. Martinsen BJ, Frasier AJ, Baker CVH, Lohr JL (2004) Cardiac neural crest ablation alters Id2 gene expression in the developing heart. Dev Biol 272:176–190 51. Anderson RH, Webb S, Brown NA et al (2003) Development of the heart: (2) Septation of the atriums and ventricles. Heart 89:949–958 52. Lamers WH, Moorman AFM (2002) Cardiac septation: a late contribution of the embryonic primary myocardium to heart morphogenesis. Circ Res 91:93–103

B.J. Martinsen and J.L. Lohr 53. Komiyama M, Ito K, Shimada Y (1987) Origin and development of the epicardium in the mouse embryo. Anat Embryol (Berl) 176:183–189 54. Noden DM, Poelmann RE, Gittenberger-de Groot AC (1995) Cell origins and tissue boundaries during outflow tract development. Trends Cardiovasc Med 5:69–75 55. Mikawa T, Gourdie RG (1996) Pericardial mesoderm generates a population of coronary smooth muscle cells migrating into the heart along with ingrowth of the epicardial organ. Dev Biol 174:221–232 56. Noden DM (1990) Origins and assembly of avian embryonic blood vessels. Ann N Y Acad Sci 588:236–249 57. Hood LC, Rosenquist TH (1992) Coronary artery development in the chick: origin and deployment of smooth muscle cells, and the effects of neural crest ablation. Anat Rec 234:291–300 58. Bu L, Jiang X, Martin-Puig S et al (2009) Human ISL1 heart progenitors generate diverse multipotent cardiovascular cell lineages. Nature 460:113–117 59. Laugwitz K-L, Moretti A, Lam J et al (2005) Postnatal isl1+ cardioblasts enter fully differentiated cardiomyocyte lineages. Nature 433:647–653 60. Musunuru K, Domian IJ, Chien KR (2010) Stem cell models of cardiac development and disease. Annu Rev Cell Dev Biol 26:667–687 61. Anderson PAW (2000) Developmental cardiac physiology and myocardial function. In: Moller JH, Hoffman JIE (eds) Pediatric cardiovascular medicine. Churchill Livingstone, New York, pp 35–57 62. Huttenbach Y, Ostrowski ML, Thaller D, Kim HS (2001) Cell proliferation in the growing human heart: MIB-1 immunostaining in preterm and term infants at autopsy. Cardiovasc Pathol 10:119–123 63. Kern FH, Bengur AR, Bello EA (1996) Developmental cardiac physiology. In: Pediatric intensive care, 3rd edn. Lippincott, Williams and Wilkins, Baltimore, pp 397–423 64. Kim HD, Kim DJ, Lee IJ et al (1992) Human fetal heart development after mid-term: morphometry and ultrastructural study. J Mol Cell Cardiol 24:949–965 65. Beltrami AP, Urbanek K, Kajstura J et al (2001) Evidence that human cardiac myocytes divide after myocardial infarction. N Engl J Med 344:1750–1757 66. Anversa P, Leri A (2013) Innate regeneration in the aging heart: healing from within. Mayo Clin Proc 88:871–883 67. Rota M, Leri A, Anversa P (2014) Human heart failure: is cell therapy a valid option? Biochem Pharmacol 88:129–138 68. Vick GW, Fisher DA (1998) Cardiac metabolism. In: Garson A (ed) The science and practice of pediatric cardiology. Williams and Wilkens, Baltimore, pp 155–169 69. Opie LH (1991) Carbohydrates and lipids. In: Opie LH (ed) The heart: physiology and metabolism, 2nd edn. Raven, New York, pp 208–246 70. Price KM, Littler WA, Cummins P (1980) Human atrial and ventricular myosin light-chains subunits in the adult and during development. Biochem J 191:571–580 71. Morano M, Zacharzowski U, Maier M et al (1996) Regulation of human heart contractility by essential myosin light chain isoforms. J Clin Invest 98:467–473 72. Morano I (1999) Tuning the human heart molecular motors by myosin light chains. J Mol Med (Berl) 77:544–555 73. Boheler KR, Carrier L, de la Bastie D et al (1991) Skeletal actin mRNA increases in the human heart during ontogenic development and is the major isoform of control and failing adult hearts. J Clin Invest 88:323–330 74. Anderson PAW, Kleinman CS, Lister G, Talner N (1998) Cardiovascular function during normal fetal and neonatal development and with hypoxic stress. In: Polin RA, Fox WW (eds) Fetal and neonatal physiology, 2nd edn. Saunders, Philadelphia, pp 837–890

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75. Hewett TE, Grupp IL, Grupp G, Robbins J (1994) Alpha-skeletal actin is associated with increased contractility in the mouse heart. Circ Res 74:740–746 76. Muthuchamy M, Grupp IL, Grupp G et al (1995) Molecular and physiological effects of overexpressing striated muscle beta-tropomyosin in the adult murine heart. J Biol Chem 270:30593–30603 77. Palmiter KA, Kitada Y, Muthuchamy M et al (1996) Exchange of beta- for alpha-tropomyosin in hearts of transgenic mice induces changes in thin filament response to Ca2+, strong cross-bridge binding, and protein phosphorylation. J Biol Chem 271:11611–11614 78. Muthuchamy M, Boivin GP, Grupp IL, Wieczorek DF (1998) Betatropomyosin overexpression induces severe cardiac abnormalities. J Mol Cell Cardiol 30:1545–1557 79. Kim SH, Kim HS, Lee MM (2002) Re-expression of fetal troponin isoforms in the postinfarction failing heart of the rat. Circ J 66:959–964 80. Hunkeler NM, Kullman J, Murphy AM (1991) Troponin I isoform expression in human heart. Circ Res 69:1409–1414 81. Purcell IF, Bing W, Marston SB (1999) Functional analysis of human cardiac troponin by the in vitro motility assay: comparison of adult, foetal and failing hearts. Cardiovasc Res 43:884–891

33 82. Morimoto S, Goto T (2000) Role of troponin I isoform switching in determining the pH sensitivity of Ca(2+) regulation in developing rabbit cardiac muscle. Biochem Biophys Res Commun 267:912–917 83. Tanaka H, Sekine T, Nishimaru K, Shigenobu K (1998) Role of sarcoplasmic reticulum in myocardial contraction of neonatal and adult mice. Comp Biochem Physiol A Mol Integr Physiol 120:431–438 84. Buchhorn R, Hulpke-Wette M, Ruschewski W et al (2002) Betareceptor downregulation in congenital heart disease: a risk factor for complications after surgical repair? Ann Thorac Surg 73:610–613 85. Schiffmann H, Flesch M, Häuseler C et al (2002) Effects of different inotropic interventions on myocardial function in the developing rabbit heart. Basic Res Cardiol 97:76–87 86. Sun LS (1999) Regulation of myocardial beta-adrenergic receptor function in adult and neonatal rabbits. Biol Neonate 76:181–192 87. Dees E, Baldwin HS (2002) New frontiers in molecular pediatric cardiology. Curr Opin Pediatr 14:627–633 88. McFadden DG, Olson EN (2002) Heart development: learning from mistakes. Curr Opin Genet Dev 12:328–335

Anatomy of the Thoracic Wall, Pulmonary Cavities, and Mediastinum

4

Mark S. Cook and Anthony J. Weinhaus

Abstract

This chapter will review the mediastinum and pulmonary cavities within the thorax and discuss their contents. The wall of the thorax and its associated muscles, nerves, and vessels will be covered in relationship to respiration. The surface anatomical landmarks that designate deeper anatomical structures and sites of access and auscultation will be reviewed. The goal of this chapter is to provide a complete picture of the thorax and its contents, with detailed anatomy of thoracic structures excluding the heart. Keywords

Thorax • Cardiac anatomy • Thoracic wall • Superior mediastinum • Middle mediastinum • Anterior mediastinum • Posterior mediastinum • Pleura • Lungs

4.1

Introduction

The thorax is the body cavity, surrounded by the bony rib cage, that contains the heart and the lungs, the great vessels, the esophagus and trachea, the thoracic duct, and the autonomic innervation for these structures. The inferior boundary of the thoracic cavity is the respiratory diaphragm, which separates the thoracic and abdominal cavities. Superiorly, the thorax communicates with the root of the neck and the upper extremity. The wall of the thorax contains the muscles that assist with respiration and those connecting the upper extremity to the axial skeleton. The wall of the thorax is responsible for protecting the contents of the thoracic cavity and for generating the negative pressure required for respiration. The thorax is covered by muscle, superficial fascia containing the mammary tissue, and skin. A detailed description of cardiac anatomy is the subject of Chap. 5.

M.S. Cook, PT, PhD (*) • A.J. Weinhaus, PhD Program in Human Anatomy Education, Department of Integrative Biology and Physiology, University of Minnesota, 6-125 Jackson Hall, 321 Church St. SE, Minneapolis, MN 55455, USA e-mail: [email protected]

4.2

Overview of the Thorax

Anatomically, the thorax is typically divided into compartments—the pleural cavities and the mediastinum. The two pleural cavities contain the lungs and their pleural coverings. The space between the pleural cavities is the mediastinum, which contains all the other structures found in the thorax (Fig. 4.1). The mediastinum is divided into the superior and inferior compartments by a plane referred to as the transverse thoracic plane, passing through the mediastinum at the level of the sternal angle and the junction of the T4 and T5 vertebrae (Fig. 4.1). The superior mediastinum contains the major vessels supplying the upper extremity, the neck, and the head. The inferior mediastinum, the space between the transverse thoracic plane and the diaphragm, is further divided into the anterior, middle, and posterior mediastinum. The middle mediastinum is the space containing the heart and pericardium. The anterior mediastinum is the space between the pericardium and the sternum. The posterior mediastinum extends from the posterior pericardium to the posterior wall of the thorax. The inferior aperture of the thorax is formed by the lower margin of the ribs and costal cartilages and is closed off from the abdomen by the respiratory diaphragm (Fig. 4.1).

© Springer International Publishing Switzerland 2015 P.A. Iaizzo (ed.), Handbook of Cardiac Anatomy, Physiology, and Devices, DOI 10.1007/978-3-319-19464-6_4

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M.S. Cook and A.J. Weinhaus

Fig. 4.1 The left panel is a diagrammatic representation of pulmonary cavities on each side of the thorax with the mediastinum in between. The right panel illustrates the divisions of the mediastinum. Figure

adapted from Grant’s Dissector, 12th edn. by EK Sauerland (Fig. 1.14, left; Fig. 1.24, right)

The superior aperture of the thorax leads to the neck and the upper extremity; it is formed by the first ribs and their articulation with the manubrium and first thoracic vertebra. The superior aperture of the thorax, or root of the neck, allows for the passage of structures between the neck and thoracic cavity. The clavicle crosses the first rib at its anterior edge close to its articulation with the manubrium. Structures exiting the superior thoracic aperture and communicating with the upper extremity pass between the first rib and clavicle. Anatomists often refer to the superior thoracic aperture as the thoracic inlet due to the entrance of air and food through the trachea and esophagus, respectively. However, clinicians may refer to the superior thoracic aperture as the thoracic outlet due to the fact that arteries and nerves leave the thorax through this area to enter the neck and upper extremities.

spinous process and extending bilaterally are transverse processes. The transverse processes of thoracic vertebrae become progressively shorter from superior to inferior. The parts of the neural arch between the body and transverse processes are the pedicles, while the parts between the transverse processes and spinous process are the laminae (Fig. 4.3). Thoracic vertebrae have several articular surfaces, called facets. Superior and inferior articular facets form facet joints with vertebrae above and below, respectively. Costal facets are sites of articulation with ribs. Generally, each rib articulates with two adjacent vertebrae such that the head fits between adjacent bodies and the tubercle (slightly distal to the neck of the rib) articulates with the transverse process of the vertebra below. Therefore, a rib articulates with its corresponding thoracic vertebrae through the body and transverse process and with the vertebra above through its body. The articular surfaces on transverse processes are called costal facets, while those on the bodies, which generally share rib articulation with the vertebra above, are referred to as costal demifacets. There are a few exceptions to this general relationship between thoracic vertebrae and ribs. The first thoracic vertebra shares the articulation with the second rib, but receives all of the articulation of the first rib superiorly. Ribs 10, 11, and 12 only articulate with their corresponding vertebrae. The ribs form the largest part of the bony wall of the thorax (Fig. 4.2). Each rib articulates with one or two thoracic vertebrae, and the upper ten ribs articulate directly or indirectly with the sternum anteriorly. The upper seven ribs are referred to as true ribs because each connects to the sternum via its own costal cartilage. Ribs 8–10 are referred to as false ribs because they connect to the sternum (indirectly) by joining the articular cartilage of the seventh rib. Ribs 11 and 12

4.3

Bones of the Thoracic Wall

4.3.1

The Thoracic Cage

The skeleton of the thoracic wall is composed of the 12 pairs of ribs, the thoracic vertebra (and intervertebral disks), and the sternum. Articulating with the thorax are the bones of the pectoral girdle, the clavicle and the scapula (Fig. 4.2). Nerves and blood vessels entering the upper extremity pass between the clavicle and first rib. The 12 thoracic vertebrae, which comprise the midline of the posterior wall of the thorax, articulate with the 12 pairs of ribs. Each thoracic vertebra has a body anteriorly and a neural arch which form a vertebral foramen. Extending from the neural arch posteriorly is an elongated, inferiorly slanting,

4

Anatomy of the Thorax

37

Fig. 4.2 The left panel illustrates the bones of the thorax from an anterior view. The right panel is a posterior view of the bony thorax. ©1998 Elsevier Inc. All rights reserved. www.netterimages.com, Frank Netter

Fig. 4.3 The T6 vertebra as viewed from above (upper left) and laterally (upper right), and a typical rib (lower). ©1998 Elsevier Inc. All rights reserved. www. netterimages.com, Frank Netter

are referred to as floating ribs because they do not connect to the sternum, but end in the musculature of the abdominal wall. Each rib has a head that articulates with the thoracic vertebra and a relatively thin flat shaft that is curved (Fig. 4.3). The costal angle, the sharpest part of the curved shaft, is located where the rib turns anteriorly. At the inferior margin of the shaft, the internal surface of each rib is recessed to form

a costal groove. This depression provides some protection to the intercostal neurovascular bundle, something that must be considered when designing devices for intercostal access to the thorax. The heads of ribs 2–9 have two articular facets for articulation with the vertebra of the same level and the vertebra above. The heads of ribs 1, 10, 11, and 12 only articulate with the vertebra of the same number and, consequently, have

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only one articular facet. In ribs 1–10, the head is connected to the shaft by a narrowing called the neck. At the junction of the head and the neck is a tubercle that has an articular surface for articulation with the costal facet of the transverse process. Ribs 11 and 12 do not articulate with the transverse process of their respective vertebra and do not have a tubercle or, therefore, a defined neck portion. The sternum is the flat bone making up the median anterior part of the thoracic cage (Fig. 4.2). It is composed of three parts—the manubrium, body, and xiphoid process. The manubrium (from the Latin word for handle, like the handle of a sword) is the superior part of the sternum; it is the widest and thickest part of the sternum. The manubrium alone articulates with the clavicle and the first rib. The sternal heads of the clavicle can be readily seen and palpated at their junction with the manubrium. The depression between the sternal heads of the clavicle above the manubrium is the suprasternal, or jugular, notch. The manubrium and the body of the sternum lie in slightly different planes and thus form a noticeable and easily palpated angle, the sternal angle (of Louis), at the point where they meet. The second rib articulates with the body of the sternum and the manubrium at the sternal angle. The body of the sternum is formed from the fusion of segmental bones (the sternebrae). The remnants of this fusion may be seen in the transverse ridges of the sternal body, especially in young people. The third through sixth ribs articulate with the body of the sternum, and the seventh rib articulates at the junction of the body and xiphoid process. The xiphoid process is the inferior-most part of the sternum and is easily palpated. It lies at the level of T9–T10 vertebrae and marks the inferior boundary of the thoracic cavity anteriorly. It also lies at the level even with the central tendon of the diaphragm and the inferior border of the heart. When a median sternotomy is performed on a patient, typically a sternal saw is used to cut through the manubrium, the sternal body, and the xiphoid process. For more details, refer to Chap. 33.

4.3.2

The Pectoral Girdle

Many of the muscles encountered on the wall of the anterior thorax are attached to the bones of the pectoral girdle and the upper extremity. Since movement of these bones can impact the anatomy of vascular structures communicating between the thorax and upper extremity, it is important to include these structures in a discussion of the thorax. The clavicle is a somewhat “S”-shaped bone that articulates at its medial end with the manubrium of the sternum and at its lateral end with the acromion of the scapula (Fig. 4.2). It is convex medially and concave laterally. The scapula is a flat triangular bone, slightly concave anteriorly, that rests upon the posterior thoracic wall. It has a raised

ridge posteriorly called the spine that ends in a projection of bone called the acromion that articulates with the clavicle. The coracoid process is an anterior projection of bone from the superior border of the clavicle that serves as an attachment point for muscles that act on the scapula and upper extremity. The head of the humerus articulates with the shallow glenoid fossa of the scapula forming the glenohumeral joint. The clavicle serves as a strut to hold the scapula in position away from the lateral aspect of the thorax. It is a highly mobile bone, with a high degree of freedom at the sternoclavicular joint that facilitates movement of the shoulder girdle against the thorax. The anterior extrinsic muscles of the shoulder pass from the wall of the thorax to the bones of the shoulder girdle.

4.4

Muscles of the Thoracic Wall

4.4.1

The Pectoral Muscles

Several muscles of the thoracic wall, including the most superficial ones that create some of the contours of the thoracic wall, are muscles that act upon the upper extremity. Some of these muscles form important surface landmarks on the thorax, and others have relationships to vessels that communicate with the thorax. In addition to moving the upper extremity, some of these muscles also can play a role in movement of the thoracic wall and participate in respiration. The pectoralis major muscle forms the surface contour of the upper lateral part of the thoracic wall (Fig. 4.4). It originates on the clavicle (clavicular head), the sternum, and ribs (sternocostal head), and inserts near the greater tubercle of the humerus. The lower margin of this muscle, passing from the thorax to the humerus, forms the major part of the anterior axillary fold. The pectoralis major muscle is a powerful adductor and medial rotator of the arm. The pectoralis minor muscle is a much smaller muscle and lies immediately deep to the pectoralis major muscle (Fig. 4.4). It originates on ribs 3–5 and inserts upon the coracoid process of the scapula. This muscle forms part of the anterior axillary fold medially. It acts to depress and stabilize the scapula when upward force is exerted on the shoulder. The anterior part of the deltoid muscle also forms a small aspect of the anterior thoracic wall. This muscle has its origin on the lateral part of the clavicle and the acromion and spine of the scapula (Fig. 4.4). It inserts upon the deltoid tubercle of the humerus and is the most powerful abductor of the arm. The anterior deltoid muscle borders the superior aspect of the pectoralis major muscle. The depression found at the junction of these two muscles is called the deltopectoral groove. Importantly, within this groove, the cephalic vein can consistently be found. The muscles diverge at their origins on the clavicle, creating an opening bordered by these two muscles

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Anatomy of the Thorax

39

Fig. 4.4 The musculature of the anterior thoracic wall. The left panel shows the superficial muscles intact. The left panel shows structures deep to the pectoralis major muscle. ©1998 Elsevier Inc. All rights reserved. www.netterimages. com, Frank Netter

Fig. 4.5 A lateral view of the musculature of the thoracic wall. ©1998 Elsevier Inc. All rights reserved. www. netterimages.com, Frank Netter

and the clavicle known as the deltopectoral triangle. Through this space the cephalic vein passes to join the axillary vein. The subclavius is a small muscle originating on the lateral inferior aspect of the clavicle and inserting on the sternal end of the first rib (Fig. 4.4). This muscle depresses the clavicle and exerts a medial traction on the clavicle that stabilizes the sternoclavicular joint. In addition to these actions, the subclavius muscle provides a soft surface on the inferior aspect of the clavicle that serves to cushion the contact of this bone with structures passing under the clavicle (i.e., nerves of the brachial plexus and the subclavian artery) when the clavicle

is depressed during movement of the shoulder girdle and especially when the clavicle is fractured. The serratus anterior muscle originates on the lateral aspect of the first eight ribs and inserts upon the medial aspect of the scapula (Fig. 4.5). This muscle forms the serrated contour of the lateral thoracic wall in individuals with good muscle definition. The serratus anterior forms the medial border of the axilla and acts to pull the scapula forward (protraction) and to stabilize the scapula against a posterior force on the shoulder; it also assists with cranial rotation of the scapula with elevation.

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Fig. 4.6 The deep musculature of the anterior thoracic wall viewed from the posterior side. ©1998 Elsevier Inc. All rights reserved. www.netterimages.com, Frank Netter

4.4.2

The Intercostal Muscles

Each rib is connected to the one above and below by a series of three intercostal muscles. The external intercostal muscles are the most superficial (Fig. 4.5). These muscles course in an obliquely medial direction as they pass from superior to inferior between the ribs. Near the anterior end of the ribs, the external intercostal muscle fibers are replaced by the external intercostal membrane. Deep to the external intercostals are the internal intercostals (Figs. 4.5 and 4.6). The direction of the internal intercostal muscle fibers is perpendicular to the external intercostals. Near the posterior end of the ribs, the internal intercostal muscle fibers are replaced by the internal intercostal membrane. The deepest layer of intercostal muscle is the innermost intercostal muscle (Fig. 4.6). These muscles have a fiber direction similar to the internal intercostals, but they form a separate plane. The innermost intercostal muscles become membranous near the anterior and posterior ends of the ribs. The intercostal nerves and vessels pass between the internal and innermost intercostal muscles, which help to distinguish between the two muscular layers. There are two additional sets of muscles in the same plane as the innermost intercostals—the subcostals and the transversus thoracic muscles. The subcostal muscles are located posteriorly and span more than one rib. The transversus thoracic muscles are found anteriorly and pass from the internal surface of the sternum to ribs 2–6, extending superiorly and laterally (Fig. 4.6). The intercostal muscles, especially the external and internal intercostals, are involved with respiration by elevating or depressing the ribs. The external intercostal muscles and the

anterior interchondral part of the internal intercostals act to elevate the ribs. The interosseous parts of the internal intercostal muscles depress the ribs. The innermost intercostals likely have an action similar to the internal intercostals. The subcostal muscles probably help to elevate the ribs. The action of transversus thoracis is not well understood. It may, by virtue of its attachments, help to depress the ribs with forced exhalation or play a role in proprioception. In so-called less or minimally invasive surgical procedures performed to gain access to the heart, one needs to transect through the intercostal muscles (see Chap. 35).

4.4.3

Respiratory Diaphragm

The respiratory diaphragm is the musculotendinous sheet separating the abdominal and thoracic cavities (Figs. 4.6 and 4.7). It is considered the primary muscle of respiration. The diaphragm originates along the inferior border of the rib cage, the xiphoid process of the sternum, the posterior abdominal wall, and the upper lumbar vertebra. The medial and lateral arcuate ligaments are thickenings of the investing fascia over the quadratus lumborum (lateral) and the psoas major (medial) muscles of the posterior abdominal wall that serve as attachments for the diaphragm (Fig. 4.7). The right and left crura of the diaphragm attach to lumbar vertebrae. They originate on the bodies of lumbar vertebrae 1–3, their intervertebral disks, and the anterior longitudinal ligament spanning these vertebrae. The diaphragm ascends from its origin to form a right and left dome, the right dome being typically higher than the left. The muscular part of the

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Anatomy of the Thorax

41

Fig. 4.7 The abdominal side of the respiratory diaphragm illustrating the origins of the muscle. ©1998 Elsevier Inc. All rights reserved. www.netterimages.com, Frank Netter

diaphragm is dome-shaped at rest. Contraction (during inhalation) causes the dome of the diaphragm to flatten (downward), increasing the volume of the thoracic cavity. The aponeurotic central part of the diaphragm, called the central tendon, contains the opening for the inferior vena cava (Fig. 4.7). The esophagus also passes through the diaphragm, and the hiatus for the esophagus is created by a muscular slip originating from the right crus of the diaphragm. The aorta passes from the thorax to the abdomen behind the diaphragm, under the median arcuate ligament created by the intermingling of fibers from the right and left crura of the diaphragm. The inferior vena cava, esophagus, and aorta pass from the thorax to the abdomen at thoracic vertebral levels 8, 10, and 12, respectively.

4.4.4

Other Muscles of Respiration

The scalene muscles and the sternocleidomastoid muscle in the neck also contribute to respiration, especially during deep inhalation (Figs. 4.4 and 4.5). Collectively, the scalene muscles have their origin on the transverse processes of cervical vertebra 2–7. The anterior and middle scalenes insert on the first rib and the posterior scalene on the second rib. As its name suggests, the sternocleidomastoid originates on the sternum and medial clavicle and inserts on the mastoid process of the skull. Although the primary action of sternocleidomastoid is on the head and neck, it is also capable of exerting an upward force on the thorax with forced respiration. The muscles of the anterior abdominal wall are also involved with respiration. These muscles, the rectus abdominis, external and internal abdominal obliques, and the transverses abdominis, act together during forced exhalation to depress the rib cage and to increase intra-abdominal pressure forcing the dia-

phragm to expand upward, reducing the volume of the pulmonary cavities. The mechanics of respiration are explained in detail in Sect. 4.11.2.

4.5

Nerves of the Thoracic Wall

The wall of the thorax receives its innervation from intercostal nerves (Fig. 4.8). These nerves are the ventral rami of segmental nerves, leaving the spinal cord at the thoracic vertebral levels. Intercostal nerves are mixed nerves, carrying both somatic motor and sensory fibers, as well as autonomics to the skin. The intercostal nerves pass out of the intervertebral foramina and run inferior to the ribs. As they reach the costal angle, the nerves pass between the innermost and the internal intercostal muscles. The motor innervation to all the intercostal muscles comes from the intercostal nerves. These nerves give off lateral and anterior cutaneous branches that provide cutaneous sensory innervation to the skin of the thorax (Fig. 4.8). The intercostal nerves also carry sympathetic nerve fibers to the sweat glands, smooth muscle, and blood vessels. However, the first two intercostal nerves are considered atypical. The first intercostal nerve divides shortly after it emerges from the intervertebral foramen. The larger superior part of this nerve joins the brachial plexus to provide innervation to the upper extremity. The lateral cutaneous branch of the second intercostal nerve is large and typically pierces the serratus anterior muscle to provide sensory innervation to the floor of the axilla and medial aspect of the arm. The nerve associated with the 12th rib is the subcostal nerve and, since there is no rib below this level, is considered a nerve of the abdominal wall. The pectoral muscles receive motor innervation from branches of the brachial plexus of nerves (derived from

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M.S. Cook and A.J. Weinhaus

Fig. 4.8 A typical set of intercostals arteries and nerves. ©1998 Elsevier Inc. All rights reserved. www.netterimages.com, Frank Netter

Fig. 4.9 The nerves and arteries of the axilla viewed with the pectoralis major and minor muscles reflected. ©1998 Elsevier Inc. All rights reserved. www.netterimages. com, Frank Netter

cervical levels 5–8 and thoracic level 1) which supply the muscles of the shoulder and upper extremity. The lateral and medial pectoral nerves, branches of the lateral and medial cords of the brachial plexus, supply the pectoralis major and minor muscles (Fig. 4.9). The pectoralis major muscle is innervated by both nerves and the pectoralis minor muscle by only the medial pectoral nerve, which pierces this muscle before entering the pectoralis major. The serratus anterior muscle is innervated by the long thoracic nerve which originates from ventral rami of C5, C6, and C7 (Figs. 4.5 and 4.9). The deltoid muscle is innervated by the axillary nerve, a branch of the posterior cord of the brachial plexus (Fig. 4.9). Finally, the subclavius muscle is innervated by its own nerve from the superior trunk of the brachial plexus.

4.6

Vessels of the Thoracic Wall

The intercostal muscles and the skin of the thorax receive their blood supply from both the intercostal arteries and the internal thoracic artery (Figs. 4.6 and 4.8). Intercostal arteries 3–11 (and the subcostal artery) are branches directly from the thoracic descending aorta. The first two intercostal arteries are branches of the supreme intercostal artery, which is a branch of the costocervical trunk from the subclavian artery. The posterior intercostals run with the intercostal nerve and pass with the nerve between the innermost and internal intercostal muscles. The intercostals then anastomose with anterior intercostal branches arising from the internal thoracic artery descending lateral to the sternum. The internal thoracic arteries are anterior branches from the subclavian

4

Anatomy of the Thorax

arteries. The anterior and posterior intercostals anastomoses create an anastomotic network around the thoracic wall. The intercostal arteries are accompanied by intercostal veins (Fig. 4.6). These veins drain to the azygos system of veins in the posterior mediastinum. The anatomy of the azygos venous system is described in detail in Sect. 4.10.2. Anteriorly, the intercostal veins drain to the internal thoracic veins which, in turn, drain to the subclavian veins in the superior mediastinum (Fig. 4.7). The intercostal nerves, arteries, and veins run together in each intercostal space, just inferior to each rib. They are characteristically found in this order (vein, artery, and nerve) with the vein closest to the rib. The diaphragm receives blood from the musculophrenic arteries and terminal branches of the internal thoracic arteries, which runs along the anterior superior surface of the diaphragm (Fig. 4.6). There is also a substantial blood supply to the inferior aspect of the diaphragm from the inferior phrenic arteries, the superior-most branches from the abdominal aorta that branch along the inferior surface of the diaphragm (Fig. 4.7). The muscles of the pectoral region get their blood supply from branches of the axillary artery. This artery is the continuation of the subclavian artery emerging from the thorax and passing under the clavicle (Fig. 4.9). The first branch of the axillary artery, the superior (supreme) thoracic artery, supplies blood to the first two intercostal spaces. The second branch forms the thoracoacromial artery or trunk.

Fig. 4.10 Contents of the superior and middle mediastinum. ©1998 Elsevier Inc. All rights reserved. www.netterimages.com, Frank Netter

43

Subsequently, this artery gives rise to four branches (pectoral, deltoid, clavicular, acromial) that supply blood to the pectoral muscles, the deltoid muscle, the clavicle, and the subclavius muscle. The lateral thoracic artery, the third branch from the subclavian artery, participates along with the intercostal arteries in supplying the serratus anterior muscle. Additional distal branches from the axillary artery, the humeral circumflex arteries, also participate in blood supply to the deltoid muscle. Venous blood returns through veins of the same names to the axillary vein.

4.7

The Superior Mediastinum

The superior mediastinum is the space behind the manubrium of the sternum (Fig. 4.1). It is bounded by parietal (mediastinal) pleura on each side and the first four thoracic vertebrae behind. It is continuous with the root of the neck at the top of the first ribs and with the inferior mediastinum below the transverse thoracic plane, a horizontal plane that passes from the sternal angle through the space between the T4 and T5 vertebrae. The superior mediastinum contains several important structures including the branches of the aortic arch, the veins that coalesce to form the superior vena cava, the trachea, the esophagus, the vagus and phrenic nerves, the cardiac plexus of autonomic nerves, the thoracic duct, and the thymus (Fig. 4.10).

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Fig. 4.11 Vessels of the superior and middle mediastinum. ©1998 Elsevier Inc. All rights reserved. www.netterimages.com, Frank Netter

4.7.1

Arteries in the Superior Mediastinum

As the aorta emerges from the pericardial sac, it begins to arch posteriorly and to the left (Fig. 4.11). At the level of the T4 vertebra, the aorta has become vertical again, descending through the posterior mediastinum. The aortic arch passes over the right pulmonary artery and ends by passing posterior to the left pulmonary artery. The trachea and esophagus pass posterior and to the right of the aortic arch. The arch of the aorta gives off the major arteries that supply blood to the head and to the upper extremity. This branching is asymmetrical. The first (from the right) and most anterior branch from the aorta is the brachiocephalic trunk. This arterial trunk bends toward the right as it ascends, and as it reaches the upper limit of the superior mediastinum, it bifurcates into the right common carotid and right subclavian arteries. The next two branches from the aortic arch are the left common carotid and the left subclavian arteries. These two arteries ascend almost vertically to the left of the trachea. The common carotid arteries will supply the majority of the blood to the head and neck. The subclavian arteries continue as the axillary and brachial arteries and supply the upper extremity. The arch of the aorta and its branches make contact with the upper lobe of the right lung, and their impressions are normally seen on the fixed lung after removal. Neither the brachiocephalic trunk, left common carotid, nor the left subclavian gives off consistent branches in the superior mediastinum. However, the subclavian arteries at the root of the neck give off the internal thoracic arteries which reenter the superior mediastinum and descend along each side of the sternum. On occasion there will be an artery branching from

either the aortic arch, the right common carotid, or one of the subclavian arteries, and supplying the thyroid gland in the midline. This variant artery is called a thyroid ima. Since this artery is often found crossing the region where a tracheostomy is performed, it is important to remember that this artery is present in ~10 % of individuals.

4.7.2

Brachiocephalic Veins

The bilateral brachiocephalic veins are formed by the merging of the internal jugular vein and the subclavian vein on both sides at the base of the neck (Figs. 4.10 and 4.11). The right brachiocephalic vein descends nearly vertically, while the left crosses obliquely behind the manubrium to join the right and form the superior vena cava. The superior vena cava continues inferiorly into the pericardial sac. The brachiocephalic veins run anteriorly in the superior mediastinum. The left brachiocephalic vein passes anterior to the three branches of the aortic arch and is separated from the manubrium only by the thymus gland (Fig. 4.10). The brachiocephalic veins receive blood from the internal thoracic veins, the inferior thyroid veins, and the small pericardiacophrenic veins. They also receive blood from the superior intercostal veins from behind.

4.7.3

The Trachea and Esophagus

The trachea is a largely cartilaginous tube that runs from the larynx inferiorly through the superior mediastinum and ends by branching into the main bronchi (Fig. 4.11). It serves as a

4

Anatomy of the Thorax

conduit for air to the lungs. The trachea can be palpated at the root of the neck, superior to the manubrium in the midline. The esophagus is a muscular tube that connects the pharynx with the stomach. The upper part of the esophagus descends behind the trachea and, in contact with it, through the superior mediastinum (Fig. 4.11). The esophagus continues through the posterior mediastinum behind the heart, pierces the diaphragm at the level of T10, and enters the stomach at the cardia. Both the trachea and esophagus are crossed on the left by the arch of the aorta. The impression of the aorta on the esophagus can usually be seen on a posterior to anterior radiograph of the esophagus coated with barium contrast. The trachea and esophagus are crossed on the right side by the azygos vein at the lower border of the superior mediastinum. Both the trachea and esophagus come into contact with the upper lobe of the right lung. The esophagus also contacts the upper lobe of the left lung. The arch of the aorta and its branches shield the trachea from the left lung. Fig. 4.12 Course of the phrenic nerve and the vagus nerve in the superior and middle mediastinum. ©1998 Elsevier Inc. All rights reserved. www.netterimages. com, Frank Netter

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4.7.4

Nerves of the Superior Mediastinum

The vagus and phrenic nerves pass through the superior mediastinum on either side.. The phrenic nerve originates from the ventral rami from cervical levels 3, 4, and 5. This nerve travels inferiorly in the neck on the surface of the anterior scalene muscle, entering the superior mediastinum behind the subclavian vein and passing under the internal thoracic artery (Fig. 4.12). The right phrenic nerve passes through the superior mediastinum lateral to the subclavian artery and the arch of the aorta. The left phrenic nerve passes lateral to the brachiocephalic vein and the superior vena cava. The phrenic nerves then enter the middle mediastinum where they pass anterior to the root of the lung, across the pericardium, finally piercing the diaphragm lateral to the base of the pericardium. Throughout their course, the phrenic nerves pass under the mediastinal pleura. The phrenic nerve is the motor innervation to the diaphragm (“C-3-4-5 keeps your

46

diaphragm alive”), and it also provides sensory innervation to the pericardium, mediastinal, and diaphragmatic pleura and to the diaphragmatic peritoneum on the inferior surface of the diaphragm. The course of the phrenic nerves adjacent to the heart makes them susceptible to stimulation (via leak currents from a pacing lead within the cardiac veins) or damage (temporary or permanent) during cardiac ablation procedures. The vagus nerves pass out of the skull via the jugular foramen and descend through the neck in the carotid sheath, just lateral to the common carotid arteries. These nerves are the parasympathetic supply to the thorax and most of the abdomen. On the right, the vagus crosses anterior to the subclavian artery and then turns posterior to pass behind the root of the lung and onto the esophagus. Before the right vagus enters the superior mediastinum, it gives off a recurrent laryngeal branch that passes behind the subclavian artery and ascends into the neck. On the left, the vagus passes lateral to the arch of the aorta and then turns posterior to pass behind the root of the lung and onto the esophagus (Fig. 4.12). At the level of the aortic arch, it gives off the left recurrent laryn-

Fig. 4.13 Pattern of innervation in the superior mediastinum. ©1998 Elsevier Inc. All rights reserved. www.netterimages.com, Frank Netter

M.S. Cook and A.J. Weinhaus

geal nerve that passes under the aorta, just posterior to the ligamentum arteriosum, and ascends into the neck. The recurrent laryngeal nerves are motor to most of the muscles of the larynx. It should be noted that an aneurism in the arch of the aorta can injure the left recurrent laryngeal nerve and manifest as hoarseness of the voice due to unilateral paralysis of the laryngeal musculature. The right and left vagi contribute to the esophageal plexus of nerves in the middle mediastinum. The right and left vagus nerves give off cardiac branches in the neck (superior and inferior cardiac nerves) and a variable number of small cardiac nerves in the superior mediastinum (thoracic cardiac branches) that provide parasympathetic innervation to the heart via the cardiac nerve plexus. Sympathetic innervation to the heart is also found in the superior mediastinum. The heart receives postganglionic branches from the superior, middle, and inferior cardiac nerves, each branching from their respective sympathetic ganglia in the neck (Fig. 4.13). There are also thoracic cardiac nerves emanating from the upper 4 or 5 thoracic sympathetic

4

Anatomy of the Thorax

ganglia. The uppermost thoracic ganglion and the inferior cervical ganglion are often fused to form an elongated ganglion called the cervicothoracic (or stellate) ganglion which will give off the inferior cardiac nerve. The cardiac plexus is located between the trachea, the arch of the aorta, and the pulmonary trunk (Fig. 4.13). It is a network of sympathetic and parasympathetic nerves derived from the branches described above and provides autonomic innervation to the heart. Nerves from the plexus reach the heart by traveling along the vasculature and primarily innervate the conduction system and the atria. The sympathetic components cause the strength and pace of the heart beats to increase, while the parasympathetics counter this effect. Pain afferents from the heart travel with the sympathetic nerves to the upper thoracic and lower cervical levels. This distribution accounts for the pattern of referred heart pain to the upper thorax, shoulder, and arm.

4.7.5

The Thymus

The thymus is found in the most anterior part of the superior mediastinum (Fig. 4.10). It is considered an endocrine gland but is actually more important as a lymphoid organ. The thymus produces lymphocytes that populate the lymphatic system and bloodstream. It is particularly active in young individuals and becomes much less prominent with aging.

Fig. 4.14 The position of the heart in the middle mediastinum and the relationship of the pericardium to the heart and great vessels. ©1998 Elsevier Inc. All rights reserved. www.netterimages. com, Frank Netter

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The thymus is located directly behind the manubrium and may extend up into the neck and inferiorly into the anterior mediastinum. It lies in contact with the aorta, the left brachiocephalic vein, and trachea.

4.8

The Middle Mediastinum

4.8.1

The Pericardium

The middle mediastinum is the central area of the inferior mediastinum occupied by the great vessels, pericardium, and the heart (Fig. 4.14). Within this space, the heart is situated with the right atrium on the right, the right ventricle anterior, the left ventricle to the left and posterior, and the left atrium entirely posterior. The apex, a part of the left ventricle, is projected inferiorly and to the left. The pericardium is the closed sac that contains the heart and the proximal portion of the great vessels. It is attached to the diaphragm inferiorly. The pericardium is a serous membrane, with both visceral and parietal layers into which the heart projects such that there is a potential space within pericardial sac called the pericardial cavity. The visceral pericardium, also called the epicardium, covers the entire surface of the heart and base of the great vessels, reflecting from the great vessels to become parietal pericardium. The parietal pericardium is characterized by a thickened, strong

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outer layer called the fibrous pericardium. The fibrous pericardium is fused to the layer of parietal serous pericardium, creating a single layer with two surfaces. The fibrous pericardium has little elasticity and, by its fusion with the base of the great vessels, effectively creates a closed space in which the heart beats. The pericardial cavity can accumulate fluids under pathological conditions and create pressure within the pericardium, a condition known as cardiac tamponade. For a complete description of the pericardium and its features, see Chap. 9.

4.8.2

The Great Vessels

Great vessels is a composite term used to describe the large arteries and veins directly entering and exiting the heart (Figs. 4.11 and 4.15). They include the superior and inferior vena cava, the aorta, pulmonary trunk, and pulmonary veins. All of these vessels, except for the inferior vena cava, are found within the superior mediastinum. The inferior vena cava and the pulmonary veins are the shortest of the great vessels. The inferior vena cava enters the right atrium from below almost immediately after passing through the diaphragm. The pulmonary veins (there are normally two emerging from each lung) enter the left atrium with a very short intrapericardial portion. The superior vena cava is formed from the confluence of the right and left brachiocephalic veins. It also receives the azygos vein from behind and empties into the superior aspect of the right atrium. The pulmonary trunk ascends from the right ventricle on the anterior surface of the heart at an oblique angle to the left

Fig. 4.15 The great vessels as viewed from the posterior side of the heart. ©1998 Elsevier Inc. All rights reserved. www.netterimages. com, Frank Netter

and posterior, passing anterior to the base of the aorta in its course. As the pulmonary trunk emerges from the pericardium, it bifurcates into left and right pulmonary arteries which enter the hilum of each lung (Fig. 4.11). The right pulmonary artery passes under the arch of the aorta to reach the right lung. The left pulmonary artery is connected to the arch of the aorta by the ligamentum arteriosum, the remnant of the ductus arteriosus—the connection between the aorta and pulmonary trunk present in the fetus. The aorta ascends from the left ventricle at an angle to the right and then curves back to the left and posterior as it becomes the aortic arch. As the aorta exits the pericardium, it arches over the right pulmonary trunk, passing to the left of the trachea and esophagus and entering the posterior mediastinum as the descending aorta (Fig. 4.15). Backflow of blood from both the aorta and the pulmonary trunk is prevented by semilunar valves. The semilunar valves, each with a set of three leaflets, are found at the base of each of these great vessels. Immediately above these valves are the aortic and pulmonary sinuses, which are regions where the arteries are dilated. The coronary arteries branch from the right and left aortic sinuses (see Chap. 5). Also passing through the middle mediastinum are the phrenic nerves and the pericardiacophrenic vessels (Fig. 4.10). The phrenic nerves pass out of the neck and through the superior mediastinum. They travel through the middle mediastinum on the lateral surfaces of the fibrous pericardium and under the mediastinal pleura to reach the diaphragm. The phrenic nerve on each side is accompanied by a pericardiacophrenic artery, a branch from the proximal internal thoracic artery, and a pericardiacophrenic vein, which empties into the subclavian vein. These vessels, as

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Anatomy of the Thorax

49

their name implies, supply the pericardium and the diaphragm, as well as the mediastinal pleura.

4.9

The Anterior Mediastinum

The anterior mediastinum is the subdivision of the inferior mediastinum bounded by the sternum anteriorly and the pericardium posteriorly (Fig. 4.1). It contains sternopericardial ligaments, made up of loose connective tissue, the internal thoracic vessels and their branches, lymphatic vessels and nodes, and fat. In children the thymus often extends from the superior mediastinum into the anterior mediastinum.

4.10

The Posterior Mediastinum

The posterior mediastinum is the division of the inferior mediastinum bounded by the pericardium anteriorly and the posterior thoracic wall posteriorly (Fig. 4.1). Structures found in the posterior mediastinum include the descending aorta, azygos system of veins, thoracic duct (common drainage of the lymphatic system; see below), esophagus, esophageal plexus, thoracic sympathetic trunk, and thoracic splanchnic nerves.

4.10.1 The Esophagus and Esophageal Plexus The esophagus descends into the posterior mediastinum, passing along the right side of the descending aorta (Fig. 4.11). It passes directly behind the left atrium and veers to the left before passing through the esophageal hiatus of the diaphragm at the level of T10. Because of the juxtaposition of the esophagus to the heart, high-resolution ultrasound images of the heart can be obtained via the esophagus. It should be noted that it is possible to damage the esophagus during cardiac ablative procedures (see Chap. 29). As the vagus nerves approach the esophagus, they divide into several commingling branches forming the esophageal plexus (Fig. 4.16). Toward the distal end of the esophagus, the plexus begins to coalesce into an anterior and a posterior vagal trunk that pass with the esophagus into the abdomen. The left side of the esophageal plexus (from the left vagus nerve) contributes preferentially to the anterior vagal trunk and likewise for the right vagus and the posterior vagal trunk, reflecting the normal rotation of the gut (during development). The parasympathetic branches of the anterior and posterior vagal trunks comprise the innervation to the abdominal viscera as far as the splenic flexure.

4.10.2 The Azygos System of Veins The azygos venous system in the thorax is responsible primarily for draining venous blood from the thoracic wall to

Fig. 4.16 Course of the esophagus in the posterior mediastinum and the esophageal plexus of nerves. ©1998 Elsevier Inc. All rights reserved. www.netterimages.com, Frank Netter

the superior vena cava (Fig. 4.17). The azygos veins also receive venous blood from the viscera of the thorax, such as the esophagus, bronchi, and pericardium. The term azygos means unpaired and describes the asymmetry in this venous system. The system consists of the azygos vein on the right and the hemiazygos and accessory hemiazygos veins on the left. Both the azygos and hemiazygos veins are formed from the lumbar veins ascending from the abdomen uniting with the subcostal vein. On the right, the azygos vein is continuous, collecting blood from the right intercostal veins before arching over the root of the lung to join the superior vena cava. On the left, the hemiazygos vein ends typically at the level of T8 by crossing over to communicate with the azygos vein on the right. Above the hemiazygos vein, the accessory hemiazygos vein collects blood from the posterior intercostal veins. It typically communicates with the hemiazygos vein and crosses over to communicate with the azygos vein. On both sides, the second and third intercostal spaces are drained to a superior inter-

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Fig. 4.17 The azygos venous system in the posterior mediastinum. This figure illustrates a “typical” pattern of the azygos and hemiazygos veins. ©1998 Elsevier Inc. All rights reserved. www. netterimages.com, Frank Netter

costal vein that drains directly to the subclavian vein but also communicates with the azygos and accessory hemiazygos veins on their respective sides. The first intercostal vein drains directly to the subclavian vein. There is a tremendous amount of variation in the azygos system of veins, all of which is functionally inconsequential. However, it should be noted that the azygos system can be quite different in some of the large animal models used to study cardiac function (see Chap. 6).

4.10.3 The Thoracic Duct and Lymphatics The thoracic duct is the largest lymphatic vessel in the body (Fig. 4.18). It conveys lymph from the cisterna chyli, which is the collection site for all lymph from the abdomen, pelvis, and lower extremities back to the venous system. The thoracic duct enters the posterior mediastinum through the aortic hiatus and travels between the thoracic aorta and the azygos vein behind the esophagus. It ascends through the superior mediastinum to the left and empties into the venous system at or close to the junction of the internal jugular and subclavian veins. The thoracic duct often appears white due to the presence of chyle in the lymph and beaded due to the many valves within the duct. The thoracic duct also receives lymphatic drainage from posterior mediastinal lymph nodes

Fig. 4.18 The course of the thoracic duct in the posterior mediastinum through the superior mediastinum and ending at the junction of the internal jugular and subclavian veins. ©1998 Elsevier Inc. All rights reserved. www.netterimages.com, Frank Netter

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4.10.5 The Thoracic Sympathetic Nerves

Fig. 4.19 Course of the descending aorta in the posterior mediastinum with posterior intercostals branches and branches to the esophagus and bronchi. ©1998 Elsevier Inc. All rights reserved. www.netterimages. com, Frank Netter

that collect lymph from the esophagus, posterior intercostal spaces, and posterior parts of the pericardium and diaphragm. Approximately 2.5 L of lymph fluid return to the general circulation via this drainage daily.

4.10.4 The Descending Thoracic Aorta The descending thoracic aorta is the continuation of the aortic arch through the posterior mediastinum (Fig. 4.19). It begins to the left of the T5 vertebra and gradually moves to the middle of the vertebral column as it descends. It passes behind the diaphragm, under the median arcuate ligament (the aortic hiatus), and into the abdomen at the level of T12. The thoracic aorta gives off the 3rd through 11th posterior intercostal arteries and the subcostal artery. It also supplies blood to the proximal bronchi and the esophagus via bronchial and esophageal branches. The superior phrenic arteries supply the posterior aspect of the diaphragm and anastomose with the musculophrenic and pericardiacophrenic branches of the internal thoracic artery.

The sympathetic chain of ganglia, or sympathetic trunk, extends from the pelvic cavityto the cervical spine. It is also called the thoracolumbar division of the autonomic nervous system because preganglionic neurons of this system have their cell bodies in the thoracic and lumbar segments of the spinal cord, from T1 to L2. The thoracic portion of the sympathetic trunk is found in the posterior mediastinum (Fig. 4.16). It is composed of sympathetic ganglia, located along the spine at the junction of the vertebrae and the heads of the ribs, and the intervening nerve segments that connect the ganglia. These sympathetic ganglia also called paravertebral sympathetic ganglia due to their position alongside the vertebral column (see Chap. 5). There is approximately one sympathetic chain ganglion for each spinal nerve. There are fewer ganglia than nerves because some adjacent ganglia fuse during embryologic development. Such fusion is most evident in the cervical region where there are eight spinal nerves but only three sympathetic ganglia—the superior, middle, and inferior cervical ganglia (Fig. 4.13). The inferior cervical ganglion and the first thoracic (T1) ganglion are often fused, forming the cervicothoracic, or stellate (star-shaped) ganglion. An axon of the sympathetic nervous system that emerges from the spinal cord in the thorax travels with the ventral nerve root to a ventral ramus (in the thorax, this would be an intercostal nerve) (Fig. 4.20). After traveling a short distance on this nerve, this presynaptic (preganglionic) neuron enters the chain ganglion at its level (Fig. 4.21). Within the ganglion, it either synapses or travels superiorly or inferiorly to synapse at another spinal cord level (C1 to S4). After synapsing, the postsynaptic (postganglionic) neuron travels out of the ganglion and onto the ventral ramus to its target structure or organ. Presynaptic sympathetic neurons travel from the ventral ramus to the chain ganglion, and postsynaptic neurons travel back to the ventral ramus, via small connections called rami communicantes (so named because they communicate between the ventral ramus and the sympathetic ganglion). The presynaptic neuron has a myelin protective coating and the postsynaptic neuron does not. This pattern of myelination is true of all nerves in the autonomic system. The myelin coating appears white and thus the presynaptic (myelinated) rami communicantes form white rami communicantes, and the postsynaptic (unmyelinated) neurons form gray rami communicantes. The gray and white rami communicantes can be seen spanning the short distance between the intercostal nerves and the sympathetic ganglia in the posterior mediastinum (Fig. 4.8). Also present in the posterior mediastinum are the thoracic splanchnic nerves which are seen leaving the sympathetic trunk and running inferiorly toward the midline (Fig. 4.20). Splanchnic nerves are mainly preganglionic sympathetic neu-

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Fig. 4.20 A typical spinal nerve showing the communication of sympathetic nerves with the chain ganglia via white and gray rami communicantes. ©1998 Elsevier Inc. All rights reserved. www.netterimages. com, Frank Netter

Fig. 4.21 The three options taken by presynaptic sympathetic fibers are illustrated. All presynaptic nerves enter the sympathetic trunk via white rami communicans. They can synapse at their level and exit via gray rami communicantes and travel up or down the chain before synapsing, or they can exit before synapsing in the splanchnic nerves. Figure adapted from Clinically Oriented Anatomy, 4th edn. by KL Moore and AF Dalley (Fig. 1.32)

rons that emerge from the spine and pass through the chain ganglion without synapsing (Fig. 4.21). In the thorax, these preganglionic splanchnic nerves emerge from spinal cord segments T5 to T12 and travel into the abdomen where they

synapse in collateral ganglia called prevertebral ganglia, located along the aorta. The postganglionic fibers then innervate the abdominal organs. There are three splanchnic nerves that emerge in the thorax. The greater splanchnic nerves

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Anatomy of the Thorax

emerge from spinal cord segments T5 to T9, although a few studies report that they can emerge from T2 to T10. The axons of the lesser and least splanchnic nerves emerge from segments T10, T11, and T12, respectively.

4.11

Pleura and Lungs

4.11.1 The Pleura The bilateral pulmonary cavities contain the lungs and the pleural membranes (Fig. 4.1). The pleural membrane is a continuous serous membrane forming a closed pleural cavity within (Fig. 4.10). The relationship of the lung to this membrane is the same as a fist (representing the lung) pushed into an under inflated balloon (representing the pleural membrane). The fist becomes covered by the membrane of the balloon, but it is not “inside” the balloon. In the case of the lung, the pleura that is in contact with the lung is the visceral pleura, and the outer layer, which is in contact with the inner wall of the thorax and the mediastinum, is the parietal pleura (Fig. 4.22). The space within the pleural sac is the pleural cavity. Under normal conditions, the pleural cavity contains only a small amount of serous fluid and has no open space at all. It is referred to as a potential space because a real space can be created if outside materials, such as blood, pathologic fluids, or air, are introduced into this space. The parietal pleura is commonly subdivided into specific parts based on the part of the thorax it contacts (Figs. 4.10 and 4.22). Costal pleura overlies the ribs and intercostal spaces. In this region, the pleura is in contact with the endothoracic fascia, the fascial lining of the thoracic cavity. The mediastinal and diaphragmatic pleura are named for their contact with these structures. The cervical pleura extends

Fig. 4.22 Relationship of the lungs and walls of the thoracic cavity to the pleural membrane. Figure adapted from Grant’s Dissector, 12th edn. by EK Sauerland (Fig. 1.15)

53

over the cupola of the lung, above the first rib into the root of the neck; it is strengthened by the suprapleural membrane, an extension of the endothoracic fascia over the cupola of lung. The lines of pleural reflection are the lines along which the parietal pleura transitions from one region to the next (Fig. 4.23). The sternal line of reflection is the point where costal pleura transitions to mediastinal pleura on the anterior side of the thorax. The costal line of pleural reflection lies along the origin of the diaphragm where the costal pleura transitions to diaphragmatic pleura. Both the costal and sternal lines of reflection are very abrupt. The vertebral line of pleural reflection lies along the line where costal pleura becomes mediastinal pleura posteriorly. This angle of reflection is shallower than the other two. The surface projections of the parietal pleura are discussed in Sect. 4.12.2. The parietal pleura reflects onto the lung to become the visceral pleura at the root of the lung. A line of reflection descends from the root of the lung, much like the sleeve of a loose robe hangs from the forearm, forming the pulmonary ligament (Fig. 4.24). The visceral pleura covers the entire surface of each lung, including the surfaces in the fissures, where the visceral pleura on one lobe is in direct contact with the visceral pleura of the other lobe. The pleural cavity is the space inside the pleural membrane (Fig. 4.22). It is a potential space that, under normal conditions, contains only a small amount of serous fluid that lubricates the movement of the visceral pleura against the parietal pleura during respiration. During expiration, the lungs do not entirely fill the inferior-most aspect of the pulmonary cavity. This creates a region, along the costal line of reflection, where the diaphragmatic and costal pleura come into contact with each other, with no intervening lung tissue. This space is known as the costodiaphragmatic recess.

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Fig. 4.23 Surface anatomy and important surface landmarks on the anterior and posterior thorax. ©1998 Elsevier Inc. All rights reserved. www. netterimages.com, Frank Netter

4.11.2 The Lungs The primary function of the lungs is to acquire O2, required for metabolism in tissues, and to release CO2, which is the metabolic waste product from tissues. The lungs fill the pulmonary cavities and are separated from each other by structures in the mediastinum. In the living, the lung tissue is soft, light, and elastic, filling the pulmonary cavity and accommodating surrounding structures that impinge on the lungs. In the fixed cadaveric lung, the imprint of structures adjacent to the lungs is easily seen. Blood and air enter and exit the lung at the hilum or root of the lung via the pulmonary vessels and the bronchi. Each lung is divided into a superior and inferior lobe by an oblique (major) fissure (Fig. 4.24). The right lung has a second horizontal (minor) fissure that creates a third lobe called the middle lobe. Each lung has three surfaces—costal, mediastinal, and diaphragmatic—and an apex extending into the cupula at the root of the neck. The costal surface is smooth and convex while diaphragmatic surfaces are smooth and concave. The mediastinal surface is concave and is the site of the root of the lung, where the primary bronchi and pulmonary vessels enter and exit the lungs. The mediastinal surface has several impressions created by structures in the mediastinum. The left lung has a deep

impression accommodating the apex of the heart called the cardiac impression. There is also a deep impression of the aortic arch and the descending thoracic aorta behind the root of the lung. At the superior end of the mediastinal surface, there are impressions from the brachiocephalic vein and the subclavian artery and a shallow impression from the esophagus and trachea. On the right side, there are prominent impressions of the esophagus, behind the root of the lung, and the arch of the azygos vein, extending over the root of the lung. An impression of the superior vena cava and the brachiocephalic vein appear anterior and above the root of the lung. An impression of both the trachea and esophagus are seen close to the apex of the lung. Descending from the root of both lungs, the pulmonary ligament can be seen. The lungs also have three borders where the three surfaces meet. The posterior border is where the costal and mediastinal surfaces meet posteriorly. The inferior border is where the diaphragmatic and costal surfaces meet. The inferior border of the lung does not extend to the costal pleural reflection. The anterior border is where the costal and mediastinal surfaces meet anteriorly. On the left lung, the cardiac impression creates a visible curvature on the anterior border called the cardiac notch. Below the cardiac notch, a tongue-like segment of lung called the lingula protrudes around the apex of the heart.

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Fig. 4.24 Surface anatomy of the right (right) and left (left) lungs. ©1998 Elsevier Inc. All rights reserved. www.netterimages.com, Frank Netter

The main bronchi are the initial right and left branches from the bifurcation of the trachea that enter the lung at the hilum (Fig. 4.25). They, like the trachea, are held open by C-shaped segments of hyaline cartilage. The right main bronchus is wider and shorter and enters the lung more vertically than the left main bronchus. This is the reason aspirated foreign objects more often enter the right lung than the left. The left main bronchus passes anterior to the esophagus and under the aortic arch to enter the lung. Once in the lung, the main bronchi branch multiple times to form the bronchial tree (Fig. 4.25). The first branching supplies each lobe of the lung. These are the secondary or lobar bronchi. There are three lobar bronchi on the right and two on the left supplying their respective lobes. The lobar bronchi branch into several segmental bronchi, each of which supplies air to a subpart of the lobe called a bronchopulmonary segment. Each bronchopulmonary segment has an independent blood supply and can be resected without impacting the remaining lung. The segmental bronchi then further divide into a series of intersegmental bronchi. The smallest intersegmental bronchi branch to become bronchioles, which can be distinguished from bronchi in that they contain no cartilage in their wall. The terminal bronchioles branch into a series of respiratory bronchioles, each of which contain alveoli. The respiratory bronchioles terminate by

branching into alveolar ducts that lead into alveolar sacs, which are clusters of alveoli. It is in the alveoli where gasses in the air are exchanged with the blood. Each lung is supplied by a pulmonary artery that carries deoxygenated blood (thus they are colored blue in anatomical atlases) from the right ventricle of the heart (Fig. 4.25). Each pulmonary artery enters the hilum of the lung and branches with the bronchial tree to supply blood to the capillary bed surrounding the alveoli. The arterial branches have the same names as the bronchial branches. Oxygenated blood is returned to the left atrium of the heart via the paired pulmonary veins emerging from the hilum of both lungs. The pulmonary veins do not run the same course as the pulmonary arteries within the lung. At the hilum of the lung, the pulmonary artery is typically the most superior structure with the main bronchus immediately below. On the right, the main bronchus is somewhat higher and the superior lobar bronchus crosses superior to the pulmonary artery; it is referred to as the eparterial bronchus. The pulmonary veins exit the hilum of the lung inferior to both the main bronchus and the pulmonary artery. Lymphatic drainage of the lungs is to tracheobronchial lymph nodes located at the bifurcation of the trachea (Fig. 4.26). A subpleural lymphatic plexus lies under the vis-

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Fig. 4.25 Pattern of structure entering and leaving the root of the lung (left) and the branching pattern of the bronchi (right). ©1998 Elsevier Inc. All rights reserved. www.netterimages.com, Frank Netter

Fig. 4.26 Pattern of lymphatic drainage from the lungs. ©1998 Elsevier Inc. All rights reserved. www. netterimages.com, Frank Netter

ceral pleura and drains directly to the tracheobronchial nodes. A deep lymphatic plexus drains along the vasculature of the lungs to pulmonary nodes along the bronchi, which communicate with bronchopulmonary nodes at the hilum and from there to the tracheobronchial nodes. The lymphatic drainage from the lungs may drain directly to the subclavian veins via the bronchomediastinal trunks or into the common thoracic duct. The lungs receive innervation from the pulmonary plexus (Fig. 4.16). The parasympathetic nerves are from

the vagus (CN X), and they are responsible for the constriction of the bronchi and vasodilatation of the pulmonary vessels. They are also secretomotor to the glands in the bronchial tree. The sympathetics act opposite to the parasympathetics. Pain afferents from the costal pleura and the outer parts of the diaphragmatic pleura are derived from the intercostal nerves. The phrenic nerves contain sensory afferents for the mediastinal pleura and the central part of the diaphragmatic pleura.

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Fig. 4.27 The participation of muscles in respiration. ©1998 Elsevier Inc. All rights reserved. www.netterimages.com, Frank Netter

4.11.3 Mechanics of Respiration Respiration is controlled by: (1) the muscles of the thoracic wall, (2) the respiratory diaphragm, (3) the muscles of the abdominal wall, and (4) the natural elasticity of the lungs (Fig. 4.27). The diaphragm contracts during inspiration, causing the dome of the diaphragm to descend and the vertical dimension of the thoracic cavity to increase. Simultaneously, the ribs are elevated by the contraction of external intercostal muscles and the interchondral parts of the internal intercostals. During deep inspiration, the ribs are fur-

ther elevated by the contraction of muscles in the neck. Elevation of the ribs increases the diameter of the thoracic cavity. The net result is the expansion of the pulmonary cavities. When the walls of the thorax expand, the lungs expand with them due to the negative pressure created in the pleural cavity and the propensity of the visceral pleura to maintain contact with the parietal pleura due to the surface tension of the liquid between these surfaces (somewhat like two plates of glass sticking together with water in between them). The resultant negative pressure in the lungs forces the subsequent intake of air.

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Quiet expiration of air is primarily caused by the elastic recoil of the lungs when the muscles of inspiration are relaxed. Further expiration is achieved by the contraction of the lateral internal intercostal muscles, depressing the ribs, and the contraction of abdominal muscles, causing increased abdominal pressure which pushes up on the diaphragm. At rest, the inward pull of the lungs (trying to deflate further) is at equilibrium with the springlike outward pull of the thoracic wall.

4.12

Surface Anatomy

4.12.1 Landmarks of the Thoracic Wall There are several defined vertical lines that demark regions of the anterior and posterior thoracic wall (Fig. 4.23). These lines are used to describe the location of surface landmarks and the locations of injuries or lesions on or within the thorax. The anterior median line runs vertically in the midline; it is also referred to as the midsternal line. The midclavicular line bisects the clavicle at its midpoint and typically runs through, or close to, the nipple. Three lines demarcate the axilla. The anterior axillary line runs vertically along the anterior axillary fold, and the posterior axillary line runs parallel to it along the posterior axillary fold. The midaxillary line runs in the midline of the axilla, at its deepest part. The scapular line runs vertically on the posterior thorax, through the inferior angle of the scapula. The posterior median line, also called the midvertebral or midspinal line, runs vertically in the midline on the posterior thorax. The sternum lies subcutaneously in the anterior median line and can be palpated throughout its length. The jugular notch is found at the upper margin of the sternum, between the medial ends of the clavicle. The jugular notch is easily palpated and can usually be seen as a depression on the surface. The jugular notch represents the anterior junction of the superior mediastinum and the root of the neck. It lies at the level of the T2 vertebra posteriorly. The manubrium intersects with the body of the sternum about 4 cm inferior to the jugular notch, at the manubriosternal joint; this joint creates the sternal angle which is normally visible on the surface of the thorax. The sternal angle(of Louis) demarcates the inferior border of the superior mediastinum and lies at the level of the intervertebral disk between T4 and T5. The second rib articulates with the sternum at the sternal angle, making this site an excellent landmark for determining rib number. Immediately adjacent to the sternal angle is rib 2; the other ribs can be found by counting up or down from rib 2. Intercostal spaces are numbered for the rib above. On the posterior thorax, the fourth rib can be found at the level of the medial end of the spine of the scapula and eighth rib at the inferior angle.

The manubrium overlies the junction of the brachiocephalic veins to form the superior vena cava (Fig. 4.23). The superior vena cava passes at the level of the sternal angle and at (or slightly to the right of) the border of the manubrium. The superior vena cava typically enters the right atrium behind the costal cartilage of the third rib on the right and is sometimes accessed for various procedures; knowledge of this surface anatomy is critical. The xiphoid process is the inferior part of the sternum and lies in a depression called the epigastric fossa at the apex of the infrasternal angle formed by the convergence of the costal margins at the inferior border of the thorax (Fig. 4.23). Note that the location of the xiphisternal joint is used as a landmark to determine hand position for cardiopulmonary resuscitation. The breasts are also surface features of the thoracic wall. In women, the breasts vary greatly in size and conformation, but the base of a breast usually occupies the space between ribs 2 and 6, from the lateral edge of the sternum to the midaxillary line. The nipples, surrounded by an area of darker pigmented skin called the areola, are the prominent features of the breast. In men, the nipple is located anterior to the fourth intercostal space in the midclavicular line. Because of the variation in breast anatomy in the female, the location of the nipple is difficult to predict.

4.12.2 The Lungs and Pleura The pleural sac is outlined by the parietal pleura as it projects onto the surface of the lungs (Fig. 4.23). From the root of the neck, these projections follow the lateral edge of the sternum inferiorly. On the left, the border of the parietal pleura moves laterally at the level of fourth costal cartilage to accommodate the cardiac notch within the mediastinum. The pleura follows a line just superior to the costal margin, reaching the level of the tenth rib at the midaxillary line. Posteriorly the inferior margin of the plural cavity lies at the level of T12, and the medial margin follows the lateral border of the vertebral column to the root of the neck. In the superior parts of the pleural cavity, the visceral pleura of the lungs is in close contact with the parietal pleura, with the lungs consequently filling the plural cavity. Both lungs and parietal pleura (cervical part) extend above the clavicles into the supraclavicular fossae, at the root of the neck. At the inferior reaches of the pleural cavities, the lungs stop short of filling the plural cavity, reaching only to the level of the sixth rib in the midclavicular line, the eighth rib in the midaxillary line, and the tenth rib posteriorly, creating the costodiaphragmatic recesses. The major (oblique) fissures of the lungs extend along a line from the spinous process of T2 to the costal cartilage of the sixth rib. The minor (horizontal) fissure of the right lung lies under the fourth rib.

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Fig. 4.28 Illustration of thoracocentesis. Figure adapted from Grant’s Dissector, 12th edn. by EK Sauerland (Fig. 1.16)

Under pathologic conditions, fluid can accumulate in the pleural cavity. This fluid normally drains inferiorly and accumulates in the costodiaphragmatic recess. Thoracocentesis refers to the procedure used to drain such fluid (Fig. 4.28). To do so, a needle is commonly inserted into the costodiaphragmatic recess by passing it through the middle of the intercostal space, being careful to avoid the primary intercostal neurovascular bundle immediately below the rib above and collaterals above the rib below.

4.12.3 The Heart The heart and great vessels are covered by the sternum and central part of the thoracic cage (Fig. 4.23). The apex of the heart usually lies in the fifth intercostal space just medial of the midclavicular line. The upper border of the heart follows a line from the inferior border of the left second costal cartilage to the superior border of the right costal cartilage. The inferior border of the heart lies along a line from the right sixth costal cartilage to the fifth intercostal space at the midclavicular line, where the apex of the heart is located. The right and left borders follow lines connecting the right and left ends of the superior and inferior borders. All four heart valves, the closing of which account for the heart sounds, lie well protected behind the sternum. The sounds of the individual valves closing are best heard at auscultatory sites to which their sounds are transmitted (see Chap. 18). The bicuspid (mitral) valve is heard at the apex of the heart in the region of the fourth or fifth intercostal spaces on the left near the midclavicular line. The tricuspid valve can be heard along the left margin of the sternum at the level of the fourth or fifth intercostal space. The pulmonary valve is heard along the left border of the sternum in the second intercostal space. The

aortic valve is heard at the second intercostal space on the right sternal border.

4.12.4 Vascular Access Understanding the surface landmarks relative to the axilla and subclavian region is critical for the successful access of the venous system via the subclavian vein. The subclavian vein passes over the first rib and under the clavicle at the junction of its middle and medial thirds; it courses through the base of the neck where it passes anterior to the apex of the lung and the pleural cavity (Fig. 4.29). The subclavian vein is immediately anterior to the subclavian artery and is separated from the artery medially by the anterior scalene muscle. To access the subclavian vein, a needle is inserted approximately 1 cm inferior to the clavicle at the junction of its medial and middle thirds and aimed toward the jugular notch, parallel with the vein to minimize risk of injury to adjacent structures. The most common complication of subclavian venous access is puncture of the apical pleura with resulting pneumothorax or hemopneumothorax. In addition, the subclavian artery, lying behind the vein, also has the potential to be injured by this procedure. If subclavian access is attempted on the left, one must also be aware of the junction of the thoracic duct with the subclavian vein. Injury to the thoracic duct can result in chylothorax, the accumulation of lymph in the plural cavity. This is difficult to treat and has an associated high morbidity. When access of the subclavian is attempted for cardiac lead placement, care must be taken to avoid piercing the subclavius muscle or costoclavicular ligament. Passing the lead through these structures tethers it to the highly mobile clavicle which may cause premature breakage of the lead.

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Fig. 4.29 Anatomy of the subclavian veins and surrounding structures. ©1998 Elsevier Inc. All rights reserved. www.netterimages. com, Frank Netter

4.13

Summary

Options for accessing the heart, in a minimally invasive fashion, are limited by the vascular anatomy of the superior mediastinum and the axilla. Percutaneous access strategies are limited by the bony anatomy of the thoracic cage. How a device interacts with the thorax, and accommodates basic thoracic movements and movements of the upper extremity and neck, must be understood in order for design devices that will endure in the body. Thus, a thorough understanding of the thoracic anatomy surrounding the heart is important to those seeking to design and deploy devices for placement and use in the heart. With an understanding of the important thoracic anatomical relationships presented in this chapter, the engineer should be able to design devices with an intuition for the anatomical challenges that will be faced for proper use and deployment of the device.

References 1. Moore KL, Dalley AF (1999) Thorax. In: Moore KL, Dalley AF (eds) Clinically oriented anatomy, 4th edn. Lippincott Williams & Wilkins, Philadelphia, pp 62–173 2. Hollinshead WH, Rosse C (1985) Part IV: thorax. In: Hollinshead WH, Rosse C (eds) Textbook of anatomy, 4th edn. Harper & Row, Philadelphia, pp 463–575 3. Netter FH (ed) (2003) Atlas of human anatomy, 3rd edn. Icon Learning Systems, Teterboro 4. Sauerland EK (1999) The thorax. In: Sauerland EK (ed) Grant’s dissector, 12th edn. Lippincott Williams & Wilkins, Philadelphia, pp 1–39 5. Weinberger SE (1998) Pulmonary anatomy and physiology–the basics. In: Weinberger SE (ed) Principles of pulmonary medicine, 3rd edn. Saunders, Philadelphia, pp 1–20 6. Magney LE, Flynn DM, Parsons JA, Staplin DH, Chin-Purcell MV, Milstein S, Hunter DW (1993) Anatomical mechanisms explaining damage to pacemaker leads, defibrillator leads, and failure of central venous catheters adjacent to the sternoclavicular joint. Pacing Clin Electrophysiol 16:445–457

Anatomy of the Human Heart

5

Anthony J. Weinhaus

Abstract

This chapter covers the internal and external anatomy of the heart, its positioning within the thorax, and its basic function. Briefly, the heart is a muscular pump, located in the protective thorax, which serves two functions: (1) collect blood from the tissues of the body and pump it to the lungs and (2) collect blood from the lungs and pump it to all the tissues of the body. The heart’s two upper chambers (or atria) function primarily as collecting chambers, while two lower chambers (ventricles) are much stronger and function to pump blood. The right atrium and ventricle collect blood from the body and pump it to the lungs, and the left atrium and ventricle collect blood from the lungs and pump it throughout the body. There is a one-way flow of blood through the heart which is maintained by a set of four valves (tricuspid, bicuspid, pulmonary, and aortic). The tissues of the heart are supplied with nourishment and oxygen by a separate vascular supply committed only to the heart; the arterial supply to the heart arises from the base of the aorta as the right and left coronary arteries, and the venous drainage is via cardiac veins that return deoxygenated blood to the right atrium. Keywords

Cardiac anatomy • Mediastinum • Pericardium • Atrium • Ventricle • Valves • Coronary artery • Cardiac veins • Cardiac skeleton • Cardiopulmonary circulation

5.1

Introduction

The heart is a muscular pump which serves two functions: (1) collect blood from the tissues of the body and pump it to the lungs and (2) collect blood from the lungs and pump it to all of the tissues of the body. The human heart lies in the protective thorax, posterior to the sternum and costal cartilages, and rests on the superior surface of the diaphragm. The heart assumes an oblique position in the thorax, with two-thirds to the left of midline. It occupies a space between

A.J. Weinhaus, PhD (*) Department of Integrative Biology and Physiology, University of Minnesota, 6-125 Jackson Hall, 321 Church St. SE, Minneapolis, MN 55455-0328, USA e-mail: [email protected]

the pleural cavities called the middle mediastinum, defined as the space inside of the pericardium, the covering around the heart. This serous membrane has an inner and an outer layer, with a lubricating fluid in between. The fluid allows the inner visceral pericardium to “glide” against the outer parietal pericardium. The internal anatomy of the heart reveals four chambers composed of cardiac muscle or myocardium. The two upper chambers (or atria) function mainly as collecting chambers; the two lower chambers (ventricles) are much stronger and function to pump blood out of the heart. The role of the right atrium and ventricle is to collect blood from the body and pump it to the lungs. The role of the left atrium and ventricle is to collect blood from the lungs and pump it throughout the body. There is a one-way flow of blood through the heart; this flow is maintained by a set of four valves. The atrioventricular or AV valves (the right tricuspid and left bicuspid or

© Springer International Publishing Switzerland 2015 P.A. Iaizzo (ed.), Handbook of Cardiac Anatomy, Physiology, and Devices, DOI 10.1007/978-3-319-19464-6_5

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mitral) allow blood to flow only from atria to ventricles. The semilunar valves (pulmonary and aortic) allow blood to flow only from the ventricles out of the heart and through the great arteries. A number of structures that can be observed in the adult heart are remnants of fetal circulation. In the fetus, the lungs do not function as a site for the exchange of oxygen and carbon dioxide, and the fetus receives all of its oxygen from the mother. In the fetal heart, blood arriving to the right side of the heart is passed through specialized structures to the left side. Shortly after birth, these specialized fetal structures normally collapse, and the heart takes on the “adult” pattern of circulation. However, in rare cases, some fetal remnants and defects can occur (see Chap. 37). Although the heart is filled with blood, it provides very little nourishment and oxygen to the tissues of the heart. Instead, the tissues of the heart are supplied by a separate vascular supply committed only to the heart. The arterial supply to the heart arises from the base of the aorta as the right and left coronary arteries (running in the coronary sulcus). The venous drainage is via cardiac veins that return deoxygenated blood to the right atrium (see Chap. 8). It is important to note that besides pumping oxygen-rich blood to the tissues of the body for exchange of oxygen for carbon dioxide, the blood also circulates many other important substances. Nutrients from digestion are collected from the small intestine and pumped through the circulatory

Fig. 5.1 Position of the heart in the thorax. The heart lies in the protective thorax, posterior to the sternum and costal cartilages, and rests on the superior surface of the diaphragm. The heart assumes an oblique position in the thorax, with two-thirds to the left of midline. It is located between the two lungs which occupy the lateral spaces called the pleural cavities. The space between these two cavities is referred to as the mediastinum. The heart lies obliquely in a division of this space, the middle mediastinum, surrounded by the pericardium. Marieb, Elaine N.: Wilhelm, Paticia Brady; Mallatt, Jon B., Human Anatomy, 7th, © 2013. Printed and electronically reproduced by permission of Pearson Education, Inc., New York, New York

A.J. Weinhaus

system to be delivered to all cells of the body. Hormones are produced from one type of tissue and distributed to all cells of the body. The circulatory system also carries waste materials (salts, nitrogenous wastes, and excess water) from cells to the kidneys, where they are extracted and passed to the bladder. The pumping of interstitial fluid from the blood into the extracellular space is an important function of the heart. Excess interstitial fluid is then returned to the circulatory system via the lymphatic system.

5.2

Position of the Heart in the Thorax

The heart lies in the protective thorax, posterior to the sternum and costal cartilages, and rests on the superior surface of the diaphragm. The thorax is often referred to as the thoracic cage because of its protective function of the delicate structures within. The heart is located between the two lungs which occupy the lateral spaces called the pleural cavities. The space between these two cavities is referred to as the mediastinum (“that which stands in the middle”; Fig. 5.1). The mediastinum is divided first into the superior and inferior mediastinum by a midsagittal imaginary line called the transverse thoracic plane. This plane passes through the sternal angle (junction of the manubrium and body of the sternum) and the space between thoracic vertebrae T4 and T5. This plane acts as a convenient landmark as it also passes

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Fig. 5.2 Human cadaver dissection in which the ribs were cut laterally and the sternum and ribs reflected superiorly. This dissection exposes the contents of the thorax (the heart, great vessels, lungs, and diaphragm)

through the following structures: the bifurcation of the trachea, the superior border of the pericardium, the artificial division of the ascending and arch of the aortic artery, and the bifurcation of the pulmonary trunk into the pulmonary arteries. The human heart assumes an oblique position in the thorax, with two-thirds to the left of midline (Figs. 5.2 and 5.3). The heart is roughly in a plane that runs from the right shoulder to the left nipple. The base is located below the 3rd rib as it approaches the sternum (note that the sternal angle occurs at the level of the 2nd rib). The base is directed superiorly, to the right of midline, and posterior. The pointed apex projects to the left of midline and anterior. Thus, the heartbeat can be easily palpated between the 5th and 6th ribs (just inferior to the left nipple) from the apex of the heart where it comes into close proximity of the thoracic wall. Importantly, the heart lies in such an oblique plane that it is often referred to as being horizontal. Thus, the anterior side may be imagined as the superior and the posterior side as inferior (for additional detail on attitudinally correct cardiac anatomy, see Chap. 2). The heart is composed of four distinct chambers. There are two atria (left and right) responsible for collecting blood and two ventricles (left and right) responsible for pumping blood. The atria are positioned superior to (or posterior to) and somewhat to the right of their respective ventricles (Fig. 5.3). From superior to inferior down the anterior (or superior) surface of the heart runs the anterior interventricular sulcus (“a groove”). This sulcus separates the left and right ventricles. This groove continues around the apex as the posterior interventricular sulcus on the posterior (inferior) surface. Between these sulci, located within the heart, is the interventricular septum (“wall between the ventricles”). The base of the heart is defined by a plane that separates the

atria from the ventricles also called the atrioventricular groove or sulcus. This groove appears like a belt cinched around the heart. Since this groove appears as though it might also be formed by placing a crown atop the heart, the groove is also called the coronary (corona = “crown”) sulcus. The plane of this sulcus also contains the AV valves (and the semilunar valves) and a structure that surrounds the valves called the cardiac skeleton. The interatrial (“between the atria”) septum is represented on the posterior surface of the heart as the atrial sulcus. Also on the posterior (inferior) side of the heart, the crux cordis (“cross of the heart”) is formed from the atrial sulcus, posterior interventricular sulcus, and the relatively perpendicular coronary sulcus. Note that the great arteries, aorta, and pulmonary trunk arise from the base of the heart and the inferior angle of the heart is referred to as the apex; this resembles an inverted pyramid. The right and left atrial appendages (or auricles, so named because they look like dog ears, auricle = “little ear”) appear as extensions hanging off each atrium. The anterior (superior) surface of the heart is formed primarily by the right ventricle. The right lateral border is formed by the right atrium, and the left lateral border by the left ventricle. The posterior surface is formed by the left ventricle and the left atrium which is centered equally upon the midline. The acute angle found on the right anterior side of the heart is referred to as the acute margin of the heart and continues toward the diaphragmatic surface. The rounded left anterior side is referred to as the obtuse margin of the heart and continues posteriorly and anteriorly. Both right and left ventricles contribute equally to the diaphragmatic surface, lying in the plane of the diaphragm.

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Fig. 5.3 The anterior surface of the heart. The atria are positioned superior to (posterior to) and to the right of their respective ventricles. From superior to inferior, down the anterior surface of the heart, runs the anterior interventricular sulcus (“a groove”). This sulcus separates the left and right ventricles. The base of the heart is defined by a plane that separates the atria from the ventricles called the atrioventricular groove or sulcus. Note that the great arteries, aorta, and pulmonary trunk arise from the base of the heart. The right and left atrial appendages appear as extensions hanging off each atrium. The anterior (superior) surface of the heart is formed primarily by the right ventricle. The right lateral border is formed by the right atrium, and the left lateral border by the left ventricle. The posterior surface is formed by the left ventricle and the left atrium which is centered equally upon the midline midline. © 2006 Elsevier Inc. All rights reserved. www.netterimages. com, Frank Netter

5.3

The Pericardium

The pericardium (peri = “around” + cardia = “heart”) is the covering around the heart. It is a serous membrane, composed of two distinct but continuous layers that are separated from each other by a potential space containing a lubricating substance called serous fluid. During embryological development, the heart moves from a peripheral location into a space or cavity. This cavity has a serous fluid-secreting lining. As the heart migrates into the cavity, the serous lining wraps around the heart. This process can be described as being similar to a fist being pushed into a balloon (Fig. 5.4). Note that the fist is surrounded by balloon; however, it does not enter the balloon, and the balloon is still one continuous layer of material. These same properties are true for the

pericardium. Furthermore, although it is one continuous layer, the pericardium is divided into two components. The part of the pericardium that is in contact with the heart is called the visceral pericardium (viscus = “internal organ”) or epicardium (epi = “upon” + “heart”). The part of the pericardium forming the outer border is called the parietal pericardium (parietes = “walls”). The free or opposing surfaces of these serous membranes (epicardium and parietal pericardium) are covered by a single layer of flat-shaped epithelial cells called mesothelium. The mesothelial cells secrete a small amount of serous fluid to lubricate the movement of the epicardium against the parietal pericardium. The serous surfaces of the epicardium and parietal pericardium are often referred to as the serous pericardium. The outer surface of these serous membranes is a thin layer of fibroelastic connective tissue which supports the mesothelium. The epicardium also

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Fig. 5.4 The pericardium. The pericardium is the covering around the heart that is composed of two distinct but continuous layers that are separated from each other by a potential space containing a lubricating serous fluid. During embryological development, the heart migrates into the celomic cavity and a serous lining wraps around it, a process similar to a fist being pushed into a balloon (the balloon and pericardium is one continuous layer of material). The pericardium can be divided into the visceral pericardium (epicardium) and the parietal pericardium. A small amount of serous fluid is secreted into the pericardial space to lubricate the movement of the epicardium on the parietal pericardium. The parietal pericardium contains an epipericardial layer called the fibrous pericardium

contains a broad layer of adipose tissue between the fibroelastic layer and the heart muscle or myocardium. The parietal pericardium contains an additional layer referred to as the fibrous pericardium. This layer contains collagen and elastin fibers to provide strength to the parietal pericardium. It is important to note, however, that there is no potential space between the parietal and fibrous pericardium. The parietal pericardium, together with the fibrous pericardium, is often referred to as the fibrous pericardium. Inferiorly, the parietal pericardium is attached to the diaphragm. Anteriorly, the superior and inferior pericardiosternal ligaments secure the parietal pericardium to the manubrium and the xiphoid process, respectively. Laterally, the parietal pericardium (specifically, the fibrous pericardium) is in contact with the parietal pleura (the covering of the lungs). Trapped between the fibrous pericardium and the parietal pleura are the phrenic nerves (motor innervation to the diaphragm). Accompanying these nerves are the pericardiacophrenic arteries and veins (supplying the nerve, pericardium, and diaphragm). Under normal circumstances, only serous fluid exists between the visceral and parietal layers in the pericardial space or cavity. However, the accumulation of fluid (blood from trauma, inflammatory exudate following infection) in the pericardial space leads to the compression of the heart. This condition, called cardiac tamponade (“heart” + tampon = “plug”), occurs when the excess fluid limits the expansion of the heart (the fibrous pericardium resists stretching) between beats and reduces the ability to pump blood, leading to hypoxia (hypo = “low” + “oxygen”).

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Superiorly, the parietal pericardium surrounds the aorta and pulmonary trunk (about 3 cm above their departure from the heart) and is referred to as the arterial reflections or arterial mesocardium; the superior vena cava, inferior vena cava, and pulmonary veins are surrounded by the venous reflections or venous mesocardium. The outer fibrous (epipericardial) layer merges with the outer adventitial layer of the great vessels, which is continuous with the visceral pericardium. The result of this reflection is that the heart hangs “suspended” within the pericardial cavity. For more details on the Pericardium, see Chap. 9. Within the parietal pericardium, a blind-ended saclike recess called the oblique pericardial sinus is formed from the venous reflections of the inferior vena cava and pulmonary veins (Fig. 5.5). A space called the transverse pericardial sinus is formed between the arterial reflections above and the venous reflections of the superior vena cava and pulmonary veins below. This sinus is important to cardiac surgeons in various procedures when it is important to stop or divert the circulation of blood from the aorta and pulmonary trunk. By passing a surgical clamp or ligature through the transverse sinus and around the great vessels, the tubes of a circulatory bypass machine can be inserted. For more details on cardiopulmonary bypass, see Chap. 33.

5.4

Internal Anatomy of the Heart

A cross-section cut through the heart reveals a number of layers (Fig. 5.6). From superficial to deep, these are (1) the parietal pericardium with its dense fibrous layer, the fibrous pericardium; (2) the pericardial cavity (containing only serous fluid); (3) a superficial visceral pericardium or epicardium (epi = “upon” + “heart”); (4) a middle myocardium (myo = “muscle” + “heart”); and (5) a deep lining called the endocardium (endo = “within”). The endocardium is the internal lining of the atrial and ventricular chambers and is continuous with the endothelium (lining) of the incoming veins and outgoing arteries. It also covers the surfaces of the AV valves, pulmonary and aortic valves, as well as the chordae tendineae and papillary muscles. The endocardium is a sheet of epithelium called endothelium that rests on a dense connective tissue layer consisting of elastic and collagen fibers. These fibers also extend into the core of the previously mentioned valves. The myocardium is the tissue of the heart wall, the layer that actually contracts. The myocardium consists of cardiac muscles which are circularly and spirally arranged networks of muscle cells that squeeze blood through the heart in the proper directions (inferiorly through the atria and superiorly through the ventricles). Unlike all other types of muscle cells, (1) cardiac muscle cells branch; (2) cardiac muscles join together at complex junctions called intercalated disks, so that they form cellular networks; and (3) each cell contains

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Fig. 5.5 Pericardial sinuses. (a) A blind-ended sac called the oblique pericardial sinus is formed from the venous reflections of the inferior vena cava and pulmonary veins. (b) Another sac, the transverse pericardial sinus, is formed between the arterial reflections above and the venous reflections of the superior vena cava and pulmonary veins below below. © 2006 Elsevier Inc. All rights reserved. www. netterimages.com, Frank Netter

single centrally located nuclei. A cardiac muscle cell is not called a fiber. The term cardiac muscle fiber, when used, refers to a long row of joined cardiac muscle cells. Like skeletal muscle, cardiac muscle cells are triggered to contract by Ca2+ ions flowing into the cell. Cardiac muscle cells are joined by complex junctions called intercalated disks. The disks contain adherens to hold the cells together,

and there are gap junctions to allow ions to pass easily between the cells. The free movement of ions between cells allows for the direct transmission of an electrical impulse through an entire network of cardiac muscle cells. This impulse, in turn, signals all the muscle cells to contract at the same time. For more details on the electrical properties of the heart, the reader is referred to Chap. 13.

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67 Dense fibrous layer

Pericardial cavity

Areolar connective tissue

MYOCARDIUM (cardiac muscle tissue)

Parietal pericardium

Mesothelium Artery

Cut edge of pericardium

Vein

Connective tissues

Pericardial cavity

Mesothelium

Anterior view

Areolar connective tissue

all ar t w

EPICARDIUM (visceral pericardium)

He

Areolar connective tissue

Sectional view

ENDOCARDIUM

Endothelium

Fig. 5.6 Internal anatomy of the heart. The walls of the heart contain three layers—the superficial epicardium, the middle myocardium composed of cardiac muscle, and the inner endocardium. Note that cardiac muscle cells contain intercalated disks which enable the cells to commu-

nicate and allow direct transmission of electrical impulses from one cell to another. Martini, Frederic H.; Timmons, Michael J.; Tallitsch, Robert B., Human Anatomy, 4th, © 2003. Printed and electronically reproduced by permission of Pearson Education, Inc., New York, New York

5.4.1

the term “artery” is always used for a vessel that carries blood AWAY from the heart. This is irrespective of the oxygen content of the blood that flows through the vessel. Once oxygenated, the oxygen-rich blood returns to the heart from the right and left lung through the right and left pulmonary vein, respectively (“vein”—a vessel carrying blood toward the heart). Each pulmonary vein bifurcates before reaching the heart. Thus, there are typically four pulmonary veins entering the left atrium. Oxygen-rich blood is pumped out of the heart by the left ventricle and into the aortic artery. Observing the heart from a superior vantage point, the pulmonary trunk assumes a leftmost anterior location projecting upward from the base of the heart, the aorta is located in a central location, and the superior vena cava has the rightmost posterior location.

Cardiopulmonary Circulation

In order to best understand the internal anatomy of the heart, it is desirable to first understand its general function. The heart has two primary functions—collect oxygen-poor blood and pump it to the lungs for the release of carbon dioxide in exchange for oxygen and collect oxygen-rich blood from the lungs and pump it to all tissues in the body to provide oxygen in exchange for carbon dioxide. The four chambers in the heart can be segregated into the left and the right side, each containing an atrium and a ventricle. The right side is responsible for collecting oxygen-poor blood and pumping it to the lungs. The left side is responsible for collecting oxygen-rich blood from the lungs and pumping it to all tissues in the body. Within each side, the atria are the sites where blood collects and passes through to the ventricles and then they contract to eject the final volumes of blood into the ventricles. The ventricle is much stronger, and it is a site for the pumping of blood out and away from the heart (Figs. 5.7 and 5.8). The right ventricle is the site for the collection of ALL oxygen-poor blood. The large superior and inferior venae cavae, among other veins, carry oxygen-poor blood from the upper and lower parts of the body to the right atrium. The right ventricle pumps the blood out of the heart and through the pulmonary trunk. The term trunk, when referring to a vessel, is a convention that indicates an artery that bifurcates. The pulmonary trunk bifurcates into the left and right pulmonary arteries that enter the lungs. It is important to note that

5.4.2

The Right Atrium

The interior of the right atrium has three anatomically distinct regions, each a remnant of embryologic development. The posterior portion of the right atrium has a smooth wall and is referred to as the sinus venarum (embryologically derived from the right horn of the sinus venosus). The wall of the anterior portion of the right atrium is lined by horizontal, parallel ridges of muscle bundles that resemble the teeth of a comb, hence the name pectinate muscle (pectin = “a comb,” embryologically derived from the primitive right atrium).

68 Fig. 5.7 Cardiopulmonary circulation. The four chambers in the heart can be segregated into the left and the right side, each containing an atrium and a ventricle. The right side is responsible for collecting oxygen-poor blood and pumping it to the lungs. The left side is responsible for collecting oxygen-rich blood from the lungs and pumping it to the body. An artery is a vessel that carries blood away from the heart, while a vein is a vessel that carries blood toward the heart. The pulmonary trunk and arteries carry blood to the lungs. Exchange of carbon dioxide for oxygen occurs in the lung through the smallest of vessels, the capillaries. Oxygenated blood is returned to the heart through the pulmonary veins and collected in the left atrium atrium. © 2006 Elsevier Inc. All rights reserved. www. netterimages.com, Frank Netter

Fig. 5.8 Cardiac circulation. Blood collected in the right atrium is pumped into the right ventricle. Upon contraction of the right ventricle, blood passes through the pulmonary trunk and arteries to the lungs. Oxygenated blood returns to the left atrium via pulmonary veins. The left atrium pumps the blood into the left ventricle. Contraction of the left ventricle sends the blood through the aortic artery to all tissues in the body. The release of oxygen in exchange for carbon dioxide occurs through capillaries in the tissues. Return of oxygenpoor blood is through the superior and inferior vena cavae which empty into the right atrium. Note that a unidirectional flow of blood through the heart is accomplished by valves

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Fig. 5.9 Internal anatomy of the right atrium. The interior of the right atrium has three anatomically distinct regions: (1) the posterior portion (sinus venarum) which has a smooth wall; (2) the wall of the anterior portion which is lined by horizontal, parallel ridges of muscle referred to as pectinate; and (3) the atrial septum septum. © 2006 Elsevier Inc. All rights reserved. www.netterimages. com, Frank Netter

Finally, the interatrial septum is primarily derived from the embryonic septum primum and septum secundum. For more details on the embryology of the heart, refer to Chap. 3. The smooth posterior wall of the right atrium holds the majority of the named structures of the right atrium. It receives both the superior and inferior vena cavae and the coronary sinus. It also contains the fossa ovalis, the sinoatrial (SA) node, and the AV node. The inferior border of the right atrium contains the opening or ostium of the inferior vena cava and the os or ostium of the coronary sinus (Fig. 5.9). The coronary sinus is located on the posterior (inferior) side of the heart and receives almost all of the deoxygenated blood from the vasculature of the heart. The os of the coronary sinus opens into the right atrium anteriorly/ inferiorly to the orifice of the inferior vena cava. A valve of the inferior vena cava (Eustachian valve, a fetal remnant) guards the orifice of the inferior vena cava (Bartolommeo E. Eustachio, Italian Anatomist, 1520–1574). The valve of the coronary sinus (Thebesian valve) covers the opening of the coronary sinus (fetal remnant to prevent backflow, Adam C. Thebesius, German physician, 1686–1732). Both of these valves vary in size and presence. These two venous valves insert into a prominent ridge, the Eustachian ridge (sinus septum), that runs medial–lateral across the inferior border of the atrium and separates the os of the coronary sinus and inferior vena cava. For more details on the valves of the heart, refer to Chap. 34. On the medial side of the right atrium, the interatrial septum (atrial septum) has an interatrial and an atrioventricular part.

The fossa ovalis (a fetal remnant) is found in the interatrial part of the atrial septum. It appears as a central depression surrounded by a muscular ridge or limbus. The fossa ovalis is positioned anterior and superior to the ostia of both the inferior vena cava and the coronary sinus. A tendinous structure, the tendon of Todaro, crosses the floor of the right atrium. It connects the valve of the inferior vena cava to a portion of the interventricular septum (between ventricles). More specifically, the tendon connects to the central fibrous body (the right fibrous trigone) as a fibrous extension of the membranous portion of the interventricular septum. It courses obliquely within the Eustachian ridge and separates the fossa ovalis above from the coronary sinus below. This tendon likely has a structural role to support the inferior vena cava via the Eustachian valve and is a useful landmark in approximating the location of the AV node (conduction system). To approximate the location of the AV node, found in the floor of the right atrium and the atrial septum, it is necessary to form a triangle (triangle of Koch; Walter Koch, German surgeon, unknown–1880) using the following structures: (1) the os of the coronary sinus, posteriorly; (2) the right AV opening, anteriorly; and (3) the tendon of Todaro, posteriorly (Fig. 5.10). In the lateral wall and the septum of the smooth portion of the right atrium are numerous small openings in the endocardial surface. These openings are the ostia of the smallest cardiac (Thebesian) veins. These veins function to drain deoxygenated blood from the myocardium to

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Fig. 5.10 Koch’s triangle. Three landmarks are used to triangulate (dotted red lines) the location of the atrioventricular node (Taware’s node) of the conduction system: (1) coronary sinus, (2) atrioventricular opening, and (3) tendon of Todaro

empty into the right atrium which is the collecting site for all deoxygenated blood (for more details on cardiac vasculature, see Chap. 8). In the anterior–superior portion of the right atrium, the smooth wall of the interior becomes the pectinate portion of the right atrium. The smooth and pectinate regions are separated by a ridge, the crista terminalis (crista = “crest” + “terminal”). The ridge represents the end of the smooth wall and the beginning of the pectinate wall. It begins at the junction of the right auricle with the atrium and passes inferiorly over the “roof” of the atrium. The crista runs inferiorly and parallel to the openings of the superior and inferior vena cavae. As early as the developing embryo, the crista terminalis separates the sinus venosus and the primitive atrium and remains to separate the smooth and the pectinate portion of the right atrium in the definitive heart. The crista terminalis on the internal side results in a groove on the external side of the atrium called the sulcus terminalis. The SA node is the “pacemaker” of the conduction system. The SA node is located between the myocardium and epicardium in the superior portion of the right atrium. The intersection of three lines indicates the location of the SA node: (1) the sulcus terminalis, (2) the lateral border of the superior vena cava, and (3) the superior border of the right auricle (Fig. 5.11). The name of the SA node is derived from its location between the sinus venarum and primitive atrium. The crista terminalis is the division between these two components in the fetus and adult. It seems logical that the sulcus terminalis is a useful landmark for the approximation of the location of the SA node.

5.4.3

The Right Ventricle

The right ventricle receives blood from the right atrium and pumps it to the lungs through the pulmonary trunk and arteries. Most of the anterior surface of the heart is formed by the right ventricle (Fig. 5.12). Abundant, coarse trabeculae carneae (“beams of meat”) characterize the walls of the right ventricle. Trabeculae carneae are analogous to pectinate muscle of the right atrium and are found in both the right and left ventricles. The outflow tract, conus arteriosus (“arterial cone”), and infundibulum (“funnel”) carry blood out of the ventricle in an anterior–superior direction and can be quite variable in structure—smooth walled or highly trabeculated. A component of the conus arteriosus forms part of the interventricular septum. This small septum, the infundibular (conal) septum, separates the left and right ventricular outflow tracts and is located just inferior to both semilunar valves. Four distinct muscle bundles, collectively known as the semicircular arch, separate the outflow tract from the rest of the right atrium. These muscle bundles are also known as the supraventricular crest and the septomarginal trabeculae.

5.4.3.1 Tricuspid Valve Blood is pumped from the right atrium through the AV orifice into the right ventricle. When the right ventricle contracts, blood is prevented from flowing back into the atrium by the right AV valve or tricuspid (“three cusps”) valve. The valve consists of the annulus, three valvular leaflets, three papillary muscles, and three sets of chordae tendineae (Figs. 5.12 and 5.13). The AV orifice is reinforced by the annulus fibro-

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Fig. 5.11 Location of the sinoatrial node. Human cadaver heart demonstrating that the intersection of three lines indicates the position of the sinoatrial node (pacemaker of the conduction system) in the smooth muscle portion of the right atrium: (1) the sulcus terminalis, (2) the lateral border of the superior vena cava, and (3) the superior border of the right auricle. Note the muscle fiber bundles in the wall of the pectinate portion of right atrium. IVC inferior vena cava, SVC superior vena cava

sus of the cardiac skeleton (dense connective tissue). Medially, the annulus is attached to the membranous interventricular septum. The tricuspid valve has three leaflets—anterior (superior), posterior (inferior), and septal. The anterior leaflet is typically the largest and extends from the medial border of the ventricular septum to the anterior free wall. This, in effect, forms a partial separation between the inflow and outflow tracts of the right ventricle. The posterior leaflet extends from the lateral free wall to the posterior portion of the ventricular septum. The septal leaflet tends to be somewhat oval in shape and extends from the annulus of the orifice to the medial side of the interventricular septum (on the inflow side), often including the membranous part of the septum (see also Chaps. 2 and 7 for other nomenclature describing these leaflets). Papillary (“nipple”) muscles contract and “tug” down on chordae tendineae (“tendinous cords”) that are attached to the leaflets, in order to secure them in place in preparation for the contraction of the ventricle. This is done to prevent the prolapse of the leaflets up into the atrium. This is somewhat analogous to the tightening of the sails on a yacht, in preparation for a big wind. Note that the total surface area of the cusps of the AV valve is approximately twice that of the

respective orifice, so that considerable overlap of the leaflets occurs when the valves are in the closed position. The leaflets remain relatively close together even during ventricular filling. The partial approximation of the valve surfaces is caused by eddy currents that prevail behind the leaflets and by tension that is exerted by the chordae tendineae and papillary muscle. As the filling of the ventricle reduces, the valve leaflets float toward each other, but the valve does not close. The valve is closed by ventricular contractions, and the valve leaflets, which bulge toward the atrium but do not prolapse, stay pressed together throughout ventricular contraction. The junction between two leaflets is called a commissure and is named by the two adjoining leaflets (anteroseptal, anteroposterior, and posteroseptal). Each commissure contains a relatively smooth arc of valvular tissue that is delineated by the insertion of the chordae tendineae. There are three papillary muscles, just as there are three leaflets or cusps. The anterior papillary muscle is located in the apex of the right ventricle. This is the largest of the papillary muscles in the right ventricle, and it may have one, two, or more heads. When this papillary muscle contracts, it pulls on chordae tendineae that are attached to the margins of the anterior and posterior leaflets. The posterior papillary

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Fig. 5.12 Internal anatomy of the right ventricle. Coarse trabeculae carneae characterize the walls of the right ventricle. The conus arteriosus makes up most of the outflow tract. The right atrioventricular or tricuspid valve is made up of three sets of cusps, chordae tendineae, and papillary muscles. © 2006 Elsevier Inc. All rights reserved. www. netterimages.com, Frank Netter

muscle is small and located in the posterior lateral free wall. When this papillary muscle contracts, it pulls on chordae tendineae that are attached to posterior and septal leaflets. The septal papillary muscle (including the variable papillary of the conus) arises from the muscular interventricular septum near the outflow tract (conus arteriosus). This papillary muscle may consist of a collection of small muscles in close proximity and has attachments to the anterior and septal valve leaflets. In addition, chordae tendineae in this region may extend simply from the myocardium and attach to the valve leaflets directly without a papillary muscle. The most affected is the septal leaflet which has restricted mobility due to extensive chordae tendineae attachment directly to the myocardium. In addition, there is a variable set of papillary muscles that should be considered. The medial papillary muscle complex is a collection of small papillary muscles with chordae attachments to septal and anterior cusps. This complex is located in the uppermost posterior edge of the septomarginal trabeculae, just inferior to the junction of the septal and anterior leaflets of the tricuspid valve, and is superior and distinct from the septal papillary muscles. An important feature of this complex is that it serves as an important landmark for identification of the right bundle branch as it runs posterior to it, deep to the endocardium [1].

Near the anterior free wall of the right ventricle is a muscle bundle of variable size, the moderator band, which is occasionally absent. This muscle bundle extends from the interventricular septum to the anterior papillary muscle and contains a primary portion of the right bundle branch of the conduction system. It seems logical that the anterior papillary muscle, with its remote location away from the septum, would need special conduction fibers in order for it to contract with the other papillary muscles and convey control of the valve leaflets equal to the other valve leaflets. The moderator band is a continuation of another muscle bundle, the septal band (septal trabeculae). Together they are called septomarginal trabeculae and are components of the semicircular arch (delineation of the outflow tract).

5.4.3.2 Pulmonary Semilunar Valve During ventricular systole, blood is pumped from the right ventricle into the pulmonary trunk and arteries toward the lungs. When the right ventricle relaxes, in diastole, blood is prevented from flowing back into the ventricle by the pulmonary semilunar valve (Figs. 5.12 and 5.13). The semilunar valve is composed of three symmetric semilunar-shaped cusps. Each cusp looks like a cup composed of a thin membrane. Each cusp acts like an upside-down parachute facing into the pulmonary trunk, opening as it

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Fig. 5.13 Valves of the heart. During ventricular systole, atrioventricular (AV) valves close in order to prevent the regurgitation of blood from the ventricles into the atria. The right AV valve is the tricuspid valve; the left is the bicuspid valve. During ventricular diastole, the AV valves open as the ventricles relax, and the semilunar valves close. The semilunar valves prevent the backflow of blood from the great arteries into the resting ventricles. The valve of the pulmonary trunk is the pulmonary semilunar valve, and the aortic artery has the aortic semilunar valve. To the right of each figure are human cadaveric hearts. © 2006 Elsevier Inc. All rights reserved. www.netterimages. com, Frank Netter

fills with blood. This filled space or recess of each cusp is called the sinus of Valsalva. Upon complete filling, the three cusps contact each other and block the flow of blood. Each of the three cusps is attached to an annulus (“ring”) such that the cusp opens into the lumen, forming a U shape. The annulus is anchored to both the right ventricular infundibulum and the pulmonary trunk. The cusps are named according to their orientation in the body—anterior, left (septal), and right. During ventricular systole, as the right ventricle contracts, the cusps collapse against the arterial wall as blood is flowing past them. When the ventricle rests (diastole), the cusps meet in the luminal center. There is a small thickening on the center of the free edge of each cusp, at the point where the cusps meet. This nodule (of Arantius or Morgagni) ensures central valve closure (Giulio C. (Aranzi) Arantius, Italian anatomist and physician, 1530–1589; Giovanni B. Morgagni, Italian anatomist and pathologist, 1682–1771). Radiating from this nodule around the free edge of the cusp is a ridge, the linea alba (“line” + “white”).

5.4.4

The Left Atrium

The left atrium (Fig. 5.14) receives oxygenated blood from the lungs via the left and right pulmonary veins. The pulmonary veins typically enter the heart as two pairs of veins inserting posteriorly and laterally into the left atrium (individuals with 3 or 5 pulmonary veins have also been identified). The left atrium is found midline, posterior to the right atrium and superior to the left ventricle. Anteriorly, a left atrial appendage (auricle) extends over the atrioventricular (coronary) sulcus. The walls of the atrial appendage are pectinate, and the walls of the left atrium are smooth, reflecting their embryological origin. The atrial appendage is derived from the primitive right atrium (which was pectinate). The left atrium is derived from the fetal pulmonary vein as a connection with the embryonic pulmonary venous plexus. These venous structures are absorbed into the left atrium, resulting in the posterolateral connections of the right and left pulmonary veins. The portion of the interatrial septum on the left atrial side is derived from the embryonic septum primum. In the left

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Fig. 5.14 Internal anatomy of the left atrium and ventricle. The left atrium receives oxygenated blood from the lungs via the left and right pulmonary veins. The pulmonary veins enter the heart as two pairs of veins inserting posteriorly and laterally. Anteriorly, the pectinate left auricle extends over the smooth-walled atrium. Most of the left lateral surface of the heart is formed by the left ventricle. Trabeculae carneae characterize the walls and the myocardium is much thicker than the left ventricle. The interventricular septum bulges into the right ventricle, creating a barrel-shaped left ventricle. © 2006 Elsevier Inc. All rights reserved. www. netterimages.com, Frank Netter

atrium, the resulting structure in the adult is called the valve of the foramen ovale (a sealed valve flap).

5.4.5

The Left Ventricle

The left ventricle receives blood from the left atrium and pumps it through the aortic artery to all the tissues of the body (Fig. 5.14). Most of the left lateral surface of the heart is formed by the left ventricle, also forming part of the inferior and posterior surfaces. As with the right ventricle, abun-

dant trabeculae carneae (“beams of meat”) characterize the walls of the left. However, in contrast to the right ventricle, the muscular ridges tend to be relatively finer. Also in contrast to the right ventricle, the myocardium in the wall of the left ventricle is much thicker. The interventricular septum appears from within the left ventricle to bulge into the right ventricle. This creates a barrel-shaped left ventricle.

5.4.5.1 Bicuspid (Mitral) Valve Blood is pumped from the left atrium through the left AV orifice into the left ventricle. When the left ventricle contracts, blood

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Fig. 5.15 The mitral valve. The mitral (left atrioventricular or bicuspid) valve is so named because of its resemblance to a cardinal’s hat, known as a miter. Left: Photo of Pope John Paul II from the Vatican web site; Right: © 2006 Elsevier Inc. All rights reserved. www.netterimages.com, Frank Netter

is prevented from flowing back into the atrium by the left AV valve or bicuspid (“two cusps”) valve (Figs. 5.13 and 5.14). The valve consists of the annulus, two leaflets, two papillary muscles, and two sets of chordae tendineae. The atrioventricular orifice is partly reinforced by the annulus fibrosus of the cardiac skeleton. The annulus fibrosus supports the posterior and lateral two-thirds of the annulus. The remaining medial third is supported by attachment to the left atrium and by fibrous support to the aortic semilunar valve. The bicuspid valve typically has two leaflets—anterior (medial or aortic) and posterior (inferior or mural, “wall”). The two opposing leaflets of the valve resemble a bishop’s hat or miter. Thus, the bicuspid valve is often referred to as the mitral valve (Fig. 5.15). The anterior leaflet is trapezoidal-shaped. The distance from its attachment on the annulus to its free edge is longer than the length of attachment across the annulus. In contrast, the posterior leaflet is relatively narrow, with a very long attachment distance across the annulus. The distance from annulus to free edge in the anterior cusp is twice as long as the posterior cusp. The posterior cusp is so long and narrow that the free edge is often subdivided into the anterior, central, and posterior crescent shapes. Note that each of these two leaflets may also have numerous scallops within them (see also Chap. 7). Papillary muscles, in conjunction with chordae tendineae, attach to the leaflets in order to secure them in place. This is done in preparation for the contraction of the ventricle to prevent the prolapse of the leaflets up into the atrium. As with the other AV valve, the total surface area of the two cusps of the valve is significantly greater than the area described by

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the orifice. There is considerable overlap of the leaflets when the valves are in the closed position (Fig. 5.13). As with the tricuspid valve, the leaflets remain relatively close together even when the atrium is contracting and the ventricle is filling. The partial approximation of the valve surfaces is caused by eddy currents that prevail behind the leaflets and by tension that is exerted by the chordae tendineae and papillary muscle. In the open position, the leaflets and commissures are in an oblique plane of orientation that is roughly parallel to the ventricular septum. The valve is closed by ventricular contractions. The valve leaflets, which bulge toward the atrium, stay pressed together throughout the contraction and do not prolapse. The junctions of the two leaflets are called the anterolateral and the posteromedial commissures. The line of apposition of the leaflets during valvular closure is indicated by a fibrous ridge. There are commonly two papillary muscles of the left ventricle that extend from the ventricular free wall toward and perpendicular to the atrioventricular orifice. The anterior papillary muscle is slightly larger than the posterior, and each papillary muscle consists of a major trunk that often may elicit multiple heads from which extend the chordae tendineae. The chordae tendineae of each papillary muscle extend to the two valvular commissures and to the multiple crescent shapes of the posterior cusp. Thus, each papillary muscle pulls on chordae from both leaflets. In addition, the posterior leaflet occasionally has chordae that extend simply from the ventricular myocardium without a papillary muscle.

5.4.5.2 Aortic Semilunar Valve During ventricular systole, blood is pumped from the left ventricle into the aortic artery to all of the tissues of the body. When the left ventricle relaxes in diastole, blood is prevented from flowing back into the ventricle by the aortic semilunar valve (Figs. 5.13 and 5.14). Like the pulmonary semilunar valve, the aortic valve is composed of three symmetric semilunar-shaped cusps, and each cusp acts like an upsidedown parachute facing into the aortic artery, opening as it fills with blood. The filled space or recess of each cusp is called the sinus of Valsalva (Antonio M. Valsalva, 1666– 1723). Upon complete filling, the three cusps contact each other and block the flow of blood. Each of the three cusps is attached to an annulus (“ring”) such that the cusp opens into the lumen forming a U shape. The cusps are firmly anchored to the fibrous skeleton within the root of the aorta (Fig. 5.16). A circular ridge on the innermost aspect of the aortic wall, at the upper margin of each sinus, is the sinotubular ridge—the junction of the sinuses and the aorta. At the sinotubular ridge, the wall of the aorta is thin, bulges slightly, and is the narrowest portion of the aortic artery. The cusps are named according to their orientation in the body—left and right (both facing the pulmonary valve) and posterior. Within the sinuses of Valsalva, there are open-

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Fig. 5.16 The cardiac skeleton. The cardiac skeleton consists of a dense connective tissue that functions to attach the atrial and ventricular myocardium, support and reinforce the openings of the four valves of the heart, and electrically separate the ventricles from the atria. Courtesy of Jean Magney, University of Minnesota

ings or ostia (ostium = “door or mouth”) into the blood supply of the heart called coronary arteries. These ostia are positioned below the sinotubular junction near the center of the sinuses. Only the two sinuses facing the pulmonary valve (left and right) have ostia that open into the left and right coronary arteries, respectively. Coronary arteries carry oxygenated blood to the myocardium of the heart. During ventricular diastole, the aortic valve snaps shut as pressure in the aorta increases. Under such pressure, the walls of the

great artery distend, the sinuses fill, and blood is sent under great pressure through the coronary ostia into the coronary arteries. The posterior (noncoronary) sinus is in a position that it abuts the fibrous skeleton and the annuli of both AV valves (Fig. 5.13). When the left ventricle contracts, the cusps collapse against the arterial wall as blood flows past them. When the ventricle rests (diastole), the cusps meet in the luminal center. As with the pulmonary valve, there is a small thickening

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on the center of the free edge of each cusp, at the point where the cusps meet. This nodule (of Arantius or Morgagni) ensures central valve closure. Radiating from this nodule around the free edge of the cusp is a ridge, the linea alba (“line” + “white”). This valve is exposed to a greater degree of hemodynamic stress than the pulmonary valve. The aortic cusps can thicken and the linea alba can become more pronounced. For this and other reasons, the aortic pulmonary valve is the most likely valve to be surgically repaired or replaced.

5.5

The Cardiac Skeleton

Passing transversely through the base of the heart is a fibrous framework or “skeleton” made of dense connective tissue, not bone as the name might suggest. The purpose of this tough, immobile scaffold is to (1) provide an attachment for the atrial and ventricular myocardium, (2) anchor the four valves of the heart, and (3) electrically insulate the myocardium of the ventricles from the atria (see also Chap. 13). The supporting framework of the cardiac skeleton (Figs. 5.13 and 5.16) provides immobile support for the AV openings during atrial and ventricular contractions and support for the semilunar valves against the high pressures generated during and after ventricular contractions. The skeleton is a formation of four attached rings with the opening for the aortic semilunar valve in the central position and the other valve rings attached to it. The triangular formation between the aortic semilunar valve and the medial parts of the tricuspid and bicuspid valve openings is the right fibrous trigone (“triangle”) or the central fibrous body, the strongest portion of the cardiac skeleton. The smaller left fibrous trigone is formed between the aortic semilunar valve and the anterior cusp of the mitral valve. Continuations of fibroelastic tissue from the right and left fibrous trigone partially encircle the AV openings to form the tricuspid and bicuspid annulus or annulus fibrosus. The annuli serve as attachment sites for the AV valves as well as atrial and ventricular myocardium. Strong collagenous tissue passes anteriorly from the right and left fibrous trigones to encircle and support the aortic and pulmonary semilunar valve annuli. The membranous interventricular septum is an inferior extension of the central fibrous body that attaches to the muscular interventricular septum. The membranous septum provides support for the medial (right and posterior) cusps of the aortic semilunar valve and continues superiorly to form part of the atrial septum. The tendon of Todaro is a fibrous extension of the membranous septum that is continuous with the valve (Eustachian) of the inferior vena cava. The AV bundle of conduction fibers from the AV node penetrates the central fibrous body, passes through the membranous septum, and splits into left and right bundle branches at the apex

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of the muscular septum (or the junction of the right and posterior cusps of the aortic semilunar valve).

5.6

The Fetal Heart

By the third month of fetal development, the heart and all major blood vessels are basically formed, and the blood flow is generally in the same direction as the adult. However, there are some major differences between fetal and postnatal circulation (Fig. 5.17). First, oxygenated blood flows toward the fetus and into the heart in umbilical veins, and deoxygenated blood flows away from the fetus in umbilical arteries. Second, the fetus obtains oxygen from the uterus through the placenta, and the fetal lungs are essentially nonfunctional. Therefore, fetal circulation has a number of features to direct most of the blood away from the lungs. In fetal circulation, oxygenated blood from the placenta flows through the umbilical cord as the umbilical vein. The vein passes through the anterior abdominal wall (umbilicus) and then through the abdomen, into the thorax, and into the heart. As the umbilical vein travels through the abdomen, most of the blood is diverted away from entering the liver (through the ductus venosus) and into the inferior vena cava. Thus, unlike the adult heart, oxygenated blood mixes with deoxygenated blood and collects in the right atrium. Because very little of this blood is required in the lungs, the fetus has three unique features to ensure that the blood is shunted from the right (pulmonary) side of the heart to the left (systemic) side. The first is an oval hole in the interatrial septum called the foramen ovale (the foramen ovale is not really a hole but rather a valve composed of two flaps that prevent the regurgitation of blood). For more information on this topic, the reader is referred to Chap. 3. Before birth, pressure is higher in the right atrium than in the left because of the large vasculature from the placenta. The foramen ovale is a passage for blood to flow from the right atrium into the left. A second feature of the fetal heart is the ligament of the inferior vena cava. This ligament is located inferior to the opening of the vena cava and extends medially to the atrial septum, passing inferior to the foramen ovale. It is much more prominent in the fetus than in the adult. It functions in fetal circulation to direct, in a laminar flow, the blood coming into the right ventricle toward the foramen ovale of the interatrial septum, so blood can pass into the left atrium. The third feature of fetal circulation is a way for oxygenated blood that has been pumped from the right atrium to the right ventricle to be diverted from the pulmonary circulation into the systemic circulation. Despite the shunt from the right atrium to the left, much of the oxygenated blood that enters the right atrium gets pumped into the right ventricle. The ductus arteriosus

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Fig. 5.17 Fetal circulation. The fetal heart has unique features to shunt blood away from the relatively nonfunctional lungs: (1) foramen ovale, (2) ductus arteriosus, and (3) valve (Eustachian) of the inferior vena cava. © 2006 Elsevier Inc. All rights reserved. www. netterimages.com, Frank Netter

(“duct of the artery”) is a connection between the left pulmonary artery and the aortic artery. Blood is diverted from the pulmonary artery to the aorta so that very little blood reaches the immature lungs. Because the pulmonary vascular resistance of the fetus is large, only one-

tenth of right ventricular output passes through the lungs. The remainder passes from the pulmonary artery through the ductus arteriosus to the aorta. In the fetus, the diameter of the ductus arteriosus can be as large as the aorta.

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Fig. 5.18 Chiari network. Left: The sinus venosus incorporates into the posterior wall of the primitive right atrium. This becomes the sinus venarum (smooth) portion of the right atrium. A pair of tissue flaps, the left and right venous valves, develops on either side of connection between the sinus venarum and the right atrium. The left valve eventually gives rise to the septum secundum (definitive interatrial septum); the right valve gives rise to the valve of the inferior vena cava

(Eustachian), the valve of the coronary sinus (Thebesian), and the crista terminalis. Incomplete resorption of the right valve of the embryonic sinus venarum leads to the presence of a meshwork of fibrous strands attached to the edges of the Eustachian valve or the Thebesian valve inferiorly and the crista terminalis superiorly. Right: human cadaveric heart. IVC inferior vena cava, SVC superior vena cava

Shortly after birth, the umbilical cord is cut and the newborn takes its first breath. Rising concentrations of the hormone prostaglandin are believed to result in the closure of the ductus arteriosus (ligamentum arteriosum), and the lungs receive much more blood. The increase in pressure is translated to the left atrium. This pressure pushes together the two valve flaps of the interatrial septum. One of the flaps covers the foramen ovale, thus closing it to form the fossa ovalis. This prevents the flow of blood from the right to the left atrium.

superiorly. This is called a “Chiari net or network” (Fig. 5.18). Remnants of the other valve, the left sinus venarum valve, may be found adherent to the superior portion of the atrial septum or the fossa ovalis. For more information on this topic, see Chap. 3.

5.7

Other Fetal Remnants: Chiari Network

Around 4–5 weeks of fetal development, the sinus venosus incorporates into the posterior wall of the primitive right atrium. This becomes the sinus venarum (smooth) portion of the right atrium. A pair of tissue flaps, the left and right venous valves, develops on either side of connection between the sinus venarum and the right atrium. The left valve eventually becomes part of the septum secundum (which becomes a portion of the definitive interatrial septum). The right valve remains intact and forms the valve of the inferior vena cava (Eustachian), the crista terminalis, and the valve of the coronary sinus (Thebesian) (Fig. 5.18). Infrequently, incomplete resorption of the right valve of the sinus venarum may lead to the presence of a meshwork of fibrous strands attached to the edges of the Eustachian valve or Thebesian valve inferiorly and the crista terminalis

5.8

Other Fetal Remnants: Atrial Septal Defect

The first step in the separation of the systemic and pulmonary circulation in the fetal heart is the separation of the definitive atrium. The adult interatrial septum is formed by the fusion of two embryonic septa. Note that this embryonic septum always contains a hole such that right-to-left shunting of oxygenated blood remains. Between 3 and 4 weeks of development, the roof of the atrium becomes depressed and produces a wedge of tissue called the septum primum (“first partition”) that extends inferiorly. During the fifth week, this septum reaches the “floor” of the atrium, thus separating the right and left atria. Note that a crescent shape forms along its leading edge. This forms an “arch way” under the septum to function as an opening for the flow of blood called the ostium primum (“first mouth opening”). At the end of the sixth week, the growing edge of the septum primum reduces the ostium primum to nothing. At the same time, the septum primum grows perforations near the superior end of the septum that

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Fig. 5.19 Atrial septal defect (ASD). Incomplete formation of the interatrial septum results in a persistent opening or defect. After birth, the pressure in the left atrium is greater than the right, and there is modest left-to-right shunting of blood. The right atrium will frequently respond to the continuous increases in volume. The result is increased pressure generated by the right atrium and a reverse in the flow from the right to the left atrium. This results in oxygen-poor blood in the left atrium, ventricle, and aortic artery leading to symptoms of hypoxia. Modified from VanDeGraaf KM (ed) (1995) Human anatomy. Wm. C. Brown Publishers, Dubuque, p. 557

coalesce to form a new foramen, the ostium secundum (“second opening”). Thus, a new channel for right-to-left blood flow opens before the old one closes. At the same time, a second crescent-shaped wedge of tissue, the septum secundum (“second partition”), grows from the roof of the atrium. It is located adjacent to the septum primum on the side of the right atrium. Unlike the septum primum, the secundum is thick and muscular as it grows posteroinferiorly. It completely extends to the floor of the right atrium. The crescent shape at the leading edge leaves a hole in the inferior portion called the foramen ovale (“oval hole”); this might be considered the third hole. Throughout the rest of fetal development, blood shunts from the right to the left atrium. This shunt closes at birth due to the abrupt dilation

of the pulmonary vasculature, combined with the loss of flow through the umbilical vein. The increase in pressure in the left atrium and the loss of pressure in the right pushes the flexible septum primum against the septum secundum. The septum primum covers the foramen ovale as the valve of the foramen ovale. There are various mechanisms by which an opening can persist in the interventricular septum postnatally. This is referred to as an atrial septal defect (Fig. 5.19; see also Chap. 37). This abnormality is generally asymptomatic during infancy. However, the persistent increase in flow of blood into the right atrium can lead to hypertrophy of the right atrium, right ventricle, and the pulmonary trunk. In some cases, the left-to-right flow of blood between the atria con-

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verts to right-to-left shunt. This causes oxygen-poor blood to mix with the oxygen-rich blood returning to the left atrium from the lungs. Oxygen-poor blood is then pumped out of the heart through the aortic artery and the symptoms of hypoxia (“low oxygen”) result. Approximately 30 % of normal hearts have a small potency with a valve-competent foramen ovale.

5.9

Other Fetal Remnants: Ventricular Atrial Septal Defect

The developmental formation of the interventricular septum is extremely complex. Simply, the septum forms as the growing walls of the right and left ventricles become more closely apposed to one another. The growth of the muscular septum commences at the inferior end and proceeds superiorly.

Fig. 5.20 Ventricular septal defect. Caused by abnormal development of the interventricular septum. This condition results in massive left-to-right shunting of blood. This is associated with pulmonary hypertension and deficient closure of atrioventricular valves after birth. Emergent surgical repair of this hole is indicated. Modified from VanDeGraaf KM (ed) (1995) Human anatomy. Wm. C. Brown Publishers, Dubuque

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Septation of the ventricles and formation of the ventricular outflow tracts must occur in tight coordination. Ventricular septal defects can occur because of errors in this complex process. Failure of complete fusion of the membranous septum growing inferiorly from the superior portion of the ventricles and the muscular septum results in one type of ventricular septal defect (Fig. 5.20). Ventricular septal defects are the most common congenital heart defect. Whatever the origin of a ventricular septal defect, the result is a massive left-to-right shunting of blood due to the ability of the left ventricle to generate higher pressures than the right. This is associated with postnatal pulmonary hypertension and deficient closure of AV valves. This type of condition is often referred to, in lay terms, as “baby being born with a hole in the heart.” Because of extreme hypoxia and

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pulmonary hypertension, there is usually immediate surgical repair of the defect. For additional information on ventricular septal defects and their repair, refer to Chap. 37.

5.10

Vasculature of the Heart

The arterial supply to the heart arises from the base of the aorta as the right and left coronary arteries (running in the coronary sulcus). The venous drainage is via cardiac veins that return deoxygenated blood to the right atrium. The coronary arteries arise from the ostia in the left and right sinuses of the aortic semilunar valve, course within the epicardium, and encircle the heart in the AV (coronary) and interventricular sulci (Fig. 5.21).

5.10.1 Right Coronary Artery The right coronary artery emerges from the aorta into the AV groove. It descends through the groove, then curves posteriorly, and makes a bend at the crux of the heart and continues downward in the posterior interventricular sulcus. Within millimeters after emerging from the aorta, the right coronary artery gives off two branches (Figs. 5.21 and 5.22). The conus (arteriosus) artery runs to the conus arteriosus (right Fig. 5.21 Vascular supply to the heart. Arterial supply to the heart occurs via the right and left coronary arteries and their branches. Venous drainage occurs via cardiac veins. © 2006 Elsevier Inc. All rights reserved. www. netterimages.com, Frank Netter

ventricular outflow tract), and the atrial branch to the right atrium. This atrial branch gives off the SA nodal artery (in 50–73 % of hearts, according to various reports), which runs along the anterior right atrium to the superior vena cava, encircling it in a clockwise or counterclockwise direction before reaching the SA node. The SA nodal artery supplies the SA node, Bachman’s bundle, crista terminalis, and the left and right atrial free walls. The right coronary artery continues in the AV groove and gives off a variable number of branches to the right atrium and right ventricle. The most prominent of these is the right marginal branch which runs down the right margin of the heart supplying this part of the right ventricle. As the right coronary curves posteriorly and descends downward on the posterior surface of the heart, it gives off two to three branches. One is the posterior interventricular (posterior descending) artery that runs in the posterior interventricular sulcus. It is directed toward the apex of the heart to supply the posterior free wall of the right ventricle. In 85–90 % of hearts, branches of this artery (posterior septal arteries) supply the posterior one-third of the interventricular septum (Fig. 5.23). The second artery is the AV nodal artery which branches from the right coronary artery at the crux of the heart and passes anteriorly along the base of the atrial septum to supply the AV node (in 50–60 % of hearts), proximal parts of the bundles (branches) of His, and the parts of the posterior interventricular septum that surround the

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Fig. 5.22 Atrial branch of right coronary artery. This atrial branch gives off the sinoatrial (SA) nodal artery which runs along the anterior right atrium to the superior vena cava and encircles it in a clockwise, or sometimes counterclockwise, direction before reaching the SA node. The nodal artery can also pass intramurally through the right atrium to the SA node. The SA nodal artery supplies the SA node, Bachman’s bundle, crista terminalis, and the left and right atrial free walls

Fig. 5.23 Arterial supply to the interventricular septum. Left: Sites of coronary artery occlusion, in order of frequency and percentage of occlusions involving each artery. Right: The right coronary artery supplies the posterior one-third of the interventricular septum, and the left coronary supplies the anterior two-thirds. The artery to the atrioven-

tricular node commonly branches off of the posterior interventricular artery. Occlusions occur most frequently in the anterior interventricular artery, which is the primary blood supply to the interventricular septum (and bundle branches within). AV atrioventricular

bundle branches. Another artery crosses the crux into the left AV groove to supply the diaphragmatic surface of the left ventricle and the posterior papillary muscle of the bicuspid valve. The right coronary artery also serves as an important collateral supply to the anterior side of the heart, left ventricle, and anterior two-thirds of the interventricular septum via the conus artery and communicating arteries in the interventricular septum (Fig. 5.23). Kugel’s artery, which originates from either the right or left coronary artery, runs from anterior to posterior through the atrial septum. This artery serves

as an important collateral connection from anterior arteries to the AV node and posterior arteries.

5.10.2 Left Coronary Artery The left coronary artery (left main coronary artery) emerges from the aorta through the ostia of the left aortic cusp within the sinus of Valsalva (Fig. 5.21). The plane of the semilunar valve is tilted so that the ostium of the left coronary artery is superior

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and posterior to the right coronary ostium. The left coronary artery travels from the aorta and passes between the pulmonary trunk and the left atrial appendage. Under the appendage, the artery divides (and is thus a very short vessel) into the anterior interventricular (left anterior descending artery) and the left circumflex artery. The left coronary artery may be completely absent, i.e., the anterior interventricular and circumflex arteries arise independently from the left aortic sinus. The anterior interventricular artery appears to be a direct continuation of the left coronary artery which descends into the anterior interventricular groove. Branches of this artery, anterior septal perforating arteries, enter the septal myocardium to supply the anterior two-thirds of the interventricular septum (in about 90 % of hearts) (Fig. 5.23). The first branch, the first septal perforator, supplies a major portion of the AV conduction system. In about 80 % of hearts, the second or third perforator is the longest and strongest of the septal arteries and is often called the main septal artery. This artery supplies the middle portion of the interventricular septum. This artery also sends a branch to the moderator band and the anterior papillary muscle of the tricuspid valve (right ventricle), which is reasonable considering that the moderator band is part of the septomarginal trabeculae of the interventricular septum. This artery is often called the moderator artery. Other branches of the anterior interventricular artery extend laterally through the epicardium to supply adjacent right and left ventricular free walls. The anterior interventricular artery also sends a branch to meet the conus artery from the right coronary to form an important collateral anastomosis called the circle of Vieussens as well as branches to the anterior free wall of the left ventricle called diagonal arteries. These are numbered according to their sequence of origin as first, second, etc. diagonal arteries. The most distal continuation of the anterior interventricular artery curves around the apex and travels superiorly in the posterior interventricular sulcus to anastomose with the posterior descending from the right coronary artery. In summary, the anterior interventricular artery and its branches supply most of the interventricular septum—the anterior, lateral, and apical wall of the left ventricle; most of the right and left bundle branches; and the anterior papillary muscle of the bicuspid valve (left ventricle). It also provides collateral circulation to the anterior right ventricle, the posterior part of the interventricular septum, and the posterior descending artery. The circumflex artery branches off of the left coronary artery and supplies most of the left atrium—the posterior and lateral free walls of the left ventricle and (with the anterior interventricular artery) the anterior papillary muscle of the bicuspid valve. The circumflex artery may give off a variable number of left marginal branches to supply the left ventricle. The terminal branch is usually the largest of these branches. More likely, the circumflex artery may continue through the AV sulcus to supply the posterior wall of the left ventricle and (with the right coronary artery) the posterior

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papillary muscle of the bicuspid valve. In 40–50 % of hearts, the circumflex artery supplies the artery to the SA node. In 30–60 % of hearts, the left coronary artery may give off one or more intermediate branches that originate between the anterior interventricular and circumflex arteries. These extend diagonally over the left ventricle toward the apex of the heart and are thus named diagonal or intermediate arteries. The anterior interventricular artery is the most commonly occluded of the coronary arteries (Fig. 5.23). It is the major blood supply to the interventricular septum and the bundle branches of the conducting system. It is easy to see why coronary artery disease can lead to impairment or death (infarction) of the conducting system. The result is a “block” of impulse conduction between the atria and the ventricles known as “right/left bundle branch block.” Furthermore, branches of the right coronary artery supply both the SA and AV nodes in at least 50 % of hearts. An occlusion in this artery could result in necrosis of the SA or AV nodes, thus preventing or interrupting the conduction of electrical activity across the heart. For more details on the coronary arteries, see Chaps. 6 and 8.

5.10.3 Cardiac Veins An extensive network of intercommunicating veins provides venous drainage from the heart. The venous drainage of deoxygenated blood from the rest of the body is returned to the right atrium, as is the venous drainage of the heart. Venous drainage of the heart is accomplished through three separate systems: (1) the cardiac venous tributaries which converge to form the coronary sinus, (2) the anterior cardiac (anterior right ventricular) veins, and (3) the smallest cardiac (Thebesian) venous system (Fig. 5.24). Most of the myocardium is drained by the cardiac veins that course parallel to the coronary arteries. These three large veins (the great, middle, and small cardiac veins) converge to form the coronary sinus. On the anterior side of the heart, the anterior interventricular vein lies within the anterior interventricular sulcus and runs from inferior to superior beside the anterior interventricular artery (Figs. 5.24 and 5.25). At the base of the heart, near the bifurcation of the left coronary artery, it turns and runs within the AV groove as the great cardiac vein around the left side of the heart to the posterior. In the AV groove on the posterior side of the heart, the great cardiac vein becomes the coronary sinus, which then empties into the right atrium. From the inside of the right atrium, it can be seen that the coronary sinus opens into the right atrium forming an opening or os that is located anteriorly and inferiorly to the orifice of the inferior vena cava. There is a valve (Thebesian valve) that covers the opening of the coronary sinus to prevent backflow. The great cardiac vein is formed

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Fig. 5.24 Venous drainage of the heart. Three separate venous systems carry blood to the right atrium—the coronary sinus and its tributaries, the great, middle and small cardiac veins; the anterior cardiac veins; and the smallest (Thebesian) cardiac veins. © 2006 Elsevier Inc. All rights reserved. www. netterimages.com, Frank Netter

by the confluence of small venous tributaries from the left and right ventricles and anterior portion of the interventricular septum. As it ascends toward the coronary sinus, it receives small venous tributaries from the left atrium and left ventricle. It also receives a large left marginal vein, which runs parallel to the left marginal artery. There are two structures that serve as the boundary between the termination of the great cardiac vein and the beginning of the coronary sinus. The first is the valve of Vieussens, which has the appearance of a typical venous valve and functions to prevent the backflow of blood from

the coronary sinus into the great cardiac vein (Raymond Vieussens, French anatomist, 1641–1715). The second is the space between the entry points of the oblique vein of the left atrium (of Marshall) and the posterior (posteriolateral) vein of the left ventricle (John Marshall, English anatomist, 1818–1891). The oblique vein of Marshall runs superior to inferior along the posterior side of the left atrium, providing venous drainage of the area. The posterior vein ascends to the coronary sinus from the inferior portion of the left ventricle and provides drainage of the area.

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Fig. 5.25 The great cardiac vein. On the anterior side of the heart, the anterior interventricular vein lies within the anterior interventricular sulcus and runs from inferior to superior beside the anterior interventricular artery. At the base of the heart, it changes to the great cardiac vein as it runs within the atrioventricular groove around the left side of the heart to the posterior. In the atrioventricular groove on the posterior side of the heart, the great cardiac vein becomes the coronary sinus and empties into the right atrium

In addition to the great cardiac vein, the coronary sinus receives the posterior interventricular (or middle cardiac) vein (Figs. 5.24 and 5.26). Located on the posterior surface of the heart, it arises near the posterior aspect of the apex of the heart and runs from inferior to superior through the posterior interventricular sulcus. It then joins the coronary sinus within millimeters of the sinus entering into the right atrium. The middle cardiac vein is formed from venous confluence of tributaries that drain the posterior left and right ventricles and the interventricular septum. The coronary sinus also receives the highly variable small cardiac vein. The small cardiac vein arises from the anterior/ lateral/inferior portion of the right ventricle. It ascends and runs inferior to and roughly parallel with the marginal branch of the right coronary artery until it reaches the right AV sulcus. At this point, it turns and runs horizontally around to the posterior side of the heart and enters the coronary sinus with the middle cardiac vein. The small cardiac vein is extremely small or absent in 60 % of hearts. In about 50 % of hearts, the small cardiac vein enters the right atrium directly, and it infrequently drains into the middle cardiac vein. Typically, about 85 % of the venous drainage of the heart occurs through the great, middle, and small cardiac veins through the coronary sinus to the right atrium. This elaborate system of veins drains the left ventricle, some of the right ventricle, both atria, and the anterior portion of the interventricular septum. The second system of venous drainage of the heart involves the variable and delicate anterior cardiac veins (Figs. 5.24 and 5.27). This system is distinguished from the other cardiac

A.J. Weinhaus

Fig. 5.26 The middle cardiac vein. The middle cardiac vein, located on the posterior surface of the heart, arises near the posterior aspect of the apex of the heart and runs from inferior to superior through the posterior interventricular sulcus before entering the coronary sinus. The middle cardiac vein is formed from venous confluence of tributaries that drain the posterior left and right ventricles and the interventricular septum

venous system because the anterior cardiac veins do not drain into the coronary sinus. The two to four anterior cardiac veins originate and drain the anterior right ventricular wall, travel superiorly to cross the right AV sulcus, and enter the right atrium directly. The sulcus is usually packed with adipose tissue. Through this adipose tissue run the anterior cardiac veins, the right coronary artery, and a branch of the coronary artery, the right atrial or nodal artery. The anterior cardiac veins pass over the right coronary artery in close proximity and in a perpendicular angle. A right marginal vein (when present) runs parallel with the right marginal artery before entering the right atrium directly and is usually considered part of the anterior cardiac venous system. The third system of venous drainage of the heart is the smallest cardiac venous system (Fig. 5.27). This system is composed of a multitude of small intramural (“within the walls”) intramyocardial veins also called Thebesian veins (Adam C. Thebesius, German physician, 1686–1732). These are minute vessels that begin in the capillary beds of the myocardium and open directly into the chambers of the heart. Although called veins, they are valveless communications between myocardial capillaries and a chamber of the heart. Interestingly, ostia of Thebesian veins may be found in all chambers of the heart, but are most prevalent in the atrial and ventricular septa. They are more prevalent on the right side than the left. As much as 17 % of myocardial drainage occurs through these smallest cardiac veins, with 49 % through the cardiac veins and coronary sinus and 24 % through anterior

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Fig. 5.27 Anterior cardiac veins. Two to four anterior cardiac veins originate and drain the anterior right ventricular wall. These veins travel superiorly to cross the right atrioventricular sulcus and enter into the right atrium. These veins are part of the smallest cardiac venous system which empties oxygen-poor blood directly into the right atrium without communication with the coronary sinus

cardiac veins. For additional details on the cardiac venous system, see Chap. 8.

5.10.4 Myocardial Bridges The coronary arteries typically course upon the myocardium or under/within the epicardium of the heart. Frequently, a portion of an artery deviates from its usual subepicardial position to follow an intramyocardial (intramural) course, either by traveling a significant length within the myocardium or beneath an arrangement of muscular slips (“myocardial bridges”). Myocardial bridging is most common in the middle segment of the anterior interventricular artery [2]. The myocardial fibers that cover or “bridge over” the anterior interventricular artery are direct extensions of the myocardium of the conus arteriosus of the right ventricle and cross the artery in a perpendicular direction. Myocardial bridges over the right coronary and the circumflex arteries are much less common. When present, these bridges are extensions of the respective atrial myocardium [3]. The prevalence of myocardial bridges from various sources is reported to occur in 5–85 % of hearts when measured from the cadaver [4–6] and 0.5–16 % when measured from angiography in catheterization labs [4, 5, 7]. Coronary arteries have a tortuous pattern as they run across the heart. Interestingly, studies employing angiography followed by detailed microdissection show that a coronary artery with a typical tortuous shape takes on a

perfectly straight pattern when it follows an intramyocardial course [8]. Angiography has also shown that myocardial bridges are associated with narrowing of the lumen of the coronary artery. The narrowing appears during systole and disappears during diastole [2]. The appearance of straight running or systolic narrowing patterns appears to be an important diagnostic technique during angiography to discover intramyocardial segments of coronary arteries [2]. Myocardial bridging is usually a benign condition. Although there is contrasting evidence, atherosclerosis is uncommon within a myocardial bridge [4]; bridging might provide some protection against plaque formation [2].

5.11

Autonomic Innervation of the Heart

The SA node spontaneously produces an impulse for contraction of the atrial myocardium, depolarizes the AV node, and sends an impulse through the bundle fibers to the ventricular myocardium. In addition to the pacemaker activity of the SA node, the heart is also under autonomic, or involuntary, control. The autonomic nervous system is separated into the sympathetic and parasympathetic nervous systems. These two systems send neurons to the same target, but convey opposite effects. In emergency situations, sympathetic nerves travel to the heart and innervate the SA and AV nodes in order to increase the rate and force of contraction. In resting

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situations, parasympathetic nerves that innervate the SA and AV nodes to slow down the heart rate reduce the force of contraction, thus saving energy. Both the sympathetic and parasympathetic nerves are composed of a two-neuron pathway. These two neurons meet or synapse somewhere in the middle and form a structure called a ganglion (“swelling”). Neurons of the sympathetic nervous system emerge from the spinal cord. They emerge from all eight of the cervical segments and the first five of the thoracic spinal cord segments. These neurons travel laterally just centimeters from the spinal cord before they synapse. All of the neurons to the heart are believed to synapse in only two places—the middle cervical ganglion and the cervicothoracic (fused inferior cervical/1st thoracic or stellate “star-shaped”) ganglion. Multitudes of fibers then emanate from these ganglia and run to the heart as sympathetic cardiac nerves. Parasympathetic neurons emerge directly from the brain as part of the vagus nerve or cranial nerve X. The vagus nerve and its branches form the parasympathetic part of the cardiac nerves running toward the heart. Sympathetic and parasympathetic cardiac nerves interconnect. In addition, nerves of the right and left side have connections. All together, this huge group of connections forms the cardiac plexuses. The dorsal cardiac plexus is located posterior to the arch of the aorta near the bifurcation of the trachea. The ventral plexus is located anterior to the aorta. Nerves from the cardiac plexuses extend to the atria and ventricles, SA node, AV node, coronary arteries, and the great vessels. It is generally believed that there is sympathetic and parasympathetic innervation of the myocardium that forms a network from the atria to the ventricles. For more details about the role of the autonomic nervous system in the physiological control of the heart, refer to Chap. 14.

5.12

Summary

This chapter covered the general internal and external anatomy of the human heart, its positioning within the thorax, and its basic function. It is important to note that this

anatomy can be quite varied and also progressively modified by pathophysiologic conditions.

References 1. Wenink ACG (1977) The medial papillary complex. Br Heart J 39:1012–1018 2. Kalaria VG, Koradia N, Breall JA (2002) Myocardial bridge: a clinical review. Catheter Cardiovasc Interv 57:552–556 3. Garg S, Brodison A, Chauhan A (2000) Occlusive systolic bridging of circumflex artery. Cathet Cardiovasc Diagn 51: 477–478 4. Polacek P (1961) Relation of myocardial bridge and loops on the coronary arteries to coronary occlusions. Am Heart J 61:44–52 5. Irvin RG (1982) The angiographic prevalence of myocardial bridging. Chest 81:198–202 6. Noble J, Bourassa MG, Petitclerc R, Dyrda I (1976) Myocardial bridging and milking effect of left anterior descending artery: normal variant or obstruction. Am J Cardiol 37:993–999 7. Greenspan M, Iskandrin AS, Catherwood E, Kimbiris D, Bemis CE, Segal BL (1980) Myocardial bridging of the left anterior descending artery: evaluation using exercise thallium-201 myocardial scintigraphy. Cathet Cardiovasc Diagn 6:173–180 8. Lachman N, Satyapal KS, Vanker EA (2002) Angiographic manifestation and anatomical presence of the intra-mural LAD: surgical significance. Clin Anat 15:426

Further Reading Berne RM, Levy MN, Koeppen BM, Stanton BA (eds) (2004) Physiology, 5th edn. Mosby, St. Louis Garson A (ed) (1997) The science and practice of pediatric cardiology, 2nd edn. Williams and Wilkins, Baltimore Goss CM (ed) (1949) Anatomy of the human body: Gray’s anatomy. Lea and Febiger, Philadelphia Hurst JW (ed) (1990) Hurst’s the heart. McGraw-Hill, New York Kumar V, Cotran RS, Robbins SL (eds) (2003) Robbins basic pathology, 7th edn. Saunders, Philadelphia Larson WJ (ed) (1997) Human embryology, 2nd edn. Churchill Livingstone, New York Moore KL, Dalley AF (eds) (2006) Clinically oriented anatomy, 5th edn. Lippincott Williams and Williams, Philadelphia Netter FH (ed) (2003) Atlas of human anatomy, 3rd edn. ICON Learning Systems, Teterboro Stedman TL (ed) (1972) Stedman’s medical dictionary. Williams and Wilkins, Baltimore

Comparative Cardiac Anatomy

6

Alexander J. Hill and Paul A. Iaizzo

Abstract

The need for appropriate animal models to conduct translational research is vital for advancements in the diagnosis and treatment of heart disease. The choice of animal model to be employed must be critically evaluated. In this chapter, we present the comparative cardiac anatomies of several of the commonly employed animal models for preclinical research (dog, pig, and sheep). General comparisons focus on several specific anatomical features: the atria, ventricles, valves, coronary system, lymphatics, and the conduction system. Finally, we present novel qualitative and quantitative data obtained from perfusionfixed specimens of these commonly used animal models. Keywords

Comparative anatomy • Human • Sheep • Dog • Pig • Heart • Cardiac

6.1

Historical Perspective of Anatomy and Animal Research

Anatomy is one of the oldest branches of medicine, with historical records dating back at least as far as the third century BC; animal research dates back equally as far. More specifically, Aristotle (384–322 BC) studied comparative animal anatomy and physiology, and Erasistratus of Ceos (304–258 BC) studied live animal anatomy and physiology [1]. Galen of Pergamum (129–199 AD) is probably the most notable early anatomist who used animals in research in which he attempted to understand the normal structure and function of the body [2]. He continuously stressed the centrality of anatA.J. Hill, PhD Department of Surgery, University of Minnesota, 420 Delaware St. SE, B 172 Mayo, MMC 107, Minneapolis, MN 55455, USA Medtronic, 8200 Coral Sea Street NE, Mounds View, MN 55112, USA P.A. Iaizzo, PhD (*) Department of Surgery, University of Minnesota, 420 Delaware St. SE, B 172 Mayo, MMC 107, Minneapolis, MN 55455, USA e-mail: [email protected]

omy and made an attempt to dissect every day, as he felt it was critical to learning [3]. His most notable work was De Anatomicis Administrationibus (On Anatomical Procedures) which, when rediscovered in the sixteenth century, renewed interest in anatomy and scientific methods [2]. The Renaissance was a period of great scientific discovery and included important advances in our understanding of human and animal anatomy. Andreas Vesalius (1514–1564 AD) was arguably the greatest anatomist of the era [4]. To teach anatomy, he performed public nonhuman dissections at the University of Padua and is credited with creating the field of modern anatomy [2]. His immediate successors at Padua were Matteo Realdo Colombo (1510–1559 AD) and Gabriele Falloppio (1523–1562 AD). It was Colombo who, in great detail, described the pulmonary circulation and both the atrial and ventricular cavities; Falloppio is credited with the discovery of the Fallopian tubes among other things [4]. Animal research flourished during this period due to a number of popular ideas launched by both the Christian Church and one of the prominent scientific leaders at that time, Rene Descartes. The Church asserted that animals were under the dominion of man and, although worthy of respect, could be used to obtain information if it was for a “higher” purpose [2]. Descartes described humans and other animals as complex

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machines, with the human soul distinguishing man from all other animals. This beast-machine concept was important for early animal researchers because if animals had no souls, it was thought that they could not suffer pain. Interestingly, it was believed that the reactions of animals were responses of automata and not pain [2]. The concept of functional biomedical studies can probably be attributed to another great scientist and anatomist, William Harvey (1578–1657 AD). He is credited with one of the most outstanding achievements in science and medicine—a demonstration of the circulation of blood which was documented in his publication Exercitatio Anatomica De Motu Cordis et Sanguinis in Animalibus (De Motu Cordis) in 1628. Very importantly, his work ushered in a new era in science, where a hypothesis was formulated and then tested through experimentation [4]. Many great anatomists emerged during this period and made innumerable discoveries; many of these discoveries were named after the individuals who described them and include several researchers who studied cardiac anatomy such as the Eustachian valve (Bartolomeo Eustachio), the Thebesian valve and Thebesian veins (Thebesius), and the sinus of Valsalva (Antonio Maria Valsalva). It should be noted that during this time period, in addition to animal research, dissections on deceased human bodies were performed, but not to the degree that they are today. In fact, it is written that, in general, during the postRenaissance era, there was a serious lack of human bodies available for dissection. Oftentimes, bodies were obtained in a clandestine manner, by grave robbing or using bodies of executed criminals for dissection. In spite of the lack of bodies, most structures in the human body, including microscopic ones, were described by various anatomists and surgeons between the fifteenth and early nineteenth centuries. Early in the nineteenth century, the first organized opposition to animal research occurred. In 1876, the Cruelty to Animals Act was passed in Britain. It was followed in the United States by the Laboratory Animal Welfare Act of 1966, which was amended in 1970, 1976, and 1985. These two acts began a new era in how laboratory animals were treated and utilized in experimental medicine. Importantly, the necessity of animal research is still great, and therefore animals continue to be used for a variety of purposes including cardiovascular device research.

6.2

Importance of Anatomy and Preclinical Animal Research

Anatomy remains as quite possibly one of the most important branches of medicine. In order to diagnose and treat medical conditions, normal structure and function must be known, as it is the basis for defining what is abnormal. Furthermore, structure typically has a great impact on the

function of an organ, such as with the heart. For instance, a stenotic aortic valve will usually cause functional impairment of the left ventricle and lead to further pathologic conditions (e.g., ventricular hypertrophy). Thus, knowledge of anatomy and pathology is fundamental in understanding not only how the body is organized but also how the body works and how disease processes can affect it. Likewise, preclinical animal research has been at the core of much of the progress made in medicine. Most, if not all, of what we know about the human body and biology, in general, has been initially made possible through animal research. A publication by the American Medical Association in 1989 listed medical advances emanating from animal research, including studies on AIDS, anesthesia, cardiovascular disease, diabetes, hepatitis, and Parkinson’s disease, to name only a few [2]. More recently, in the field of transcatheter-delivered cardiac valves (see Chap. 36), the use of various animal models for preclinical research has been essential not only to optimize the device designs but also to ensure relative safety prior to their use in man. Furthermore, it has been through animal research that nearly all advances in veterinary medicine have also been established. Animal research is still fundamental in developing new therapies aimed at improving the quality of life for patients with cardiovascular disease. Specifically, early cardiac device prototype testing is commonly performed utilizing animal models, both with and without cardiovascular disease. More specifically, before any invasively used device (a class III medical device) can be tested in humans, the Food and Drug Administration (FDA) requires that sufficient data be obtained from animal research indicating that the device functions in the desired and appropriate manner. It is also critical to subsequently extrapolate that a given device will be safe when used in humans, that is, it will behave in humans in a manner similar to its function in the chosen animal models in which it was tested. More specifically, this extrapolation of animal testing data to the human condition requires that the animal model(s) chosen for testing possesses similar anatomy and physiology as that of humans (normal and/or diseased). Unfortunately, detailed information relating human cardiac anatomy to that of the most common large mammalian animal models has been relatively lacking. The following historical example illustrates how such a lack of knowledge can have a dramatic effect on the outcomes of cardiovascular research. During the 1970s and 1980s, dogs were employed as the primary animal model in numerous studies to identify potential pharmacological therapies for reducing infarct size. However, a detailed understanding of the coronary arterial anatomy was lacking or overlooked at the time; subsequently, it was shown that dogs have a much more extensive coronary collateral circulation relative to humans (Fig. 6.1). Thus, even when major coronary arteries were occluded, reliable and consistent

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Fig. 6.1 Drawing of the coronary arterial circulation in the: (A) dog, (B) pig, and (C) human. Notice the extensive network of coronary collateralization in the dog heart, including many arterial anastomoses. The normal pig and human hearts have significantly less collateralization; each area of myocardium is usually supplied by a single coronary artery. Ao aorta, LAD left anterior descending artery, LCx left circumflex artery, PA pulmonary artery, RCA right coronary artery

myocardial infarcts were difficult to create. This led to false claims about the efficacy of many drugs in reducing infarct size which, when subsequently tested in humans, usually did not produce the same results as those observed in the canine experiments [5]. Therefore, ischemia studies with humansized hearts have shifted to alternative species such as swine, which are considered to resemble the coronary collateral circulation of humans more precisely [6–9].

6.3

Literature Review of Large Mammalian Comparative Cardiac Anatomy

In general, the hearts of large mammals share many similarities, and yet the size, shape, and position of the hearts in the thoracic cavities can vary considerably between species [10].

Typically, the heart is located in the lower ventral part of the mediastinum in large mammals [11]. Most quadruped mammals tend to have a less pronounced left-sided orientation and a more ventrally tilted long axis of the heart when compared to humans [11] (Fig. 6.2). Additionally, hearts of most quadruped mammals tend to be elongated and have a pointed apex, with the exception of: (1) dogs which tend to have an ovoid heart with a blunt apex [11], (2) sheep which may have a somewhat blunt apex [12], and (3) pigs which have a blunt apex that is oriented medially [12]. Comparatively, human hearts typically have a trapezoidal shape [13] with a blunt apex. However, the apices of normal dog, pig, sheep, and human hearts are all formed entirely by the left ventricles [12–15] (Fig. 6.3). It is important to note that differences exist in the heart weight to body weight ratios reported for large mammals. It is generally accepted that adult sheep and adult pigs have

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Fig. 6.2 Lateral radiograph of sheep thorax showing orientation of the heart while the animal is standing. The cranial direction is to the left and ventral to the bottom. The apex of the heart is more ventrally tilted (down toward the sternum) than is seen in humans, due to the posture of quadruped mammals. It should be noted, however, that this tilting is limited due to extensive attachments of the pericardium to the sternum and diaphragm

Fig. 6.3 The anterior aspect of the dog (A), pig (B), and sheep (C) hearts. The apex is formed entirely by the left ventricle in these hearts. Also notice the differences in overall morphology of the hearts. The dog heart is much more rounded than the pig and sheep hearts and has a blunt apex. The pig heart has more of a valentine shape with a somewhat blunt apex compared to the sheep heart. The sheep heart is much more conical in shape and has a much more pronounced apex than dog or pig hearts. Also noteworthy is the presence of significant amounts of epicardial fat on the sheep heart, compared with dog and pig hearts. LA left atrium, LV left ventricle, RA right atrium, RV right ventricle

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smaller heart weight to body weight ratios than those of adult dogs. More specifically, the adult dog may have as much as twice the heart weight to body weight ratio (6.9 to 7 g/kg) as pigs (2.9 to 2.5 g/kg) or sheep (3.0 to 3.1 g/kg) [16, 17], yet such findings will also likely be breed specific. The normal adult human heart weight to body weight ratio has been reported to be 5 g/kg which, on a comparative note, is similar to that of young pigs (25–30 kg animals) [7]. All large mammalian hearts are enclosed by the pericardium, which creates the pericardial cavity surrounding the heart. The pericardium is fixed to the great arteries at the base of the heart and is attached to the sternum and diaphragm in all mammals, although the degree of these attachments to the diaphragm varies between species [10, 11]. Specifically, the attachment to the central tendinous aponeurosis of the diaphragm is firm and broad in humans and pigs, the phrenopericardial ligament is the only pericardial attachment in dogs, and the caudal portion of the pericardium is attached via the strong sternopericardial ligament in sheep [10, 11]. The pericardium consists of three layers—the serous visceral pericardium (epicardium), the serous parietal pericar-

6

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dium, and the fibrous pericardium. The serous parietal pericardium lines the inner surface of the fibrous pericardium, and the serous visceral pericardium lines the outer surface of the heart. The pericardial cavity is found between the serous layers and contains the pericardial fluid. The pericardium is considered to serve many functions including: (1) preventing dilatation of the heart, (2) protecting the heart from infection and adhesion to surrounding tissues, (3) maintaining the heart in a fixed position in the thorax, and (4) regulating the interrelations between the stroke volumes of the two ventricles [18–20]. However, it should be noted that the pericardium is not essential for survival, since humans with congenital absence of the pericardium and pericardiectomized animals or humans can survive with minimal consequences for many years [18, 21]. Although the basic structure of the pericardium is the same, there are important differences between species [18, 19, 22]. For instance, pericardial wall thickness increases with increasing heart size [18]. Humans are the notable exception to this rule, having a much thicker pericardium than animals with similar heart sizes [18]. Specifically, the pericardium of the human heart varies in thickness between 1 and 3.5 mm [20], while the average thickness of the pericardium of various animal species was found to be considerably thinner (sheep hearts, 0.32 ± 0.01 mm; pig hearts, 0.20 ± 0.01 mm; dog hearts, 0.19 ± 0.01 mm) [19]. Differences in the amount of pericardial fluid are considered to exist as well. Holt reported that most dogs have 0.5–2.5 mL of pericardial fluid with some dogs having up to 15 mL, compared to 20–60 mL in adult human cadaver hearts [18]. For additional information on the pericardium, see Chap. 9. The normally formed hearts of large mammals consist of four chambers—two thin-walled atria and two thicker walled ventricles. From both anatomical and functional perspectives, the heart is divided into separate right and left halves, with each half containing one atrium and one ventricle. In the fully developed heart with no associated pathologies, deoxygenated blood is contained in the right side of the heart and kept separate from oxygenated blood, which is on the left side of the heart. The normal path of blood flow is similar among all large mammals. Specifically, systemic deoxygenated blood returns to the right atrium via the caudal (inferior in humans) vena cava and the cranial (superior in humans) vena cava, subsequently passing into the right ventricle through the open tricuspid valve. At the same time, oxygenated blood returns from the lungs via the pulmonary veins to the left atrium and then through the open mitral valve to fill the left ventricle. After atrial contraction forces the last of the blood into the ventricles, ventricular contraction ejects blood through the major arteries arising from each ventricle, specifically the pulmonary trunk from the right ventricle and the aorta from the left ventricle. Via the pulmonary arteries, blood travels to the lungs to be oxygenated, whereas aortic blood travels through both the coronary arterial system (to

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feed the heart) and to the systemic circulation (to oxygenate bodily tissue). For additional discussions of flow patterns and function, see Chaps. 1 and 20.

6.3.1

The Atria

The right and left atria of the adult mammalian heart are separated by the interatrial septum. They are located at what is termed “the base” of the heart. The base receives all of the great vessels and is generally oriented cranially or superiorly, although there are reported differences in orientation among species, which are mostly dependent on the posture of the animal [13, 14, 23]. During fetal development, blood is able to pass directly from the right atrium to the left atrium, effectively bypassing the pulmonary circulation through a hole in the interatrial wall termed the foramen ovale. The foramen ovale has a valve-like flap located on the left atrial side of the interatrial septum, which prevents backflow into the right atrium during left atrial contraction [24]. At the time of birth or soon thereafter, the foramen ovale closes and is marked in the adult heart by a slight depression on the right atrial side of the interatrial wall termed the fossa ovalis [14, 24, 25]; it should be noted that it can remain patent in some individuals, and the rate of patent foramen ovale is comparable in adult humans and domestic swine at approximately 10–30 %. As compared to humans, the fossa ovalis is more posteriorly (caudally) positioned in dogs and sheep [11], but more deep-set and superior in the pig heart [13]. The sinus venosus, a common separate structure in nonmammalian hearts, is incorporated into the right atrium and is marked by the sinoatrial node in large mammals [24, 25]. According to Michaëlsson and Ho [11], all the mammals studied (including dogs, pigs, and sheep) have principally the same atrial architecture including: the sinus venosus, crista terminalis, fossa ovalis, Eustachian valve (valve of the inferior vena cava), and Thebesian valve (valve of the coronary sinus). All large mammalian atria also have an earlike flap called the auricle or appendage [13, 14, 25], although the size and shape of the auricles vary considerably between species [11, 13] (Fig. 6.4). In general, the junction between the right atrium and the right appendage is wide, whereas the junction on the left side is much more narrow [13]. Multiple pectinate muscles are found in both the right and left atrial appendages and on the lateral wall of the right atrium [11, 13, 14] (Figs. 6.5 and 6.6). Commonly, there is one posterior (caudal or inferior) and one anterior (cranial or superior) vena cava, although in some mammals there are two anterior venae cavae [24], and the location of the ostia of the venae cavae entering into the atrium varies [11, 13]. Specifically, the ostia of the inferior and superior vena cavae enter at right (or nearly right) angles in large mammalian animal models while entering the atrium nearly in line in humans [13].

94 Fig. 6.4 Differences in large mammalian atria. Human: (left) Right atrial appendage is generally triangular in shape and may be larger or smaller than the left atrial appendage; (right) Left atrial appendage is generally tubular in shape. Canine: (left) Right atrial appendage is generally tubular and is larger than or similar in size to the left atrial appendage; (right) left atrial appendage is usually tubular. Ovine: (left) Right atrial appendage is generally half-moon in shape and is larger than the left atrial appendage; (right) left atrial appendage is generally triangular in shape. Swine: (left) Right atrial appendage is usually half-moon in shape and is generally smaller than the left atrial appendage; (right) left atrial appendage is generally triangular in shape. Source: www.vhlab.umn.edu/ atlas, Comparative Anatomy Tutorial

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Fig. 6.5 The cranial (superior) aspect of dog (A and B), pig (C and D), and sheep (E and F) hearts. Images on the left of the figure (A, C, and E) show opened right atrial appendages, while images on the right (B, D, and F) show opened left atrial appendages. White arrows point to pectinate muscles that line the right and left atrial appendages. Notice that the right and left atrial appendages of the dog heart are tubular in nature. In contrast, the right and left atrial appendages of the pig and sheep heart are more triangular in morphology. LV left ventricle, RV right ventricle

Typically, the extent of the inferior vena cava between the heart and liver is long in domestic animals (>5 cm) and short in humans (1–3 cm) [11]. The coronary sinus ostium is normally located in the posterior wall of the right atrium, but its location can differ slightly between species. Interestingly, the number of pulmonary veins entering the left atrium also varies considerably between species; human hearts typically

have four [13] or occasionally five [15], dog hearts have five or six [14], and pig hearts have two primary pulmonary veins [13]. In all large mammalian hearts, the atria are separated from the ventricles by a layer of fibrous tissue called the cardiac skeleton, which serves as an important support for the valves as well as to electrically isolate the atrial myocardium from the ventricular myocardium [23].

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Fig. 6.6 A human heart opened on the inferior and superior aspects of the right ventricle, to show the anterior and posterior walls. White arrows point to pectinate muscles in the right atrial appendage on the anterior aspect. RV right ventricle

6.3.2

The Ventricles

The left and right ventricles of the large mammals used for cardiovascular research essentially contain the same components which are also structurally very similar to those in humans, including: an inlet (inflow) region, an apical region, and an outlet (outflow) region. The ventricles can be considered the major ejection/pumping chambers of the heart, and, as expected, their walls are significantly more muscular in nature than those of the atria. It should also be noted that the left ventricular walls are notably more muscular than those of the right ventricle, due to the fact that the left ventricle must generate enough pressure to overcome the resistance of the systemic circulation, which is much greater than the resistance of the pulmonary circulation (normally more than 4 times greater). The walls of both ventricles near the apex have interanastomosing muscular ridges and columns termed the trabeculae carneae which serve to strengthen the walls and increase the force exerted during contraction [11, 14, 24, 25]. However, large mammalian hearts reportedly do not have the same degree of trabeculation located in the ventricles as normal adult human hearts, and the trabeculations in animal hearts are commonly more coarse than those of human hearts [11, 13] (Figs. 6.7 and 6.8). One can also compare these relative anatomies by carefully studying various prepared plastinated cardiac specimens of large mammalian hearts, including humans. Papillary muscles supporting the

atrioventricular valves are found attached to the walls of the ventricles. Similar to human anatomy, in the majority of large mammalian animal hearts, the right ventricle has three papillary muscles, and the left ventricle has two, although variations in individuals and species do occur [11]. It should be noted that, in general, each papillary muscle supplies chordae tendineae to at least 2 leaflets, ensuring redundancy. Both ventricles typically have cross-chamber fibrous or muscular bands, which usually contain Purkinje fibers. Within the right ventricle of most dogs, pigs, and ruminants, a prominent band termed the moderator band is typically present [11]. However, the origin and insertion of the band, as well as the composition of the band, differ notably between species. For example, in the pig heart, the band originates much higher on the septal wall compared to the analogous structure in the human heart [13], and the sheep heart has a similar moderator band as the pig heart (Figs. 6.6, 6.7, 6.8, and 6.9). In the dog heart, a branched or single muscular strand extends across the lumen from the septal wall near, or from the base of, the anterior papillary muscle [14] (Figs. 6.7, 6.8, 6.10, and 6.11). However, Truex and Warshaw [26] did not find any moderator bands in the dog hearts they examined (n = 12), but did observe them in all sheep hearts (n = 12) and all pig hearts (n = 12), compared to 56.8 % of the human hearts they examined (n = 500). Furthermore, they described three subtypes of moderator bands: a free arching band, a partially free arching band, and a completely adherent band.

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Fig. 6.7 Images showing dog (A), pig (B), and sheep (C) hearts that have been opened along the long axis to show both ventricular cavities. The anterior half of the heart is shown (left ventricle on the left and right ventricle on the right). Black arrows point to ventricular trabeculations which are large and coarse. White arrows point to the moderator band. Notice that a fibrous, branched moderator band extends from the anterior papillary muscle to the free wall in the canine heart. In contrast, a muscular, nonbranched moderator band extends from the septal wall to the anterior papillary muscle in pig and sheep hearts. Additionally, notice the presence of fibrous bands in the left ventricle. LV left ventricle, PA pulmonary artery, RV right ventricle

Nevertheless, one must also consider the potential for breed differences in animals and ethnic variability in humans. It is interesting to note that while, in general, anatomical textbooks state there is no specific structure named the moderator band in the left ventricle, left ventricular bands similar to the moderator band of the right ventricle have been described in the literature. For example, Gerlis et al. found left ventricular bands in 48 % of the hearts of children and in 52 % of the adult human hearts studied [27] (Fig. 6.8). They also reported that left ventricular bands were highly prevalent in sheep, dog, and pig hearts [27] (Fig. 6.7).

6.3.3

The Cardiac Valves

Large mammalian hearts have four cardiac valves with principally similar structures and locations. Two atrioventricular valves are located between each atrium and ventricle on both

the right and left sides of the heart, and two semilunar valves lie between the ventricles and the major arteries arising from their outflow tracts (the pulmonary artery and aorta). Chordae tendineae connect the fibrous leaflets of both atrioventricular valves to the papillary muscles in each ventricle and serve to keep the valves from prolapsing into the atria during ventricular contraction, thereby preventing backflow of blood into the atria. The semilunar valves—the aortic and pulmonic—do not have attached chordae tendineae and close due to pressure gradients developed across them. See Chap. 34 for more details on valvular structures, function, and defects. The valve separating the right atrium from the right ventricle is termed the tricuspid valve because it has three major cusps—the anterosuperior (anterior), inferior (posterior), and septal cusps. Typically, there are also three associated papillary muscles in the right ventricle. Interestingly, the commissures between the anterosuperior leaflet and the

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Fig. 6.8 Image of a human heart opened on the long axis to show both ventricular cavities. The left ventricle is on the left and the right ventricle on the right. Black arrows point to ventricular trabeculations, which are fine and numerous. The white arrow points to the moderator band, which is thick and muscular. It is different in size, shape, and location from the animal hearts shown in Fig. 6.7. LV left ventricle, RV right ventricle

inferior leaflets can be fused in dog hearts [14], giving the appearance of only two leaflets. Interindividual and interspecies variations in the number of papillary muscles have also been reported [11]. The valve separating the left atrium from the left ventricle is termed the mitral or bicuspid valve because it typically has two cusps, the anterior (aortic) and the posterior (mural). However, according to Netter [15], the human mitral valve actually can be considered to have four cusps, including the two major cusps listed above and two small commissural cusps or scallops; further publications on the mitral valve describe large variations in the number of scallops present in human hearts. Quill et al. studied the relative frequency of such variations in 38 human hearts and showed that the commonly described clefts on the posterior leaflet separating that leaflet into three regions (P1, P2, P3) were present in the majority of hearts; deviant clefts were also present in unexpected locations, such as the anterior leaflet, in some hearts [28]. In large mammalian hearts, two primary leaflets of the mitral valve are always present, but variations in the number of scallops exist and can be quite marked, giving the impression of extra leaflets [11]. A fibrous continuity between the mitral valve and the aortic valve is present in humans and most large mammals, extending from the central fibrous body to the left fibrous trigone [11] (Fig. 6.12). The length of this fibrous continuity, termed the intervalvar septum or membranous septum, varies considerably in length in different animals but notably is completely

Fig. 6.9 Plastinated hearts of various species. Human: Trabeculae carneae in the apex are notably more numerous and finer than in the hearts of swine, canines, or sheep. Canine: Trabeculae carneae are coarser than those of humans; compared to swine and sheep hearts, the right ventricle has greater trabeculation though the left has similar trabeculation compared to these other animals. Ovine: Trabeculae carneae are noticeably fewer and coarser compared to those in human hearts. Swine: Trabeculae carneae are noticeably fewer and coarser compared to humans. Source: www.vhlab.umn.edu/atlas, Comparative Anatomy Tutorial

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Fig. 6.10 Drawing of an opened right ventricular cavity in dog (A), pig and sheep (B), and human (C) hearts. The structure of the moderator band differs greatly between these hearts. In the dog heart, there is a branching fibrous band that runs from the anterior papillary muscle to the free wall of the right ventricle. In the human heart, the moderator band is typically located near the apex and is thick and muscular. In the pig and sheep hearts, the moderator band originates much higher on the interventricular septum and travels to the anterior papillary muscle. It is not as thick as in the human heart but is still muscular in nature. Also, note that the anterior papillary muscle in the dog heart originates on the septal wall, as opposed to originating on the free wall of the human, pig, and sheep hearts. APM anterior papillary muscle, IVS interventricular septum, MB moderator band, PV pulmonary valve

absent in sheep [29]. There are also differences in the fibrous ring supporting the mitral valve and in the composition of the leaflets of the mitral valve between species. For instance, according to Walmsley, a segment of the ring at the base of the mural cusp is always present in the human heart, but is difficult to distinguish in certain breeds of dogs and is inconspicuous in the sheep heart [29]. Differences in aortic valve anatomy have also been reported in the literature. For example, Sands et al. compared aortic valves of human, pig, calf, and sheep hearts [30], and they reported that interspecies differences in leaflet shape exist, but that all species examined had fairly evenly spaced commissures. Additionally, they found that variations in leaflet thickness existed; in particular, sheep aortic valves were described as especially thin and fragile. They also noted that there was a substantially greater amount of myocardial tissue supporting the right and left coronary leaflet bases in the animal hearts relative to humans [30].

6.3.4

The Coronary System

Mammalian hearts have an intrinsic circulatory system that originates with two main coronary arteries [11] whose ostia are located directly behind the aortic valve cusps. Deoxygenated coronary blood flow returns to the right atrium via the coronary sinus (into which the coronary veins drain) and also to the right atrium, the right and left ventricles [24, 31], and the left atrium [32, 33] by Thebesian veins. According to Michaëlsson and Ho [11], differences in perfusion areas exist between large mammalian species as well as within species (e.g., between breeds); these differences have also been described in humans. Dogs and sheep typically have a left coronary type of supply, such that the majority of the myocardium is supplied via branches arising from the left coronary artery. In contrast, pigs typically have a balanced supply where the myocardium is supplied equally from both right and left coronary arteries [11]. Yet, Crick et al. [13] reported that most of the pig hearts they examined

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Fig. 6.12 Fibrous continuity between the mitral valve and aortic valve in a human heart. Source: www.vhlab.umn.edu/atlas, Left ventricle/ Aortic valve/Visible Heart (functional)/Heart0284-2

Fig. 6.11 Images showing the moderator band in the right ventricle of an ovine heart (A) and canine heart (B). The moderator band in the sheep is muscular, originating on the septal wall and running to the anterior papillary muscle. In contrast, the moderator band in the canine heart appears fibrous. It originates on the septal wall, runs to the anterior papillary muscle, and continues to the free wall of the right ventricle. APM anterior papillary muscle, MB moderator band, SW septal wall

(80 %) possessed right coronary dominance. Additionally, Weaver et al. [34] found that the right coronary artery was dominant in 78 % of the pigs they studied. Most human hearts (approximately 90 %) also display right coronary arterial dominance [35]. Another important aspect of the coronary arterial circulation, one that is of great importance in myocardial ischemia research, is the presence or absence of significant collateralization of the coronary circulation. Normal human hearts tend to have sparse coronary collateral development, which is very similar to that seen in normal pig hearts [34]. In contrast, it is now widely known that extensive coronary collateral networks can be seen in normal dog hearts [5, 36–39]. Furthermore, Schaper et al. [40] found that the coronary collateral network of dogs was almost exclusively located at the

epicardial surface, while that of pig hearts, when present, was located subendocardially. They were unable to detect a significant collateral network in the hearts of sheep (Fig. 6.1). There are three major venous pathways that drain the heart—the coronary sinus, anterior cardiac veins, and Thebesian veins [33, 41]. Drainage from each of these venous systems is present in human hearts as well as in dog, pig, and sheep hearts [13, 14, 24, 33]. While the overall structure of the coronary venous system is similar across species, interindividual variations are common. Nevertheless, there is one notable difference in the coronary venous system between species that warrants mention, that is, the presence of the left azygos vein draining the left thoracic cavity directly into the coronary sinus; a left azygos vein is typically present in both pig [13] and sheep [11] hearts (Fig. 6.13).

6.3.5

The Lymphatic System

In addition to an intrinsic circulatory system, large mammalian hearts have an inherent and substantial lymphatic system which serves the same general function of the lymphatic system in the rest of the body. More specifically, the mammalian lymphatic system has been described as follows. Hearts have subepicardial lymphatic capillaries that form continuous plexuses covering the whole of each ventricle [42]. Furthermore, the lymphatic channels are divided into five orders, with the first order draining the capillaries and joining to become the second order and so on, until the lymph is drained from the heart via one large collecting duct of the fifth order. In general, it has been described that dogs, pigs, and humans have extensive subepicardial and subendocardial networks with collecting channels directed toward large ducts in the atrioventricular sulcus that are continuous with

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Fig. 6.13 Images showing the left azygos (hemiazygos) vein entering the coronary sinus in the pig (A) and sheep (B) hearts. The left azygos vein drains the thoracic cavity directly into the coronary sinus in these animals, rather than emptying into the superior vena cava via the azygos as seen in dog and human hearts. Notice that it travels between the

left atrial appendage and the pulmonary veins; the oblique vein of Marshall (oblique vein of the left atrium) travels this path in human and dog hearts. CS coronary sinus, LAA left atrial appendage, LAZV left azygos vein, LV left ventricle

the main cardiac lymph duct [43]. Furthermore, it was found that the lymphatic vessels of the normal heart are distributed in the same manner as the coronary arteries and follow them as two main trunks to the base of the heart [44].

The presence of the os cordis has been noted to be present in the sheep heart, but not in dog, pig, or human hearts. Specifically, it is a small, fully formed bone that lies deep in the atrial septum which, in turn, influences the location and course of the bundle of His in sheep hearts. Other known differences in the atrioventricular conduction system between human, pig, dog, and sheep hearts are illustrated in Table 6.1. For more details on the conduction system, see Chap. 13.

6.3.6

The Conduction System

All large mammalian hearts have a very similar conduction system whose main components are the sinoatrial node, atrioventricular node, bundle of His, right and left main bundle branches, and Purkinje fibers. Yet, interspecies variations are well recognized, especially with regard to the finer details of the arrangement of the transitional and compact components of the atrioventricular node [11]. In the mammalian heart, the sinoatrial node is the normal pacemaker [11, 24, 25] and is situated in roughly the same location in all hearts: high on the right atrial wall near the junction of the superior vena cava and the right atrium. Conduction spreads through the atria to the atrioventricular node (which interestingly is unique to both birds and mammals) [25] and then to the bundle of His, which is the normal conducting pathway from the atria to the ventricles, penetrating through the central fibrous body. The right and left main bundle branches emanate from the bundle of His and branch further into the Purkinje fibers which then rapidly spread conduction to the ventricles [11]. The atrioventricular node and bundle of His are typically located subendocardially in the right atrium within a region known as the triangle of Koch, which is delineated by the coronary sinus ostium, the membranous septum, and the septal/posterior commissure of the tricuspid valve (Fig. 6.14).

6.4

Qualitative and Quantitative Comparisons of Cardiac Anatomy in Commonly Used Large Mammalian Cardiovascular Research Models

The following section describes original research conducted at the University of Minnesota by the authors of this chapter.

6.4.1

Importance for Comparing the Anatomy of Various Animal Models

Selection of the proper experimental model for use in cardiovascular research depends on many factors including: (1) cost, (2) quality and quantity of data, (3) familiarity with the model, and/or (4) relevance to the human condition [49]. Typically, a balance as to the relative importance of these factors is determined when optimizing any experimental protocol. Yet, one important parameter that is often overlooked in such a design is the comparative cardiac anatomy of the model in question relative to that of humans.

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Fig. 6.14 The triangle of Koch in human, dog, sheep, and pig hearts

Even today, there is often considerable debate over which cardiovascular research model most closely resembles the human heart anatomically. Surprisingly, in spite of this debate, the comparative cardiac anatomy of such models as a specific topic is largely unexplored. Nevertheless, this question is especially important for biomedical device design and testing in which the goal is to test a product that directly interacts with specific anatomical structures. Furthermore, such comparisons often become even more complicated due to: (1) the relative orientation and/or position of each species’ heart and (2) the various terminologies used to describe heart anatomy and position (attitudinally correct anatomy) which can vary between various animal models and in comparison to humans. In addition, one hopes to match the cardiac dimensions across species, but this can be further complicated by both gender and age. For example, a 6–7-month-old Yorkshire swine has a typical cardiac mass between 300 and 400 g, which is similar to that of the healthy adult human. Finally, genetic heritage influences expressed cardiac anatomy, and specific descriptors are often missing in previous reports (i.e., specific breeds of animals studied). Thus, the following studies were designed to elucidate the major similarities and differences between the hearts of several major large mammalian cardiovascular research models and then relate these findings to humans. Specifically, qualitative

and quantitative techniques were employed on post-mortem, formalin-fixed porcine, ovine, canine, and human hearts.

6.4.2

Methods and Materials

For this study, we obtained fresh hearts of humans (Homo sapiens; man), pigs (Sus domestica; swine, porcine), dogs (Canis lupus familiaris; canine), and sheep (Ovis aries; ovine). Human hearts (n = 8) were obtained from the Anatomy Bequest Program at the University of Minnesota. All human hearts were previously unfixed and devoid of clinically diagnosed heart disease or defect. Swine (Yorkshire cross), canine (hound cross), and ovine (Polypay cross) (n = 10 each) hearts were obtained from either Research Animal Resources at the University of Minnesota or the Physiological Research Laboratories at Medtronic, Inc. These animals were used for prior research studies that did not alter their anatomy. In other words, in all cases, care was taken to insure that hearts were only obtained from individuals and animals in which cardiac anatomy was not considered to be altered by disease processes or any prior experimental protocols.

6.4.2.1 Heart Preservation To preserve the hearts and prepare them for comparative anatomical study, specimens were all similarly pressure

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Table 6.1 Similarities and differences in the atrioventricular conduction systems of dog, pig, sheep, and human hearts [45–48]

Human

Location of AV node Located at the base of the atrial septum, anterior to the coronary sinus, and just above the tricuspid valve

AV node and bundle of His junction End of the AV node and the beginning of bundle of His are nearly impossible to distinguish

Length of bundle of His Total length of the unbranched portion is 2–3 mm. Penetrating bundle is 0.25–0.75 mm in length. Bundle bifurcates just after emerging from the central fibrous body Penetrating bundle is very short in comparison to humans

Pig

Lies on the right side of the crest of the ventricular septum and is lower on the septum than in humans

No explicit information found

Dog

Same as in humans

Consists of internodal tracts of myocardial fibers

Penetrating bundle is 1–1.5 mm long, significantly longer than the human penetrating bundle

Sheep

Located at the base of the atrial septum, anterior to the coronary sinus, just above the tricuspid valve, and at the junction of the middle and posterior one-third of the os cordis

Junction is characterized by fingerlike projections, where the two types of tissue overlap; size and staining qualities of the initial Purkinje cells of the bundle of His make it easy to distinguish between the end of the AV node and the beginning of the bundle of His

Portion of the bundle passing through the central fibrous body is ~1 mm. Bundle extends 4–6 mm beyond the central fibrous body before it bifurcates

Route of bundle of His Bundle lies just beneath the membranous septum at the crest of the interventricular septum

Climbs to the right side of the summit of the ventricular septum, where it enters the central fibrous body. The bifurcation occurs more proximally than in humans His bundle runs forward and downward through the fibrous base of the heart, just beneath the endocardium. There are at least three discrete bundle of His branches of myocardium that join the atrial end of the AV node via a proximal His bundle branch Unbranched bundle must pass beneath the os cordis to reach the right side of the ventricular septum. The bundle of His then remains relatively deep within the confines of the ventricular myocardium. Branching occurs more anteriorly in sheep than in humans

AV atrioventricular

perfusion fixed. Briefly, this consisted of suspending each heart in a large container of 10 % buffered formalin from cannulae tied into the following major vessels: the superior caval vein, the pulmonary trunk, the aorta, and one pulmonary vein. All remaining vessels were sealed, with the exception of small vents positioned in both the inferior caval vein and in one of the pulmonary veins. Formalin was gravity fed down the cannulae from a reservoir chamber positioned 35–40 cm above the fluid level in the suspension chamber. This system generated a reproducible perfusion pressure between 45 and 50 mmHg. The hearts were allowed to fix under these conditions for a minimum of 24 h in order to allow for adequate penetration of fixative. This method of fixation was quite reproducible to ensure that the hearts maintained a similar anatomical configuration.

6.4.2.2 Qualitative Anatomical Assessment of Perfusion-Fixed Hearts Several observational assessments, similar to those conducted and previously described by Crick et al. [13], were completed on each heart. In addition to these assessments, a

6 mm endoscopic camera (Olympus Optical, Tokyo, Japan) was inserted into each chamber of each heart, with care taken not to distort any structure to be observed. This allowed for direct visualization of the internal chambers of the heart without dissection, hence allowing the anatomical structures to be examined in a more realistic state. Specific anatomical features assessed included: • Overall shape of entire heart (conical, valentine, trapezoidal, elliptical, or rounded with blunt apex; Fig. 6.3) • Overall shape and size of atria and free portions of the appendages (triangular, half-moon, or tubular) • Ventricular formation of the apex (right, left, or both ventricles) • Number of pulmonary veins (best estimates were made as some pulmonary veins were dissected close to the atrium) • Presence or absence of noncardiac coronary sinus tributaries (left azygos vein) • General shape of: – Inferior caval vein ostium – Superior caval vein ostium – Pulmonic valve

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Fig. 6.15 Anterior surface of a fixed sheep heart and end-diastolic volumetric reconstruction of a sheep heart from magnetic resonance images. Note that the apex of the sheep heart is pointed inferiorly and slightly anteriorly. LA left atrium, LV left ventricle, RA right atrium, RV right ventricle

• •

• • •

– Tricuspid valve – Aortic valve – Mitral valve – Coronary sinus ostium Presence or absence of the valve of the coronary sinus ostium (Thebesian valve) Presence or absence of the moderator bands of the right ventricles (if present, the locations of attachment points were noted) Number of papillary muscles found in the right and left ventricles Degree of trabeculation of right and left ventricular endocardium (1–5; 1 = no trabeculations, 5 = highly trabeculated) Presence or absence of any left ventricular bands (i.e., similar structures to the moderator bands of the right ventricle).

6.4.2.3 Quantitative Anatomical Assessments of Perfusion-Fixed Hearts The following quantitative measurements were performed on each heart by employing a novel 3D technique. Briefly, a MicroScribe® 3D digitizing arm (3DX, Immersion Corp., San Jose, CA, USA), consisting of a touch probe with six degrees of freedom, was used to gather the 3D data points. First, each heart was suspended and stabilized within a rectangular metal frame via sutures placed into the aorta, the right and left lateral ventricular walls, and the apex. More specifically, the heart was suspended in the classic valentine heart position, with the apex pointing toward the bottom of the frame and base toward the top, for easy com-

parison between hearts. In all cases, attitudinally correct nomenclature was used to describe structures in a more meaningful manner (Figs. 6.15 and 6.16; see also Chap. 2). To allow for the generation of a consistent coordinate axis system, three small holes for touch probe placement were drilled into a right angle scribe that was affixed to a corner of the support structure. This setup allowed for a consistent reference frame for all subsequent digitizations; each heart was maintained within the same 3D space, allowing for precise measurement between all digitized locations. Furthermore, this overall setup and experimental design allowed for free movement of the 3DX probe as the reference frame could be regenerated following each movement, allowing for complete probe access to all desired aspects of the heart. For probe initialization, the coordinate axes were set up using the acquisition software (Inscribe, Immersion Corp.) on the right angle scribe by digitizing the location of the three holes that were set up as the origin, a point on the x-axis, and a point on the y-axis; the software then automatically generated the z-axis. Prior to dissection, eight external locations were digitized in each heart (Table 6.2) such that comparisons of the major external dimensions could be performed (Table 6.3). Then, small incisions were made in the right and left atrial appendages to allow for internal access in each heart. With the simultaneous use of endoscopic cameras, the touch probe was navigated to specific locations in each heart such that comparisons of valve dimension, ventricular chamber dimension, and those of the coronary sinus ostium could be subsequently calculated (Tables 6.2 and 6.3). It should be noted that all orientational terms are in rela-

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and Bonferroni post analyses; significance was set at α = 0.05. All values are presented as means ± standard deviation.

6.4.3

Results

The average heart weights were 367.3 ± 65.8 g for humans, 274.6 ± 50.4 g for pigs, 258.1 ± 36.2 g for dogs, and 353.1 ± 120.7 g for sheep. Human heart weights were significantly larger than dog heart weights (p < 0.05). The average age of the human donors was 63.8 ± 19.5 years. Although the exact age of the animals was not known, all porcine hearts were from younger rapidly growing animals (1.2 cm2; due to

M.D. Plunkett and J.D. St. Louis

its small size, this pump has more recently been used in children. To date, over 160 implants have been reported worldwide in the pediatric age groups. The Medos HIA VAD (Medos Medizintechnik GmbH, Stolberg, Germany) is similar to the Berlin Heart VAD. It is a pulsatile VAD, pneumatically driven with a pump chamber made of polyurethane that is available in various sizes from 10 to 80 mL so it can be used in pediatric patients as small as 3.0 kg. It can also be used in a right, left, or biventricular configuration. It still has limited availability in the United States and does not have FDA approval at this time. Thoratec Corp. also offers both an intracorporeal (Thoratec® IVAD) and paracorporeal (Thoratec® PVAD) VAD system. They both allow the option of right, left, or biventricular support and are approved for use as a bridge to transplantation and for support in the setting of postcardiotomy shock. They provide pulsatile flow with a 65-mL blood chamber, and unidirectional flow is achieved with tilting disk mechanical valves. The paracorporeal placement of the PVAD allows use in patients with a BSA of 45 years for men; >55 years for women) • Physical inactivity • Family history of early cardiovascular disease or hypertension (men 90 mmHg [8, 9], yet less than half (47 %) of these individuals have their blood pressure controlled. Unfortunately, this not only increases morbidity and mortality but ultimately impacts healthcare consumption and cost.

26.4.1 Goals of Therapy for Hypertension

26.3

Evidence-Based Medicine

In order to describe the drug therapy regimens for the disease states listed above, first there needs to be a brief explanation of how general clinical guidelines are developed and implemented. As such, evidence-based medicine is the process of conscientious, explicit, and judicious use of current best evidence in making decisions about the care of an individual patient [5]. Several expert working groups and agencies have developed systems for grading recommendations and classifying evidence according to the scientific rigor of the study results available. The system used most often in medicine is GRADE, the Grading of Recommendations Assessment, Development, and Evaluation system. For the purposes of this chapter, which focuses on pharmacotherapy for the treatment of cardiac diseases, strength of recommendation and evidence levels developed by the American College of Cardiology Foundation (ACCF)/American Heart Association (AHA) clinical data standards will be utilized for the discussion that follows (Tables 26.2 and 26.3) [6]. Treatment recommendations will focus primarily on those that have a class I or IIa strength of recommendation.

Left untreated, hypertension can lead to target organ disease in the cardiovascular system and also within the cerebrovascular system, peripheral vascular system, kidneys, and/or eyes; it can eventually lead to consequences such as stroke, transient ischemic attacks, peripheral artery disease, chronic kidney disease, and retinopathy. Figure 26.1 illustrates the generally accepted continuum of hypertensive disease and, specifically, its effects on the myocardium. The primary goal of treatment for hypertension is to reduce the blood pressure to a level below that which was used to diagnose the condition; however, these thresholds have been recently debated in the literature. In addition, the role that an individual’s race plays in the development of hypertension is rightfully gaining more research and clinical attention, e.g., African Americans develop hypertension earlier in life and have higher average blood pressures than Caucasians [10]. Recent guidelines account for this difference and contain specific recommendations for black and non-black patients [11]. The highly anticipated and debated Eighth Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC8) outlines nine recommendations for the management of

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Table 26.3 American College of Cardiology Foundation/American Heart Association classification of recommendations Class I Class II

Class III

Conditions for which there is evidence and/or general agreement that a given procedure or treatment is beneficial, useful, and effective Conditions for which there is conflicting evidence and/or a divergence of opinion about the usefulness or effectiveness of a procedure or treatment • Class IIa: Weight of evidence/opinion favor usefulness/efficacy • Class IIb: Usefulness/efficacy is less well established by evidence/opinion Conditions for which there is evidence and/or general agreement that a procedure or treatment is not useful or effective and, in some cases, may be harmful

Fig. 26.1 Continuum of hypertensive disease and its effects on the myocardium

hypertension based on evidence published exclusively from randomized controlled trials [11]. While continuing to endorse a hypertension goal of 3 consecutive beats but less than 30 s. Key markers of VT on an ECG, if present, include ventriculo-atrial dissociation, capture, and fusion beats. The presentation, prognosis, and management of VT largely depend on the underlying cardiovascular state. Antiarrhythmic medical therapy includes amiodarone, sotalol, mexiletine, and sometimes dofetilide. Class I antiarrhythmics can be used in the absence of structural heart disease. Amiodarone is the most commonly used drug for termination of hemodynamically stable and sustained VT. If the VT is hemodynamically unstable, immediate synchronized electrical cardioversion should be performed. Therapy also includes implantable cardiac defibrillators (ICD) for prevention of SCD among patients with underlying structural heart disease and catheter ablation. Ablation can provide a cure for idiopathic VT in an otherwise normal heart. However, in patients with diminished LV function, it is frequently appropriate to place an ICD even after successful ablation. A complete guideline for management of ventricular arrhythmias was recently published in 2006 [8].

28.5.5.2 Ventricular Flutter and Ventricular Fibrillation Electrocardiographically, ventricular flutter (Fig. 28.10b) usually appears as a sine wave with a rate between 150 and 300 bpm. It is essentially impossible to assign a specific morphology for these oscillations. In contrast, ventricular fibrillation (Fig. 28.10c) is recognized by grossly irregular

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28 Catheter Ablation

undulations of varying amplitudes, contours, and rates. The spontaneous conversion of ventricular fibrillation to sinus rhythm is rare, and thus prompt electrical defibrillation is essential. Longer-term prevention of SCD in these patients predominately depends on ICDs.

include atropine, isoproterenol, or temporary pacing. When the underlying cause is reversible, such as in the case of drug toxicity (e.g., excess digitalis or beta-blocker), temporary pacing and elimination of the offending agent is usually a sufficient therapy. However, if the cause is irreversible, the implantation of a permanent pacemaker is usually warranted.

28.5.5.3 Accelerated Idioventricular Rhythm Accelerated idioventricular rhythm can be regarded as a type of slow VT with a rate between 60 and 110 bpm. This rhythm usually occurs in patients with acute myocardial infarction, particularly during reperfusion. Since the rhythm is usually transient without significant hemodynamic compromise, treatment is rarely required.

28.5.5.4 Torsades de Pointes In the presence of prolonged QT intervals (congenital or acquired), a unique form of polymorphic VT, termed Torsades de Pointes (TdP), may occur. A long-short sequence of QRS complexes (e.g., produced by AFib or PVCs) will typically initiate this arrhythmia (Fig. 28.10d). TdP often presents with multiple nonsustained episodes causing recurrent syncope, but it also has a predilection to degenerate into ventricular fibrillation leading to SCD. Identification of TdP has important therapeutic implications because its treatment is different from that of common polymorphic VT. Magnesium, overdrive pacing, and isoproterenol can be used in the acute management of TdP. An ICD is recommended for TdP that does not have a reversible cause. Left cervicothoracic sympathectomy may reduce the incidence of TdP and may be used as adjunctive therapy (after ICD implant) in patients with congenital long QT syndrome. In selected cases, ablation of the PVCs preceding the onset of TdP may reduce TdP recurrences (Fig. 28.11).

28.5.5.5 Nonparoxysmal Junctional Tachycardias Nonparoxysmal junctional tachycardia, also called accelerated junctional rhythm, is recognized by a narrow QRS complex without a consistent P-wave preceding each QRS complex, and has a typical rate between 70 and 130 bpm usually associated with a warm-up period at its onset. Nonparoxysmal junctional tachycardia frequently results from conditions that produce enhanced automaticity or triggered activity in the AV junction, such as inferior acute myocardial infarction, digitalis intoxication, and post valve surgery. Treatment should be primarily directed toward the underlying diseases.

28.6

Bradyarrhythmias

As discussed in the introduction, bradycardia may be caused by either an SND, sick sinus syndrome, or an AV conduction block. Acute treatment options for symptomatic bradycardia

28.6.1 Sinus Node Dysfunction Often sinus node performance deteriorates as we age and/or is associated with age-related disease states, thus the clinical syndrome of SND emerges. In such cases, the clinical manifestations may be: (1) excessive sinus bradycardia; (2) alternating periods of bradycardia and atrial tachycardia; and/or (3) AFib. Additionally, the sinus node may simply become less responsive to physical exertion over time, in terms of generating an appropriate heart rate; this is a special form of SND called chronotropic incompetence. Sinus bradycardia is defined as a sinus rate of 3 seconds induced by a 5-second unilateral carotid sinus massage is usually considered clinically significant. Because one’s sinus rate can be slowed by vagal tone, the resultant intrinsic heart rate after complete autonomic blockage is often used to assess the relative integrity of the patient’s

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Fig. 28.11 Torsades de pointes. Successful catheter ablation of premature ventricular ectopics in the anteroseptal wall of the right ventricular outflow tract eliminates frequent episodes of Torsades de pointes (top)

that are refractory to medical management. The bottom shows an activation map using the Ensite NavX system. The red dots indicate the ablation lesions

sinus nodal function. As such, complete autonomic blockade can be achieved after intravenous propranolol (0.2 mg/kg) and atropine (0.04 mg/kg). A patient’s normal intrinsic heart rate can be estimated by the following equation: 118 − (0.57 × age). An intrinsic heart rate 50 ms in AH interval associated with a 10 ms decrease in coupling interval is called a jump, indicating the presence of dual physiology of the atrioventricular node. I surface ECG lead I, II surface ECG lead II, V1 surface ECG lead V1, V5 surface ECG lead V5, CS coronary sinus, d distal, His His bundle, p proximal, RVa right ventricular apex, stim stimulation

H. Roukoz et al.

Ablations of AVNRT The abnormal conduction circuits of most AVNRTs proceed antegrade through the slow pathways and then retrogradely through the fast pathways (these are typical AVNRTs). In a small number of patients (4 %), the tachycardia circuits may run in the opposite direction (atypical AVNRT). The common characteristic of most AVNRTs is dual pathways or dual physiology, which is demonstrated as sudden increases of at least 50 ms in AH intervals, with 10 ms decreases in coupling intervals from an atrial stimulus (Fig. 28.16). Dual pathway conduction can be detected in the majority (85 %)

28 Catheter Ablation

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Fig. 28.17 The slow pathway (posterior) and fast pathway (anterior) ablation sites for atrioventricular nodal reentry tachycardia. Reproduced from reference [24] with permission. See text for discussion. The New England Journal of Medicine by Massachusetts Medical Society. Reproduced with permission of Massachusetts Medical Society, in the format reuse in a standard/ custom book (basic rights) via Copyright Clearance Center

of patients with an AVNRT, whereas dual physiology exists in 25 % of patients without SVTs. Ablation of AVNRT is commonly aimed at ablating first the slow pathways in the posteroinferior areas of the Koch’s triangle, those between the coronary sinus ostium and the tricuspid annulus (posterior approach; Fig. 28.17). The A/V ratios for slow pathway ablations from the distal electrode pairs in sinus rhythm should be less or equal to 1:3. Ablations of the fast pathways in the anterosuperior areas of the Koch’s triangle are rarely attempted due to the increased risk of damaging normal AV conduction (anterior approach). For example, the reported risk of AV block is 1.0 % with the posterior approach and 5.1 % with the anterior approach. Nevertheless, in experienced clinical hands, the success rate of these procedures is almost 100 %, with recurrence rates of > > Risk. Procedure/treatment should be performed/administered. Conditions for which there is conflicting evidence and/ or a divergence of opinion about the usefulness/ efficacy of a procedure or treatment. Benefit > > Risk. Additional studies with focused objectives needed. It is reasonable to perform procedure/administer treatment. Benefit > Risk. Additional studies with broad objectives needed; additional registry data would be helpful. Procedure/treatment may be considered. Classified as “No benefit” (Procedure/test is not helpful with no proven treatment benefit) or “Harm” (Procedure/test is associated with excessive cost without benefit or is harmful and the treatment is harmful to the patient).

For each classification listed above, a Level of Evidence is also referenced: Level A—multiple populations evaluated with data derived from multiple randomized clinical trials or metaanalyses; Level B—limited populations evaluated with data derived from a single randomized trial or nonrandomized studies; and Level C—very limited populations evaluated and only consensus opinions of experts, case studies, or standards of care. Cardiac pacing can be used for both temporary and permanent management of heart rhythm and function. Although the permanent pacing systems are the most well known, there are numerous indications for temporary pacing. The most common

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551

Table 30.4 Recommendations for permanent pacing in sinus node dysfunction Class I

Permanent pacemaker implantation is indicated for: 1. SND with documented symptomatic bradycardia, including frequent sinus pauses that produce symptoms (Level of Evidence: C) 2. symptomatic chronotropic incompetence (Level of Evidence: C) 3. symptomatic sinus bradycardia that results from required drug therapy for medical conditions (Level of Evidence: C) Class IIa Permanent pacemaker implantation is reasonable for: 1. SND with heart rate less than 40 bpm when a clear association between significant symptoms consistent with bradycardia and the actual presence of bradycardia has not been documented (Level of Evidence: C) 2. syncope of unexplained origin when clinically significant abnormalities of sinus node function are discovered or provoked in electrophysiological studies (Level of Evidence: C) Class IIb Permanent pacemaker implantation may be considered in minimally symptomatic patients with chronic heart rate less than 40 bpm while awake (Level of Evidence: C) Class III Permanent pacemaker implantation is not indicated for: 1. SND in asymptomatic patients (Level of Evidence: C) 2. SND in patients for whom the symptoms suggestive of bradycardia have been clearly documented to occur in the absence of bradycardia (Level of Evidence: C) 3. SND with symptomatic bradycardia due to nonessential drug therapy (Level of Evidence: C) SND sinus node dysfunction Adapted from ACCF/AHA/HRS Guidelines [2]

temporary pacing systems utilize transcutaneous wires that are stitched directly into the myocardium and connected to an external stimulator. The stimulator is usually a small portable unit, but it can be a console. Common indications for temporary pacing include: postsurgical heart block, heart block following an acute myocardial infarction, pacing for post- or intra-operative cardiac support, pacing prior to implantation of a permanent pacemaker, and/or pacing during a pulse generator exchange. The primary indication for the implantation of a permanent pacing system (pacemaker and leads) is to chronically eliminate the symptoms associated with the inadequate cardiac output due to bradyarrhythmias. Typical causes of these bradyarrhythmia are: (1) sinus node dysfunction; (2) acquired permanent or temporary atrioventricular block; (3) chronic bifascicular or trifascicular block; (4) hypersensitive carotid sinus syndrome; (5) neurocardiogenic in origin; and/or (6) a side effect due to a drug therapy. The type of pacing system to be employed is dependent on the nature and location of the arrhythmia, the patient’s age, previous medical/surgical history, as well as additional medical conditions. For conditions related to dysfunction of the sinoatrial node, an IPG with atrial features is commonly used in combination with a lead placed in (or on) the atrium. When management of the ventricular rate is required, a device with ventricular functionality and a ventricular lead are used. When management of the rhythms of both the upper and lower chambers of the heart is required, a dual-chamber system is implanted. Two clinical situations are outlined below to illustrate common indications for pacing, as well as the decision tree

that is often used to determine the type of pacing system for the particular indication. The indications for pacing in a patient with sinus node dysfunction are found in Table 30.4 [2] and the decision tree in Fig. 30.7 [12]. The indications for pacing in an adult with acquired atrioventricular block are found in Table 30.1 and the decision tree in Fig. 30.8 [2]. As an example, a patient with symptomatic chronotropic incompetence would have a Class I indication for pacing (Table 30.4). Since this is related to dysfunction of the sinus node, Fig. 30.7 would then be used to determine the type of pacing system required. In this situation, a rate response system (a pacing system that responds to patient activity/ exercise) would clearly be desired. If atrioventricular synchrony were also required, a rate-responsive ventricular pacemaker would be implanted (mostly commonly a DDDR system; see the next section on the standard coding system and Table 30.2).

30.4.4 NASPE/BPEG Codes In order to describe the function of a pacing system in a standardized manner, the North American Society of Pacing and Electrophysiology (NASPE) and British Pacing and Electrophysiology Group (BPEG) had developed a standard coding system [3]. This code describes the pacing system’s functionality using a multi-letter designation. The first four letters are typically used, although this practice is evolving as new pacing features and indications are being developed. In the four letter code system, the first letter indicates the pacing activity (A = atrial pacing, V = ventricular pacing, D = dual-chamber pacing, O = no pacing), the second letter

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Fig. 30.7 A typical decision tree employed for determining proper therapy when the implantation of a pacemaker for sinus node dysfunction is being considered. AV atrioventricular. Adapted from ACC/AHA/HRS Guidelines [12]

Fig. 30.8 A typical decision tree employed for determining proper therapy when the implantation of a pacemaker for atrioventricular (AV) block is being considered. Adapted from ACC/AHA/HRS Guidelines [12]

indicates sensing (A = atrial sensing, V = ventricular sensing, D = dual-chamber sensing, O = no sensing), the third letter indicates the reaction to a sensed event (I = inhibit pacing, T = trigger pacing, D = inhibit and trigger, O = no reaction to sensing), and the fourth letter is used to describe unique device functionality (R = rate responsive, for example).

Thus, a VVIR system would pace the ventricles (V---), sense ventricular activity (-V--), inhibit or withhold pacing upon detection of a sensed event in the ventricle (--I-), and provide rate response to manage chronotropic incompetence (---R). See Table 30.2 for a more complete explanation of the coding system.

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Pacing and Defibrillation

30.4.5 Implantable Pulse Generators The IPG is an implantable computer with an integral pulse generator and battery. The componentry is typically encased within a hermetically sealed stamped titanium housing with the battery taking up approximately half of the device volume. The most common battery chemistry used in modern pacemakers is lithium iodide. Device longevity is typically 8–10 years, but may vary significantly depending on system utilization (Fig. 30.9). Electrically insulated feedthroughs connect the internal circuitry to an external connector block, which acts as the interface between the internal circuitry of the IPG and the leads. Typically today, the connector block consists of a molded polyurethane superstructure which houses metallic contacts. The contacts may be simple machined blocks or “spring-type” metallic beams. Most connector blocks employ set screws to ensure permanent retention of the leads and these may also enhance electrical contact. A cutaway view of an IPG can be found in Fig. 30.10, and the scheme for connection between the IPG and the leads is shown in Fig. 30.11 and online Video 30.13. In addition to the standard IS-1 and DF-1 connectors shown in Fig. 30.11, a new standard connection scheme is now available. Fig. 30.10 Cutaway view of an implantable pulse generator (IPG or “pacemaker”)

553

The so-called DF-4 connector is an in-line quadripolar connector that includes electrical connections for both the pacing and defibrillation electrode circuits. The new connector is documented in ISO 30186:2010 (Active implantable medical devices—Four-pole connector system for implantable cardiac rhythm management devices—Dimensional and test requirements).

Fig. 30.9 Schematic of a lithium iodide battery. This is the most common chemistry used in modern pacemakers

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Fig. 30.11 Schematic of the implantable pulse generatorto-lead interface. The IS-1 connector is the standard configuration for pacing. The DF-1 connector is the standard configuration for high-voltage defibrillation (see Video 30.13)

Fig. 30.12 The electrogram amplification and rectification scheme that is used in most modern implantable pacing and defibrillation systems. EGM electrogram

Bandpass Filter

35

(center frequency is 30 -40 Hz) 30

25

Amplitude in Millivolts

Fig. 30.13 Plot of electrical signals (amplitude and frequency) frequently encountered by pacing and defibrillation sensing algorithms. A bandpass filter for preferential detection of P-waves and R-waves is shown (parabolic line). This filter is designed to “reject” myopotentials and T-waves

PVC ’s

20 R -waves

15

10

5 P -waves

T -waves

Myopotentials 0

1

10

100

1000

Frequency in Hertz

30.4.6 Sensing Algorithms In order to assess the need for therapeutic intervention, the pacing system must be able to accurately detect and interpret the various electrical activities of the heart. The instantaneous electrical activity of the heart, or electrogram (EGM), is recorded as a differential voltage measured between the bipolar electrode pair on the lead (bipolar lead) or between

the cathode on the lead and the housing of the IPG (unipolar lead). This signal is then processed within the IPG and analyzed by the sensing algorithms. Typically, such signals are amplified, filtered, and rectified prior to undergoing analyses by the device (Figs. 30.12 and 30.13). The resulting signals are then passed through a level detector to determine if they exceed the minimum threshold for detection that was preprogrammed into the device by the clinician. The sensitivity

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Fig. 30.14 A typical dual-chamber timing diagram, including subdiagrams for the atrial and ventricular channels. The sequence of events begins with a paced atrial beat (P). This paced beat occurs when the maximum allowable interval between sensed atrial events is exceeded. For example, if the minimum rate is programmed to 60 beats per minute, an atrial pace will occur when a 1000 ms interval between sensed events is exceeded. Immediately following this pacing pulse, both the atrial and ventricular sensing algorithms are blanked. This means that the threshold detector ignores all sensed activity. The system is blanked to avoid sensing the resultant atrial depolarization on the atrial channel, and the atrial pacing spike and the atrial depolarization on the ventricular channel. Concurrently in the atrium, a sensed atrioventricular (SAV) interval occurs. This is the longest interval that will be allowed by the device without a paced ventricular beat. The SAV is commonly programmed to 150 ms, and is set to optimize filling of the ventricle due to the atrial

contraction. During a cardiac cycle, if the SAV value is reached (meaning an intrinsic ventricular beat does not occur within the programmed interval following the intrinsic or paced atrial beat), a ventricular pacing pulse is then delivered. This pacing pulse is again accompanied by blanking in both channels to avoid oversensing of the pacing pulse and the resultant ventricular depolarization. This interval is referred to as the postventricular atrial blanking (PVAB) period on the atrial channel. Concurrently, the postventricular atrial refractory period (PVARP) occurs on the atrial channel in which the device attempts to avoid sensing of retrograde P-waves (i.e., atrial contractions conducted through the atrioventricular node in a retrograde manner) and the ventricular refractory period (VRP) occurs on the ventricular channel to avoid oversensing of T-waves. Following these intervals, the timing is repeated. If the atrial rate stays above the minimum programmed rate (the lower rate) and the SAV is never reached, the device will never pace unless inappropriate sensing occurs

setting (in mV) determines what is discarded as noise by the algorithm and which signals will be detected. An ideal sensitivity setting is one that will reliably detect the depolarization spike of the chamber (P-wave in the atrium; R-wave in the ventricle) while ignoring repolarization and other physiologic and nonphysiologic signals. Most rhythm management decisions are based on the heart rate detected. The modern IPG continuously measures the time from one sensed event to the next, and compares the interval to the rates and intervals programmed by the clinician. For example, if two atrial events occur with a separation of 1500 ms (1.5 s), the heart rate is 40 beats per minute (HR = 60/measured beat-to-beat interval; 60/1.5 = 40 beats per minute). In order to understand the logic behind sensing algorithms and pacing timing diagrams, the terminology needs to be introduced. Table 30.3 includes the most commonly used terms and abbreviations. These terms will be freely used in further discussions of the logic behind pacing and defibrillation sensing and therapies without further explanation.

This table will also provide the reader with the vocabulary required for interpreting and understanding current literature and publications on the topic. The decision processes and behaviors of the typical pacing algorithm are usually described using a timing diagram (Fig. 30.14). An understanding of this diagram will provide the basis for analysis of the behavior of pacing systems and will communicate the various parameters that the clinician and device manufacturer must be concerned with. The concepts associated with pacemaker timing are shown in Fig. 30.14; the information is presented in an alternate form in Fig. 30.15. The actual behaviors of pacing systems can deviate from the ideal for a number of reasons. For example, the pacing pulse can be of an inadequate energy to pace the chamber, losing capture on one or more beats (Fig. 30.16). Another undesired situation that commonly arises is oversensing. In this case, the device inappropriately identifies electrical activities as an atrial or ventricular event (Fig. 30.17). Clinically, oversensing is resolved by reprogramming the

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Fig. 30.15 Blanking and refractory periods. The top trace represents the electrocardiogram. The portion of the diagram on the left is a situation in which both the atrial and ventricular leads are pacing. The portion on the right is a situation where the system is sensing intrinsic atrial and ventricular activity (i.e., no pacing is occurring). AP atrial pace, AS atrial sense, AV atrioventricular, PVAB postventricular atrial blanking period, PVARP postventricular atrial refractory period, VP ventricular pace, VS ventricular sense

Fig. 30.16 An electrocardiogram (above) and pacemaker marker channel (below) printed from a programmer. Note the loss of capture on the atrial channel (indicated by the arrow); notice that no P-wave follows the pacing pulse

device to a lower sensitivity. Conversely, if a system is undersensing, the sensitivity is increased. Assessment of the behavior of the pacing system is vastly simplified through the use of marker channels. These are shown below the electrograms in both Figs. 30.16 and 30.17. The marker channel is used to report the overall behavior of the pacing system (i.e., documenting how the pacing system interprets the signals transmitted by the device and/or is sensed), allowing a quick assessment of the performance of the algorithms and device output levels.

30.4.7 Drug Interactions with Pacing Systems It is important to note that certain drug therapies have been reported to impact pacing system performance. Although it is rare for antiarrhythmic drugs to significantly affect pacing

thresholds, they have been found to alter stimulation thresholds by inducing changes in the lead-myocardial interfacial conductivity and excitability. Additionally, they can slow the intrinsic sinus rate or atrioventricular rate, which then necessitates pacing of the resultant bradycardia or heart block, respectively. In general, Class Ia antiarrhythmic drugs can increase pacing thresholds at toxic dosages and sotalol and amiodarone, Class III antiarrhythmic drugs can increase pacing thresholds while at therapeutic levels; however, due to the advent of steroid-coated leads and efficient pacing systems, these potential interactions are rarely clinically significant [13, 14]. Rate controlling agents such as betablockers, calcium channel blockers, and digoxin decrease the sinoatrial node and atrioventricular rates thereby decreasing heart rate and increasing the PR interval, respectively, which may increase the need for pacing. A summary of the more commonly administered drugs and their impact on

30

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Fig. 30.17 An electrocardiogram (above) and pacemaker marker channel (below) printed from a programmer. Note the ventricular oversensing (indicated by the arrow); notice that no QRS complex is associated with the detected event

Table 30.5 Effect of antiarrhythmic drugs on pacing thresholds Increase at normal drug levels Flecainide Propafenone Amiodarone Sotalol

Increase at toxic drug levels Quinidine Procainamidea Disopyramide

No increase Lidocaine

a Procainamide, a Class Ia antiarrhythmic drug, is metabolized to N-aceylprocainamide (NAPA) which has Class III activity

pacing thresholds, action potentials, and the physiologic consequences of their action is found in Tables 30.5 and 30.6.

30.4.8 New Indications/Recent Clinical Trials Today, single- and dual-chamber pacing systems have become the standard method of treating many bradyarrhythmias. Recent clinical evidence has raised interest in the selection of the frequency at which patients are paced and the optimal site of stimulation [15]. It has long been known that pacing produces a nonphysiologic contraction pattern, but recent research has also indicated that potentially detrimental effects may result from long-term pacing [16–19]. Currently, alternate choices in ventricular stimulation sites are of particular interest due to the presumed physiologic and hemodynamic benefits. For example, pacing of the bundle of His is thought to produce a more physiologic contraction pattern, while additional evidence exists that there may also be hemodynamic benefits associated with right ventricular septal and outflow tract pacing [16, 20–25]. In patients with heart failure and associated wide QRS complexes, biventricular pacing has been adopted [26, 27] (see online Video 30.14). Finally, research in atrial pacing has focused on reducing atrial fibrillation, improving methods of pace terminating atrial tachycardias, and/or improving ventricular

filling and atrial hemodynamics [28–30]. Recent research is even investigating the possibility of genetically engineering a biologic pacemaker [31].

30.5

Cardiac Defibrillation

Today, sudden cardiac arrest is one of the most common causes of death in developed countries. During 2013, the incidence of in-hospital and out-of-hospital cardiac arrest in the USA was 209,000 and 359,400, respectively. Sudden cardiac arrest claims more lives in the USA each year than the combination of deaths from Alzheimer’s disease, assault with firearms, breast cancer, cervical cancer, colorectal cancer, diabetes, HIV, house fires, motor vehicle accidents, prostate cancer, and suicides [32]. Several studies have identified multiple risk factors for sudden cardiac arrest, which include: (1) coronary artery disease; (2) heart failure and/or decreased left ventricular ejection fraction; (3) previous events of sudden cardiac arrest; (4) prior episodes of ventricular tachycardia; (5) hypertrophic cardiomyopathies; and/or (6) long QT syndrome [33]. The combination of any three of these factors significantly increases the risk for sudden cardiac arrest. Ninety percent of sudden deaths occur in patients with two or more occlusions in their major coronary arteries [34].

30.5.1 History The first documentation of ventricular fibrillation was noted in 1850 [35]. A little over a century later, in 1962, the first direct current defibrillator was developed. Ventricular fibrillation began to be recognized as a possible cause of sudden death in the 1970s and the first transvenous ICD was implanted in the 1990s. Since then, the medical device industry has provided dramatic reductions in ICD size, while

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558 Table 30.6 Antiarrhythmic drugs, action potential phases, and physiologic consequences Class Ia

Ib

Ic

II

III

IV

Drug Quinidine Procainamide Disopyramide Lidocaine Mexiletine Tocainide Phenytoin Flecainide Propafenone Encainide Moricizine Propranolol Atenolol Metoprolol Bretylium Sotalol Amiodarone Ibutilide Dofetilide Dronedarone Verapamil Diltiazem

Action potential phase 0

0

Physiologic consequence Decreases automaticity of the sodium channel Slows conduction velocity Prolongs refractory period Decreases automaticity of the sodium channel May or may not slow conduction velocity Decreases refractory period

0

Decreases automaticity of the sodium channel Slows conduction velocity No effect on refractory period

SA node

Decreases automaticity of nodal tissue Decreases conduction velocity Increases refractory period Increases refractory period No effect on conduction velocity No effect on automaticity

3

SA node

Decreases automaticity of nodal tissue Decreases conduction velocity Increases refractory period

SA sinoatrial

simultaneously increasing safety, efficacy, battery longevity, diagnostics, and memory capability. Figure 30.18 shows the evolution in the size of one manufacturer’s ICD model.

30.5.2 Tachyarrhythmias The commonly recognized mechanisms that lead to tachyarrhythmias (tachycardias and fibrillation) include reentry circuits, triggered activities, and automaticity. Reentry is considered as the most common tachyarrhythmia mechanism. It can be described as an electrical loop within the myocardium that has a circular, continuous series of depolarizations and repolarizations (Fig. 30.19). In general, there are three requirements for reentry to occur: (1) the presence of a substrate, for example, an area of ischemia or scar tissue; (2) two parallel pathways which encircle the substrate; and (3) one pathway that conducts slowly and one that exhibits unidirectional block. An impulse reaching the substrate is slowed by the unidirectional block and is allowed to slowly conduct down the slow pathway. As the impulse continues to move around the substrate, it conducts in a retrograde manner up the fast pathway and the impulse continues to conduct in a circular fashion. Inappropriate atrial or ventricular tachycardias can be further classified as either hemodynamically stable or unstable. The level of hemodynamic compromise that occurs is typically considered to depend on both the rate and the pathway

of the arrhythmia. In general, atrial tachycardias usually result in higher ventricular rates due to conduction through the atrioventricular node. As atrial rates increase, the rate conducted to the ventricles may or may not be 1:1, since the atrioventricular node has inherent limitations in its ability to conduct depolarizations. If, however, an abnormal pathway exists from the atria to the ventricles, then 1:1 conduction may be possible even at very high rates. Nevertheless, a patient’s clinical risks are related to the level of hemodynamic compromise, with the most extreme case being ventricular fibrillation which, if not immediately reversed, most often results in death. Triggered activity, or hyperautomaticity, is typically not consistently spontaneous and is a less common mechanism. Early and delayed after depolarizations seen in phase 3 and 4 of the action potential are associated with triggered activity. Automaticity is defined as the ability of the cell to depolarize spontaneously at regular intervals. However, in a diseased heart, often cells will exhibit abnormal automaticity that causes them to depolarize at rates faster than the intrinsic nodal rates. Common symptoms observed in patients with tachyarrhythmias may include syncopal episodes, palpitations, fatigue, and/or dyspnea. Both invasive and noninvasive diagnostic tools are available for diagnosing tachyarrhythmias. The typical noninvasive procedures include: (1) a thorough patient interview; (2) blood work; (3) a 12-lead ECG; (4) tilt table testing; (5) holter monitoring; (6) exercise stress

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Fig. 30.18 The evolution of the implantable cardioverter defibrillator (ICD). Dramatic reductions in size have occurred, with simultaneous improvements in longevity, diagnostics, functionality, and memory

Fig. 30.19 Reentrant circuits. Panel A = unidirectional block, Panel B = slow conduction, Panel C = reentry circuit

test; (7) echocardiography; (8) signal average ECG; and/ or (9) SPECT/MuGA. Currently, an electrophysiological study using cardiac catheterization and/or insertable cardiac monitors is the most commonly used invasive diagnostic procedure. Therapeutic interventions to manage tachyarrhythmias have a common objective of affecting the behavior of myocardial cells or the conduction of the electrical impulse in the diseased tissue. They include attempts to correct the underlying complication such as coronary reperfusion in the presence of a myocardial infarction, restoration and maintenance of normal sinus rhythm with antiarrhythmic drugs, use of

electrical therapies such as antitachycardia pacing, cardioversion, defibrillation, and lastly, ablation performed surgically or with the assistance of a catheter. The role of medical devices in the management of these arrhythmias will become clear as device function is described in subsequent text.

30.5.3 ICD Indications As was the case for the pacing indications previously discussed, the indications for an ICD are also complex. The indications by class are shown in Table 30.7 [2].

ICD therapy is indicated in: 1. patients who are survivors of cardiac arrest due to VF or hemodynamically unstable sustained VT after evaluation to define the cause of the event and to exclude any completely reversible causes (Level of Evidence: A) 2. patients with structural heart disease and spontaneous sustained VT, whether hemodynamically stable or unstable (Level of Evidence: B) 3. patients with syncope of undetermined origin with clinically relevant, hemodynamically significant sustained VT or VF induced at electrophysiological study (Level of Evidence: B) 4. patients with LVEF less than 35 % due to prior MI who are at least 40 days post-MI and are in NYHA functional Class II or III (Level of Evidence: A) 5. patients with nonischemic DCM who have an LVEF less than or equal to 35 % and who are in NYHA functional Class II or III (Level of Evidence: B) 6. patients with LV dysfunction due to prior MI who are at least 40 days post-MI, have an LVEF less than 30 %, and are in NYHA functional Class I (Level of Evidence: A) 7. patients with nonsustained VT due to prior MI, LVEF less than 40 %, and inducible VF or sustained VT at electrophysiological study (Level of Evidence: B) ICD implantation is reasonable for: 1. patients with unexplained syncope, significant LV dysfunction, and nonischemic DCM (Level of Evidence: C) 2. patients with sustained VT and normal or near-normal ventricular function (Level of Evidence: C) 3. patients with HCM who have one or more major risk factors for SCD (Level of Evidence: C) 4. the prevention of SCD in patients with ARVD/C who have one or more risk factors for SCD (Level of Evidence: C) 5. reducing SCD in patients with long-QT syndrome who are experiencing syncope and/or VT while receiving beta-blockers (Level of Evidence: B) 6. nonhospitalized patients awaiting transplantation (Level of Evidence: C) 7. patients with Brugada syndrome who have had syncope (Level of Evidence: C) 8. patients with Brugada syndrome who have documented VT that has not resulted in cardiac arrest (Level of Evidence: C) 9. patients with catecholaminergic polymorphic VT who have syncope and/or documented sustained VT while receiving beta-blockers (Level of Evidence: C) 10. patients with cardiac sarcoidosis, giant cell myocarditis, or Chagas disease (Level of Evidence: C) ICD therapy may be considered in patients with: 1. nonischemic heart disease who have an LVEF of less than or equal to 35 % and who are in NYHA functional Class I (Level of Evidence: C) 2. long-QT syndrome and risk factors for SCD (Level of Evidence: B) 3. syncope and advanced structural heart disease in whom thorough invasive and noninvasive investigations have failed to define a cause (Level of Evidence: C) 4. a familial cardiomyopathy associated with sudden death (Level of Evidence: C) 5. LV noncompaction (Level of Evidence: C) ICD therapy is not indicated: 1. for patients who do not have a reasonable expectation of survival with an acceptable functional status for at least 1 year, even if they meet ICD implantation criteria specified in the Class I, IIa, and IIb recommendations above (Level of Evidence: C) 2. for patients with incessant VT or VF (Level of Evidence: C) 3. in patients with significant psychiatric illnesses that may be aggravated by device implantation or that may preclude systematic follow-up (Level of Evidence: C) 4. for NYHA Class IV patients with drug-refractory congestive heart failure who are not candidates for cardiac transplantation or CRT-D (Level of Evidence: C) 5. for syncope of undetermined cause in a patient without inducible ventricular tachyarrhythmias and without structural heart disease (Level of Evidence: C) 6. when VF or VT is amenable to surgical or catheter ablation (e.g., atrial arrhythmias associated with the Wolff-Parkinson-White syndrome, RV or LV outflow tract VT, idiopathic VT, or fascicular VT in the absence of structural heart disease) (Level of Evidence: C) 7. for patients with ventricular tachyarrhythmias due to a completely reversible disorder in the absence of structural heart disease (e.g., electrolyte imbalance, drugs, or trauma) (Level of Evidence: B)

ARVD/C arrhythmogenic right ventricular dysplasia/cardiopathy, CRT-D cardiac resynchronization therapy device and defibrillator, DCM dilated cardiomyopathy, HCM hypertrophic cardiomyopathy, ICD implantable cardioverter defibrillator, LV left ventricle, LVEF left ventricular ejection fraction, MI myocardial infarction, RV right ventricle, SCD sudden cardiac death, VF ventricular fibrillation, VT ventricular tachycardia Adapted from Adapted from ACCF/AHA/HRS Guidelines [2]

Class III

Class IIb

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Table 30.7 Recommendations for implantable cardioverter defibrillators

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30.5.4 External Cardiac Defibrillators External defibrillators have become ubiquitous in most countries worldwide. In addition to traditional use in hospitals and by paramedics, these systems are now commonly found in many schools, public buildings, airplanes, and even in homes. As with ICDs, these systems are used to treat sudden cardiac death. These systems deliver high-voltage shocks (up to 360 joules) directly to the chest of the patient, using either patches or paddles. One electrode is typically placed in the right pectoral region and the second in the left axilla for delivery of this energy (Fig. 30.20).

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face between the internal circuitry of the ICD and the leads. The connector block is commonly fabricated from a molded polyurethane superstructure, which houses metallic contacts for interconnection with the leads. The contacts may be simple machined blocks or “spring-type” metallic beams. Most connector blocks used today have set screws to ensure permanent retention of the leads. A cutaway view of an ICD can be found in Fig. 30.21.

30.5.5 Implantable Cardioverter Defibrillators Similar to a pacemaker, an ICD is a self-contained, implantable computer with an integral pulse generator and battery. In addition to providing pacing therapies for bradyarrhythmia and tachyarrhythmia, ICDs also deliver high-energy discharges. The major components of an ICD include: (1) a battery; (2) electronic circuitry and associated components; (3) highvoltage capacitors; (4) high-voltage transformers; (5) a telemetry antenna; (6) a reed switch triggered upon application of a magnetic field; and (7) a connector block. To date, this componentry is most commonly housed within a hermetically sealed stamped titanium case. Feedthroughs connect the internal circuitry to an external connector block, which acts as the interFig. 30.21 The inner workings of a modern implantable cardioverter defibrillator (ICD). A portion of the titanium housing has been removed to expose the typical internal components

Fig. 30.20 An external cardiac defibrillator (LIFEPAK® 1000, Medtronic, Inc.)

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30.5.6 Sensing and Detection

Fig. 30.22 A typical example of an implantable cardioverter defibrillator (ICD) depletion curve for a silver vanadium oxide battery. Lithium iodide and mercury zinc batteries included for comparative purposes

Today, most ICDs will use one or two batteries with silver lithium vanadium oxide chemistry. A typical full charge of this type of battery is 3.2 V. As the ICD battery energy starts to deplete, the voltage will follow the path shown in Fig. 30.22, where there are two characteristic plateaus. The voltage is provided to the clinician upon device interrogation to determine if the battery is at the beginning of life, middle of life, elective replacement indicator, or end of life [36]. Each manufacturer and each device will have its own elective replacement indicator voltage. This value is representative of the voltage and current drain from the circuitry, and is also related to the characteristics of the capacitor used. All devices should be replaced before end of life is reached. The longevity of such devices depends on the number of therapies delivered, but is typically between 6 and 8 years. The primary function of the ICD’s capacitor is the accumulation and storage of an adequate amount of energy to shock-terminate a fibrillating heart. As previously mentioned, a typical voltage of an ICD battery is 3.2 V, whereas the capacitor can store up to 800 V (delivering energy of 30–35 joules). Periodic conditioning of each capacitor is required to maintain charge efficiency and therefore guarantee short charge times to allow rapid conversion of the arrhythmia [37]. The materials currently used in the capacitors slowly lose efficiency, especially when they are not used for a period of time due to a chemical decay process. This process (termed deformation) is mitigated by conditioning the capacitors (termed reformation). Reforming of the capacitor should be performed regularly by charging the capacitor to its maximum capacity and leaving the charge on it until it gradually discharges the energy. Fortunately, reformation can be easily programmed at regular intervals in most modern devices (e.g., every 6 months) without affecting the patient.

It is desirable for an ICD to be able to accurately sense ventricular rhythms that vary in amplitude, rate, and/or regularity, in order to distinguish between normal sinus rhythm, ventricular tachycardia, ventricular flutter, ventricular fibrillation, and/or supraventricular (atrial) arrhythmias (see examples in Fig. 30.23). Current devices adjust their sensitivity on a beat-to-beat basis in order to sense fine waves of ventricular fibrillation and to avoid oversensing of intrinsic T-waves. If an ICD undersenses (misses cardiac activity that it was intended to detect), the device may fail to treat a ventricular tachycardia, which subsequently may accelerate into ventricular fibrillation. If an ICD oversenses, overestimating the cardiac rate, it may deliver inappropriate therapy which will lead to patient discomfort or, more seriously, it may even induce a tachyarrhythmia. The steps involved in sensing and detection are similar to those discussed previously for the pacemakers. In fact, almost all ICDs on the market today include the pacing algorithms described previously, with additional functionality/ logic for detection and management of tachyarrhythmias. Arrhythmia detection typically occurs via the following steps: (1) sense the R-wave or P-waves; (2) measure the interval or cycle length between consecutive beats; and (3) compare the cycle length to prescribed detection zone intervals to classify the arrhythmia (Fig. 30.24). For the sake of simplicity, this chapter will focus on only two detection zones—the ventricular fibrillation and ventricular tachycardia zones. A fibrillation zone is commonly programmed to detect any interval faster than the interval prescribed by the clinician (e.g., 320 ms = 187.5 beats per minute). If a minimum number/percentage of beats is sensed within this interval, the rhythm will be detected as ventricular fibrillation and the device will treat the rhythm using the high-energy shock amplitudes preprogrammed by the clinician. During the process of arrhythmia detection, the device counts the number of events in each of the detection zones and compares them to prescribed rules in order to classify the arrhythmia. Most ICD designs employ two different counters when classifying whether an arrhythmia is ventricular fibrillation or a ventricular tachycardia. The ventricular fibrillation counter uses a probabilistic approach. Since ventricular fibrillation waves are chaotic and vary in amplitude and cycle length, the device will look for a programmed percentage of cycle lengths to fall within the fibrillation detection zone (e.g., 75 %, Fig. 30.25); if that criterion is met, the device will detect a ventricular fibrillation and deliver the appropriate therapy. Ventricular tachycardias, on the other hand, usually have regular cycle lengths. A consecutive event counter is used which states that a programmed number of

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Fig. 30.23 Examples of recorded tachyarrhythmias and the associated device response (refer to the marker channel). Panel A = sinus rhythm; Panel B = spontaneous ventricular tachycardia; Panel C = atrial fibrilla-

tion resulting in ventricular fibrillation. ECG electrocardiogram, EGM electrogram

cycle lengths (e.g., 18 out of 18) needs to be within the tachycardia detection zone in order to classify the rhythm as a ventricular tachycardia. If one cycle length falls out of the tachycardia detection zone, the consecutive counter is reset to zero and the count begins again. Each ICD has the capability to redetect the same arrhythmia if the initial therapy was not successful. Redetection criteria will often be more aggressive (fewer number of beats sampled) than the initial detection criteria to ensure that subsequent therapies can be delivered quickly. An example of when the redetection criteria may not be as aggressive is in cases where the patient has a long QT interval and is prone to developing Torsades de Points which may spontaneously terminate. Typical devices available today have the option of programming an additional detection zone, which is referred to as a fast ventricular tachycardia zone. This is a zone that can be programmed for those patients with a fast ventricular tachycardia who may benefit from antitachycardia pacing. Treating a fast ventricular tachycardia with antitachycardia pacing may decrease the number of high-voltage shocks

delivered, increase the patient’s quality of life, and prolong device longevity [38]. Evidence of the benefit of this therapeutic approach was seen in the PainFREE Rx trial which concluded that fast ventricular tachycardias with ventricular cycle length less than 320 ms could be terminated by antitachycardia pacing 3 out of 4 times with a low incidence of acceleration into ventricular fibrillation and syncopal episodes [38]. If a fast ventricular tachycardia zone is programmed, the device will always ensure that the most aggressive therapy is being delivered. For example, if a fast ventricular tachycardia is detected, the device will verify that no ventricular fibrillation intervals falls within that fast ventricular tachycardia zone before delivering antitachycardia pacing. When targeting treatment of ventricular arrhythmias, it is important to verify that the arrhythmia is of a ventricular origin. Therefore, it is common that each manufacturer will have a unique algorithm for distinguishing a supraventricular tachycardia from a ventricular tachycardia. This is very important in order to avoid inappropriate shocking of a

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Fig. 30.24 Tachyarrhythmia detection intervals. The top three traces represent typical electrocardiograms that might be encountered by the device. The detection zones for ventricular fibrillation, ventricular tachycardia, and sinus rhythm are shown at the bottom. Note that an event with a cycle length of 700 ms is categorized as sinus rhythm, 350 ms as a ventricular tachycardia, and 280 ms as ventricular fibrillation. VF ventricular fibrillation, VT ventricular tachycardia

Fig. 30.25 An example of an implantable cardioverter defibrillator (ICD) device record including 16 consecutive beats and their classification. Since 12 of 16 events (75 %) were within the ventricular fibrillation detection zone, the arrhythmia would be classified as ventricular fibrillation and high-voltage shocks would be delivered. ECG electrocardiogram, VF ventricular fibrillation, VT ventricular tachycardia

Surface ECG

Previous 16 Sensed Intervals

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Fig. 30.26 Antitachycardia pacing therapy. A pacing stimulus is applied to entrain an excitable gap in the reentrant circuit. This disrupts the reentrant circuit and terminates the tachycardia. ATP antitachycardia pacing

patient with sinus tachycardia due to exercise or an atrial arrhythmia (atrial fibrillation or atrial flutter).

30.5.7 ICD Therapies ICD therapies are programmed to ensure maximum patient safety, while attempting to deliver the lowest energy therapies (least painful and least impact on device longevity) that will terminate the arrhythmia. ICD therapies can be tiered, such that the device initially delivers low energy which is subsequently increased until the desired treatment is obtained. A typical delivery order is as follows: antitachycardia pacing (delivering the least amount of energy), followed by cardioversion, and finally defibrillation. Nevertheless, each of these therapies can be programmed to the physician’s preference. Antitachycardia pacing is typically used in a clinical situation where one reentrant circuit is repeatedly activating the ventricles and causing a rapid, but regular, ventricular tachycardia. The goal of the antitachycardia pacing therapy is to deliver, via a pacing stimulus, a depolarization wave into the area of the excitable gap (an area of repolarized tissue) of the reentry circuit. Recall that a reentrant circuit causes the majority of tachyarrhythmias. Thus, if a pacing pulse reaches the excitable gap before a new wavefront of the reentrant circuit, the reentrant activity is terminated (Fig. 30.26). Cardioversion and defibrillation shocks are high-energy shocks that are delivered between two or three high-voltage electrodes, one of which is typically the ICD itself (i.e., the titanium housing acts as an electrode). The goal of these shocks is to defibrillate a critical mass of the myocardial cells

Fig. 30.27 Electric field between high-voltage electrodes during a shock; note that the implantable cardioverter defibrillator (ICD) is functioning as one of the electrodes

that are depolarizing at a rapid and irregular rate (Figs. 30.27 and 30.28), thus returning the heart to a normal rhythm. Cardioversion can be described as a synchronized highvoltage shock because the shock needs to be synchronized to an R-wave or the shock will not be delivered. Cardioversion shocks are used to treat ventricular tachycardias or regular fast ventricular tachycardias. Therefore, the shock is delivered on an R-wave that has been detected in the tachycardia detection zone. If the shock would happen to be delivered on a T-wave, the underlying arrhythmia could be dangerously accelerated into ventricular fibrillation, which is why a cardioversion shock will be aborted if it is not synchronized

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Fig. 30.28 Examples of successful defibrillation (top electrogram) and cardioversion (lower electrogram) therapies. VF ventricular fibrillation, VT ventricular tachycardia

Fig. 30.29 Monophasic and biphasic shock waveforms

to an R-wave. The chaotic nature of ventricular fibrillation is treated by delivering an asynchronous shock. Both cardioversion and defibrillation gain their energy from the discharge of the ICD’s high-voltage capacitor. Depending on the manufacturer, each device will offer a number of programmable therapies per detection zone, again all of which can be programmed to physician preferences. Yet, the programming of the defibrillation therapy is typically based on a specific patient’s defibrillation threshold. This threshold is defined as the minimum amount of energy needed to rescue the heart from the fibrillating state (various algorithms exist for determining this energy). The physician commonly will set the first defibrillation therapy at an energy output that is greater than the defibrillation threshold, to provide a margin of safety for the patient. A safety margin of at least 10 joules greater than the defibrillation threshold is common. For example, if a patient’s defibrillation threshold has been determined to be 15 joules, the device will be programmed to deliver its first therapy at 25 joules. Therefore, the maximum output of the device needs to be considered when assessing an appropriate safety margin. If a device has a maximum output of 35 joules and the patient’s defibrillation threshold is 30 joules, there would only be an 5-joule safety margin.

The relative shape of shock waveforms delivered by the ICD has evolved over time. Early systems used a monophasic waveform delivered between a dedicated set of electrodes (i.e., delivered with a constant direction of current flow or polarity). Later, sequential monophasic shocks between selected pairs of electrodes were employed, since they were found to produce lower defibrillation thresholds in certain patients. Modern devices typically use a biphasic shock that reverses polarity during the discharge of the capacitors (Fig. 30.29). The development of biphasic waveforms was considered as a significant improvement in ICD technology, and they have been almost exclusively used since the mid-1980s [39]. The percentage of the drop in voltage, prior to termination of the waveform, is the current polarity, also known as tilt. Tilt is measured from the instant the current starts to flow in one direction (leading edge) to the time that it ends its flow in that same direction (trailing edge). A tilt value can be measured for each direction that the current is flowing; typical tilts are between 50 and 65 % (Fig. 30.30). As mentioned previously, most modern ICDs also include pacemaker functionality. As a final summary of the similarities and differences between IPGs and ICDs, Table 30.8 is provided.

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Fig. 30.30 Determination of the percent tilt of a defibrillation waveform. LE leading edge, TE trailing edge

Table 30.8 Comparison of the principal differences between implantable pulse generator (IPG) and implantable cardioverter defibrillator (ICD) ICD Senses intrinsic rhythms, ventricular tachycardia/ ventricular fibrillation, and prefers to oversense Paces and shocks when appropriate Saves episode data Battery requires high current capability for shocking

30.5.8 Pharmacologic Considerations in the Management of Tachyarrhythmias In contrast to the relatively small effect that antiarrhythmic drugs typically have on pacing thresholds, the defibrillator threshold of an ICD may be significantly altered when used in conjunction with antiarrhythmic drug therapies. Nevertheless, there are several positive benefits that have been considered useful in the concomitant use of ICDs and antiarrhythmic drugs. For example, antiarrhythmic drugs may act to decrease the frequency and duration of sustained and nonsustained ventricular tachycardia events that would otherwise require a shock from an ICD. In addition, they may also slow the rate of the ventricular tachycardia to increase the efficacy of antitachycardia pacing, decreasing the need for shock therapy. Lastly and importantly, antiarrhythmic agents may lower defibrillation thresholds. Therefore, the use of antiarrhythmic drugs with ICDs can decrease the frequency and/or amplitude of therapeutic shocks, thereby improving patient comfort and prolonging battery longevity [40]. As opposed to the benefits explained earlier, there are also potentially undesired consequences associated with the concurrent use of ICDs and antiarrhythmic drugs [13]. Specifically, antiarrhythmic drugs may: (1) alter the detection of the arrhythmia leading to an increase in the duration of a tachyarrhythmia; (2) increase defibrillation thresholds, making it more difficult to successfully defibrillate the heart; (3) slow the rate of the tachyarrhythmia so much that it no longer falls within the detection zone for both antitachycardia pacing and shock; and/or (4) increase the width of the QRS complex on the EKG, thus causing double counting

IPG Senses intrinsic rhythms, and prefers to undersense

Paces when appropriate Rejects signals that occur at high rates Battery optimized for long-term, low current use

Table 30.9 Impact of select antiarrhythmic drugs on defibrillation thresholds Increase Flecainide Propafenone Lidocaine

Mixed effect Quinidine Procainamidea Amiodaroneb

Decrease Sotalol Bretylium Dofetilide

a Procainamide, a Class Ia antiarrhythmic drug, is metabolized to N-aceylprocainamide (NAPA) which has Class III activity b Amiodarone decreases defibrillation thresholds initially but increases defibrillation thresholds with chronic utilization

and inappropriate shocks. The typical antiarrhythmic drugs that may affect defibrillation thresholds are: (1) Type I agents, those with sodium channel blocking activities and the membrane stabilization effects; (2) beta-blockers and calcium channel antagonists due to their effect on the nodal tissues; and (3) Type III agents which may either increase or decrease defibrillation thresholds after long-term therapy (Table 30.9) [14]. Studies have also revealed that the use of illicit drugs, such as cocaine, may increase defibrillation thresholds. Antiarrhythmic agents can also be proarrhythmic, which may even lead to an increased requirement for ICD therapies. Predisposing factors to proarrhythmias are: (1) prolonged ventricular repolarization (i.e., prolonged QT wave); (2) electrolyte imbalances such as hypomagnesemia or hypokalemia; (3) underlying ventricular arrhythmias; (4) ischemic heart disease; and/or (5) poor left ventricular function. One of the most dangerous forms of proarrhythmia is considered to be Torsades de Pointes or “twisting of the points.” Specifically, Torsades is a rapid form of polymorphic ventricular tachycardia that is associated with delayed ventricular repolarization. It should be noted that both inherited conditions such as long QT syndrome and exposure to Type Ia or Type III

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of an ICD in such patients resulted in improved survival and decreased mortality by 28 % after 3 years. Importantly, the noted benefits of this study have changed practice in that physicians now routinely implant an ICD in postmyocardial infarction patients with left ventricular dysfunction [42].

30.5.9 New Indications/Recent Clinical Trials This section will focus on some of the recent clinic trials assessing the value of ICD therapy. Clinical trials serve the important role of assessing therapeutic safety and efficacy for: (1) determining the validity of current clinical indications; (2) discovering new indications for use; and/or (3) driving reimbursement through identification of clinical value. Properly run clinical studies continue to play an important role in continuous improvement of patient outcomes. Yet, an important distinction to make here is that there are major differences between primary and secondary studies. Specifically, primary studies seek to find morbidity and mortality benefit in those patients who have not experienced an event. These studies identify a patient population that is considered “at risk” and attempt to determine means to treat such patients before they experience an event such as myocardial infarction or sudden cardiac arrest. In contrast, secondary studies evaluate post-treatment morbidity and mortality benefits to patient populations that have already suffered from an event (e.g., postmyocardial infarction patients or patients who have survived sudden cardiac arrest). An example of an important clinical trial associated with the identification of the indications for ICD therapy is the Multicenter Automatic Defibrillator Implantation Trial (MADIT). This trial was instrumental in providing clinical evidence for identifying patients who would benefit from an ICD therapy. The clinical hypothesis stated “in patients with previous myocardial infarction and left ventricular dysfunction, prophylactic therapy with an ICD improves survival versus treatment with conventional medical therapy” [41]. The primary end point of the study was a reduction in total patient mortality, and the secondary end points evaluated mortalityassociated with arrhythmias as well as cost-effectiveness. Of 196 patients included in the study, there were 39 deaths in the conventional therapy arm and 15 deaths in the ICD group. The stated conclusions were that, in postmyocardial infarction patients at a high risk for ventricular tachycardia, prophylactic therapy with an ICD reduced overall mortality by 54 % and arrhythmic mortality by 75 % when compared with conventional therapy. A follow-up to MADIT was the Multicenter Automatic Defibrillator Implantation Trial-II (MADIT-II). The purpose of this study was to investigate the effects of prophylactic implantation of an ICD on the survival of patients postinfarction who presented with significant left ventricular dysfunction (left ventricular ejection fraction ≤30 %). The primary conclusion of this study was that prophylactic implantation

30.5.10 Pacing and Defibrillation Leads Cardiac pacing and defibrillation leads are the electrical conduit between the IPG or ICD and the heart. Specifically, they transmit therapeutic energy to the cardiac tissue and return sensed information to the IPG or ICD for diagnostic and monitoring purposes. It is noteworthy that such leads must: (1) withstand the extremely harsh environment of the internal human body and its intense foreign body responses; (2) permanently span multiple anatomic and physiologic features, e.g., the moving body and heart (Fig. 30.31); and (3) undergo approximately 400 million heartbeat-induced deformations over each 10-year period within the heart (see online Video 30.15). Leads can be placed either endocardially or epicardially, depending on the patient’s indication, physician preference, and/or anatomic considerations. In the case of the endocardial pacing systems (those implanted through the venous system to the endocardial surface of the cardiac chambers), the lead travels from subcutaneous tissue including muscle and fat into the blood stream. These leads then pass through the upper vasculature and finally are permanently placed within the beating heart. Today, the vast majority of pacing and defibrillation systems utilize endocardial leads (this lead placement technique can be viewed in online Video 30.6). In contrast, epicardial leads are attached directly to the surface of the heart and are routed through the subcutaneous tissue to the ICD or IPG. Epicardial leads are most commonly used in pediatric patients and in adults with compromised venous accesses to their hearts. Typical implanted configurations for endocardial single- and dual-chamber pacing systems are shown in Fig. 30.32, endocardial defibrillation systems in Fig. 30.33 and online Video 30.16, and an epicardial defibrillation system with epicardial pacing leads in Fig. 30.34. Modern leads are generally constructed of highly biostable and biocompatible polymers and metals. Configurations for the body of the leads (i.e., the portion traveling from the IPG or ICD to the distal electrodes) are chosen based on the number of circuits required, as well as considerations relating to size, handling, and manufacturer preferences (Fig. 30.35). The electrodes for stimulation and sensing are designed to provide stable electrical performance acutely and chronically. In order to provide stability at the cardiac–tissue interface, leads often use a mechanism for fixation to cardiac tissue and structures. Passive mechanisms for fixation include

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Fig. 30.31 The anatomic regions commonly spanned by transvenous endocardial pacing leads

Fig. 30.32 Examples of single- and dual-chamber endocardial lead configurations

Fig. 30.33 Implanted configurations for two endocardial defibrillation systems with pectoral ICD placements. The single coil system (left) delivers the shock energy from the right ventricular coil to the ICD. The dual coil system (right) can deliver the energy from right ventricular coil to the ICD, or from the right ventricular coil to a superior vena cava coil and/or the ICD (see Video 30.16). RV right ventricle, SVC superior vena cava

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Fig. 30.34 Implanted configuration of an epicardial defibrillation system with an abdominal ICD placement. The system shown includes two unipolar epicardial pacing leads for stimulation and sensing as well as a pair of epicardial defibrillation patches

Fig. 30.35 Typical constructions used for cardiac pacing and defibrillation leads: (1) the single lumen design (left) has a central conductor surrounded by a polymeric insulation; (2) the multilumen design (center) uses an extruded polymer to insulate the conductors from one another and from the implanted environment; and (3) the coaxial design

polymeric tines and shaped segments along the length of the lead. They are termed passive because they do not require an active deployment by the clinician. Common active means of fixation include helices, hooks, or barbs. Additionally, some epicardial leads require sutures to maintain a stable position. Finally, some leads have no fixation means whatsoever and count solely on lead stiffness to maintain locational stability (Figs. 30.36, 30.37, 30.38, and 30.39). To view examples of leads placed within the Visible Heart® preparation, see the following online material: Video 30.17, Video 30.18, Video 30.19, Video 30.20, and Video 30.21. Various electrode configurations have been utilized on a variety of commercially available leads. As described previously, unipolar pacing circuits use a lead with a single cathodal electrode, with the IPG serving as the anode. Bipolar pacing systems use electrodes placed distally on the lead as both the cathode and anode. Pacing leads commonly use a cylindrical electrode placed along the lead body (ring electrode) as the anode, while defibrillation leads may use a dedicated ring (the so-called true bipolar leads) or a defibrillation coil as the anode (an integrated bipolar lead). Defibrillation leads utilize electrodes with large surface areas, which allow for the delivery of high-energy shocks within and

has conductors embedded within concentric layers of insulation. Today, the most commonly used insulation materials are silicones and polyurethanes and the conductors are usually coiled or cabled wires. Modern lead body diameters range from approximately 4–10 French (one French = 1/3 of a millimeter)

Fig. 30.36 Endocardial pacing leads: passive fixation leads (tined) are shown on the left and right. An active fixation lead (extendable, retractable helix) is shown in the center

around the heart. Defibrillation leads may be unipolar (defibrillation electrode only) or they may have a combination of defibrillation electrodes and pacing electrodes. The most common defibrillation lead configurations used today

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Fig. 30.37 Epicardial pacing leads: stab-in active fixation lead (top), active fixation lead with helical fixation (middle), and a hemispherical electrode secured by sutures (bottom)

Fig. 30.38 Cardiac defibrillation leads. Clockwise from upper left: a passive fixation endocardial lead (“integrated bipolar”), an active fixation endocardial lead (“true bipolar”), an endocardial lead with no fixation, and an epicardial patch (commonly sewn to the pericardium)

Fig. 30.39 Pacing leads designed for placement in the cardiac veins; they are shaped to enhance stability. The leads shown are primarily used in biventricular pacing systems for the management of heart failure patients with the appropriate clinical indications

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are shown in Figs. 30.38, 30.39, and 30.40. For examples of leads placed within the Visible Heart® preparation, see the following online material: Video 30.22 and Video 30.23. Typically, the portion of the lead that interfaces with the cardiac tissue has been designed to: (1) minimize inflammatory responses; (2) provide low polarizations; (3) provide high capacitances and impedances; and/or (4) act as a fixation mechanism. This distal electrode is most commonly used as the cathode but, in some cases, a similar electrode is used as the anode on a separate unipolar lead. To suppress inflammation, most modern electrodes incorporate a system for the elution of an anti-inflammatory agent (e.g., dexamethasone sodium phosphate); this helps to manage acute changes in the local tissue which will then aid in stabilizing pacing and sensing performance. Coatings are also applied to many pacing electrodes to produce a large surface area that is

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Fig. 30.40 Endocardial defibrillation leads. Various configurations are shown, including leads with active and passive fixation mechanisms, true and integrated bipolar pace/sense circuits, and/or single and dual defibrillation electrodes. The designs shown are typically placed in the right ventricle with the distal defibrillation coil within the right ventricular chamber and the proximal coil located in the superior vena cava

Fig. 30.41 Common electrode coatings for high capacitance and low polarization. The left panel (A) shows a platinized surface at 20,000× and the right panel (B) a titanium nitride (TiN) surface at 20,000×

highly capacitive (i.e., to reduce battery drain), and have a low level of polarization following a pacing pulse (to avoid undersensing; Fig. 30.41). Interestingly, the size of the pacing cathode has decreased over time, as a means to increase the cathode-tissue impedance and increase system efficiency by reducing current drain (Figs. 30.42 and 30.43) [43].

30.5.11 Leadless Pacing Although pacing systems with leads have been utilized since the inception of cardiac pacing, recent advances in miniaturization technology and battery chemistry have made it possible to develop a self-contained pacemaker small enough to be implanted entirely within the heart, i.e., while still aiming to provide similar battery longevity as in conventional pacemakers. In general, leadless pacemakers (or transcatheterdelivered pacemakers) are self-contained devices designed to be implanted within the chambers of the heart directly at

the site of desired pacing. Further, by eliminating the need for a subcutaneous device pocket and insertion of permanent leads within the vasculature, some of the complications associated with traditional pacing systems can be avoided, including pocket infection/erosion/hematoma and lead dislodgement/fracture/infection. To date, leadless pacemakers have been developed for both bradycardia and CRT patients. For example, the Micra™ Transcatheter Pacing System (Medtronic, Inc., Minneapolis, MN, USA; not available for sale, but currently under clinical investigation) is a self-contained, percutaneously delivered transcatheter pacemaker (VVIR) that is designed to be implanted in the right ventricle via femoral vein access [44, 45]. The pacemaker is 0.8 cc, 1.76 g, 25.9 mm long, and 6.7 mm in diameter and contains a 3-axis accelerometer used for rate response pacing (Fig. 30.44). In addition, the fixation mechanism consists of four selfexpanding nitinol tines which are used to anchor the system within the right ventricle and to stabilize the pacing electrode

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573

Fig. 30.42 Evolution of pacing lead impedances and pacing thresholds. Modified from Brabec and Laske [43]

Fig. 30.44 Micra™ Transcatheter Pacing System (Medtronic, Inc., Minneapolis, MN, USA; not available for sale, but currently under clinical investigation) Fig. 30.43 Passive fixation leads with low (top; ~400–600 Ω), medium (middle; ~600–800 Ω), and high (bottom; ~800–1200 Ω) impedance pacing cathodes

against viable myocardium. This system can be seen implanted in an isolated human heart using direct visualization in online Video 30.24, as published in Eggen et al. [44]. In another recent example, a VVIR leadless pacemaker is implanted in the right ventricle and attached to the myocardium

using a helix mechanism (Nanostim, St. Jude Medical, St. Paul, MN, USA); this device has shown promise in the LEADLESS clinical trial [46] and in animal studies [47]. These leadless pacemakers are currently restricted to clinical investigation in the USA. Lastly, a leadless ultrasoundbased endocardial left ventricular resynchronization system (WiCSw-LV system, EBR Systems Inc., Sunnyvale, CA, USA) has been developed for heart failure patients [48].

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The WiCSw-LV system is a hybrid system which consists of a traditional lead system that stimulates the right atrial and right ventricular chambers, and a transmitter/receiver combination that stimulates the left ventricular endocardium. As such, after activation of the right ventricle by the traditional system, an ultrasound wave is emitted by a subcutaneous transmitter, and the ultrasound energy is converted into pacing energy by a receiver (containing a pacing electrode) implanted in the left ventricle which results in left ventricular stimulation. With these recent developments in pacemaker technology, we can expect the leadless pacemaker to partially eclipse the use of the traditional pacing systems in the near future.

30.6

Summary

This chapter has reviewed the basic methodologies and devices employed to provide pacing and/or defibrillation therapy to the patient with specific needs. A brief history was provided on the use of external electricity to deliver lifesaving therapy to the heart. Although significant progress has been made, future developments in materials, electronics, and communication systems (e.g., wireless) will allow everincreasing utility and patient value. Acknowledgements We would like to thank Mike Leners for the development of procedural animations, Medtronic Training and Education for the use of various graphics, the Visible Heart® team for support in capturing the intracardiac footage, Monica Mahre for editorial support, LifeSource, and Drs. Anne Fournier and Suzanne Vobecky of Sainte-Justine Hospital, Montreal, Quebec, Canada for the radiographic images.

References 1. Maisel WH, Sweeney MO, Stevenson WG, Ellison KE, Epstein LM (2001) Recalls and safety alerts involving pacemakers and implantable cardioverter-defibrillator generators. JAMA 286:793–799 2. Epstein AE, Darbar D, DiMarco JP et al (2012) ACCF/AHA/HRS focused update incorporated into the ACCF/AHA/HRS 2008 guidelines for device-based therapy of cardiac rhythm abnormalities: a report of the American College of Cardiology Foundation/ American Heart Association Task Force on Practice Guide. Circulation 127:e283–e352 3. Bernstein AD, Daubert JC, Fletcher RD et al (2002) The revised NAPSE/BPEG generic code for antibradycardia, adaptive-rate, and multisite pacing. Pacing Clin Electrophysiol 25:260–264 4. Furman S (1995) A brief history of cardiac stimulation and electrophysiology—the past fifty years and the next century. NASPE Keynote Address 5. His W Jr (1893) Die Tatigkeit des embryonalen Herzens und deren Bedcutung fur die Lehre von der Herzbewegung beim Erwachsenen. Artbeiten aus der Medizinischen Klinik zu Leipzig 1:14–49 6. Tawara S (1906) Das reizleitungssystem des saugetierherzens, Eine anatomisch-histologische studie uber das atrioventrikularbundel und die purkinjeschen faden, Jean, Germany: Gustav Fischer 9–70, 114–156

7. Lillehei CW, Gott VL, Hodges PC, Long DM, Bakken EE (1960) Transistor pacemaker for treatment of complete atrioventricular dissociation. JAMA 172:2006–2010 8. Furman SC. Walton Lillehei http://www.naspe.org/ep-history/ notable_figures/walton_lillehei. Accessed 25 Nov 2003 9. Winters SL, Packer DL, Marchlinski FE et al (2001) Consensus statement on indications, guidelines for use, and recommendations for follow-up of implantable cardioverter defibrillators. Pacing Clin Electrophysiol 24:262–269 10. Parsonnet V (1984) Indications for dual-chamber pacing. NASPE Position Statement, June 1, 1984 11. Stokes KB, Kay GN (1995) Artificial electrical stimulation. In: Ellenbogen KA, Kay GN, Wilkoff BL (eds) Clinical cardiac pacing. W.B. Saunders, Philadelphia 12. Epstein AE, DiMarcok JP, Ellenbogen KA et al (2008) ACC/AHA/ HRS 2008 Guidelines for device-based therapy of cardiac rhythm abnormalities. Circulation 117:e350–e408 13. Fogoros RN (1997) Antiarrhythmic drugs: a practical guide. Blackwell Science, Boston, p 112 14. Legreid Dopp A, Miller JM, Tisdale JE (2008) Effect of drugs on defibrillation capacity. Drugs 68:607–630 15. Wilkoff BL, Cook JR, Epstein AE et al (2002) Dual-chamber pacing or ventricular backup pacing in patients with an implantable defibrillator: the Dual-chamber and VVI Implantable Defibrillator (DAVID) Trial. JAMA 288:3115–3123 16. Karpawich PP, Rabah R, Haas JE (1999) Altered cardiac histology following apical right ventricular pacing in patients with congenital atrioventricular block. Pacing Clin Electrophysiol 22:1372–1377 17. Andersen HR, Nielsen JC, Thomsen PE et al (1997) Long-term follow-up of patients from a randomised trial of atrial versus ventricular pacing for sick-sinus syndrome. Lancet 350:1210–1216 18. Lamas GA, Orav EJ, Stambler BS et al (1998) Quality of life and clinical outcomes in elderly patients treated with ventricular pacing as compared with dual-chamber pacing. Pacemaker Selection in the Elderly Investigators. N Engl J Med 338:1097–1104 19. Lamas GA, Lee K, Sweeney M et al (2000) The mode selection trial (MOST) in sinus node dysfunction: design, rationale, and baseline characteristics of the first 1000 patients. Am Heart J 140:541–551 20. Deshmukh P, Casavant DA, Romanyshyn M, Anderson K (2000) Permanent direct His bundle pacing: a novel approach to cardiac pacing in patients with normal His-Purkinje activation. Circulation 101:869–877 21. Karpawich P, Gates J, Stokes K (1992) Septal His-Purkinje ventricular pacing in canines: a new endocardial electrode approach. Pacing Clin Electrophysiol 15:2011–2015 22. Karpawich PP, Gillette PC, Lewis RM, Zinner A, McNamera DG (1983) Chronic epicardial His bundle recordings in awake nonsedated dogs: a new method. Am Heart J 105:16–21 23. Scheinman MM, Saxon LA (2000) Long-term His-bundle pacing and cardiac function. Circulation 101:836–837 24. Williams DO, Sherlag BJ, Hope RR, El-Sherif N, Lazzara R, Samet P (1976) Selective versus non-selective His bundle pacing. Cardiovasc Res 10:91–100 25. de Cock CC, Giudici MC, Twisk JW (2003) Comparison of the haemodynamic effects of right ventricular outflow-tract pacing with right ventricular apex pacing: a quantitative review. Europace 5:305–308 26. Cleland JG, Daubert JC, Erdmann E et al (2001) The CARE-HF study (CArdiac REsynchronisation in Heart Failure study): rationale, design and end-points. Eur J Heart Fail 3:481–489 27. Leclercq C, Daubert JC (2003) Cardiac resynchronization therapy is an important advance in the management of congestive heart failure. J Cardiovasc Electrophysiol 14:S30–S39 28. Saksena S (2003) The role of multisite atrial pacing in rhythm control in AF: insights from sub-analyses of the dual-site atrial pacing for prevention of atrial fibrillation study. Pacing Clin Electrophysiol 26:1565

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29. Leclercq JF, De Sisti A, Fiorello P, Halimi F, Manot S, Attuel P (2000) Is dual-site better than single site atrial pacing in the prevention of atrial fibrillation? Pacing Clin Electrophysiol 23:2101–2107 30. Kindermann M, Schwaab B, Berg M, Frohlig G (2000) The influence of right atrial septal pacing on the interatrial contraction sequence. Pacing Clin Electrophysiol 23:1752–1757 31. Miake J, Marban H, Nuss B (2002) Biological pacemaker created by gene transfer. Nature 419:132–133 32. Go AS, Mozaffarian D, Roger VL et al (2014) Heart disease and stroke statistics—2014 update: a report from the American Heart Association. Circulation 129:e28–e292 33. Myerburg RJ (ed) (1997) Heart disease: a textbook of cardiovascular medicine (Chapter 24), 5th edn. W.B. Saunders, Philadelphia 34. Coronary artery disease overview. http://imaginis.com/heart-disease/ cad_ov.asp?mode=1. Accessed 1 Dec 2014 35. Electricity and the heart: a historical perspective. http://www.naspe. org/ep-history/timeline. Accessed 25 Nov 2003 36. Hayes DL, Lloyd MA, Friedman PA (eds) (2000) Cardiac pacing and defibrillation: a clinical approach. Blackwell Publishing, Inc., New York, pp 1–599 37. Cummins RO (1989) From concept to standard-of-care? Review of the clinical experience with automated external defibrillators. Ann Emerg Med 18:1269–1275 38. Wathen MS, Sweeney MO, DeGroot PJ et al (2001) Shock reduction using antitachycardia pacing for spontaneous rapid ventricular tachycardia in patients with coronary artery disease. Circulation 104:796–801 39. Electricity and the heart: a historical perspective. http://www.naspe. org/ep-history/timeline/1980s. Accessed 26 Nov 2003 40. Carnes CA, Mehdirad AA, Nelson SD (1998) Drug and defibrillator interactions. Pharmacotherapy 18:516–525 41. Moss AJ, Hall WJ, Cannom DS et al (1996) Improved survival with an implanted defibrillator in patients with coronary disease at high risk for ventricular arrhythmia. Multicenter Automatic Defibrillator Implantation Trial Investigators. N Engl J Med 335:1933–1940

575 42. Kloner RA, Birnbaum Y (eds) (2002) Cardiovascular trials review, 7th edn. Le Jacq Communications Inc., Shelton, CT, pp 1065–1066 43. Brabec S, Laske TG (2003) The evolution of bradycardia pacing electrodes. XII World Congress on Cardiac Pacing & Electrophysiology (Hong Kong) 44. Eggen MD, Bonner MD, Williams ER, Iaizzo PA (2014) Multimodal imaging of a transcatheter pacemaker implantation within a reanimated human heart. Heart Rhythm 11:2331–2332. 1 0 . 1 0 1 6 / d o i : j.hrthm.2014.03.052 45. Micra Transcatheter Pacing Study [cited 2014 November 13]; Available from: http://clinicaltrials.gov/show/NCT02004873 46. Reddy VY, Knops RE, Sperzel J et al (2014) Permanent leadless cardiac pacing: results of the LEADLESS trial. Circulation 129: 1466–1471 47. Koruth JS, Rippy MK, Khairkhahan A et al (2015) Feasibility and efficacy of percutaneously delivered leadless cardiac pacing in an in vivo ovine model. J Cardiovasc Electrophysiol 26:322–328. doi:10.1111/jce.12579 48. Auricchio A, Delnoy PP, Butter C et al (2014) Feasibility, safety, and short-term outcome of leadless ultrasound-based endocardial left ventricular resynchronization in heart failure patients: results of the Wireless Stimulation Endocardially for CRT (WiSE-CRT) study. Europace 16:681–688

Additional Text Sources Furman S, Hayes DL, Holmes DR (eds) (1993) A practice of cardiac pacing. Futura Publishing Company, Inc., New York, pp 1–753 Ellenbogen KA, Kay GN, Wilkoff BL (eds) (1995) Clinical cardiac pacing. W.B. Saunders, Philadelphia

Cardiac Resynchronization Therapy

31

Nathan A. Grenz and Zhongping Yang

Abstract

Congestive heart failure (CHF) continues to be a major source of morbidity, mortality, and health-care spending in today’s society. In the past 20 years, device-based therapies such as implantable cardioverter defibrillators (ICDs), cardiac resynchronization therapy (CRT), and left ventricular assist devices have been developed and demonstrated to improve outcomes in patients with CHF and systolic dysfunction. These therapies treat two of the major causes of death associated with CHF, namely sudden cardiac death and pump failure. This chapter focuses on the application of CRT for treatment of CHF, with a focus on the therapeutic mechanisms, historical development, evolution of the technologies, implant techniques and patient follow-ups, clinical trials, evolving indications, approaches for optimizing therapies, and future directions. Keywords

Cardiac resynchronization therapy • Physiologic pacing • Cardiac function • Implantable cardioverter defibrillator • Congestive heart failure • Biventricular pacing • Mechanical remodeling

Abbreviations 6MWD AF AV BiV CCS CHF CRT CS EP ESV ICD ICM

6-minute hall walk distance Atrial fibrillation Atrioventricular Biventricular Clinical composite score Congestive heart failure Cardiac resynchronization therapy Coronary sinus Electrophysiology End-systolic volume Implantable cardioverter defibrillator Ischemic cardiomyopathy

N.A. Grenz, BSEE, CCDS, CEPS (*) • Z. Yang, PhD Therapy Delivery Systems Research, Cardiac Rhythm and Heart Failure, Medtronic plc, 8200 Coral Sea St NE, MVN 41, Mounds View, MN 55126, USA e-mail: [email protected]

IPG IVCD LBBB LGE LV LVEF LVLED MRI NCM NICM NYHA PEA PNS QoL RA RBBB RV SPECT TDI

Implantable pulse generator Interventricular conduction delay Left bundle branch block Late gadolinium enhancement Left ventricular Left ventricular ejection fraction Left ventricular lead electrical delay Magnetic resonance imaging Noncontact mapping Nonischemic cardiomyopathy New York Heart Association Peak Endocardial Acceleration Phrenic nerve stimulation Quality of life Right atrial Right bundle branch block Right ventricular Single-photon emission computed tomography Tissue Doppler imaging

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N.A. Grenz and Z. Yang

Introduction

Congestive heart failure (CHF) is a cardiovascular syndrome associated with high morbidity, mortality, and major healthcare expenditures. In general, it can be characterized by pump dysfunction, reduced functional capacity, neurohumoral imbalance, and/or myocardial remodeling [1]. The prevalence of CHF continues to grow, estimated in 2013, at approximately five million people in the USA alone [2]. As the number of patients with CHF grows, expenditures have also continued to climb, with estimated associated costs of $31 billion in the USA in 2012 [2]. Pharmacological treatments with beta-blockers, angiotensin-converting enzyme inhibitors, and/or angiotensin receptor blockers revolutionized therapeutic options in the 1980s and 1990s [3–7]. Also in the 1990s, interest in device-based therapies gained ground and led to the application of implantable cardioverter defibrillators (ICDs) and cardiac resynchronization therapy (CRT), which helped to reduce mortality and morbidity associated with CHF [8–12]. It should be noted that the development of new pacing leads that were able to reliably stimulate the left ventricle and new stimulator technologies enabled multisite pacemakers that could resynchronize the contractions of both ventricles and improve outcomes for CHF patients.

31.2

Development of CRT

By the early 1990s, in the decades preceding the development of CRT, advances in lead and pacing generator technologies led to reliable dual-chamber pacing systems. More specifically, the development of polyurethane leads with smaller and more lubricious lead bodies made it easier to implant two leads for both right atrial (RA) and right ventricular (RV) pacing [13]. Advances in tined lead design reduced the rate of atrial lead dislodgement from 14 % to less than 2 % [14]. Also noteworthy, lead tips with steroid elution reduced the foreign body response at the implant site, reducing chronic thresholds and the incidence of exit block [15]. Similarly, advances in integrated circuit technologies and microprocessor-based pacemakers led to the development of implantable pulse generators (IPG) with more sophisticated algorithms for novel treatments and monitoring, and the development of rate responsive pacemakers improved the quality of life and exercise capacity for patients with chronotropic incompetence [16]. Prior to development of CRT, multisite stimulation in the form of biatrial pacing had been proposed as a therapy to suppress atrial tachyarrhythmias (AT), by pacing the left atrium through the coronary sinus (CS) [17]. The Model 2188 CS lead (Medtronic plc, Minneapolis, MN, USA) was developed specifically for this purpose in collaboration

with French investigators. In 1994, a patient with dilated cardiomyopathy, New York Heart Association (NYHA) class 4, QRS durations >150 ms, and left ventricular ejection fractions (LVEF) or = 90 years of age. Am J Cardiol 74:960–962 36. Smith N, McAnulty JH, Rahimtoola SH (1978) Severe aortic stenosis with impaired left ventricular function and clinical heart failure: results of valve replacement. Circulation 58:255–264 37. Connolly HM, Oh JK, Orszulak TA et al (1997) Aortic valve replacement for aortic stenosis with severe left ventricular dysfunction. Prognostic indicators. Circulation 95:2395–2400 38. Makkar RR, Fontana GP, Jilaihawi H et al (2012) Transcatheter aortic-valve replacement for inoperable severe aortic stenosis. N Engl J Med 366:1696–1704 39. Smith CR, Leon MB, Mack MJ et al (2011) Transcatheter versus surgical aortic-valve replacement in high-risk patients. N Engl J Med 364:2187–2198 40. Monin JL, Monchi M, Gest V, Duval-Moulin AM, Dubois-Rande JL, Gueret P (2001) Aortic stenosis with severe left ventricular dysfunction and low transvalvular pressure gradients: risk stratification by low-dose dobutamine echocardiography. J Am Coll Cardiol 37:2101–2107 41. Grossman W, Jones D, McLaurin LP (1975) Wall stress and patterns of hypertrophy in the human left ventricle. J Clin Invest 56:56–64 42. Nitenberg A, Foult JM, Antony I, Blanchet F, Rahali M (1988) Coronary flow and resistance reserve in patients with chronic aortic regurgitation, angina pectoris and normal coronary arteries. J Am Coll Cardiol 11:478–486 43. Fortuin NJ, Craige E (1972) On the mechanism of the Austin Flint murmur. Circulation 45:558–570 44. Parker E, Craige E, Hood WP Jr (1971) The Austin Flint murmur and the A wave of the apexcardiogram in aortic regurgitation. Circulation 43:349–359 45. Miller RR, Vismara LA, DeMaria AN, Salel AF, Mason DT (1976) Afterload reduction therapy with nitroprusside in severe aortic regurgitation: improved cardiac performance and reduced regurgitant volume. Am J Cardiol 38:564–567

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Heart Valve Disease

46. Smith MD, Cassidy JM, Souther S et al (1995) Transesophageal echocardiography in the diagnosis of traumatic rupture of the aorta. N Engl J Med 332:356–362 47. Cigarroa JE, Isselbacher EM, DeSanctis RW, Eagle KA (1993) Diagnostic imaging in the evaluation of suspected aortic dissection. Old standards and new directions. N Engl J Med 328:35–43 48. Yacoub MH et al (1983) Results of valve sparing operations for aortic regurgitation. Circulation 68:311–321 49. David TE (2001) Aortic valve-sparing operations for aortic root aneurysm. Semin Thorac Cardiovasc Surg 13:291–296 50. Gorlin R, Gorlin S (1951) Hydraulic formula for calculation of the area of stenotic mitral valve, other cardiac values and central circulatory shunts. Am Heart J 41:1–29 51. Rowe JC, Bland EF, Sprague HB, White PD (1960) The course of mitral stenosis without surgery: ten- and twenty-year perspectives. Ann Intern Med 52:741–749 52. Wood P (1954) An appreciation of mitral stenosis. I. Clinical features. Br Med J 4870:1051–1063 53. Edwards JE, Rusted IE, Scheifley CH (1956) Studies of the mitral valve. II. Certain anatomic features of the mitral valve and associated structures in mitral stenosis. Circulation 14:398–406 54. Roberts WC, Perloff JK (1972) Mitral valvular disease. A clinicopathologic survey of the conditions causing the mitral valve to function abnormally. Ann Intern Med 77:939–975 55. Olesen KH (1962) The natural history of 271 patients with mitral stenosis under medical treatment. Br Heart J 24:349–357 56. Carroll JD, Feldman T (1993) Percutaneous mitral balloon valvotomy and the new demographics of mitral stenosis. JAMA 270:1731–1736 57. Selzer A, Cohn KE (1972) Natural history of mitral stenosis: a review. Circulation 45:878–890 58. Hugenholtz PG, Ryan TJ, Stein SW, Abelmann WH (1962) The spectrum of pure mitral stenosis. Hemodynamic studies in relation to clinical disability. Am J Cardiol 10:773–784 59. Braunwald E, Moscovitz HL, Amram SS et al (1955) The hemodynamics of the left side of the heart as studied by simultaneous left atrial, left ventricular, and aortic pressures; particular reference to mitral stenosis. Circulation 12:69–81 60. Holen J, Aaslid R, Landmark K, Simonsen S (1976) Determination of pressure gradient in mitral stenosis with a non-invasive ultrasound Doppler technique. Acta Med Scand 199:455–460 61. Hatle L, Brubakk A, Tromsdal A, Angelsen B (1978) Noninvasive assessment of pressure drop in mitral stenosis by Doppler ultrasound. Br Heart J 40:131–140 62. Currie PJ, Seward JB, Chan KL et al (1985) Continuous wave Doppler determination of right ventricular pressure: a simultaneous Doppler-catheterization study in 127 patients. J Am Coll Cardiol 6:750–756 63. Coulshed N, Epstein EJ, McKendrick CS, Galloway RW, Walker E (1970) Systemic embolism in mitral valve disease. Br Heart J 32:26–34 64. Daley R, Mattingly TW, Holt CL, Bland EF, White PD (1951) Systemic arterial embolism in rheumatic heart disease. Am Heart J 42:566 65. Abernathy WS, Willis PW 3rd (1973) Thromboembolic complications of rheumatic heart disease. Cardiovasc Clin 5:131–175 66. Adams GF, Merrett JD, Hutchinson WM, Pollock AM (1974) Cerebral embolism and mitral stenosis: survival with and without anticoagulants. J Neurol Neurosurg Psychiatry 37:378–383 67. Orrange SE, Kawanishi DT, Lopez BM, Curry SM, Rahimtoola SH (1997) Actuarial outcome after catheter balloon commissurotomy in patients with mitral stenosis. Circulation 95:382–389 68. Higgs LM, Glancy DL, O'Brien KP, Epstein SE, Morrow AG (1970) Mitral restenosis: an uncommon cause of recurrent

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Less Invasive Cardiac Surgery

35

Kenneth K. Liao

Abstract

To date, more and more cardiac surgeons are moving toward smaller incisions and the use of specialized less invasive surgical methodologies. The use of (and advances in) less invasive approaches or minimally invasive cardiac surgery can minimize or eliminate complications that may occur in conventional cardiac surgery. For example, for some surgeons, partial sternotomy and minithoracotomy have supplanted standard sternotomy as their preferred route for aortic valve and mitral surgeries. Keywords

Less invasive cardiac surgery • Cardiac robotic surgery • Minimally invasive cardiac surgery • Incision size • Laparoscopic surgery • Thoracoscope • Minithoracotomy • Partial sternotomy • Partial thoracotomy • Off-pump beating heart coronary artery bypass grafting surgery

35.1

Introduction

The history of cardiac surgery reflects a constant search by cardiac surgeons for safer and less invasive ways to treat their patients. Since Dr. F. John Lewis’ pioneering operation in 1952, followed by Dr. C. Walton Lillehei’s first successful series of intracardiac defect repairs in the mid-1950s, cardiac surgery as a surgical subspecialty has expanded dramatically. Notably, one of the most important technological innovations in cardiac surgery was the development and modification of a cardiopulmonary bypass machine. For years, this machine has been used extensively by cardiac surgeons. Its use has enabled cardiac surgery to become a safe and reproducible daily routine in many hospitals across the world. Nowadays, though most cardiac operations are con-

K.K. Liao, MD (*) Department of Surgery, University of Minnesota, 420 Delaware Street SE, MMC 207, Minneapolis, MN 55455, USA e-mail: [email protected]

sidered somewhat standardized, the continued pursuit of less invasive surgical approaches, as well as recognition of the importance of quick postoperative recovery and quality of life, remains significant for patients and physicians. In recent years, there have been continued efforts to provide and adapt “less invasive cardiac surgery” as standard care. All four of the major steps used in conventional cardiac surgery need to be considered when attempting to develop less invasive modifications: (1) gaining access to the heart through a full sternotomy; (2) supporting the vital organs through a cardiopulmonary bypass machine; (3) arresting the heart by administering cardioplegia; and/or (4) manipulating the ascending aorta during aortic cannulation, during crossclamping and side-clamping, and during proximal anastomosis in coronary artery bypass grafting. Unfortunately, any of these steps can impose significant risks or adverse effects. More specifically, a large incision typically corresponds to greater pain, a more noticeable scar, more complications, and/or a longer recovery time. Similarly, cardiopulmonary bypass has been known to trigger adverse inflammatory reactions and/or subsequently cause multiple organ dysfunction. Finally, manipulating the aorta can lead to strokes

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(e.g., plaque dislodgement) and/or other neurologic deficits. Importantly, less invasive approaches or minimally invasive cardiac surgery can minimize or eliminate complications that may occur relative to each of the four steps commonly used in conventional cardiac surgery. This chapter focuses on less invasive methodologies commonly employed in adult cardiac surgical procedures.

35.2 Impact of Incision Size For years, the physical and emotional impact of a large incision size on the individual patient has been ignored by most cardiac surgeons. Historically, adequate exposure of the target tissue or organ through large skin incisions took priority over concern about incision size; this mind-set remained unchallenged until the early 1990s. Subsequently, with novel specially designed instruments, experience with laparoscopic surgery demonstrated that those surgical procedures traditionally performed through large incisions could actually be accomplished with much smaller incisions. More recently, the patient benefits of small incisions have been clearly shown including less pain, quicker recovery, lower infection rate, shorter hospital stays, and/or better quality of life [1, 2]. In some studies, less immune function disturbance has also been reported [3]. Encouraged by positive results from the laparoscopic surgical community, cardiac surgeons began to modify their approaches to perform less invasive cardiac surgery. Currently, a variety of approaches have been used to replace full sternotomy: (1) thoracoscopy or minithoracotomy and/or (2) partial sternotomy. Nevertheless, cardiopulmonary bypass support, if required, is established through cannulation in the peripheral vessels such as the femoral arteries, femoral veins, and internal jugular veins. Various studies have reported advantages with smaller incisions or sternum-sparing incisions in terms of pain, blood loss, postoperative respiratory function, time to recovery, infection, cosmesis, and survival rate [4–7]. However, one must also consider that smaller incisions have certain drawbacks. In order to have the same access and visualization as with larger incisions, special instruments and specialized surgical skills are required, and only selected patients are eligible. For surgeons, the initial learning curve to be able to perform such procedures clinically can be very steep. Nevertheless, smaller incisions are certainly very appealing to both patients and referring physicians. To date, more and more surgeons are moving toward smaller incisions and the use of these specialized less invasive surgical methodologies. For some surgeons partial sternotomy and minithoracotomy have supplanted standard sternotomy as their preferred route for aortic and mitral valve surgeries.

K.K. Liao

35.3 Side Effects of Cardiopulmonary Bypass Cardiopulmonary bypass procedures have become commonplace in cardiac surgical suites; however, capabilities to perform the same clinical procedure safely without its use would be desirable, for such bypass procedures are not performed without risk. More specifically, cardiopulmonary bypass has been associated with a complex systemic inflammatory reaction in the host patient. The hallmarks of this reaction are typically increased microvascular permeability in multiple organs, resulting in an increase in interstitial fluid and the activation of humoral amplification systems. The complement system, including the kallikrein-bradykinin cascade, the coagulation cascade, the fibrinolytic cascade, and the arachidonic acid cascade, is activated. Inflammatory mediators, such as cytokines and proteolytic enzymes, are released. In most classic cardiac cases where cardiopulmonary bypass is utilized, the heart is stopped to provide for a motionless field. Cardiac arrest is initiated with infusion of cardioplegia to the myocardium. Unfortunately, subsequent reperfusion of the heart can cause ischemic reperfusion injury to the myocardium. Clinical manifestations of this systemic inflammatory reaction and myocardial ischemic reperfusion injury can be subtle but also serious and even lethal in some patients. The incidence of this systemic reaction has been reported in 5–30 % of cardiac surgery patients after cardiopulmonary bypass [8–13]. Importantly, this inflammatory response can affect multiple organs. More specifically, examples of this systemic response can vary: (1) from transient subtle cognitive impairment to a permanent stroke, (2) from coagulopathy requiring transfusion of blood products to disseminated intravascular coagulation, (3) from pulmonary edema to adult respiratory distress syndrome requiring prolonged ventilation support, (4) from low cardiac output to acute heart failure requiring inotropic or mechanical circulatory support, and/or (5) from transient kidney insult with increased creatinine to permanent kidney failure requiring hemodialysis. Any of these, or a combination thereof, commonly result in prolonged intensive care unit stays requiring intense monitoring and often increased patient mortality. Importantly, the severity of these reactions tends to be related to cardiopulmonary bypass time, the patient’s age, and/or comorbidities [11, 12]. To date, coronary artery disease remains as the leading cause of death for individuals living in developed countries. Despite widespread use of drug-eluting stents in treating coronary artery disease and sharply decreased patient volume for coronary artery bypass grafting (CABG) numbers,

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CABG operations still remain the most commonly performed cardiac procedures in the United States. Compared to percutaneous coronary artery interventions such as stenting, CABG has shown advantages of improved patient event-free survival and lower re-intervention rate, especially in patients with multivessel coronary artery disease, diabetes, and decreased left ventricular function. These benefits are attributed mainly to the use of in situ left internal mammary artery bypass to the left anterior descending artery, in which the patency rate remains over 90 % even after 15 years of implantation. Furthermore the use of bilateral internal mammary arteries as bypass conduits has shown to offer a better patient survival rate and less reoperation rate, when compared with the use of only left internal mammary artery as a bypass conduit. In the past 15 years, off-pump beating heart coronary artery bypass grafting surgery (OPCABG, a less invasive surgical approach) has entered the mainstream of clinical cardiac surgical practice, and the number of such procedures has been steady in the United States, making up ~10–20 % of all CABG surgeries performed annually. An increasing number of studies, including prospective randomized studies, have demonstrated that when compared to conventional CABG, OPCABG procedures result in: (1) a lower incidence of postoperative neurologic deficits, (2) fewer blood transfusions, (3) shorter intubation times, (4) less release of cardiac enzyme, (5) less renal insult, (6) shorter ICU stays, (7) less release of cytokines IL 8 and IL 10, and/or (8) lower mortality [13–17]. It should be noted that the difference in these parameters between OPCABG and CABG procedures mostly ranges from 2 to 10 %. In most OPCABG procedures, however, there has been the tendency to bypass fewer vessels; this may result in an incomplete revascularization. Moreover, certain anatomic locations and the nature of target coronary arteries may preclude safe and reliable anastomoses with OPCABG, e.g., arteries located in the posterolateral wall of hypertrophied hearts, intramyocardial arteries, and severely calcified arteries. Furthermore, with today’s available methodologies, OPCABG is more challenging technically for most cardiac surgeons. It should also be noted that emergency conversion of OPCABG to conventional CABG because of hemodynamic instability carries a significantly higher morbidity and mortality rate than conventional CABG (about 6 times higher mortality) [18]; fortunately, the overall conversion is rare, with a rate of only 3.7 %. Though OPCABG surgery took off rapidly in the earlier part of the last decade, the enthusiasm for OPCABG has faded in recent years due to the lack of highly anticipated “drastic” clinical benefits of this procedure over conventional CABG and the additional technical challenges faced by the surgeons. Currently OPCABG comprises 10–20 % of all CABG procedures performed in the United States, which has decreased compared to 10 years ago. Although isolated

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centers perform virtually all CABG procedures off-pump, in many centers, OPCABG is a seldom-used procedure. Such a large discrepancy appears due to the lack of effective education of practicing surgeons and a steep learning curve to master the tricks of performing OPCABG.

35.4 Effects of Manipulating the Aorta Coronary artery disease is often considered as a component of systemic vascular disease. The same risk factors that contribute to coronary artery disease, such as smoking, diabetes, hypertension, and hyperlipidemia, also contribute to carotid artery disease and atherosclerotic changes in the aorta; this is especially true for the ascending aorta. Atheroma in the aorta can present with calcified plaques or with “cheese-like” soft plaques, which can be disrupted (dislodged) during: (1) cannulation of the ascending aorta for cardiopulmonary bypass, (2) cross-clamping in general, and/or (3) side-clamping of ascending aorta for attachment of proximal anastomoses of bypassed grafts. The mobilized plaques can then cause microembolization or macroembolization of brain vessels, resulting in neurologic deficits. Multiple episodes of microembolic events have been documented by transcranial Doppler studies during routine CABG surgery. The number of microembolic signals is reported to be related to the extent that the ascending aorta is manipulated [19]. Nevertheless, calcified areas of the aorta (or porcelain aorta) can be identified by palpation and thus avoided during surgery, whereas soft plaques are typically unnoticed until they are disrupted during surgical manipulation. The incidence of plaque formation in the ascending aorta can be as high as 30 % [20]. Recently, several methodologies have been described to avoid disrupting plaques when working in the region of the ascending aorta. For example, topical ultrasound devices have been used to identify hidden plaques, especially the soft types. In addition, a single aortic cross-clamp technique has been shown to reduce the risk of plaque disruption during conventional CABG surgery [21]. Similarly, aortic crossclamping or side-clamping can be avoided by using proximal anastomotic devices during OPCABG. More recently, totally aortic non-touch techniques have been described that can be applied during OPCABG by using: (1) bilateral in situ internal mammary arteries; (2) sequential grafts; (3) in situ gastroepiploic arteries; (4) radial artery Y or T grafts from internal mammary arteries; (5) radial artery or vein grafts from innominate, subclavian, and axillary arteries; or (6) descending thoracic aorta. Currently, non-touch techniques during OPCABG are gaining popularity, especially in highrisk patients (Fig. 35.1). Nevertheless, given limited patient numbers and short follow-up times, the long-term graft patency rate for the latter procedures remains unknown.

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Fig. 35.1 Totally aortic “non-touch” technique in off-pump three-vessel coronary artery bypass grafting surgery via left minithoracotomy; the inflow vein grafts come from the distal left subclavian artery in addition to in situ left internal mammary artery graft

35.5

Technological Innovations

New technologies have played a crucial role in the evolution of less invasive cardiac surgery. Importantly, they have changed the perceptions of cardiac surgeons regarding how cardiac surgery can or should be performed. With the help of new instruments specifically designed to meet the surgeon’s need, less invasive cardiac surgical procedures once deemed impossible or impractical have now become reality, or even common practice, in some medical centers. These technological innovations have typically involved the following aspects of cardiac surgery.

35.5.1 Sternum-Sparing Surgery: Partial Sternotomy, Minithoracotomy, and Thoracoscopy Major advances in this area include the development of a cardiopulmonary bypass support system via peripheral access. The application of suction to the venous drainage has made possible aortic valve and mitral valve surgery via partial sternotomy and minithoracotomy. An earlier breakthrough device in this field was the HeartPort system (developed by Stanford University and New York University Hospital in 1994) which was composed of peripheral vesselbased cardiopulmonary bypass perfusion, an endo aortic balloon occlusion catheter, transvenously placed venting and

cardioplegia cannulas, and extra-long operating instruments. Though its early use proved impractical in most cardiac operations, its potential to be less invasive has significantly changed cardiac surgeons’ and medical engineers’ perception of future technologies. Furthermore, the concept of the HeartPort system led to numerous other technological modifications and innovations in the field of less invasive cardiac surgery. Such innovations include: (1) the development of small caliber multistage peripheral venous cannula, (2) the safe application of vacuum-assisted venous drainage to ensure bloodless exposure inside heart, (3) the small thin blade minithoracotomy retractor and atrial retractor, (4) development of the Chitwood aortic cross-clamp, (5) thoracoscopy or endoscopic robotics to assist in the mitral valve repair or replacement, and (6) liberal use of transesophageal echocardiography to guide the insertion of various intracardiac cannulas.

35.5.1.1 Upper Partial Sternotomy or Minithoracotomy Approaches for Aortic Valve Replacement Currently more and more aortic valve replacements are performed via upper partial sternotomy or minithoracotomy. In such procedures, a limited partial sternotomy is made and the splitting of sternum is terminated at the 3rd or 4th intercostal space with either a “J” or inverted “T” incision, or a 6 cm incision is made at the right 2nd intercostal space (Fig. 35.2). Even an aortic valve replacement surgery can be performed via such a small incision, by using a combination

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Fig. 35.2 Drawing of incisions used in minimally invasive aortic valve replacement. An upper sternotomy incision ends at the 3rd intercostal space at a “J” angle; a minithoracotomy incision is located at the right 2nd intercostal space

Fig. 35.3 The small incision allows for insertion of a combination of central and peripheral cannula for the establishment of cardiopulmonary bypass

of central and peripheral cardiopulmonary bypass circuits. Note that the aortic valve can be adequately exposed and replaced (Figs. 35.3 and 35.4). A right minithoracotomy procedure is increasingly being used for minimally invasive mitral valve repair and/ or replacement surgery. In these procedures, a 6 cm inci-

sion is typically made at the right 3rd intercostal space and a specially designed small retractor is inserted. A combination of central and peripheral cardiopulmonary bypass circuits is established, and intracardiac cannulas are inserted under the guidance of transesophageal echocardiography (Fig. 35.5). Currently, special instruments

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Fig. 35.4 The exposure is adequate for aortic valve replacement. A bioprosthetic valve is visible

Fig. 35.5 A right minithoracotomy incision at the 3rd intercostal space. A combination of central and peripheral cannula insertion is used for the establishment of cardiopulmonary bypass

including clamps, scissors, forceps, and a knot-tying device are used for these procedures (Fig. 35.6). In other words, both mitral valve repair and replacement procedures can be safely performed using this approach

(Fig. 35.7). The main advantages of these procedures are decreased blood loss and the quick return of the patient to physical activities when compared to conventional sternotomy approach (Fig. 35.8).

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Fig. 35.6 Special instruments with extra-long handles and small tips are used for minimally invasive mitral valve surgery

Fig. 35.7 Mitral valve repair with minithoracotomy can achieve good exposure

35.5.2 OPCABG Improvement New instruments have also been developed to position the heart and to stabilize and improve the visualization of target arteries. For example, an available left ventricle suction device applies −400 mmHg suction to the left ventricular apex and can hold the heart up in different positions. Now

widely used in OPCABG surgery, this device has less of an effect on the venous return as compared with the old “suture retraction” technique. Similarly, a focal myocardial stabilization device has been developed to stabilize segments of target arteries; it has both suction and compressing effects on the topical epicardial tissue and thus significantly decreases the motion of target arteries (Fig. 35.9). An additional note-

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Fig. 35.8 Minithoracotomy results in less blood loss, quick return to work, and a better cosmetic outcome

distal coronary artery anastomotic devices, C-PortxA (for the open sternotomy approach) and C-Port Flex A™ (for the minithoracotomy or endoscopic robotic approach) (Cardica Inc., Redwood City, CA, USA), were developed and recently approved for clinical use by the FDA. It should be noted that although the early clinical results of such devices are encouraging [22], their clinical adaption has been lackluster.

35.5.3 Aortic Non-touch Techniques

Fig. 35.9 An “octopus” myocardium-stabilizing device was used to steady the coronary artery during direct bypass grafting anastomosis

worthy device is the temporary intracoronary plastic shunt that can be inserted via arteriotomy to maintain blood flow to the distal myocardium during anastomosis, thus avoiding or minimizing ischemia time. Importantly, the use of such a shunt is considered to be crucial when the target artery supplies a large territory of myocardium. In order to facilitate the distal coronary anastomosis during OPCABG, especially in the anatomically difficult-to-reach areas, two innovative

Different proximal anastomotic devices or hand-sewn facilitators have been developed and used to avoid clamping on the aorta during OPCABG surgery. Unfortunately, the clinical performance of most of these devices has been unsatisfactory, resulting in denial of FDA approval or termination of the products after FDA approval, i.e., the previously FDAapproved symmetry (St. Jude Medical, St. Paul, MN, USA) automated proximal connector being one example. Currently the Heartstring proximal seal system (Boston Scientific, Inc., Marlborough, MA, USA) is the only clinically available facilitator for proximal hand-sewn suture anastomosis. It temporarily occludes aortotomy during direct suture anastomosis of the proximal vein graft to the aortotomy; yet, to date, one of the major drawbacks of its use is that the suture can catch the device, which requires that the anastomosis be redone.

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35.5.4

Endoscopic Robotics

Someday soon will operating rooms be devoid of cardiac surgeons? Perhaps, with the addition of robotics as a forefront technology. For example, Intuitive Surgical’s da Vinci robotic system (Sunnyvale, CA, USA) has improved significantly in the past 15 years and has made operating inside the chest cavity possible. As of today, they have developed three generations of this technology; its 3rd generation, which is smaller and more user-friendly and has a “third arm” (one more arm than the 1st generation) and dual operating consoles for training purposes, has been recently available for clinical use. Its three-dimensional visualization, seven degrees of wrist motion, and capability to eliminate human hand tremors facilitate fine cutting and suturing tasks. For an increasing number of surgeons that are currently using this sophisticated machine, it has made both internal mammary artery takedown and OPCABG surgery via thoracoscopy or minithoracotomy easier (Fig. 35.10). Further, it has been described to have been used to repair atrial septal defects and mitral valves without sternotomy or thoracotomy. Currently, the employment of such systems will lead the way in moving toward total endoscopic CABG surgery (Figs. 35.11 and 35.12). Nevertheless, complementary innovations have been required to allow for robotic surgery on the heart. For example, to make OPCABG surgery easier when it is performed via minithoracotomy or total endoscopic robotic approaches, an endo suction device and an endo myocardium stabilizer (Medtronic, Inc., Minneapolis, MN, USA) have been developed to position the heart and stabilize the target artery through port accesses.

Fig. 35.11 Robotic arms in the operating room

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The endoscopic robotic has greatly enhanced surgeons’ ability to perform OPCABG via thoracoscopy and minithoracotomy. Robotic-assisted OPCABG performed at our institution and others [23] has shown the advantages of less pain, less blood loss, shorter length of stay, and fewer complications when compared to conventional CABG, especially in elderly high-risk patients. Another robotic application in cardiac surgery is mitral valve repair and replacement via thoracoscopy and minithoracotomy. When comparing robotic mitral surgery with standard sternotomy, major reductions in blood product utilization and length of stay are observed, while equivalence in complexity and success of mitral repairs is preserved [24]. Recent use of robotics to

Fig. 35.10 Robotic arms operating inside the chest cavity to take down the left internal mammary artery

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Fig. 35.12 Surgeon is operating on the robotic console away from the patient

Fig. 35.13 Two left ventricular epicardial leads are placed by a robotic grasper in a patient who had previous coronary artery bypass grafting surgery

implant left ventricular pacing leads as part of cardiac resynchronization therapy for congestive heart failure has shown the advantages of accuracy of locating the optimal pacing site and shorter procedure length compared to the cathlab percutaneous implantation (Fig. 35.13) [25].

35.6

Future Directions

The ultimate goal of less invasive cardiac surgery is to avoid cardiopulmonary bypass support and sternotomy and rather to perform surgery through tiny incisions. Various specially designed instruments are still being developed to make such procedures possible, including: (1) automated proximal and

Fig. 35.14 Small incisions after multivessel off-pump sternum-sparing coronary artery bypass grafting surgery

distal CABG anastomotic devices, (2) the endo myocardium stabilizer, (3) the endo suture device, and (4) the endo vascular clamp. The da Vinci surgical robotic system has enabled the use of such instruments inside the closed chest cavity. It is likely that in the very near future, cardiac surgery will be performed utilizing only three to four key holes in the chest wall (Fig. 35.14). The following cardiac procedures will likely advance in the near future with regard to the less invasive approaches: (1) total endoscopic robotic OPCABG using single or bilateral in situ internal mammary artery, with the help of flexible distal coronary artery anastomotic devices; (2) hybrid robotic-assisted OPCABG and percutaneous stenting in the hybrid operating room or hybrid CathLab (Fig. 35.15 );

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Fig. 35.15 Surgeon is performing robotic-assisted hybrid surgery in the CathLab

(3) total endoscopic robotic mitral valve repair; (4) increased the use of robotic-assisted left ventricular pacing lead implantation or hybrid electrophysiology ablation therapy; and (5) aortic valve replacement via percutaneous or transpical approaches in the hybrid operating room or CathLab.

References 1. Grace PA, Quereshi A, Coleman J et al (1991) Reduced postoperative hospitalization after laparoscopic cholecystectomy. Br J Surg 78:160–162 2. Southern Surgeons Club (1991) A prospective analysis of 1518 laparoscopic cholecystectomies. N Engl J Med 324:1073–1078 3. Bruce DM, Smith M, Walker CBJ et al (1999) Minimal access surgery for cholelithiasis induces an attenuated acute phase response. Am J Surg 178:232–234 4. Szwerc MF, Benchart DH, Wiechmann RJ et al (1999) Partial versus full sternotomy for aortic valve replacement. Ann Thorac Surg 68:2209–2214 5. Cosgrove DM, Sabik JF, Navia JL (1998) Minimally invasive valve operations. Ann Thorac Surg 65:1535–1539 6. Svensson LG (2007) Minimally invasive surgery with a partial sternotomy “J” approach. Semin Thorac Cardiovasc Surg 19:299–303 7. Bakir I, Casselman FP, Wellens F et al (2006) Minimally invasive versus standard approach aortic valve replacement: a study in 506 patients. Ann Thorac Surg 81:1599–1604 8. Zilla P, Fasol R, Groscurth P et al (1989) Blood platelets in cardiopulmonary bypass operations. J Thorac Cardiovasc Surg 97:379 9. Ko W, Hawes AS, Lazenby WD et al (1991) Myocardial reperfusion injury. J Thorac Cardiovasc Surg 102:297 10. Sladen RN, Berkowity DE (1993) Cardiopulmonary bypass and the lung. In: Graylee GP, David RF, Utley JR (eds) Cardiopulmonary bypass. William & Wilkins, Baltimore, p 468 11. Tuman KJ, McCarthy RJ, Najafi H et al (1992) Differential effects of advanced age on neurologic and cardiac risks of coronary artery operations. J Thorac Cardiovasc Surg 104:1510 12. Abel RM, Buckley MJ, Austen WG et al (1976) Etiology, incidence and prognosis of renal failure following cardiac operations: results of a prospective analysis of 500 consecutive patients. J Thorac Cardiovasc Surg 65:32

13. Castillo FC, Harringer W, Warshaw AL et al (1991) Risk factors for pancreatic cellular injury after cardiopulmonary bypass. N Engl J Med 325:382 14. Cleveland JC, Shroyer AJ, Chen AY et al (2001) Off-pump coronary artery bypass grafting decrease risk-adjusted mortality and morbidity. Ann Thorac Surg 72:1282–1289 15. Ascione R, Lloyd CT, Underwood MJ et al (2000) Inflammatory response after coronary revascularization with or without cardiopulmonary bypass. Ann Thorac Surg 69:1198–1204 16. Diegeler A, Doll N, Rauch T et al (2000) Humoral immune response during coronary artery bypass grafting: a comparison of limited approach, “off-pump” technique, and conventional cardiopulmonary bypass. Circulation 102:III95–III100 17. Reston JT, Tregear SJ, Turkelson CM (2003) Meta-analysis of short-term and mid-term outcomes following off-pump coronary artery bypass grafting. Ann Thorac Surg 76:1510–1515 18. Edgerton JR, Dewey TM, Magee MJ et al (2003) Conversion in off-pump coronary artery bypass grafting: an analysis of predictors and outcomes. Ann Thorac Surg 76:1138–1142 19. Stump DA, Newman SP (1996) Embolic detection during cardiopulmonary bypass. In: Tegler CH, Babikian VL, Gomez CR (eds) Neurosonology. Mosby, St. Louis, pp 252–255 20. Goto T, Baba T, Matsuyama K et al (2003) Aortic atherosclerosis and postoperative neurological dysfunction in elderly coronary surgical patients. Ann Thorac Surg 75:1912–1918 21. Tsang JC, Morin JF, Tchervenkov CI et al (2003) Single aortic clamp versus partial occluding clamp technique for cerebral protection during coronary artery bypass: a randomized prospective trial. J Card Surg 18:158–163 22. Matschke KE, Gummert JF, Demertzis S et al (2005) The Cardica C-Port System: clinical and angiographic evaluation of a new device for automated, compliant distal anastomoses in coronary artery bypass grafting surgery—a multicenter prospective clinical trial. J Thorac Cardiovasc Surg 130:1645–1652 23. Poston RS, Griffith B, Bartlett (2008) Superior financial and quality metrics with robotic-assisted coronary artery revascularization (abstract), presented at the 128th annual American Surgical Association, New York, 26 April 2008 24. Woo YJ, Nacke EA (2006) Robotic minimally invasive mitral valve reconstruction yields less blood product transfusion and short length of stay. Surgery 140:262–267 25. Liao K (2008) Surgical implantation of left ventricular epicardial pacing leads for cardiac resynchronization therapy. In: Lu F, Benditt D (eds) Cardiac pacing and defibrillation–principle and practice. People’s Medical Publishing House, Beijing

Transcatheter Valve Repair and Replacement

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Lars M. Mattison, Timothy G. Laske, and Paul A. Iaizzo

Abstract

Cardiac device technologies continue to advance at a rapid pace, with heart valve design and placement procedures continuing to be one of the major focus areas. Minimally or less invasive procedures to replace cardiac valves will enable an increasing number of individuals to receive this therapy, including the older and more frail individual, the adult patient with prior surgeries for repair of congenital defects, and/or an individual with previous valve replacement (valve-in-valve procedures). Transcatheter-delivered replacement valves for the four heart valves are either available on the market today or are in development. This chapter provides a brief introduction to this rapidly emerging device area, as well as general considerations related to delivering a device via catheter into the heart (e.g., percutaneous beating heart interventional procedures performed under fluoroscopic and/or echocardiographic guidance). Keywords

Transcatheter valve repair • Transcatheter valve replacement • Transcatheter-delivered valve system • Pulmonic valve • Aortic valve • Mitral valve • Tricuspid valve

36.1

Introduction

Transcatheter valve repairs and replacements have the potential to reduce operative morbidity, expand the indications for valve replacements for nonsurgical candidates, and treat patients who have been declined for (or choose to decline) surgery. Worldwide, catheter-based valve therapies are rapidly expanding entry into the medical practitioner’s arsenal.

L.M. Mattison, BS (*) • P.A. Iaizzo, PhD Department of Surgery, University of Minnesota, 420 Delaware Street SE, B172 Mayo, MMC 195, Minneapolis, MN 55455, USA e-mail: [email protected] T.G. Laske, PhD Department of Surgery, University of Minnesota, 420 Delaware Street SE, B172 Mayo, MMC 195, Minneapolis, MN 55455, USA

Balloon valvuloplasties for aortic and mitral stenoses were perhaps the earliest incarnations of this current, rapidly changing environment. In 1990, Cribier demonstrated the technique of balloon aortic valvuloplasty for patients with calcific degenerative aortic stenosis. Although temporarily very successful, these patients often experienced restenosis of the aortic valve and then even worsening of their symptoms. Balloon valvuloplasty was also a popular technique to treat post-rheumatic mitral stenosis but, with rheumatic fever essentially eliminated in most developed nations, this technique is currently not in widespread practice. Similarly, pulmonic stenting with bare metal stents has been utilized as a treatment for patients with recurrent pulmonary stenosis due to repaired congenital heart malformations over the past two decades or so. Both types of treatment were radically changed when Andersen demonstrated the feasibility of the first transcatheter valve replacement in 1992 in animals [1]. While this device was not suitable for use in humans at that time (device required a 41 Fr delivery system), it sparked the

Cardiovascular Division, Medtronic, Inc., Minneapolis, MN, USA

© Springer International Publishing Switzerland 2015 P.A. Iaizzo (ed.), Handbook of Cardiac Anatomy, Physiology, and Devices, DOI 10.1007/978-3-319-19464-6_36

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minds of other inventors who soon expanded on the idea of a transcatheter-delivered valved stent. The first report of a transcatheter valve replacement was in 2000 by Professor Philipp Bonhoeffer and colleagues in France who successfully delivered and implanted a valved stent in a right ventricle to pulmonary artery conduit of a patient with a congenital heart malformation [2, 3]. Shortly thereafter, Cribier et al. reported on a transcatheter-delivered valve stent into the aortic position of a patient with degenerative calcific aortic stenosis [4]. Since that time, large and small medical device corporations, as well as individual inventors, have been developing techniques to treat valvular heart disease which can be delivered (or affected) via catheter. The focus of these developments has been to treat the pulmonic and aortic valves with valve replacement, with a recent shift to mitral valves as well. Currently, there are approved devices in the United States, Europe, and Canada for pulmonic and aortic valve replacement for select groups of patients. Additionally, there is a big push to develop transcatheter mitral valves; we noted 18 potential valves in development, from filing for intellectual property to first in man studies. In addition to market-released devices and formalized clinical trials, there are many devices which are currently being tested in preclinical animal and human cadaver feasibility trials around the world. These devices and trials will be discussed in greater detail in the following sections. The development of transcatheter-delivered valve systems requires a combination of numerous technologies including access systems, delivery systems, a stent or support structure with a valve or repair system (i.e., a clip to capture native leaflets), closure systems, and imaging and/ or navigation systems. Currently, transcatheter valve replacement stents can generally be classified as balloonexpandable or self-expanding. Balloon-expandable devices are typically made from materials such as cobalt chromium, stainless steel, or platinum iridium alloys, while self-expanding devices are usually made from nitinol (a temperature-dependent, shape memory material). Typically, the valves themselves employ either bovine jugular vein valves or bovine/porcine pericardial constructs. It should be noted that valvuloplasty is often recommended or employed prior to the placement of a transcatheter-delivered valve, but it is not necessarily required in many transcatheter repair procedures [5]. Additionally, if a minimally invasive surgical approach or procedure is employed, then additional specific technologies and/or devices are needed as well. Furthermore, depending on the valve design, a company may also be required to develop systems to load the valves within the delivery systems (e.g., crimping systems). Finally, many device developers are simultaneously creating training

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simulation systems for the delivery of each product type or procedural approach.

36.2

Pulmonic Valve

A transvenously delivered transcatheter pulmonic valve can be employed as a novel nonsurgical means to treat complications associated with congenital heart disease, such as pulmonary valve insufficiency [3]. A minimally invasive surgical approach is also an option if warranted, depending on individual patient history and/or other interventions that need to be performed. For example, Fig. 36.1 demonstrates that a transcatheter pulmonic valve could be delivered into position either transvenously (via the superior or inferior vena cava) through the tricuspid valve or via a transventricular puncture through the right ventricular wall. The needs of congenital heart patients inspired the original creation of the transcatheter-delivered stented valve. As noted above, Philipp Bonhoeffer is the pioneer of this technology. One example of such a replacement system is the Melody® Transcatheter Pulmonary Valve (Medtronic, Inc., Minneapolis, MN, USA) [3]. The stent supporting the valve is composed of a platinum iridium alloy, which is expanded during delivery by balloons located within the delivery system. The valve is that of a native bovine jugular valve isolated from the vein, which is sewn to the stent. The Melody valve is delivered using the Ensemble® Transcatheter Delivery System (Medtronic, Inc.) through the cardiovascular system, eliminating the need to open the patient’s chest

Fig. 36.1 Two potential approaches for the delivery of a transcatheter pulmonic valve: (A) transvenously into the right atrium, then through the tricuspid valve, or (B) transapically through the right ventricular wall. The later approach would require a minimally invasive surgery

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Fig. 36.2 The Melody® Transcatheter Pulmonary Valve and Ensemble® Transcatheter Delivery System (Medtronic, Inc.) has received CE mark approval and is available for distribution in Europe. Additionally, a Medical Device License has been granted and the system is available for

distribution in Canada. Products are available for sale in the United States for patients that have congenital heart disease. The system consists of a bovine jugular valve vein sewn inside a platinum iridium stent (A) and delivered via a sheathed balloon-in-balloon delivery catheter (B)

(Fig. 36.2). The overall procedure minimizes trauma and offers a quicker recovery than traditional surgical procedures. Furthermore, it is considered that such procedures: (1) could reduce the total number of surgeries required by these patients during their lifetimes (e.g., by postponing time to surgery while restoring pulmonic function), (2) would allow for earlier intervention and potentially better outcomes for patients while avoiding surgical complications, (3) avoid the risks of bleeding and infection associated with reoperation, and/or (4) reduce costs by avoiding postoperative intensive care [3, 6, 7]. Currently, there are two commercially available valves that have been used for transcatheter pulmonary valve replacements: the Melody (Medtronic, Inc.) and SAPIEN XT (Edwards Lifesciences, Irvine, CA, USA). To date, the Melody valve is FDA approved for patients with congential heart disease in the United States and CE marked in Europe, whereas the SAPIEN XT valve is CE marked in Europe. The largest difference between these two balloon-expandable valves is their sizing, with the Melody® valve being 18–22 mm in diameter and the Sapien XT being 23 or 26 mm. In a recent clinical assessment, both valves performed very comparably [8]. It is common that developers of these technologies partner with leading congenital interventional cardiologists and cardiac surgeons. Furthermore, managing these complex congenital heart disease patients requires a cohe-

sive team approach. It is likely that such patients will be treated in the hybrid catheter lab/operating room by a “heart team,” including an interventional cardiologist and cardiac surgeon.

36.3

Aortic Valve

Currently, transcatheter aortic valve replacement is considered for high- or extreme-risk patients with severe calcific aortic stenosis; these patients are not considered as appropriate candidates for conventional surgical valve replacements. In general, these procedures have similar benefits as those mentioned above, such as eliminating the need for cardiopulmonary bypass and allowing for shorter patient recovery times. It is conceivable that a transcatheter aortic valve could be delivered by one of four different approaches: (1) transarterially (e.g., via the femoral artery, subclavian artery, or the ascending aorta), (2) transseptally via the right heart, (3) transatrially through the left atrial wall or a port in the atrial appendage, or (4) transapically through the left ventricular wall (Fig. 36.3). Currently, the transfemoral approach for the delivery of transcatheter aortic valves is the most common access route; this approach is used 69–91 % of the time [9, 10] and is the preferred access route. Primary alternate access routes are transapical (through the apex of the heart in the myocardium), transaortic (through the aorta), and subclavian (subclavian

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Fig. 36.3 Four potential approaches for the delivery of a transcatheter aortic valve or repair tool: (A) transarterially (e.g., via femoral artery access); (B) transseptally from the right heart (transvenous access) into the left atrium, then through the mitral valve; (C) transatrially through the left atrial wall or through a port in the left atrial appendage, then through the mitral valve; or (D) transapically through the left ventricular wall. The latter two approaches would currently require a minimally invasive surgical procedure

artery) routes. These alternate routes are typically used when the transfemoral approach is deemed not possible due to: (1) the size of the patient’s arteries; (2) the tortuosity of the arteries and/or aorta; and/or (3) the degree of calcification within the aorta, some which could potentially be knocked free by the delivery system. Note that the transfemoral, transaortic, and subclavian routes all require retrograde delivery, while transapical requires an antegrade approach. In current practice, both the transapical and transaortic approaches require a minimally invasive surgery (see Chap. 35), yet they provide the most direct anatomical approach. The transapical approach must go through the left ventricular wall (myocardium) which can be difficult to close if a large delivery system is used and/or if the myocardial tissue is abnormally frail. The transaortic approach also requires closure of a hole that is placed into the ascending aorta. This can be especially difficult if the aorta is extremely calcified, a condition known as a porcelain aorta. As technology advances, the need for minimally invasive surgery with these approaches may be eliminated. The transseptal approach, which has the advantage of employing transvenous access for the delivery system, has the potential draw-

back that if the system passing through the interatrial wall is large, the physician may create a septal defect which will require a subsequent repair (see Chap. 37). Additionally, the system must make a turn of approximately 180 degrees in the left ventricle, after passing through the complex structures of the mitral valve, to be positioned in the aortic valve, a maneuver that can be technically challenging. Anatomically, inferior access via a femoral vein is considered advantageous due to the proximity of the inferior vena caval ostium and the fossa ovalis, which is the preferred transseptal puncture location. It has been reported that rapid ventricular burst pacing can be employed to facilitate transcatheter heart valve implantation. Pacing rates between 150 and 220 bpm with durations of 12 ± 3 s were relatively well tolerated (n = 40) when cautiously used. Rapid pacing was associated with a rapid and effective reduction in systemic blood pressure, pulse pressure, transvascular flow, as well as cardiac and catheter motion [11]. As can be observed in Fig. 36.3, the potential pathways/ approaches to place a transcatheter-delivered valve in the aortic position are quite varied and have dramatic differences

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Fig. 36.4 (A) The Edwards Lifesciences SAPIEN XT transcatheter heart valve consists of a cobalt chromium balloon-expandable stent with an attached pericardial valve. It has been designed for transfemoral placement with the NovaFlex+ delivery system or for transapical placement with the Ascendra delivery system. It has been approved for high-

and extreme-risk surgical patients in the United States and Europe. (B) The ReValving System by CoreValve, Inc. (Medtronic, Inc.), consists of a self-expandable nitinol stent with an attached pericardial valve. It is designed for transarterial delivery and is currently approved for highand extreme-risk cases in the United States and Europe

in the angles and anatomical features that would be required to be navigated within or through, e.g., vessels, chamber walls, valves, or chordae tendineae. Due to this complexity, the flexibility of the delivery system (with the valve loaded inside) will be a major factor to consider when selecting a delivery approach; furthermore, the patient’s cardiac anatomy is a major consideration. This is true for the delivery of the system and also for the positioning of the valve stent into the aortic position, as one must prevent obstruction to the ostia of the coronary arteries. Currently, there are several transcatheter aortic valves available for clinical use, in clinical trials, or in animal testing. The CoreValve (Medtronic, Inc.) and the SAPIEN XT (Edwards Lifesciences) are FDA approved for high- and extreme-risk patients, and to date, several hundred thousand devices have been implanted in patients worldwide (Fig. 36.4). More specifically, for the transarterial placement of the SAPIEN XT transcatheter heart valve, the surgeon uses the NovaFlex+ delivery system (Edwards Lifesciences), whereas he/she uses the Ascendra+ delivery system (Edwards Lifesciences) for a transapical placement. The CoreValve system is also delivered via a transarterial approach in a specialized delivery catheter. In addition, several other companies that have developed (and continue to develop) competing technologies, including Boston Scientific (Marlborough, MA, USA) and St. Jude Medical (St. Paul, MN, USA) as well as smaller companies such as Direct Flow Medical, Inc. (Santa Rosa, CA, USA) and Heart Leaflet Technologies Inc. (Maple Grove, MN, USA). Nevertheless, nearly all the major players in cardiac valve replacement have a keen interest in these technologies and clinical approaches (Fig. 36.5) [12].

It is important to note that, currently, a percentage of patients that have received transcatheter-delivered aortic valves have elicited conduction abnormalities which may include heart block. Most of the self-expanding or balloonexpanded valve prostheses exert radial forces on the interventricular septal wall and surrounding structures which is required to maintain proper position and to minimize paravalvular leaks. This force, coupled with the close anatomic proximity of the atrioventricular node, the bundle of His, and/or the left bundle branch with the basal annulus of the aortic valve, is the likely explanation for this phenomenon (Fig. 36.6) (see Chap. 13).

36.4

Mitral Valve

Mitral valve dysfunction can be related to several factors including diseased leaflets [13], annular changes [14], abnormal or damaged chordae [15], and ventricular dilatation [16] causing displacement of the papillary muscles. Due to this large variability in disease process, a wide variety of transcatheter devices are being investigated for the mitral valve. These transcatheter devices can be subdivided into five general types: (1) devices for Alfieri-type edge-to-edge repair, (2) indirect annuloplasty devices deployed into the coronary sinus, (3) direct annuloplasty devices placed on or near the mitral annulus, (4) devices for dimensional control of the left ventricle or left atrium, and (5) devices for mitral valve replacement [17, 18]. The edge-to-edge technique involves placing a stitch to join the anterior and posterior leaflets at the location of regurgitation [19–21]. This technique is most commonly

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Fig. 36.5 This figure shows a variety of transcatheter aortic valves that are currently working through the regulatory process. It provides an insight into the design and delivery of the valve as well [12]. SC subclavian, TA transapical, TAo transaortic, TF transfemoral. ©2013 Fig. 36.6 A dissected human heart that shows the proximity of the aortic valve to the left bundle branch. The noncoronary cusp is 6.3 ± 2.4 mm from left bundle branch as depicted in the right picture. It is more common in self-expanding valves to experience issues with the conduction system in the heart [12], ©2013 Heart Valves: From Design to Clinical Implantation, Transcatheter aortic valve implantation, Piazza N, Mylotte D, Martucci G. With kind permission of Springer Science+Business Media, New York

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Heart Valves: From Design to Clinical Implantation, Transcatheter aortic valve implantation, Piazza N, Mylotte D, Martucci G. With kind permission of Springer Science+Business Media, New York

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used in patients with A2 or P2 prolapse, and the simplicity of the edge-to-edge technique has led to opportunities for percutaneous valve repair [22–24]. More recently, the MitraClip repair system was designed to use transcatheter clips to grasp the ventricular sides of the anterior and posterior mitral leaflets, leaving the clip in place upon deployment (Abbott Vascular, Bloomington, IN, USA). This technology was FDA approved in 2013. For patients with annular dilatation, many devices are currently being developed to simulate a traditional annuloplasty procedure. These products are classified as either indirect, which typically involves a transvenous coronary sinus approach, or direct, which involves placing the device in direct contact with the mitral annulus. Percutaneous, transvenous mitral annuloplasty is a technology that implants a metal bar with flexible ends and a stiff midsection to reshape the posterior leaflet; it is a reversible procedure (Viacor, Inc., Wilmington, MA, USA). The Monarc system features two self-expanding stents tethered together which reshape the posterior region of the annulus in 2–3 weeks (Edwards Lifesciences). Similar to the Monarc, Carillon XE (Cardiac Dimensions, Inc., Kirkland, WA, USA) utilizes tethered stents in the coronary sinus to reshape the posterior annulus. These technologies rely on the proximity of the coronary sinus to the posterior aspect of the mitral annulus. Additionally, direct mitral annuloplasty is also being investigated; these devices are in direct contact with the mitral annulus either temporarily or permanently. MiCardia Corporation (Irvine, CA, USA) is developing adjustable annuloplasty devices which are currently implanted surgically but can be adjusted on the beating heart. The Mitralign device (Mitralign, Inc., Tewksbury, MA, USA) places implants around the annulus and then cinches them closer together, thereby reducing the orifice area of the valve. Nevertheless, the goal of these devices is to restore valve coaptation and thus eliminate mitral regurgitation. Indirect approaches to mitral valve repair that influence left ventricular or left atrial dimensions are also under investigation. By changing left ventricular dimensions, products such as Coapsys and iCoapsys (Myocor® Inc., Maple Grove, MN, USA) are designed to improve mitral valve and left ventricular performance. The PS3 system (Ample Medical, Inc., Foster City, CA, USA) shortens the left atrial dimension between the fossa ovalis and the great cardiac vein and consequently the septal-lateral dimension of the mitral annulus [25]. As described for the aortic valve, it is possible to deploy a transcatheter mitral valve or affect a transcatheter repair using four different approaches: (1) transarterial (e.g., via the femoral artery), (2) transseptal via the right heart, (3) transatrial through the left atrial wall or a port in the atrial appendage, or (4) transapical through the left ventricular

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wall (Fig. 36.7). The human mitral valve is a very complex, dynamic, and highly variable structure. Therefore, complications in the deployment of a replacement valve or repair device into this position will potentially interact with the (1) valve leaflets themselves, (2) the chordae tendineae, and/or (3) the papillary muscles. As mentioned earlier, the valvular and subvalvular anatomy can be quite variable, with some individuals eliciting bifurcated or trifurcated papillary muscles, distinct chordae tendineae patterns, and numerous scallops of each mitral valve leaflet. Due to the complexity of the mitral valve apparatus and underlying disease processes, it is likely that a combination of the aforementioned devices will be required to provide percutaneous solutions for mitral valve repair. There is currently intense competition to develop the first reliable transcatheter-delivered mitral valve replacement. For example, we identified more than 18 transcatheter valves that are in production phases, ranging from filing intellectual property to first in man clinical studies (see Table 36.1) [26]. At present, most of these devices are further along the clinical trial process in Europe than the United States, due to different regulations (see Chap. 43). To date, the valves that are in first in man studies are the Fortis (Edwards Lifesciences), CardiAQ (Irvine, CA, USA), Tiara (Neovasc, Richmond, BC, Canada), and Tendyne/Lutter TMVR (Tendyne, Roseville, MN, USA). At least 18 additional devices have been developed to help treat mitral regurgitation. It will be exciting and interesting to see how these transcatheter mitral valve products continue to develop in the upcoming years.

36.5

Tricuspid Valve

As described for the mitral valve, the human tricuspid valve is a very complex, dynamic, and highly variable structure. The transcatheter approach to this valve structure is similar to those described for the pulmonic valve (Fig. 36.1). It is envisioned that a transcatheter mitral valve or repair tool could be delivered into position either transvenously (via the superior or inferior vena cava) or via a transapical puncture through the right ventricular wall. Furthermore, as described above for the repair and/or replacement of the mitral valve, nearly all options would hold true for the tricuspid valve, which many surgeons feel is often overlooked when treating heart failure patients (for a more detailed discussion, see Chap. 34). On the other hand, the potential complications of damaging or altering the conduction system would also be evident for procedures that involve the tricuspid septal annular structures, i.e., atrioventricular node, the bundle of His, and/or the right bundle branch of the conduction system (see Chap. 13).

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Fig. 36.7 Four potential approaches for the delivery of a transcatheter mitral valve or repair tool: (A) transarterially (e.g., via femoral artery access) retrograde through the aortic valve and up to the mitral valve via the left ventricular chamber; (B) transseptally from the right heart (transvenous access) into the left atrium, then to the mitral valve; (C) transatrially through the left atrial wall or through a port in the left atrial appendage, then to the mitral valve; or (D) transapically through the left ventricular wall. The latter two approaches currently require a minimally invasive surgical procedure

36.6

Imaging

The development and use of transcatheter-delivered cardiac valves has transformed (and will continue to transform) heart valve procedures for those requiring open-heart surgery and/ or cardiopulmonary bypass (see Chap. 33) to a “percutaneous beating heart interventional procedure performed under image guidance” (fluoroscopy or echocardiography). Yet, these imaging modalities are considered to have advantages and disadvantages. For example, cardiac computed tomography (CT) imaging is considered extremely useful for identifying the relative degree of calcification that exists on a heart valve leaflet as well as the delivery anatomy, but is not useful as an intraoperative technique, and it exposes the patient to considerable radiation doses. Importantly, advanced imaging modalities will be required for preplanning and intraoperative guidance of these interventions. More specifically, to date, there is no single imaging modality for intracardiac interventions with-

out clinical limitations, which include low temporal or spatial resolution, excessive exposure to ionizing radiation, and interference with the clinical operator’s freedom of movement. We believe that, in the near future, a combination of imaging modes will provide the information required to guide these complex interventions. Recently, our group set out to provide “a glimpse into the future” by demonstrating the unique direct visualization of transcatheter pulmonary valve implantation utilizing the Visible Heart® techniques (Figs. 36.7, 36.8 and 36.9) [27, 28]. See also Chap. 41. Current pre-procedural imaging consists of a combination of CT scans and echocardiography. This is important for determining the sizes of the various valve annuli and the relative amounts of calcification that may exist along the given delivery route, as well as the position of the coronary artery ostia for aortic valve replacement. Utilization of these 3D renderings can be invaluable to aid the interventional cardiologist and/or cardiac surgeon to make informed decisions about the proper treatment for each given patient (Fig. 36.10).

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Table 36.1 Current products that are being developed for transcatheter mitral valve repair Valve name Company Edwards Caisson CardiAQ* CardiAQ* Emory University HighLife INVALVE Medtronic Micro Interventional Devices MitrAssist Mitralix MITRICARES NCSI Neovasc Tendyne Twelve Valtech

Fortis Caisson TMVR TMVI-TA TMVI-TF MitraCath HighLife mitral valve replacement INVALVE device Medtronic TMVR Endovalve-transapical MitrAssist valve MAESTRO MITRICARES device Navigate TMVR Tiara Tendyne/Lutter TMVR TMVR Cardiovalve

Status International First in man

First in man Preclinicals IP Preclinicals Preclinicals In development IP Clinical implants First in man First in man

United States In development Preclinicals Preclinicals Preclinicals In development

Preclinicals In development

Preclinicals First in man Preclinicals IP

Preclinicals

Note that there are several first in man studies in Europe, while most valves in the United States are only in the preclinical level. A few valves are only conceptual at the moment, as intellectual property has just been filed * CardiAQ was recently acquired by Edwards Fig. 36.8 Comparison of a human pulmonic valve (A) during diastole and (B) during systole to a transcatheter pulmonic valve placed in a human heart (C) during diastole and (D) during systole [28]. ©2008 Expert Review in Medical Devices, vol. 5, Cardiac device testing enhanced by simultaneous imaging modalities: the Visible Heart®, fluoroscopy, and echocardiography. Permission granted by Informa (http:// informahealthcare.com/)

We also suggest that, as cardiac repair and device implantation procedures become less invasive, we will need to study the deployment of these systems or techniques within beating heart models. Utilization of Visible Heart® methodologies provides unique visualization of cardiac device technologies. The preparation and images obtained can be used by design engineers and physicians to develop implant methodologies as

well as support clinical education and training. As more of these devices are implanted within the beating heart, unique means will be required to train individuals in the techniques to navigate and deploy them. For example, Fig. 36.9 shows simultaneously obtained images of a stent being placed in the aortic position, including endoscopic views and time-synchronized images from fluoroscopy and ultrasound (Fig. 36.11).

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Fig. 36.9 Simultaneous endoscopic images on the left and right depict a deployed transcatheter pulmonary valve (Melody® Transcatheter Pulmonary Valve, Medtronic, Inc.) in the native right ventricular outflow tract, with the corresponding ultrasound image displayed in the

center [28]. ©2008 Expert Review in Medical Devices, vol. 5, Cardiac device testing enhanced by simultaneous imaging modalities: the Visible Heart, fluoroscopy, and echocardiography. Permission granted by Informa (http://informahealthcare.com/)

Fig. 36.10 Positioning (A), deployment (B and C), and function (Panels D–F) of a transcatheter aortic valve implanted into a surgically placed bioprosthetic aortic valve. It is interesting to note the lack of (or minimal) interactions between the implanted aortic valve and the native mitral valve [28]. ©2008 Expert Review in Medical Devices, vol. 5, Cardiac device testing enhanced by simultaneous imaging modalities: the Visible Heart®, fluoroscopy, and echocardiography. Permission granted by Informa (http://informahealthcare.com/)

36.7

Training Systems

The complexity of intracardiac interventions has increased with the advent of transcatheter valve replacement and is expected to further escalate as clinicians become more comfortable with complicated cardiac repairs within the beating heart and as engineers invent new product solutions. Simulators designed to

demonstrate the technical aspects of transcatheter-delivered valves have already been developed. Many state-of-the-art patient simulators enable pseudo-visualization via various imaging modes. For instance, one can practice using fluoroscopy for the valve implant without any exposure to radiation. The delivery systems for these transcatheter valves are often complex and require guidewires, introducers, and/or dilators; hence, prior practice on handling such tools is essential.

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Fig. 36.11 3D model of a patient’s ascending aorta, aortic arch, and descending aorta. The vessel is modeled in the gold color, while the calcium deposits are white in color. It is also possible to see the coronary arteries that come off the root. Using this model the size of the aortic annulus can be measured, as well as the height of the coronaries from the annulus [29]

Furthermore, for those physicians not familiar with performing such catheter-delivered and/or minimally invasive surgical approaches, these training sessions can be invaluable and highly educational. If such procedures are performed in a newly instrumented hybrid catheter lab/operating room, then the dynamics of team interactions could also be developed in such training sessions. More specifically, studies employing virtual reality simulation of such procedures have indicated that there is a documented learning curve, and catheter handling errors significantly decrease as assessed with measurable dynamic metrics with high test-retest reliability [30] (Fig. 36.12).

36.8

Summary

The clinical application of transcatheter delivery systems to repair or replace cardiac valves is an area of intense growth, and there is also continued research development.

The potential to treat patients with valvular disease without the use of open-heart surgery will ultimately affect millions of individuals worldwide, improving quality of life for these patients. The future of this field will likely see smaller delivery systems with greater intracardiac mobility, as well as replacement valves that better mimic healthy native valve function. Affecting the ultimate clinical success of these therapies will be adequate cardiac visual and function assessments prior to, during, and after these procedures. One can also foresee that simulation training will be employed even before such techniques are performed in preclinical animal studies, as many procedures will require numerous tool components (e.g., introducers, dilators, balloon catheters, delivery catheters, etc.). For additional detailed discussions on these topics, the reader is referred to manuscripts by Schoenhagen and To [31], Quill et al. [32], Scheivano et al. [3], and Piazza et al. [5].

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Fig. 36.12 Top images show endoscopic views of a prototype stent placed in the aortic position, and bottom images show time-synchronized images from fluoroscopy (lower left) and ultrasound (lower right). The upper left image shows the view from the ventricle; the interventricular septum (IVS) is at the top and the mitral valve (MV) is located on the right. The upper right image is a view from the aorta, specifically showing the interaction of the stent and left coronary artery ostium (LCO); in this case, there would be minimal obstruction of flow into the left coro-

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nary artery. The fluoroscopic image clearly shows the stent as well as the endoscopes in the left ventricle and aorta. The stent is also visible on the ultrasound image, projecting slightly into the left ventricle (LV). The right ventricle (RV) is located at the top of this image [23]. ©2008 Expert Review in Medical Devices, vol. 5, Cardiac device testing enhanced by simultaneous imaging modalities: the Visible Heart®, fluoroscopy, and echocardiography. Permission granted by Informa (http:// informahealthcare.com/)

References 1. Andersen HR, Knudsen LL, Hasenkam JM (1992) Transluminal implantation of artificial heart valves. Description of a new expandable aortic valve and initial results with implantation by catheter technique in closed chest pigs. Eur Heart J 13:704–708 2. Bonhoeffer P, Boudjemline Y, Saliba Z et al (2000) Percutaneous replacement of pulmonary valve in a right-ventricle to pulmonary-artery prosthetic conduit with valve dysfunction. Lancet 356:1403–1405 3. Schievano S, Taylor AM, Bonhoeffer P (2013) Percutaneous pulmonary valve implantation: the first transcatheter valve. In: Iaizzo PA, Bianco RW, Hill AJ, St. Louis JD (eds) Heart valves: from design to clinical implantation. Springer, New York, pp 211–226 4. Cribier A, Eltchaninoff H, Bash A et al (2002) Percutaneous transcatheter implantation of an aortic valve prosthesis for calcific aortic stenosis: first human case description. Circulation 106:3006–3008 5. Piazza N, Mylotte D, Martucci G (2013) Transcatheter aortic valve implantation. In: Iaizzo PA, Bianco RW, Hill AJ, St. Louis JD (eds)

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11. Webb JG, Pasupate S, Achtem L, Thompson CR (2006) Rapid pacing to facilitate transcatheter prosthetic heart valve implantation. Catheter Cardiovasc Interv 68:199–204 12. Iaizzo PA, Bianco RW, Hill AJ, St. Louis JD (eds) (2013) Heart valves: from design to clinical implantation. Springer, New York 13. Roberts WC (1983) Morphologic features of the normal and abnormal mitral valve. Am J Cardiol 51:1005–1028 14. Yiu SF, Enriquez-Sarano M, Tribouilloy C, Seward JB, Tajik AJ (2000) Determinants of the degree of functional mitral regurgitation in patients with systolic left ventricular dysfunction: a quantitative clinical study. Circulation 102:1400–1406 15. Hickey AJ, Wilcken DE, Wright JS, Warren BA (1985) Primary (spontaneous) chordal rupture: relation to myxomatous valve disease and mitral valve prolapse. J Am Coll Cardiol 5:1341–1346 16. Kono T, Sabbah HN, Rosman H, Alam M, Jafri S, Goldstein S (1992) Left ventricular shape is the primary determinant of functional mitral regurgitation in heart failure. J Am Coll Cardiol 20:1594–1598 17. Babaliaros V, Block P (2007) State of the art percutaneous intervention for the treatment of valvular heart disease: a review of the current technologies and ongoing research in the field of percutaneous valve replacement and repair. Cardiology 107:87–96 18. Feldman T, Leon MB (2007) Prospects for percutaneous valve therapies. Circulation 116:2866–2877 19. Nakanishi K, Raman J, Hata M, Buxton B (2001) Early outcome with the Alfieri mitral valve repair. J Cardiol 37:263–266 20. Alfieri O, Maisano F, De Bonis M et al (2001) The double-orifice technique in mitral valve repair: a simple solution for complex problems. J Thorac Cardiovasc Surg 122:674–681 21. Alfieri O, Maisano F (1999) An effective technique to correct anterior mitral leaflet prolapse. J Card Surg 14:468–470 22. Alfieri O, Maisano F, Colombo A (2004) Percutaneous mitral valve repair procedures. Eur J Cardiothorac Surg 26:S36–37; discussion S37–38

683 23. Alfieri O, De Bonis M, Lapenna E et al (2004) “Edge-to-edge” repair for anterior mitral leaflet prolapse. Semin Thorac Cardiovasc Surg 16:182–187 24. Alfieri O, Maisano F, Colombo A, Pappone C, La Canna G, Zangrillo A (2004) Percutaneous mitral valve repair: an attractive perspective and an opportunity for teamwork. Ital Heart J 5:723–726 25. Rogers JH, Macoviak JA, Rahdert DA, Takeda PA, Palacios IF, Low RI (2006) Percutaneous septal sinus shortening: a novel procedure for the treatment of functional mitral regurgitation. Circulation 113:2329–2334 26. Maisano, Francesco. "Transcatheter Mitral Valve Implantation." EuroPCR 2014. Paris, France. Lecture. 27. Quill JL, Laske TG, Hill AJ, Bonhoeffer P, Iaizzo PA (2007) Direct visualization of a transcatheter pulmonary valve implantation within the Visible Heart®—a glimpse into the future. Circulation 116, e548 28. Iaizzo PA, Hill AJ, Laske TG (2008) Cardiac device testing enhanced by simultaneous imaging modalities: The Visible Heart®, fluoroscopy, and echocardiography. Expert Rev Med Devices 5:51–58 29. Edwards Scientific. (2015 November). A Less Invasive Treatment Option For Severe Aortic Stenosis. Retrieved November 2015 from promotional CD 30. Patel AD, Gallagher AG, Nicholson WJ, Cates CU (2006) Learning curves and reliability measures for virtual reality simulation in the performance assessment of carotid angiography. J Am Coll Cardiol 47:1796–1802 31. Schoenhagen P, To ACY (2013) Advanced 3D imaging and transcatheter valve repair/implantation. In: Iaizzo PA, Bianco RW, Hill AJ, St. Louis JD (eds) Heart valves: from design to clinical implantation. Springer, New York, pp 159–186 32. Quill JL, Menk AR, Tang GHL (2013) Transcatheter mitral repair and replacement. In: Iaizzo PA, Bianco RW, Hill AJ, St. Louis JD (eds) Heart valves: from design to clinical implantation. Springer, New York, pp 187–210

Cardiac Septal Defects: Treatment via the Amplatzer® Family of Devices

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John L. Bass

Abstract

The majority of patients with congenital heart disease present with defects resulting from vascular narrowing or absence (such as interruption or coarctation of the aorta or pulmonary arteries) or failure of structures to fuse or separate during development (total anomalous pulmonary venous connection, septal defects, fusion of valve cusps). Correction of these defects initially began with open-heart surgery, but now many of these repairs can be performed through catheter-delivered closure devices (e.g., Amplatzer closure devices). This chapter will present a brief history of defect repairs and provide information on the design, development, and preclinical animal testing of such systems. Keywords

Interventional cardiac catheterization • Atrial septal defect • Transcatheter closure • Patent ductus arteriosus • Muscular ventricular septal defect • Perimembranous ventricular septal defect

37.1

Introduction

Congenital heart disease affects eight of every thousand live births. Correction of these defects initially began with openheart surgery and was originally limited to repairs that could be performed without stopping the patient’s circulation (patent ductus arteriosus or coarctation of the aorta). The subsequent development of cardiopulmonary bypass allowed the surgeon to safely visualize the inside of the heart, and more complex repairs were successful developed. This was the true beginning of caring for children with congenital heart disease, dramatically extending and improving the quality of their lives. However, with these advances, the art of diagnosis by physical examination was no longer sufficient to provide details of anatomy needed by the surgeon. Cardiac

J.L. Bass, MD (*) University of Minnesota Children’s Hospital, 2450 Riverside Avenue, East Building Room MB547, Minneapolis, MN 55454, USA e-mail: [email protected]

catheterization and X-ray visualization during the 1950s and 1960s also underwent a similar clinical explosion as the primary diagnostic tool. Still, surgeons had to be prepared to deal with the unique individual anatomies found during a given operation, i.e., as some details were unexpected. This surgical license to make plans “on the fly” is critical to a successful operation and explains the historical liberation of surgery from restrictions by the Food and Drug Administration (FDA) and Institutional Review Boards. Next, echocardiography developed to the point where it began to replace cardiac catheterization as the primary diagnostic tool for congenital heart disease (see Chap. 22). Thus, the number of cardiac catheterizations diminished. On the other hand, interventional cardiac catheterization, pioneered by Dr. Gruntzig’s coronary angioplasty, became an important clinical tool; these techniques were applied to relieve congenital narrowing of the pulmonary arteries and aorta. Experimental testing preceded the use of these techniques in children with congenital heart disease [1, 2]. Importantly, it was observed that no foreign materials were left behind while performing these angioplasty procedures. Interventional cardiac catheterization further expanded

© Springer International Publishing Switzerland 2015 P.A. Iaizzo (ed.), Handbook of Cardiac Anatomy, Physiology, and Devices, DOI 10.1007/978-3-319-19464-6_37

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with Dr. Porstmann’s use of an Ivalon plug to close the persistent patent ductus arteriosus (PDA) [3], as well as Dr. King’s [4] and Dr. Rashkind’s [5] devices for closure of secundum atrial septal defects (ASDs). Nevertheless, technical difficulties (i.e., limited retrievability and large delivery systems) and residual shunts plagued the early development of these devices and their application remained limited. Two companies in particular—NuMED, Inc. (Hopkinton, NY, USA) and the former AGA Medical Corporation (now St. Jude Medical, St. Paul, MN, USA)—focused their efforts on developing devices aimed at correcting congenital cardiac defects. In 2001, the Amplatzer Septal Occluder became the first device to receive FDA approval for closure of secundum ASDs, followed in 2003 by the Amplatzer Ductal Occluder. This, along with development of stents that could be applied to the larger vascular narrowings of congenital heart diseases, opened the floodgates for interventional cardiac catheterization in children. We consider that both Allen Tower (NuMED, Inc.) and Kurt Amplatz (AGA Medical Corporation) deserve special recognition for choosing to focus their innovative efforts on improving care for children with congenital heart disease, instead of the larger volume and remuneration of fixing adult problems with coronary artery stents or patent foramen ovale closure devices.

37.2

Amplatzer Devices

The Amplatzer devices designed to close congenital cardiac defects are all quite similar; basically, they all are selfexpanding stents shaped to fit a specific anatomical defect. These devices are primarily composed of a closed nitinol wire frame fashioned with a waist containing polyester fabric baffles or stuffing to fill the defect, as well as retention discs. The shapes of the wire frames are tailored to fit the various abnormal vascular or intracardiac communications. In other words, the retention discs fix the device against vascular or cardiac walls. The central waist further holds the device in place by placing radial forces against the margins of the communications, i.e., providing stable fixation of the device. Most available devices are concentric and designed to fill defects that are centrally located and thus are surrounded by cardiac structures that will not be injured by the edges of these devices. In general, subsequent occlusion occurs through thrombosis within the polyester baffles or stuffing inside of the wire frame. Importantly, within approximately 3 months, these devices are considered to be covered with protein and cellular layers, reducing the potential for forming a surface thrombus and eliminating the risk of infective endocarditis [6]. Historically, the development of Amplatzer devices began when thin wire technologies reached a point that allowed for the unique construction of frames employing nontoxic nitinol

wires. Like all stents, the collapsed device is required to be long and narrow to fit through the delivery sheath. Uniquely, nitinol metal has shape memory such that, as it exits the sheath, the device expands and assumes its original shape at body temperatures. Each device has a microscrew fixed to the proximal end allowing attachment to a delivery cable. Thus, these devices can be retrieved with the cable after deployment and then either removed or repositioned. Finally, the Amplatzer devices can be detached via unscrewing once an optimal, secure, and effective position is confirmed.

37.2.1 Safety Nickel-containing alloys, such as stainless steel, have been employed in human medicine for over 100 years. They have been used in surgical instruments as well as implants such as pacemaker wires, vascular clips, mechanical cardiac valves, orthopedic prostheses, Harrington rods, and inferior vena cava filters. This demonstrates the relative lack of toxicity of nickel-containing metallic implants; no systemic effects were observed or have been reported. Local fibrotic reactions surrounding stainless steel implants were thought to be due to passivation of nickel ions into surrounding tissue, despite the absence of microscopically visible corrosion. Interestingly, the US Navy developed the new nickel-containing metal, nitinol, in the 1960s. This alloy of nickel and titanium displayed superior corrosion resistance, and it still carries the name of its heritage—NIckel TItanium-Naval Ordnance Laboratory. Nitinol has numerous properties besides corrosion resistance that make it desirable for use in medical devices, including: (1) super elasticity (pseudo-elasticity), (2) thermal shape memory, (3) high resiliency, and (4) fatigue resistance. Originally, thin wire technology, more specifically the development of the diamond-drawn wire, provided a shape that could be used in endodontic appliances. The tendency for nitinol to return to its nominal shape when deformed was especially useful in this application. This property also made nitinol a valuable material in the production of endoluminal devices. Importantly, a nitinol device can be stretched for introduction through a small delivery catheter, and then it expands back to its original shape when deployed. This new alloy replaced most stainless steel devices, especially selfexpanding stents. Furthermore, nitinol’s fatigue resistance properties prevent wire fractures and extend device durability. The absence of ferromagnetic properties is compatible with magnetic resonance imaging. To date, all Amplatzer devices have proven to be nontoxic [7]. In addition, such devices performed well in fatigue testing, and when immersed in a saline bath, they did not corrode. A patient’s serum nickel levels may rise immediately after insertion of an Amplatzer device, but return to normal over 3 months. Furthermore, devices examined 18 months

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post implantation in humans and animals have not revealed any detectable surface corrosion. It should be noted that the incidence of cutaneous nickel allergy is approximately 10 % in humans. Yet, with over 100,000 current implants of Amplatzer devices worldwide over the past 13 years, no definitive case of a reaction has been reported in the literature.

37.3

Animal Models Mimicking Congenital Defects

Originally, the diagnosis of an ASD was established solely by typical findings on physical examination, electrocardiogram, and chest roentgenogram [8]. Surgical repair of cardiac defects, such as those of the atrial or ventricular septa, specifically required the surgeon to evaluate the shape and surrounding structures on an individual basis. Associated abnormalities, such as anomalous pulmonary venous connection, could be identified and dealt with by the surgeon at the time of the operative repair. Animal models created to test experimental devices may not always account for associated anatomic details encountered in human congenital defects. For most congenital heart defects, an exact animal model is not readily available. Nevertheless, devices can be tested for ease of use, reliability, and efficacy, i.e., by creating an experimental defect by dilating a thin septum, sewing in an artificial vascular connection, or removing a portion of the thicker muscular septum. It should be noted that the concept of these “defects” is chosen from imaging and/or examination of pathological specimens, but may not always mimic the actual defect in humans.

37.4

operations performed, with a mortality rate under 0.5 % [9]. Nevertheless, surgical closure may include morbidity from the median sternotomy (or a right thoracotomy), the risk of exposure to blood products, insertion of a chest tube, a 3–5day hospitalization, convalescence of 4–6 weeks, and/or the chance of postpericardiotomy syndrome. Hence, the potential consequences of these procedures spurred attempts to develop a safe and less invasive method of transcatheter closure. It is generally accepted that transcatheter closure to treat secundum ASDs is an ideal procedure. These types of ASDs are typically surrounded by rims of tissue that a device can clasp, with no borders formed by or thus impeding the valves or the walls of the heart. King and Mills reported the first attempted transcatheter closure of a secundum ASD in 1974 [4]. This was followed by development of the Clamshell/CardioSEAL (NMT Medical, Inc., Boston, MA, USA) [11], Sideris button (Custom Medical Devices, Inc., Gainesville, FL, USA) [12], ASDOS (Sulzer Osypka, Rheinfelden, Germany) [13], and Angel Wings (Das et al.) [14] devices. Each of these devices provided an alternative to surgical closure, but also resulted in a number of new challenges. For example, large devices were required with the central post design, yet most of these early designs were not self-centering, and the center post could move within the defect. Further, these early devices required large delivery systems, and, additionally, some were plagued by unwanted embolization (e.g., unbuttoning) [15]. It was also found that frame fatigue and arm fracture occurred in up to 10 % of some of these designs, with asymptomatic wire embolization observed in several patients. It was concluded that most of these designs were difficult or impossible to recapture or retrieve after deployment. Hence, surgical removal was required if they were deployed in an improper position, and residual shunt rates were significant [16].

Atrial Septal Defects

37.4.1 History

37.5

Amplatzer Device Designs

Atrial septal defects are congenital deficiencies in the wall separating the systemic and pulmonary venous returns as they enter the heart. These ASDs allow blood from the lungs to flow through the defect and increase the volume of blood passing through the pulmonary arteries. In most patients, after 2 decades of life with this flow pattern, this defect can permanently damage the pulmonary vasculature. Therefore, to prevent this and other problems such as associated cardiac arrhythmias, closure of an ASD is recommended during the first few years of life [9]. The University of Minnesota performed the first surgical closure of an ASD in 1952 [10] (see Chap. 25). This successful operative approach for correction of a congenital intracardiac defect remains as one of the safest open-heart

An ideal septal closure device should be: (1) easily delivered and implanted, (2) self-centering, (3) able to pass through a small delivery system, (4) recapturable and redeployable, (5) highly resilient (without fracturing), and (6) highly effective (without significant residual shunts). The materials used in the construction of such devices should also be biocompatible and nontoxic. It should be emphasized that durability is important, for the majority of patients are children and there is a long device “lifetime” after implantation. The Amplatzer ASD devices were designed to fulfill these requirements. For example, the Amplatzer Septal Occluder is a woven mesh of 72 nitinol wires 0.003–0.008 in. in diameter with shape memory. There are two retention discs with a central waist that is placed within the defect (Fig. 37.1); the

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Fig. 37.1 Amplatzer Septal Occluder device. (A) Right atrial angiogram performed after deployment of the device in a secundum atrial septal defect, but before release. The right atrial disc is obscured by contrast with the waist within the atrial septal defect. (B) The levophase of the right atrial angiogram opacifying the left atrium. Contrast outlines the left atrial disc completely within the left atrium

left atrial disc is 12–14 mm larger than the waist. The stenting action of the waist and the retention discs clasps the atrial septum, thus holding the device stable and in place. Additionally, fabric baffles sewn inside the discs and waist promote thrombosis and thus the overall occlusive ability of the device. Importantly, the delivery systems are also relatively small (6–12 Fr delivery sheaths). In addition, these devices are recapturable and redeployable with microscrew/ cable attachments. Available waist diameters range from 4 to 40 mm, thus allowing closure of relatively large defects [16].

37.5.1 Animal Testing of the Amplatzer Device Designs The Amplatzer Septal Occluder device was originally designed for occlusion of a secundum ASD. Initial animal studies focused on reproducibly creating such atrial septal communications, as a natural model of a secundum ASD did not exist. To do so, nonsurgically the flap of the foramen ovale in the experimental animal was perforated and dilated with a balloon to induce an atrial communication [6]; subsequently, devices were implanted, and, in most cases, there were no complications or residual leaks. It was important to show that no thrombus formed on the devices. Afterwards, human clinical trials confirmed that no retroaortic rim was required for stable device position and complete closure. Importantly, patients could be discharged the morning after device placement, and they remained on low dose aspirin and endocarditis prophylaxis for 6 months after closure [16].

37.5.2 Required Testing for FDA Approval An FDA-approved study to provide clinical evidence of the effectiveness of the Amplatzer Septal Occluder was originally initiated, based on the prior success of animal studies and European trials in humans. Yet, the clinical study design for this device was considered difficult. In general, patients and their families wanted to avoid surgery, despite the long history of safe surgical closure and the lack of long-term follow-up with this new device. Therefore, a blinded randomization was unsuccessful, as many patients and families that were chosen for the surgical group simply opted out of the trial, preferring to wait for final FDA approval. The overall study design was subsequently modified to allow device closure at some institutions with patients recruited to designated surgical centers. This is not true randomization, but is representative of the difficulty of study design in the real world. Later, the results of Phase II of the FDA trial also showed that the Amplatzer Septal Occluder was an effective and safe therapy as compared to the surgical group. Importantly, at the end of 12 months, there was complete closure or a small (0 mmHg) in 6/13 (46 %) of consecutive adults. This was caused by incomplete chest wall recoil alone or combined with prolonged, positive ventilations. With standard CPR and incomplete chest wall recoil, insufficient intrathoracic vacuum pressures are achieved. In contradistinction, when active compression and decompression are performed in conjunction with the use of an ITD, a significant intrathoracic vacuum results. In 2005, Yannopoulos et al. conducted an animal study to address the question of the physiological impact of incomplete chest wall recoil [14]. Nine pigs in VF for 6 min were treated with an automated CPR device with compressions at 100/min, a compression depth of 25 % of the anteroposterior diameter, and a compression to ventilation ratio of 15:2. After complete (100 %) chest wall decompression for 3 min during standard CPR, the decompression depth was reduced to 75 % of complete decompression for one minute of CPR and then restored for another one min of CPR to 100 % decompression. CPP was calculated as the diastolic aortic— right atrial (RA) pressure. Cerebral perfusion pressure (CePP) was calculated by measuring the area between the aortic pressure curves and the ICP curves. Figure 38.7 sum0.5

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Fig. 38.8 Effect of incomplete chest wall recoil on reducing cerebral perfusion (see text for details). AoPR aortic pressure, ICP intracranial pressure, ITP intrathoracic pressure, blue tracings = aortic pressure, pink tracings = intracranial pressures

marizes the results of this study including the differences in aortic systolic pressure, CPP, intratracheal pressure (ITP), and CePP. With 100 %–75 %–100 % chest wall recoil, the CPP was 24.2 ± 2.0, 15.0 ± 1.2, and 15.6 ± 1.3 mmHg (p < 0.05); CePP was 320 ± 120, 95 ± 15, and 150 ± 30 mmHg min (p < 0.05); diastolic aortic pressure was 26.8 ± 2.8, 18.9 ± 2.3, and 18.2 ± 2.1 mmHg (p < 0.05); ICP during decompression was 18.1 ± 2.8, 21.6 ± 2.3, and 17.4 ± 2.6 mmHg (p < 0.05); RA diastolic pressure was 2.7 ± 1.9, 3.9 ± 1.9, and 2.7 ± 1.6 mmHg (p < 0.05); and mean arterial pressure (MAP) was 41.4 ± 2.8, 32.5 ± 2.2, and 36.6 ± 1.9 mmHg (p < 0.05). The CPP and CePP never fully recovered after treatment with the 75 % incomplete chest wall decompression. It is striking that a small reduction of chest wall recoil (1 cm), which is a common occurrence during the performance of CPR, resulted in such a marked reduction in cerebral and CPPs. The effect of incomplete chest wall recoil on reducing cerebral perfusion can be seen graphically in Figs. 38.8 and 38.9 [14]. Figure 38.8a represents, condensed in time, the sequential 100 % chest recoil, 75 % chest wall recoil, and return to 100 % chest wall recoil. Tracings of ITP, aortic pressure (AoPr), and ICP with 200 ms per division are indicated with arrows. Piston throw (in cm) is also shown to sequentially demonstrate the complete (100 %) chest wall recoil (38.8b), 75 % chest wall recoil (38.8c), and return to complete chest wall recoil (38.8d). The positive area between the AoPr and ICP tracing represents cerebral perfusion (marked as black). Note how the area decreases, especially during decompression with incomplete chest wall recoil

(75 %) and that it partially recovers when full recoil was restored. Figure 38.9 shows the effect of positive pressure ventilation on CePP. The first tracing shows the aortic and ICP waveforms with full chest wall recoil after a ventilation cycle, while the second tracing shows the aortic and ICP waveforms with incomplete chest wall recoil after a ventilation cycle. Positive pressure gradient (Ao-ICP) is colored black. Note the marked difference in total area during each compression-decompression cycle with and without a positive pressure breath. The bar graphic shows the mean 4-beat area of all animals during and after a ventilation cycle. The mean ± SEM values during 100 and 75 % decompression have been graphed. During positive pressure ventilation, ICP rises and the positive gradient disappears. There was effectively no blood flow to the brain (Fig. 38.9, second panel). This study demonstrated that incomplete decompression has significant deleterious effects on both CPP and CePP. The residual positive intrathoracic pressure during the decompression phase associated with incomplete chest wall recoil decreased forward blood flow, impeded venous return, increased ICP, and undermined the efficiency of CPR. These recent animal studies underscore the fundamental hemodynamic importance of complete chest wall decompression during CPR. Whether rescuers can be retrained to allow for complete chest wall decompression during standard CPR remains an important issue. A change in CPR technique to allow for the palm of the compressing hand to lift off the chest at the end of decompression may be important to assure full chest wall recoil during standard CPR. Accordingly, Aufderheide et al.

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Fig. 38.9 Effect of incomplete chest wall recoil on reducing cerebral perfusion (see text for details). CerPP cerebral perfusion pressure

implemented a randomized prospective clinical trial using an independent group of 30 actively practicing and certified EMS providers, not aware of the ongoing trial, in a controlled setting using a recording CPR manikin. The purpose of the study was to evaluate three alternative CPR techniques to determine if they would improve complete chest wall recoil compared with standard CPR while maintaining adequate compression depth and proper hand position placement. The three alternative CPR techniques were: (1) two-finger fulcrum technique (lifting the heel of the hand slightly but completely off the chest during the decompression phase of CPR while using the thumb and little finger as a fulcrum), (2) five-finger fulcrum technique (lifting the heel of the hand slightly but completely off the chest during the decompression phase of CPR, using all five fingers as a fulcrum), and (3) hands-off technique (lifting the heel and all fingers of the hand slightly but completely off the chest during the decompression phase of CPR). In this study, during standard CPR using the traditionally taught hand position (standard hand position), complete chest wall decompression was recorded in only 16.3 % of all compression-decompression cycles, adequate depth of compression in 48.5 %, and acceptable hand placement in 85.0%

of compression-decompression cycles. When compared with standard CPR, the hands-off technique achieved the highest rate of complete chest wall recoil (95.0 % versus 16.3 %, P < 0.0001) and was 129 times more likely to provide complete chest wall recoil (OR: 129.0; CI: 43.4–382.0) [19]. There were no significant differences in the accuracy of hand placement, depth of compression, or reported increase in fatigue or discomfort with its use compared with the standard hand position. The hands-off technique was easily learned and applied by participating EMTs, because it uses the same hand configuration as is currently recommended by the AHA.

38.5

Optimizing Outcomes with Standard CPR and the Impedance Threshold Device

Aufderheide and colleagues have recently analyzed and applied the combined lessons learned from the initial clinical trials of the ITD and standard CPR. They analyzed data from seven EMS systems that serve a population of more than 3 million patients and reported that, when CPR is performed

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Fig. 38.10 Code blue survival rates in St. Cloud, Minnesota (January 2005 to December 2007). CPR cardiopulmonary resuscitation

correctly with the ITD and the mistakes described above are reduced or eliminated by rigorous training and correct ITD used, survival rates increased from 7.9 to 15.7 % for all patients who presented with cardiac arrest; survival rates for those with an initial rhythm of VF increased from 17 to 28 % [11]. Therapeutic hypothermia was not yet in use in these EMS systems and their associated hospitals when these data were obtained. Similar benefits from performing CPR according to the AHA 2005 and 2010 guidelines and the use of the ITD have also been reported for patients in in-hospital cardiac arrest. For example, Thigpen reported that hospital discharge rates in one large Mississippi hospital increased from 17 to 28 % with the administration of this new resuscitation approach [20, 21]. Similar data from St. Cloud Hospital in Minnesota are shown in Fig. 38.10; data from before the change in practice in July 2006 were compared to data after implementation of the new CPR techniques and the ITD. Importantly, the survival rates after an in-hospital cardiac arrest nearly doubled. A study by Lick et al. investigated the effects of stricter adherence to the AHA guidelines for CPR which included the recommended use of the ITD. The Take Heart America initiative was started in an attempt to increase survival from cardiac arrest by focusing on the implementation of the 2005 and 2010 AHA guidelines. It is centered not on a single treatment but rather on a bundle of care approach including community-wide initiatives, including: (1) increased cardiac arrest awareness, (2) increased bystander CPR rates, (3) promoting the use of automated external defibrillator, and (4) the administration of immediate high-quality CPR with the use of the ITD throughout the duration of the code. Further, additional in-hospital treatments such as therapeutic hypothermia, revascularization, and implantable cardiac defibrillators were also emphasized. Survival and outcomes data for patients receiving the bundled interventions were compared to control data prior to implementation of the initiative.

Importantly, survival to hospital discharge increased significantly from 8.5 to 19.0 %. These differences were especially striking in the subset of patients who had VF as the initial arrest rhythm; their numbers increased from 17.0 % versus 41.0 % [22]. These results show that when focus is applied to the AHA guidelines including recommended use of the ITD, cardiac arrest survival rates can be greatly improved. In summary, with greater attention to enhancing circulation, based on the newly discovered mechanisms underlying circulation during CPR, significant progress has been made by simply using a pair of hands and the ITD. It should be noted that a large multicenter study conducted by the Resuscitation Outcomes Consortium (ROC) group looked at outcomes from cardiac arrest using an active ITD versus a sham ITD. The results, originally published in 2011, reported no statistical differences in survival with good neurological function in the active group and the sham group [23]. Additional analyses revealed that the chest compression rates varied widely throughout the study, ranging from 50 compressions/minute to 240 compressions/minute [24]. When the subset of patients received compressions at a rate of 100 ± 10 compressions/minute, the active device showed a marked benefit on survival with good neurological function compared to the sham device. There was also a significant benefit identified for subjects who suffered VF arrests. This second look at the ROC data shows that when CPR is performed correctly, per AHA guidelines, the ITD can increase the rate of survival to hospital discharge with improved neurological function. Another analysis of the ROC data was independently performed by Yannopoulos et al. [25]. In addition to investigating compression rates as a surrogate for quality CPR, they also included only subjects receiving CPR at a depth of 4–6 cm (AHA recommends depth of 2 in or 5 cm) and a compression fraction (% of time performing chest compressions in a given minute) of >50 %. When these filters were

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applied, 7.2 % of subjects receiving CPR with the active ITD survived to hospital discharge with good neurological function, while the rate was only 4.1 % for subjects receiving CPR with the sham ITD (p = 0.006). This represents a 43 % increase in survival rate with good neurological function with the active ITD, over the sham ITD. Again, when quality CPR is delivered according to guidelines, the use of an ITD provides benefits to patients.

38.6

Active Compression-Decompression CPR

It has been shown that despite training, it is difficult to perform standard manual CPR correctly, e.g., allowing for the chest to fully recoil following each compression. These problems result in significantly less blood flow back to the heart and reemphasize that perhaps another device is needed to correct this widespread problem. Correction of this basic flaw (incomplete chest wall recoil) through the use of a technique that ensures full chest wall recoil and user guidance has the potential to significantly improve the chance for survival after cardiac arrest. One such technique is ACD-CPR which is performed with an ACD-CPR device. More specifically, ACD-CPR increases the naturally occurring negative intrathoracic pressure by physically lifting the chest wall and helping it to return to its resting decompressed position. During standard CPR, the chest wall’s natural elasticity will partially recoil from compression. Several factors can contribute to less than optimal recoil: (1) patient age, (2) brittle or broken ribs, (3) a separated or broken sternum, (4) a barrel-shaped chest, (5) the Fig. 38.11 ResQPUMP®, the US version of the active compression-decompression cardiopulmonary resuscitation device. The force gauge and metronome are used to guide the rescuer in the proper performance

presence of chest concavity, and/or (6) the tendency for rescue personnel to lean on the chest and thus cause incomplete chest wall recoil during performance of CPR. The use of an ACD-CPR helps ensure that the chest re-expands to generate the negative intrathoracic pressure needed to allow passive filling of the heart. For example, ACD-CPR can be performed with a handheld suction device (ResQPUMP®, Advanced Circulatory Systems) fixed on the anterior chest wall. During the compression phase, the chest is compressed, and blood is forced out of the heart to perfuse the vital organs, as with standard CPR. Next, when the chest is actively pulling up with the device, a vacuum is created within the thorax, drawing more blood back into the heart. This technique improves hemodynamics [26, 27] and, in some studies, long-term survival rates with patients in cardiac arrest, as compared with patients receiving standard CPR alone [28, 29]. The ACDCPR device is currently being used in many countries throughout the world including France and Israel, as well as parts of China, Japan, and Germany (Fig. 38.11). ACD-CPR in combination with the ITD, known as the ResQCPRTM System, received regulatory clearance in May of 2015 from the Food and Drug Administration (FDA) with an indication for use as a CPR adjunct to improve the likelihood of survival in adult patients with non-traumatic cardiac arrest. It should also be noted that ACD-CPR + ITD has been evaluated in multiple animal and clinical trials and is currently recommended in the AHA guidelines as an alternative to standard CPR. Importantly, the device combination has been shown to quadruple blood flow to both the heart and brain, compared with manual standard CPR alone.

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Fig. 38.12 Blood flow in a porcine model. The cumulative effect of ACD-CPR and ITD devices [9]. Solid horizontal line represents normal baseline values. STD standard, ACD active compression-decompression, CPR cardiopulmonary resuscitation, ITD impedance threshold device

This device combination also significantly increases blood pressures and survival rates [29–31]. Lurie et al. specifically studied the effects of ACD-CPR and an ITD on blood flow; the results are summarized in Fig. 38.12. Preclinical animal studies demonstrated that left ventricle and cerebral blood flows were markedly improved with ACDCPR + ITD [10, 32]. In these studies, CPPs were >20 mmHg, the minimum CPP thresholds needed to optimize the chance for survival in both humans and in a porcine model of cardiac arrest [33, 34]. The device combination also optimized perfusion within the brain, which was found to be even greater than baseline levels after a prolonged arrest, when comparing standard CPR to the combination of ACD-CPR + ITD [10]. The investigators believe that one of the reasons that the clinical trials with ACD-CPR + ITD have been successful is secondary to the marked increases in cerebral perfusion that can be achieved with this new approach. These findings have been reproduced by several other investigators using both pediatric and adult pigs in cardiac arrest [4, 35]. Improved forward blood flow and vital organ perfusion with use of ACD-CPR + ITD also enhances drug efficacy during CPR [36]. For example, it was shown that the effects of exogenous vasopressin were significantly enhanced with ACD-CPR + ITD for hypothermic pigs, as reflected by higher coronary and CePPs and improved cerebral metabolic profiles. In general, the use of the combination of ACD-CPR and the ITD can be considered to be synergistic. To date, four randomized clinical trials have been performed to evaluate the relative effectiveness and safety of the ACD-CPR + ITD in humans [30, 31, 37, 38]. The first blinded randomized clinical trial focused on resultant hemodynamics in patients with out-of-hospital cardiac arrest [37]. Eleven patients were treated with an active (functional) ITD and 10 with a sham (placebo) ITD. In that study, end-tidal carbon dioxide (ETCO2) levels rose more rapidly and reached higher levels with the active ITD; systolic and diastolic blood pressures were nearly normal in the active ITD group (109/57 mmHg)

versus the sham ITD group (89/35 mmHg, P < 0.01). In addition, ROSC occurred more rapidly in the active ITD group compared with the sham ITD group. Based upon these data, the use of ACD-CPR + ITD was recommended as an alternative to standard CPR in the 2000 AHA guidelines [39]. Another study demonstrated that the ITD augments negative intrathoracic pressure when applied to a face mask [38]. This is important because it indicates that inspiratory impedance can be added during BLS airway management (by first responders and perhaps even lay rescuers prior to intubation). Patients with out-of-hospital cardiac arrest were randomized prior to endotracheal intubation to either a sham or active ITD, and intrathoracic pressure tracings were recorded. Addition of the active ITD to the face mask resulted in an immediate decrease in intrathoracic pressures during ACDCPR. Each time the active ITD was used, there were significant reductions in the decompression phase intrathoracic pressures. These studies demonstrated, for the first time, the degree of negative intrathoracic pressures achieved with ACD-CPR + ITD in humans. The average maximum negative intrathoracic pressure was −7.3 mmHg with the active ITD on an endotracheal tube versus only −1.3 mmHg with the sham ITD. A second important finding was that it took up to 5 compression-decompression cycles to achieve the maximum negative intrathoracic pressures, as respiratory gases are expelled from the chest and prevented from reentry. This mechanism plays a key role in the function of the ITD. Each time an active, positive pressure, ventilation was delivered, the decompression phase intrathoracic vacuum was lost and required regeneration. Thus, the less frequently the ventilation rate was employed, the greater the blood flow back to the heart. A recent study using standard CPR with the ITD in pigs confirmed this important observation [12]. This has become an important theme for all types of CPR; ventilations interrupt CPP and should be reduced to the minimum required to maintain oxygenation and transpulmonary circulation.

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Fig. 38.13 Outcomes associated with comparison of standard cardiopulmonary resuscitation (STD) and ACD-CPR + ITD (n = 210) in Mainz, Germany. 1HrS 1-hour survival, 24HrS 24-hour survival, ACD active compression-decompression, Admis hospital admission, CPR cardiopulmonary resuscitation, Disch hospital discharge, ITD impedance threshold device, ROSC return of spontaneous circulation

Fig. 38.14 Outcomes in patients randomized with either standard CPR (STD) or ACDCPR + ITD with witnessed ventricular fibrillation in Mainz, Germany (n = 70). 1HrS 1-hour survival, 24HrS 24-hour survival, ACD active compression-decompression, Admis hospital admission, CPR cardiopulmonary resuscitation, Disch hospital discharge, ITD impedance threshold device, ROSC return of spontaneous circulation

It is generally accepted that ACD-CPR with an ITD improves short-term survival rates after cardiac arrest. A recent prospective controlled trial was performed in Mainz, Germany [37]; patients with out-of-hospital arrest of presumed cardiac etiology were sequentially randomized to ACD-CPR + ITD or standard CPR (control subjects) by the advanced life support team after intubation. Patients with an identified initial heart rhythm of VF (42 % of the total), who could not be resuscitated by BLS early defibrillation, were enrolled in this clinical trial, as well as patients with an initial rhythm of asystole or PEA. The primary endpoint was 1-h survival after a witnessed arrest. With ACD-CPR + ITD (n = 103), ROSC, 1-h and 24-h survival rates were 55 %, 51 %, and 37 % versus 37 %, 32 %, and 22 % for standard CPR alone (n = 107; p = 0.016, 0.006, and 0.033), respectively (shown in Fig. 38.13). One-hour and twenty-four-hour survival rates in patients with a witnessed arrest were dramatically higher after ACD = CPR + ITD—68 and 55 %, respectively, versus 27 and 23 % with standard CPR (p = 0.002 and 0.009) (shown in Fig. 38.14).

Hospital discharge rates were 18 % after ACD-CPR + ITD versus 13 % in control subjects (P = 0.41). Overall neurological function trended higher with ACD-CPR + ITD versus control subjects (P = 0.07). Importantly, patients randomized >10 min after the call for help to the ACD + ITD CPR group had a greater than three times higher 1-h survival rate (44 %) than control subjects (14 %) (P = 0.002). These time-related benefits were observed regardless of presenting rhythm. It should be noted that neurological outcomes in the survivors with delays to treatment with ACD-CPR + ITD were similar to those who were treated with ACD-CPR + ITD more rapidly. Another prospective blinded study performed in France also demonstrated significantly increased 24-h survival rates with use of ACD-CPR + ITD [31]. In one arm of this study, 200 patients were treated by advanced life support personnel with ACD-CPR and an active ITD, and another 200 patients were randomized to the control group and received treatment with ACD-CPR and a sham ITD. As in other studies from France, most of the patients had an initial rhythm of asystole [28, 29]. The group treated with ACD-CPR and an active

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38 Treatment of Sudden Cardiac Arrest and Shock Fig. 38.15 Percentage survival to hospital discharge with favorable neurological outcome in patients randomized to either standard CPR (S-CPR) or ACD-CPR + ITD (n = 1653). ACD-CPR active compression-decompression cardiopulmonary resuscitation, ITD impedance threshold device

ITD had 24-h survival rates of 32 % compared with 24-h survival rates of 22 % in the control population (P < 0.05). Because of long EMS response times, survival rates in both groups were very low, but differences in neurological function in the survivors trended in favor of the ACD-CPR + ITD group. Only 1/8 (12 %) of survivors treated with the sham device had normal cerebral function at the time of hospital discharge, versus 6/10 (60 %) in the functional ITD group (p < 0.07). Perhaps the most definitive proof of the effect of ACDCPR + ITD on long-term survival was demonstrated in a large prospective, randomized clinical trial funded by the National Institutes of Health [40]. This out-of-hospital study compared ACD-CPR plus an ITD to manual standard CPR in adult, nontraumatic cardiac arrest patients. A total of 2470 subjects were randomized and received CPR with one of the two CPR methods, with 1653 subjects meeting final inclusion criteria: 813 in the control group (standard CPR) and 840 in the intervention (ACD-CPR + ITD) group. First, the results of the study demonstrated that the use of these devices was safe. The overall rate of major adverse events, including chest fractures, was not significantly different between groups, although there were more reports of pulmonary edema in the intervention group; this was coexistent with increased survival in this group. Neurological function was similar between groups at 90 days and one year after cardiac arrest. There were no increases in the number of patients with severe neurological impairments in the intervention group. This study also demonstrated the efficacy of these employed devices. ACD-CPR with the augmentation of negative intrathoracic pressure using an ITD improved long-

term survival (to hospital discharge) with favorable neurological function by 53 % (p = 0.019), and the survival benefits persisted to a 1-year time point following cardiac arrest, as shown in Fig. 38.15. In the patient population which typically resulted in poor neurological function at hospital discharge, the use of ACD-CPR with an ITD and therapeutic hypothermia resulted in a sixfold improvement in neurological function by 90 days, compared to standard CPR with therapeutic hypothermia [41]. In patients with outof-hospital cardiac arrest from a variety of nontraumatic etiologies, ACD-CPR with an ITD resulted in a 38.5 % increase in survival to hospital discharge, with favorable neurological function (p = 0.027) and a 35.4 % increase in survival at 1 year with favorable neurological function (not significant), compared to patients receiving S-CPR [42]. In the absence of treatment with therapeutic hypothermia after cardiac arrest, survival rates with favorable neurological function at hospital discharge and 90 days after cardiac arrest were nearly twice as high with ACD-CPR plus an ITD compared to standard CPR, indicating that the combination therapy is neuroprotective, independent of in-hospital therapeutic hypothermia.

38.7

Treatment of Life-Threatening Hypotension with the ITD in Spontaneously Breathing Patients

Shock can be defined as life-threatening hypotension and results in inadequate tissue perfusion. Hypovolemia caused by uncontrolled hemorrhage in trauma is the most common form or cause of shock and is referred to as hemorrhagic

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shock. Death following severe blood loss commonly develops secondary to profound hypotension and vital organ ischemia. In other words, in the absence of a critical central blood volume, both stroke volume and cardiac output are decreased and hypotension ensues. Intravenous fluids and vasopressor agents have traditionally been the mainstay of therapy for patients with marked hypotension. Commonly, intravenous fluids and blood replacement, together with intravenous therapies such as epinephrine and other vasopressors, have been effective as short-term therapies, i.e., providing a bridge to more definitive repair of the primary injury. Yet, their use is also associated with significant clinical shortcomings such as the following: (1) they require intravenous or intraosseous access; (2) nonblood volume expanders can decrease the effectiveness of normal thrombus formation (by dilution of critical clotting factors); and (3) their use can ultimately reduce the oxygen carrying capacity of the blood. In addition, massive intravenous fluid replacement can in turn cause both pulmonary and peripheral edema (in some cases, cerebral edema), as well as hypothermia. Furthermore, vasopressors can also cause ischemia, especially to the gut. Vasopressors and fluids have been associated with “popping the clot” in the patient with significant blood loss secondary to sudden increases in blood pressure to normal or above normal values. Moreover, vasopressors like epinephrine can cause supraventricular or ventricular tachycardias, which can lead to a further compromise of the patient’s already tenuous hemodynamic status. It should be noted that even the sinus tachycardia that is normally observed after epinephrine therapy can be detrimental in the setting of shock, as it results in a decreased amount of time for cardiac filling after each ventricular systole. This is an important issue since blood flow back to the heart is markedly decreased because of the low central venous pressures. In other words in this setting, one needs more time (and thus a slower heart rate) for effective refilling of the heart after each contraction. As such, there is strong evidence that one of the primary mechanisms that contribute to reduced cardiac filling, decreased stroke volumes, and ultimately shock following an acute hemorrhage is the reduction in the circulating blood volume and a subsequent reduction in cardiac filling pressures (i.e., lower central venous pressures or cardiac preloads). Therefore, countermeasures designed to increase venous return and decrease cardiac filling without causing hemodilution and without “popping the clot” may be an effective therapy for the acute treatment of massive blood loss. It is important to recognize that the primary goal of any therapy used for the treatment of hemorrhagic shock is the restoration of sufficient vital organ perfusion to prevent death, even if the primary cause of the blood loss has not yet been established or repaired. Such therapies should act primarily to

A. Metzger and K. Lurie

Fig. 38.16 ResQGARD® impedance threshold device on a face mask

increase stroke volumes rather than to increase peripheral resistance, as the latter may cause more harm than good. Ideally, a new therapy designed to improve vital organ perfusion in the setting of hemorrhagic shock should act primarily to optimize stroke volumes, improve vital organ blood flow by a mechanism that is independent of increasing peripheral vascular resistance, and help to stabilize a permissive hypotensive state that provides adequate cerebral perfusion. Building upon the needs described above, two new technologies have been developed by Advanced Circulatory Systems to treat clinically significant hypotension. One is termed the ITD for spontaneously breathing patients (ResQGARD® ITD), and the other is called the intrathoracic pressure regulator (ITPR, CirQlator®). The ResQGARD, shown in Fig. 38.16, is designed for the spontaneously breathing patient and can be considered as a natural extension of a normal physiological process, i.e., the transformation of the normal respiratory muscle function from a primary gas exchange function to the dual functions of gas exchange and augmentation of venous return, as well as enhancement of cardiac stroke volume. The ITPR was designed for the mechanically ventilated patient where it actively provides a low level of negative pressure during the expiratory phase of ventilation, thereby increasing venous return and improving cardiac output, stroke volume, and blood pressure. To avoid confusion, the differences between the ITDs and the ITPR device are summarized in Fig. 38.17.

38 Treatment of Sudden Cardiac Arrest and Shock

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Fig. 38.17 Differences between an impedance threshold device (ITD) for spontaneously breathing patients and for those in cardiac arrest and the intrathoracic pressure regulator (ITPR)

The ITD works by lowering intrathoracic pressure in the thorax with each inspiration, thereby enhancing venous blood flow back to the heart and lowering ICPs. These mechanisms serve to enhance both cardiac output and blood pressure. There is also experimental data suggesting that the use of the ITD will reduce the amount of vasopressors needed, since it increases overall cardiac outputs and circulation [36]. In this manner, the ITD provides an indirect drug-enhancing effect, enabling the rescuers to use less of a vasopressor drug, and perhaps less fluid resuscitation, to obtain the same or greater hemodynamic effectiveness. The spontaneously breathing version of the ITD is a small disposable plastic airflow regulator that can be attached to a face mask, mouthpiece, or tracheal tube. The device has a spring-loaded diaphragm that requires a certain threshold (cracking pressure) to be achieved before it opens to allow airflow, thus functioning like a partial Mueller maneuver (inhaling against a closed glottis) to augment negative intrathoracic pressure with each inspiration [9]. In this manner, the device harnesses the patient’s own respiratory pump to enhance circulation. In 1947, Cournand was the first to show that increases in mean airway pressure result in decreased systemic venous return, decreased pulmonary blood flow, and a fall in cardiac output. Lower negative intrathoracic pressure during spontaneous inspiration, however, represents a natural mechanism for enhancing venous return and cardiac filling. Several natural physiological reflexes, such as

gasping and the Mueller maneuver, augment negative intrathoracic pressure and increase cardiac output. Several authors have shown that artificially induced negative pressure ventilation can be used to increase cardiac output [43, 44]. The ITD has been evaluated in animals and humans for the treatment of: (1) cardiac arrest, (2) hemorrhagic and heat shock, and (3) orthostatic hypotension and (4) for enhancing blood donation. In 2004, Lurie et al. demonstrated that spontaneous breathing through the ITD during hemorrhagic and heat shock in a porcine animal model resulted in an immediate sustained rise in systolic blood pressure in both conditions [45]. As shown in Fig. 38.18, addition of the ITD (set to open at a cracking pressure of −12 cmH2O) after an acute hemorrhage resulted in immediate rises in systolic blood pressure that was sustained for 30 min. Upon removal of the ITD, the blood pressure decreased back to values identical with the controls. These studies showed a 30 % increase in cardiac output when the ITD was utilized for the pigs in shock. Subsequent studies showed that the use of the ITD in spontaneously breathing pigs after severe hemorrhage resulted in increased cardiac output, blood pressure, cardiac chamber dimensions, transvalvular blood flow, and survival rates [46]. These studies demonstrate how the ITD augments cardiac output, improves hemodynamics, and increases survival in spontaneously breathing pigs under conditions of hypovolemic hypotension [47].

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A. Metzger and K. Lurie

Fig. 38.18 Changes in systolic blood pressure (SBP) with and without impedance threshold device (ITD) breathing following controlled hemorrhage and shock in spontaneously breathing pigs

More recently, Metzger et al. studied the use of the ITD in a porcine hemorrhagic model to determine if the negative intrathoracic pressure therapy provided by the device could improve systolic blood pressure but still allow permissive hypotension, thereby avoiding “popping the clot” [48]. They compared the use of the ITD to the current standard of care, i.e., infusing normal saline to treat a 55 % hemorrhage. Maximum systolic blood pressure during 15 min of treatment was significantly higher in the normal saline group compared to the ITD and control groups, but at a level of 131 ± 7.6 mmHg, it was well above the threshold believed for the risk clot dislodging in animals (94 ± 3 mmHg). Conversely, pigs treated with the ITD had significant improvements in systolic blood pressure throughout the 30-min course of treatment compared to controls, but the levels were much more moderate and well within the levels of permissive hypotension. Another benefit to the ITD was that blood pressures were considered adequate for organ perfusion, but importantly the ICPs were not elevated. This allowed for improved perfusion to the brain, while increased ICP resulting from normal saline infusion would likely impede cerebral blood flow. These results show that the ITD can be effective in treating hypotension secondary to trauma or hemorrhage without the negative effects associated with excessive systolic blood pressure. The ITD with a cracking pressure of −6 cmH2O was first studied in normal volunteers by Convertino et al. at NASA, in studies related to post-flight orthostatic hypotension [49]. Inspiration through the ITD increased cardiac output by about 1.5 L/min in supine subjects and was well tolerated. The ITD increased stroke volume and was shown to maintain blood pressure in normal volunteers subjected to acute orthostatic stresses and later in patients with symptomatic orthostatic hypotension. The use of the ITD in normal volunteers resulted in: (1) an immediate increase in cardiac stroke volume, (2) increases in both systolic blood pressure and heart rate, and (3) improved cardiac output as shown in Fig. 38.19

[50]. It was also observed that total peripheral resistance was reduced by the ITD. Also highly relevant is how the ITD affects the work of breathing. To assess the work of breathing associated with the use of the ITD, the power of breathing was measured in collaboration with NASA scientists in 9 female and 9 male subjects breathing through a face mask at two separate ITD conditions: (1) −6 cmH2O and (2) control (0 cmH2O). The results from this study demonstrated that breathing through the ITD was well tolerated by all subjects. For the sham and active ITD groups, respectively, peak inspiratory pressures were −1.13 ± 0.63 cmH2O and −9.92 ± 6.2 cmH2O (p < 0.0001); tidal volumes were 958 ± 396 mL and 986 ± 389 mL (not significant); and inspiratory times were 189 ± 81 ms and 296 ± 109 ms (p = 0.002). For the sham and active ITD groups, respectively, imposed work of breathing (WOBi) was 0.064 ± 0.04 J/L and 0.871 ± 0.117 J/L (p < 0.0001); power of breathing (POBi) was 0.88 ± 0.63 J/ min and 7.56 ± 3.55 J/min (p < 0.0001); peak inspiratory pressures were −1.13 ± 0.63 cmH2O and −9.92 ± 6.2 cmH2O (p < 0.0001); tidal volumes were 958 ± 396 mL and 986 ± 389 mL (not significant); and inspiratory times were 189 ± 81 ms and 296 ± 109 ms (p = 0.002). Interestingly, there were no significant observable differences between men and women in terms of work of breathing [51]. To put these data into perspective, one must understand the power of breathing for a normal individual, where power is work per unit time (W = W × f, where f is respiratory frequency). The maximal power output for normal young adults is 613 cal/min (range: 500–860) [52]. Thus, the amount of power output required during quiet breathing or the use of the ITD seems rather minimal, amounting to less than 1.0 % of maximum. Vigorous exercise requiring minute volume of 60–80 L requires ~80 J/min of power. The −6 cmH2O ITD requires about 1–2 cal/min of respiratory power. For the ITD to be functional, the energy required for its operation should not exceed the energy available in the patient population in

38 Treatment of Sudden Cardiac Arrest and Shock

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Sham ITD

120 115 110 105 100 Breath 150

75

70

65

10 Cardiac Output, liters/min

130 120 110 100 90 Breath

5 min Rec

65 60 55 50

P = 0.001

9 10

9

Breath

Breath

5 min Rec

6

80

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40

60 Breath

P = 0.013

P = 0.049

45

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75 Heart Rate, bpm

125

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80

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Systemic Peripheral Resistance, PRU

P = 0.005

Diastolic Blood Pressure, mmHg

Systolic Blood Pressure, mmHg

130

5 min Rec

15 P = 0.003 13 11 9 7 5 Breath

5 min Rec

Fig. 38.19 Hemodynamic results. Systolic and diastolic blood pressures, heart rate, stroke volume, cardiac output, and total peripheral vascular resistance during (breath) and after (5-min recovery) spontane-

ous breathing on the impedance threshold device (ITD) at 0 cmH2O resistance (sham control, open bars) and −6 cmH2O resistance (solid bars) (n = 20)

which it is expected to be applied, for example, ill and injured patients with hypotension. It is known that ill patients who require mechanical ventilator support use about 1–2 cal/ min for self-triggered ventilation and are generally able to sustain this level of effort for long periods (hours to days) [52]. Therefore, we expect that most patients will be able to tolerate the use of the ITD without excessive fatigue, given that it requires only a fraction of the respiratory power needed for a similarly ill group of patients to self-trigger a mechanical ventilator. Based on these measurements, we conclude that the vast majority of conscious but hypotensive patients will be able to inspire through the ITD with a resistance of −7 cmH2O and should therefore benefit hemodynamically from the device. Most recently, the ITD was studied by Convertino et al. at the US Army Institute of Surgical Research, using a lower body negative pressure chamber (LBNP) to lower central blood volume and thus induce a state of severe hypotension [53]. A photo of the LBNP chamber is shown in Fig. 38.20. The application of negative pressure to the lower body

(below the iliac crest) results in a redistribution of blood away from the upper body (head and heart) to the lower extremities and abdomen. Thus, this model provides a unique method of investigating interventions such as the ITD under conditions of controlled, experimentally induced hypovolemic hypotension. Absolute equivalence between the magnitude of negative pressure applied and the magnitude of actual blood loss has recently been evaluated in a baboon model which demonstrated the absolute equivalence between the simulated bleed and the actual blood loss [54]. On the basis of the magnitude of central hypovolemia induced, Convertino et al. provide data to support that 10–20 mmHg negative pressure induces hemodynamic responses that are equivalent to those resulting from blood loss ranging from 400 to 550 mL, 20 to 40 mmHg negative pressure induces hemodynamic responses that are equivalent to those resulting from blood loss ranging from 550 to 1000 mL, and greater than 40 mmHg negative pressure induces hemodynamic responses that are equivalent to those resulting from blood loss approximating 1000 mL or more

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A. Metzger and K. Lurie

Fig. 38.20 Lower body negative pressure chamber used to simulate severe hypotension

Fig. 38.21 Representative tracings of beat-to-beat mean arterial blood pressure obtained from the same subject while breathing on a sham impedance threshold device (ITD; top panel) and active ITD (bottom panel) during the final two minutes of lower body negative pressure chamber exposure prior to cardiovascular collapse

[53]. Nine healthy normotensive volunteers completed two counterbalanced protocols with (active) and without (sham) an ITD set to open at −6 cmH2O pressure. Continuous noninvasive measures of systolic (SBP), diastolic (DBP), and mean (MAP) arterial blood pressures were obtained during a LBNP protocol consisting of a 5-min rest period (baseline) followed by 5 min of chamber decompression at −15, −30, −45, and −60 mmHg, as well as additional increments of −10 mmHg every 5 min until the onset of cardiovascular collapse. Overall, SBP (79 ± 5 mmHg), DBP (57 ± 3 mmHg), and MAP (65 ± 4 mmHg) at the time of cardiovascular col-

lapse were lower (P < 0.02) when subjects breathed through the sham ITD than when they breathed through the active ITD at the same time points of LBNP (102 ± 3, 77 ± 3, 87 ± 3 mmHg, respectively). Elevated blood pressures were associated with a 23 % increase (P = 0.02) in LBNP tolerance using an active ITD (1639 ± 220 mmHg-min) compared with a sham ITD (1328 ± 144 mmHg-min). A representative tracing of data obtained in these studies is shown in Fig. 38.21. These results are the first to demonstrate, in humans, that the time to cardiovascular collapse associated with progressive reduction in central blood volume and subsequent

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38 Treatment of Sudden Cardiac Arrest and Shock

Fig. 38.22 Typical continuous recording of mean cerebral blood flow (CBF) velocity in a subject before, during (On ITD), and at the cessation (Off ITD) of spontaneous breathing on the impedance threshold device (ITD)

development of severe hypotension can be significantly improved by inspiratory resistance induced by spontaneous breathing through an ITD. The results from the present experiment demonstrated an average elevation in SBP of 23 mmHg when estimated central blood volume was reduced by more than 2 L [53]. Importantly, the use of an ITD also has striking effects on cerebral artery blood flow. With each inspiration through the ITD, ICPs are lowered, and simultaneously cardiac output is increased. Measurement of middle cerebral intracranial Doppler demonstrated that the use of the ITD increased middle cerebral artery blood flow in spontaneously breathing adult humans, as shown in Fig. 38.22 [55]. Our group recently performed another clinical trial which evaluated the use of the ITD to treat non-life-threatening hypotension (SBP < 95 mmHg) in the emergency room setting. In this randomized double-blind clinical trial, patients received the current standard of care for hypotension, which consists of controlling the bleeding, reversing other potential causes of low blood pressure such as correcting hyperthermia, and administering fluids, oxygen, and/or blood products as appropriate. The use of the ITD did not interfere with standard therapy. Once it was determined that the subjects met enrollment criteria based upon the inclusion and exclusion criteria and informed consent was obtained, subjects were randomized to either a sham ITD or an active (functional) ITD; the sham and active ITDs appeared identical. The devices were kept in an opaque package, preventing anyone involved with the study from knowing whether any given device was a sham or active ITD based upon visual inspection. Baseline blood pressure, heart rate, respiratory rate, oxygen saturation, and clinical findings including quality of the pulse and quality of respirations were recorded immediately. The ITD was then placed, and hemodynamic

parameters were assessed every 2 min, for a minimum of 6 min and up to 10 min. Standard therapies, including intravenous fluids, were administered as deemed clinically necessary, regardless of the effect of the ITD. The active device was found to be significantly more effective than the sham. Specifically, the mean rise in SBP for the active ITD group was 13.2 ± 7.8 mmHg (n = 16) versus 5.9 ± 5.5 mmHg for the sham ITD group (n = 19) (p = 0.003). Mean fluids given during the study were 92 ± 170 ml for the active ITD group and 192 ± 200 ml for the sham ITD group (p = 0.13). In a subgroup of patients that received no fluids during device use, the maximum rise in SBP (mean ± STD) was 12.8 ± 7.8 mmHg for the active ITD group and 5.6 ± 5.0 mmHg for the sham ITD group (p = 0.04). MAP was also statistically higher in the active ITD group (9.2 ± 7.8 versus 4.8 ± 3.3, p = 0.03) [56]. More recently, a study conducted by Wampler et al. looked at the use of the ITD in patients with hypotension, which was defined as a SBP less than 90 mmHg [57]. The primary endpoint was MAP before application of the ITD versus MAP after 2–4 min of ITD use. They found that average systolic and diastolic blood pressures and MAPs all increased by a statistically significant amount with ITD use in all patients (78 ± 13 mmHg versus 97 ± 19 mmHg, 51 ± 13 mmHg versus 63 ± 15 mmHg, and 60 ± 10 mmHg versus 70 ± 15 mmHg, respectively). Additionally, systolic and diastolic pressures were increased for the subset of patients who elicited hypotension due to trauma. These findings support the use of the ITD as a safe and tolerable means to treat hypotension from traumatic and nontraumatic causes. It is now the general consensus that the ITD harnesses the patient’s own thoracic pump to enhance circulation and offers a noninvasive means to treat some of these patients. However, the spontaneous breathing version of the ITD requires that patients be able to breathe on their own, and most patients in severe shock are usually intubated and require assisted ventilation. To fill this gap, the ITPR was developed. This technology was developed based on the concept of lowering intrathoracic pressures to enhance circulation for patients with life-threatening hypotension that are dependent upon assisted ventilation.

38.8

ITPR Therapy: A Potential Novel Treatment of Severe Hypotension in Severely Ill Patients

To date, the ITPR described below has been tested in animals and in limited clinical studies. It combines a way to generate a controlled intrathoracic vacuum with a method to provide controlled positive pressure ventilation. It can be used for the treatment of cardiac arrest, multiple forms of shock to buy time until more definitive therapy is available, or cerebral

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injuries. The device can be used with a handheld resuscitator bag or it can be attached to a mechanical ventilator or anesthesia machine. While multiple designs are possible to embody this concept, the main function of the ITPR is to create a preset continuous and controlled expiratory phase negative intrathoracic pressure that is interrupted only when positive pressure ventilation is needed to maintain oxygenation and provide gas exchange. Today, the ITPR has been cleared for sale by the FDA with the approved indication of a device to “temporarily decrease intrathoracic pressure to increase blood circulation.” It was recognized from the start of device development that it would be important to develop a modification of the ITD for the use with nonbreathing and more critically ill hypotensive patients; this resulted in the concept of the ITPR. The ITPR employs an external vacuum source to lower intrathoracic pressures and thus enhance venous blood flow back to the heart in nonbreathing hypotensive patients. This refinement is based on the breakthrough in our clinical understanding of the basic physiological principles of blood flow in hypotensive states. By transforming the chest into an active bellows during CPR, the combination of a relatively low level expiratory phase intrathoracic vacuum and intermittent positive pressure ventilation results in a significant augmentation of venous blood flow to the right heart, thereby increasing both stroke volume and cardiac output. Contemporaneously, the decrease in intrathoracic pressure results in decreases in ICP and thus provides an additional mechanism whereby the ITPR increases CePP; this is illustrated in Fig. 38.23. When the ITPR is turned on, the intrathoracic pressure between positive pressure breaths is lowered immediately, as is the ICP. Based on these findings,

Fig. 38.23 Changes in airway pressure and intracranial pressure (ICP) when the intrathoracic pressure regulator (ITPR) is turned on and then off again

A. Metzger and K. Lurie

the ITPR may also ultimately have the potential for treatment of brain injury. To date, the potential beneficial effects of the ITPR have been studied in pigs in VF during CPR. In this setting, the ITPR was used to lower intrathoracic pressure and thus enhance venous return to the heart and increase overall efficacy [58]. Vital organ perfusion pressures and end-tidal carbon dioxide levels were significantly improved with ITPR-CPR, and animal survival was 100 % (10/10) with ITPR-CPR versus 10 % (1/10) with standard CPR alone. The use of ITPR-CPR improved hemodynamics, vital organ perfusion pressure, and carotid blood flow in animals eliciting both VF and hypovolemic cardiac arrest. Figure 38.24 demonstrates the significant hemodynamic differences observed when using the ITPR during standard CPR in this animal model of cardiac arrest. The physiological goals of the ITPR are to lower intrathoracic pressure during the expiratory phases of ventilation and provide positive pressure ventilation in patients requiring assisted ventilation. The first preclinical studies evaluating the effects of the ITPR on vital organ perfusion pressure were performed in both normovolemic and hypovolemic swine [59, 60]. Six anesthetized animals received 5-min interventions with endotracheal pressure (ETP) set to 0, −5, 0, −10, 0, −10, 0, −5, 0 mmHg during euvolemia and then after a fixed hemorrhage of 50 % of their total blood volumes. Hemodynamic parameters were continuously measured, and blood gases were obtained at the end of the first four 5-min intervals. Under both euvolemic and hypovolemic conditions, right atrial pressure and ICP decreased proportionally to the intrathoracic pressure, with the more marked changes observed with hypovolemic conditions. By contrast, the increases in MAP, coronary perfusion pressure, and CePPs

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38 Treatment of Sudden Cardiac Arrest and Shock

Fig. 38.24 Effect of intrathoracic pressure regulator (ITPR) CPR on carotid blood flow, coronary perfusion pressure, blood pressure, and cerebral perfusion pressure compared to standard CPR (Std-CPR). BP blood pressure, CPR cardiopulmonary resuscitation Table 38.1 Basic hemodynamic parameters with endotracheal pressure set at 0, −5, and −10 mmHg with the ITPR for blood volumes after 0 and 50 % blood loss Blood loss (%) 0

50

ETP MAP RAP CPP CerPP ICP MAP RAP CPP CerPP ICP

0 89.9 ± 4.5 1.8 ± 0.4 80 ± 3.9 74 ± 4.8 15.6 ± 0.6 28.8 ± 4.3 −2 ± 0.9 25.8 ± 5 18.1 ± 4.4 10.7 ± 1.3

−5 104.3 ± 7.3* −0.8 ± 0.6* 94.2 ± 6.4* 90.3 ± 7.4* 14 ± 0.7 39.8 ± 5.9* −5.7 ± 0.6* 38.5 ± 3.7* 32.9 ± 5.8* 6.8 ± 1.4*

−10 108.5 ± 6.1* −4.8 ± 0.4†,* 103.3 ± 5.3*,† 95.1 ± 6* 13.5 ± 0.6* 47.3 ± 7.3*,† −9.3 ± 0.3*,† 48.3 ± 3.8*,† 43.1 ± 7.2*,† 4.2 ± 1*,†

ETP endotracheal pressure, MAP mean arterial pressure, RAP right atrial pressure, CPP coronary perfusion pressure, CerPP cerebral perfusion pressure, ICP intracranial pressure *Statistically significant difference (0.05 > p > 0.001) when compared to the values with ETP of 0 mmHg † Statistically significant difference between values with −5 and −10 mmHg of ETP (p < 0.05)

were inversely proportional to the negative intrathoracic pressure both in the normovolemic pigs and after induced hemorrhage. These data are consistent with findings in spontaneously breathing adult and pediatric swine models of shock and the use of the ITD [45, 46]. The major hemodynamic parameters for 0, −5, −10 mmHg of ETP are shown in Table 38.1. Based on the data available to date, we believe that the generation of intrathoracic pressures greater than −15 mmHg may be excessive and not beneficial with long-term use. Our initial studies demonstrated that the ITPR could reproducibly decrease ETP, intrathoracic pressure (as seen

by the decreases in right atrial pressure), and ICP. The ITPR provided hemodynamic improvements with no acid-base changes during normovolemia. We have applied the ITPR in euvolemic anesthetized pigs for up to 6 h, with an intrathoracic vacuum set to −9 mmHg, without obvious adverse effects on gas exchange or the overall metabolic state of these animals. The long-term benefits of the ITPR after hemorrhage are considered to be much more dependent upon the degree of hypotension. During 50 % hypovolemia, there was more acidosis associated with the generation of negative ETP, as reflected by a lower pH and higher PaCO2. However,

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despite the lower pH values, which may be secondary to greater clearance of lactate, ITPR use increased blood pressure, pulse pressure, vital organ perfusion pressure, and ETCO2 levels suggesting there was improved balance between the increase in circulation and the potential for induced metabolic acidosis with ITPR use. Oxygenation saturations remained at 100 % with ITPR use. To date, the 510k cleared IPR device (CirQlator®) has been used by emergency medical personnel in Toledo, Ohio, during CPR administration [61]. In these cases, end-tidal CO2 (ETCO2) was assessed as an indirect surrogate for circulation. ETCO2 values in 11 patients were compared pre- and during IPR therapy and then compared to 74 patients that were not treated with IPR therapy, but that were treated with an ITD. ETCO2 levels increased from 21 ± 1 mmHg immediately prior to IPR application to an average of 32 ± 5 mmHg and a maximum of 45 ± 5 mmHg during IPR treatment (p < 0.0001). Note that ETCO2 levels did not change significantly in the group not receiving active IPR therapy. More importantly, ROSC rates were 46 % in the standard CPR plus ITD group (34/74) and 74 % in the IPR-treated group (8/11) (p < 0.001). Huffmyer et al. reported that in 20 patients about to undergo coronary artery bypass graft surgery, thermodilution cardiac output increased significantly with the application of the ITPR (4.9 versus 5.5 L/min, p = 0.017); similarly, cardiac output measured by transesophageal echocardiography was 5.1 versus 5.7 L/min, respectively (p = 0.001). There were also significant increases in pulmonary artery systolic blood pressure (35 mmHg versus 38 mmHg, p < 0.001) and mean pulmonary artery pressure (24 mmHg versus 26 mmHg, p = 0.008) with this therapy [62]. Additional clinical experiences with the IPR device have further demonstrated the potential of this technology to treat brain insult. For example, Kiehna et al. recently reported the first use of the ITPR (10-min applications) in 10 patients with compromised cerebral perfusion, highlighting increases in CePP and decreases in ICP with use of this new technology [63].

Fig. 38.25 Sequential changes in mean arterial pressure (MAP), coronary perfusion pressure (CPP), cerebral perfusion pressure (CerPP), right atrial pressure (RAP), and intracranial pressure (ICP) for sequential changes of endotracheal pressure (a surrogate for intrathoracic pressure) of 0, −5, 0, −10, 0, −10, 0, −5, 0 mmHg during 50 % hypovolemia. Differences between the values of all parameters are statistically significant with p < 0.05

A. Metzger and K. Lurie

To date, studies on the potential benefits of longer-term application of negative intrathoracic pressure have been initiated in a preliminary manner. For example, in pilot studies on spontaneously breathing swine, in collaboration with researchers at the US Army Institute of Surgical Research, we applied the ITD to spontaneously breathing animals in severe hemorrhagic shock, an uncontrolled model of severe blood loss [47, 64]. These splenectomized swine were subjected to a 60 % blood loss, followed by a 4 mm hole created in their abdominal aortas. Remarkably, the use of the ITD in pilot studies stabilized these animals for about 60 min after the hemorrhage and injury occurred. However, after 75 min, we observed the development of a significant metabolic acidosis, as reflected by a progressive negative base excess. At that point, the swine were hemodynamically stable, but shortly thereafter they became extremely agitated, hypotensive, and then died [47]. These pilot studies provided us with some fundamental insights related to the limitations of using the ITD, and by analogy the ITPR by itself, in the setting of severe blood loss. While these devices can be used to “buy time,” ultimately some fluid resuscitation and correction of the underlying causes of the blood loss are essential. Although some fluids are ultimately needed, we hypothesize that the use of the ITD and ITPR can function by actually being fluid sparing and will extend the window of opportunity to provide lifesaving care in the setting of severe blood loss. The ITPR was designed to provide a noninvasive means to increase MAP in the setting of cardiac arrest and significant hypotension in apneic patients. The effects are rapid and can be turned on or off by the flip of a switch, unlike more long-lasting and sometimes harmful effects of fluid and drug administration. This switch-like effect is shown in Fig. 38.23. In another study (shown in Fig. 38.25), the intrathoracic pressures were varied between 0, −5, and −10 mmHg; with each change, there were rapidly adjustments in key hemodynamic variables and ICPs. Based upon the combined effects of the ITPR shown in multiple preclinical studies, we believe

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38 Treatment of Sudden Cardiac Arrest and Shock

that that ITPR has the potential to become a first-line therapy for all patients in cardiac arrest, as well as provide benefits for many individuals eliciting hypotension from a wide variety of causes. Importantly, the device can be applied quickly, often before intravenous access and intraosseous access, or fluids may be available, and it safely and quickly increases systemic, coronary, and CePPs. Based upon our experience in noncardiac preclinical arrest models, the use of the ITPR may be of significant benefit after traditional therapies have been provided, in that the ITPR application may reduce: (1) the amount of fluid volume needed for resuscitation from multiple etiologies, (2) secondary brain injury, and/or (3) the amount of vasopressors needed to maintain “permissive hypotension.” The clinical use of ITPR may thereby become a commonplace therapy in both operating rooms and intensive care units, to help maintain vital organ perfusion. To date, the ITPR has been used in patients with acute hypotension intraoperatively; it has been well tolerated and resulted in significant increases in MAP, pulse pressure, and systolic blood pressure in the absence of fluid administration or vasopressor therapy [65]. Studies to date have also shown that the application of ITPR therapy in cardiac arrest cases results in marked improvements in hemodynamics in both human and animal models. Application of the device in hypovolemic pigs was shown to enhance circulation, stroke volume, MAP, CPP, and CePP and decrease ICP. Studies in a porcine model of peritonitis (septic shock) have indicated an augmentation in cardiac index and MAP while simultaneously lowering pulmonary artery pressure during ITPR use [66, 67]. Yet, it should be noted that the longer-term potential consequences of the ITPR remain unknown. One known limitation is that, in order for this technology to be of clinical benefit, the thorax must be intact; otherwise, it is not possible to generate expiratory phase negative intrathoracic pressure with the ITPR. Furthermore, it is not possible to lower the expiratory phase intrathoracic pressure and use positive end expiratory pressure concurrently, unless the ITPR is used as a pulsed therapy (currently under evaluation). Thus, the benefit of circulatory enhancement with the ITPR must be balanced clinically with the need to concurrently maintain at least minimally adequate ventilator support. Animal studies to date have suggested the ITPR can provide both circulatory and ventilatory support for up to 24 h in duration, without negative pulmonary consequences.

38.9

Summary

Clinicians and researchers continue to investigate methods for enhancing standard CPR techniques and design various novel devices to treat sudden cardiac arrest and shock. The limitations of standard CPR are discussed, as well as meth-

ods to improve this technique to enhance the delivery of oxygenated blood to the heart and brain. A recent advance in CPR research has been the rediscovered benefit of therapeutic hypothermia after successful resuscitation, a therapy that has shown increased long-term survival rates and improved neurological function. Further, we described some novel noninvasive technologies that can be used to increase the patient’s chance for survival, such as IPR therapy to improve perfusion in profound states of shock, impedance threshold devices, and ACD-CRP treatment.

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34. Paradis NA, Martin GB, Rosenberg J et al (1991) The effect of standard- and high-dose epinephrine on coronary perfusion pressure during prolonged cardiopulmonary resuscitation. JAMA 265:1139–1144 35. Bahlmann L, Klaus S, Baumeier W et al (2003) Brain metabolism during cardiopulmonary resuscitation assessed with microdialysis. Resuscitation 59:255–260 36. Raedler C, Voelckel WG, Wenzel V et al (2002) Vasopressor response in a porcine model of hypothermic cardiac arrest is improved with active compression-decompression cardiopulmonary resuscitation using the inspiratory impedance threshold valve. Anesth Analg 95:1496–1502 37. Wolcke BB, Mauer DK, Schoefmann MF et al (2003) Comparison of standard cardiopulmonary resuscitation versus the combination of active compression-decompression cardiopulmonary resuscitation and an inspiratory impedance threshold device for out-ofhospital cardiac arrest. Circulation 108:2201–2205 38. Plaisance P, Soleil C, Lurie KG, Vicaut E, Ducros L, Payen D (2005) Use of an inspiratory impedance threshold device on a facemask and endotracheal tube to reduce intrathoracic pressures during the decompression phase of active compression-decompression cardiopulmonary resuscitation. Crit Care Med 33:990–994 39. (2000) Guidelines for cardiopulmonary resuscitation and emergency cardiovascular care. Part 2: ethical aspects of CPR and ECC. Circulation 102:I12-21 40. Aufderheide TP, Frascone RJ, Wayne MA et al (2011) Standard cardiopulmonary resuscitation versus active compressiondecompression cardiopulmonary resuscitation with augmentation of negative intrathoracic pressure for out-of-hospital cardiac arrest: a randomised trial. Lancet 377:301–311 41. Wayne M, Tupper D, Swor R, Frascone R, Mahoney B, Lurie KG (2012) Improvement of long-term neurological function after sudden cardiac death and resuscitation: impact of CPR method and post-resuscitation care. Prehosp Emerg Care 16:152–153 42. Frascone RJ, Wayne MA, Swor RA et al (2013) Treatment of nontraumatic out-of-hospital cardiac arrest with active compression decompression cardiopulmonary resuscitation plus an impedance threshold device. Resuscitation 84:1214–1222 43. Fritsch-Yelle JM, Convertino VA, Schlegel TT (1999) Acute manipulations of plasma volume alter arterial pressure responses during Valsalva maneuvers. J Appl Physiol 86:1852–1857 44. Shekerdemian LS, Bush A, Shore DF, Lincoln C, Redington AN (1997) Cardiopulmonary interactions after Fontan operations: augmentation of cardiac output using negative pressure ventilation. Circulation 96:3934–3942 45. Lurie KG, Zielinski TM, McKnite SH et al (2004) Treatment of hypotension in pigs with an inspiratory impedance threshold device: a feasibility study. Crit Care Med 32:1555–1562 46. Marino BS, Yannopoulos D, Sigurdsson G et al (2004) Spontaneous breathing through an inspiratory impedance threshold device augments cardiac index and stroke volume index in a pediatric porcine model of hemorrhagic hypovolemia. Crit Care Med 32:S398–S405 47. Sigurdsson G, Yannopoulos D, McKnite SH, Sondeen JL, Benditt DG, Lurie KG (2006) Effects of an inspiratory impedance threshold device on blood pressure and short term survival in spontaneously breathing hypovolemic pigs. Resuscitation 68:399–404 48. Metzger A, Rees J, Segal N et al (2013) “Fluidless” resuscitation with permissive hypotension via impedance threshold device therapy compared with normal saline resuscitation in a porcine model of severe hemorrhage. J Trauma Acute Care Surg 75:S203–S209 49. Convertino VA, Ratliff DA, Crissey J, Doerr DF, Idris AH, Lurie KG (2005) Effects of inspiratory impedance on hemodynamic responses to a squat-stand test in human volunteers: implications for treatment of orthostatic hypotension. Eur J Appl Physiol 94:392–399

38 Treatment of Sudden Cardiac Arrest and Shock 50. Convertino VA, Ratliff DA, Ryan KL et al (2004) Hemodynamics associated with breathing through an inspiratory impedance threshold device in human volunteers. Crit Care Med 32:S381–S386 51. Idris A, Convertino VA, Ratliff MS et al (2007) Imposed power of breathing associated with use of an impedance threshold device. Respir Care 52:177–183 52. Milic-Emili J (1991) The lung: scientific foundations. Raven Press, New York 53. Cooke WH, Ryan KL, Convertino VA (2004) Lower body negative pressure as a model to study progression to acute hemorrhagic shock in humans. J Appl Physiol 96:1249–1261 54. Hinojosa-Laborde C, Shade RE, Muniz GW et al (2014) Validation of lower body negative pressure as an experimental model of hemorrhage. J Appl Physiol 116:406–415 55. Convertino VA, Cooke WH, Lurie KG (2005) Inspiratory resistance as a potential treatment for orthostatic intolerance and hemorrhagic shock. Aviat Space Environ Med 76:319–325 56. Smith SW, Parquette B, Lindstrom D, Metzger AK, Kopitzke J, Clinton J (2010) An impedance threshold device increases blood pressure in hypotensive patients. J Emerg Med 41:549–558 57. Wampler D, Convertino VA, Weeks S, Hernandez M, Larrumbide J, Manifold C (2014) Use of an impedance threshold device in spontaneously breathing patients with hypotension secondary to trauma: an observational cohort feasibility study. J Trauma Acute Care Surg 77:S140–S145 58. Yannopoulos D, Nadkarni VM, McKnite SH et al (2005) Intrathoracic pressure regulator during continuous-chestcompression advanced cardiac resuscitation improves vital organ perfusion pressures in a porcine model of cardiac arrest. Circulation 112:803–811

723 59. Yannopoulos D, Metzger A, McKnite S et al (2006) Intrathoracic pressure regulation improves vital organ perfusion pressures in normovolemic and hypovolemic pigs. Resuscitation 70:445–453 60. Yannopoulos D, McKnite S, Metzger A, Lurie KG (2007) Intrathoracic pressure regulation improves 24-hour survival in a porcine model of hypovolemic shock. Anesth Analg 104:157–162 61. Segal N, Parquette B, Ziehr J, Yannopoulos D, Lindstrom D (2013) Intrathoracic pressure regulation during cardiopulmonary resuscitation: a feasibility case-series. Resuscitation 84:450–453 62. Huffmyer JL, Groves DS, Desouza DG, Littlewood KE, Thiele RH, Nemergut EC (2011) The effect of the intrathoracic pressure regulator on hemodynamics and cardiac output. Shock 35:114–116 63. Kiehna E, Huffmyer J, Thiele R, Scalzo D, Nemergut E (2013) Utilizing the intrathoracic pressure regulator to lower intracranial pressure in patients with altered intracranial elastance: a pilot study. J Neurosurg 119:756–759 64. Sigurdsson G, McKnite SH, Sondeen JL, Benditt DB (2005) Extending the golden hour of hemorrhagic shock in pigs with an inspiratory impedance threshold valve. Paper presented at Critical Care in Medicine, 2005 65. Birch M, Beebe D, Kwon Y et al (2010) A novel intrathoracic pressure regulator improves hemodynamics in hypotensive patients during surgery. Circulation 122:A27 66. Cinel I, Goldfarb R, Carcasses P et al (2008) Intrathoracic pressure regulation augments cardiac index in porcine peritonitis. Crit Care Med 36:A6 67. Cinel I, Goldfarb RD, Metzger A et al (2014) Biphasic intrathoracic pressure regulation augments cardiac index during porcine peritonitis: a feasibility study. J Med Eng Technol 38:49–54

End-Stage Congestive Heart Failure in the Adult Population: Ventricular Assist Devices

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Kenneth K. Liao and Ranjit John

Abstract

Congestive heart failure (CHF) is a major cause of morbidity and mortality within the adult population. If these patients progress to the end stages of this disease, then heart transplantation or ventricular support devices are required. However, due to a shortage of donor hearts, the use of ventricular assist devices (VADs) as either a bridge to transplant or destination support has grown dramatically as a therapy. Furthermore, with the increased use of these devices, there have been major efforts to develop these technologies as well. Keywords

Congestive heart failure • Ventricular assist device

39.1

Introduction

Approximately five million Americans have congestive heart failure (CHF), and approximately 50,000 new cases are diagnosed every year. Furthermore, CHF is the most frequent cause of hospital admissions in patients older than 65 years, and it is the largest single expense for Medicare [1]. To date, with current medical management the 5-year mortality rate of CHF can be as high as 50 %. Fortunately, advances in medical therapy such as biventricular pacing, defibrillator implantation, and the ability to successfully perform surgery in high-risk patients have revolutionized the management of patients with CHF and greatly delayed the progression of CHF to end stage. Note that once a patient develops end-stage CHF, the treatment options are limited and typically ineffective, and thus subsequent mortality is high. In such patients, heart transplant becomes the last resort. Yet, in general, it is a very effective therapy which offers an excellent short-term and long-term survival benefits (over 90 and 50 % survival rates at one year and 10 years, K.K. Liao, MD (*) • R. John, MD Division of Cardiothoracic Surgery, University of Minnesota, 420 Delaware Street, SE, Minneapolis, MN 55455, USA e-mail: [email protected]

respectively); most patients enjoy a near-normal lifestyle after heart transplant [2]. However, the donor hearts available for transplantation are limited to an average of 2200 per year, compared to over 35,000 people per year who could benefit from such a therapy [1]. Besides the scarcity of donor hearts, many patients die each year while waiting for an acceptably matched donor heart. Importantly in the past fifteen years, ventricular assist devices (VADs), especially left ventricular assist devices (LVADs), have been increasingly used to support such patients as a bridge to transplant [3]. After the landmark REMATCH trial, the LVAD has been used more and more as the destination therapy for end-stage CHF [4, 5]. In addition to the increased use of these devices, newer generations of VADs with better mechanics, smaller size, and longer durability have been developed in recent years [6–11]. Nevertheless, the ultimate goal of future VAD development is to produce a small, totally implantable, biocompatible, and durable heart pump that can physiologically function like a human heart. Clinically effective VADs should be judged by a variety of mechanical and physiological performance parameters; specifically, they should: (1) provide sufficient cardiac output to allow patients to perform their usual daily activities, (2) have a low risk of thromboembolism and pump or driveline infections, (3) have a low incidence of device malfunction, (4) be easily implantable and removable, and (5) be small in size.

© Springer International Publishing Switzerland 2015 P.A. Iaizzo (ed.), Handbook of Cardiac Anatomy, Physiology, and Devices, DOI 10.1007/978-3-319-19464-6_39

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39.2

K.K. Liao and R. John

Classification of VADs

In general, VADs can be classified based on: (1) their internal mechanics (volume displacement, axial flow, or centrifugal), (2) therapeutic purposes (temporary, bridge to decision, bridge to recovery, bridge to transplant, and destination), (3) sites of support (LVAD, right VAD, or BiVAD), (4) location of the pump (implantable, paracorporeal, or extracorporeal), and/or (5) implanting approaches (sternotomy, thoracotomy, laparotomy, subcostal, or percutaneous).

39.3

VADs Defined by Mechanics and Clinical Applications

39.3.1 Volume Displacement Pumps (Pulsatile Pumps) The functioning human left and right ventricles are physiologic volume displacement pumps. During each cardiac cycle, they generate over 60 cc of stroke volume, and each ventricle has a pair of inflow and outflow valves to maintain a unidirectional blood flow. The end result is that a human heart generates a pulsatile blood pressure and yet a steady cardiac output. The mitral and tricuspid valves function as the inflow valves, while the aortic and pulmonary valves function as outflow valves. A volume displacement VAD functions exactly like human ventricles; it has a pump chamber that generates a stroke volume between 40 and 80 cc during each cardiac cycle, and it has two artificial valves—either bioprostheses or mechanical valves. The valves used inside VADs (i.e., bioprosthetic versus mechanical) are considered to ultimately determine the durability of the VAD and the need for anticoagulation. More specifically, bioprostheses may have the advantage of not requiring anticoagulation therapy, thus reducing the patient’s risk for thromboembolism. However, the valve’s limited life span inside the VAD may result in premature VAD failures, thus requiring VAD replacement. On the other hand, mechanical valves have the advantage of being durable, but then the patient will require adequate anticoagulation therapy to prevent clotting. Under- or over-anticoagulation treatment can increase the risk of thromboembolism or bleeding which can subsequently affect the patient’s outcome. Typically one of the two mechanisms is used to eject blood in this type of VAD: (1) compressed air is employed to squeeze the blood-filled sac or to displace a flexible diaphragm within a hard shell to generate stroke volume, or (2) a slow torque electrical motor is used to displace a flexible diaphragm inside the implantable unit within a hard shell to generate stroke volume. In general, the compressed air approach seems to provide a simple and reliable way of either moving the diaphragm or compressing the sac, with a pres-

sure more comparable to a physiologically acceptable waveform. However to date, this design has required a bulky driving console, compromising the patient’s mobility. In addition such driving consoles typically will make loud noises. If the diaphragm is propulsed by an electrical motor within a noncompressible metal chamber, the early systolic pressure generated by this pump is much higher than the pump driven by the compressed air. It has been found that such unphysiologically high pressures can speed the calcification process in the inflow bioprostheses and/or even cause early valve failures [12]. The blood to pump contact surface interaction plays an important role in determining the relative degree of resultant thrombogenicity of the pump and therefore the required needs for anticoagulation. This is particularly important for volume displacement pumps, because of their relatively large contact surface areas with blood, as compared to an axial flow pump. Historically, first the smooth surface was pursued during VAD design and then manufactured to avoid thrombosis, but later it turned out that an evenly distributed textured surface actually generated less thrombosis. More specifically, such textured surfaces promote early platelet and fibrin depositions during initial contact with blood, which in turn results in formation of stable pseudointima which subsequently prevents the formation of thrombosis [13]. Common volume displacement pumps include: (1) HeartMate® XVE LVAD (Figs. 39.1 and 39.2) and (2) Thoratec VAD (Fig. 39.2) (Thoratec Corp., Pleasanton, CA, USA). The HeartMate XVE was once the mostly implanted and most studied pulsatile LVAD worldwide until axial flow pumps, the second-generation LVAD such as HeartMate II, demonstrated the superiority in durability, easy to implant, and pump-related complications. It was approved by the FDA for use as both a bridge to heart transplant and as destination therapy for endstage CHF. This system is driven by an electrical motor, but it can also be driven by compressed air if and when the electrical motor wears out. It is implantable and powered through the driveline which exits from the abdominal wall; common implant locations are in the abdomen or in the preperitoneal space. The inflow cannula is inserted into the left ventricle via an opening in the left ventricular apex, and the outflow graft is connected in the proximal ascending aorta. It has textured interface surfaces and thus has a very low risk of thromboembolism (Fig. 39.3). Therefore, patients with these implanted systems do not need to be anticoagulated with coumadin or Plavix, yet it is recommended that they take aspirin once a day. The HeartMate XVE LVAD is no longer used in the adult clinical setting, yet it played a very significant historical role in demonstrating that end-stage CHF patients could be successfully supported with an LVAD. When compared to maximal medical management including home inotropic therapy, the use of the HeartMate XVE LVAD significantly improved the quality of life and survival of end-stage CHF patients [5].

39 End-Stage Congestive Heart Failure: VADs Fig. 39.1 Schematic of a HeartMate SNAP-VE ventricular assist device system. One can see the internal connections at the apex of the left ventricle where there is inflow into the device and outflow connected directly to the aorta. This system utilizes an external battery pack and controller system. LVAD left ventricular assist device

Fig. 39.2 Thoratec ventricular assist device (VAD). Left: pump with both inflow and outflow valve housing connectors pointing upward and the compressed air driveline pointing downward. Right: cannulas and grafts are implanted inside the body cavity, while the pumps are connected outside the body cavity

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Fig. 39.3 Textured inner surface of HeartMate XVE left ventricular assist device. The textured surface promotes formation of pseudointima which subsequently prevents thrombosis formation

It is the first implantable LVAD that was approved as the destination therapy for end-stage heart failure in the USA. However, the disadvantages of this system include (1) its overall heavy weight, (2) its bulky size, and (3) frequent inflow valve and/or electrical motor failures, after an average of 12 months of implantation [3–5, 14, 15]. The Thoratec VAD [16] can be used as an LVAD, RVAD, or BiVAD. It is commonly described as an implanted paracorporeal pump, with the inflow cannula inserted in the left ventricle via the left ventricular apex and the outflow graft sewed to the ascending aorta when used as an LVAD (or the inflow cannula inserted in the right atrium and the outflow graft sewed to the pulmonary artery as an RVAD). This system allows for numerous cannulation options. Its pump is made of a flexible sac housed in a plastic ball-shaped container. Currently, the sac material is composed of Thoralon which has a smooth surface to reduce the risk of thrombosis. This sac is squeezed by the compressed air via an air-driven console, and it has two mechanical valves, one as an inflow and the other an outflow valve. Importantly, these units can be implanted in small- or large-size patients (weight between 17 and 144 kg) and can be readily employed for short-term as well as long-term support. To date, this device is approved by the FDA to be used as a bridge to heart transplant and as postcardiotomy support to recovery. The disadvantages of this system include the paracorporeal pump being attached outside the body, which can be inconvenient to patients, and patients require anticoagulation with coumadin to maintain an INR between 2.5 and 3.0 to prevent thromboembolism.

39.3.2 Continuous Flow Pumps: Axial Design The axial flow pumps are typically regarded as secondgeneration VADs, as compared to the first generation of volume displacement pumps. Such pumps incorporate both

Fig. 39.4 HeartMate II left ventricular assist device. (A) HeartMate II pump and the high-speed rotor. The inflow cannula is connected to the pump. (B) Size comparison between the HeartMate VE and HeartMate II pumps. The inflow cannulas of both pumps are the same

continuous flow and rotary pump technologies as the foundation of their design and construction. They have an impeller inside the pump that can generate high-speed rotations in a blood system (Fig. 39.4). Depending on the motor capacity and rotational speed, an axial flow pump can function either as a partial-flow or full-flow support VAD. The speed of a rotor can reach an RPM of 9000, and it can generate up to 10 L/min of flow with a mean pressure of 100 mmHg. Initially, serious doubts about the utility of such pumps were raised due to the concerns of red blood cell destruction and heat generated by the high-speed motor inside the blood system. But (starting with conjunction) such theoretical concerns were discarded when a Hemopump was successfully used in a clinical setting without significant hemolysis [17]. The Hemopump thus set the stage for evaluation of other types of axial flow pumps that could be used to pump blood in the human body [6, 7, 9–11]. The common features of axial flow pumps include the following: (1) the simpler design of continuous flow rotary

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39 End-Stage Congestive Heart Failure: VADs

pump technology promises increased long-term mechanical reliability; (2) they do not require valves to create a unidirectional flow nor do they require an external vent or a compliance chamber, thus making them more likely to be used as the platform for future development of a totally implantable VAD; (3) the inflow cannulas are inserted into the left ventricular apexes or totally inside the left ventricle, and the outflow grafts can be connected to either the ascending or descending thoracic aorta (i.e., which is important if abnormalities in the ascending aorta exist); (4) the size of such pumps is relatively small, one-fifth to one-seventh the size of the volume displacement pumps, thereby extending therapy to underserved patient populations including women and even some children; and/or (5) these pumps are associated with minimal noise generation and overall greater patient comfort [6, 7, 9–11, 14, 15]. The HeartMate II LVAD (Thoratec Corp.), the DeBakey MicroMed LVAD (MicroMed Cardiovascular, Inc., Houston, TX, USA), and Jarvik 2000 (Jarvik Heart, Inc., Manhattan, NY, USA) are currently available representatives of this group of VADs. Among them the HeartMate II and the DeBakey MicroMed LVAD have many similarities: (1) they are about the same size, (2) both devices consist of an internal blood pump with a percutaneous lead that connects the pump to an external system driver and power source, and (3) both pumps can generate up to 10 L/min of flow. The initial results appeared to be encouraging, with data supporting effective circulatory support and durability [6, 7, 9–11, 14, 15]. Of particular interest is that the diminished pulse pressures that are associated with utilizing an axial flow pump seemed to be tolerated well in patients, at least for the short term. Importantly, the long-term consequences of using axial flow pumps have yet to be evaluated. Additionally, hemolysis associated with the use of axial flow pumps has been detectable, yet the level has been considered clinically insignificant. Nevertheless, these pumps seem to activate platelets because of the physical strain on blood cells; such activation could be an important source of intravascular thrombosis and/or embolic complications. It should be noted that the incidence of thromboembolism seems to be particularly high for the MicroMed LVAD. Therefore, intense anticoagulation regimens targeting platelet activation and clotting cascade have been employed to deal with these potential problems. A combination of coumadin and Plavix has been recommended for patients who have been provided with a MicroMed LVAD. The HeartMate II LVAD has shown improved clinical outcomes both as bridge to transplant and destination therapy, with markedly better functional status and quality of life. An actuarial survival of 89 % at 1 month and 75 % at 6 months was reported [14]. The HeartMate II LVAD has proven to be safe and effective as bridge to transplantation. Furthermore, compared to HeartMate XVE, the HeartMate

II significantly reduced the device- and surgery-related complications. It is considered that the lower incidence of postoperative bleeding and device-related infection may be due to its smaller size and the lack of need for a large pocket to house its pump and smaller driveline. The absence of a large preperitoneal pocket (which was required with the larger pulsatile devices) has reduced: (1) the need for extensive dissection, (2) postoperative bleeding, and (3) LVAD pocket hematomas and the development of pocket infection. Based on multiple clinical trial outcomes [14, 15, 18], the FDA approved the HeartMate II LVAD to be used as bridge to transplant as well as destination therapy for end-stage CHF patients in 2008 and 2010, respectively. To date, the clinical use of the HeartMate II LVAD has increased rapidly since FDA approval, and thus far over 17,000 patients have received implantation of the HeartMate II LVAD worldwide.

39.3.3 Continuous Flow Pumps: Centrifugal Design The continuous flow pumps with centrifugal designs are considered the third-generation VADs. The technology used in these pumps includes noncontact bearings and hydrodynamic levitation that offer the advantages of (1) minimizing the friction of blood flow, (2) reducing platelet damage, and (3) reducing wear of the rotor (Fig. 39.5). The HeartWare pump (HeartWare, Framingham, MA, USA) is representative of this type of LVAD. Compared to the HeartMate II system, the HeartWare pump is smaller and can fit inside the pericardial space; anatomically, it can fit into smaller adults as well as congenital patients. The pump can be inserted via a minimally invasive procedure, and this, in turn, potentially minimizes blood transfusions. Today, this is the only pump that can be readily used as an implantable RVAD and thus can be used for BiVAD support in those patients requiring such therapy. Initial clinical trials of the HeartWare LVAD as bridge to heart transplant showed that patients’ 30-day and 1-year survival rates were 99 and 86 %, respectively [19]. The pump received FDA approval for implantation as bridge to heart transplantation in 2012 and currently is in clinical trials to assess its use as destination therapy for end-stage CHF patients. So far over 6000 thousand patients have received HeartWare LVAD implantation worldwide.

39.4

VAD Implantation Techniques

In general, the implantation techniques currently employed for these three types of VADs are not very different from each other. The implantation for the latter two VADs is

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Fig. 39.5 HeartWare left ventricular assist device pump. (A) HeartWare pump. (B) Cross section of the inside structure of the pump showing the contactless design as well as magnetic and hydrodynamic bearings

probably easier because the need for tissue dissection is less for the smaller pumps and subsequently there is less bleeding. Typically a median sternotomy is made, and the patient is placed on cardiopulmonary bypass. The HeartMate II pump is inserted in the pre-created preperitoneal pocket, below the posterior rectus sheath. The HeartWare LVAD is inserted inside the pericardial space. The inflow cannula is inserted through a cored out portion of the apex of the left ventricle. The outflow graft is sewn to a longitudinal aortotomy in the proximal ascending aorta. Following appropriate connections, the patient is weaned off cardiopulmonary bypass, and the pump is started. Optimizing pump speed is performed under echocardiographic guidance, as well as by continuously monitoring the patient’s hemodynamic status. Adequate flow is achieved by adjusting pump speed and by ensuring adequate preload and appropriate inotropic support for right ventricular function. After meticulous hemostasis is achieved, the chest is closed with appropriately placed chest tubes. The HeartWare LVAD can be inserted via a combination of left mini-thoracotomy and upper sternotomy or right mini-thoracotomy.

39.5

Device Management

It is imperative that standard postoperative care is used in the management of these patients. First, device settings can be monitored and adjusted based on patient hemodynamics as well as echocardiographic findings. Additionally, a combination of aspirin and warfarin is typically used as part of the anticoagulation protocol to maintain an INR between 2.5 and 3.5 for all the devices, except for patients with the HeartMate XVE for which only aspirin is needed. The VAD flow is generally maintained above 4 L/min, and the mean blood pressure is maintained over 60 mmHg. After LVAD placement, typically a patient does not change defibrillator and/or biventricular pacing settings if s/he had such a device implanted prior to VAD implantation. Finally, all patients undergo a standard postoperative rehabilitation program.

39.6

University of Minnesota VAD Experience

The University of Minnesota VAD and heart transplant program is one of the largest programs in the world. We have been among the participating centers and leaders in multiple NIHsponsored clinical trials. Ten different types of VADs had been tried or used at our center. Since 1995, we have implanted 700 VADs, including over 250 continuous flow VADs for bridge to heart transplantation, bridge to bridge, bridge to recovery, and/or for destination therapy. We developed an effective VAD implantation algorithm to successfully treat patients with refractory acute cardiogenic shock and multiorgan failure who would typically die (Fig. 39.6) [20]. We also pioneered a minimally invasive LVAD exchange technique to avoid sternotomy (Figs. 39.7 and 39.8) [21].

39.7

Summary

Over the last 15 years, VADs (especially continuous flow LVADs) have been increasingly used in the clinical management of the chronic heart failure patient, as either a bridge to transplant or as the destination therapy. Abundant and important knowledge and experience has been obtained from the early clinical use of VADs. We believe that the future of VADs is very promising. The ideal design of any future VAD should embody, at a minimum, the following features: 1. It can provide adequate blood flow to meet the various physiological requirements. 2. It must be reliable and durable. For a VAD to be used as a destination therapy, 5–7 years has been suggested as an acceptable length of time for durability. 3. It must be biocompatible with the host patient and also require no, or minimal, anticoagulation therapy.

39 End-Stage Congestive Heart Failure: VADs

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Fig. 39.6 Algorithm depicting the management of patients with refractory acute cardiogenic shock with multiorgan failure

Fig. 39.7 Left ventricular assist device exchange is performed via laparotomy only; sternotomy is avoided

4. It must be small in size to minimize patient discomfort and ensure an improved quality of life. 5. It should be easy to implant, preferably through developing minimally invasive approaches. It is considered that within the next ten years, we will see the birth of the “dream” VAD that meets these criteria.

Perhaps one day implanting a VAD will be similar to implanting a prosthetic valve. Ultimately, the future of treating end-stage CHF lies in the cell therapy which can either reverse myocardium remodeling or regrow new myocardium, yet such a therapy may require VAD support of the patient during administration. For additional information on LVADs and their use in congenital populations, the reader is referred to Chap. 11.

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Fig. 39.8 Patient who received the fifth left ventricular assist device (LVAD) exchange. Photo was taken together with the author/surgeon 3 weeks after his fifth LVAD exchange surgery

References 1. Franco KL (2001) New devices for chronic ventricular support. J Card Surg 16:178–192 2. Hosenpud JD, Bennett LE, Keck BM, Boucek MM, Novick RJ (2001) The Registry of the International Society for Heart and Lung Transplantation: eighteenth official report. J Heart Lung Transplant 20:805–815 3. Frazier OH, Rose EA, Oz MC et al (2001) Multicenter clinical evaluation of the HeartMate vented electric left ventricular assist system in patients awaiting heart transplantation. J Thorac Cardiovasc Surg 122:1186–1195 4. Rose EA, Moskowitz AJ, Packer M et al (1999) The REMATCH trial: rationale, design, and end points. Randomized evaluation of mechanical assistance for the treatment of congestive heart failure. Ann Thorac Surg 67:723–730 5. Rose EA, Gelijns AC, Moskowitz AJ et al (2001) Long-term use of a left ventricular assist device for end-stage heart failure. N Engl J Med 345:1435–1443 6. Griffith BP, Kormos RL, Borovetz HS et al (2001) HeartMate II left ventricular assist system: from concept to first clinical use. Ann Thorac Surg 71:116–120 7. Frazier OH, Myers TJ, Westaby S et al (2004) Clinical experience with an implantable, intracardiac, continuous flow circulatory support device: physiologic implications and their relationship to patient selection. Ann Thorac Surg 77:133–142 8. Esmore D, Kaye D, Spratt P et al (2008) A prospective, multicenter trial of the VentrAssist left ventricular assist device for bridge to transplant: safety and efficacy. J Heart Lung Transplant 27:579–588 9. Goldstein DJ (2003) Worldwide experience with the MicroMed DeBakey ventricular assist device as a bridge to transplantation. Circulation 108:II272–II277 10. Westaby S, Banning AP, Jarvik R et al (2000) First permanent implant of the Jarvik 2000 Heart. Lancet 356:900–903

11. Wieselthaler GM, Schima H, Hiesmayr M et al (2000) First clinical experience with the DeBakey ventricular assist device continuousaxial-flow pump for bridge to transplantation. Circulation 101: 356–359 12. Liao K, Li X, John R et al (2008) Mechanical stress: an independent determinant of early bioprosthetic calcification in human. Ann Thorac Surg 86:491–495 13. Rose EA, Levin HR, Oz MC et al (1994) Artificial circulatory support with textured interior surfaces. A counterintuitive approach to minimizing thromboembolism. Circulation 90:II87–II91 14. Miller LW, Pagani FD, Russell SD et al (2007) Use of a continuousflow device in patients awaiting heart transplantation. N Engl J Med 357:885–896 15. Feller ED, Sorensen EN, Haddad M et al (2007) Clinical outcomes are similar in pulsatile and nonpulsatile left ventricular assist device recipients. Ann Thorac Surg 83:1082–1088 16. Farrar DJ (2000) The Thoratec ventricular assist device: a paracorporeal pump for treating acute and chronic heart failure. Semin Thorac Cardiovasc Surg 12:243–250 17. Wampler RK, Baker BA, Wright WM (1994) Circulatory support of cardiac interventional procedures with the Hemopump cardiac assist system. Cardiology 84:194–201 18. Slaughter S, Rogers JG, Milano C et al (2009) Advanced heart failure treated with continuous-flow left ventricular assist device. N Engl J Med 361:2241–2251 19. Aaronson KD, Slaughter MS, Miller LW et al (2012) Use of an intrapericardial, continuous-flow, centrifugal pump in patients awaiting heart transplantation. Circulation 125:3191–3200 20. John R, Liao K, Lietz K et al (2007) Experience with the Levitronix CentriMag Circulatory support system as a bridge to decision in patients with refractory acute cardiogenic shock and multisystem organ failure. J Thorac Cardiovasc Surg 134:351–358 21. Liao K, Barksdale A, Park S et al (2007) Non-sternotomy approach for left ventricular assist device implantation, exchange or explantation. J Heart Lung Transplant 26:S199

Cell Transplantation for Ischemic Heart Disease

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Jianyi Zhang and Daniel J. Garry

Abstract

Recent studies support the notion that cardiomyocyte regeneration may occur during physiological and pathological states in the adult heart. These data highlight the possibilities that myocardial regeneration may occur via cardiomyocyte proliferation and/or differentiation of putative cardiac stem cells. To date, various cell types have been used for cardiac repair, including skeletal myoblasts, bone marrow-derived cells, mesenchymal stem cells (MSCs), endothelial progenitor cells (EPCs), umbilical cord blood (UCB) stem cells, cardiac stem cells, and embryonic stem cells (ESCs). This chapter will review each of these different stem cell populations in regards to the potential treatment of heart disease. We will examine the in vitro and in vivo animal studies, and then briefly discuss the cell therapy clinical trials that are currently underway for the treatment of ischemic heart disease. Keywords

Embryonic stem cells • Adult stem cells • Skeletal myoblasts • Bone marrow-derived stem cells • Mesenchymal stem cells • Endothelial progenitor cells • Umbilical cord blood stem cells • Cardiac stem cells

Abbreviations CPCs EPCs ESCs HGF hiPSCs IGF-1 LV MI MSCs Sca-1 SDF-1

Cardiac progenitor cells Endothelial progenitor cells Embryonic stem cells Hepatocyte growth factor Human induced pluripotent stem cells Insulin-like growth factor Left ventricular Myocardial infarction Mesenchymal stem cells Stem cell antigen-1 Stromal cell-derived factor-1

J. Zhang, MD, PhD (*) • D.J. Garry, MD, PhD Lillehei Heart Institute, Minneapolis, MN, USA University of Minnesota, 268 Variety Club Research Center, 401 East River Road, Minneapolis, MN 55455, USA e-mail: [email protected]

SP Side population UCB Umbilical cord blood VEGF Vascular endothelial growth factor

40.1

Introduction

Although coronary interventions and associated medical therapies have improved postinfarction cardiac function in patients with coronary artery disease, approximately half of the patients will still progress to end-stage or advanced heart failure [1]. To date, cardiac transplantation remains the only definitive therapy for replacing the lost muscle, but it is a widespread approach limited by the inadequate supply of donor hearts (approximately 2000 donor hearts are available each year in the USA). An alternative potential therapy for limiting postinfarction left ventricular (LV) remodeling, and thus the development of congestive heart failure, is the directed replacement of infarcted myocardium with the new myocardium being generated from transplanted stem cells.

© Springer International Publishing Switzerland 2015 P.A. Iaizzo (ed.), Handbook of Cardiac Anatomy, Physiology, and Devices, DOI 10.1007/978-3-319-19464-6_40

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Recent studies have provided evidence to support the notion that cardiomyocyte regeneration may occur during physiological and pathological states in the adult heart. These data highlight the possibility that myocardial regeneration may occur via cardiomyocyte proliferation and/or differentiation of putative cardiac stem cells [2]. To date, various cell types have been used for cardiac repair including skeletal myoblasts, bone marrow-derived cells, mesenchymal stem cells (MSCs), endothelial progenitor cells (EPCs), umbilical cord blood (UCB) stem cells, cardiac stem cells, and embryonic stem cells (ESCs). This chapter will review each of these different stem cell populations with regard to their potential treatment of heart disease. We will begin by examining the in vitro and in vivo animal studies, and then briefly discuss the cell therapy clinical trials that are currently underway for treating ischemic heart disease. We will conclude by summarizing selected techniques that have been used to enhance the beneficial effects of stem cell transplantation.

40.2

Cells for Myocardial Repair in Ischemic Heart Disease

40.2.1 Embryonic Stem Cells ESCs can differentiate into all three developmental germ layers (including the mesoderm, which is the source of the cardiac lineage) and can proliferate with self-renewal in an unlimited fashion. Thus, ESCs have the potential of producing a limitless number of cells and cell types for regenerative therapy. However, ESCs must be differentiated into specific cell lineages before transplantation as the ESCs themselves are tumorigenic [3], and the cells derived from ESCs must be administered with immunosuppressive therapy [4] because ESCs can only be obtained from an allogenic source. Yet, the use of human ESCs (hESCs) is limited due to ethical concerns regarding the need to destroy human embryos in order to produce hESCs.

40.2.1.1

Mouse ESCs

The cardiogenic potential of mouse ESCs was first demonstrated in 1985 when these cells were cultured in suspension and formed 3D cystic bodies, termed embryoid bodies, which differentiated into cell types of the visceral yolk sac, blood islands, and myocardium [5]. Currently, such cells are separated from their feeder layer and then resuspended in leukemia inhibitory factor-free culture medium at a low density [6]. Mouse ESCs are then cultured in small drops which are formed on the lid of tissue culture dishes. When kept in this hanging droplet setting for 2 days, the cells aggregate and form differentiating embryoid bodies [6]. Embryoid bodies are then transferred into ultralow attachment dishes

where they further differentiate. Spontaneous contracting cells (cardiomyocytes) can be observed between 7 and 8 days of differentiation [6]. This process of cardiac differentiation can be further enhanced by the use of selective growth factors and inhibitors of signaling pathways. Importantly, mouse ESCs have been shown to engraft and regenerate myocardium after an experimentally induced myocardial infarction (MI) [7–9]. These cells can form cardiomyocytes that electrically couple with the host myocardium, endothelial cells, and blood vessels [7–9]. More recently, multipotent cardiac progenitor cells (CPCs) derived from mouse ESCs have been characterized from three independent laboratories [10–12]; Brachyury+/Flk+ and Isl1+ CPC cell lines were shown to differentiate into cardiomyocytes, endothelial cells, and smooth muscle cells, while Nkx2-5/c-kit CPCs could differentiate into cardiomyocytes and smooth muscle cells.

40.2.1.2 Human ESCs Human ESCs were first isolated from the human blastocyst in 1998 [3], and later it was shown that they could differentiate into cardiomyocytes [13]. Human ESCs also form embryoid bodies when cultured in suspension form; these are positive for cardiomyocyte markers such as myosin heavy chain, α-actinin, desmin, and troponin I [13]. Electrophysiological studies showed that most of the human ESC-derived cardiomyocytes resemble human fetal ventricular myocytes that can propagate action potentials [14]. Human ESCs can also differentiate into endothelial and smooth muscle cell lineages. Initial in vivo studies have demonstrated that human ESCderived cardiomyocytes can form new myocardium in the uninjured heart of athymic rats [15] or immunosuppressed pigs [14]. It was shown that the size of the graft could be increased fourfold by prior heat shock treatment of the cells [15]. When human ESCs are implanted in animal models that have a slow heart rate (such as in pigs or guinea pigs), they can form pacemakers when the native pacemaker (node) is dysfunctional, implying electrical integration with surrounding cardiomyocytes [14, 16]. However, when these cells are transplanted in the setting of MI, only 18 % form myocardial grafts and these grafts also contain substantial noncardiac elements [17]. To enhance the yield and purity of cardiomyocytes from human ESCs, Laflamme et al. developed a new technique to direct the differentiation of human ESCs into cardiomyocytes using sequential treatment of high-density undifferentiated monolayer cultures with activin A and bone marrow morphogenic protein 4 [17]. This protocol has yielded greater than 30 % cardiomyocytes, as compared to less than 1 % with the embryoid body-based system which used serum to induce differentiation [17]. Furthermore, Percoll gradient centrifugation, which allows specific enrichment of human ESC-derived cardiomyocytes, resulted in cultures containing 82.6 ± 6.6 % cardiomyocytes

40

Cell Transplantation

[17]. Moreover, this laboratory used a prosurvival engraftment cocktail to improve graft survival in infarcted hearts. This cocktail included Matrigel to prevent anikis, a cellpermeant peptide from Bcl-XL to block mitochondrial death pathways, cyclosporine A to attenuate cyclophilin D-dependent mitochondrial pathways, a compound that opens ATP-dependent K+ channels (pinacidil) to mimic ischemic preconditioning, insulin-like growth factor (IGF-1) to activate Akt pathways, and the caspase inhibitor ZVADfmk [17]. Importantly, transplantation of human ESCderived cardiomyocytes, in combination with this prosurvival cocktail into infarcted hearts, resulted in myocardial grafts with improved ventricular function [17]. The other intriguing aspect of this study was that almost all noncardiac human ESC-derived cells died by the 4-week period [17].

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myocardial therapy if the hiPSCs were reprogrammed from cardiac lineage cells rather than from other organ-specific lineages. Notably, Zhang et al. [26] have successfully generated hiPSCs from cardiac fibroblasts which were obtained from the hearts of patients who were undergoing openchest surgery. When these cardiac lineage hiPSCs (hciPSCs) were used to generate sheets of cardiomyocytes, the efficiency of the differentiation protocol exceeded 92 %, compared to 60–85 % when dermal- or cord blood lineage hiPSCs have been used [21]. Approximately 30 % of the hciPSC-derived cardiomyocytes were retained for at least 28 days after administration to the infarcted hearts of immunodeficient mice.

40.2.3 Adult Stem Cells 40.2.2 Human Induced Pluripotent Stem Cells The immunogenicity and ethical concerns associated with hESCs have led to the development of human induced pluripotent stem cells (hiPSCs), which possess an ESC-like capacity for differentiation and self-replication but can be generated from an individual patient’s own somatic cells. The somatic cells are reprogrammed with pluripotency factors such as Oct3/4, Sox2, Klf4, and c-Myc; however, hiPSCs (like hESCs) can be tumorigenic and must be differentiated into specific cell types before administration. Effective protocols for differentiating hiPSCs into smoothmuscle cells (hiPSC-SMCs) have been available for several years [18, 19], while methods for obtaining sufficiently large, pure, and stable populations of hiPSC-derived endothelial cells (hiPSC-ECs) [20] and cardiomyocytes (hiPSCCMs) [21, 22] have recently been established. Studies in pigs with experimentally induced ischemia-reperfusion injury indicate that all three hiPSC-derived cell lineages are retained at the site of administration for at least 4 weeks after injection, and that the combined treatment can lead to improvements in contractile performance, myocardial wall stress, and cellular metabolism [22]; furthermore, treatment with hiPSC-CMs alone was not associated with arrhythmogenic complications such as those reported when hESC-derived cardiomyocytes (hESC-CMs) were administered to monkeys [23], perhaps because the number of cells administered was much smaller (i.e., 10 million hiPSC-CMs versus 1 billion hESC-CMs). Although hiPSCs can in principle be used to generate cells of any lineage, the efficiency of the differentiation protocol and function of the hiPSC-derived cells after transplantation may be influenced by epigenetic factors that the hiPSCs retain from their tissues of origin [24, 25]. Thus, hiPSC-derived cells may be more effective for regenerative

40.2.3.1 Skeletal Myoblasts Skeletal myoblasts can be derived from myogenic stem cells also known as satellite cells. These myogenic stem cells are quiescent and located in a niche; they are sublaminar and sandwiched between the basal lamina and the plasmalemma of the skeletal muscle fibers. In response to injury, the myogenic stem cells become activated, they proliferate and differentiate, and typically completely restore the skeletal muscle architecture [27]. Previous studies have demonstrated that skeletal myoblasts form viable, long-term skeletal myotube grafts following transplantation into adult hearts [28]. In one study, it was shown that transplantation of autologous skeletal myoblasts in cryoinfarcted rabbit myocardium leads to myoblast engraftment by 3 weeks with subsequent improvement in systolic performance [27]. Importantly, as these cells are specified and committed to the skeletal muscle lineage, they do not differentiate into cardiomyocytes [29], and thus they are also not electromechanically coupled to each other or to the surrounding cardiomyocytes of the host [30, 31].

40.2.3.2 Bone Marrow-Derived Stem Cells The bone marrow contains many adult stem cells which have been used to treat hematological disorders for decades. It has recently been shown that bone marrow-derived stems can traverse cell lineage boundaries and, upon appropriate stimulation, transdifferentiate into hepatocytes, endothelial cells, skeletal muscle, and/or neurons [32–34]. Yet, the ability of bone marrow-derived cells to differentiate into cardiomyocytes remains controversial. For example, Bittner et al. were the first researchers to suggest that cardiac muscle cells may be derived from bone marrow cells [35]. Goodel et al. demonstrated that transplantation of murine bone marrow side population (SP) cells (c-kit+, Sca-1+, CD34−/low) resulted in donor-derived cells with cardiomyocyte morphologies, as well as smooth muscle and endothelial cells which were

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found in the heart following left anterior descending coronary artery ligation [36]. Orlic et al. [37] demonstrated that transplantation of GFP-labeled Lin−c-kit+ cells (presumably containing both hematopoietic stem cells and MSCs) into the ventricular wall after left anterior descending coronary artery ligation resulted in improved function of the ventricle, and they also detected a large number of GFP+ cells that coexpressed myocardial proteins in the myocardium. In contrast to these findings, other laboratories using genetic mouse models to label cell populations (and their derivatives) have shown that lineage negative, c-kit-positive cells were not able to differentiate into cardiomyocytes [38, 39]. Alternatively, Anversa and colleagues have shown, using similar genetic techniques, that c-kit+ bone marrow cells can engraft in the injured myocardium and differentiate into cells of the cardiogenic lineage, forming functionally competent cardiomyocytes and vascular structures [40].

40.2.3.3 Mesenchymal Stem Cells Phenotype and Differentiation Potential In the late 1980s and through the 1990s, Caplan’s laboratory identified a subset of cells within the bone marrow which gave rise to osteoblasts and adipocytes. These cells were termed MSCs [41]. MSCs are present in many different organs of the body including muscle, skin, adipose tissue, and bone marrow. They can be isolated from the bone marrow by a simple process involving Ficoll centrifugation and adhering cell culture in a defined serum-containing medium. In the early studies, MSCs were shown to be expanded for 4–20 population doublings only [42], with preservation of the karyotype, telomerase activity, and telomere length [43, 44]. Phenotypically, these cells were negative for CD31, CD34, and CD45, unlike hematopoietic progenitors from bone marrow, and were positive for CD29, CD44, CD71, CD90, CD105, CD106, CD120a, CD124, SH2, SH3, and SH4 [45, 46]. In the bone marrow, only 0.001–0.01 % of the initial unfractionated bone marrow mononuclear cell population consists of MSCs [33, 36]. However, in a number of rodent studies, the adherent fibroblastic cells obtained from the unfractionated mononuclear class of the bone marrow are termed MSCs [47, 48]. MSCs were reported to have the potential to differentiate into any tissue of mesenchymal origin [41]. MSCs derived from rodent marrow aspiration have been shown to differentiate into cardiomyocyte-like cells in the presence of 5-azacytidine [49, 50]. The cellular morphology changes from spindle-shaped to ball-shaped, and finally a rodshaped form; thereafter, these cells fuse together to form a syncitium which resembles a myotube [51]. In addition, these cells exhibit markers of fetal cardiomyocytes [50]; specific transcription factors of the myocyte and cardiac lineage including GATA4, Nkx2.5, and HAND 1/2 can be detected [49]. Yet compared to native cardiomyocytes,

J. Zhang and D.J. Garry

there are noteworthy differences in those which are derived from MSCs. First, the β-isoform of cardiac myosin heavy chain is more abundant than the α-isoform in these cells. Second, there is increased α-skeletal actin relative to α-cardiac actinin; myosin light chain 2v is also present. Third, both MEF2A and MEF2D isoforms replace MEF2C from early to late passages. Additionally, it was reported that these cells will beat spontaneously and synchronously, which is most likely due to the formation of intercalated discs, as has been shown when they are co-cultured with neonatal myocytes [52]. Finally, the differentiated cells will express competent α- and β-adrenergic and muscarinic receptors, as indicated by increased rates of contraction in response to isoproterenol and by decreased rates of contraction induced by β-adrenergic blockers [53]. Yet, it should be noted that other studies suggest that bone marrow stem cells cannot differentiate to cardiac myocytes [38, 39]. Whether or not MSCs can differentiate into functional cells of the other three lineages will require further investigation. MSCs for Myocardial Repair MSCs have several unique features that make them attractive candidates for cell transplantation. First, as they are easily accessible and expandable, MSCs could potentially become a so-called “off the shelf” allogeneic product, one which would be more cost-effective, easier to administer, and allow a greater number of cells to be transplanted. Additionally, they may also permit transplantation at the time of urgent interventions, e.g., to relieve ischemia and injury such as percutaneous or surgical revascularization procedures. Importantly, these cells appear to be hypoimmunogenic [54– 56]. Additionally, these cells lack MHC-II and B-7 costimulatory molecule expression and thus limit T-cell responses [57, 58]. Yet, they are considered to directly inhibit inflammatory responses via paracrine mechanisms including production of transforming growth factor beta 1 and hepatocyte growth factor (HGF) [59, 60]. Importantly, all the above properties taken together make them attractive candidates for cell transplantation. It should be noted that MSC transplantation was tested in a study in which isogenic adult rats were used as donors and recipients to simulate autologous transplantation clinically. MSC intracoronary delivery in these rat hearts following an experimentally induced MI showed that there was a milieudependent differentiation of these cells, a fibroblastic phenotype within the scar, and cardiomyocyte phenotype outside the infarction area [61]. However, direct intramyocardial injection of autologous MSCs into the region of the scar resulted in the focal differentiation of these cells into “cardiac-like” muscle cells within the scar tissue. There was also noted increased angiogenesis and improved myocardial function [62]. In a different approach, the delivery of MSCs

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Cell Transplantation

via direct left ventricular cavity infusion in a rat MI model resulted in the preferential migration and colonization of these cells in the ischemic myocardium (i.e., at 1 week) [63]. This MSC infusion also resulted in both increased vascularity and improved cardiac function 2 months following delivery in a canine model of chronic ischemic disease [64]. However, it should be noted that Kloner’s laboratory, using a rat model of postinfarction LV remodeling, found that the beneficial effects on left ventricular function were short term and were absent after 6 months [65]. Importantly, MSC transplantation has been reported to result in functional improvement in large animal ischemic models. For example, the direct intramyocardial injection of 5-azacytidine-treated autologous MSCs was performed 4 weeks after MI in a swine model; these injected cells formed islands of cardiac-like tissue, induced angiogenesis, prevented thinning and dilatation of the infarct region, and ultimately improved regional and global contractile functions [66]. Similarly, allogeneic intramyocardial transplantation of MSCs in a porcine model of MI resulted in profound improvements in border zone energetics and regional contractile function [67]. These latter findings were hypothesized to be related to a paracrine mechanism, as evidenced by increased vascularity in the border zone and spared native cardiomyocytes in the infarct zone [67]. Finally, the percutaneous delivery of allogenic MSCs 3 days after MI in a porcine model resulted in long-term engraftments (detected at 8 weeks), profound reductions in scar sizes, and near normalization of cardiac function [68].

40.2.3.4 Endothelial Progenitor Cells EPCs were first isolated from blood in 1997 [69]. They originate from a common hemangioblast precursor in the bone marrow [70]. However, many other cells including myeloid/ monocyte (CD14+) cells and stem cells from adult organs can also differentiate into cells with EPC characteristics. Thus, circulating EPCs are a heterogeneous group of cells originating from multiple precursors within the bone marrow and can be isolated in different stages of endothelial differentiation within peripheral blood. Therefore, the characterization of these cells can be challenging because they share certain surface markers of hematopoietic cells and adult endothelial cells. Typically, they express CD34 (a hematopoietic cell characteristic), CD-133 (a more specific marker of EPCs), and KDR (kinase insert domain-containing receptor), which is the receptor for vascular endothelial growth factor (VEGF). Interestingly, in a study of sex-mismatched bone marrow transplant patients by Hebbel and coworkers, 95 % of circulating endothelial cells in the peripheral blood of transplant patients had the recipient genotype, but 5 % had the donor genotype [71]. It was found that the endothelial cells with the donor phenotype had delayed growth in culture, but had a high proliferative capacity with more than a

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1000-fold expansion within 1 month; these were termed endothelial outgrowth cells. It was concluded that the endothelial outgrowth cells were of bone marrow origin [71]. In contrast, the cells with the recipient phenotype only had a 17-fold expansion within the same time period; these circulating endothelial cells most likely originated from the vessel wall [71]. EPCs have been used for treatment in different animal models of cardiovascular disease. For example, the intravenous delivery of CD34+ cells into athymic nude rats following MI was shown to promote angiogenesis in the peri-infarct region, leading to decreased myocyte apoptosis, reduced interstitial fibrosis, and improvement of left ventricular function [72]. Similarly, intramyocardial implantation of CD34+ selected human peripheral blood mononuclear cells into nude rats after MI resulted in neovascularization and improved LV function [73].

40.2.3.5 UCB Stem Cells Human UCB is rich in stem and progenitor cells, which have high proliferative capacities [74–76]. Human UCB also contains fibroblast-like cells termed unrestricted somatic stem cells, which adhere to culture dishes, are negative for c-kit, CD34, and CD45, and differentiate both in vitro and in vivo into a variety of tissue types, including cardiomyocytes [77]. Direct intramyocardial injection of these human unrestricted somatic cells into the infarcted hearts of immunosuppressed pigs resulted in: (1) improved perfusion and wall motion; (2) reduced infarct size; and (3) enhanced cardiac function [78]. Further, intravenous injection of human mononuclear UCB cells, a small fraction of which were CD34+, into NOD/ SCID mice led to enhanced neovascularization with capillary endothelial cells of both human and mouse origin and reduced infarct sizes [79]. However, no myocytes of human origin were found, thus arguing against cardiomyogenic differentiation and regeneration of cardiomyocytes from donor cells. Finally, the direct intramyocardial injection of UCB CD34+ cells into the peri-infarct rim in a rat model resulted in improved cardiac function [80]. To date, there have been no reported clinical studies of UCB transplantation for cardiac repair.

40.2.3.6 Cardiac Progenitor Cells The innate ability of the cardiomyocytes to replicate has been a highly controversial issue for a long time. Previous studies have established that increases in cardiac mass in mammals during fetal life occur mainly due to cardiomyocyte proliferation. However, during the perinatal period, mammalian cardiomyocytes withdraw from the cell cycle, thus limiting their ability to divide and increase in number [81–83]. Thus, normal postnatal growth and adaptive increases in cardiac mass in adults, as a result of hemodynamic burden, are achieved mainly through the increases in

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cell sizes, known as hypertrophy [81–83]. This belief was supported by the inability to identify mitotic figures in myocytes, as well as the observation that regions of transmural infarction evolved into essentially avascular, thin collagenous scar. This paradigm of heart growth had been dominant over the past 50 years, i.e., the heart is a postmitotic organ, consisting of a predetermined number of parenchymal cells, that is defined at birth and preserved throughout life until the death of the organ and/or organism. However, recent studies have challenged this concept of the heart being a postmitotic organ, one being incapable of regeneration. For example, it has been shown that the human heart contains cycling myocytes undergoing mitosis and cytokinesis under normal and pathological conditions [84–87]. The occurrence of these mitotic events is considered to support the hypothesis that CPC populations reside in the adult heart and can contribute to limited growth, turnover, and/or regeneration. This notion further supports that the adult heart belongs to the group of renewable adult tissues, and that this capacity for renewal is provided by a population of stem cells (i.e., CPCs) that reside in the myocardium [88, 89]. Origins of CPCs To date, the primary origins of CPCs remain unclear. It is feasible that the cycling cardiomyocytes might be derived from uncommitted stem-like population cells that reside in the heart which expand and differentiate into cardiomyocytes in response to signals and cues in response to growth and/or injury. Alternatively, these stem-like cells may reside in extracardiac tissues such as the bone marrow, and are capable of being recruited into the circulation and induced to home to the heart by signals emanating from the injured heart. For example, Mouquet et al. demonstrated that cardiac SP cells are maintained by local progenitor cell proliferation under physiological conditions [90]. After MI, this cardiac SP is decreased by as much as 60 % in the infarct and to a lesser degree in the noninfarct regions within 1 day. Cardiac SP pools are subsequently reconstituted to baseline levels within 7 days after MI, through both proliferation of resident cardiac SP cells and by homing of bone marrow-derived stem cells to specific areas of myocardial injury. These cells then undergo immunophenotypic conversions and adopt a cardiac SP phenotype (CD45+ to CD45−) [90]. Interestingly, bone marrow-derived stem cells accounted for approximately 25 % of the SP cells in the heart under pathological conditions, as compared to 77 %) decline in infarct size and complete functional recovery. Note that this was only when the cells seeded into the rings included a population of cardiomyocytes [136]. A recent, and much more extensive, review of the various materials and methods used to create myocardial patches has been published elsewhere [137].

heart failure [140, 141]. The transplantation of stem cells, or especially a patch of hiPSC-derived cells [142], can reduce adverse structural changes and partially restore a more native-like metabolic profile in the myocardium, thereby preserving or perhaps improving myocardial performance during the chronic phase of heart disease. For more details on cardiac bioenergetics, the reader is referred to Chap. 21.

40.5

40.5.3 Improved Perfusion

Mechanisms of Beneficial Effects of Stem Cell Treatment

Several studies using animal models have established that stem cell treatment leads to a functional benefit after MI. The initial results from the human clinical trials are also promising; however, the mechanisms underlying the beneficial effects of stem cell transplantation remain somewhat unclear. The proposed mechanisms are discussed below.

40.5.1 Primary Remuscularization First, the replacement of infarcted tissue by new myocardium generated by the transplanted cells is one explanation for the beneficial effects. This was observed in the case of human cardiac stem cells, which are able to form functional myocardium after transplantation into mice with MI; the transplanted cardiomyocytes were structurally integrated with the host myocardium and led to improvement in ventricular function [96]. This was also observed after the delivery of cardiomyocytes derived from human ESCs which were transplanted into mice with induced MIs [17]. To date, the ability of bone marrow cells to transdifferentiate into cardiomyocytes remains controversial with some reports suggesting that these cells can transdifferentiate into cardiomyocytes [40], while other reports refute this claim [38]. Other adult stem cells such as skeletal myoblasts and EPCs are not able to form cardiomyocytes, but have been found to still exert a beneficial effect, thus suggesting other mechanisms for improvement in LV function.

Enhanced blood flow, as measured by microspheres, has been shown to increase after stem cell transplantation in a rat model following MI [143]. Increased blood flow can be due to new vessel formation (angiogenesis) or enlargement of preexisting collaterals (arteriogenesis). A number of the stem cell populations discussed in this chapter have been shown to promote or contribute to neovascularization after transplantation in the setting of MI. Yet, some groups have challenged this concept and have shown that stem cells home to the region of developing vascular collateralization, but do not anatomically incorporate into the vessel as either endothelial or smooth muscle cells [144]; however, the delivery of these cell populations still improve collateral flow.

40.5.4 Paracrine Effects Stem cells may secrete factors that act through totally different repair pathways to ultimately promote cardioprotection. Evidence supporting such a hypothesis recently emerged from Dzau’s laboratory; they showed that the injection of the conditioned medium from Aktoverexpressing MSCs alone can decrease the infarct size and lead to functional improvement in an animal model of MI [145, 146]. Hypoxic Akt-transduced MSCs showed increased release of VEGF, FGF-2, IGF-1, HGF, and thymosin β4. It is likely that various factors acting in concert will ultimately exert numerous beneficial effect, as antiVEGF and anti-FGF antibodies only partially decrease the conditioned medium-induced proliferation of endothelial and smooth muscle cells [147, 148].

40.5.2 Attenuation of Adverse Remodeling The structural changes that occur after myocardial injury, such as ventricular dilatation, wall thinning, increased chamber volume, and hypertrophy of the surrounding myocardium [138], are accompanied by substantial hypoxiainduced changes in cellular ATP metabolism [139]. After the heart recovers from the initial infarction, these metabolic changes can persist and are believed to contribute to progressive declines in cardiac function that eventually lead to

40.5.5

Immunomodulation of the Infarct Environment

The inflammatory response after a MI has been recognized as a potential target for improving functional outcome after acute MI. Some stem cells may act, in part, by modulating the immune environment within the recently infarcted heart. For example, MSCs have been shown to directly inhibit the

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inflammatory responses via paracrine mechanisms including the production of transforming growth factor beta 1 and HGF [60, 61].

40.5.6

Modulation of Extracellular Matrix Homeostasis

Remodeling of the ventricle is also known to involve modifications in the extracellular matrix which are thought to contribute to myocardial dysfunction. As such, MSC implantation in a rat model of MI significantly attenuated the increased expression of collagen types I and III, TIMP-1, and TGF-β, but had no effects on MMP-1 levels [149, 150]. This was associated with reduced LV dilatation and improved global ventricular function.

40.6.2

Homing

An important goal is to enhance the homing of stem cells to the injured region of the heart. It is known that factors that contribute to the homing of stem cells include stromalderived growth factor (SDF-1) [152, 153], high mobility group box protein 1 [154], and integrins. It is also known that the microenvironment after acute MI is more favorable to cell homing as compared to the chronically infarcted myocardium. For example, Lu et al. [155] examined the local conditions requisite for cell homing and migration using a rat model of permanent coronary artery ligation, and concluded that the optimal time period for cell homing and migration is within the 2-week period following an MI.

40.6.3 Function and Survival 40.5.7 Stimulation of Endogenous Cardiac Progenitors Cells Stem cell treatment could also lead to increased mobilization, differentiation, survival, and function of endogenous CPCs that are associated with the paracrine effects. This possibility is receiving intense interest as cell therapy has uniformly been shown to improve cardiac function but has variable contributions to newly regenerated myocardium.

40.6 Techniques of Enhancing Efficacy of Stem Cell Therapy Although stem cell transplantation improves LV function after MI, to date, the observed stem cell engraftment is still found to be minimal. Furthermore, the majority of transplanted cells that do engraft remain as spindle-shaped stem cells and do not fully differentiate into the host cardiac cell phenotypes. Therefore, other techniques are considered necessary to enhance the efficacy of stem cell transplantation.

40.6.1

Mobilization

Granulocyte colony stimulating factor, VEGF, stromal cellderived factor-1 (SDF-1), angiopoietin-1, placental growth factor, and erythropoietin are several factors that may be utilized as therapies to mobilize stem cells from the bone marrow to the systemic circulation. Once these stem cells are mobilized, they may participate in endogenous repair or alternatively be collected and expanded in vitro for future cell therapy uses. As an example, intracoronary infusion of peripheral blood stem cells mobilized by granulocyte colony stimulating factor resulted in the improvement of LV function in patients with MI [151].

Assuming that the number of transplanted cells that survive is critical to therapeutic benefit, multiple research groups are exploring new methods to increase the survival of transplanted cells As such, apoptosis can be decreased by the constitutive expression of Akt (a serine threonine kinase with potent prosurvival activity) or by heat shock prior to transplantation [156]. Furthermore, rat MSCs transduced to overexpress Akt1 (encoding the Akt protein) transplanted into ischemic myocardium were found to inhibit cardiac remodeling by reducing inflammation, collagen deposition, and myocyte hypertrophy in a dose-dependent fashion [157]. Similarly, MSCs transduced to express Akt were also studied in an ischemic porcine model, which showed an improvement in ejection fraction as compared to nontransduced MSCs. Recently, in order to determine the exact mechanisms of these beneficial effects, the effects of the apoptotic stimulus, H2O2, on MSCs transduced with Akt was studied in vitro. Specifically, Akt-MSCs were found to be more resistant to apoptosis and were related to higher levels of extracellular signal-regulated protein kinase activation and VEGF expression [158]. Yet, a significant concern also exists regarding the potential tumorigenicity of Akt-transduced cells, particularly when Akt is constitutively expressed because Akt has been shown to be sufficient to induce oncogenic transformation of cells and tumor formation; therapeutic efforts are underway to target the Akt pathway for the treatment of malignancies [159]. Additional strategies that have been widely tested involve those which increase vasculogenesis with VEGF; transfection with VEGF and IGF-1 improved survival of transplanted bone marrow cells in a rat model of MI [160]. Furthermore, it was observed that the delivery of cells which had undergone adenoviral transduction and overexpressed VEGF also resulted in improved LV function and neovascularization [161], but the addition of VEGF protein alone to cells did not show any benefit in a rat model of fetal cardiomyocyte transplantation [162].

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Enhanced expression of other gene products has also been examined and found to be effective, including cardiotrophin1, heme oxygenase-1, an IL-1 inhibitor, and CuZn-superoxide dismutase. It was also shown that MSCs transfected with a hypoxia-regulated heme oxygenase-1 vector were found to be more tolerant to hypoxia-reoxygen injury in vitro and result in improved viability in ischemic hearts [163]. Likewise, treatment with CuZn-superoxide dismutase has been shown to attenuate the initial rapid cell death following transplantation, leaving a twofold increase in the total number of engrafted cells at 72 h compared with controls [164]. To date, the use of viruses for gene expression cannot be translated into clinical studies due to the risk of mutagenesis, carcinogenesis, and induction of an immune response. Yet recently, Jo et al. [165] developed a nonviral carrier of cationized polysaccharide for the genetic engineering of MSCs. When genetically engineered by a spermine-dextran complex with plasmid DNA of adrenomedullin, MSCs secreted a large amount of adrenomedullin, an anti-apoptotic and angiogenic peptide. Transplantation of these adrenomedullin gene-engineered MSCs improved cardiac function after MI significantly more than did nontransduced MSCs. Thus, this genetic engineering technology using the nonviral spermine-dextran (and other promising new methods) is an emerging strategy to improve MSC therapy for ischemic heart disease.

40.6.4 Use of Biomaterials to Design Microenvironment The microenvironment in which the cells are injected is of extreme importance for their survival and subsequent beneficial effects. It has been shown that biomaterials can be designed to regulate quantitative timed release of factors, which direct cellular differentiation pathways such as angiogenesis and vascular maturation. Moreover, it is believed that smart biomaterials are capable of responding to the local environment, such as protease activity or mechanical forces, with controlled release or activation [166]. Recently, Davis et al. [167] designed self-assembling peptide nanofibers for the prolonged delivery of IGF-1, a cardiomyocyte growth and differentiation factor, to the myocardium using a “biotin sandwich” strategy. Specifically, biotinylated IGF-1 was complexed with tetravalent streptavidin and then bound to biotinylated selfassembling peptides. After injection into rat myocardium, biotinylated nanofibers provided sustained IGF-1 delivery for 28 days, and targeted delivery of IGF-1 in vivo increased the activation of Akt in the myocardium. Therefore, cell therapeutic strategies using IGF-1 delivery by biotinylated nanofibers improved systolic function after experimental MI, demonstrating the importance of engineering the local

cellular microenvironment and the impact of these and future interventions to improve the outcomes of cell therapy. Importantly, many of these new biomaterials provide improved flexibility for regenerating tissues ex vivo, but emerging technologies such as self-assembling nanofibers can now establish intramyocardial cellular microenvironments following injection. This may allow percutaneous cardiac regeneration and repair approaches, i.e., injectable tissue engineering. It has been shown that materials can be made to multifunction by providing sequential signals with the custom design of differential release kinetics for individual factors. Thus, new rationally designed biomaterials no longer simply coexist with tissues, but can provide precision bioactive control of the microenvironment that may be required for cardiac regeneration and repair.

40.7

Summary

Recent studies continue to support the notion that cardiomyocyte regeneration may occur both during normal physiological adaptation and during the expression of pathological states in the adult human heart. Such findings may indicate the possibility for myocardial regeneration to occur via cardiomyocyte proliferation and/or differentiation of putative cardiac stem cells. To date, various cell types have been used for cardiac repair, including: skeletal myoblasts, bone marrow-derived cells, MSCs, EPCs, UCB stem cells, cardiac stem cells, and ESCs. This chapter has reviewed the current knowledge relative to these different stem cell populations being utilized for the potential treatment of heart disease. Findings to date continue to be promising, but much work remains before these therapeutic approaches become commonplace. Furthermore, specific cardiac devices/technologies for the clinical delivery of such cellular therapies will be required and are being currently being developed.

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49. Fukuda K (2002) Molecular characterization of regenerated cardiomyocytes derived from adult mesenchymal stem cells. Congenit Anom 42:1–9 50. Makino S, Fukuda K, Miyoshi S et al (1999) Cardiomyocytes can be generated from marrow stromal cells in vitro. J Clin Invest 103:697–705 51. Fukuda K (2003) Use of adult marrow mesenchymal stem cells for regeneration of cardiomyocytes. Bone Marrow Transplant 32:S25–S27 52. Tomita S, Nakatani T, Fukuhara S et al (2002) Bone marrow stromal cells contract synchronously with cardiomyocytes in a coculture system. Jpn J Thorac Cardiovasc Surg 50:321–324 53. Hakuno D, Fukuda K, Makino S et al (2002) Bone marrow-derived regenerated cardiomyocytes (CMG Cells) express functional adrenergic and muscarinic receptors. Circulation 105:380–386 54. Bartholomew A, Sturgeon C, Siatskas M et al (2002) Mesenchymal stem cells suppress lymphocyte proliferation in vitro and prolong skin graft survival in vivo. Exp Hematol 30:42–48 55. Le Blanc K, Tammik L, Sundberg B et al (2003) Mesenchymal stem cells inhibit and stimulate mixed lymphocyte cultures and mitogenic responses independently of the major histocompatibility complex. Scand J Immunol 57:11–20 56. Tse WT, Pendleton JD, Beyer WM et al (2003) Suppression of allogeneic T-cell proliferation by human marrow stromal cells: implications in transplantation. Transplantation 75:389–397 57. Zimmet JM, Hare JM (2005) Emerging role for bone marrow derived mesenchymal stem cells in myocardial regenerative therapy. Basic Res Cardiol 100:471–481 58. Ryan JM, Barry FP, Murphy JM et al (2005) Mesenchymal stem cells avoid allogeneic rejection. J Inflamm 2:8 59. Le Blanc K, Tammik C, Rosendahl K et al (2003) HLA expression and immunologic properties of differentiated and undifferentiated mesenchymal stem cells. Exp Hematol 31:890–896 60. Di Nicola M, Carlo-Stella C, Magni M et al (2002) Human bone marrow stromal cells suppress T-lymphocyte proliferation induced by cellular or nonspecific mitogenic stimuli. Blood 99:3838–3843 61. Wang JS, Shum-Tim D, Chedrawy E et al (2001) The coronary delivery of marrow stromal cells for myocardial regeneration: pathophysiologic and therapeutic implications. J Thorac Cardiovasc Surg 122:699–705 62. Tomita S, Li RK, Weisel RD et al (1999) Autologous transplantation of bone marrow cells improves damaged heart function. Circulation 100:II247–II256 63. Barbash IM, Chouraqui P, Baron J et al (2003) Systemic delivery of bone marrow-derived mesenchymal stem cells to the infarcted myocardium: feasibility, cell migration, and body distribution. Circulation 108:863–868 64. Silva GV, Litovsky S, Assad JA et al (2005) Mesenchymal stem cells differentiate into an endothelial phenotype, enhance vascular density, and improve heart function in a canine chronic ischemia model. Circulation 111:150–156 65. Dai W, Hale SL, Martin BJ et al (2005) Allogeneic mesenchymal stem cell transplantation in postinfarcted rat myocardium: shortand long-term effects. Circulation 112:214–223 66. Tomita S, Mickle DA, Weisel RD et al (2002) Improved heart function with myogenesis and angiogenesis after autologous porcine bone marrow stromal cell transplantation. J Thorac Cardiovasc Surg 123:1132–1140 67. Zeng L, Hu Q, Wang X et al (2007) Bioenergetic and functional consequences of bone marrow-derived multipotent progenitor cell transplantation in hearts with postinfarction left ventricular remodeling. Circulation 115:1866–1875 68. Amado LC, Saliaris AP, Schuleri KH et al (2005) Cardiac repair with intramyocardial injection of allogeneic mesenchymal stem cells after MI. Proc Natl Acad Sci U S A 102:11474–11479

747 69. Asahara T, Murohara T, Sullivan A et al (1997) Isolation of putative progenitor endothelial cells for angiogenesis. Science 275:964–967 70. Masuda H, Asahara T (2003) Post-natal endothelial progenitor cells for neovascularization in tissue regeneration. Cardiovasc Res 58:390–398 71. Lin Y, Weisdorf DJ, Solovey A et al (2000) Origins of circulating endothelial cells and endothelial outgrowth from blood. J Clin Invest 105:71–77 72. Kocher AA, Schuster MD, Szabolcs MJ et al (2001) Neovascularization of ischemic myocardium by human bonemarrow-derived angioblasts prevents cardiomyocyte apoptosis, reduces remodeling and improves cardiac function. Nat Med 7:430–436 73. Kawamoto A, Tkebuchava T, Yamaguchi J et al (2003) Intramyocardial transplantation of autologous endothelial progenitor cells for therapeutic neovascularization of myocardial ischemia. Circulation 107:461–468 74. Lewis ID, Verfaillie CM (2000) Multi-lineage expansion potential of primitive hematopoietic progenitors: superiority of umbilical cord blood compared to mobilized peripheral blood. Exp Hematol 28:1087–1095 75. Murohara T, Ikeda H, Duan J et al (2000) Transplanted cord blood-derived endothelial precursor cells augment postnatal neovascularization. J Clin Invest 105:1527–1536 76. Mayani H, Lansdorp PM (1998) Biology of human umbilical cord blood-derived hematopoietic stem/progenitor cells. Stem Cells 16:153–165 77. Kogler G, Sensken S, Airey JA et al (2004) A new human somatic stem cell from placental cord blood with intrinsic pluripotent differentiation potential. J Exp Med 200:123–135 78. Kim BO, Tian H, Prasongsukarn K et al (2005) Cell transplantation improves ventricular function after a MI: a preclinical study of human unrestricted somatic stem cells in a porcine model. Circulation 112:I96–I104 79. Ma N, Stamm C, Kaminski A et al (2005) Human cord blood cells induce angiogenesis following MI in NOD/scid-mice. Cardiovasc Res 66:45–54 80. Hirata Y, Sata M, Motomura N et al (2005) Human umbilical cord blood cells improve cardiac function after MI. Biochem Biophys Res Commun 327:609–614 81. MacLellan WR, Schneider MD (2000) Genetic dissection of cardiac growth control pathways. Annu Rev Physiol 62:289–319 82. Rubart M, Field LJ (2006) Cardiac regeneration: repopulating the heart. Annu Rev Physiol 68:29–49 83. Soonpaa MH, Field LJ (1998) Survey of studies examining mammalian cardiomyocyte DNA synthesis. Circ Res 83:15–26 84. Beltrami AP, Urbanek K, Kajstura J et al (2001) Evidence that human cardiac myocytes divide after MI. N Engl J Med 344:1750–1757 85. Quaini F, Urbanek K, Beltrami AP et al (2002) Chimerism of the transplanted heart. N Engl J Med 346:5–15 86. Anversa P, Kajstura J (1998) Ventricular myocytes are not terminally differentiated in the adult mammalian heart. Circ Res 83:1–14 87. Nadal-Ginard B, Kajstura J, Leri A et al (2003) Myocyte death, growth, and regeneration in cardiac hypertrophy and failure. Circ Res 92:139–150 88. Anversa P, Sussman MA, Bolli R (2004) Molecular genetic advances in cardiovascular medicine: focus on the myocyte. Circulation 109:2832–2838 89. Sussman MA, Anversa P (2004) Myocardial aging and senescence: where have the stem cells gone? Annu Rev Physiol 66:29–48 90. Mouquet F, Pfister O, Jain M et al (2005) Restoration of cardiac progenitor cells after MI by self-proliferation and selective homing of bone marrow-derived stem cells. Circ Res 97:1090–1092

748 91. Kucia M, Dawn B, Hunt G et al (2004) Cells expressing early cardiac markers reside in the bone marrow and are mobilized into the peripheral blood after MI. Circ Res 95:1191–1199 92. Cerisoli F, Chimenti I, Gaetani R et al (2006) Kit-Positive Cardiac Stem Cells (CSCs) can be generated in damaged heart from bone marrow-derived cells. Circulation 114:II-164 93. Leri A, Kajstura J, Anversa P (2005) Cardiac stem cells and mechanisms of myocardial regeneration. Physiol Rev 85:1373–1416 94. Beltrami AP, Barlucchi L, Torella D et al (2003) Adult cardiac stem cells are multipotent and support myocardial regeneration. Cell 114:763–776 95. Wang X, Hu Q, Nakamura Y, Lee J, Zhang G, From AH, Zhang J. The Role of Sca-1+/CD31- Cardiac Progenitor Cell Population in Postinfarction LV Remodeling. Stem Cells. 2006;24(7): 1779–88 96. Bearzi C, Rota M, Hosoda T et al (2007) Human cardiac stem cells. Proc Natl Acad Sci U S A 104:14068–14073 97. van Berlo JH, Kanisicak O, Maillet M et al (2014) C-Kit+ cells minimally contribute cardiomyocytes to the heart. Nature 509:337–341 98. Oh H, Bradfute SB, Gallardo TD et al (2003) Cardiac progenitor cells from adult myocardium: homing, differentiation, and fusion after infarction. Proc Natl Acad Sci U S A 100:12313–12318 99. Matsuura K, Nagai T, Nishigaki N et al (2004) Adult cardiac Sca1-positive cells differentiate into beating cardiomyocytes. J Biol Chem 279:11384–11391 100. Martin CM, Meeson AP, Robertson SM et al (2004) Persistent expression of the ATP-binding cassette transporter, Abcg2, identifies cardiac SP cells in the developing and adult heart. Dev Biol 265:262–275 101. Pfister O, Mouquet F, Jain M et al (2005) CD31- but Not CD31+ cardiac side population cells exhibit functional cardiomyogenic differentiation. Circ Res 97:52–61 102. Laugwitz KL, Moretti A, Lam J et al (2005) Postnatal isl1+ cardioblasts enter fully differentiated cardiomyocyte lineages. Nature 433:647–653 103. Messina E, De Angelis L, Frati G et al (2004) Isolation and expansion of adult cardiac stem cells from human and murine heart. Circ Res 95:911–921 104. Smith RR, Barile L, Cho HC et al (2007) Regenerative potential of cardiosphere-derived cells expanded from percutaneous endomyocardial biopsy specimens. Circulation 115:896–908 105. Dawn B, Stein AB, Urbanek K et al (2005) Cardiac stem cells delivered intravascularly traverse the vessel barrier, regenerate infarcted myocardium, and improve cardiac function. Proc Natl Acad Sci U S A 102:3766–3771 106. Wang X, Hu Q, Nakamura Y et al (2006) The role of the sca-1+/ CD31- cardiac progenitor cell population in postinfarction left ventricular remodeling. Stem Cells 24:1779–1788 107. Urbanek K, Rota M, Cascapera S et al (2005) Cardiac stem cells possess growth factor-receptor systems that after activation regenerate the infarcted myocardium, improving ventricular function and long-term survival. Circ Res 97:663–673 108. Linke A, Muller P, Nurzynska D et al (2005) Stem cells in the dog heart are self-renewing, clonogenic, and multipotent and regenerate infarcted myocardium, improving cardiac function. Proc Natl Acad Sci U S A 102:8966–8971 109. Bearzi C, Muller P, Amano K et al (2006) Identification and characterization of cardiac stem cells in the pig heart. Circulation 114:II-125 110. Johnston P, Sasano T, Mills K et al (2006) Isolation, expansion and delivery of cardiac derived stem cells in a porcine model of MI. Circulation 114:II-125 111. Hosoda T, Bearzi C, Amano S et al (2006) Human cardiac progenitor cells regenerate cardiomyocytes and coronary vessels repairing the infarcted myocardium. Circulation 114:II-51

J. Zhang and D.J. Garry 112. Torella D, Elliso GM, Karakikes I et al (2006) Biological properties and regenerative potential, in vitro and in vivo, of human cardiac stem cells isolated from each of the four chambers of the adult human heart. Circulation 114:II-87 113. Menasche P, Hagege AA, Vilquin JT et al (2003) Autologous skeletal myoblast transplantation for severe postinfarction left ventricular dysfunction. J Am Coll Cardiol 41:1078–1083 114. Herreros J, Prosper F, Perez A et al (2003) Autologous intramyocardial injection of cultured skeletal muscle-derived stem cells in patients with non-acute MI. Eur Heart J 24:2012–2020 115. Pagani FD, DerSimonian H, Zawadzka A et al (2003) Autologous skeletal myoblasts transplanted to ischemia-damaged myocardium in humans. Histological analysis of cell survival and differentiation. J Am Coll Cardiol 41:879–888 116. Siminiak T, Kalawski R, Fiszer D et al (2004) Autologous skeletal myoblast transplantation for the treatment of postinfarction myocardial injury: phase I clinical study with 12 months of follow-up. Am Heart J 148:531–537 117. Smits PC, van Geuns RJ, Poldermans D et al (2003) Catheterbased intramyocardial injection of autologous skeletal myoblasts as a primary treatment of ischemic heart failure: clinical experience with six-month follow-up. J Am Coll Cardiol 42:2063–2069 118. Siminiak T, Fiszer D, Jerzykowska O et al (2005) Percutaneous trans-coronary-venous transplantation of autologous skeletal myoblasts in the treatment of post-infarction myocardial contractility impairment: the POZNAN trial. Eur Heart J 26:1188–1195 119. Hagege AA, Carrion C, Menasche P et al (2003) Viability and differentiation of autologous skeletal myoblast grafts in ischaemic cardiomyopathy. Lancet 361:491–492 120. Assmus B, Schachinger V, Teupe C et al (2002) Transplantation of progenitor cells and regeneration enhancement in acute myocardial infarction (TOPCARE-AMI). Circulation 106:3009–3017 121. Schachinger V, Assmus B, Britten MB et al (2004) Transplantation of progenitor cells and regeneration enhancement in acute MI: final one-year results of the TOPCARE-AMI Trial. J Am Coll Cardiol 44:1690–1699 122. Wollert KC, Meyer GP, Lotz J et al (2004) Intracoronary autologous bone-marrow cell transfer after MI: the BOOST randomised controlled clinical trial. Lancet 364:141–148 123. Schachinger V, Erbs S, Elsasser A et al (2006) Intracoronary bone marrow-derived progenitor cells in acute MI. N Engl J Med 355:1210–1221 124. Lunde K, Solheim S, Aakhus S et al (2006) Intracoronary injection of mononuclear bone marrow cells in acute MI. N Engl J Med 355:1199–1209 125. Janssens S, Dubois C, Bogaert J et al (2006) Autologous bone marrow-derived stem-cell transfer in patients with ST-segment elevation MI: double-blind, randomised controlled trial. Lancet 367:113–121 126. Seeger F, Tonn T, Krzossok N et al (2006) Cell isolation procedures matter: a comparison of different isolation protocols of bone marrow mononuclear cells used for cell therapy in patients with acute MI. Circulation 114:II-51 127. Assmus B, Honold J, Schachinger V et al (2006) Transcoronary transplantation of progenitor cells after MI. N Engl J Med 355:1222–1232 128. Chen SL, Fang WW, Qian J et al (2004) Improvement of cardiac function after transplantation of autologous bone marrow mesenchymal stem cells in patients with acute MI. Chin Med J (Engl) 117:1443–1448 129. Chen SL, Fang WW, Ye F et al (2004) Effect on left ventricular function of intracoronary transplantation of autologous bone marrow mesenchymal stem cell in patients with acute MI. Am J Cardiol 94:92–95 130. Zambrano J, Traverse JH, Henry T et al (2007) Abstract 1014: The impact of intravenous allogeneic human mesenchymal stem cells

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The Use of Isolated Heart Models and Anatomical Specimens as Means to Enhance the Design and Testing of Cardiac Devices

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Michael G. Bateman, Michael D. Eggen, Julianne H. Spencer, Tinen L. Iles, and Paul A. Iaizzo

Abstract

In recent years, the use of perfusion-fixed cadaveric specimens and isolated heart models has helped to develop an improved understanding of the device-tissue interface and has also contributed to the rapid evolution of surgically and percutaneously delivered cardiac therapies. This chapter describes a novel series of techniques utilized within the Visible Heart® laboratory by engineers, scientists, and anatomists to visualize and analyze the heart and assess potential repair or replacement therapies. The study of reanimated large mammalian hearts (including human hearts) and specially prepared anatomical specimens, using various clinical and nonclinical imaging modalities, has provided feedback for design engineers and clinicians that seek to develop and/or employ cardiac therapies for patients with acquired or congenital heart disease. Keywords

Isolated heart model • Cardiac device design and development • Human cardiac anatomy • Reanimated heart

41.1

Introduction

A detailed and comprehensive understanding of human cardiac anatomy remains a crucial component of cardiovascular medical practice, research, and cardiac device design and development [1, 2]. The successful deployment and performance of a particular cardiac device is continually impacted by the ability of the device to conform and adapt to the changing anatomical landscape of the heart, as well as to anatomical variations that may exist in a given patient. In other words, successful device design and development

M.G. Bateman, PhD (*) • M.D. Eggen, PhD • J.H. Spencer, PhD Medtronic, Inc., 8200 Coral Sea Street NE, Mounds View, MN 55112, USA e-mail: [email protected] T.L. Iles, BS • P.A. Iaizzo, PhD Department of Surgery, University of Minnesota, Minneapolis, MN, USA

requires a well-developed understanding of the relevant cardiovascular anatomies (in relation to both vascular approaches and within the heart itself) at every stage of the process [3–5]. The study of fixed and reanimated human hearts, using the various methodologies described here, has provided for novel insights as to the details of human cardiac anatomy. For almost two decades, the Visible Heart® methodologies have provided a unique perspective on functional cardiac anatomy. By reanimating human hearts not deemed viable for transplant, we have been able to visualize the beating heart using a variety of imaging modalities, including: (1) endoscopes placed directly within the various heart chambers and/or within the large diameter vessels, (2) echocardiography, (3) fluoroscopy, (4) magnetic resonance imaging (MRI), (5) infrared thermography, and/or (6) high-speed cameras. This database of images and videos exemplifies the large degree of variability that exists in human cardiac anatomy (from both a static and functional perspective) [6]. Additionally, such imaging techniques allow for visualization of the anatomical changes that occur as a result of various

© Springer International Publishing Switzerland 2015 P.A. Iaizzo (ed.), Handbook of Cardiac Anatomy, Physiology, and Devices, DOI 10.1007/978-3-319-19464-6_41

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pathologies and/or those that may occur following the deployment of devices within the heart. Recent advances in intracardiac interventions have increased the need for a greater understanding of the anatomical complexities of the heart prior to the respective procedure. Further, as clinicians become more comfortable with the delivery of novel devices within beating hearts, the already widespread utilization of percutaneous technologies such as coronary stenting and transcatheter valve replacement will continue to intensify. This is highlighted today by the highly competitive field of transcatheter aortic valve implants, where competing designs attempt to provide the most effective treatment for the patient in a package that enables physicians to comfortably and reliably administer the therapy. Consequently, it has become more critical than ever for device developers to have a thorough understanding of: (1) the variations of cardiac anatomy that will present in the patient populations they treat and (2) the results they obtain from in vitro and in vivo testing of potential therapies. This chapter will discuss the use of anatomical specimens and isolated heart preparations as important methodologies to provide the required educational foundation needed for the fields of cardiac device design, development, and deployment.

41.2

Anatomical Specimens and Static Imaging

Throughout history, anatomists such as Galen, Vesalius, da Vinci, and more recently Hunter, Gray, and Netter have recreated their knowledge gained from the dissection of animal and human cadavers in elegant treatises. However, with the advent of high-resolution noninvasive imaging in the past century, our understanding of the functional internal anatomy of the body has progressed even more rapidly. This accelerated growth of knowledge has led to the proposed utilization of attitudinally correct nomenclature, in an attempt to ensure that anatomists, surgeons, radiologists, cardiologists, echocardiographers, and biomedical engineers are able to communicate using common anatomical terms (see Chap. 2) [7]. Combined with these advances in our understanding of cardiac anatomy, there has also been progress in the preparation of anatomical specimens for research. The ancient Egyptians, as part of the ritual preparation of their deceased kings for burial, preserved bodies through the technique of embalming. However, until the discovery of glutaraldehyde and formaldehyde in the mid-nineteenth century, human cadavers used for medical dissections were not typically preserved in embalming solutions with anatomists relying on

the cooler temperatures of winter to extend their dissection times. The introduction of powerful chemical preservation techniques extended the period of time anatomists could study a particular specimen and also increased the integration of anatomical classes in medical teaching. However, the fixation of the heart within the body as prepared for an anatomical study preserves the myocardium in a state of rigor, usually with the various heart chambers collapsed and potentially full of clotted materials (blood). In 1978, researchers at the Mayo Clinic (Rochester, MN, USA) adapted a formalin pressure perfusion system used in the study of pulmonary disorders to prepare the heart for anatomical investigations [8, 9]. However, the technique was time consuming and did not become more commonly used until Thomas and Davies reported the use of a simple apparatus to allow for the perfusion fixation of fresh cardiac specimens [10]. This technique has since been used extensively for the preparation of cardiac specimens by cardiac morphologists such as Robert Anderson [11] and has been adopted by the Visible Heart® laboratory as the preferred method of preparation for the cardiac specimens within the Visible Heart® library [5].

41.3

The Visible Heart® Library

Our laboratory has the privilege to obtain fresh human heart specimens for educational and research purposes from: (1) organ donors whose hearts are not deemed viable for transplantation and are donated for research (via LifeSource, the Upper Midwest Organ Procurement Organization, St. Paul, MN, USA) and (2) bodies donated to the University of Minnesota’s Anatomy Bequest Program. After excision, these fresh, unfixed specimens are subsequently cleaned and perfusion fixed in 10 % buffered formalin, by attaching the cannulated great vessels of each heart to a pressure head of approximately 50 mmHg. This technique, modified from Thomas and Davies [10] and described by Anderson et al. [5], fixes the hearts in an approximation of the end-diastolic state, providing a unique insight into the anatomical dimensions of a given specimen. Figure 41.1 demonstrates various images that can be acquired from these specimens and shows some of the cardiac pathologies (those depicted here are diseases of the cardiac valves) that can be subsequently visualized [12]. To date, our library of more than 350 hearts of various disease states continues to provide researchers with the ability to investigate how the cardiac anatomy may change/ remodel under specific pathologies. In addition to anatomical investigations, these specimens can be employed to provide information as to how a specific device will fit the cardiac anatomies of the intended patient population, or how a delivery system will navigate through the chambers and

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Isolated Heart Models

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Fig. 41.1 Images from perfusion-fixed hearts from the Visible Heart® laboratory’s library: (1) calcified aortic valve (upper left panel), (2) pulmonary valve (upper right panel), (3) subvalvular apparatus of the

mitral valve (lower left panel), and (4) tricuspid valve from the right ventricle (lower right panel). Modified from The Atlas of Human Cardiac Anatomy [12]

vasculature of the heart. Such resources have allowed for the placement of multiple prototype devices and rapid comparison of how specific devices interact with the surrounding cardiac anatomies in a variety of human specimens [13, 14]. This information is critical in the development process, as it allows for engineers to highlight challenges regarding implantation of the device or the navigation of the delivery system that may have been overlooked in bench top testing. Fresh cadaver hearts received by the Visible Heart® laboratory are documented at each stage of the acquisition process to record global anatomical changes during the fixation process, such as tissue weight and overall dimensions. Images of the fresh preparation, the resulting fixed specimen, and the nondestructive imaging of a sample specimen from the library (adapted from the Atlas of Human Cardiac Anatomy [12]) can be seen in Fig. 41.2. Recent advances in high-resolution noninvasive cardiac imaging have fostered extensive work in the in vivo analyses of anatomical variations from patient to patient using a variety of imaging modalities:

3. Multi-slice computed tomography [17] 4. Magnetic resonance imaging (MRI, e.g., 1.5 T, 3 T, or greater) [18]

1. Cardiac ultrasound (e.g., transthoracic, transesophageal, intracardiac, 2D, 3D, and/or 4D) [15] 2. Computed tomography (CT) [16]

Nondestructive imaging of specimens from the Visible Heart® library via ultrasound, CT, and MRI has been used to collate a digital database of these hearts for educational and research purposes. The perfusion-fixed specimens are prepared by suspending them in a gel medium, allowing for a full complement of multimodal imaging to be performed on the hearts without changing the orientation [19]. Obtaining high-resolution images has allowed for detailed analyses of cardiac anatomies for a variety of normal and pathologic specimens; this spectrum of imaging is considered not possible with available clinical imaging protocols. For example, the analysis of fiber orientations of specimens obtained from patients in end-stage heart failure, using diffusion tensor MRI [20], provided critical insight into the remodeling of the ventricular tissue in patients with chronic heart failure. In addition, it has been possible to compare the ability of different imaging modalities to assess the anatomical characteristics of specific cardiac pathologies such as aortic stenosis, thus building on the work of other researchers [21, 22]. For additional imaging of such specimens, see Chaps. 6, 7, and 8.

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Fig. 41.2 Images of a heart received by the Visible Heart® library and imaged fresh (upper left panel), after perfusion fixation (upper right panel), and scanned in a 3 T Siemens MRI scanner (bottom left panel)

41.4

In Vitro Isolated Heart Models

A comprehensive understanding of the cardiac anatomy provides device designers with fundamental information regarding the anatomical dimensions and variations of the environment into which the device or therapy will be delivered. However, these static human heart specimens do not address the complications surrounding the delivery and function of a device or therapy in a beating heart. Before embarking upon complex and expensive chronic animal testing protocols which are required to prove the efficacy of novel cardiac devices, there is exceptional value in testing in reanimated beating heart models. Our laboratory at the University of Minnesota has reanimated over 1500 large mammalian hearts (canine, ovine, swine, mini-pigs, and human) for such studies in the last 15 years. There have been several other academic institutions and private companies that have developed in vitro large mammalian heart models, with many

and GE Vivid I ultrasound (lower right panel) in the four-chamber longaxis view. Modified from The Atlas of Human Cardiac Anatomy [12]

groups effectively developing systems based upon the mechanical reanimation of cadaveric large mammalian hearts. For example, Richards et al. were able to consistently and reliably quantify mitral regurgitation across a range of severity in explanted porcine hearts and investigate the efficacy of various repair techniques [23]. Further, two other groups have succeeded in studying the electrophysiology of explanted human hearts by sustaining the heart with a pressurized coronary flow of oxygen saturated salt solution via Langendorff perfusion [24, 25]. However, it should be noted that the true reanimation of large mammalian hearts (whereby the heart functions independently of any mechanical or electrical assistance) has only been achieved by a small number of research groups. Araki et al. (Nagoya University, Japan) reported that they were able to complete optical and hemodynamic analyses of cardiac valves in reanimated swine hearts [26]. Most recently, Weger et al. at the Leiden University Medical Center, Netherlands, have monitored transcatheter valve implantations in reanimated swine hearts

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Fig. 41.3 Images of a human heart connected to the Visible Heart® apparatus from an approximation of the anterior-posterior aspect (A) and from the left anterior oblique aspect (B)

using their described PhysioHeart system [27]. However, it should be noted that in these preparations, the researchers were limited by the amount of time the heart remained viable, a factor considered key to the accessibility of the heart for device testing. The Visible Heart® laboratory partnered with Medtronic, Inc. in 1997 to develop the Visible Heart® methodologies, which consist of a large mammalian isolated heart model that can be controlled to function in either Langendorff [25], right-side working, or four-chamber working modes [28]. Over this time and continuing today, we have been developing/optimizing this apparatus for reanimation whereby isolated large mammalian hearts are perfused and then actively pump a clear crystalloid perfusate in the place of blood. Images of a human heart connected to the Visible Heart® apparatus can be seen in Fig. 41.3. This approach has allowed our group to visualize what occurs inside the heart during device deployment procedures and subsequently to determine how such devices interact with the specific anatomies of the heart throughout all the phases of the cardiac cycle. Briefly, our approach includes the initial step of removing hearts from humans or animals using standard cardioplegia procedures [28, 29]. Once isolated, cannulae are inserted into the great vessels allowing the placement of endoscopes or devices into all four working chambers. Following reanimation, cardiac and systemic pressures and outputs can be monitored and preloads and afterloads adjusted accordingly to simulate systemic vascular pathologies such as hypertension. Additionally, the isolated heart apparatus allows researchers to quickly switch the perfusion system to operate in Langendorff, right-side working, or four-chamber working modes. During the Langendorff mode, the left-side afterload is held constant with a coronary perfusion pressure of approximately 60 mmHg [28]; thus, the flow through the coronaries is determined by dilation or constriction of the

coronary arteries. Right-side working mode combines Langendorff retrograde aortic perfusion with antegrade, or physiologic, flow through the right atrium and right ventricle (adjustable between ~3–5 L/min). During four-chamber working mode, the flow through a heart is normally determined by its intrinsic heart rate, preloads, afterloads, and the relative contractility of the various heart chambers. By controlling the orientation of the heart in our apparatus and determining the preload and afterload pressures exerted on the specimen, we can recreate specific cardiac states. Interestingly, the intrinsic heart rate and hemodynamic performance can be modified by altering the temperature of the buffer or by adding pharmacological agents (e.g., catecholamines or anesthetics), which are discussed later in this chapter. Although no model can perfectly mimic in vivo conditions, to date our apparatus has allowed researchers to simulate a broad range of particular physiological environments that are observed in various clinical settings.

41.5 How Can an Isolated Heart Prep Augment and Complement Bench Top Testing? The combination of a “live” functional anatomy within a controlled “bench top” experimental setting provides a unique stepping stone between in vitro device testing and in vivo implantation required for implantable medical devices. Figure 41.4 shows how the typical stages of device testing and development compare in terms of the relevance of the testing environment to the intended functional environment, the quantity of data one can reasonably expect to collect, and the cost of performing such investigations. It can easily be observed that as the relevance of a particular testing methodology increases, the relative costs will dramatically

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Fig. 41.4 Proposed hierarchy between the relevance of various experimental approaches, the amount of data one can obtain, and the relative costs. For example, if you wish to perform medical device design research in the field of prosthetic valves, ideally you would like to perform human trials in vivo, but this not only raises medical ethical issues but is highly costly and may provide useful data for one specific valve design and

procedure. Whereas if you move the research approach downward (i.e., employ an isolated large mammalian heart model in vitro), you can obtain more data at a lower cost, but then you must justify the appropriateness of the chosen model. Yet, in one given study, it may be possible to perform multiple procedures for comparison or at least multiple implants in multiple hearts with fairly consistent anatomies

increase; thus, the likely number of possible iterations decreases. Consequently, any possible augmentations to device testing prior to chronic animal implants (e.g., via isolated beating heart preps) can, in turn, greatly reduce the overall product development costs and speed clinical use of novel valve repair, implant, and their associated delivery systems. Due to the large number of cycles seen in the lifetime of a cardiac device, accelerated wear and fatigue testing are required gold standards for the assessment of durability. In accelerated wear testing for bioprosthetic valves, the hydrodynamic conditions are tightly controlled and easily varied allowing the durability of the valve leaflets to be assessed under a variety of predetermined conditions. Similarly, the boundary conditions imposed on the valve frame or commissure posts during fatigue testing can assess frame durability. Isolated heart preparations, including the Visible Heart® methodologies, will never replace these forms of testing, but unique information regarding the device-tissue interactions in the later can be observed. It should be noted that since the hydrodynamics of isolated heart preparations are typically less aggressive environments than what is experienced during accelerated wear testing, the boundary conditions observed for a device in such studies are not directly transferable to accelerated wear test methodologies. Yet on the other hand, they can serve as means to obtain additional information to ascertain the validity of any boundary conditions within the accelerated testing protocol, ensuring that all forms of boundary conditions have been taken into account,

i.e., the change in curvature throughout the cardiac cycle of a left-sided pacing lead within the coronary vasculature. Most importantly, such experimentation has provided us with a socalled physiological link between bench top testing of devices and animal testing. Acute phenomena observed during accelerated wear testing and the insights gained with both invasive and noninvasive imaging techniques in animal studies may be directly observed during a device implant study in vitro. For example, a procedural issue observed under fluoroscopy during an in vivo animal implant could be recreated by employing the Visible Heart® approach (under direct visualization) with simultaneous fluoroscopy, thus gaining a better understanding of potential adverse issues. We consider that having the Visible Heart® apparatus as a tool for device design has allowed us to obtain a more rapid understanding of phenomena observed in both bench top and preclinical settings; as such, it is an invaluable tool for a device designer, especially at the early stages of development. See other chapters for addition descriptions and images of cardiac devices that have been implanted in reanimated human hearts [30].

41.6

The Importance of Species Selection in In Vitro Cardiac Device Research

The ultimate utility of studies performed with Visible Heart® methodologies, such as transcatheter valve development, is in part determined by the heart chosen for reanimation.

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We suggest that the criteria for species selection for acute in vitro studies are slightly different from those for chronic valve assessments, due to the elimination of all systemic factors that may contribute to device performance. In other words, the species of the donor can be chosen specifically for its relative cardiac anatomy rather than for factors such as thrombogenesis, immune response, and/or growth rates. For years, the canine heart has been used for such experimentation and has provided useful information. Yet it should be recognized that canine hearts have an unusually large amount of collateral coronary circulation (similar to humans in end-stage chronic heart failure), and this in turn results in the inconsistent creation of ischemic (infarct) regions. Sheep have been historically employed for chronic valve implantation studies, as valve function and valve orifice sizes observed in sheep are very similar to those of a human heart. Additionally, the relatively large atria of the sheep’s heart allow for straightforward surgical approaches to the atrioventricular valves. However, it has recently been proposed that swine are an excellent model for acute cardiac device testing, as porcine hearts have very similar anatomy to that of humans with respect to the cardiac valves, conduction system, coronary arteries, and great vessels. Importantly the relationship between the cardiac conduction system and surrounding anatomical features is comparable between swine and human anatomies. Nevertheless, it is important to note that there are some specific variations in animal anatomy that should be known; such interindividual and interspecies variations have been extensively researched [28, 29, 31] and are described in greater detail in Chaps. 6 and 27. Due to their specific anatomical similarity with human hearts and the relative ease of procurement (excision and reanimation), the mainstay of cardiac research done in the Visible Heart® laboratory is completed using swine hearts. Nevertheless, as previously mentioned, our laboratory has also had the privilege to obtain fresh human heart specimens for reanimation, for both educational and research purposes. Such hearts, if received in a timely manner and with complete anatomies including the great vessels, have been reanimated using the same methodologies as previously described for swine hearts. By reanimating these hearts using a clear perfusate, visualization of the internal cardiac anatomy has provided novel insights into the relative variations of human cardiac anatomy (in healthy individuals) and has highlighted the alterations that occur with various pathologies. Finally, this approach provides the unique opportunity to deliver existing or novel devices within functional human anatomies without the concerns and considerations required in clinical trials; thus, it has allowed researchers to garner invaluable knowledge about their device designs that otherwise could not be generated using animal models.

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41.7

Understanding and Controlling Heart Function In Vitro

The performance of the reanimated heart can be influenced by several additional mechanisms. For example, subsequent cardiac function will be compromised by the amount of cell injury that occurs, governed in part by the amount of time between heart explant and reanimation. It is considered that if this period exceeds 6 h, performance will be compromised, even if the heart is stored under ideal conditions. To reduce such time-associated myocardial injury due to global ischemia, we have investigated the use of cardioprotective agents delivered before explanting the heart [32]. Most recently, we have been investigating the effect of omega-3 polyunsaturated fatty acids administered before explant on the acute function upon reanimation; for additional discussion of these topics, see Chap. 16. Because of the isolation process, the reanimated heart has no direct parasympathetic or sympathetic innervation and thus is not affected by any signals from the autonomic nervous system. However, pharmaceuticals/hormones such as dobutamine and epinephrine can be administered to the circulating perfusate. These catecholamines work by stimulating the β1 receptor on the myocytes, acting as chronotropes and inotropes, increasing heart rate and contractility and, thus, overall cardiac output. Furthermore, the ionic balance of the circulating buffer can have very dramatic effects; e.g., increasing the calcium Ca2+ concentration in the buffer will act as a potent inotrope by increasing the Ca2+ inside the cell during the action potential. We will often utilize such inotropic agents shortly after deploying a prosthetic valve within an isolated heart to increase cardiac output and ejection fraction and therefore optimize function of the device. Understanding the electrophysiology of the reanimated specimen is important during the assessment of cardiac devices and therapies designed to monitor and/or treat cardiac rhythm disease. It should be noted that by utilizing our Visible Heart® methodologies, the reanimated heart tissue is alive on the apparatus, and the heart rate is driven by the sinoatrial node. However, occasionally the heart will display an anomalous intrinsic rhythm, such as 2 to 1 block, and will consequently require pacing to ensure a consistent heart rate. This is of less concern when testing the ability of cardiac rhythm devices such as pacemakers or defibrillators to pace, as these will override any native signal to control the heart rate. However, such heart rate irregularities must be monitored and understood when testing the sensing capabilities of a particular device. For such studies, the electrophysiology can be monitored either on a gross scale using a 3-lead electrocardiogram or in detail using intracardiac electrical mapping techniques such as noncontact mapping systems. These systems are described at length in Chap. 32,

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and the clinical setup can be adapted to record an accurate endocardial activation map of the heart in reanimated hearts on the Visible Heart® apparatus. Such detailed assessment of the cardiac electrophysiology is of particular interest when researching cardiac ablation therapies, as electrical mapping can provide information about the size and efficacy of ablation sites. Additionally, the use of the noncontact mapping system in the Visible Heart® apparatus has augmented the assessment of acute post-procedural conduction complications during transcatheter aortic valve implantations. See also Chaps. 29 and 36 for additional discussion of these devices.

The ability to reanimate, control, and optically visualize human hearts has allowed for the collection of unique videoscopic footage of the functional human heart [28, 29]. By utilizing endoscopic video systems in conjunction with clinically relevant imaging modalities, such as fluoroscopy (continuous X-ray) and cardiac ultrasound (echocardiography), we have been able to create novel comparative

anatomy footage. This has provided a direct visualization of what the physician would see in the clinical setting and has also offered valuable insights into device and delivery system performance. Examples of the imaging capabilities of the Visible Heart® methodology within a human specimen can be seen in Fig. 41.5. In addition to video images of the functional anatomies, extensive footage of device implantations has been obtained utilizing Visible Heart® methodologies, including transcatheter-delivered valve prostheses to the pulmonary and aortic positions as seen in Figs. 41.6 and 41.7 [33, 34]. Such visualization of the delivery of a transcatheter pulmonic valve has provided new information to assist designers in the adaptation of the valve leaflets in the pulmonary position to accommodate the low pressure gradients that may be encountered in this anatomic location [33]. Furthermore, the implantation of transcatheter aortic valve replacements into the native aortic root of human hearts has highlighted the interaction of the frame with the native leaflets of the mitral valve and the interventricular septum, thus illustrating the importance of precise frame sizing and positioning in order to avoid interaction with the anterior leaflet of the mitral valve and excessive pressure on the cardiac conduction system [34]. Such simultaneous imaging in the Visible Heart® can be used

Fig. 41.5 Unique views of the tricuspid valve within a reanimated human heart imaged using (1) an endoscope placed within the right ventricle (upper left panel), (2) an endoscope placed within the right

atrium (upper right panel), (3) fluoroscopy with an anterior-posterior orientation (lower left panel), and (4) ultrasound (lower right panel). Modified from The Atlas of Human Cardiac Anatomy [29]

41.8

Comparative Imaging in the Visible Heart® Apparatus

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Fig. 41.6 Images of a transcatheter-delivered pulmonary valve which was imaged with endoscopes placed within (1) the pulmonary trunk during diastole (upper left panel), (2) the right ventricle during diastole

(upper right panel), (3) the pulmonary trunk during systole (lower left panel), and (4) the right ventricle during systole (lower right panel). Modified from Quill et al. [33]

to capture unique internal and/or external images of device implantations during near normal hemodynamic conditions (left ventricular systolic pressures of 70–90 mmHg).

cardiac function (i.e., Langendorff or four-chamber working modes) and allows for independent control of the chambers in order to augment the pressure gradients across the valves. This novel system allows for the isolated heart to be placed safely on the patient bed of the scanner (Fig. 41.8). To date, this system has been successfully used to obtain MR and CT images in both swine and human hearts (Figs. 41.9 and 41.10) [35, 36]. We consider that some of the advantages of isolating and reanimating a heart within the MRI/CT environment for device testing with such a portable system include the following:

41.9

The Portable Visible Heart®

Due to the inherent advantages of MRI and CT for assessment of cardiac function and anatomy in vivo, it was considered desirable for our group to develop a portable Visible Heart® system which would allow MR or CT imaging of an isolated beating heart. A portable system would enable physiologic perfusion of an isolated large mammalian heart during simultaneous MR or CT imaging. Full details of the development of a portable apparatus and associated methodologies for isolated heart imaging in the CT and MRI environment were described by Eggen et al. [35]. Briefly, one needs to first consider the strong magnetic field in the MR environment that poses specific design challenges; we considered that this required the construction of a two-unit system to remove all ferromagnetic materials from the proximity of the MR scanner. The apparatus contains the necessary preload and afterload chambers required for physiological

• High-resolution studies of use conditions or device-tissue interactions with precise controls over physiological conditions. Without the need for breath holds, as is required for the intact animal or human scan sessions, image averaging and sequence times can be increased, thereby increasing the ultimate signal-to-noise ratios. • The function and efficacy of MRI-safe devices can be tested in a dynamic beating heart environment without the costs incurred during intact animal testing. • Comparative imaging. Direct imaging methods (i.e., endoscope) can be subsequently compared to MRI/CT imaging

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Fig. 41.7 Images of a transcatheter-delivered aortic valve imaged using (1) an endoscope placed within the ascending aorta (upper left panel), (2) an endoscope placed within the left ventricle (upper right

panel), (3) fluoroscopy with an anterior-posterior orientation (lower left panel), and (4) ultrasound (lower right panel). Modified from Iaizzo et al. [34]

of cardiac function and anatomy or interaction with devices as a means to evaluate the best clinical imaging modalities for the desired target variable/interaction of interest. • Multiple device implantation studies can be conducted under endoscopic visualization before analyzing the implantations using MRI/CT imaging, without requiring an XRM suite or combination CT-X-ray surgical suite.

heart on the apparatus may also affect its overall performance. Furthermore, the use of a clear perfusate, without a specific oxygen carrier (i.e., a hemoglobin substitute like a perfluorocarbon), will lead to progressive global ischemia and the development of tissue edema which has effects on the longterm viability of these reanimated hearts. The altered hydrodynamic state of the heart and progressive edema that occurs during reanimation on the Visible Heart® apparatus limits use of the apparatus for certain types of device testing. For example, deterioration of the tissue does not allow for chronic valve testing and limits most investigations related to the acute consequences of device implantations. Additionally, bench top tests such as accelerated wear testing have established guidelines for testing valves, which cannot be reliably reproduced on the Visible Heart® apparatus. Valve testing conducted in animals typically includes an artificially induced “challenge” state, which produces hemodynamic profiles that are unattainable on the isolated heart preparation. In other words, while the Visible Heart® apparatus in its current form does not replicate or replace bench top or preclinical testing, it can provide unique comparative imaging of functional anatomy and devicetissue interface which is not available in bench top or preclinical animal testing.

41.10

Limitations of Visible Heart® Methodologies

The Visible Heart® methodologies are not without known limitations. For example, ischemic time prior to reanimation can compromise cardiac function, specifically contractility and thus pressure generation. Additionally, the lack of a pericardium may contribute to overexpansion of the atrial chambers, slightly different respective anatomical orientations of the great vessels and chambers, and/or differences in contractility compared to in vivo performance. However, it should also be noted that one can isolate these large mammalian hearts for the use with the pericardium primarily intact [37]. Additionally, the relative positioning of a given

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Fig. 41.8 Portable Visible Heart® apparatus. The isolated heart support system enables the heart to be positioned in the anatomically correct position during imaging in a magnetic resonance scanner (left panel;

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human heart shown). The isolated heart system with receiver coil positioned on the patient bed prior to MR imaging (right panel)

Fig. 41.9 MRI images obtained from a reanimated human heart placed in a 1.5 T MRI scanner: short-axis view (left) and long-axis view (right)

41.11

Acute Testing of Pathological Animal Models

The successful reanimation of human hearts using the Visible Heart® approach described in this chapter requires a level of cardiac health not always present in the available specimens (those deemed nonviable for transplant). Additionally, it is considered that the therapies for a specific category of pathologies often cannot be adequately or ideally tested by

using “healthy” swine hearts as a model (e.g., severe aortic stenosis, dilated cardiac myopathy, or complex cardiac arrhythmias). In order to test therapies for these pathologies, a number of acute animal models have been created to mimic the anatomy and morphology of various human disease states. One example of this has been the development of various models for severe aortic stenosis, e.g., with the specific aim of determining how large calcific deposits on the leaflets affect the deployment and function of devices. To approximate severe stenosis of the aortic valve, we have: (1) directly

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Fig. 41.10 Contrast-enhanced CT image of an isolated swine heart. The right coronary artery, aorta, and left ventricular endocardium are enhanced

adhered plastic models of calcification to the leaflets to reduce leaflet motion and (2) partially adhered the leaflet commissures to reduce the effective orifice areas of these valves. To date, such a model has allowed for expanded procedural testing of these devices (e.g., from balloon valvuloplasty to device deployment), providing useful insights into device performance as well as the potential interaction of deployed devices and the calcific deposits relative to the native anatomy. Another example has been the chronic use of high rate pacing to force the heart to remodel and dilate, mimicking the shape and function of patients with end-stage heart failure that often require cardiac resynchronization therapy. The ability to deliver, implant, and ensure capture of left-sided pacing leads in the relevant cardiac vascular anatomy has allowed designers to fine-tune lead and delivery system performance before entering into preclinical or first in man testing. With the understanding that testing cardiac devices in relevant anatomies is key for better prediction of in vivo performance, there is ongoing research to further develop models, specifically models designed to simulate certain pathological states to test devices and delivery systems.

41.12

Future Directions

As anatomical resources develop and functional in vitro cardiac systems such as the Visible Heart® library and methodologies continue to evolve, so will the research possibilities within the realm of anatomical visualization and in vitro reanimation. Further, successful collaborations with the University of Manchester (UK) and Washington University (St. Louis, MO, USA) have been cultivated to determine the particular anatomical structure of the cardiac conduction system [38, 39]. Additionally, continued imaging should provide further anatomical information on cardiac disease

states highlighting how disease management could, in turn, be effecting reverse remodeling on a cellular scale as well as a global scale of cardiac anatomy. Currently, all collected datasets (videoscopic, CT, echocardiographic, and MRI) are being used to create a digital database of human anatomies by rendering 3D computational models using software packages such as Mimics (Materialise, Leuven, Belgium); such datasets are being used to create physical representations of certain specimens via 3D printing [12]. Along with the plastination of select specimens, our work in creating real-life and computational 3D models (e.g., for both object printing and computation simulations) will pave the way for ongoing investigations and provide anatomically correct models for investigations related to device design and/or for educational purposes. In addition, our laboratory is continually improving the Visible Heart® methodologies with systems designed to optimize the physiological function and control of the heart to improve the reproducibility, longevity, and utility of investigations. New cardioplegia and perfusate solutions are being tested as means to better protect the heart from ischemia and edema (some may be delivered as a pretreatment to specimens before extraction). Further, there is a continuing need to modify the setup/apparatus itself to better accommodate various delivery system designs (such as subclavian and femoral access systems). It should also be noted that the use of Visible Heart® methodologies to augment chronic studies has allowed for the validation of surgically created anatomies and the direct visualization of chronic device implants that were not previously possible. We consider that the utilization of both fixed specimens and Visible Heart® methodologies for device evaluation should be used in a complementary fashion with other techniques that utilize in vivo or in vitro methods to test the reliability, durability, biocompatibility, and/or other design parameters of newly developed transcatheter-delivered devices [30]. There is little doubt that the continued testing of novel cardiac prostheses via in vitro and in vivo studies will provide scientists, engineers, and/or clinicians working in this field with the necessary tools to drive the required research and development of the next generation of transcatheter-delivered cardiac devices.

41.13

The Atlas of Human Cardiac Anatomy

As novel therapies become clinically available and are implanted by more and more physicians, individuals will require continued education in the techniques required to navigate and deploy such devices. In response to this need, our laboratory has created a free access website, The Atlas of Human Cardiac Anatomy (www.vhlab.umn.edu/atlas), which can be utilized by cardiac device developers and clinical

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implanters to gain insights on the relative variability in functional cardiac anatomy [12]. This website uniquely includes downloadable movie clips of functional cardiac anatomy; comparative imaging using echo, fluoroscopy, and MRI; and digital reconstruction images obtained from the human hearts of organ donors whose hearts were deemed not viable for transplant.

41.14

Summary

In summary, the study of fixed and reanimated human hearts, using the various methodologies described here, provides an individual with novel insights on normal and pathological human cardiac anatomies. Additionally, one can better visualize anatomical alterations that occur with specified pathologies and/or those that may occur following the deployment of devices within the heart. More specifically, the Visible Heart® methodologies to reanimate large mammalian hearts have provided a unique perspective on functional cardiac anatomies. By reanimating hearts using a clear perfusate, we are able to visualize functional anatomies with endoscopes placed directly within various heart chambers and/or within the vessels of the heart. Such anatomical knowledge is critical for device designers and developers, as well as clinicians who utilize these less invasive cardiac repair approaches for patients with acquired or congenital structural heart defects. Furthermore, when direct visualization is simultaneously coupled with clinically employed imaging modalities, it provides critical insights that can be used to more quickly and precisely advance such technologies. We consider that the utilization of both fixed specimens and Visible Heart® methodologies for device evaluation should be used in a complementary fashion with other techniques that utilize in vivo or in vitro methods to test the reliability, durability, biocompatibility, and/or other parameters of newly developed transcatheter devices. The continued testing of novel cardiac devices via in vitro and in vivo studies will provide scientists and engineers working in this field with tools to drive the required research and development of the next generation of cardiac devices.

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Current Status of Development and Regulatory Approval of Cardiac Devices

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Stephen A. Howard, Michael G. Bateman, Timothy G. Laske, and Paul A. Iaizzo

Abstract

Medical devices are rapidly advancing and changing the medical field. Progress has been demonstrated in many fields such as minimally invasive surgical techniques for valve replacement and 3D cardiac mapping of arrhythmias. These medical device advances allow physicians to help more patients quicker and more efficiently. The field of cardiac device development can be considered as relatively new, beginning in the early 1950s, and today new technologies in this field are presented at ever increasing rates. Many times, these advances come from an unmet clinical need. In some ways, physicians are unable to treat (or are at best ineffectively treating) certain types of patients in this aging society. Motivated by these needs, medical device designers—scientists, physicians, patients, or simply individuals with good ideas—choose to undergo the rigorous, yet rewarding, path of medical device development. The development path follows a certain route from device conception, intellectual property generation, and testing to regulatory approval. Since cardiac medical devices are created to help patients, they must also undergo stringent testing for durability, biocompatibility, and manufacturability. To complete these assessments, both animal and clinical testing can be utilized, especially with regard to valve replacement devices. Once an adequate amount of data pertaining to the safety and efficacy of the device has been collected, it will then be sent to a regulatory body to gain approval to market the device. Keywords

Cardiac device design • Cardiac device development • Device ideation • Risk mitigation • Intellectual property • Device testing • Regulatory approval

Abbreviations DFM FDA FMEA HDE

Design for manufacturability Food and Drug Administration Failure mode and effect analysis Humanitarian device exemption

S.A. Howard, PhD (*) • M.G. Bateman, PhD • T.G. Laske, PhD Medtronic, Inc., Mounds View, MN 55112, USA e-mail: [email protected] P.A. Iaizzo, PhD Department of Surgery, University of Minnesota, Minneapolis, MN, USA

IDE IFU IP USPTO VOC

42.1

Investigational device exemption Instructions for use Intellectual property United States Patent and Trademark Office Voice of customer

Introduction

All it takes is a napkin drawing or a rough shape crafted with clay. Such humble beginnings can spark an idea or revolution for the way that cardiac care is administered. Ideas can blossom into intricate high-tech medical devices that push

© Springer International Publishing Switzerland 2015 P.A. Iaizzo (ed.), Handbook of Cardiac Anatomy, Physiology, and Devices, DOI 10.1007/978-3-319-19464-6_42

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the envelope of design and advance the field of medicine. These are exciting opportunities, yet the journey of creating a medical device can be daunting. However, for those who are successful in developing such devices, there can be great rewards. This is the reason for so many entrepreneurs entering the medical device space! When you consider what it takes to fully create, develop, manufacture, and market a cardiac device, there are many points to discuss. First and foremost, the device needs to serve an unmet need (whether or not it is apparent). Within the cardiac space, this can range from the inability to measure a particular pressure to finding a way to successfully repair or replace failing myocardium. Any cardiac device must be technically feasible, and it requires that issues of design, quality, manufacturability, regulation, cost, and reimbursement must be considered during the design process. In many cases, the earlier these areas are considered in the design space, the more effectively the device can be brought to market. Even if a device is the best idea in the world and can cure a disease, if you cannot successfully make it or if no one can afford to buy it, then the product is doomed to fail.

42.2

Anatomy of a Cardiac Device

For a product to be viable, there are some key characteristics that must be incorporated or considered in the design. These characteristics demonstrate that the device has been tested and manufactured correctly, and they also take into consideration the risks inherent to the device. This next section will discuss the different design considerations that need to be developed while creating a medical device. These will drive toward a device that functions the way it is required and will do as little harm to the patient as possible. These topics on design characteristics can be used in other areas of medical product design, but, for the sake of brevity, this chapter will focus on cardiac devices.

42.2.1 Functionality Consumers—including physicians, patients, and buyers—all have certain expectations of a cardiac device. When a physician uses a device, he/she expects that it will function in the manner in which it is intended. This may seem elementary, but the idea that the device must always work as specified is integral to the design, and the first device must work the same as the one thousandth device. To be successful, a new product must elicit functionality above and beyond the currently available solutions and techniques. The functionality of a given cardiac device ideally also encompasses an ability to perform the desired tasks without compromising any other biological process. For example, an atrial septal occluder

device should not impede the function of the tricuspid or mitral valve, nor should it increase the potential risks of embolism and stroke which it is trying to mitigate. These specifications are often outlined by regulatory committees such as the International Organization for Standardization (ISO). For therapeutic devices deployed in the left atrium, the functionality of the device also encompasses the delivery of such therapies. For instance, left atrial cardiac ablation requires a transseptal puncture to be performed before the device can be inserted into the left atrium. The delivery path is such that it must create a hole in the interatrial septum and thus provide an access point to get to the left atrium. If the hole is misplaced, or if during the puncture the needle is advanced too far, it can cause unwanted complications of either cardiac tamponade or aortic perforation. Neither one of these situations is desired and, as such, must be considered while thinking about the left atrial ablation therapy (see Sect. 42.3.4 on risk mitigation). To ignore this portion of the procedure may result in unforeseen issues with the procedure which may or may not have been caused by the delivery of the device. In many cases, the delivery of a device has a larger impact on the ability to perform the procedure. For some mitral valve repair procedures, the location of the puncture in the atrial septum is paramount to having a quick and successful procedure [1]. In summary, the device being developed must be thought of as a device delivery procedure and include everything involved with its successful use. This approach takes into consideration the system as a whole instead of a single part; the system must be considered as a whole; otherwise, issues may occur due to the unforeseen interactions between parts of the procedure. Another aspect of functionality is related to unforeseen uses or the off-label use of devices by physicians. An offlabel use of a device is one where the manufacturer of the device has clearly specified the use conditions in which such a device can be utilized, yet the physician has elected to use it in another fashion or in a patient in which the device is not intended to be used. An interesting thing to note is that the physicians have a fair bit of freedom to use the cardiac device however they see fit. Since they are ultimately responsible for the well-being of the patient, if they believe that a cardiac catheter would better serve the patient in a manner other than what is listed or suggested by the company in their instructions for use (IFU), they can and may decide to use the device however they choose. In other words, in most cases, they will use the devices as intended, but may also use them outside of the bounds of the IFU if they believe it is in the best interest of the patient. Nevertheless, an off-label use of devices puts medical device companies in a peculiar position. On the one hand, the company likely enjoys the benefits of their product helping more people than was originally intended, as well as possibly

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higher sales. On the other hand, the action of using the device in such an off-label fashion cannot be condoned, marketed, or suggested by the company without potential repercussions for promoting the device to be used in such a way that has not been tested or cleared through regulatory channels.

42.2.2

Biocompatibility

In 1987, Williams described how the biocompatibility of a material can be qualitatively evaluated to assess its relative performance when implanted. He said that biocompatibility can be defined as the ability of a material to perform with an appropriate host response under specified conditions [2]. The succinctness of the term biocompatibility can be misleading when applying the principle to cardiac devices. Often within a single medical device, there may be a multitude of different materials that are utilized. For example, the WATCHMAN™ left atrial appendage (LAA) closure device (Boston Scientific, Marlborough, MA, USA) is made of a collapsible nitinol structure with a polyethylene terephthalate (PET) mesh covering which is permanently implanted into the patient, whereas the delivery system is made of another polymer that will be in contact with the patient for 8F defibrillation leads were the standard of care, but in 2002, St. Jude Medical released their 7.6F Riata defibrillation lead. In response, Medtronic, Inc., released their 6.7F Sprint Fidelis in 2004, shortly followed by the 6.3F Riata ST by St. Jude Medical. The perception was that a smaller lead would decrease the blockage caused within the venous system at

the level of the subclavian vein. However, it was found that these systems were unable to perform at adequate levels of durability within the body [5]. Both companies ended up having issues where their leads broke or eroded to the point where the conductor wires could penetrate and cause misreading of the cardiac signals and potentially lead to excessive shocks being delivered to the patient (or even worse, no shocks were delivered when they were needed). In 2007, Medtronic, Inc., sent a letter to physicians informing them that they had seen failures in the field both at the distal portions of these leads and at points near the anchoring sleeve tie-down. Further, they reported that the distal failures were significantly affected by the bending of the lead body due to tortuous anatomy in the veins. The failures at the tie-down location were potentially caused by the way physicians implanted and secured the leads within the body. Each of these failure modes suggested that the way in which the lead was implanted could make a significant impact on the longevity of these devices and their potential for failure. Ultimately in late 2007, Medtronic, Inc. issued a voluntary market suspension that the FDA formally considered to be a recall. During this time, St. Jude Medical was also seeing similar issues with their leads. They reported that portions of their leads were being eroded to the point where the wires were being externalized in both styles of the Riata leads. It was also reported that the primary reason for this externalization was due to abrasion of the lead insulation with either the anatomy (e.g., tricuspid valve) or the internal components of the lead (e.g., the pacing/sensing wires). In one study, they found that a common defect was due to the internal abrasion of either the pace/sense coils or the shocking coils against the silicone insulation. This would be in response to the repetitive motion of the lead and the ability for the internal components to move relative to the external insulation. This caused what they deemed to be an inside-out abrasion, where these wires were wearing away at the insulation and become externalized and readily visible under fluoroscopy [6]. Due to these failures, St. Jude Medical ended up removing the Riata family of leads from the market in 2010 and recalling them in 2011. Since these recalls, the defibrillator lead market has stayed at >8F, due to the perception that smaller leads could be associated with potential failures in patients. Both of these cases are prime examples for why device durability testing is essential for the development of robust cardiac devices. Notice that it is not always a matter of how the device will react within the body (which seemed to be the case for the Riata leads), but also how the devices are implanted that may lead to potential failure modes. Ultimately, if a cardiac device is not tested properly in relevant use conditions, certain factors can be overlooked and may ultimately end up negatively impacting patients.

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42.2.4

Design for Manufacture

The ability to put together a device, or manufacturability, is something that should not be overlooked during the design processes. By incorporating early feedback about manufacturing the product, the risks of not being able to build the device efficiently enough or to produce adequate quantities to fulfill demand will be greatly reduced. Failure in either case could cause the product to be stifled, no matter how successful or clinically helpful it is. As such, design for manufacturability (DFM) has become a common practice in the cardiac device industry, a practice that emphasizes how a successful design should ensure the highest-quality products while decreasing manufacturing costs. This is accomplished by making manufacturing cost estimates to proactively guide and prioritize cost reduction efforts involved with design. Consequently, DFM should have significant effects on product lead times, development costs, and ultimate product quality. As such, DFM specifically requires input from a multidisciplinary team, including manufacturing engineers, cost accountants, and production personnel, in addition to the design engineers [7]. Yet, when applying these principles to cardiac device design, it is imperative to understand that the quality of care impacted by the device must not be compromised by the need for a more cost-effective manufacturing process. One needs to consider that production costs can be controlled by using existing technologies and established manufacturing techniques. There are many methods for ensuring that the requirements for manufacturing are being taken into consideration, and there are several numerical methods of design and testing (also known as in silico testing) that can be used to streamline the design for the manufacturing process.

42.3

Development Process

There are often two types of development referred to by designers—iterative and disruptive. Those that fall into the iterative category are devices that generally are perceived as logical next steps in the development chain. For example, this would include the addition of a third and fourth electrode to a left-sided lead that would give the physician more vectors to choose from when programming a pacemaker, as discussed in Chap. 30. The ideas and devices that are considered to be disruptive are those that medical industry professionals would consider as game changers. These are devices like transcatheter-delivered cardiac valves. The option prior to these transcatheter valves was open-heart surgery, which often involved placing the patient on cardiac bypass and fully stopping the heart; this procedure limited the population of patients who could receive the treatment to those that were able to physically undergo an invasive surgery and

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required weeklong recovery periods in the hospital. In other words, these devices have effectively provided a means to treat more of the patient populations which were underserved by prior medical management. Although there may be a valid unmet clinical need, oftentimes there are points along the product development pathway that may ultimately put a halt to a device or therapy. This can be as simple as the product not working as intended or a business decision to not pursue a particular therapy because it does not align with their internal objectives. This, along with other reasons, is generally why larger companies will often focus their efforts on incremental improvement of devices as opposed to disruptive technologies. The incremental improvements are much more predictable and lower risk, since the market is already known and the needs often come directly from their voice of customer (VOC). Disruptive technology offers a greater amount of risk and, conversely, often a higher reward. This volatility of the device can be a deterrent for larger, publicly held companies that rely on stability, but it provides an opportunity for smaller companies willing to take the risk. Whether it is an iterative or disruptive technology, the development process generally follows a similar pathway (also utilized in nonmedical device development), with the hope of producing a marketable product. Often, a problem is identified within the field, and to better understand the clinical needs, the designers must empathize with those experiencing the problem. This can be the physician, patient, payers, or any other stakeholders. While studying and understanding these situations, the designers gain invaluable insights as to the root cause(s) of the clinical problem or need, as well as what confounding factors are present. Then, by defining which portion of the issue they are trying to address, designers can begin to hone in on a potential solution. In turn, this will spark ideas and a multitude of solutions (partial or complete) will be generated. These solutions (as you will see in Sect. 42.3.3) will be prototyped and selected based on technical and market feasibility. Promising options will then be tested for usability and functionality; if an acceptable option is produced, the design will be frozen to move on to preclinical animal testing and eventual clinical testing (Fig. 42.2) (see Chap. 43). The generalized overarching progression of how cardiac devices develop from concept to market will be presented in the following sections.

42.3.1 Six-Phase Approach to Device Development There are many ways that device development can be approached, but often they follow a similar pattern: (1) generate an idea, (2) prove it to be feasible, (3) test the idea, (4) market the idea, (5) and make sure that it does not cause unfavorable

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Fig. 42.2 Flowchart of the design thinking process

issues in the field. This is obviously oversimplifying things, and each of these steps requires a vast amount of work to “get it right.” Despite the simplification, all of these steps are essential to fully develop and market a cardiac device. This section will describe a more commonly used phase– gate system that breaks up the process into six phases of development, as shown in Fig. 42.3. Importantly, throughout each of these phases, a number of different elements need to be checked and rechecked in order to create a successful device. As the development process advances along the phases, the subsequent tasks are generally associated with higher costs. For instance, the first phase of the development process is device conception, in which a clay model or a sketch of the product may be the only thing required, along with asking some key stakeholders whether or not the idea is worth the time and effort. This requires very little monetary investment. The next phases require creating animations and prototypes and testing of these advanced concept devices; these phases will incur greater costs. Prior to market release, at a minimum, preclinical and even some clinical testing will be necessary, which may require the investment of millions of dollars and multiple years of study before finally being able to market and realize profit from the device. Phase 0 is the planning phase during which much of the groundwork is completed, including developing prototype devices, creating a product platform, assessing market opportunities (determining if it will be worth pursuing financially), and identifying product constraints associated with intellectual property (see Sect. 42.3.2). The decision to move on to the next phase often requires insights related to perceived market value versus return on investment, an evaluation that is required to bring any device to the market. Phase 1 is considered the concept development phase. This is when the development/refinement process, as well as benchtop testing, of the device begins. For example, feasibility studies are performed to determine whether the product is technically possible to manufacture and create, as well as to estimate the potential market size. Ultimately, the market

Fig. 42.3 Flowchart of the device development process. The six phases of device design are shown, as well as the associated cost and profit factors related to marketing a medical device

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size will determine the profitability of the device. It should be noted that there remains a special need for pediatric-sized cardiac devices, partly because they are often considered nonprofitable to manufacture at small volumes and are thus generally developed as a humanitarian effort. Phase 2 (durability and compatibility testing) occurs after the device design meets the previous criteria from Phase 1. This is where further benchtop tests are performed for both accelerated failure and required function of the devices. In vitro work or acute animal studies can also be initiated to assess potential biocompatibility. The end of Phase 2 generally involves a design freeze where nothing can be changed on the device without going back to Phase 1 or 0. At this point in time, the design engineers, in partnership with the entire development team, must determine the most optimal design and cease all design work and begin the preclinical and clinical testing. Phase 3 (animal and clinical testing), which is initiated after the design freeze, assures that testing will provide an accurate assessment of the device function within a living organism. Testing often includes chronic implantation in appropriate animal models, which is then followed by regulatory approvals before the onset of clinical trials in humans. Yet, even subsequent to a success clinical trial, final approval for market release of the product is sought. Phase 4 is initiated when the product is actually market released. Usually, this is the phase of the overall process where the company expects to see a return on investment. Yet profitability is contingent on successful clinical trials, approval of the device for market release by the regulatory body of the country, and the ability of the company to commercialize and market the device, as well as receive payment (reimbursement) for sales. Phase 5 is considered to be the post-market assessment. Even though a product is fully marketed and approved by a regulatory agency, the company is still required to perform follow-up studies to ensure that the device does not cause any unforeseen issues with patients over time. This acts as a safeguard to the patients that are being served by the device. In some cases, even though stringent testing in animal and human trials has been performed, there may be unexpected issues with the longevity of the device or unanticipated failures. This also provides the company with additional information for future improvement of the device. Assessment that can be performed in this phase includes postmortem studies, where the company may receive the explanted device and then analyze its status/condition.

42.3.2 Intellectual Property Before finalizing any design, one aspect that must be taken into consideration is the intellectual property (IP) associated

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with the device idea. Generally, IP refers to a work or invention to which one has rights. This is often associated with patents, copyrights, trademarks, or trade secrets. In all of these cases, there are specific actions that need to take place to protect the creator of the idea, so they can utilize their ideas without others unduly copying or inappropriately using their works or inventions. Ultimately, a major part of the product design process is to maintain ownership or licensing agreements of IP relative to the technologies being developed. A trademark is a name or symbol that is associated with a product or brand in which a company (and only that company) has full rights to use that name or symbol. This prevents others from using the name and associated marketing as a means of promoting their products or services. Similarly, a copyright may be granted for any written and/or graphical materials to an individual or group of individuals to protect their work and reduce the risk of plagiarization [8]. Another method to protect an idea or product is to keep it a trade secret. Simply put, this is the act of not divulging any information regarding how a product is made, operates, or performs (e.g., a device running on proprietary software or novel circuitry) while banking on the notion that no one can reverse engineer the product and thus replicate it. Yet it should be noted that anyone successful in reverse engineering a product may then duplicate the product or procedure (even without knowing the trade secret) with no legal consequences [8]. Within the medical device arena, a primary way of protecting IP is to file and obtain a device patent with broad claims. A patent is a legal document that explicitly describes how a device works or how a procedure is completed, providing enough information that anyone within the field could duplicate the device or process. In the USA, patents provide legal protection for 20 years, thus guaranteeing exclusive marketing rights during that period. However, upon expiration, the device can be copied by competitors without legal recourse [8]. With the long life span of patents, there is often little concern of the patent expiring due to the speed at which devices are developed or improved, as newly created and updated products will likely hold new patent protection. For this reason, it is vital for any product developer to have a solid understanding of how to read patents in order to avoid patent infringement upon the development and release of their own device. Typically, patents are classified according to device type and use and will first provide the filing number(s), inventor(s), and the date filed. Next, a description of the device/process is presented, generally involving sketches and other images of IP. The most pertinent information is contained within the claims section, which specifically describes what part of the IP is novel and hence what is officially patented and protected by the law. The claims section is generally the portion that legal teams will address when reviewing a patent case.

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To obtain a patent, the United States Patent and Trademark Office (USPTO) requires that the idea must be novel, useful, and nonobvious. As such, the idea must fall into one of the categories of a process, machine, article of manufacture, composition of matter, or improvement of any of the previous items [9]. The USA has recently changed to a first-to-file patent system, which is similar to the current European patent procedure. Previously, the USPTO granted ownership of a patent to individuals who were the first to invent. This would mean that documentation was vitally important with dates and signatures referencing the date of the initial invention of the idea. While this method has its merits, the USA decided to move to a first-to-file system which means the patent is awarded to the individual or group of individuals who were the first to file a patent on that particular process, machine, and/or patentable idea. In general, in order to determine if an idea is patentable, one must first search existing patents to see if it has already been invented. In many cases, finding and utilizing patent information can benefit medical device designers. According to the European Patent Office, there are a number of reasons and ways to use patents to your benefit including to “find out what currently exists and build on it,” “keep track of who’s doing what,” and/or “avoid infringing on other people’s patent rights” [10]. To find pertinent patents relative to the cardiac device you hope to develop, there are many online databases that can be searched for specific information. A few examples of such databases include the European publication server [11], FreePatentsOnline [12], and Google [13].

42.3.3

Device Ideation

While a “new” medical device is still in the early conceptualization phase, it is important to fully investigate the potential landscape of the design space. This is often referred to as brainstorming and is an easy way to obtain a multitude of device options to solve the underlying problem(s). A good approach to a brainstorming session is to understand that any idea is a good idea, which is similar to the idea employed in acting/improvisation comedy of “yes, and….” This statement is seemingly insignificant, but it emphasizes the idea that you need to build upon the ideas of others. If one actor says that they are just coming home from the circus, their counterpart must go along with the premise that it is where they came from and add upon the story. If the counterpart were to say “no, that is not what you did,” they effectively stopped all progression in the scene and added nothing of value. In the same way, during a brainstorming session, even though an idea suggested by a colleague may be completely impossible, it is important to run with the idea instead of shooting it down outright. For example, even though it is currently impossible to physically levitate the patient during

open-heart surgery, the notion that you could gain access to both the front and the back of the patient without flipping them may spark an idea of how to support patient management during a procedure. In that sense, it is important to maintain these “off-the-wall” ideas because often they can lead to alternative solutions to the problem that was not previously considered. Once the ideas are compiled, then a session to downselect to the best options or routes is required. Often for a smaller project, 4–10 options may be initially considered, and prototyping can begin on each of them. Generally during this time, the resources are limited, so “quick and dirty” prototypes are often the way to go. The purpose is not to obtain fully working prototypes that portray all of the intended features, but to create rough models (i.e., out of clay or cardboard) that may help one to understand a proposed feature. In many ways, the act of prototyping over the past decade has seen some huge changes. Often when someone says prototyping, a common conception is an engineer sitting in his garage and building a model of a device. However, in recent years, this has transformed to that same engineer, although still likely to work in his garage, creating a CAD model of possible designs and sending it to a 3D printer to have the part(s) actualized from the computer. Due to technologies such as 3D design software and 3D printers, prototyping offers even more possibilities for generating ideas. Note that the New Product Design and Business Development course at the University of Minnesota has required, for several years, that all design teams utilize 3D technology to create at least one of their prototypes. Whether designers decide to 3D print or build their initial prototypes, they can begin to down-select from these concepts and refine their ideas, to understand the best path forward for their design space. One of the primary purposes of Phase 0 is to develop proof of concept and to confirm that the idea can be constructed and eventually manufactured into a viable product. After proof of concept has been attained and market potential assessed, the design team should select a handful of devices from their initial mock-ups that will be fully prototyped and can be shown to customers for feedback. This is generally a part of Phase 1, where feedback is obtained by collecting the VOC from a large sample size of potential users with varied backgrounds and clinical experiences. The VOC can be obtained through direct questioning, observation, and/or discussions (or use of a prototype) with the customer. The “customers” that will be addressed may consist of many different groups of individuals, including: (1) those who will use the device, (2) those who may be on the receiving end of the device, (3) those who would purchase or pay for the device (reimbursement, insurance companies), and (4) those who could potentially profit from the successful device (investors). These groups of individuals will often

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aid in the design process and hopefully improve the overall design of the product, to fully meet the expectations of all the primary customers. For instance, a user may want the device to be easy and intuitive to use, while the payer’s focus is on expense and potential benefit to the patient in order to ultimately reduce healthcare costs (e.g., including a reduction in the number of required future procedures). Those who expect to profit from the product (e.g., a company’s chief financial officer) may demand that the costs of product development are minimized. Hence, all of these design criteria and concerns must be proactively considered and addressed by the design team, if their desire is to create a product that satisfies the majority of their potential customers.

42.3.4 Risk Mitigation An important fact to remember is that there are no cardiac devices without risks. These risks may be simple, such as an implantable device recording for longer than required for each time segment, in turn causing the battery to deplete faster and require more frequent replacement. The risks can be as significant as a turbine in a ventricular assist device being stressed to the point where it fractures and sends fragments into the bloodstream. Obviously, neither of these situations is favorable, but, at the same time, one is certainly more acceptable than the other based on the risk that it poses to the patient. In addition to brainstorming, it follows that all of the potential device defects and failures need to be tracked and accounted. Note that early on in the development process, one needs to consider the risks and benefits of employing any new procedure that utilizes a newly developed device (Fig. 42.4). In order to complete the risk analysis on a device,

Fig. 42.4 Example flowchart for performing risk estimations

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one typically employs a failure mode and effect analysis (FMEA), generally defined as a procedure in product development and operations management for identifying potential failure modes within a system, including classification of the severity and likelihood of failure. It is considered that any successful FMEA activity helps the research and development team to identify potential failure modes based on past experiences with similar products or processes. This, in turn, enables the team to eliminate such failures with minimum effort and resource expenditure, thereby reducing development time and cost. Complete FMEA on a new prosthetic valve typically creates a 150-page spreadsheet of potential problems, including everything from leaflet material breakdown to misalignment of the prosthesis within a heart. Each identified failure mode must be assessed for how likely it will happen and how severe the impact on the patient could potentially be. If one particular failure mode could feasibly occur in 1 out of every 100,000 patients and have minimal impact on the patient’s health, it will not create a drastic design change. However, if within the same occurrence rate a patient may potentially die from the resulting complications, such a failure mode would need to be addressed.

42.3.5

Device Testing

When a cardiac device design moves from Phase 0 into Phase 1 of the design process, a series of testing regimens are initiated to ensure that the device meets the standards set forth by various international governing organizations. These testing methodologies are not only required for the successful market release of a new cardiac device, but they also provide insights into the design and development of the device and/or subsequent devices. For example, the testing results

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from a cardiac ablation catheter can elicit information to the design team on which portions of anatomy need to be ablated to treat the underlying arrhythmia more effectively. Based on this information, an anatomically shaped catheter like the Arctic Front Advance cryoballoon (Medtronic, Inc.) can be developed to address circumferential ablation needs for the pulmonary vein ostia. Cardiac device testing can take many forms and often starts with basic static benchtop testing without the use of native biological tissues. In place of biological tissues, surrogate materials can be used as tissue analogues such as silicone, nylon, sponge, or foam [8]. For example, mock silicone substrates approximating the anatomy of a human left atrium and pulmonary veins can be created to investigate the ability for ablation catheters to reach key arrhythmogenic locations within the left atrial anatomy. This is not only a more repeatable procedure due to a decrease in substrate variability, but it is also more cost-effective than obtaining live tissue or live animals to perform such initial basic testing. However, these techniques may not provide necessary insights into specific tissue interactions and/or biocompatibility, which are primary concerns when developing catheters that must be placed and manipulated within a human body. In the case of cardiac pacemakers and defibrillators, all current therapies involve devices, delivery systems, and monitoring tools that are inserted into the body and exposed to a harsh biological environment. Some of these products (e.g., delivery systems and introducer sheaths) will only be in contact for a short period of time, yet the pacemaker and the cardiac lead may remain in the patient for the rest of his/her life. Note that specific concerns regarding biocompatibility are discussed at length in Sect. 42.2.2 of this chapter. In general, the potential for device rejection can be assessed with in vitro immunological responses to the device; a strong immunological response would be indicative of a possible problem relative to biocompatibility and thus a possible device rejection. However, today most pacemakers and leads are constructed from well-studied materials with known levels of biocompatibility as well as several years of clinical experience. As such, adverse reaction testing is predominantly assessed during chronic animal studies if new materials are used, and adequate data on the materials cannot be leveraged during regulatory submissions to agencies like the FDA. Another important factor to consider when designing medical devices is the combined effect that temperature and pressure may have on the device. For instance, the polymers and metal wires inside a deflectable delivery sheath will have altered properties after being subjected to human body temperatures while being submerged in a fluid (blood) for prolonged periods of time. In some cases, these altered properties can be advantageous depending on how the device is designed. The informed engineer may choose to design the

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device, a percutaneous delivery system, for example, to be stiff when entering into the vein/artery, thus allowing for easier placement, and then become more malleable inside the body, as the temperature increases, so as not to cause internal damage to the vasculature. It is important to consider that before embarking upon the expensive animal testing protocols, which are required to prove the efficacy of a potential replacement valve technology, there is exceptional value in testing the device in reanimated beating heart models. Described at length in Chap. 41, such an approach allows researchers to employ an isolated, living heart as a model to visualize what occurs inside the heart during device deployment and/or how the device may interact with the myocardium throughout all the phases of the cardiac cycle. Additionally, the reanimation of human donor hearts, deemed not viable for transplant, allows for the visualization of specific valve interaction with the varied endocardial anatomy of human hearts, both healthy hearts and those with indications of heart valve disease. Once in vitro testing techniques have been properly utilized and the device design has been locked in, the development process moves into Phase 3, whereupon the device must be proven safe in appropriate preclinical testing. Generally, this requires extensive testing on animal models (acute and/or chronic) before it can progress into a human clinical trial. With this, a well-written preclinical testing protocol defines that in order to predict the safety and performance of clinical use, a sufficient number of animals of the same species must be used (preferably the same gender and age). In addition, the animals should have both experimental and control valves implanted in them in each position, as indicated by the IFU. The number of animals to be studied may be best determined based upon the risk analysis of the device and the required statistical significance of the experimental design. The duration of the experiment is typically specified in accordance to the parameter(s) under investigation, and each animal must undergo a macroscopic and microscopic postmortem examination. Once the preclinical animal testing is performed using good laboratory practices, a third-party observer (outside auditor) typically will produce a report summarizing all data collected and making a recommendation regarding the clinical safety and performance of the device.

42.3.6 Clinical Testing and Regulatory Approval Once a cardiac device has been proven safe and efficacious during rigorous animal testing, device developers will then embark upon human clinical trials before it can be properly market released. Current regulatory processes in the USA and European Union differ significantly in the requirements

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Regulatory Approval of Devices

and guidelines laid out for clinical testing and market approval. However, both regulatory committees share the same fundamental principles and apply frameworks designed to ensure the safe and effective release of medical devices into the market. This section will briefly highlight features of both approval processes, and additional details about the clinical trial process can be found in Chap. 43. From a legal standpoint, human clinical testing of an unapproved cardiac device in the USA that poses a significant risk to the patient population cannot be initiated without preapproval from the Food and Drug Administration (FDA) in the form of an investigational device exemption (IDE). The IDE is designed to provide the FDA with relevant data on device design and preclinical testing, as well as the intended study protocol. A device company must also apply for an IDE if they wish to expand the indication of an existing device. These clinical investigations may begin at an approved site 30 days after the FDA receives the IDE application, assuming that in-house Institutional Review Board approval has already been obtained and that the FDA has not notified the sponsor that the investigation may not begin [14]. To date, FDA approval is contingent on various factors and based upon the intentions of the device; the rigor associated with the approval process increases with the classification of the device. These device classifications are briefly defined as: • Class I devices which pose the lowest risk to the patient and include noninvasive devices such as surgical bandages and tongue depressors. These devices are placed under the general rules applied to all medical devices and nothing more. Controls include prohibitions against adulteration and misbranding, requirements on establishing registration and device listing, adverse event reporting, and good manufacturing practices [15]. • Class II devices, such as cardiac catheters, are deemed to pose a high enough risk that regulation through the general controls alone is not sufficient. The majority of class II devices require a premarket notification in the form of a 510(k), to provide data demonstrating that the described device is “of substantial equivalence” to an existing product with regard to its safety and effectiveness. Although a 510(k) can be substantiated through preclinical testing, approximately 10 % of applications include clinical data [14]. • Class III devices which are used to support and sustain human life and would also present a high risk of injury or fatality if the device fails (i.e., implanted cardiac valves). Almost all class III devices require premarket approval by the FDA before they can be legally marketed, thus requiring clinical data demonstrating that the devices are safe and effective in the target population [14]. As such, all

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types of cardiac replacement valves fall exclusively into this category. Since the valve aids in sustaining human life and device failure could be fatal, the valve must be tested to ensure that it meets the testing required for class III devices. Another approach for device regulatory approval is the humanitarian device exemption (HDE). This is a regulatory pathway for the accelerated market release of class III devices, an exemption which is intended for devices that address diseases or conditions that affect fewer than 4000 patients a year in the USA. Nevertheless, approval of an HDE requires the sponsor to prove that the device is safe and effective and that all possible risks associated with it are outweighed by the foreseen benefits. Typically, such approval requires smaller clinical trials in fewer institutions, allowing smaller companies to develop class III devices beyond preclinical investigations. The idiosyncrasies of clinical trial requirements, development, and completion are described in Chap. 43. In summary, gaining market approval in either the USA or the European Union can be a lengthy, expensive, and timeconsuming endeavor. Before embarking on the development of a cardiac device, an understanding of these pathways and the intricacies of each regulatory body will help the designer complete the process in the most timely and cost-effective manner possible. To date, the differences between the US and the European Union regulatory bodies result in a large portion of pilot clinical trials and early device testing occurring outside of the USA. Thus, the typical cardiac device is introduced into general clinical practice in the USA 1–3 years after its market release in the European Union [14]. For more details on the design and execution of clinical trials for cardiac devices, the reader is referred to Chap. 43.

42.4

Summary

The key principles for designing any medical device generally hold true for all cardiac devices. A generalize path is to (1) critically define the clinical problem; (2) sketch concepts, develop animations, and build prototype; (3) test the concepts and perform benchtop testing; (4) conduct preclinical studies; (5) initiate clinical trials as needed; and ultimately (6) obtain regulatory approval prior to full market launch of the device. Throughout this process, there are a multitude of factors that need to be considered and taken into account when determining the requirements of the device. These factors include its planned function, biocompatibility, manufacturability, and marketability, to name a few. Although difficult to manage at times, these considerations will be vital for creating a successful product. Any development process for a medical/cardiac device requires a great deal of

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upfront effort to ensure that the product will thrive. In today’s world, this process relative to cardiac devices can take many years, even up to a decade before a device receives approval to be used in a patient and/or before any real profit may be realized. As such, the cardiac device industry can be a very difficult environment for a start-up, yet it can be exceedingly rewarding not only financially but also due to the fact that the product can directly and indirectly affect millions. When you consider the breadth and depth of the cardiac medical device field, it is encouraging to observe how it continues to rapidly develop and expand the industry and, in turn, provide innovative and revolutionary clinical technologies. Although many therapies are conceived from a need within the operating room or cardiac catheterization laboratory, their design and development will lead to future novel procedures and techniques that continue to improve treatment for patients with various pathologies. There is little doubt that these innovative improvements will continue to extend and enhance the overall quality of life for millions of patients worldwide.

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8. 9. 10. 11. 12.

References 1. Altioke E, Becker M, Hamada S, Reith S, Marx N, Hoffmann R (2011) Optimized guidance of percutaneous edge to edge repair of the mitral valve using real-time 3-D transesophageal echocardiography. Clin Res Cardiol 100:675–681 2. Williams DF (1987) Definitions in biomaterials: proceedings of a consensus conference of the European Society for Biomaterials,

13. 14.

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Chester, England, March 3–5, 1986. Elsevier, Amsterdam and New York Schoen FJ, Goodenough SH, Ionescu MI et al (1984) Implications of late morphology of Braunwald-Cutter mitral heart valve prostheses. J Thorac Cardiovasc Surg 88:208–216 Schoen FJ, Levy RJ (2005) Calcification of tissue heart valve substitutes: progress toward understanding and prevention. Ann Thorac Surg 79:1072–1080 Ellis CR (2013) The extinction of small caliber transvenous ICD leads: downsizing in a race to a recall. Heart Rhythm 10:191–192 Hauser RG, McGriff D, Retel LK (2012) Riata implantable cardioverter-defibrillator lead failure: analysis of explanted leads with a unique insulation defect. Heart Rhythm 9:742–749 Myken PSU, Bech-Hansen O (2009) A 20-year experience of 1712 patients with the Biocor porcine bioprosthesis. J Thorac Cardiovasc Surg 137:76–81 Ulrich KT, Eppinger SD (1995) Product design and development. McGraw-Hill, New York The United States Patent and Trademark Office website www. uspto.gov. Accessed 10 Aug 2014 Zenios SA (2010) Biodesign: the process of innovating medical technologies. Cambridge University Press, Cambridge The European Patent Office website www.epo.org. Accessed 10 Aug 2014 European Publication Server https://data.epo.org/publicationserver/?lg=en. Accessed 17 Dec 2014 Google Patents website www.google.com/patents. Accessed 17 Dec 2014 Kaplan AV, Baim DS, Smith JJ et al (2004) Medical device development: from prototype to regulatory approval. Circulation 109:3068–3072 Chai JY (2000) Medical device regulation in the United States and the European Union: a comparative study. Food Drug Law J 55:57–80

Clinical Trial Requirements for Cardiac Devices

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Jenna C. Iaizzo

Abstract

Early medical device concepts that show promising safety and/or efficacy results in preclinical trials, bench top testing (including accelerated wear testing), a virtual prototyping environment, and/or computation modeling studies will eventually be implanted in humans. Currently in the United States, the required time to develop a new cardiac device and gain approval for market release is highly dependent on the time it takes to perform proper clinical trials, i.e., to receive the needed clearance or approval from the Federal Drug Administration. Keywords

Clinical trial • Cardiac devices • Regulatory agency • Food and Drug Administration

Abbreviations

43.1

CE CEC CFR DSMB EC EOA FDA GCP GLP GMP IDE IRB ISO OPC PMA

Clinical trials play a crucial role in the process of bringing medical devices, specifically cardiac devices, to the market and for providing continued scientific clinical data after commercialization (Fig. 43.1). Prior to executing a clinical trial, researchers, scientists, and engineers cannot predict how the newly developed devices will perform in a human body. Furthermore, most cardiac devices are typically class III life-sustaining devices that are implanted in patients with life-threatening conditions, but there is a broad spectrum of the patients receiving these therapies that will likely have many other clinical complications; in some cases, these complications may adversely affect the potential success of novel technologies. Therefore, carrying out a carefully designed and comprehensive clinical trial provides an significant opportunity to examine the outcomes of the new cardiac device in humans and, in turn, the resultant clinical data gives patients, physicians, and the entire scientific community the information needed to potentially use the new device. Yet today, the primary purpose of a clinical trial is to provide valid scientific data about the safety and/or efficacy of a device, resulting in clinical evidence for future use or retraction of a therapy.

Conformité Européenne or European Conformity Clinical Events Committee Code of Federal Regulations Data Safety Monitoring Board Ethics Committee Effective orifice area Federal Drug Administration Good Clinical Practice Good Laboratory Practice Good Manufacturing Practice Investigational Device Exemption Institutional Review Board International Organization for Standardization Objective performance criteria Premarket approval

J.C. Iaizzo, MBA (*) Medtronic, Inc., Minneapolis, MN 55428, USA e-mail: [email protected]

Introduction

© Springer International Publishing Switzerland 2015 P.A. Iaizzo (ed.), Handbook of Cardiac Anatomy, Physiology, and Devices, DOI 10.1007/978-3-319-19464-6_43

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Fig. 43.1 Timeline of medical device development ©2013 Heart Valves: From Design to Clinical Implantation, Clinical trial requirements for cardiac valves, Iaizzo JC, Lovas ATF. With kind permission of Springer Science+Business Media, New York

Fig. 43.2 Clinical trial oversight ©2013 Heart Valves: From Design to Clinical Implantation, Clinical trial requirements for cardiac valves, Iaizzo JC, Lovas ATF. With kind permission of Springer Science+Business Media, New York

With the diversity of cardiac devices, there are various types of clinical trials that can be defined, from trials where a novel valve technology is being used for the first time (first in human studies) to post-market trials in which a cardiac therapy has obtained regulatory approval but is studied further to examine long-term effects, pursue additional indications, and/ or to obtain more specific information about the overall therapy. In other words, clinical evidence is vital not only to demonstrate the safety and efficacy of a device/therapy in humans but also to further examine how well the device works compared to standard of care, other devices, and/or concomitant treatments. In the specific case of a newly developed heart valve, studies will often be designed to compare the new valve against the native valve, other heart valve devices, and/or the current standard of care treatments. Using the example of planning a clinical trial for a new heart valve, this chapter provides a general summary of the present state of clinical trials,

including an overview of (1) the current stance of regulatory bodies that oversee trials, (2) specific features of a trial design, and (3) the many considerations involved in the proper implementation of heart valve clinical trials. Regarding the design of a clinical trial, the following groups/individuals may be identified, each with their specific role(s) (Fig. 43.2): Sponsor(s): The developer of the technology seeking approval for market release. Investigator(s): Non-biased individuals that will implant/ deploy the novel technology and will also be responsible for individual patient follow-ups. In some cases, investigators can also develop their own field clinical trial(s). Monitor(s): Individuals responsible to ensure that the trial is performed in an ethical and proper fashion. They usually work for the sponsor and make frequent visits to participating institutions to review data and regulatory documents.

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Regulatory bodies also have their own process for auditing sponsors and investigators through their Bioresearch Monitoring group(s). Institutional Review Board (IRB)/Ethics Committee (EC): The overseeing body at a given institution that is ultimately responsible for ensuring that the clinical protocol is appropriate and that the institutional investigators perform the study in a proper and ethical manner. These boards may have different names according to the institutional structure. Subjects: Individual patients who were deemed appropriate to be enrolled (meeting all inclusion criteria and none of the exclusion criteria) into the planned clinical trial and who provided informed consent to participate.

43.2

Regulatory Bodies

Regulations and the regulatory bodies that govern both cardiac devices and clinical trials play important roles in how new technologies reach the market. A solid partnership between a sponsor and a regulatory body, aided by clear communication, can affect whether the technology can reach the market in an expeditious manner. Regulatory bodies are important, as they ensure consistency in clinical trials and that they are run properly in order to provide the supportive scientific evidence required. Specifically, there are numerous regulatory bodies that provide oversight for cardiac device clinical trials throughout the world. A brief overview of the regulatory bodies from three different countries follows, yet our discussion focuses mainly on the Food and Drug Administration (FDA) in the United States.

43.2.1 Food and Drug Administration (United States) The FDA is responsible for regulating medical devices and therefore oversees the associated clinical trials exclusively within the United States. The FDA’s mission statement consists of two primary parts: (1) promoting public health by promptly and efficiently reviewing clinical research and taking appropriate action on marketing of regulated products in a timely manner and (2) protecting public health by ensuring a reasonable assurance of safety and effectiveness of devices intended for human uses [1]. The Center for Devices and Radiological Health (CDRH) is the branch that oversees medical devices. Cardiac devices that incorporate other therapies (i.e., pharmacological agents) will need to confirm if they will work through CDRH and/or the Center for Drug Evaluation and Research (CDER). In the United States, there are three regulatory classes of devices based on the considered levels of risk involved. All class I–III devices are subject to general controls, meaning the FDA reviews factors such as labeling, registrations, etc.

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Class I devices have the lowest amount of risk and regulatory controls (devices such as elastic bandages and surgical gloves). Class II devices must meet specific performance standards in addition to all class I requirements (devices such as surgical drapes). Most stringently, class III devices require premarket approval (PMA) to ensure their safety and efficacy. As such, class III devices are considered as the riskiest category of devices and include devices such as implantable pacemakers and heart valves. It should be noted that the FDA regulations for medical device products are detailed in Title 21 of the Code of Federal Regulations (CFR). The most applicable parts of CFR 21 that apply to cardiac devices and clinical trials include Part 812 (Investigational Device Exemption, or IDE) and Part 814 (PMA). Most new and novel cardiac devices are required to undergo IDE clinical trials before receiving FDA approval. As the regulatory landscape is typically in constant flux, it is crucial to reference and follow current guidance and regulations set forth by the respective governing regulatory body. In the example of heart valves, there is specific guidance in documents like the FDA’s Heart Valves—IDE and PMA Applications Draft Guidance; these documents state that “a replacement heart valve is a device intended to perform the function of any of the heart’s natural valves” [2]. A replacement heart valve is defined as a pre-amendment-type device, that is, a device marketed prior to passage of the Medical Device Amendments to the Federal Food, Drug, and Cosmetic Act (the Act). Furthermore, this FDA draft explains that clinical trials are necessary to evaluate most new replacement heart valve designs, and it also recommends that clinical investigations are executed by following the methods described in ISO 5840:2005 or an equivalent document. Specifically, the document ISO 5840:2005 is a guide for cardiovascular implants and valve prostheses provided by the International Organization for Standardization (ISO) [3]. When developing a clinical database and trial strategy, the appropriate FDA guidance should be referenced.

43.2.2 Other Regulatory Bodies In Europe there are various notified bodies that provide oversight of clinical trials. The most prevalent regulatory oversight applies to the 27 countries in the European Economic Area; these are countries required to obtain a CE mark (Conformité Européenne or European Conformity). Importantly, the criteria to receive a CE mark in Europe are notably different than those for securing FDA approval. As mentioned previously, to receive approval for a new technology in the United States, the manufacturer must demonstrate the device to be reasonably safe and effective. To receive approval to release a device to market in the European Union, the manufacturer must demonstrate that the medical

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device is safe and that it performs in a manner consistent with the manufacturer’s intended use [4]. Interestingly, given these differences in geographic regulatory approval, most manufacturers typically seek approval in Europe or other countries before the United States. Moving into other countries poses different obstacles which may influence the intended quality and importance of every clinical trial completed for the new device.

43.2.3 Good Clinical Practice Oversight Similar to the importance of following Good Manufacturing Practice (GMP) and Good Laboratory Practice (GLP) when prototyping cardiac devices, it is important to follow guidelines for how to appropriately conduct clinical studies that could affect the safety and well-being of human participants. Good Clinical Practice (GCP) was developed by a collaborative group of regulatory authorities worldwide, including the European Union, Japan, and the United States by the International Conference on Harmonisation. Effective in 1997, GCP provides international assurance that data and results of clinical investigations are credible and accurate and that the rights, safety, and confidentiality of participants in clinical research studies are respected and protected. More specifically, GCP consists of 13 principles which are detailed in Table 43.1. Table 43.1 13 Principles of good clinical practice [5] Ethics 1. Ethical conduct of clinical trials 2. Benefits justify risks 3. Rights, safety, and well-being of subject prevail Protocol and science 4. Nonclinical and clinical information supports the trial 5. Compliance with a scientifically sound, detailed protocol Responsibilities 6. Institutional Review Board/Independent Ethics Committee approval prior to initiation 7. Medical care and decisions by qualified physicians 8. Each individual qualified (education, training, experience) to perform his/her tasks Informed consent 9. Freely given from every subject prior to participation Data quality and integrity 10. Accurate reporting, interpretation, and verification 11. Protects confidentiality of records Investigational products 12. Conform to Good Manufacturing Practice and used per protocol Quality control/quality assurance 13. Systems with procedures to ensure quality of every aspect of the trial

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43.3

The Generalized Clinical Trial Cycle/ Process

Addressing all aspects of a clinical trial in depth is an enormous undertaking and beyond the scope of this chapter; thus, the following sections will highlight some of the foundational methods and processes of a typical heart valve clinical trial which can generally be translated to the complexities of other cardiac devices. As you can see in Table 43.2, there are many tasks that need to be addressed with the development and execution of a clinical trial. It is important to note that some of these tasks may occur simultaneously.

43.3.1 Features of a Trial Design for a Newly Developed Cardiac Device It is pertinent to research and understand all current published information and relevant heart valve trial data prior to planning and executing a clinical trial. There is much to be gained from studying the details of previous trial designs, as well as the subsequent outcomes associated with those trials. In regards to gaining FDA approval for any cardiac device, the importance of clinical evidence cannot be stressed enough. In the beginning stages of planning a clinical trial design, associated publications and previous research may help shape important components for the new trial, such as: patient inclusion/exclusion criteria, statistical designs employed in such trials, and/or the general patient populations to be studied.

Table 43.2 Standardized clinical research process 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16. 17. 18.

Prepare a clinical plan Recruit investigators Prepare protocol Prepare case report forms Prepare informed consent form Perform investigator site visit One-on-one investigator reviews, including clinical plan, protocol, case report forms, and informed consent form Obtain an investigator agreement Obtain IRB approvals for each participating institution File an IDE Obtain IDE approval Perform periodic investigator meetings Conduct the clinical study, i.e., a multicenter study Monitor the multicenter study Conclude study Compile data from each institution Analyze overall collected data Write final clinical report

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A well-controlled clinical investigation includes a clear objective and defined methods of analysis. More specifically, the objectives should address the proposed medical claims for the investigational device and these objectives should be refined to explicitly address the safety and efficacy of the heart valve in a defined population. Next, it is important to structure a trial so there can be a valid comparison to controls. For example, in current transcatheter valve therapy trials, the new therapy (transcatheter valves) is directly compared to a standard open-heart valve surgery. A control group gives the results a meaningful comparison to an existing therapy or treatment, which is important to the scientific community and may be crucial for future marketing. Often, an appropriate control group can be identified by performing a careful and thorough literature search or seeking out the key opinion leaders in the related field. Furthermore, performing early research on the specific disease or conditions that the heart valve will treat is equally important, in order to understand the natural progression of the disease or condition and the current benefits or limitations of other treatments. It should be noted this step is often completed in earlier phases of device prototyping, but it is recommended that designers review the research once again just prior to planning the clinical trial. Finally, literature searches on similar treatments/heart valves can also assist in identifying the appropriate disease populations and justifying the inclusion and exclusion criteria for the trial. When the patient population and treatment/control cohorts are clearly identified, one needs to consider the next set of factors that impact the ultimate design. First, the type of trial design must be determined, whether it is randomized, blinded, or double blinded. Each of the designs may strengthen the significance of the trial results, while also

minimizing bias and providing comparability of groups. Well-defined trial endpoints are of great significance for the overall success of a clinical trial. For example, typical heart valve trial endpoints should encompass both safety and efficacy measures. Note that adverse events often comprise the safety endpoint for a given trial. Typically, effectiveness endpoints are found in the form of the presence or absence of a clear, definite effect on a patient, e.g., death or the resultant effective orifice area (EOA). Table 43.3 provides a list of key steps to consider in designing a clinical trial for the development of a new heart valve technology. An often overlooked aspect of the early execution or startup of a clinical trial is a high degree of physician involvement or engagement. While physicians play a major role throughout the execution of the trial, it is important to gain physician insights into the overall design and planning of a clinical trial early on in the process. Being that physicians are ultimately the users of the heart valve being studied, their clinical knowledge can be valuable in creating a welldesigned and thorough clinical trial.

43.3.2 Reimbursement and Payer Information While the process for development of clinical trials is essential to understanding the appropriate use of medical interventions of all types, it is also important for payers to understand potential coverage for the device. When designing a clinical trial, it is recommended that one reads the National Coverage Determination for Routine Costs in Clinical Trials (310.1) provided by Centers for Medicare and Medicaid Services [6].

Table 43.3 General steps in the development of a clinical study design •

• •

• • •

•

Develop study objective which includes research objective, device claims, and pilot of feasibility study – Note that the study objective should be phrased as a research question posed to address medical claims for the device – Refine the research question to specifically address the safety/effectiveness of the device in a well-defined patient population for one or more outcomes – Perform a pilot or feasibility study; if claims are inadequately known, conduct a pilot or feasibility study on a small subgroup of patients or subjects. As such, the pilot study objectives are to identify claims more precisely, test study procedures, and/or obtain estimates of properties of outcome and/or other variables Properly identify and select variables/parameters Define study population(s) and appropriate clinical controls – Prior to study, define rigorous inclusion/exclusion criteria – Define subset of the general population representing the target population for the device List all parameters of the specific study design Define study masking (i.e., your bias control) Define number of study sites and potential investigators – Fit the needs for a sufficient number of eligible patients in a timely fashion – Center must be capable of processing patients – Engage competent staff members who work well on the trial – Identify investigators willing to recruit patients and conduct the study as specified in the protocol – All center individuals need be qualified to perform trial parameters Determine proper patient sample size, i.e., the study is properly statistically powered

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43.3.3 Clinical Trial Site Selection By definition, investigational sites include all centers implanting the cardiac device that submit data as part of the investigation. The initial selection of the proper hospitals/ institutions and physicians to participate in a given clinical trial is a crucial step toward executing a successful clinical research trial. After time and money are invested in creating the trial design and protocol, the actual execution can affect the outcome of the trial. Therefore, all possible steps should be taken to eliminate extraneous variables such as reeducation or elimination of a site that does not abide by the set protocol. Furthermore, the selection of appropriate physicians to participate in a clinical research trial is another variable to carefully examine before proceeding with the trial. It is critical to qualify the experience of the physicians relative to their ability to utilize novel or investigational therapies similar to the device you are investigating. It would be strategic to identify and recruit physicians already well established in the related therapy or device and those that are familiar with conducting complex clinical trials. These physicians will become the trial investigators responsible for the precise execution of the protocol at each institution or site. Not only should the physician investigators have adequate experience with clinical trials, but it is important to ensure that the institution’s support staff is knowledgeable and skilled in their execution as well. It is good practice to check the institution’s previous clinical trial performance. Finally, it is essential to make sure the physician investigators have not been disbarred, banned, or excluded from participating in any type of clinical trial. Another pertinent variable to consider when selecting sites is the actual geographic location. The clinical trial design and projected subject population(s) are helpful when identifying the amount of sites needed in the trial. As such, typically large metropolitan area hospitals are chosen to participate in clinical trials from the perspective that they should be able to quickly recruit the desired patients. However, there are regional hospitals that receive a high amount of referrals; thus, these hospitals may be able to effectively contribute to enrollment in clinical trials. Ensuring that an investigational site has an adequate potential patient population is important, given the amount of time it takes to train the personnel at a site and activate them as a part of the trial. It is interesting to note that a very small percentage of American senior citizens participate in clinical trials, although the elderly bear a disproportionate burden of disease in the United States [7]. Sites that have experience working with and successfully recruiting the appropriate patient populations can be immensely helpful in enrolling subjects in a timely manner to complete a trial. The potential for conflicts of interest is also something to manage when choosing clinical sites for a trial. More specifically,

J.C. Iaizzo

cardiac device clinical trials typically involve a high level of physician engagement in the trial and the technology/therapy being tested. Therefore, to legitimize their participation, it is critical to rule out any potential bias with regard to how the trial is run and the quality of the data being captured. It should be noted that many sponsors and clinical sites have built-in regulations or processes to cover any potential conflicts of interest.

43.3.4 Clinical Trial Execution Throughout the execution of a clinical trial, there are multiple activities happening simultaneously that need to be managed (also dependent on design of the trial). For example, most subjects in the trial will require follow-up visits. Specifically for heart valve trials, it is important to design a trial with multiple follow-up visits in order to capture longterm data on the subject population(s). With clinical evidence being the primary end product of a clinical trial, it is crucial to ensure that institutions capture valid and accurate data in a highly efficient manner. Recently, there have been several technological advances to make capturing trial data more efficient and user-friendly for the hospital/sites. The trial data is captured on what most clinical trial sponsors called case report forms. Historically, the hospitals/sites would complete hard copy forms and send them back to sponsor(s); this could be quite cumbersome especially with monitoring and processing the data to ensure accuracy. Currently, nearly all trial data are collected electronically (sites enter data directly into an online case report form, and the sponsor can see the data in real time). Therefore, as new trials are rolled out and more heart valves are being studied, it will be critical to keep up with the ever-evolving technologies that are being developed and deployed to ensure the integrity, quality, and efficiency of clinical trials. An interesting trend in recent transcatheter heart valve trials is the development and utilization of screening committees. For example, a screening committee for a heart valve transcatheter trial would typically be compromised of wellestablished, objective cardiac surgeons and interventional cardiologists. As such, it is imperative that these individuals also be familiar with the details of heart valve technologies and the trial design. Furthermore, it is important that the screening committee be knowledgeable about the patient population which the trial is enrolling as well as the specific inclusion/exclusion criteria. The screening committee could also be used to assist in determining and identifying the appropriate patients for a properly designed trial. It is critical to recruit an overall subject population that is highly consistent; this is especially important when multiple clinical sites/ hospitals are participating in the trial. Assuming the trial has progressed to the point of near completion, there are several other factors to consider.

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For example, all subjects should be accounted for in the final clinical report. It is recommended that complete subject accounting, on a per subject basis, for each cohort is provided. Therefore, the report should include: (1) the total number of subjects expected for follow-up, (2) number of subjects discontinued because of death or device removal, and (3) number of subjects that were actually evaluated at each preplanned time point. Depending on the type of trial and the primary endpoints listed in the protocol, submitting for regulatory approval may happen before the trial is fully complete. For example, in an IDE study with primary endpoints at 1 year of subject follow-up, an application for PMA may be submitted and granted prior to the end of all subject follow-up. Nevertheless, this will depend on the accepted trial design. It should be noted that the FDA expects long-term data for most IDE heart valve trials. Therefore, in some trials, the specific heart valve may be commercialized prior to the end of all followup visits, but regular reports continue to be submitted to regulatory bodies containing the long-term data. Finally, the overall timeline for submission for regulatory approval will ultimately depend on the statistical methods and analytical processes laid out in the final trial protocol. It is important that this section of the device trial protocol be carefully followed, as it is agreed upon by the FDA or regulatory body prior to initiation. Excerpts from the Draft Guidance for Industry and FDA Staff Heart Valves—IDE and PMA Applications are outlined below to provide clear direction from FDA’s perspective on the conduct of a heart valve clinical trial [2]. Again, it is important to reference the appropriate FDA guidance that your cardiac device may fall under.

43.3.5 Data Collection Within the Clinical Trial As clinical evidence to support the use of the investigative heart valve is the ultimate product of conducting a clinical trial, the remainder of this chapter will focus on the collection of data and various regulations one needs to consider related to clinical evidence. FDA guidance provides detailed insight into what is expected in a data collection plan and therefore should be referenced frequently throughout development of the protocol. Listed below is an important narrative from the FDA Guidance document that one should understand prior to data collection: The sponsor who discovers that an investigator is not complying with the signed agreement, the investigational plan, requirements in 21 CFR Part 812 or other applicable FDA regulations, or any conditions of approval imposed by the reviewing investigational review board or FDA is responsible for promptly securing the investigators compliance or discontinuing shipment of the device to the investigator and terminating the investigator’s participation in the investigation (21 CFR 812.46(a)). Your protocol must

ensure that the investigation is scientifically sound by ensuring consistency between the indication studied and the subject inclusion and exclusion criteria (21 CFR 812.25(b)). In all study designs, you should ensure that investigators collect the appropriate information. Specifically, you should ensure that the clinical data collection forms used by the investigators and institutions are consistent with the clinical protocol. You should also ensure that informed consent document(s) is consistent with the clinical protocol [2].

43.3.6 Data Collected for Each Subject Enrolled into a Clinical Trial Each subject enrolled in the study should be followed and appropriate data collected according to the study protocol. Additionally, follow-up data should be collected for each subject until the entire study is terminated for all subjects; this follow-up data is typically collected during office, clinic, or hospital visits. It is recommended that telephone followup should be used only to verify death or loss to follow-up. Being data should be collected until the entire study is terminated for all patients, the follow-up period may be significantly longer than stated in the original study protocol for most patients. Accordingly, an informed consent must be received for the planned follow-up period from all subjects (21 CFR 50.25(a)(1)). Therefore, any subject not willing to fully participate in the study, which includes the follow-up period, should not be enrolled [2]. Most institutions have a thorough consent process, as governed by regulatory bodies and their own IRBs. This consenting process will ensure that subjects being enrolled in the trial will complete all followup visits; however, trial attrition still occurs. There is the potential that some patients will enroll in a clinical trial to obtain the latest technologies, with little or no intent of being part of post-monitoring. The FDA’s guidance goes into more detail about the specific data they would like to see collected, as it will help ensure consistency across populations receiving heart valves (Table 43.4). For example, follow-up data for most heart valve trials should include the normal ranges for the clinical laboratory blood tests evaluated, according to the normal

Table 43.4 Echocardiographic hemodynamic data (stratified by valve size for each patient enrolled) • • • • • • • •

Peak pressure gradients Mean pressure gradients Effective orifice areas Existence and/or relative degree of valvular regurgitation Native valve’s effective orifice area index Native valve’s performance index Resting cardiac output Average cardiac index

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ranges used by the laboratories that conduct the testing. Plasma free hemoglobin is preferable to serum lactate dehydrogenase, haptoglobin, and reticulocyte count for the evaluation for hemolysis because it is considered that plasma free hemoglobin has higher clinical sensitivity for the detection of hemolysis than the other three laboratory tests. The diagnostic preoperative data collected should include the normal ranges for the clinical laboratory blood tests that are evaluated, with the normal ranges being determined by the laboratories used [2]. As detailed, it should be apparent the amount of data and work institutions will undertake to participate in new heart valve trials. Typically, enrolled patients will be followed subsequent to the procedure by their personal cardiologists (not the implant surgeon/interventionalist), and often there will be preclinical data available for a given patient as well. Therefore, the study investigators should work in conjunction with the patients’ physicians to collect all appropriate data from the correct time periods. This may be better accomplished if the study investigator or the sponsor obtains contact information for the following physician, so he/she can be advised of the actual study protocol. It is important to note that only study procedures (out of the standard of care scope) should be performed by investigators trained on the trial protocol. As there is increasing interest in all valve positions, FDA guidance has started to address specific details for these different positions. It is recommended for trials that involve replacement of pulmonic valves and/or pulmonic-valved conduits that one should calculate the effective valve orifice area, since the cone shape of the right ventricular outflow tract makes echocardiographic measurements of the right ventricular outflow tract diameters very difficult. This measurement, if identified within a clinical design, may lead to potentially inaccurate calculations, i.e., if one employs a continuity equation method for the pulmonic valve EOA. Similarly, for replacement pulmonic valves and pulmonic-valved conduits, the FDA does not recommend calculation of EOA indexes and performance index data, which are determined using EOA data [2].

43.3.7 Clinical Trial Follow-Ups In general, each subject entered into the study should be followed and appropriate data collected according to the study protocol, and associated follow-up data should be collected for each subject until the entire study is terminated for all subjects. Unfortunately, this is not always the case; therefore, it is important to plan for potential attrition in the statistical plan by having an adequate population enrolled greater than the minimum number of patients needed for an appropriate

J.C. Iaizzo

analysis. It is helpful to determine the appropriate subject population by referring to the term follow-up in patientyears. For example, the recommended follow-up of 800 patient-years is statistically derived as follows. Single sample one-sided hypothesis testing can be used to demonstrate that each of the complication rates associated with the investigational device is less than 2 times the objective performance criteria (OPC) for that complication. The appropriate null hypothesis is that the true rate associated with the investigational device is 2 or more times its OPC. To reject this null hypothesis is to accept the alternative hypothesis that the true rate associated with the investigational device is less than 2 times its OPC [2]. Generally, in order to provide a clinically sufficient amount of data on the investigational heart valve technology, it is generally recommended by the FDA that all subjects be followed for 1 year or more. If a clinical investigation is for one valve position, it is recommended that at least 300 subjects are followed for 1 year or more, for a total of 800 patient-years of follow-up. If the study is for two valve positions (i.e., aortic and mitral), it is recommended that at least 150 subjects are followed for 1 year or more for each valve position, for a total of 400 patient-years of follow-up per valve position. It is generally recommended that one conducts a valve technology clinical study at eight or more primary centers, with 30+ subjects implanted at each center for a one-position study and 15+ subjects implanted at each center for a two-position study [2]. As noted within the FDA recommendations, using fewer than eight primary centers can introduce unanticipated bias into these complex clinical trials. Some heart valve technologies may be implanted or deployed in more than one of the four heart valves. Therefore, it has been specifically recommended by the FDA that, for one-position and two-position studies, trials be designed for the subsequent implanting of 15+ subjects for each size and each position of valve. In other words, if a study assesses the potential for both aortic and mitral replacement with a given technology, the study should enroll 15+ subjects at the aortic position and an additional 15+ subjects at the mitral position, for each valve size. It should be noted that this recommendation of 15 subjects implanted per size per position criterion is based on statistical calculations for echocardiographic EOA data; these calculations showed that in order to assure a sufficiently narrow 95 % confidence interval, the minimum number of subjects implanted with each valve size was 15. If you were to design a trial in which you hoped to omit any valve size, the FDA specifically recommends that you explain how the data you plan to collect would still remain representative of all the sizes that you intend to market. With the rapid development of cardiac imaging capabilities, any well-designed clinical trial on a valve technology will also require follow-up image assessments (Table 43.5).

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43.3.8 Complications and Complication Rates The types of complications to expect from patients treated with newly developed valve technologies include valve thrombosis, major hemorrhage, perivalvular leak, and/or stroke. For the initial three complications, the rate of occurrence with current technologies is typically less than 1.2 % per patient-year (i.e., within 800 patient-years) for aortic and mitral positions combined [2]. Therefore, such rates typically must be matched or exceeded by the novel technology. It is generally recommended for valve technologies that the complication data include hemorrhages resulting from all causes (all-cause hemorrhage) rather than just hemorrhages related to anticoagulant therapy (anticoagulant-related hemorrhage). Additionally, it is typical that the complication data include all-cause reoperations, valve-related reoperations, explants, all-cause deaths, and valve-related deaths. The clinical trial sponsors are ultimately responsible for ensuring proper monitoring of the investigation and must select non-biased monitors qualified by appropriate training and experience. For example, the FDA generally suggests

Table 43.5 Reports included as follow-up data • • • •

Echocardiograms Cardiac catheterizations Other cardiovascular imaging procedures, including CT and MR scans Chest X-rays

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that each trial sponsor (designer) establishes a Data Safety Monitoring Board (DSMB) to review adverse events and recommend study termination if safety concerns are warranted. Nevertheless, the DSMB should establish criteria for recommending study termination for safety reasons before the study begins and should meet at least two times during the study to monitor adverse events. Furthermore, it is recommended that the DSMB should include members who are independent from the study sponsors and investigators; additionally, two or more members should be physicians including a cardiothoracic surgeon and a cardiologist. Additionally, if the study involves statistical analyses, one member should be a qualified statistician. It is also recommended that the sponsor establish a Clinical Events Committee (CEC) in order to adjudicate adverse events as being valve technology related or not and to classify the severity of an elicited adverse event. Similar to the DSMB, the CEC should have members who are independent from the study sponsors as well as selected clinical investigators. It is important to charter CEC and DSMB committees for a trial, as they add independent validation to the credibility of the research. As the execution of the study proceeds and endpoints are reached, the CEC and DSMB committees will be commissioned to adjudicate the data which will be necessary for the PMA submission. Table 43.6 outlines the recommendations for what should be included in a PMA submission. A PMA should include the actual number of all noted adverse events. In addition, it is generally recommended that

Table 43.6 FDA recommendations for a final premarket approval report • • •

• • • • •

• • • • • • •

Summary of patients/subjects not completing the study (stratified by lost to follow-up, death, or explant) Specific locations of all investigational sites in which procedures were performed Relative comparison of preoperative and postoperative NYHA functional class (presented as the percentage of subjects in each class at baseline, at each follow-up time point, and as the percentage of subjects at each follow-up time point who improved, worsened, or did not change in class) Pre-implant/procedure effective orifice area of the given heart valve Number of implanted patients/subjects stratified by the given investigational sites, replacement/repair valve positions (e.g., aortic, mitral, or double valve), and/or employed valve sizes Number of treated patients/subjects followed to 1 year post-procedure, stratified by investigational site, valve treated (e.g., aortic, mitral, or double valve), and/or employed valve sizes Follow-up duration information (total and by valve position) including mean follow-up times, standard deviations, range of follow-up, and cumulative follow-up in patient-years Any identified confounding factors (e.g., by hazard regression analysis applied to identify risk factors, gender, age at implant, preoperative NYHA functional classification, previous valve surgery, concomitant coronary artery bypass surgery, implant position, and implant size) which might affect the incidence of reoperation, explant, and/or death Patient compliance data for follow-up visits (e.g., NYHA functional classification data, echocardiographic data, and/or clinical laboratory results) Complete list of complications by patient identification number Summary of any and all subject complaints received All case report forms (i.e., for a 10 % random sampling of the subject population) All copies of case report forms for each and every subject not completing the study Explant analysis data obtained for each and every case (i.e., when a valve was explanted or an autopsy was performed) All death reports, including autopsy reports when available, especially when the cause of death was classified as non-valve related

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the trial sponsor expresses early complication rates as the number of adverse events divided by the total number of subjects [2]. A sponsor should also include linearized late complication rates; these rates are calculated as the number of late adverse events divided by the total number of late patient-years. With the rapidly changing regulatory environment and concerns for ensuring safety of cardiac valves, the clinical trial process will continually evolve. It is important to keep up to date on additional requirements and landmark trials that are testing devices similar to the new heart valves being developed today. The FDA provides valuable resources on their website along with a repository for most clinical trials that are occurring in the United States (www.clinicaltrials.gov).

43.4

Summary

Clinical trials are an important and critical step in bringing new technologies, such as cardiac devices, to the market. As detailed above, there are many facets involved in the development and execution of a clinical trial. This chapter provides a high-level overview of these aspects, which may vary from product to product. Setting up a calculated trial and executing it proficiently will affect the ability to successfully market a cardiac device. The clinical trial requirements and regulatory and reimbursement landscape are vast and constantly changing. When designing a clinical trial, it is important to keep in mind the various regulatory requirements, the importance of GCP, the selection of participating institutions, data collection, endpoints, and overall execution of the trial. With such a heavily regulated environment as well as the intricacies of cardiac devices, ensuring proper conduct to ensure high

quality data is crucial. This chapter provides a general overview of the present state of human heart valve clinical trials, including: (1) the current positions of regulatory bodies that oversee trials, (2) specific features of a trial design, and (3) considerations involved in the proper implementation of trials.

References 1. U.S. Food and Drug Administration (2010) What we do. U.S. Department of Health & Human Services. http://www.fda.gov/ AboutFDA/WhatWeDo/default.htm. Accessed 17 Dec 2014 2. U.S. Food and Drug Administration (2010) Draft guidance for industry and FDA Staff Heart Valves—Investigational Device Exemption (IDE) and Premarket Approval (PMA) Applications Draft Guidance. http://www.fda.gov/downloads/medicaldevices/ deviceregulationandguidance/guidancedocuments/ucm198043.pdf. Accessed 17 Dec 2014 3. International Organization for Standardization (ISO), ISO 5840:2005, “Cardiovascular Implants - Cardiac Valve Prostheses” (ISO 5840) 4. Kaplan AV, Baim DS, Smith JJ et al (2004) Medical device development: from prototype to regulatory approval. Circulation 109:3068–3072 5. U.S. Food and Drug Administration (2011) Good Clinical Practice 101: an introduction. http://www.fda.gov/downloads/training/cdrhlearn/ ucm176414.pdf. Accessed 17 Dec 2014 6. Centers for Medicare & Medicaid Services (2012) Medicare clinical trial policies. https://www.cms.gov/ClinicalTrialPolicies. Accessed 17 Dec 2014 7. Centers for Medicare & Medicaid Services (2012) National Coverage Determination (NCD) for Routine Costs in Clinical Trials (310.1) – Current Policy – July 2007 NCD. Medicare Clinical Trial Policies. http://www.cms.gov/medicare-coverage-database/details/ ncd-details.aspx?NCDId=1&ncdver=2&bc=BAABAAAAA AAA&. Accessed 17 Dec 2014

Cardiac Devices and Technologies: Continued Rapid Rates of Development

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Abstract

The primary goals of this last chapter are to: (1) make note of the technologies mentioned earlier in this book, (2) describe some important changes in healthcare and global markets that could have an impact on the use rate of technologies being developed, and (3) discuss several other future opportunities in the cardiac device arena. It should be noted that the chapters of this third edition were updated, and new ones were added to specifically describe recent critical advances in cardiac device technologies and/or clinical applications. There are also other areas of importance in cardiac treatment such as biological approaches to disease management (stem cell therapy), genomics (diagnostics and gene therapy), proteomics, and/or tissue engineering, all of which may have a major impact on the future of cardiac clinical care; however, detailed discussions of these approaches are beyond the scope of this book. Keywords

Medical device development • Implantable therapies • Catheter-delivered devices • Endocardial ablation devices • Device coating agents • Telemedicine • Implantable sensors Cardiac imaging • Surgical tools • Less invasive surgery

44.1

Introduction

Since the second edition of this book was published in 2009, much has changed in the field of cardiac devices. In response, several new chapters were added, and others were expanded in this third edition, so to accommodate the rapid growth and innovation in this field. In many of these chapters, the authors provided histories of cardiac device development and fairly thorough discussions of currently employed devices and/or assessment technologies. To appreciate how rapidly innovations in the area of cardiac disease continue to progress, one P.A. Iaizzo PhD (*) Departments of Surgery and Integrative Biology and Physiology, Carlson School of Management, Lillehei Heart Institute, Institute for Engineering in Medicine, University of Minnesota, 420 Delaware St. SE, B172 Mayo, MMC 195, Minneapolis, MN 55455, USA e-mail: [email protected]

can simply perform a search on the United States Patent and Trademark Office website (www.uspto.gov). This search produces an impressive number of companies and/or individuals that are attempting to secure intellectual property protection in this clinical category. More specifically, Table 44.1 summarizes the number of published patent applications identified in October of 2015, 2008, and 2004, citing the following keywords: cardiac, cardiac surgery, cardiology, cardiac electrophysiology, cardiovascular stents, and cardiac repair. Note that this list likely does not include all issued patents, as some may be foreign and many of these patents detail prospective future products. For example, in searching the same database mentioned above (at time of print for this book), the key word CARDIAC produces 93,942 issued patents in 2015 since 1976, compared to 49,017 patents issued in 2008 and 37,410 in 2004. This rapid increase includes only US patent applications, yet the same is true for the number of new international patent submissions. There are several other resources to locate information on emerging

© Springer International Publishing Switzerland 2015 P.A. Iaizzo (ed.), Handbook of Cardiac Anatomy, Physiology, and Devices, DOI 10.1007/978-3-319-19464-6_44

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788 Table 44.1 Patent applications for various key words Number of patent applications Keyword 2015 2008 2004 93,942 Cardiac 46,946 18,920 5,404 Cardiac surgery 2331 1015 14,798 Cardiology 3961 1480 869 Cardiac electrophysiology 213 79 313 Cardiovascular stents 137 52 224 Cardiac repair 127 32 Source: United States Patent and Trademark Office website (www. uspto.gov)

cardiac devices, such as the Food and Drug Administration website (http://www.fda.gov), the Google™ patent search website (https://www.google.com/?tbm=pts&hl=en&gws_ rd=ssl), and various other websites. It is important to note that, relative to medical devices, not all countries uphold patent protection to the same international standards; this is a major issue to consider as a corporation looks to expand globally. Discussion of these implications is beyond the scope of this text, but those developing cardiac devices need to be critically aware of this reality. For example, it was recently noted by Shara Aranoff, former Commissioner and Chairman of the US International Trade Commission [1], that “Over the past 20 years, the number of patent infringement disputes filed annually at the U.S. International Trade Commission (ITC) has more than tripled. Although typically associated with smartphones and semiconductor chips, the ITC has also seen quite a few disputes involving medical devices. Important trends are emerging in medical device patent litigation at the ITC.” Many novel ideas that eventually lead to new products, therapies, and/or training protocols often first occur through “basic” cardiac research or clinical patient management. Hence, in order for emerging technologies to continue to advance at a rapid rate, it is imperative that laboratories performing basic research in cardiac-related technological areas continue to receive necessary support. Furthermore, prototype testing and clinical trials are essential to insure that the best possible technologies are developed and eventually made available for general use. Yet, it is important to note that many critical lessons can be learned from trials that employ misdirected devices or technologies. When considering the design of a medical device, there are typically a number of key processes or steps involved: • A device sketch (e.g., on a cocktail napkin, iPad, or smartphone during a meeting with a clinician, with a signed nondisclosure agreement) • Detailed drawings and intellectual property disclosures • A critical study of the associated normal and pathologic anatomies • The creation of an impressive animation of device design, its function, and/or its clinical delivery/placement

P.A. Iaizzo

• Device prototype development (rapid, working, polished prototypes and/or computer simulations) • Bench testing (safety, wear, and biocompatibility testing) • Redesign: set on a final design freeze • Preclinical research: animal testing • Redesign (if needed) or initiation of clinical testing • Simulation systems of device implantation • Market release and/or corporate acquisition Some devices can be employed as life-saving measures prior to approval for market release, if a Humanitarian Device Exemption is obtained. For more details on the design process, the reader is referred to Chap. 42. As cardiac devices become more beneficial and help people live longer lives, we foresee that there will be a need to design devices that: (1) have even higher reliability and longevity; (2) can be upgraded, extracted, and/or replaced; and/or (3) allow for easy data retrieval (i.e., “big data” obtained remotely). More specifically, the retrieval of data and/or the reprogramming of implantable cardiac systems (sensor/pacing/defibrillation) should be accomplished with minimal need for patient training or education; they should function as seamlessly and simply as possible (you just implant them!). As these systems evolve, there will be growing interest from healthcare payers as well as the physicians and/or hospitals that monitor patients. Furthermore, data would ultimately and automatically be interfaced with electronic health records which are becoming commonplace in the USA and many global markets. Importantly, the increased use of home monitoring may be perceived as the only possible way to manage the growing amount of “big data” collected from the “baby boomer” patients receiving such therapies. This approach in turn may result in: (1) improved care, (2) greater levels of patient confidence, (3) better understanding of disease-specific therapies, and/or (4) overall cost savings for both the healthcare industry and consumers. It should also be noted that currently there are patient-owned medical records, as mandated in a Presidential order in 2004. Furthermore, with the passing of the Affordable Care Act in the USA, the future of cardiac device coverage will be affected, but at this time it is still not clear how and/or to what degree. To learn more about these policies, the reader is referred to http://www.hhs.gov/healthcare/facts/timeline/index.html. The Affordable Care Act was passed by Congress and then signed into law by President Obama on March 23, 2010; on June 28, 2012, the Supreme Court rendered a final decision to uphold the healthcare law. Important features of the Act include the following: 1. Coverage • Ends preexisting condition exclusions for children: health plans can no longer limit or deny benefits to children under 19 due to a preexisting condition. • Keeps young adults covered: individuals under 26 of age may be eligible for coverage under their parents’

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health plan. • Ends arbitrary withdrawal of insurance coverage: insurers can no longer cancel coverage just because an individual makes an honest mistake. • Guarantees right to appeal: individuals have the right to ask their insurance provider to reconsider denial of payment. 2. Costs • Ends lifetime limits on coverage: lifetime limits on most benefits are banned for all new health insurance plans. • Reviews premium increases: insurance companies must publicly justify any unreasonable rate hikes. • Helps individuals get the most from their premium dollars: dollars spent on premiums must be spent primarily on healthcare, not administrative costs. 3. Patient Care • Covers preventive care at no cost: individuals may be eligible for recommended preventive health services without a copayment. • Protects choice of doctors: individuals may choose their own primary care doctors from the plan’s network. • Removes insurance company barriers to emergency services: individuals can seek emergency care at a hospital outside of the health plan’s provider network. Within the last several years, we have again witnessed a fair number of cardiac device recalls due to the so-called inherent failures. However, this may be not so surprising, as the sophistication of these devices continues to increase and more and more clinicians have started to implant them. Nevertheless, it needs to be emphasized that human cardiac anatomy is highly variable and dynamic (ever changing, with reverse remodeling occurring with improved outcomes and survival); thus, we need to consider that the implant environment continues to change post-therapeutically (post-implant) and is a highly caustic environment. The human body has innate healing and foreign body response systems. Despite the occurrence of failed devices, all designs were required to pass rigorous bench testing, animal trials, and human clinical trials before approval for market release. It is of interest to note that each company often designs their own bench testing equipment because, in most cases, the device designs are novel or unique. In fact, many times this testing equipment also becomes proprietary. Therefore, it is likely that bench testing of cardiac devices with high sales volumes will become regulated by governments sometime in the near future. To provide greater perspective on the design and testing challenges facing the cardiac device industry, perhaps an example will suffice. A pacing lead moves approximately 100,000 times every day (or 37,000,000 times annually), and this can occur in multiple locations and with numerous degrees of freedom. Furthermore, when considering failure

of the lead insulation alone, we must expect failures due to abrasions, the association with the fibrous device pocket, the potential for lead-to-lead interactions, anatomical considerations (bones, ligaments, etc.), and/or other complications. It is also interesting to note that some features of lead implantation (e.g., design of the anchoring sleeves) have received little attention or study, yet this may greatly influence the potential for lead failures. For a detailed review on the bench testing of cardiac valves, the reader is referred to Kelley et al. [2]. Again, several new chapters were added to this edition of the textbook, and others were updated to provide the reader with additional information on bench top (in vitro), preclinical, and clinical testing/research (e.g., Chaps. 27 and 41–43).

44.2

Resuscitation Systems and Devices

Even before the cardiac patient enters the emergency and/or operating room, there are many new technologies being developed to aid in resuscitation. Such innovations range from improvements of existing tools (e.g., automated application of cardiopulmonary resuscitation, the use of active compression–decompression devices) to novel mechanisms that accomplish better patient outcomes (e.g., impedance threshold valve, cerebral cooling, and inducing mild hypothermia). Furthermore, automated external defibrillators have become commonplace in the USA, with units being purchased for use in schools, health clubs, emergency vehicles, shopping malls, and even personal homes. Recent clinical trials describe the success of these emerging technologies (see Chap. 38).

44.3

Implantable Therapies

Advances in microtechnology have now made it possible to create implantable therapies that can be life saving, e.g., implantable defibrillators to detect and treat thousands of episodes of sudden cardiac fibrillation. For example recently, there has been a drive to implant vagal nerve stimulators for several proposed therapies including heart rate control, blood pressure control, dietary control, and/or even the reversal of depression. The need for such devices will likely increase at an exponential rate and will be directed specifically to all types of cardiac complications.

44.3.1 Left Atrial Appendage/Atrial Fibrillation Therapy There are growing numbers of treatment for the side effects of atrial fibrillation which, in some patients, leads to crip-

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pling strokes. The focus of these devices is to modify the role of the left atrial appendage in pathologies associated with atrial fibrillation. More specifically, this tiny alcove of the heart has been described to service as a “starter heart” for the human embryo; it can be a site for blood to pool and subsequently form clots that can be expelled out of the heart and into the brain, causing strokes. Today, it is estimated that atrial fibrillation affects five million people worldwide and is considered to be responsible for up to 25 % of all strokes. It has been reported that, due to aging of the population, the number of patients with atrial fibrillation will likely increase by approximately 2.5-fold by the year 2050 [3]. At present, one of the most common treatments for atrial fibrillation is the administration of anticoagulant drugs; note that there are several new drugs available in addition to coumadin. From a device perspective, suggested approaches to treat this problem include tissue clamps, screens, and other methods to seal off the appendage; many of these approaches are being studied through ongoing clinical trials. Nevertheless, ablation is a critical tool for treating atrial fibrillation, and for more details the reader is referred to the new chapter in this textbook (Chap. 29), as well as Chap. 32 on the mapping of such arrhythmias.

P.A. Iaizzo

44.4

Catheter-Delivered Devices

Since the first edition of this textbook in 2005, there has been a boom in the delivery of specialized cardiac devices that can be introduced intravascularly or via intracardiac methods. Such devices include stents, septal occluder devices, valves, leads, implantable pacemakers, and ablation tools (see Chaps. 8, 28, 30, and 35). Currently, the field of transcatheterdelivered valves is one of great interest and high competition within the medical device industry (Chap. 36). In addition, the team approach for the clinical delivery of such systems is becoming widespread, with cardiologists and cardiac surgeons working together in hybrid catheter lab/operating rooms to perform multi-tiered treatments on patients (e.g., implanting pacing/defibrillation systems, valves, and/or bypass grafts). As the number of these centers of excellence continues to increase to perform such procedures, it is likely that older individuals will be receiving implantable devices and/or other cardiac therapies. It should be noted that there are also cardiac catheters on the market to deliver stem cell or gene therapies (see Chap. 40).

44.4.1 Stents 44.3.2 Cardiac Remodeling Chronic cardiac remodeling is a well-known response of dilated cardiomyopathy and is thought to play a central role in disease progression [4–6]. Associated heart chamber dilation and/or wall thinning will elevate overall wall stress which is considered to trigger the local release of neurohormones, thereby adversely affecting myocardial molecular biology and physiology [7]. Therapeutic approaches to treat heart failure have been described primarily as a means to inhibit or even induce reverse remodeling (e.g., betaadrenergic blockade). More recently, mechanical unloading using left ventricular assist devices (see Chap. 39), extracorporeal pumps (Chap. 33), or portable whole heart support systems (e.g., EXCOR®, Berlin Heart, Berlin, Germany) have been employed as alternatives. Such interventions can profoundly unload a heart, leading to reverse remodeling and thus improved physiological performance [4]. The design of such pump systems has been ongoing, and the goal has been to transition from external (or partially external) to fully implantable pumps (e.g., external to internal pumps with small rechargeable battery packs). Furthermore, when system developers changed from pulsatile to continuous pumps, pump size was reduced by ~1/7, pump weight was reduced by ~1/4, and they were also quieter and more reliable (e.g., fewer moving parts); see Chap. 39 for further details.

An intraluminal coronary artery stent is a small wire mesh tube that is placed within a coronary artery to keep the vessel patent (open). Stents are commonly deployed: (1) during a coronary artery bypass graft surgery to keep the grafted vessel open, (2) after balloon angioplasty to prevent reclosure of the blood vessel, and/or (3) during other heart surgeries. For delivery, a stent is collapsed to a small diameter and put over a balloon catheter. Typically with the guidance of fluoroscopy, the catheter and stent are moved into the area of the blockage. When the balloon on the delivery catheter is inflated, the stent expands, locking it in place within the vessel and thus forming a scaffold which holds the artery open. Stents were originally intended to stay in the vessel permanently, keeping it open to improve blood flow to the myocardium and thereby relieving symptoms (usually angina). Note that a stent may be used instead of angioplasty. The type of stent to be deployed depends on certain features of the artery blockage, i.e., size of the artery and where the blockage is specifically located. Today bioabsorbable stents are being deployed. Often stents need to be placed at vessel bifurcations, and thus special techniques and/or stents need to be deployed. For example, a provisional technique is a generally accepted procedure for treating a bifurcation in a coronary artery. The main branch is stented first, with the stent deployed to a diameter matching the distal side of the target vessel. This is then followed by a proximal optimization technique which addresses the malapposition of stent

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Emerging Technology

struts resulting from sizing the stent using the distal side of the target vessel. Lastly, the use of a final kissing balloon technique, in which two balloons are simultaneously deployed into the main branch and side branch, is used in order to restore patency to the jailed side branch and obtain better strut apposition at the bifurcation (see: http://www. vhlab.umn.edu/atlas/device-tutorial/stents). It should be noted that at the Transcatheter Cardiovascular Therapeutics (TCT) meetings held in 2014 and 2015, a special session was dedicated to the discussion of various stenting techniques that can be utilized in various clinical situations (see: http:// www.crf.org/tct).

44.4.2 Catheter-Delivered Leads or Pacemakers One of the continuing challenges in the area of intracardiac lead development is to downsize lead diameters and, at the same time, minimize the possibility of fractures or failures. Similarly, there is growing practice in the placement of leads within the cardiac veins, as well as in the development of tools for cannulation of the coronary sinus. For a detailed discussion of left-sided leads and resynchronization therapy, the reader is referred to Chap. 31. Although pacing systems with leads have been utilized since the inception of cardiac pacing, recent advances in miniaturization technology and battery chemistry have made it possible to develop a self-contained pacemaker small enough to be implanted entirely within the heart, while still aiming to provide similar battery longevity to conventional pacemakers. In general, leadless pacemakers (or transcatheter-delivered pacemakers) are self-contained devices designed to be implanted within the chambers of the heart directly at the desired site of pacing. By eliminating the need for a subcutaneous device pocket and insertion of a permanent lead within the vasculature, some of the complications associated with traditional pacing systems can be avoided, including pocket infection, erosion and/or hematoma as well as lead dislodgement, fracture and/or infection. For more details on these devices, see Chap. 30.

44.5

Implantable Sensors

Device and battery technologies continue to decrease in size and, at the same time, exhibit improved efficiency. Also, there have been rapid advances in printable and/or flexible micro-electronics. In turn, this creates increasing opportunities for novel approaches to long-term assessment of various physiological parameters from unique aspects of the entire cardiovascular system. Numerous innovations for the management and collection of “big data” have arisen in the field

791

of medicine, including implantable computers and sensors, wireless data transmission, and web-based repositories for collecting and organizing information. One such device, the Reveal LINQ™ Insertable Cardiac Monitor (Medtronic, Inc., Minneapolis, MN, USA), is an implantable monitoring system that records subcutaneous electrocardiograms and is indicated for human clinical use for: (1) patients with clinical syndromes or situations at increased risk of cardiac arrhythmias, and (2) patients who experience transient symptoms that may suggest a cardiac arrhythmia [8]. A common use of the system is for unexplained syncope (fainting), in which case the implanted device can capture episodes with impaired cardiac output, including bradycardias (unusually low heart rates), asystoles (long periods without a heartbeat), or tachycardias (unusually high heart rates). The Reveal LINQ is intended to continuously sense and collect unique and valuable information such as heart rate, physical activity, and body temperature from a sensor injected under the patient’s skin. Subsequently, physicians can access these data via a controlled website at any time and review screens that present summaries from the latest downloads, trend information, and/or detailed records from specified times or problem episodes. Interestingly, these human clinical devices have been recently deployed in captive and free-ranging wildlife to aid in the characterization of normal physiology and the interaction of animals with their environment, including reactions to humans (Fig. 44.1) [9].

44.6

Procedural Improvement

With pressure on the healthcare system to continually reduce treatment costs and better document the outcome benefits of a given therapy, much effort will continue to be focused on procedural improvements for cardiac care.

44.6.1 Cardiac Imaging Our ability to image internal and external features of the heart continues to improve at a rapid rate and, as indicated in Chaps. 22 and 24, the sophistication of such systems can be quite extreme. Yet, as the cost of computer hardware decreases and capabilities increase, opportunities to downsize and develop such technologies for widespread use continue to become more and more feasible.

44.7

Training Systems

As technologies have become more advanced, so has the need to teach students, residents, and physicians on how to use them. There are numerous education programs, conferences,

792

P.A. Iaizzo

Fig. 44.1 The use of a wireless telemetry system at a bear den. The insertable cardiac monitor (Reveal LINQ™, Medtronic Inc., Minneapolis, MN, USA) communicated with a relay station housed in a waterproof container via an antenna buried under the bear.

Transmissions to an Internet site were via a cellular module attached to a timber tripod fabricated at the site. The system was powered by 12 V batteries charged by a solar panel [9]. ICM insertable cardiac monitor

websites, teleconferences, and special courses offered. For example, our laboratory has developed a free access website dedicated to the education of functional cardiac anatomy, imaging, 3D models, and device deployment (see http:// www.vhlab.umn.edu/atlas/).

mapping systems, 3D echocardiography, magnetic resonance imaging, training simulators, etc.), (5) less invasive surgical approaches (off-pump, robotics, direct aortic transcatheter valve placements, etc.), (6) post-procedural follow-up/telemedicine (electrical, functional, adverse events, etc.), and (7) training tools. There is no doubt that continued improvement of these technologies, as well as advances in rehabilitation and other support services (patient education, training, home monitoring, etc.), will extend and/or save lives and enhance the overall quality of life for individuals with cardiovascular disease. Many of these developments are currently available, and the challenge for healthcare providers in the coming years will be to provide the best possible care in the most cost-effective way. Perhaps we will see the day of the family house call once again, where the healthcare provider visits the home and assesses and monitors all family members living there during a single visit (ECGs, electronic auscultations, pressure assessments, echocardiography, device reprogramming, blood and

44.8

Summary

Within this book, several devices utilized for cardiac electrophysiology, interventional cardiology, and cardiac surgery were discussed. The development of such innovative technologies continues to mature at a rapid rate and includes: (1) resuscitation systems and devices, (2) implantable therapies (pacemakers, implantable cardioverter defibrillators, stents, septal occluders, valves, annular rings, fibrin patches, etc.), (3) delivery systems/invasive therapies (angioplasty, ablations, catheters, etc.), (4) procedural improvements (noninvasive

44

Emerging Technology

genetic analyses, etc.). It should be noted that it was not that long ago, in the 1960s, that medical students were still instructed on how to perform a “traditional house call.” In conclusion, it is exciting to think about the technologies that have been employed thus far as well as those that are being developed that will positively affect the overall healthcare of the cardiac patient. It continues to be an exhilarating era to be working in the field of cardiovascular sciences.

793 5. Anversa P, Olivetti G, Capasso JM (1991) Cellular basis of ventricular remodeling after myocardial infarction. Am J Cardiol 68:7D–16D 6. Saaverda WF, Tunin RS, Paolocci N et al (2002) Reverse remodeling and enhanced adrenergic reserve from passive external support in experimental dilated heart failure. J Am Coll Cardiol 39:2069–2076 7. Francis GS (2001) Pathophysiology of chronic heart failure. Am J Med 110:37S–46S 8. REVEAL LINQ™ LNQ11 Insertable Cardiac Monitor Clinician Manual. http://manuals.medtronic.com/wcm/groups/mdtcom_sg/@ emanuals/@era/@crdm/documents/documents/contrib_185856.pdf 9. Laske TG, Garshelis DL, Iaizzo PA (2014) Big data in wildlife research: remote web-based monitoring of hibernating black bears. BMC Physiol 14:13

References 1. Aranoff S (2014) The National Law Review. 29 October 2014. http://www.natlawreview.com/author/shara-aranoff 2. Kelley TA, Marquez S, Popelar CF (2013) In vitro testing of heart valve substitutes. In: Iaizzo PA, Bianco RW, Hill AJ, St Louis JD (eds) Heart valves: from design to clinical implantation. Springer, New York, pp 283–320 3. Santini M, Ricci RP (2006) The worldwide social burden of atrial fibrillation: what should be done and where do we go? J Interv Card Electrophysiol 17:183–188 4. Cohn JN, Ferrari R, Sharpe N (2000) Cardiac remodeling–concepts and clinical implications: a consensus paper from an international forum on cardiac remodeling. J Am Coll Cardiol 35:569–582

Website Sources (All Websites Were Accessed on December 27, 2014) http://www.uspto.gov http://www.fda.gov/ http://www.google.com/patents? http://www.hhs.gov/healthcare/facts/timeline/index.html http://www.vhlab.umn.edu/atlas/ http://www.vhlab.umn.edu/atlas/device-tutorial/stents http://www.crf.org/tct http://www.crest.umn.edu/

Index

A Abiomed Impella 2.5, 191 Abnormal heart sounds, 315–316 ACC. See American College of Cardiology (ACC) Accelerated cell death, 286 Accelerated idioventricular rhythm, 507 Accelerated junctional rhythm. See Nonparoxysmal junctional tachycardias ACD. See Active compression-decompression (ACD) ACD-CPR device, 708–711 Acetylcholine-mediated atrial fibrillation, 475 Acoustic cavitation, 532 Acoustic density, 386 Acromion, 38 Action potential waveforms active and passive pacing leads, 230 catheter-based cardiac mapping systems, 230 contact mapping, 231 contact/noncontact endocardial mapping technologies, 228 electrode designs and signals, 230 glass micropipette electrodes, 228 internal conductor needle, 230 metal recording electrodes, 229 multielectrode array, 230 noncontact mapping, 231 Activated clotting time (ACT), 619 Active compression-decompression (ACD), 701 Acupuncture, 303–304 Acute coronary syndrome goals of therapy for, 460 treatment guidelines for, 460–461 Acyl-CoA synthetase, 370 AdaptivCRTTM (aCRT), 590 Adenine nucleotide transporter (ANT), 369, 371 Adenosine diphosphate (ADP), 367 cytosol and, 371 oxidative phosphorylation with, 375 Adenosine triphosphate (ATP) diffusion rates of, 371 distal phosphate bonds, 362 generation, 362 synthesis, 362, 369, 370 utilization, 365, 371, 377 Adjunct topical hypothermia, 631–632 Adrenal medulla, 239–240 Adult stem cells bone marrow-derived stem cells, 735–736 skeletal myoblasts, 735 AF. See Atrial fibrillation (AF) Afterload, 340 AHA. See American Heart Association (AHA)

“A Heart to Learn” Youth Educational Program, 450 Aldosterone antagonists, 461, 462 hypertension, 460 Alpha-adrenergic receptor (α-AR), 364 in disease states, 260 physiology, 260 American College of Cardiology (ACC), 639 American College of Cardiology (ACC)/American Heart Association (AHA) guidelines, 357 American College of Cardiology Foundation (ACCF), 458 classification of recommendations, 459 heart failure, 462 level of evidence designations, 458 American Heart Association (AHA), 458, 639, 701 classification of recommendations, 459 heart failure, 462 level of evidence designations, 458 American Society of Anesthesiologist (ASA), 296 American Society of Hypertension (ASH), 459 Ameroid occluder, in canine model, 476, 477 AMP-activated protein kinase (AMPK), 371–373 Amplatzer devices, 686 animal testing, 687 ductal occluder, 686, 690–691 aortogram, 690 pulmonary approach, 693 FDA approval, 688–689 overview, 685 safety, 686–687 septal occluder, 686 muscular ventricular, 691–692 perimembranous ventriculogram, 692–696 right atrial angiogram, 688 translation to humans, 689 Anaerobic glucose metabolism, 369 Anaplerotic process, 367 Anatomic position, 15–17 Anatomy historical perspective, 89–90 importance, 90–91 Anatomy Bequest Program, 752 Anesthesia depth of, 295, 296 heart transplant, 304 induction sequence, 295–296 inhalational (see Inhalational anesthetics) intravenous (see Intravenous anesthetics) medications for, 295 and temperature regulation, 304 Angina pectoris, 141 Angiograms, 357

© Springer International Publishing Switzerland 2015 P.A. Iaizzo (ed.), Handbook of Cardiac Anatomy, Physiology, and Devices, DOI 10.1007/978-3-319-19464-6

795

796 Angioplasty/stenting history of, 263 pathobiology of coronary, 264 Angiotensin-converting enzyme (ACE) inhibitor, 460, 462 Angiotensin receptor blocker (ARB), 459, 460 hypertension, 462 Animal models, 469 heart failure and transplantation, 477–481 in myocardial ischemia, 475–477 for stem cell research, 491 for ventricular assist device testing, 481–486 Animal trials test muscular ventricular septal defect, 692 PDA angled prototype, 690–691 fabric and flexible retention disc, 691 to human use, 690 perimembranous ventricular septal defect, 695–696 Anomalous left coronary artery from the pulmonary artery (ALCAPA), 185 Antegrade brain perfusion, 618 Antegrade cardioplegia, 625 Anterior cardiac veins, 85–87 Anterior interventricular artery, 83, 84, 86, 87 Anterior mediastinum, 49 Anterior thoracic wall, musculature of, 39, 40 Anterolateral commissures, 122 Antiarrhythmic drugs, 556–559, 567, 568 Anticoagulant agent, 460 Anticoagulant therapy, 464 Anticoagulation, 193, 619 Antioxidants, 288 Antiplatelets therapy, 460 Antitachycardia pacing therapy, 565 Aorta ascending arch, 10 principle divisions of, 5 Aortic diameters, 129 Aortic insufficiency murmur, 317 Aortic stenosis, 639–642 Aortic stenosis murmur, 316 Aortic valvar complex, 122 Aortic valvar pathologies, 115 Aortic valve, 106, 115–116 annulus, 129 aortic leaflets, 128–129 aortic root, 127–128 transcatheter, 673 CoreValve system, 675 mitral valve, 675–677 SAPIEN XT, 675 transaortic approach, 674 transapical approach, 674 transfemoral approach, 673 transseptal approach, 674 Aortic valve disease, 639 aortic regurgitation, 642 acute aortic regurgitation, 644–645 aneurysm repair, 644, 645 chronic aortic regurgitation, 643–644 dilation of ascending aorta and, 645 aortic sclerosis, 642 aortic stenosis aortic valve replacement, 641 asymptomatic patient with, 642 balloon valvotomy, 641 cause and degree of, 639

Index detection of, 643 dobutamine stress echocardiography, 642 management, 642 stress testing, 641 symptoms of, 639 transcatheter aortic valve replacements, 641 Aortopulmonary window, 182 Apex coronary sinus, 106 ARB. See Angiotensin receptor blocker (ARB) Arrhythmia, 521, 544 description, 463 electrophysiologic consequences, 495 goals of therapy for, 464 hemodynamic consequences, 495 reperfusion injury, 286 treatment goals, 522 treatment guidelines for, 464–466 Arterial blood pressure, 308–311 Arterial blood pressure monitoring, 403–405 Arterial reflections, 65, 66 Arterial return, 617–619 Arterial sinuses, 119 Arterial tonometry, 310 Arterioles, 363, 365 Artificial electrical stimulation, 547–550 ASH. See American Society of Hypertension (ASH) Aspartate, ischemia and reperfusion injury, 289 Atherosclerosis, 141 Atherosclerotic coronary vascular disease, 475 ATP-sensitive potassium channels (KATP), 364 Atresia pulmonary, 183 tricuspid, 178 Atria adult mammalian hearts, 93–96 FHF contribution, 23–25 SHF contribution, 25–26 Atrial arrhythmias, 590–591 Atrial fibrillation (AF), 590–591 accessory pathways, 517–518 autonomic nervous system, 515 AV nodal ablations for rate control, 513 AVNRT ablations, 516–517 catheter-based Maze procedure, 513 cryoballoon ablations, 515–516 definition, 463 focal ablation, 513–514 paroxysmal, 503 persistent, 503 for preclinical valve testing, 474 genetic engineering, 475 morbidity, 474 pacing-induced atrial fibrillation, 474–475 pharmacologic-induced atrial fibrillation, 475 stem cell therapy, 475 preexcited, 503 pulmonary veins circumferential isolations of, 514–515 segmental ostial isolation of, 514 stroke risk assessment, 464 substrate ablation technique, 515 tachyarrhythmias, 503–506 Atrial fibrillation therapy, 789–790 Atrial flutter catheter ablation, 512–513 tachyarrhythmias, 503, 504

Index Atrial kick, 337 Atrial septal defects (ASDs), 177–178, 686 Amplatzer devices, 687 animal testing, 687 murmur associated with, 318 secundum treatment, 687 transesophageal images, 689 Atrial tachycardias (ATs), 558 focal ablations, 512 paroxysmal supraventricular tachycardias, 498 Atrioventricular (AV) block, 585 bradyarrhythmias, 509 clinical significance, 509 conduction, 494 Atrioventricular (AV) delay, 589 Atrioventricular node cardiac catheterization procedures, 225 characteristics, 226 ventricular rhythms, maintenance and control, 224 Atrioventricular node conditions, 544 Atrioventricular (AV) optimization, 579, 589 Atrioventricular reconstruction, 218, 219 Atrioventricular septal defect (AVSD), 179–180 Atrioventricular valves components of, 116 dysfunction, 118–119 during systole, 117 Atropine treatment, 475 ATs. See Atrial tachycardias (ATs) Attain Command® coronary sinus cannulation catheter, 580 Attain Performa® LV lead, 580 Attain Performa® quadripolar LV lead, 583 Attain SelectTM II sub-selection catheter, 580 Attain Stability® Model 20066 lead, 581 Attain StarFix® Model 4195 lead, 581 Attitudinally correct cardiac anatomy, 15–21 Attitudinally correct position of heart, 17–19 Attitudinally incorrect nomenclature, 19 Atypical atrial flutter, 512–513 Auscultation method, 309 Auscultatory areas, 314–315 Automaticity, 558 Autonomic nervous system adrenal medulla, 239–240 atrial fibrillation, 515 baroreceptors, 240–241 cardiac denervation basal cardiac function, 248 exercise hemodynamics, 248–249 reinnervation, 248 effector pathways, 242–243 heart rate, 243–244 homeostasis, 241 hypothalamic control, 241–242 parasympathetic anatomy, 240 pressure regulation arteriolar, 245–248 baroreceptor, 245 stroke volume and contractility, 244–245 sympathetic anatomy, 237–239 AV block. See Atrioventricular (AV) block AV junctional premature complexes, 496–497 AV nodal ablations for rate control, 513 AV nodal reentry tachycardias (AVNRTs), 498–500, 516–517 AV reentry tachycardias (AVRTs), 500 Axial flow pump impeller, 481

797 Axial-flow pumps, 189, 191 Axial resolution, 386 Azygos factor, 443 Azygos venous system, 43, 49, 50

B Bakken Surgical Device Symposium, 450–451 Balanced fast field echo imaging, 414 Balloon laser catheter, 537–540 Barbiturates, 299–300 Baroreceptors, 10, 240–241 Basal cords, 117 Basket catheter mapping technologies, 604–606 Battery-operated pacemaker, 449 Battery-powered pacemaker, 449, 450 BAV. See Bicuspid aortic valve (BAV) Beast-machine concept (Rene Descartes), 90 Beat-to-beat blood pressure, 403 Benzodiazepines, 300–301 Berlin Heart Excor, 191 Bernoulli equation, 387, 388 Beta-adrenergic receptor (β-AR), 364, 376 activation, 254 and cardiac disease, 258–259 classification, 254 desensitization and downregulation, 258 dromotropic effects, 257 metabolic effects, 257 positive chronotropic effect, 255 positive inotropic effect, 255 positive lusitropic effects, 257 regulation, 257–258 second messenger concept, 255–257 in vasculature, 257 Beta-agonist agents, 30–31 Beta-blockers ACE inhibitor and, 460, 462 hypertension, 460 sudden cardiac death, 464 Bezold–Jarisch reflex, 248. See also Autonomic nervous system Bicuspid aortic valve (BAV), 185 Bicuspid valve. See Mitral valve Bigeminal pulse, 312 Bileaflet prosthesis, 452, 453 Bileaflet valve, 452 Binaural stethoscope, 307 Bio-artificial heart valves, 472 Biochemical cardiac markers, 460 Biomedical devices assessment, 425 cardiovascular interventions, 423–424 implantable cardiac devices, 424–425 Bio-Medicus, 621 Bioprosthetic valves, 756 Biphasic pulse. See Bisferiens pulse Biphasic shock, 566 Bipolar pacing systems, 570, 583 Birmingham solution, 627 Bisferiens pulse, 313 Bivalrudin, 619 Biventricular (BiV) pacing, 579, 585, 590–591 Black-blood imaging techniques, 415 Black-blood techniques, 414 Bland-White-Garland Syndrome, 140 Blanking and refractory periods, 556

798 Blood formed elements, 4 functions, 4–5 types, 399 Blood circulatory system, 10 Blood flow velocity, 420 Blood pressure, 307–308 bigeminal pulse, 312 bisferiens pulse, 313 dicrotic pulse, 313 inhalational anesthetics, 297 invasive methods cannulation sites, 310 catheter over needle technique, 310 complications, 311 considerations, 310–311 indications, 310 real-time ultrasound guidance, 310 Seldinger’s technique, 310 noninvasive methods arterial tonometry, 310 auscultation method, 309 Doppler method, 309 oscillometry, 309–310 palpation, 309 plethysmographic method, 310 physiology of, 308 pulse deficit, 312 pulsus alternans, 312 pulsus paradoxus, 312 pulsus parvus et tardus, 312 wide pulse pressure, 312 Blood pressure monitoring arterial blood pressure invasive, 344 noninvasive, 343–344 pressure transducer system, 346–347 transducer catheters, 347 Body surface potential mapping, 600 Bone marrow-derived multipotent stem cell cardiomyoplasty, 488 Bone marrow-derived stem cells, 735–736 BOOST study, 742 Brachiocephalic veins, 44 Bradyarrhythmia atrioventricular block, 509 causes of, 551 sinus node dysfunction, 507–508 Bretschneider solution, 627 Bretylium tosylate, 480 Bridge to bridge, 188 Bridge to decision, 188 Bridge to recovery, 188 Bridge to transplant, 188, 190–192 Bright-blood cine MRI, 415 Bright-blood techniques, 414 Bronchi, branching pattern of, 55, 56 Bronchopulmonary segment, 55 Bubble oxygenator, 615, 621 Lillehei-DeWall, 444–448 sterile, 448 University of Minnesota, 447 Buckberg’s cold blood cardioplegic solution, 629 Bulb ventricular loop, 175 Bundle of His, 216 in canine heart, 228, 229 cardiac catheterization procedures, 225

Index characteristics, 226 electrophysiologic studies, 227 histological characteristics, 226, 227 regions, 227 ventricular rhythms, maintenance and control, 224 Bundle of Kent, 219

C CABG surgery, 661 Calcification, 472, 485 Calcium channel antagonists, 288 Calcium channel blocker, 459, 460 Calcium paradox, 626 Camman binaural stethoscope, 307 Canine heart, 415 Canine model advantage, 473 ameroid occluder in, 477 bone marrow-derived multipotent stem cell cardiomyoplasty, 488 heart transplantation model, 480 ligated left anterior descending coronary artery, 475, 476 Cannulation sites, 310 Capillary blood flows, 5 classes of, 6 description, 6 primary function, 6 Capillary leak syndrome, 6 Capnometry, 409 Carbon substrate metabolic pathways regulation, 370–372 Cardiac ablation, 216 Cardiac action potentials, 222–223 Cardiac anatomy, 15 Cardiac arrhythmias catheter ablation, 494 bradyarrhythmias, 507–509 clinical presentation, 494–495 diagnosis, 494–495 electrophysiological studies, 509–517 tachyarrhythmias, 496–507 treatment considerations, 495 mechanism of, 494 Cardiac capillaries, 141–142 Cardiac catheterization, 385, 391 Cardiac cell action potentials Ca2+and K+ channel proteins, 211 excitation-contraction coupling, 211 Goldman–Hodgkin–Kat equation, 210 ionic currents, 211, 214 Nernst equation, 210 profiles for ventricular and nodal, 213 adrenergic and receptors in myocardial hypertrophy, 260 alpha-adrenergic receptors, 260 beta-adrenergic receptors activation and cardiovascular function, 254–257 and cardiac disease, 258–259 classification of, 254 regulation, 257–258 energy metabolism, 206–207 force production, 207 and velocity, 209 gap junctions, 204 intercalated disks, 203–204

Index length–tension relationship mechanical coupling, 208 practical applications of, 209 mammalian cell structure, 202 membranes, 202–203, 205 muscle cell branched structure of, 204 morphology, 201–202 myocyte hypertrophy, 209 myofibrillar structure, 204–205 pacemaker cells, 212–213 section of, 203 thick filament, 206 thin filaments, 205–206 Z-disks at ends of sarcomere, 204 Cardiac circumferential strain, in human, 429 Cardiac conduction, 131, 132, 215–221 inhalational anesthetics, 297–298 Cardiac cycle, 335–338 Cardiac defibrillation external cardiac defibrillators, 561 history, 557–558 implantable cardiac defibrillators, 561–562 tachyarrhythmias, 558–559 Cardiac denervation basal cardiac function, 248 exercise hemodynamics, 248–249 reinnervation, 248 Cardiac device, 765 deployment/performance, 751 design characteristics, 766 biocompatibility, 767–768 cardiac pacing, 768 defibrillation, 768 device delivery procedure, 766 durability, 768 functionality, 766–767 manufacturability, 769 off-label use of device, 766 development process, 769 animal and clinical testing, 771 brainstorming, 772 clinical testing, 774–775 concept development phase, 770 device conception, 770 device testing, 773–774 durability and compatibility testing, 771 FDA approval, 768 flow chart, 770 game changers, 769 HDE approval, 775 intellectual property, 770 market released, 771 planning phase, 770 post-market assessment, 771 proof of concept, 772 risk mitigation, 773 in vitro testing, 774 and technologies, 787 catheter-delivered leads/pacemakers, 791 implantable sensors, 791 implantable therapies, 789 implantable therapies: cardiac remodeling, 790 implantable therapies: left atrial appendage/atrial fibrillation therapy, 789–790 medical device, design of, 788

799 procedural improvement in, 791 resuscitation systems and devices, 789 stents, 790–791 training systems, 791–792 Cardiac electrical mapping, 600 Cardiac function, 386 with CRT, 579–580 evaluation of, 400 magnetic resonance imaging, 414–416 understanding and controlling, 757–758 Cardiac hemodynamics CO2 partial rebreathing technique, 408 echocardiography, 407–408 pulse contour wave processing, 409 ultrasonography, 407–408 Cardiac imaging, 791 Cardiac impression, 54 Cardiac lineage hiPSCs (hciPSCs), 735 Cardiac metabolism, 279–280 Cardiac myocytes, functions of, 470 Cardiac neural crest (CNC) contribution, 27–29 Cardiac notch, 54 Cardiac output (CO), 427, 544 estimation, 408, 409 NiCO device, 408 shock types, 406 Cardiac pacing, 547–557 artificial electrical stimulation, 547–550 strength-duration curve, 550 Cardiac patches, 742–743 Cardiac pressure-volume loop afterload, 340 conductance catheter, 342–343 contractility, 338–339 preload, 338 sonomicrometry crystals, 340–342 Cardiac progenitor cells (CPCs), 737 cell surface stem cell marker c-kit, 738 cell surface stem cell marker Sca-1, 739 effluxing Hoechst 33342 dye, 739–740 Islet-1 gene expression, 740 isolation of, 738–740 myocardial regeneration from, 740–741 number of, 738 origins of, 738 tissue culture, 738 Cardiac rate control, 221 Cardiac resynchronization therapy (CRT), 150, 153, 462 atrial arrhythmias, 590–591 atrial fibrillation, 590–591 AV and VV optimization, 589–590 biventricular pacing, 590–591 cardiac function with, 579–580 complications associated with, 582–583 development, 578 duration, morphology, 586–587 implantation, 580–583 LBBB and CHF, 578–579 LV lead position, 587 LV lead position baseline mechanical dyssynchrony, scar, and implications, 587–589 LV lead position scar, and mechanical dyssynchrony, 587 mild, 584–585 moderate to severe, 583–584 patient selection for, 585

800 Cardiac skeleton, 63, 71, 75–77, 95, 116–117 Cardiac tamponade, 48, 65, 165 Cardiac ultrasound clinical applications of fetal echocardiography, 390–391 standard transthoracic examination, 391–392 transesophageal echocardiography, 391 transthoracic echocardiography, 391 three-dimensional imaging technology, 393 ultrasound imaging technology, 393 Cardiac valves aortic valve, 127–129 atrioventricular valves, 117–119 cardiac skeleton, 116–117 clinical imaging of, 132 co-location, 130–132 histologies, 121–122 mitral valve, 122–124 pulmonary valve, 129–130 semilunar valves, 119–121 tricuspid valve, 124–126 Cardiomyocytes, 364, 365, 367 Cardioplegia, 624 adjunct topical hypothermia, 631–632 administration, 629–631 Birmingham solution, 627 Bretschneider solution, 627 glucose-insulin-potassium solutions, 628 principles, 625 solution types, 625–626 St. Thomas II solution, 626 Cardioplegia infusion system, roller pumps of, 629 Cardioplegic arrest, 177 Cardioprotection, 299 Cardiopulmonary bypass (CPB), 176–177, 187, 189, 659 arterial return, 617–619 critical events in, 617, 632 description, 615 heart-lung machine basics, 621–622 priming, 622–623 hemodilution, 620–621 hemodynamics, 623–624 perfusion pressure, 620 side effects CABG surgery, 660–661 coronary artery disease, 660 inflammatory response, 660 OPCABG surgery, 661 systemic inflammatory reaction, 660 temperatures of perfusion, 619–620 venous drainage, 616–617 weaning from, 624 Cardiopulmonary resuscitation (CPR), 701 Cardiovascular disease (CVD) evidence-based medicine, 458 prevalence, 457 risk factors, 458 Cardiovascular implantable electronic devices (CIEDs), 424 MR environment, 424 Cardiovascular physiology, 455–456 Cardiovascular system components, 3–4 blood, 4–5 blood flows, 7–8 blood vessels, 5–7 cardiovascular function regulation, 9–11

Index coronary circulation, 11 heart, 8–9 lymphatic system, 11–12 Cardioversion shocks, 565 Carmeda, 621 Carnitine-acylcarnitine translocase, 370 Carotid sinus, 240 Carotid sinus massage, 507 CARTO® sequential mapping system, 602 CARTO3® System, 601 Cataplerotic process, 367 Catheter ablation cardiac arrhythmias, 494 bradyarrhythmias, 507–509 clinical presentation, 494–495 diagnosis, 494–495 electrophysiological studies, 509–517 tachyarrhythmias, 496–507 treatment considerations, 495 Catheter-based cardiac mapping systems, 230 Catheter-based mapping technique, 600 Catheter-based Maze procedure, atrial fibrillation, 513 Catheter-delivered devices, 790 catheter-delivered leads/pacemakers, 791 stents, 790–791 Catheter-guided stem cell therapy, for myocardial infarction, 489 Catheter over a needle technique, 310 Catheter tip orientation, 522 Catheter-tubing-transducer system, 311 CBF. See Cerebral blood flow (CBF) CDER. See Center for Drug Evaluation and Research (CDER) CDRH. See Center for Devices and Radiological Health (CDRH) CEC. See Clinical Events Committee (CEC) Cell hypertrophy, 29 Cell-to-cell conduction, 223 Cellular cardiomyoplasty animal models for stem cell research, 487 description, 486 ideal cell population, 486 stem cell delivery methods, 487 stem cell engraftment issues, 487 stem cell therapies, functional assessment of, 488 ce-MRI. See Contrast-enhanced MRI (ce-MRI) ce-MRI images, 418–420 Center for Devices and Radiological Health (CDRH), 779 Center for Drug Evaluation and Research (CDER), 779 Central tendon, 38, 41 Central venous O2 saturation monitors, 409 Central venous pressure (CVP) monitoring, 347–350 monitoring in ICU, 403 Centrifugal pumps, 189, 190 CentriMag®, 190 Cerebral blood flow (CBF), 702 Cerebral perfusion pressure (CePP), 704, 706 Cervicothoracic ganglion, 47 Chagas disease, 495 CHD. See Coronary heart disease (CHD) Chemiosmotic theory, 375 Chemoreceptors, 10 Chronic disorders, 457 CIEDs. See cardiovascular implantable electronic devices (CIEDs) Cine loop, 415 temporal resolution, 416 Circle of Vieussens, 84

Index Circulatory support pumps axial-flow pumps, 189 centrifugal pumps, 189 counter-pulsation pumps, 189 pulsatile volume-displacement pumps, 189 Class Ia antiarrhythmic drugs, 556 Class III antiarrhythmic drugs, 556 Clicks, 316 Clinical Disorders of the Heart Beat, 323 Clinical Events Committee (CEC), 785 CNAP. See Continuous noninvasive arterial blood pressure (CNAP); Continuous noninvasive arterial pressure (CNAP) CNC. See Cardiac neural crest (CNC) contribution Coarctation of aorta, 182–183 Cold blood cardioplegia, 626, 629 Color Doppler flow mapping, 388 Common bundle. See Bundle of His Computed tomography (CT) imaging, 678 Concentric hypertrophy, 209 Conductance catheters, 342–343 Conduction velocity, 223, 244 Congenital cardiac disease, 470 Congenital heart disease atrial septal defects, 177–178 AVSD, 179–180 cardiopulmonary bypass, 176–177 coronary artery anomalies, 185 D-loop, 176 double outlet right ventricle, 183–184 great arteries aortopulmonary window, 182 coarctation of aorta, 182–183 interrupted aortic arch, 183 persistent truncus arteriosus, 181–182 transposition of, 180–181 L-looping, 176 obstructive left heart lesions bicuspid aortic valve, 185 hypoplastic left ventricle, 185 mitral valve anomalies, 185 subaortic ridge, 185 open-heart surgery in, 440 pulmonary atresia, 183 pulmonary venous anomalies, 184 systemic venous anomalies, 177 tetralogy of Fallot, 183–184 ventricular septal defects, 178–179 Congestive heart failure (CHF), 578, 583–585. See also Ventricular assist devices (VADs) Constellation® multielectrode basket catheter, 604 Contact force, 527–529 Contact/noncontact endocardial mapping technologies, 228 Continuous capillaries, 6 Continuous glucose monitoring, subcutaneous, 409 Continuous mapping systems, 601, 604 basket catheter mapping technologies, 604–606 noncontact mapping technologies, 606–609 Continuous murmur, 315 Continuous noninvasive arterial blood pressure (CNAP), 404 Continuous noninvasive arterial pressure (CNAP) finger arteries, 404 measurement, 403 Continuous wave Doppler, 387 Contractile activity, 121 Contractility, 338–339

801 Contrast-enhanced MRI (ce-MRI), 418 Conventional cardiac surgery, 659, 660 CO2 partial rebreathing technique, 408 Coracoid process, 38 CoreValve system, 675 Coronal plane, 15, 16 Coronary arterial circulation, 91, 100 Coronary arterial circulation of human, 91, 100 Coronary arterial system, 363 Coronary arteries, 62, 76 abnormal anatomy, 140 anatomical description, 139 circumflex artery, 140 coronary artery bypass graft, 149 3D contrast-computed tomography images, 157 disease angina pectoris, 141 atherosclerosis, 141 myocardial infarction, 141 pharmacological approaches, 141 plaques, 141 epicardial fatty deposits and, 154 left anterior descending artery, 140 left coronary artery, 83–84 left coronary artery and branches, 139–140 microanatomy, 146 percutaneous transluminal coronary angioplasty balloon catheter, 149–150 restenosis of, 149 right coronary artery, 82–83 right coronary artery and branches, 140 STAR, 149 stenting procedure, 149 Coronary artery anomalies, 185 Coronary artery bypass grafting (CABG), 660–661 Coronary artery development, 29 Coronary artery imaging, 393 Coronary blood flow, 298 Coronary care unit, 400 Coronary circulation, 11 signaling pathways regulation, 364 Coronary heart disease (CHD), 458 Coronary perfusion pressure (CPP), 701 incomplete chest wall recoil, effects, 704–705 ITD, 701–704 ITPR therapy, 720, 721 Coronary sinus, 69, 70, 84–86, 106 Coronary sinus ASDs, 177 Coronary sinus venography, 580 Coronary steal syndrome, 298 Coronary vascular system anastomoses, 146–148 blood flow, 137–139 cardiac capillaries, 141–142 collaterals, 146–148 coronary arteries abnormal anatomy, 140 anatomical description, 139 disease, 140–141 left coronary artery, 139–141 microanatomy of, 146 right coronary artery, 140 coronary veins anatomical description, 142 disease, 146 major cardiac venous system, 142–145

802 Coronary vascular system (cont.) microanatomy of, 146 valves, 145–146 differences between coronary arteries and veins, 137, 147 engineering parameters and design, 151 anatomical parameters assessment, 156 branch angle, 155 clinical relevant anatomy, 155–156 cross-sectional profile, 152 diameter, 151 motion characteristics, 155 ostial anatomy, 152–153 relationship with mycardium, 154 tortuosity, 153–154 vessel length, 153 wall thickness, 154 and medical devices for coronary arteries, 149–150 for coronary veins, 150–151 long-term device, 151 visualization, 148–149 Coronary veins, 137–139 abnormal anatomy, 145–146 anatomical description, 142 anterior interventricular vein, 143 great cardiac vein, 143 inferior vein, 144 lateral vein, 144 middle cardiac vein, 144 oblique vein of left atrium, 144 posterior interventricular vein, 144 right marginal vein, 144 sinus, 143 small cardiac vein, 144 Thebesian vein, 145 valve of Vieussens, 143 CRT and pacing for, 150 3D contrast-computed tomography images, 157 disease, 146 epicardial fatty deposits and, 155 lead extraction and, 151 local electrograms, 150 microanatomy, 146 valves, 145–146 Costal demifacets, 36 Costal facets, 36 Costal pleura, 53, 56 Costodiaphragmatic recess, 53, 58, 59 Counter-pulsation pumps, 189 CPCs. See Cardiac progenitor cells (CPCs) CPP. See Coronary perfusion pressure (CPP) CPR. See Cardiopulmonary resuscitation (CPR) Creatine kinase shuttle hypothesis, 371 Cristae, 369 Cross-circulation, 443–444, 615 diagram of, 446 for intracardiac operations, 443 CRT. See Cardiac resynchronization therapy (CRT) Cryoablative technologies, 529–532 Cryoballoon ablations, atrial fibrillation, 515–516 Cryoballoon catheters, 531 Cryoconsole, 530 Cryotherapy applications, 530–532 complications and clinical outcomes, 532 Cryothermal ablation, 529–532

Index Cryothermal injury, 529 Crystalloid cardioplegic solutions, 626–628 Crystalloid solutions, 623, 626, 628 Current density theory, 548 Custodiol solution. See Bretschneider solution CVD. See Cardiovascular disease (CVD) Cytosol, 364, 367, 371, 377

D Dacron graft for aortic root replacement, 647 Data Safety Monitoring Board (DSMB), 785 3D cardiac electrical imaging (3DCEI) approach, 601, 609 3DCEI approach. See 3D cardiac electrical imaging (3DCEI) approach Deep hypothermia, 618, 619 Defibrillation shocks, 565 Delayed ce-MRI, 419 Del Nido cardioplegia, 628 Deltopectoral groove, 38 Deltopectoral triangle, 39 Demand ischemia, 379, 381 Department of Physiology, 439, 455 Department of Surgery at University of Minnesota, 439, 441 Depolarizing muscle relaxant, 303 Descending thoracic aorta, 42, 51 Desflurane, 298 Design of Medical Devices (DMD) Conference, 454 Dexmedetomidine, 303 Dextro-transposition of the great arteries (d-TGA), 180 Diabetes, 248 Diagonal arteries, 84 Diastole, 9 Diastolic blood pressure, 308, 309, 311 Dicrotic pulse, 313 Dielectric hysteresis, 535 Diffusion tensor MRI (DTMRI) fiber structure, 422 normal human heart, 423 Digital stethoscopes, 320 Dihydroxyacetone phosphate, 365 Direct current (DC) ablation, 522 Direct drive method, 190 Direct epicardial-myocardial injection, 487 Diuretics, 459 hypertension, 460 D-loop, 176 Dog coronary arterial circulation, 91, 100 heart anterior aspect of, 91, 92 atrioventricular conduction systems, 103 cranial aspect of, 93, 95 opened right ventricular cavity, 69, 96, 99 triangle of Koch, 101, 102 ventricular cavities, 96, 97 weight to body weight ratios, 91 Doppler echocardiography, 388 Doppler effect, 309 Doppler method, for blood pressure, 309 Doppler principle, 387 Doppler ultrasound, 387, 391 Double outlet right ventricle (DORV), 180, 183–184 DSMB. See Data Safety Monitoring Board (DSMB) DTMRI. See Diffusion tensor MRI (DTMRI) Dual-chamber endocardial lead configurations, 569 Dual-chamber endocardial pacing system, 547, 548

Index Dual-chamber timing diagram, 555 Dual pathway electrophysiology, 217 Dynamic auscultation, 316 Dynamic distribution volume, 431

E EAM. See Electroanatomical mapping (EAM) technologies Early cardiac device prototype testing, 90 Early diastolic murmur, 317 Early systolic murmur, 318 EAS. See Endoscopic ablation system (EAS) Ebstein’s anomaly, 178 Eccentric hypertrophy, 209 ECG. See Electrocardiography (ECG) Echocardiography, 641, 685 cardiac hemodynamics, 407–408 field development, 385 imaging modalities color Doppler flow mapping, 388 continuous wave Doppler, 387 Doppler ultrasound, 387 M-mode echocardiography, 386–387 myocardial performance index, 388–389 pressure gradients using Doppler echocardiography, 388 pulse wave Doppler, 387 TAPSE, 389 tissue Doppler imaging, 389–390 two-dimensional imaging, 387 physical principles resolution of structures, 386 ultrasound imaging of tissues, 386 standard transthoracic examination, 391–393 techniques of, 388 transesophageal imaging, 391 transthoracic imaging, 391 transvaginal and transabdominal fetal, 390–391 Echocardiography Guided Cardiac Resynchronization Therapy (EchoCRT) study, 585 Ectopic focus, 221 Ectopic pacemaker, 221 ECVUE system, 601, 609, 610 Einthoven’s triangle, 323, 325–327, 329, 330 Eisenmenger’s syndrome, 178 Ejection clicks, 316 Ejection fraction, 427 calculation, 387 normal values for, 387 EKG, 400 Electric field theory, 548 Electroanatomical mapping (EAM) technologies, 602–603 Electrocardiographic Imaging (ECGI) technology, 609, 611 Electrocardiography (ECG), 385 computers for analysis, 332 devices, 322 history of, 322–324 interpretation of, 331 lead placement in clinical setting, 331–332 long-term recording devices, 332–334 measuring bipolar limb leads, 325–327 electrical axis of heart, 327–329 12-Lead ECG, 329–330 purposes of, 321–322 waveform, 324–325 Electron beam computed tomography (EBCT), 148

803 Electronic auscultation, 318 Electron transport chain (ETC), 369, 372 and oxidative phosphorylation, 374–375 regulation, 375–377 Electrophysiological (EP) mapping procedures, 600 clinical study, 600 limitations, 600 Electrophysiological study (EPS), catheter ablation, 509 AFib, 513–518 atrial flutter, 512–513 focal atrial tachycardias, 512 His-Purkinje system, 509–510 indications, 511 ISTs, 511–512 VTs, 518–519 Electrophysiology (EP) catheter, 580 Electrophysiology recording catheter, 527 Embryoid bodies, 734 Embryonic stem cells (ESCs) human, 734–735 mouse, 734 End-diastolic phase, 426 Endocardial defibrillation leads, 572 Endocardial defibrillation systems, 569 Endocardial injection, 487 Endocardial mapping, 600, 605 Endocardial pacing leads, 569 Endocardial pacing systems, 547, 568 Endocytosis, 6 Endoscopic ablation system (EAS) cardiac laser ablation system design, 538 clinical use and safety aspects, 539–540 vs. cryoballoon therapy, 529 laser energy and cardiac ablations, 538–539 touchscreen display, 539 Endothelial outgrowth cells, 737 Endothelial progenitor cells (EPCs), 737 Endothelium, 65 Endotracheal intubation, 296, 302 End-stage cardiac failure, treatment of, 478 EnGuide® locator technology, 606 EnSite NavX technology, 606 EnSite® system, 231 EnSiteTM ArrayTM noncontact mapping catheter, 601, 606 EnSiteTM NavXTM EAM system, 608 EnSite VelocityTM System, 601, 606 Entrainment technique, 519 Eparterial bronchus, 55 EPCs. See Endothelial progenitor cells (EPCs) Epicardial defibrillation systems, 570 Epicardial leads, 546 Epicardial mapping, 600 Epicardial pacing leads, 568, 570 Epicardium, 47 Epigastric fossa, 58 Erythrocytes. See Red blood cells ESCs. See Embryonic stem cells (ESCs) Etomidate, 302–303 Evidence-based medicine, cardiac pharmacotherapy, 458 Exocytosis, 6 External cardiac defibrillators, 561 Extracellular crystalloid solutions, 625, 626 Extracellular electrograms, 600 Extracorporeal circuit components, 616 Extracorporeal circulation, 443, 615 Extracorporeal membrane oxygenation (ECMO), 187, 188, 190, 193

804 F Facets, 36 Failing hearts, 381–382 False ribs, 36 Fan cords, 117 Fast spin echo imaging, 413 Fast ventricular tachycardia zone, 563 Fatty acid metabolism, 369–370, 375 Fenestrated capillaries, 6 Fentanyl, 298 Fetal echocardiography, 390–391 Fiber structure diffusion tensor MRI, 422, 423 myofiber orientation, 421–422 pathological changes in, 422 Fibrinolytic pharmacologic therapy, 461 Fibrosa, 121 Fibrous pericardium, 46, 48 Fibrous ridge, 123 Film oxygenators, 444 Finger artery, 404 Finger cuff technology, 403 FIRMapTM catheter, 605 panoramic contact-mapping tool, 605 First heart sound, 313 Flask-shaped bag. See Pericardium Flip angle, 412 Floating ribs, 37 FloTrac/VigileoTM system, 407 Flow monitoring, 356–357 Focal ablation atrial fibrillation, 513–514 atrial tachycardias, 512 Fontan circulation, 178 Food and Drug Administration (FDA), 449 Medical Device Reporting, 453 Food and Drug Administration (United States), 779 Foramen ovale, 74, 77, 80, 81, 93 Formaldehyde, 752 Fossa ovalis, 93 Fourth heart sound, 314 Frank–Starling mechanism, 9 Free fatty acids, 372 Free induction decay, 412 Fructose-6-phosphate, 365 Full cardiopulmonary bypass, 617 Functional biomedical studies (William Harvey), 90

G G-aminobutyric acid (GABA) receptor, 299 Ganglion, 88 Gap junctions, 217, 223–224 Gas technology, 355 GCP. See Good clinical practice (GCP) General anesthesia, 296 Genetic myocardial metabolic abnormalities, 382 GENius Radiofrequency Generator, 524, 526 Gibbon-IBM heart-lung machine, 187 Glass micropipette electrodes, 229 Glenn anastomosis, 177 Glucose, cellular uptake, 366 Glucose–Insulin–Potassium ischemia and reperfusion injury, 288 solutions, 627, 628

Index Glucose metabolism of heart, 365–369 Glucose-6-phosphate, 365 Glutamate, 289 Glutaraldehyde, 752 Glutaraldehyde-fixed pericardium, 169 GLUT 4 transporter, 370 Glyceraldehyde-3-phosphate, 365 Glycolysis, 367, 370, 373, 374, 379 Glycolytic pathway, 367, 373 Good clinical practice (GCP), 780 GoogleTM patent search website, 788 G-protein-coupled receptor coupling, 253 function and regulation, 254 structure, 252–253 Gradient echo (GRE) definition, 413 global cardiac function, 414–416 image contrast, 414 with magnetization preparation, 414 technique, 414 Graft types, 478 Gray rami communicantes, 51 GRE. See Gradient echo (GRE) Great arteries aortopulmonary window, 182 coarctation of aorta, 182–183 interrupted aortic arch, 183 persistent truncus arteriosus, 181–182 transposition of, 180–181 Great vessels, 48–49 membrane guanylyl cyclase A, 262 physiology, 262–263 role in cardiac disease, 263 soluble guanylyl cyclase, 261–262 Guanylyl cyclase-linked receptors CD40-CD40L signaling, 271 cross talk between receptors, 261 membrane guanylyl cyclase A, 262 muscarinic receptors, 260–261 physiology, 262–263 role in cardiac disease, 263 soluble guanylyl cyclase, 261–262 GUARd During Ischemia Against Necrosis (GUARDIAN), 287 Guideline-directed medical therapy (GDMT), HF, 462

H Harmonic phase (HARP) MR technique, 429 HARP MR technique. See Harmonic phase (HARP) MR technique Heart, 59 anterior surfaces of, 18, 20, 21 autonomic innervation, 239 autonomic innervation of, 87–88 blood flow pathway, 8 carbon substrate and oxygen delivery, 362–363 carbon substrate metabolic pathways regulation, 370–372 cardiac skeleton, 77 electron transport chain and oxidative phosphorylation, 374–375 fatty acid metabolism, 369–370 fetal circulation, 77, 78 fetal remnants atrial septal defect, 79–81 Chiari network, 79 ventricular atrial septal defect, 81–82 function of, 635

Index functions, 62 glucose metabolism, 365–369 inferior/diaphragmatic surfaces, 18, 19 internal anatomy, 65–67 cardiopulmonary circulation, 67 cross-section, 65 left atrium, 73–74 left ventricle, 74–77 right atrium, 67–71 right ventricle, 70–73 left ventricle and atrium, 21 mitochondrion, 369 myocardial blood flow regulation, 363 myocardial carbon substrate selection, 372–373 myocardial contractions, 9 pericardial fluid, 8 pericardium, 8 position in thorax, 62–64 posterior surfaces of, 18 properties, 9 pumping principles, 8 right ventricle and atrium, 20 superior surfaces of, 19 sympathetic neural reinnervation, 248–249 tricarboxylic acid cycle, 373–374 valves of replacement, 635 valvular diseases (see Mitral valve disease) vasculature cardiac veins, 84–87 left coronary artery, 83–84 myocardial bridges, 87 right coronary artery, 82–83 ventricular chambers, 17 Heart attack, 139, 148 Heart block, and pacemaker, 448–451 Heart failure (HF) classification types, 461 definition, 461 goal therapy, 461 management of, 462 neurohormonal activation in, 462 in pediatric patients, 188 treatment guidelines for, 462–463 Heart Leaflet Technologies, 452, 677 Heart-lung machine, 441, 444 basics, 621–622 priming, 622–623 HeartMate II, 191, 192 HeartMate III, 194 HeartMate II LVAD, 729 HeartMate SNAP-VE, 727 HeartMate X, 194 Heart rate control, inhalational anesthetics, 297–298 Heart sounds, 313–314 Heart transplant, anesthesia, 304 Heart valve clinical trials class III life-sustaining devices, 777 cycle/process, 780 complications, 785–786 development of design, 780–781 enrolled patients, data collection for, 783–784 execution, 782–783 FDA guidance document, 783 follow-ups, 784 site selection, 782

805 Ethics Committee, 779 Institutional Review Board, 779 investigator, 778 monitors, 778 purpose of, 771 regulatory agency, 779 Europe, notified bodies, 779–780 FDA, United States, 779 good clinical practice, 780 sponsors, 779 types of, 778 Heart valves replacement, device qualities for, 472 University of Minnesota, 451–452 Heartware HVAD™, 192 HeartWare MVAD pump, 193, 194 Hematocrit, 4, 620 Hemodilution, 620–621 Hemodynamics, 623–624 Hemoglobin, 4 Hemolysis, 472, 483 Heparin-induced thrombocytopenia (HIT), 619 Heparinoids, 619 Heparin types, 619 Hepatocyte growth factor (HGF), 736 hESC-derived cardiomyocytes (hESC-CMs), 735 Heterotopic cardiac transplantation, 478–480 HF. See Heart failure (HF) HGF. See Hepatocyte growth factor (HGF) Hibernating myocardium, 280, 284 Hibernation induction trigger (HIT), 289 High-frequency transducers, 393 High-intensity focused ultrasound balloon catheter (HIFU BC), 533–534 High-resolution images, 753 hiPSC-derived endothelial cells (hiPSC-ECs), 735 hiPSCs into smooth-muscle cells (hiPSC-SMCs), 735 His-Purkinje system bundle branches, 519 EPS, catheter ablation, 509–510 measurements, 510 Histology stains, 486 Holosystolic murmur, 318 Holter monitor, 324, 332 Homeostasis, 241 Hormonal regulatory system, 10 Human embryonic stem cells, 734–735 Human heart anterior aspect of, 91, 92 anterior surface, 104 atrioventricular conduction systems, 103 electrophysiologic properties, 228, 229 embryology and developmental timeline, 23–25 end-diastolic volumetric reconstruction, 105 mitral vs. aortic valve, fibrous continuity, 100 opened right ventricular cavity, 97, 99 triangle of Koch, 101, 102 tube fusion, cross-sectional view of, 25, 28 ventricular cavities, 96, 97 weight to body weight ratios, 91 Human induced pluripotent stem cells (hiPSCs), 735 Humanitarian device exemption (HDE), 775 Human primary linear heart tube, 25, 27 Human resting sinus heart rate, 521 Hyperacute rejection, of pig heart, 481 Hyperautomaticity, 558 Hyperglycemia, 409

806 Hypertension, 308, 350 agents with compelling indications, 460 goals of therapy for, 458–459 JNC8 guidelines, 459 treatment guidelines for, 459–460 in United States, 458 Hypertrophied hearts, 381–382 Hypertrophy, 738 Hypocalcemia, 283 Hypoplastic left heart syndrome (HLHS), 185, 396 Hypotension, 308, 711 Hypothalamus, 241–242 Hypothermia, 441, 704, 707

I ICU. See Intensive care unit (ICU) Idiopathic hypertrophic subaortic stenosis (IHSS), 340 Image acquisition, 413, 414, 416 Immature myocardium, 30 Impedance threshold device (ITD), 701 ACD-CPR device, 701–704 AHA guidelines, 701 chest compression, 701, 702 CPR, 701–704 cracking pressure, 713 hyperventilation, 702 ICPs, 702 LBNP chamber, 715 low blood pressure, 717 lowering intrathoracic pressure, 717 PEA, 702 porcine hemorrhagic model, 714 ROSC, 704 spontaneously breathing version, 713 systolic blood pressure, 713 Implantable cardiac devices, 424–425 Implantable cardioverter defibrillators (ICDs), 424, 425, 462–463, 578, 583, 584–586, 588 capacitor function, 562 clinical trials, 568 components, 561 evolution, 559 vs. implantable pulse generator, 546 indications, 559 recommendations, 545 sensing and detection, 562–565 shock waveforms, 566 silver vanadium oxide battery, depletion curve, 562 therapies, 561 workings, 561 Implantable defibrillation system, 547 Implantable pacing and defibrillation systems, 546–547 Implantable pulse generator (IPG), 546, 548 vs. implantable cardioverter defibrillator, 546 Implantable sensors, 791 Implantable therapies, 789 cardiac remodeling, 790 left atrial appendage/atrial fibrillation therapy, 789–790 Impulsive maverick, 440 Inappropriate sinus tachycardia (IST) catheter ablation, 511–512 diagnosis, 497 Incisional atrial tachycardia, 513 Infection, 195 Inferior vena cava (IVC), 177

Index Inflammation cross talk between thrombosis and, 270 molecular signaling and vascular interventions, 270–272 Inhalational anesthetics blood pressure and systemic vascular resistance, 297 cardiac conduction system and control of heart rate, 297–298 cardioprotection/preconditioning, 299 cardiovascular effects of, 298 chemical structure of, 297 contractility and cardiac output, 298–299 coronary blood flow, 298 minimum alveolar concentration, 296–297 myocardial preconditioning with, 304 pulmonary blood flow, 299 In-life stage, pathology, 483 Insertion length, 124 Instantaneous stroke volume, 544 Institute for Engineering in Medicine (IEM), 454 Institutional Animal Care and Use Committee (IACUC), 473 Insulin-like growth factor (IGF-1), 735, 739 Integrated bipolar lead, 570 IntellaMap OrionTM high resolution mapping catheter, 605 Intensive care unit (ICU) goals of monitoring cardiac function evaluation, 400 Cochrane database systems review, 402 diagnosis of shock, 400 randomized nonblinded study, 402 vasoactive therapy titration, 400–401 invasive monitoring techniques arterial blood pressure monitoring, 403–405 cardiac hemodynamics, 407–408 complications, 406–407 CVP monitoring, 403 monitoring techniques in, 400, 403 perfusion monitors, 408–409 pulmonary artery catheterization, 405–406 resuscitation clinical end points, 400 ultrasound machine in, 408 use of, 400 telemedicine, 402–403 Intercalated discs, 65, 121, 223 Intercellular crystalloid solutions, 626 Intercostal muscles, 40 Intercostal nerves, 41 Intercostals arteries and nerves, 42 Interleukin-1beta (IL-1beta), 269 Internal jugular vein, 403 Interrupted aortic arch (IAA), 183 Interstitial Cajal-like cells, 231 Intervalvar septum, 98 Interventional MRI, 411 Interventricular septum (IVS), 682 Intracranial pressure (ICP), 702, 705 Intrathoracic pressure (ITP), 700, 701, 704 Intrathoracic pressure regulation (IPR) therapy, 699 effects, 720 Intravascular ultrasound (IVUS), 148, 393, 395 Intravenous anesthetics acupuncture, 303–304 barbiturates, 299–300 benzodiazepines, 300–301 cardiovascular effects of, 298 depolarizing muscle relaxant, 303 dexmedetomidine, 303 etomidate, 302–303

Index ketamine, 301 myocardial preconditioning with, 304 nondepolarizing muscle relaxants, 303 opioids, 301propofol, 302 Intussusception process, 28 Invasisve arterial pressure monitoring systems, 310–311 Invasive monitoring techniques in ICU arterial blood pressure monitoring, 403–405 cardiac hemodynamics, 407–408 complications, 406–407 CVP monitoring, 403 monitoring techniques in, 400, 403 perfusion monitors, 408–409 pulmonary artery catheterization, 405–406 resuscitation clinical end points, 400 ultrasound machine in, 408 use of, 400 Inverse problem of electrocardiography, 601 Inversion pulse, 412 In vitro isolated heart models, 754–755 Irrigated tip RF catheter, 526 Ischemia injury acute and global assessments, 291 antioxidants, 288 calcium channel antagonists, 288 glucose–insulin–potassium, 288 glutamate/aspartate, 289 growth factors, 288–289 hibernation-specific proteins, 289 Na+/H+ exchange blockers, 287 nitric oxide, 289 pharmaceutical agents, 289–290 Ischemic cardiomyopathy (ICM), 578–579, 583 Ischemic heart disease adult stem cells cardiac progenitor cells, 737–740 endothelial progenitor cells, 737 mesenchymal stem cells, 736–737 umbilical cord blood stem cells, 737 VT ablations of, 518–519 Ischemic myocardium, 379–381 Ischemic preconditioning, 281, 282, 284 Ischemic stroke, 464 Ischemic syndromes, 280–283 heart protection from, 284–285 hibernating myocardium, 284 ischemic preconditioning, 284 maimed myocardium, 284 myocardial stunning, 283 silent ischemia, 284 Islet-1 gene expression, 740 Isochronal activation map, 608 Isochronal maps, 608 ISO 5840 document, 483 Isolated cardiomyocytes, 470 Isolated heart models anatomical specimens and static imaging, 752 four-chamber working mode, 755 preparations bench top experimental setting, 755–756 Visible Heart® methodologies, 756 right-side working mode, 755 species selection, 756–757 understanding/controlling heart function in vitro, 757–758 in vitro, 754–755 Isolated perfused heart models, 470–472

807 Isopotential activation map, 608 Isopotential maps, 600, 608 IST. See Inappropriate sinus tachycardia (IST) ITD. See Impedance threshold device (ITD) ITPR therapy, 717 benefits, 719 blood volumes, 719 cardiac arrest, 717 effects, 718 ETP, 718, 719 lower intrathoracic pressure, 718 MAP, 716, 717 IVS. See Interventricular septum (IVS)

J Jostra Rotaflow®, 190 Joules–Thomson effect, 529 Junctional escape rhythm, 509

K Kawasaki syndrome, 393 Ketamine, 301–302 Koch’s triangle, 216 Korotkoff sounds, 309 Kugel’s artery, 83

L Laminae, 36 Langendorff perfusion method advantage, 471 disadvantage, 471 Large mammalian cardiovascular research models, qualitative vs. quantitative cardiac anatomy heart preservation, 102 importance of, 101–102 materials, 102 perfusion-fixed hearts assessment, 103–104 previous studies, 110–112 qualitative results, 105–108 quantitative results, 108–110 Larmor frequency definition, 412 magnetic resonance imaging, 412–413 nuclear dipole precesses at, 413 Laryngoscopy, 296 Late diastolic murmur, 315 Lateral resolution, 386 Late systolic murmur, 315 LCO. See Left coronary artery ostium (LCO) 12-lead electrocardiography (ECG), 495 Leadless pacemakers, 572–574 LeCompte maneuver, 181 Left anterior descending artery, 17, 20 Left atrium, 61 Left bundle branch block (LBBB), 578–579 Left circumflex artery, 20 Left coronary artery (LCA), 19, 20, 185 Left coronary artery ostium (LCO), 682 Left heart bypass technique, 618 Left-sided superior vena cava (LSVC), 177 Left ventricle aortic semilunar valve, 75–77 bicuspid (mitral) valve, 74–75

808 Left ventricle (cont.) FHF contribution, 23–25 role, 61 Left ventricular assist device (LVAD), 188, 191, 196, 482, 725–728. See also Ventricular assist devices (VADs) Left ventricular ejection fractions (LVEF), 578, 580, 583 Left ventricular (LV) lead position, 587 baseline mechanical dyssynchrony, scar, and implications, 587–589 scar, and mechanical dyssynchrony, 587–589 unipolar and bipolar, 582 Left ventricular mass, 427 Less invasive cardiac surgery, 659 aorta manipulation, 661 aortic non-touch techniques, 666 aortic valve replacements, 662–665 cardiopulmonary bypass, side effects, 660–661 conventional cardiac surgery, 659, 660 endoscopic robotics, 667–668 future aspects, 668–669 incision size, 660 OPCABG surgery, 665–666 sternum-sparing surgery, 662 Leukocytes. See White blood cells LHI Lecture Series, 450 LICU®. See Low-intensity collimated ultrasound ablation system (LICU®) LiDCO monitor, 407 LifeScience Alley, 453–454 Life-threatening hypotension, 711–717 Lillehei–DeWall bubble oxygenator, 444–448 Mayon polyethylene tubing, 447 silicone antifoam solution, 447 Lillehei Endowed Scholars Program, 450 Lillehei Heart Institute (LHI) description, 450 efforts of, 450 Linear heart tube, FHF contribution, 23–25 Linear images, 386 Lingula, 54 Lithium iodide battery, 553, 562 L-looping, 176 Local blood flow, 8 Local drug delivery, 466 LocaLisa® sequential mapping system, 601, 603–604 Lone atrial fibrillation, 505 Loop recorder, 332–334 Lower body negative pressure chamber (LBNP), 715, 716 Lowers intracranial pressures (ICPs). See Intracranial pressure (ICP) Low-intensity collimated ultrasound ablation system (LICU®), 534 L-transposed great vessels, 176, 178 Lungs, 54–56 anterior border, 54 bronchi, 54 costal surface, 54 diaphragmatic surface, 54 divisions, 54 function of, 54 inferior border, 54 lymphatic drainage, 56 mediastinal surface, 54 posterior border, 54 pulmonary artery, 55 surface anatomy of, 54 LV apex, 106 Lymphatic drainage pattern, 56 Lymphatic system, 11–12

Index M Macrophage colony-stimulating factor (M-CSF), 269 Magnetic field, 412 Magnetic resonance angiography (MRA), 149 Magnetic resonance imaging (MRI) assessment of biomedical device performance, 425 benefit of, 412 blood flow velocity, 420 cardiac morphology, 414 for cardiovascular interventions, 423–424 echo, 413–414 fiber structure diffusion tensor MRI, 422, 423 myofiber orientation, 421–422 pathological changes in, 422 global cardiac function, 414–416 image contrast, 414 implantable cardiac devices, 424–425 late gadolinium enhancement on, 588 myocardial perfusion, 417–418 myocardial viability, 418–420 overview of, 412–414 quantitative analyses, 425 myocardial perfusion, 429–431 myocardial scar size, 432 regional myocardial strains, 429 relative wall motions, 427–428 ventricular function, 426–427 reanimating human hearts, 751 regional myocardial function, 417 resonance, 412–413 Magnetron, 540 Mahaim fibers, 219 Maimed myocardium, 281, 284 Main septal artery, 84 Malignant hyperthermia, 295, 299 Malonyl-CoA, 371, 372 Mammalian cardiac myocyte, 222, 223 Mammalian heart anatomical and functional perspectives, 93 atria, 93–96 cardiac valves, 97–99 conduction system, 101 coronary system, 99–100 lymphatic system, 100–101 pericardium, 92–93 ventricles, 96–97 Manganese contrast agents, 420 Marburg Attacher, 170 Mariner catheter, 153 Mayo Clinic, 752 heart–lung machine, 446 Mayo-Gibbon machine, 188 Mayon polyethylene tubing, 447 Maze procedure, 505 MCP-1, 269 Mean arterial pressure (MAP), 719, 720 Mean blood pressure, 308 Mean transit time, 431 Mechanical dyssynchrony, 585 and LV lead position, 587–589 Mechanical heart valves, 472 Mechanical valve fluid dynamic testing, 474 The Mechanism of the Heart Beat, 323 Mediastinal bleeding, 195 Mediastinum, 62

Index Medical Device Amendments to the Federal Food, Drug, and Cosmetic Act, 453 Medical Device Reporting, 453 Medical Devices Center (MDC), 454–455 MediGuideTM system, 608 Medos HIA VAD, 192 MedTech Investing Conference, 454 Medtronic Inc., 449, 451, 456, 458 Medtronic Mosaic® stented tissue valve, 473 Membrane oxygenator, 621 Membranous septum, 98 Mesenchymal stem cells (MSCs) for myocardial repair, 736–737 phenotype and differentiation potential, 736 Mesothelium, 64 Methohexital, 300 MicraTM Transcatheter Pacing System, 572, 573 Microcirculation, 6 MicroFidelity (MiFi) Sensor Technology, 527 Microplegia, 628 Microvascular damage, 286–287 Microwave ablation advantage, 535 catheter, 537 complications and clinical applications, 537 mechanism of, 535–536 microwave generators, 536–537 Middiastolic murmur, 318 Middle lobe, 54 Middle mediastinum, 61, 62 contents of, 43 great vessels, 48–49 pericardium, 47–48 phrenic and vagus nerve course, 45 position of heart, 47 vessels of, 44 Midspinal line, 58 Midsternal line, 58 Midsystolic murmur, 317 Midvertebral line, 58 Mild hypothermia, 620 Millar catheters, 347 Minimum alveolar concentration (MAC), 296–297 Minnesota Supercomputing Institute, 455 6-minute hall walk distance (6MWD), 583–585, 587–590 MIRACLE study, 580 Mitochondrial morphology, 368 Mitochondrion, 369 Mitral regurgitation murmurs, 317–319 Mitral stenosis murmur, 317–318 Mitral sub-valvar apparatus, 124 Mitral valve, 20, 93, 98–99, 107, 115, 122–124, 675 edge-to-edge technique, 677 indirect approach, 676, 677 transcatheter, 676, 677 transvenous coronary sinus approach, 677 Mitral valve annulus, 116, 126 Mitral valve anomalies, 185 Mitral valve disease, 645 aortic regurgitation, 642–645 mitral regurgitation, 651 acute severe form, 651–652 chronic, 652–654 etiology, 654 ischemic mitral regurgitation, 653–654 mitral stenosis, 645

809 and atrial fibrillation, 648 closed commissurotomy, 649 diagnosis of, 648 echocardiography and, 648 mitral valve replacement in, 646 percutaneous balloon valvotomy for, 649 symptoms of, 648 Mitral valve leaflets, 123 Mitral valve opening snap, 316 Mixed venous oxygen saturation monitoring (SvO2), 355–356 8°mm Dual-8 Therapy Catheter, 526 Moderate hypothermia, 620 Moderator artery, 84 Moderator band, 96–100, 106 Monaural stethoscope, 307 Monophasic shock, 566 Motion-mode (M-mode) echocardiography, 386–387 Mouse embryonic stem cells, 734 MPI. See Myocardial performance index (MPI) MR-conditional pacemaker, 425 MR contrast agents, 414 MRI. See Magnetic resonance imaging (MRI) MR-safe item, 424 MSCs. See Mesenchymal stem cells (MSCs) Multicenter Automatic Defibrillator Implantation Trial (MADIT), 568 Multicenter Automatic Defibrillator Implantation Trial-II (MADIT-II), 568 Multidetector computed tomography (MDCT), 148 Multielectrode array catheter, 606, 607 Multielectrode catheter, 524 Multifocal atrial tachycardias, 496 Murmurs, 315, 316 Muscular ventricular septal defects, 691–692 Myocardial blood flow carbon substrate and oxygen delivery to heart, 362–363 in diseased heart, 365 regulation of, 363 Myocardial carbon substrate selection, 372–373 Myocardial contractility, 302 Myocardial infarction goals of therapy for, 460 treatment guidelines for, 460–461 Myocardial ischemia, 11, 494 animal models of, 475 creation by experimental methods, 475–476 large and small animal models, 475–477 localization and quantification, 476 consequences of, 281 definition, 279 Myocardial mass, 426, 427 Myocardial oxygen consumption (MVO2) cardiac metabolism, 279–280 Myocardial performance index (MPI), 388–389 Myocardial perfusion, 417–418 analyses of, 429 MRI quantitative analyses, 429–431 Myocardial repair, 736–737 Myocardial strain, 417, 418, 429 Myocardial stunning, 283 Myocardial viability, 418–420 Myocardium, 378 Myofibers, 421–422 Myofilament sensitivity to calcium, 283 Myosin light chain, 30 Myosin light chain 2 (MLC 2), 30

810 N National Institutes of Health (NIH) PumpKIN trial, 194 NCM. See Noncontact catheter mapping (NCM) Near-infrared spectroscopy, 408 Necropsy procedures, 485 Neurogenic tone, 245 Neurosurgery, 400 Neutrophil trafficking, 287 New York Heart Association (NYHA), 461 Nitric oxide, 287 Nitroglycerin, 141 Nodulus Arantii, 121 Noncontact catheter mapping (NCM), 601 Noncontact mapping (NCM), 579, 601, 606–609 Nondepolarizing muscle relaxants, 303 Nonejection clicks, 316 Nonesterified, free fatty acids (NEFAs), 369 Nonhuman primate heart transplantation model, 480–481 Noninvasive cardiac mapping, 609–610 Nonischemic cardiomyopathy (NICM), 578 Nonparoxysmal junctional tachycardias, 507 Non-ST segment elevation myocardial infarction (NSTEMI), 460 Nonsustained ventricular tachycardias, 506 No-reflow phenomenon, 286–287 Normal hematocrit, 4 Normothermia, 620 NSTEMI. See Non-ST segment elevation myocardial infarction (NSTEMI) Nuclear factor kappa B (NFκB), 271 Nuclear magnetic resonance, 412 NYHA. See New York Heart Association (NYHA)

O Obstructive left heart lesions bicuspid aortic valve, 185 hypoplastic left ventricle, 185 mitral valve anomalies, 185 subaortic ridge, 185 Omega-3 fatty acids, 285, 286 Omnivore, 372 OPCABG surgery, 665–666 Open-heart operation, 615 Open-heart surgery, 440 with cross-circulation approach, 443 Lillehei–DeWall bubble oxygenator, 441 Opioids, 301 Optical coherence tomography (OCT), 148 Oral anticoagulants, 464 Orgaran, 619 Orthotopic heart transplantation, 478 Oscillometry, for blood pressure measurement, 309–310 Osmolality, of cardioplegic solutions, 623, 625 Outflow tract septation of, 26–28 SHF contribution, 26–27 Ovine model of normal bileaflet mechanical valve implantation, 473 valve replacement, 474 Oxidative phosphorylation electron transport chain and, 374–375 regulation, 375–377 Oxygen paradox, 285 Oxygen saturation, 409

Index P Pacemaker development, 448–451 Grass physiological stimulator, 448 prototype, 449 Pacing and defibrillation system, 543, 544 clinical trials, 557 drug interactions, 556–557 electrogram amplification and rectification scheme, 554 implantable pulse generators, 553 indications, 550–551 leads construction, 568, 570 description, 568 electrode configurations, 570 endocardial or epicardial placement, 568 mechanism of fixation, 568–569 NASPE/BPEG classifications, 546, 551–552 sensing algorithms, 554–556 Pacing and timing abbreviations, 546 Pacing-induced atrial fibrillation, 474–475 Paclitaxel, 266 PACs. See Premature atrial complexes (PACs) Palpation, 309 Papillary muscle complexes, 117, 122–124, 126 Paradoxical splitting, 315 Paravertebral sympathetic ganglia, 51 Parietal pleura, 53 Paroxysmal atrial fibrillation, 466, 503 Paroxysmal supraventricular tachycardias (PSVTs) atrial tachycardias, 498 AV nodal reentry tachycardias, 498–500 AV reentry tachycardias, 500 sinus nodal reentry tachycardias, 497–498 WPW syndrome, 501–503 Patent ductus arteriosus (PDA), 180, 685, 686 Amplatzer ductal occluder device, 690 animal testing angled prototype, 690–691 fabric and flexible retention disc, 691 to human use, 690 risks, 689 Patent ductus arteriosus, murmur associated with, 316, 318 PDA. See Patent ductus arteriosus (PDA) Peak Endocardial Acceleration (PEA) sensor, 589–590 Pectoral girdle, 36, 38 Pectoral muscles, 38–40 PediaFlow ventricular assist device, 194 Pediatric cardiopulmonary assist system (pCAS), 195 Pediatric Jarvik 2000, 195 Pediatric patients, heart failure in, 188 Pediatric ventricular assist devices, 192–193 Pedicles, 36 PediMag, 191 PediPump, 195 Penn State pediatric ventricular assist device (PVAD), 195 PEO. See Proepicardial organ (PEO) Percent peak enhancement, 431 Percutaneous delivery technology, 482 Percutaneous transluminal coronary angioplasty (PTCA), 263 endothelial cells, 267–268 inflammation in restenosis chemokines and proinflammatory cytokines, 268–269 cross talk between inflammation and thrombosis, 270 leukocytes recruitment, 268

Index molecular signaling, 270–272 systemic markers, 269–270 late stent thrombosis, 272–273 vascular biology of restenosis, 263–268 PerDUCER®, 170 Performer CPB machine, 621 Perfusion-contraction matching, 284 Perfusion-fixed hearts qualitative anatomical assessment of, 103–104 quantitative anatomical assessment of, 104–105 Perfusion pressure, 620 Perfusion reserve, 429 Pericardial cavity, 47 Pericardium, 64–65 anatomy arteries, 165 attachment to diaphragm, 169 epicardium, 164 ligament of left vena cava, 164 oblique and transverse sinus, 165 pericardial sac, posterior view of, 164 serous and fibrous, 165 disorders asymptomatic, 167, 168 balloon pericardiotomy, 169 congenital abnormalities, 167 diagnosis, 168 iatrogenic disorders, 168 intrapericardial therapeutics clinical pericardial access, 169–170 nonsurgical intrapericardial therapy, 170–171 transatrial technique, 170 parietal, 61, 64–65 pericardial pharmacokinetics amiodarone dose, 172 diethylenetriamine/NO, 173 5-fluorouracil dose, 171 procainamide doses, 172 tissue distribution and drug clearance, 171 physiology of mechanical effects, 165–167 pericardial fluid, 165 surgical uses of, 169 visceral, 61, 64–65 Perimembranous ventricular septal defect, 692–696 PeriPort®, 170 Permanent pacing, 545, 550, 551 Persistent atrial fibrillation, 503 Persistent truncus arteriosus, 28 classification schemes for, 181 Van Praagh classification system, 181 VSD and, 181 PET. See Positron emission tomography (PET) Pharmacologic-induced atrial fibrillation, 475 Phase contrast imaging, 421 Phase contrast MRI technique, 420 Phased array transducers, 387 Phrenic nerve stimulation (PNS), 581 PhysioHeart system, 755 Physiology–Surgery Conference, 455 PiCCO monitor, 407 Pig coronary arterial circulation, 91, 100 heart anterior aspect of, 91, 92 atrioventricular conduction systems, 103

811 cranial aspect of, 93, 95 opened right ventricular cavity, 96, 99 triangle of Koch, 101, 102 ventricular cavities, 96, 97 weight to body weight ratios, 91 Plasmalite, 623 Plastic embedding, 485 Plastinated hearts, of species, 96, 98 Platelets, 4 Plethysmographic method, for blood pressure assessment, 310 Pleura, 53–54 Pleural cavities, 61, 62 PMA. See Premarket approval (PMA) Popular Electronics magazine, 449 Porcelain aorta, 674 Porcine heart, 474 Porcine hemorrhagic model, 714 Porcine model, 709, 721 Porotamine sulfate, 619 Portable Visible Heart®, 759–760 Positive chronotropic effect, 243 Positron emission tomography (PET), 149, 418 Postcardiotomy failure, 188, 190 Posterior descending artery, 20 Posterior mediastinum azygos venous system, 49–50 descending thoracic aorta, 51 description, 48 esophagus and esophageal plexus, 49 esophagus course, 49 lymphatics, 50–51 thoracic duct, 50–51 thoracic sympathetic nerves, 51–53 Posteromedial commissures, 122 Postganglionic denervation, 248 Post-pump syndrome, 287 Preclinical animal research, 90–91 Preganglionic denervation, 248 Preload, 338 Premarket approval (PMA), 779, 783, 785 Premature atrial complexes (PACs) tachyarrhythmias, 496 Premature complexes, tachyarrhythmias AV junctional premature complexes, 496–497 multifocal atrial tachycardias, 496 premature atrial complexes, 496 premature ventricular complexes, 497 Premature ventricular complexes (PVCs), 497 Pre-procedural imaging, 678 Pressure gradients, using Doppler echocardiography, 388 Pressure regulation arteriolar, 245–248 baroreceptor, 245 Pressure transducer system, 346–347 Presynaptic sympathetic fibers, 52 Prevertebral ganglia, 52 Primary heart tones, 313 Primum type ASD, 177, 179, 180 Proarrhythmias, 567 Proepicardial cells, 25, 26 Proepicardial organ (PEO), 23, 24, 29 Profound hypothermia, 610 Prophylactic implantation, of ICD, 568 Propionyl-CoA, 370 Propofol, 302 Propranolol, 141

812 Prosthetic heart valves, 451–452 Prosthetic valve replacements, 472 Prosthetic valves biological prosthetic valves, 637 vs. mechanical valve, 637–638 endocarditis and performance, 639 mechanical valve, 636–637 Pulmonary artery catheter, 350–353 complications, 408 description, 405–406 hemodynamic measurements, 405 TEE, 408 use of, 402 Pulmonary atresia, 183 Pulmonary blood flow, 299 Pulmonary cavities, 36 Pulmonary circulation, 5, 7 Pulmonary diameters, 129 Pulmonary regurgitation murmur, 317 Pulmonary valve, 116, 129–130 Pulmonary vein ablation catheter (PVAC), 524, 526 Pulmonary vein isolation (PVI), 526 Pulmonary veins circumferential isolations of, 514–515 segmental ostial isolation of, 514 Pulmonic valve, 106 transcatheter, 672, 673 diastole, 679 systole, 679 Pulsatile volume-displacement pumps, 189 Pulse contour wave processing, 407 Pulse deficit, 312 Pulseless electrical activity (PEA), 700, 703 Pulseless perfusion, 620 Pulse oximetry, 402 Pulse pressure, 308 Pulse wave Doppler, 387 Pulse waveform contour analysis, 407 Pulse wave tissue Doppler, 390 Pulsus alternans, 312 Pulsus paradoxus, 312 Pulsus parvus et tardus, 312 PumpKIN trial, 194 Pump records, 624 Purkinje fibers, 221, 223 PVAC. See Pulmonary vein ablation catheter (PVAC) PVCs. See Premature ventricular complexes (PVCs) PVI. See Pulmonary vein isolation (PVI) Pyrolytic carbon valve leaflets, 636 Pyruvate, 367 Pyruvate dehydrogenase (PDH), 367

Q QRS complex, 586 QRS to LV EGM onset (QLV), 586–587

R Radiofrequency (RF) ablation, 522 contact force, 527–529 irrigated tip RF catheter, 526–527 MiFi Sensor Technology, 527 multielectrode catheter, 524 RF catheters, 524–526

Index RF generators, 522–524 tissue ablation, mechanism of, 522 Radiofrequency (RF) catheters design for, 524 handle of, 525 Radiofrequency (RF) generators, 522 frequency, 522 impedance, 524 power limitations, 524 temperature range, 524 Radiofrequency (RF) lesion formation depth and width, 522 schematic illustration, 523 Radiofrequency pulses, 412 application of, 414 Rami communicantes, 51 Rapamycin, 265 Rapid atrial pacing, 475 Rate-pressure product, 363 Reactive oxygen species (ROS) species, 377–378 Real-time ultrasound guidance, 310 Reanimating human hearts, 751 beating test, 751 mechanisms, 757 MRI images, 761 pathological animal models, acute testing, 761–762 tricuspid valve, 758 in vitro cardiac device research, 756–757 Reanimation of large mammalian hearts, 754 Red blood cells, 4, 7 Red blood cell (RBC) transfusion, 621 Reflectance near-infrared spectroscopy, 408 Reflected wave, 386, 387 Regional isovolumic contraction time (RIVCT), 389 Regional myocardial function, 417 Regional myocardial strains, 429 Reinfusion of Enriched Progenitor Cells and Infarct Remodeling in Acute Myocardial Infarction (REPAIR-AMI) trial, 742 Relative wall motions MRI quantitative analyses, 427–428 parameters, 428 Reperfusion injury accelerated cell death, 286 acute and global assessments, 291 antioxidants, 288 arrhythmias, 286 aspects of, 285 assessment of, 286 calcium channel antagonists, 288 glucose–insulin–potassium, 288 glutamate/aspartate, 289 growth factors, 288–289 hibernation-specific proteins, 289 mechanism, 285 microvascular damage, 286–287 myocardial stunning, 286 myocardial viability, 286 Na+/H+ exchange blockers, 287 nitric oxide, 289 no-reflow phenomenon, 286 pathologies, 285 pharmaceutical agents via target pericardial delivery, 289–290 post-pump syndrome, 287 Respiration, mechanics of, 57–58 Respiratory diaphragm, 35, 40–41

Index Respiratory sinus arrhythmia, 248 ResQGARD® impedance, 712 ResQPOD® impedance, 701 Restenosis definition, 263 DESs drugs, 265–267 role of inflammation chemokines and proinflammatory cytokines, 268–269 cross talk between inflammation and thrombosis, 270 leukocyte recruitment, 268 molecular signaling, 270–272 systemic markers, 269–270 Resting Heart System, 623 Resuscitation, 400 Retrograde (RETRO) administration, of crystalloid cardioplegia, 631 Retrograde brain perfusion, 618 Return of spontaneous circulation (ROSC), 703, 704 Reveal LINQTM, 334, 791 Reverse remodeling, 580, 586–589 Reversible suppression, 529 Rhythmia mapping system, 601 RhythmViewTM workstation, 605, 606 Right atrium, 61 Right coronary artery, 19, 20 Right ventricle pulmonary semilunar valve, 72–73 role, 61 SHF contribution, 26–27 tricuspid valve, 71–73 Riva-Rocci method. See Auscultation method Rodent heart transplantation model, 480 ROSC. See Return of spontaneous circulation (ROSC) Ross procedure, 117, 131 Roving catheter, 606 RV apex mitral valve, 106 Ryanodine receptor, 376

S Safe Medical Devices Act (SMDA), 453 Sagittal plane, 15, 16 SAPIEN XT, 673, 675 Sarcomere, 204, 206, 208 Saturation-recovery magnetization, preparation, 417 SE. See Spin-echo (SE) Second heart sound, 313 Secundum-type atrial septal defects (ASDs), 177, 178 Sedation, 296 Segmented acquisition of data, 416 Seldinger’s technique, 310 Semicircular arch, 70 Semilunar valve compositions, 121 dysfunction of, 121 functioning of, 119–121 idealized three-dimensional arrangement of, 119 Senile aortic stenosis, 639 Sensing algorithms, 554–556 Septal defects atrial septal defects, 177–178 AVSD, 179–180 ventricular (see Ventricular septal defects (VSDs)) Septomarginal trabeculae, 71, 73, 84 Septomarginal trabecularis, 178–179 Septum primum, 69, 73, 79, 80 SE pulse sequences, 414

813 Sequential mapping systems, 602 electroanatomical mapping, 602–603 LocaLisa® system, 603–604 Sevoflurane, 296–298 S4 gallop, 314 Sheep heart anterior aspect of, 91, 92 anterior surface, 104 atrioventricular conduction systems, 103 cranial aspect of, 93, 95 end-diastolic volumetric reconstruction, 104 opened right ventricular cavity, 97, 99 triangle of Koch, 101, 102 ventricular cavities, 96, 97 weight to body weight ratios, 91 thorax, lateral radiograph of, 92 Shock, 711–717 diagnosis of, 400 treatment of, 399 types, 406 Sick human heart, 441 Signaling pathways regulation, 364 Signal intensity curve, for myocardial sector, 419 Silent ischemia, 281, 284 Silicone antifoam solution, 447 Simpson’s biplane rule, 387 Single-chamber endocardial lead configurations, 569 Single-photon emission computed tomography (SPECT), 149 Single proton emission computed tomography (SPECT), 418 Sinoatrial nodal cells, features of, 216 Sinoatrial nodal rate, 544 Sinoatrial node, 216 Sinoatrial node conditions, 544 Sinotubular junction, 127 Sinus bradycardia, 507 Sinus nodal reentry tachycardias, 497–498 Sinus node dysfunction, 551 Sinus node dysfunction (SND), 507–508 Sinus of Valsalva, 73, 75, 83, 129 Sinus tachycardias inappropriate, 497 physiological, 497 Sinus venarum, 67, 69, 79 Sinus venosus-type ASD, 177 Sirolimus, 149 Situs ambiguous, 175 Situs inversus, 175 Situs solitus, 175 Skeletal muscle contractions, 7 Skeletal myoblasts, 743 Sleeper hold, 240 SMDA. See Safe Medical Devices Act (SMDA) Smooth muscle cells (SMC) biology of, 264–265 cycle and proliferation, 265 extracellular matrix accumulation, 265 SND. See Sinus node dysfunction (SND) Solar-powered organ, 362 Sonomicrometry crystals, 340–342 Spatial modulation of magnetization, 418 Specialized conduction cell, 221 SPECT. See Single proton emission computed tomography (SPECT) Spin-echo (SE), 414 Spin echo amplitudes, decay of, 413 Splanchnic nerves, 51–53

814 Spongiosa, 121 Spontaneously occurring animal models, 470 SSFP. See Steady-state free precession (SSFP) Standard cardiopulmonary resuscitation (STD), 710 Standard transthoracic cardiac echo, 391–393 Steady-state amplifier, 536 Steady-state free precession (SSFP) imaging, 414, 416 global cardiac function, 415 Stem cell delivery methods, 487 Stem cell engraftment issues, 487 Stem cell research, 487–488 Stem cell therapies, functional assessment of, 488 Stem cell treatment adverse remodeling attenuation, 743 endogenous cardiac progenitors cells, 744 extracellular matrix homeostasis, 744 function and survival, 744–745 homing, 744 improved perfusion, 743 infarct environment immunomodulation, 743–744 microenvironment designing, 745 mobilization, 744 paracrine effects, 743 primary remuscularization, 743 STEMI. See ST segment elevation myocardial infarction (STEMI) Stenosis, 119, 121 Sterile bubble oxygenator, 448 Sternum-Sparing surgery, 662 Strain gauge principle, 310 Stroke volume, 338–340, 415, 417, 544 and contractility, 244–245 Frank–Starling law, 244 increased sympathetic stimulation, 244 Strut cords, 117 ST segment elevation myocardial infarction (STEMI), 460 St. Thomas II solution, 626 Subaortic ridge, 185 Subclavian vein, 43, 45, 48, 50, 59, 403 Subcutaneous continuous glucose monitoring, 409 Sublingual capnometry, 409 Substrate ablation technique, atrial fibrillation, 515 Sudden cardiac arrest, 557 CPR techniques, 700 PEA, 700 Summer Research Scholars Program, 450 Superior mediastinum arteries in, 44 brachiocephalic veins, 44 contents of, 43 description, 43 innervation pattern, 47 nerves of, 45–46 phrenic and vagus nerve course, 45 thymus, 47 trachea and esophagus, 45 vessels of, 42–43 Superior vena cava (SVC), cannulation of, 616 Supply ischemia, 379 Supraventricular crest, 70 Supraventricular tachycardias (SVT) paroxysmal atrial tachycardias, 498 AV nodal reentry tachycardias, 498–500 AV reentry tachycardias, 500

Index sinus nodal reentry tachycardias, 497–498 WPW syndrome, 501–503 SVR. See Systemic vascular resistance (SVR) SVT. See Supraventricular tachycardias (SVT) Swine heart, 754 contrast-enhanced CT image, 762 electrophysiologic properties, 228, 229 transplantation model, 480 Sympathetic nerves, 52 Sympathetic trunk, 51 SynCardia Total Artificial Heart (TAH), 192 System calibration, 311 Systemic circulation, 5 Systemic vascular resistance, 297 Systemic vascular resistance (SVR), 406 Systole, 8 Systolic blood pressure, 308, 309, 311, 312 Systolic blood pressure (SBP), 702, 713 Systolic clicks, 316

T Tachyarrhythmias atrial fibrillation, 503–506 atrial flutter, 503, 504 detection intervals, 558–559 paroxysmal supraventricular tachycardias atrial tachycardias, 498 AV nodal reentry tachycardias, 498–500 AV reentry tachycardias, 500 sinus nodal reentry tachycardias, 497–498 WPW syndrome, 501–503 pharmacologic considerations, 558–559 premature complexes AV junctional, 496–497 multifocal atrial tachycardias, 496 premature atrial complexes, 496 premature ventricular complexes, 497 sinus tachycardias inappropriate sinus tachycardias, 497 physiological, 497 ventricular tachyarrhythmias accelerated idioventricular rhythm, 507 nonparoxysmal junctional tachycardias, 507 Torsades de pointes, 507, 508 ventricular fibrillation, 506–507 ventricular flutter, 506–507 ventricular tachycardias, 506 Tachycardias, mechanisms, 494 Tacticath Quartz Contact Force catheter, 528 TAPSE. See Tricuspid annular plane systolic excursion (TAPSE) TAPVC. See Total anomalous pulmonary venous connection (TAPVC) Targeted drug delivery, 466 Tawara’s anatomical diagram, 132 TdP. See Torsades de pointes (TdP) TEE. See Transesophageal echocardiograms (TEE) TEI. See Transmural extent of infarction (TEI) Tei index, 388 Tele-ICU, 402, 403, 409 Telemedicine, ICU, 402–403 Temperatures of perfusion, 619–620 Temporal resolution (TR) cine loop, 416 Temporary pacing systems, 551 Tendinous cords, 117, 121, 122, 124

Index Tethering length, 124 Tetralogy of Fallot, 183–184 The Atlas of Human Cardiac Anatomy, 753, 762–763 Thebesian veins, 86 Thermocool Smart touch catheter, 528 Thermodilution technique, 353–354 Thiopental, 300 Third heart sound, 313 Thoracic bioimpedance method, 354–355 Thoracic cage, 36–38 Thoracic cavity walls vs. lungs, 53 Thoracic sympathetic nerves, 51–53 Thoracic wall bones of horacic cage, 36–38 pectoral girdle, 38 landmarks of, 58 muscles of intercostal muscles, 40 pectoral muscles, 38–40 respiratory diaphragm, 40–41 scalene muscles, 41 sternocleidomastoid muscles, 41 nerves of, 41–42 vessels of, 42–43 Thoracocentesis, 59 Thoratec HeartMate III, 194 Thoratec VAD, 726, 728 Thorax compartments, 35 description, 35 inferior aperture, 35 superior aperture, 36 thoracic wall bones of, 36–38 muscles of, 38–41 nerves of, 41–42 vessels of, 42–43 Thromboembolic events, 195 Thromboembolism, 636, 637 Thymosin β4 (Tβ4), 742 Thymus, 47 Thyroid ima, 44 Tilt, 558, 566 Time to peak, 431 Tip-based catheters, 531 Tissue destruction mechanisms, 532 Tissue Doppler imaging (TDI), 389–390 Tissue heating, with RF energy, 522 Tissues, ultrasound imaging, 386 Tonometry devices, 310 Topera 3D mapping system, 605 Torsades de pointes (TdP) ventricular tachyarrhythmias, 507, 508 Total anomalous pulmonary venous connection (TAPVC), 184 Total Artificial Heart (TAH), 192 Total cardiopulmonary bypass, 616–618 Total circulatory arrest technique, 618 Total intravenous anesthetic (TIVA) technique, 296 Toxic byproducts, 377–379 TR. See Temporal resolution (TR) Trabeculae carneae, 96, 98 Trachea and esophagus, 45 Trademark, 771 Trade secret, 771

815 Transabdominal fetal echocardiography, 390–391 Transcatheter closure devices, 453 Transcatheter-delivered pulmonary valve, 759 Transcatheter-delivered valve systems, 672 Transcatheter valve repairs and replacements, 671 aortic valve, 673–676 imaging, 678–680 intracardiac interventions, 680–681 mitral valve, 675–677 pulmonic valve, 672–673 tricuspid valve, 677 Transcatheter valve replacement, 671, 672, 680 Transcutaneous energy transmission (TET), 191 Transcytosis, 6 Transdermal drug delivery systems, 466 Transducer catheters, 347 Transducers high-frequency, 386 position for standard transthoracic echocardiography, 392 for two-dimensional imaging, 387 Transesophageal echocardiograms (TEE), 391, 407–408 Transmural extent of infarction (TEI), 432 Transplantation of Progenitor Cells and Recovery of LV Function in Patients with Chronic Ischemic Heart Disease (TOPCARECHD) trial, 742 Transplantation of Progenitor Cells and Regeneration Enhancement in Acute Myocardial Infarction (TOPCARE-AMI) trial, 742 Transpulmonary dilution method, 354 Transthoracic echocardiography, 391 Transvaginal fetal echocardiography, 390–391 Transvalvular gradient, 636 Transverse pericardial sinus, 65 Transverse plane, 15, 16, 19 Transverse thoracic plane, 35, 62 Triangle of Koch, 101, 102, 124, 130–131 Tricarboxylic acid (TCA) cycle, 368 flux rate, 376 regulation, 375–377 Tricuspid annular plane systolic excursion (TAPSE), 389 Tricuspid atresia, 178 Tricuspid regurgitation murmur, 318 Tricuspid stenosis murmur, 318 Tricuspid sub-valvar apparatus, 128 Tricuspid valve, 20, 93, 97, 106, 116–118, 124–127, 677 anomalies of, 178 Tricuspid valve disease etiology, 654 tricuspid regurgitation, 654 annuloplasty, 655 valve replacement, 655 tricuspid stenosis, 654 clinical features, 654 Tricuspid valve leaflets, 126 Tricuspid valve opening snap, 316 Triggered activity, 558 Triphenyltetrazolium chloride (TTC) staining, 476, 478 Troponin I, 30 True bipolar leads, 570 TrueFISP slices, 429 True ribs, 36 Truncus arteriosus anatomy of, 181 persistent, 181–182 repair of, 181–182

816 TTC staining. See Triphenyltetrazolium chloride (TTC) staining Tumor necrosis factor alpha (TNF-α), 269 Tuohy needle, 170 T2* weighting of a gradient echo image, 414 12-lead ECG, 323, 329–330 Two-dimensional imaging, 389 Typical atrial flutter, 512

U UCB stem cells. See Umbilical cord blood (UCB) stem cells Ultrasound ablation benefits, 532 mechanisms of, 532–533 Ultrasound imaging cardiac hemodynamics, 407–408 of tissues, 386 use of, 385 Umbilical cord blood (UCB) stem cells, 737 Unipolar pacing systems, 549 United Network for Organ Sharing (UNOS) cardiac transplant waiting list registrants and donor hearts per year, 478, 479 United States Patent and Trademark Office (USPTO), 772 University of Minnesota bubble oxygenator, 447 cardiovascular physiology at, 455–456 cross-circulation, 443–444 description, 439–443 DMD Conference, 454 heart block, 448–451 heart valves, 451–453 IEM, 454 LifeScience Alley, 453–454 Lillehei–DeWall bubble oxygenator, 444–448 and Mayo Clinic, 443–444 medical device regulation, 453 Medical Devices Center, 454–455 milestones, 444 operating room environment, 443 other University-affiliated medical devices, 453 pacemaker development, 448–451 Physiology Department chair/interim head, 455 schematic of, 442 Surgery Department chair/interim head, 441 UNOS. See United Network for Organ Sharing (UNOS) Unrestricted somatic stem cells, 737 Upslope, 431 U.S. International Trade Commission (ITC), 788

V VAD testing. See Ventricular assist device (VAD) testing, animal models for Valvar incompetence, 118 Vascular access, surface landmarks of, 59–60 Vascular endothelial growth factor (VEGF), 737 Vascular steal, 417 Vasoactive therapy, titration, 400–401 Vaughn-Williams classification, 495 VEGF. See Vascular endothelial growth factor (VEGF) Vein of left atrium, 164 Venous drainage, 616–617 Venous system, blood flows, 6 Ventricles, septation of, 27–29 Ventricular arrhythmias, 463

Index Ventricular assist devices (VADs), 188. See also Left ventricular assist device (LVAD) classifications, 726 continuous flow pumps axial design, 728–729 centrifugal designs, 729 HeartMate II LVAD, 729 designing, 192–193 device management, 730 failure and durability, 196 implantation techniques, 729–730 long-term support, 191–192 LVADs, 725–728 management and complications, 195–196 pediatric patients, 188 short-term support, 189–191 University of Minnesota, 730 volume displacement pumps, 726–728 HeartMate XVE LVAD, 726 Thoratec VAD, 726, 728 thromboembolism, 726, 728 Ventricular assist device (VAD) testing, animal models for, 481 explant analysis, 482–486 federal guidelines, 481–482 mechanical VADs, 481 pathology, 483 research and development, 481 Ventricular chambers, examination of, 17 Ventricular conduction system, 216, 220 Ventricular escape rhythms, 221 Ventricular fibrillation, 463, 506–507, 557 Ventricular fibrillation (VF), 700, 702 Ventricular flutter, 506–507 Ventricular function, quantitative analyses, 426–427 Ventricular gallop, 314 Ventricular myocyte, 9, 225 Ventricular parasystole, 497 Ventricular septal defects (VSDs), 178–179 AVSD vs., 179–180 classification of, 179 murmur, 318 persistent truncus arteriosus, 181–182 physiologic sequelae, 178 redundant nomenclature, 178 surgical correction, 179 tetralogy of Fallot vs., 180 Ventricular tachyarrhythmias accelerated idioventricular rhythm, 507 nonparoxysmal junctional tachycardias, 507 Torsades de pointes, 507, 508 ventricular fibrillation, 506–507 ventricular flutter, 506–507 ventricular tachycardias, 506 Ventricular tachycardias (VTs), 506, 558, 562 bundle branch reentry, 519 in clinically normal hearts, 518 ischemic heart disease, 518–519 nonsustained, 506 Vertebrate heart development cardiac maturation, 29–31 cardiac neural crest contribution, 27–29 contributors, 24, 29 first heart field contribution, 23–25 outflow tract and ventricles, septation of, 27–29 proepicardial organ, 29 second heart field contribution, 26–27

Index Very long-chain acyl-CoA dehydrogenase (VLCAD) deficiency, 382 Visceral pleura, 53, 56, 58 Visceroatrial situs, 175 Visible Heart® Laboratory, 440, 443 Visible Heart® laboratory, 751 Anatomy Bequest Program, 752 apparatus, 753 comparative imaging in apparatus, 758–759 fresh cadaver hearts, 753 high-resolution noninvasive cardiac imaging, 753 limitation, 760–761 mammalian isolated heart model, 755 pathological animal models, acute testing, 761–762 perfusion-fixed specimens, 753 portable, 759–760 species selection, 756–757 Voice of customer (VOC), 769, 772 VSDs. See Ventricular septal defects (VSDs) V stenting technique, 150 VTs. See Ventricular tachycardias (VTs) VVIR leadless pacemaker, 573 VV optimization, 589–590

W Wall motions, 417 relative, 427–28 Wall thickening, dynamic changes, 417 Warden procedure, 177

817 Water hammer pulse. See Wide pulse pressure White blood cells, 4, 6 White rami communicantes, 51 Whole animal research model, alternatives to, 470 isolated cardiomyocytes, 470 isolated perfused heart models, 470–472 WiCSw-LV system, 573 Wide pulse pressure, 312 Wolff–Parkinson–White syndrome, 216, 219 Wolff–Parkinson–White (WPW) syndrome, 501–503, 517–518 Wolf-Parkinson-White syndrome, 178 WPW syndrome. See Wolff–Parkinson–White (WPW) syndrome Written pathology report, 485–486

X Xanthine oxidase inhibitors, 285 Xenon, 299 Xiphoid process, 38, 58 X-ray-based fluoroscopic techniques, 423

Y Y stenting technique, 150

Z Zero referencing, 311