Bücher der Reihe Developments in Cardiovascular Medicine

As the majority of cardiovascular deaths are related to myocardial ischemia, it is necessary to understand the various aspects of ischemic heart disease. In this regard, it is noteworthy that ischemic heart disease is commonly associated with atherosclerosis, coronary spasm, as well as thrombosis leading to the development of arrhythmias, cardiovascular cell damage, myocardial infarction, cardiac hypertrophy and congestive heart failure. Furthermore, it is also important to appreciate various physiological, electrophysiological and biochemical processes in the normal heart if we are to understand their significance under pathological situations. Heart Function in Health and Disease has been organized in five sections to provide an outline of a complex problem in a convenient manner. One section of this book is devoted to shedding light on the restructuring and ontogenic changes in the developing heart whereas in the next section some hypertrophic alterations due to chronic hypoxia are described. The third and fourth sections of this book are concerned with the regulation of cardiac channels as well as signal transduction mechanisms and cardiac electric field. The fifth section contains some pathophysiological events during the development of cardiac hypertrophy and heart failure. All of these areas encompass a significant body of new information that will be invaluable to those who work in the field of cardiovascular sciences, as well as those who treat people with heart disease.

The cardiac system represents one of the most exciting challenges to human ingenuity. Critical to our survival, it consists of a tantalizing array of interacting phenomena, from ionic microscopic transport, membrane channels and receptors through cellular metabolism, energy production to fiber mechanics, microcirculation, electrical activation to the global, clinically observed, function, which is measured by pressure, volume, coronary flow, heart rate, shape changes and responds to imposed loads and pharmaceutical challenges. It is a complex interdisciplinary system requiring the joint efforts of the life sciences, the exact sciences, engineering and technology to understand and control the pathologies involved. The Henry Goldberg Workshops were set up to address these challenges. Briefly, our goals are: 1. To foster interdisciplinary interaction between scientists from different areas of cardiology, identify missing links, and catalyze new questions. 2. To relate micro scale cellular phenomena to the global, clinically manifested cardiac function. 3. To relate conceptual modeling and quantitative analysis to experimental and clinical data. 4. To encourage international cooperation so as to disperse medical and technological know how and lead to better understanding of the cardiac system. Today we celebrate the 7th birthday of a dream come true; a dream to bring together the diversified expertise in the various fields of science, engineering and medicine, to relate to the numerous interactive parameters and disciplines involved in the performance of the heart.

This book is timely and challenging. Within its pages are commentaries and opinions on the scientific background and explanatory ideas for a complex of symptoms and investigations known as syndrome X. The commonest cause by far of angina pectoris is coronary artery obstruction due to atheromatous lesions both within the wall of the artery and intruding into the lumen; in such patients it is expected that there maybe ST segment depression on atrial pacing or on an exercise test indicating myocardial ischemia. Syndrome X was a term first used in an editorial written by Kemp in 1973. He was referring to patients in group X in a paper from Arbogast and Bourassa. Patients in group X had three features, namely angina as judged on a clinical history, alterations of the ST segment on the electrocardiogram during atrial pacing and smooth unobstructed coronary arteries (presumed normal) as assessed by the technique of coronary angiography. The changes on the electrocardiogram, conventionally indicative of myocardial ischemia, could not be explained on the basis of any abnormality of the coronary arteries and Kemp named the complex of fmdings syndrome X because of this seeming paradox and the lack of a single explanation. In the last thirty-one years there has been substantial scientific interest in this syndrome giving rise to a large number of publications. The name syndrome X has led to considerable confusion. Physicians are familiar with the X chromosome and with X linked congenital disorders.

Angioplasty has completely transformed the treatment of coronary artery disease and is widely used, with more than 800,000 procedures performed worldwide per year. However, the enthusiasm for angioplasty is shadowed by restenosis, which remains a critical problem after the procedure, resulting in clinical recurrence in over a third of patients. Recently, the mechanisms of restenosis have been completely reappraised with an enriched understanding that the original concept of neointimal hyperplasia may not be accounting for the bulk of the problem. There is a desperate need to heighten understanding of the remodeling process at the molecular, cellular, and arterial level. Vascular remodeling is a well established concept in the field of atherosclerosis and hypertension, but only in recent years has its applicability to the field of restenosis become pivotal. Accordingly, the editors perceived the need to assemble the first book dedicated to the concept of coronary artery remodeling in restenosis, in order to clearly review the experiments leading to the remodeling hypothesis and integrate this with the neointimal hyperplasia (tumor) model for the development of the restenotic lesion. The authors of this book present their experience to facilitate the understanding of the mechanisms for coronary restenosis and remodeling. The various experimental models, clinical issues, and basic mechanisms are reviewed in detail, resulting in a fresh approach to a vexing clinical problem. Arterial Remodeling: A Critical Factor in Restenosis will be useful to the physician and trainee who have an interest in restenosis, and specifically in the major pathophysiologic process which determines the fate of arterial healing in patients following percutaneous coronary revascularization. It is hoped that this book will lay the foundation for more effective therapies that will reduce the chance of constrictive remodeling and improve the long-term efficacy of non-surgical coronary revascularization in the future.

Cardiovascular drug therapy has markedly progressed in the recent decades. Not only have new drugs been introduced to clinical practice, but new classes of drugs have been developed. While in 1960 the practicing cardiolo­ gist had a selection of about only ten drugs, in 1987 about 150 drugs are routinely used in cardiovascular diseases. Elderly patients, however, usually do not enjoy the full benefit of this progress. This might be due to lack of knowledge, a conservative approach, or the worldwide tendency not to try new drugs in the elderly. It is now clear that the majority of patients that will be treated in car­ diovascular clinics will be, in the near future, elderly patients. Even now, elderly patients form about one-third of the patients with cardiovascular diseases. These patients are approached, however, according to criteria devel­ oped for younger populations. This is despite the fact that elderly patients differ from younger ones in most aspects, including pathology, epidemiol­ ogy, pathophysiology, diagnostic approach, management, pharmacology, pharmacokinetics, rehabilitation, and supportive treatment. It is the purpose of this book to present to the clinician all drugs with which there is clinical experience in the elderly or which might be potentially useful for the elderly with cardiovascular diseases. The data are presented without the authors taking a position. This should allow the clinicians to make their own selection and individualize treatment, vii viii Preface based on a wide data base. Comparative data are presented only when specific comparative studies were performed.

It is the mark of an instructed mind to rest satisfied with the degree of precision which the nature of the subject admits, and not to seek exactness where only an approximation of the truth is possible. Aristotle With the development of imaging techniques, the in vivo study of human anatomy and physiology has become possible with increasing "e;approximation of the truth. "e; Advances have been made not only in data acquisition, but also in processing as well as visualization of functional and morphological data. Following the successful application of planar two-dimensional imaging approaches, more recently three-dimensional data acquisition and correspond- ing tomographic image reconstruction has become possible. With the rapid growth of computer support, advanced processing allows for user-friendly interaction with complex data sets. Classical x-ray imaging techniques have matured to excellent spatial resolution and contrast, which provide specific delineation of anatomical changes occurring in cardiovascular disease. In parallel, the use of tracer principles supported the successful introduction of nuclear medicine procedures for the functional characterization of physiology and pathophysiology. The application of such techniques were initially limited by relatively poor spatial resolution, but excelled in high sensitivity 30 years, scintigraphic imaging emerged from and specificity. In the last rectilinear scanning to planar gamma camera imaging and single-photon xvi Preface emISSIOn tomography (SPECT). Based on these advances and the experi- mental success of autoradiography, the potential of scintigraphy as a clinical and research tool has been well appreciated.

The most salient feature of the infor- last four chapters of the book evaluate the mation provided by nuclear medicine is its information from an analytical and pathophysiological and functional charac- statistical point of view. This approach is ter. For adequate experimental or clinical required for correct decision-making. interpretation, such information should This book is therefore the result of necessarily be interpreted alongside the accumulated experience in nuclear cardiology views of the clinical cardiologist, who is with the invaluable cooperation of medical able to apply it to the individual patient. statisticians. It is directed to physicians This approach, which is routine in every- with an interest in nuclear cardiology, to day clinical practice, reaches its plenitude nuclear medicine specialists wishing to when the whole process is completed and learn the uses and limitations of these an intimate cooperation is established procedures in everyday clinical cardiology, between the nuclear medicine specialist and to cardiologists who feel the need to and the clinical cardiologist. In such understand the rationale and methodology instances, each one of these professionals of the studies which benefit their patients. understands the needs, limits and possi- We understand that the ultimate reason bilities of the other. for any scientific book is the transmission The present book is the fruit of such of knowledge, and we are fully conscious cooperation. In our hospital, an efficient of the enthusiasm of the authors of the nuclear cardiology team has been made up present text to achieve that aim.

The molecular basis for atrial fibrillation continues to be largely unknown, and therapy remains unchanged, aimed at controlling the heart rate and preventing systemic emboli with anticoagulation. Familial atrial fibrillation is more common than previously suspected. While atrial fibrillation is commonly associated with acquired heart disease, a significant proportion of individuals have early onset without other forms of heart disease, referred to as "e;lone"e; atrial fibrillators. It is also well recognized that atrial fibrillation occurs on a reversible or functional basis, without associated structural heart disease, such as with hyperthyroidism or of atrial fibrillation following surgery. It remains to be determined what percentage in these individuals is familial or due to a genetic predisposition. Mapping the locus for familial atrial fibrillation is the first step towards the identification of the gene. Isolation of the gene and subsequent identification of the responsible molecular genetic defect should provide a point of entry into the mechanism responsible for the familial form and the common acquired forms of the disease and eventually provide more effective therapy. We know that the ionic currents responsible for the action potential of the atrium is due to multiple channel proteins as is electrical conduction throughout the atria. Analogous to the ongoing genetic studies in patients with familial long QT syndrome, it is highly likely that defects in each of these channel proteins will be manifested in familial atrial fibrillation.

By the time a man gets well into his seventies, his continued existence is a mere miracle. -Robert Louis Stevenson It hardly seems possible that a second edition is needed after the first has been in print for only three years. However, when I reflect on what has happened in geriatric cardiology during that short period, it becomes obvious why. First, cardiologists all over the globe have begun to realize that geriatric cardiology has evolved into a science and a clinical discipline of its own. Although some of us may consider such subspecialization unfortunate, it has become clear that a variety of cardiac disorders present with different symptoms and signs, require a different diagnostic and therapeutic approach, and have a different prognostic outlook in the elderly when compared to middle-aged patients. Since the aging segment of the population has increased dramatically over the past few decades, and continues to do so, specific age-related disorders are more frequently encountered by the practicing physician, be it by the general practitioner, by the internist, or by a cardiologist. Cardiovascular Disease in the Elderly provides an up-to-date guide to help the physician deal with these problems, leading the way in what turns out to be an increasingly complex area. Second, I have been heartened by the warm reception of the first edition and by the excellent reviews that it got in the most prestigious medical journals.

Most of the progress in cardiac energetics in recent years has been spurred by the pressure-volume area concept, the natural extension into energetics of earlier pioneering work delineating the time-varying elastance framework for ventricular contraction. The book draws together a broad spectrum of researchers - basic, applied and clinical - having a shared interest in the energetics of cardiac muscle and ventricle, providing an overview of the current state of the art.

Teleologically, the hemostatic mechanism is among The of Coronary Thrombosis and the most fundamental yet complex physiologic pro- in essence, represents a heartfelt gift of cesses in humans. Early scientists and physicians were knowledge from a dedicated group of scientists and fascinated by the blood's ability to remain in a liquid clinicians, who collectively have set out on a mission state only to clot in response to vascular injury. The to minimize the societal impact of"e;hemostasis in the cellular and noncellular components of normal wrong place. "e; The book is divided into four distinct hemostasis took centuries to discover, and the intrica- sections: Part 1, Scientific Principles, lays down the cies of their delicate interactions are still being unrav- supporting foundation; Part 2, Clinical Application eled today. As is so often the case, an in-depth of Scientific Principles, places the knowledge base in appreciation of physiologic hemostasis, representing a a working perspective, directly applying science to basic life-sustaining sequence of events, paved the patient care; Part 3, New Dimensions, provides a way for understanding abnormal hemostasis or glimpse of tomorrow. Steering the field clear of se- pathologic thrombosis. Aristotle, Malpighi, and proclaimed victory and the dangers of complacency as Osier, representing but a few of the founding fathers we move into the 21st century, Part 4, Evolution of in the field, would undoubtedly be honored to see Thrombocardiology, focuses on laboratory standards, their observations form the template for lifesaving clinical trials, and drugs in development.