This book contains 55 chapters that summarize referred to the special issue of Drug Development lectures given during the Fifth International Research (Volume 31, Number 4, April 1994). Symposium on Adenosine and Adenine Measured by the number and quality of presenta- Nucleotides held in Philadelphia, Pennsylvania, tions, and by the record number of participants, U. S. A. , May 9-13, 1994. The symposium and the Fifth International Symposium on Adenosine its proceedings follow four previous symposia and Adenine Nucleotides was clearly an intel- and their published proceedings. Previous sym- lectually stimulating meeting. It is safe to posia were held in Banfff, Canada (1978), conclude that the purine research field is vibrant Charlottesville, Virginia (1982), Munich, and still growing. Adenosine has rapidly become Germany (1986), and Lake Yamanaka, Japan the drug of choice for the acute management (1990). of supraventricular tachyarrhythmias and was The program included a wide range of sub- recently approved for use in combination with jects from molecular and cellular biology to cardiac imaging for detection of ischemic heart clinical applications. Great emphasis was placed disease. Additional clinical applications of on cutting edge information derived from studies adenosine and adenosine-related drugs and ATP using molecular and cellular biology techniques seem closer than ever before. The editors would like to express their grati- applied to the field of adenosine and adenine nucleotide research. Likewise, the program tude to the distinguished contributors for their included a number of presentations on poten- excellent chapters and to all participants.

This volume sets out to consider a range of cardiac diseases for which drugs may play a therapeutic role by virtue of their effects on aspects of the immune system. The book reviews diseases of the heart which may involve an immunopharmacological component, and methods and techniques for the study of physiological and biochemical functions in the heart. An important focus is the immunopharmacology of the coronary vascular endothelium and the role of cellular and biochemical components of the immune system in the pathogenesis of atherosclerosis. The content also includes a review of the use of immunologically relevant agents in the setting of cardiac transplantation from aclinical perspective. Immunotherapy has a definite role to play in cardiology to a greater or lesser extent than other forms of intervention, depending on the type of cardiac disease. Immunopharmacology of the Heart aims to identify and clarify this role and points to potential developments of the future. Immunopharmacology of the Heart is a volume for the SYSTEMS theme of The Handbook of Pharmacology. In common with all other volumes it contains standardized illustrations and terms/abbreviations (glossaries of illustrations and terms published at the back of the volume). Other topics covered include: Leukocytes and their role in ischaemic heart disease. Complement activation. Sudden cardiac death. The stunned myocardium and reperfusion injury.

In 1962, 30 years after the discovery by du Vigneaud have pathologic consequences. One potentially sig- of a new sulfur amino acid, homocysteine; Carson and nificant health outcome of such mild to moderate Neil reported two siblings with mental retardation in hyperhomocysteinemia is an increased risk of occlu- northern Ireland with elevated urinary homocystine. sive vascular disease. Homocysteine concentrations in Nearly simultaneously, Gerritsen and Waisman patients with vascular disease were, on average, 31 % greater than in normal controls. Prospective assess- identified increased homocystine in the urine of a mentally retarded infant in Wisconsin. Within two ment of vascular disease risk among men with higher years, Harvey Mudd, James Finkelstein, and their homocysteine concentrations indicated that plasma coworkers at the National Institutes of health (USA) homocysteine at only 12% above the upper limit of that the enzyme cystathionine ~- normal levels was associated with a 3. 4-fold increase had reported synthase was lacking in a liver biopsy specimen from in risk of acute myocardial infarction. Studies from another patient with homocystinuria. This was the original Framingham Heart Study cohort (USA) the first indication of a vitamin relationship to have shown strong, positive correlation between homocystinuria, because that enzyme has as its co- plasma homocysteine concentration and degree of factor vitamin B6 (pyridoxal phosphate). Thereafter, carotid stenosis.

The unique biology of cardiac fibroblasts and related cells, such as cardiac myofibroblasts and valvular interstitial cells, distinguish them from other fibroblastic cells, a concept that is only beginning to be widely appreciated. Further, the natural signals that stimulate and inhibit cardiac fibrosis within these cells are not well understood. This volume compiles articles that address the molecular mechanisms that control the synthesis and secretion of the cardiac ECM. The book showcases chapters that highlight discussion of role of Transforming Growth Factor (TGF ), an important fibrogenic cytokine and its downstream effectors SMAD in many cardiac diseases. Further, the contributions highlight information to discuss endogenous inhibitors of cardiac fibrosis, as well as advances in tissue engineering specific to matrix in the heart. Finally, discussions of unifying mechanisms of matrix remodeling in valves and myocardium are presented. The mechanisms involved in the stimulation of cardiac fibrosis are not fully understood. In most cases the marginal attenuation of cardiac fibrosis as a result of a given therapy is a beneficial side-effect linked to other primary effects on other cells, especially cardiomyocytes. Very few drugs or agents are known to affect the function and dysfunction of cardiac fibroblasts and myofibroblasts alone. The book helps to translate the information gathered within to allow us to alter the course of fibrogenic events that are typical of cardiac fibrosis, and thereby reduce their burden on the patient and on society itself.

The topics in this book represent the presentations given at the Seventh Annual Meeting entitled "Cardiac Surgery: Current Issues," held at the Frenchman's Reef Beach Resort, St. Thomas, U.S. Virgin Islands, November 9-12, 1994. This symposium was sponsored by the American College of Chest Physicians in conjunction with the Division of Cardiothoracic Surgery of Cooper HospitallUniversity Medical Center, the University of Medicine and Dentistry of New Jersey, Robert Wood Johnson Medical School, Camden, New Jersey. Chapter authors were charged with the task of writing brief overviews of major issues related to the field of cardiac surgery. The book is specifically tailored to the needs of cardiothoracic surgeons, cardiovascular perfusionists, allied health professionals, and nurs ing personnel involved in all phases of caring for the cardiac surgical patient. Although intended as a reference source with emphasis on updated approaches applied in cardiac surgery, it is hoped that the discussion of these topics will compliment other texts and manuscripts. Obviously, a book of this length cannot cover the whole multidisciplinary and complex field of cardiac surgery. However, co-editors are certain that the annual appearance of this text will highlight comprehensive, new, and interesting approaches to the field of cardiac surgery. The co-editors are greatly thankful to the contributors for their efforts in providing comprehensive chapters. Without their expertise, this work may not have been possible. We would also like to thank Ms. Eileen Birmingham and the staff at Plenum Publishing Corporation for their tremendous help in completing this work.

One of the major biomedical triumphs of the post-World War II era was the defmitive demonstration that hypercholesterolemia is a key causative factor in atherosclerosis; that hypercholesterolemia can be effectively treated; and that treatment significantly reduces not only coronary disease mortality but also all cause mortality. Treatment to lower plasma levels of cholesterol - primarily low density lipoprotein (LDL) cholesterol - is now accepted as best medical practice and both physicians and patients are being educated to take aggressive measures to lower LDL. We can confidently look forward to important decreases in the toll of coronary artery disease over the coming decades. However, there is still uncertainty as to the exact mechanisms by which elevated plasma cholesterol and LDL levels initiate and favor the progression of lesions. There is general consensus that one of the earliest responses to hypercholesterolemia is the adhesion of monocytes to aortic endothelial cells followed by their penetration into the subendothelial space, where they differentiate into macrophages. These cells, and also medial smooth muscle cells that have migrated into the subendothelial space, then become loaded with mUltiple, large droplets of cholesterol esters . . . the hallmark of the earliest visible atherosclerotic lesion, the so-called fatty streak. This lesion is the precursor of the more advanced lesions, both in animal models and in humans. Thus the centrality of hypercholesterolemia cannot be overstated. Still, the atherogenic process is complex and evolves over a long period of time."

Since the first pacemaker implantation in October 1958 by Senning and Elmqvist in Sweden, cardiac pacing for bradycardia has become a well-established therapy. The impressive growth of clinical experience and the rapid development of pacemaker devices have greatly contributed to this situation. The electrical therapy appears to be so easy that insertion of the lead and its connection to the pacemaker generator requires little effort, skill or insight. However, after implantation a patient's condition seldom remains stable, which requires a flexible pacing program to cover all new cardiac events, and broad insight from clinician and technical colleagues. The Pacemaker Clinic of the 90's teaches anatomical and electrophysiological aspects of pacing, supports the prevention of complications, and points to new developments in the field. Apart from classical indications for cardiac pacing, the book discusses the validity of the latest indications, supporting the cardiologist and the associated professional in selecting the appropriate pacing mode and pacemaker follow-up in individual patients. The Pacemaker Clinic of the 90's will be a helpful companion for years to come.

For over a quarter of a century, echocardiography has made an unparalleled contribution to clinical cardiology as a major tool for real-time imaging of cardiac dynamics. Echocardiography is widely used to assess cardiac function, and provides noninvasive information which is invaluable for the diagnosis of various disease states. In spite of its numerous advantages, in the clinical arena echocardiography has remained mostly qualitative and subjective. However, continued progress in our understanding of the interactions between ultrasound and tissue characteristics have brought about several new developments which allow quantitative analysis of ultrasound data. Among these new developments are endocardial boundary detection (frequently referred to as Acoustic Quantification), Color Kinesis and Doppler myocardial imaging. The purpose of this book is to provide the reader with the background necessary to understand and successfully utilize these methodologies. Chapters summarize in detail the studies that have validated these techniques thus far, and discuss their future applications.

This book deals with heart failure in all its aspects, in- cluding chapters relating to receptor physiology and patho- physiological mechanisms, ventricular function and its assessment and the clinical aspects of heart failure in ischemic heart failure, cardiomyopathy, rheumatic heart disease and the timing of valve replacement. The pharmaco- therapy of heart failure deals with inotropic drugs, ACE in- hibitors, nitrates and calcium antagonists. Extending into the newer interventional techniques and surgical techniques the book includes chapters on balloon valvuloplasty, the po- tential use of the laser, the Jarvik artificial heart, car- diomyoplasty, left ventriculoplasty and heart and heart/lung transplantation.

The objective of this book is to provide the researcher and clinician with the recent developments in the analysis and assessment of cardiovascular func tion. The chapters are organized into sections that correspond with the various anatomical levels of the cardiovascular system. To a large extent, recent focus on the cardiovascular system function has been directed at the molecular level to the near exclusion of the tissue and organ function. While this may be useful in developing new therapeutic drugs, it does not aid the cardiologist or surgeon, who routinely deal with patient symptoms. This book integrates the micro-level and organ-level function so that new infor mation may be assimilated into the cardiovascular system as a whole. Within each section, the chapters have been arranged to progress from recent theoretical developments, to experimental research, and finally to clinical applications. This approach facilitates the timely transfer of infor mation from basic research to the clinic. The strength of the analytical approach will be evident to the reader. The theoretical analysis offers guidance to experimental design and, in some cases, offers solutions where measurements are as yet unattainable. In moving from newly attained knowledge to clinical practice, this book emphasizes the noninvasive meth in the future as technological advances ods. Such methods are desirable occur and the trend towards early preventive diagnosis is sought. What follows are highlights of new developments covered in each section of the book."

Cardiovascular disease is the major cause of morbidity and mortality worldwide. While the past 40 years have brought major progress in cardiac valve repair and replacement, there remain large patient populations that do not receive such therapies. This, in turn, implies a great need for future basic, applied, and clinical research and, ultimately, therapeutic developments. Heart Valves is a state-of-the-art handbook dedicated to: 1) cardiac valve anatomy, 2) models for testing and research methods; 3) clinical trials; and 4) clinical needs and applications.

This text covers the basic principles of mitochondrial dynamics in cardiovascular medicine, with particular emphasis on their functional roles in physiology and disease. The book will include articles pertaining to mitochondrial fitness on a global basis, providing therefore an update on the progress made in several aspects in the field. Thus, it will assist scientists and clinicians alike in furthering basic and translational research. Organized in sections focusing on: basic science, mitochondrial dysfunction in cardiac disorders, in vascular disorders, in metabolic disorders, in kidney disease, therapeutic challenges and options, this essential volume fills imperative gaps in understanding and potentially treating several cardiovascular disorders.

A comprehensive review of all the latest developments in cardiac electrophysiology, focusing on both the clinical and experimental aspects of ventricular repolarization, including newly discovered clinical repolarization syndromes, electrocardiographic phenomena, and their correlation with the most recent advances in basic science. The authors illuminate the basic electrophysiologic, molecular, and pharmacologic mechanisms underlying ventricular repolarization, relate them to specific disease conditions, and examine the future of antiarrhythmic drug development based on both molecular and electrophysiological properties. They also fully review the clinical presentation and management of specific cardiac repolarization conditions.

Advancements in the treatment and prevention of Atrial Fibrillation are presented in this important new book. Atrial Fibrillation affects approximately 2.5 million individuals in the United States and is projected to affect 15 million individuals by 2050. In Atrial Fibrillation: From Bench to Bedside, the reader is provided with the latest information that is critically important in the daily care and for the potential cure of patients with Atrial Fibrillation. Each chapter deals with a different aspect of Atrial Fibrillation and was authored by internationally recognized experts in the evolving field of cardiac electrophysiology. This book is a single source that provides a multi-perspective look at and approach to Atrial Fibrillation. Because Atrial Fibrillation is so prevalent and affects all areas of medicine, the information in this book will be useful to cardiologists, cardiac surgeons, researchers, and all those in the medical field.

This book deals with the basic concepts of high resolution electrocardiography: the electrophysiological basis of late potentials, mechanism of arrhythmias, the different methods of recording and analysis of high resolution, signal processed electrocardiograms and their clinical applications. This is a new edition and is more up-to-date, provides more clinical utility and addresses more basic concepts of the electrophysiology of re-entrant arrhythmias than any other book published in the same field. The book will appeal to cardiologists (academic and clinical), electrophysiologists, technicians and engineers working in the field of computerized electrocardiography and in industry.

Accurate diagnosis of arrhythmias is the goal of this volume. Before the clinician can accurately classify the multiple permutations of cardiac rhythm encountered in daily practice, several essential preconditions must be met. At the most basic level, the clinician must know the diagnostic criteria for each rhythm. Without a clear understanding of these criteria, an accurate differential diagnosis is impossible, and without accurate diagnosis, correct intervention is a mere matter of chance. A second precondition of accurate rhythm diagnosis is an understanding of the mechanism of arrhythmias. Not uncommonly, two or more arrhythmic mechanisms coexist, confronting the clinician with a baffling mixture of apparently unrelated complexes and intervals. Without an understanding of the various arrhythmic mechanisms, simple and complex, the tangled skein of data can never be unraveled. Finally accurate arrhythmia diagnosis depends on skill attained through practice. The competent electrocardiographer combines the skills of precise measurement and rational application of logic with broad theoretical knowledge. The pleasure of electrocardiography is seeing through the surface appearance to the inner workings. Interpretation of Cardiac Arrhythmias presupposes no prior knowledge of arrhythmias, and progresses from basic to the complex. The didactic sections focus extensively on the mechanism of arrhythmia, using laddergrams and other diagramatic devices to help the student visualize what is happening with the cardiac conduction system. Extensive self-assessment sections enable students to apply critical skills and test their grasp of the diagnostic criteria.

This book focuses on issues in clinical practice and research that are of general interest. The articles primarily focus on understanding the pathogenic mechanisms of diseases, their prevention, and therapy. The topics addressed include cardiovascular regulation with regard to blood pressure and heart rate variability, and to coupling blood pressure changes with subarachnoid fluid oscillations. In addition, the book discusses recent advances in the diagnostics of and targeted molecular therapy for renal and pancreatic malignancies, growth disorders, vitamin D and calcium homeostasis in children in the context of neonatal urolithiasis, and neurosurgical interventions in multifarious age-related diseases of the vertebrae. Neuropsychological aspects of patients' quality of life and of shaping medical staff's attitude toward patients are also addressed. The respective articles are intended to build a bridge between basic and clinical research. Further, the book enhances the current body of knowledge on diagnostics and patient treatment and offers valuable new perspectives on practical clinical issues. As such, it offers a unique resource for clinicians, family physicians, medical scholars, and professionals engaged in patient management.

Twenty years have elapsed since cytoplasmic proteins exhibiting high-affinity binding of long-chain fatty acids were first identified (Ockner et al., Science 177:56-58, 1972). These cellular fatty acid-binding proteins (FABPs) are now well established to comprise a ligand-defined group of macromolecules belonging to a family of cytoplasmic lipid binding proteins. Unique features of the FABPs are the existence of distinct types of FABP and that these are found in a variety of tissues in remarkable abundance, with some cells expressing more than one type. The physiological significance of the FABPs has only partly been elucidated. By increasing the cytoplasmic solubilization of fatty acids, the cellular FABPs are considered to function primarily in intracellular fatty acid transport, but may also be assigned important regulatory roles in cellular lipid homeostasis as well as in the modulation of cell growth and differentiation. The broad interests in cellular FABPs has led to the organization of the 1st International Workshop on Fatty Acid-Binding Protein, held in Maastricht, the Netherlands, in 1989. Prompted by the success of the first meeting, the 2nd International Workshop on Fatty-Acid-Binding Proteins, which was held again in Maastricht, on August 31 and September 1, 1992, brought together scientific scpecialists in the field of FABP research for two days of intensive and fruitful discussion. This volume is a collection of selected papers from this conference, and thus provides the state-of-the-art knowledge of cellular FABPs. The contributors to this issue represent pioneering as well as new investigators, and also reflect the multidisciplinary nature of research in this exciting and rapidly progressing field.

Following systematic development of technical aspects and physiological understanding, and clinical applicability of cardiac autonomic testing, this book provides a detailed guide to performing individual autonomic tests in both research and clinical settings. The book is structured in three parts covering the physiological background of cardiac autonomic regulations, description of technology and interpretation of individual autonomic tests, and applicability of the individual tests under various clinical circumstances and in defined populations of patients. The book is intended to serve both research and clinical cardiologists as well as research and clinical specialists of other medical fields who use the assessment of cardiac modulations to investigate the autonomic nervous system.

There is a paradox in hypertension: whereas the pathophysiological mechanisms of the disease have been related principally to a constriction of small arteries, most of the complications refer to damage of the large arteries, particularly at the site of the brain, the kidney and the heart. In the past, large arteries were poorly investigated in hypertension mainly in terms of change in blood flow. Recent studies clearly showed that the large arteries are largely involved in the mechanisms of hypertension not only through changes in mean blood flow, but rather through changes in stiffness of the arterial wall. This aspect may be a key-point for the development of hypertensive complications. Subsequently, the goal of treatment may be not only blood pressure reduction but also improvement of structural and functional abnormalities of the large vessels. These therapeutic aspects are analyzed in detail in the present book.

The aim of Molecular Cardiology: Methods and Protocols is to document state-of-the-art molecular and genetic techniques in the area of cardiology. These modern approaches enable researchers to readily study heart diseases at the molecular level and will promote the development of new therapeutic str- egies. Methods for genetic dissection, signal transduction, and microarray analysis are excellent tools for the study of the molecular mechanisms of cardiovascular diseases. Protocols for transgenesis take advantage of recent advances in many areas of molecular and cell biology. Transgenic models of heart diseases (cardiac hypertrophy, cardiac dysfunction, and so on. ) are powerful tools for the study of heart disease pathogenesis. Methods for gene transfer to heart tissue using viral and nonviral vectors form the basis of gene therapy for heart diseases. Heart-specific promoters containing a hypox- inducible cardioprotective gene switch are key for protection of the heart from ischemia. Gene and stem cell therapies open novel and exciting avenues for the prevention and treatment of heart diseases. Molecular Cardiology: Methods and Protocols consists of 26 chapters de- ing with various aspects of molecular cardiology, including gene transfer and gene therapy for cardiovascular disease, stem cell therapy for cardiovascular disease, gene analysis in the injured and hypertrophied heart, and transgenesis in cardiovascular research. This book provides step-by-step methods for the successful completion of experimental procedures, and would be useful for both experienced and new investigators in the field of molecular cardiology.

During the last decade we have witnessed a rapid expansion of our knowledge of the role of the endothelium in the control of vascular tone and hemostasis. In paricular, developments in molecular biology have enabled us to understand its physiology in greater detail. Furthermore, it is now clear that dysfunction of the endothelium contributes to various cardiovascular diseases. This is especially true for the coronary vascular bed. Development of atherosclerosis, disturbed vasomotor tone in stable ischemic syndromes, and the interaction of thrombocytes with the endothelium in acute ischemic syndrome are all consequences of endothelium dysfunction. Also, secondary changes in endothelial function have been described, for instance in chronic heart failure. This monograph reviews the present knowledge of the role of the endothelium in the control of coronary flow. The authors lead the reader through this topic starting at the basic physiology of endothelial function and the principles of coronary flow regulation. Next, the use of modern clinical techniques to evaluate endothelial function such as positron emission tomography and angioscopy are discussed. Subsequently, several pathophysiological processes and the role of endothelium are addressed. Finally, the interaction of various presently used cardiovascular drugs with the endothelium is indicated. It is the combination of basic sciences with clinical observations in this book which may be appreciated by a large number of scientists and physicians active in the field of cardiovascular disease. It is also this combination of different disciplines which will determine future developments and new avenues in pharmacotherapy involving the endothelium.