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How to face 'the faces' of cardiac pacing represents an editor's compiled selection of lectures on cardiac pacing and electrophysiology. Electrical stimulation of the heart is an ever-changing and, at times, explosive field. The number of implanting centres is growing tremendously and pacing is not exclusively confined to arrhythmologists. Therefore, the editors attempted to organize a course being both practical in daily clinical management and instructive in understanding technical concepts. The glossary of terms have to be clearly understood before one is able to interpret the complex electrocardiograms of DDD and especially DDDR pacemakers. Those electrocardiograms have to be approached in a system­ atic way, using a step-by-step analysis. The main clinical symptom requiring pacemaker implantation is syncope. It cannot be over-emphasized that syncope is a clinical diagnosis merely based on history and physical examination. The organization of a pacemaker follow-up clinic depends on local facilities and needs. The effectiveness of pacing controls markedly increases when using a systematic approach. Repeated optimal adjustment of pro­ grammable functions is part of the control. Antiarrhythmic drugs are loosing popularity in the treatment of tachy­ arrhythmias. Nonpharmacologic treatment (antitachypacing, implantable defi­ brillators and antiarrhythmic surgery) at the present time have definite indications, probably expanding in the future. When complexity in electronic devices increases, repercussions on ex­ penses, either by the government or social and private insurances, needs consideration.

The Symposium on New Drugs provides a forum for academic investigators, research and development personnel from the pharmaceutical industry and members of the Food and Drug Administration to discuss important clinical research issues. The Ninth Annual symposium on New Drugs addressed the problem of determining the risk versus benefit for use of three important classes of cardiovascular agents: thrombolytic, antiarrhythmic, and hypolipidemic agents. The use of thrombolytic agents has become one of the major advances in clinical intensive cardiologic care in the 1980s. While the lysis of clot(s) obstructing a major coronary artery should reverse or prevent the damage of acute myocardial ischemia and infarction, one must carefully consider the potential risks of such agents in regards to their potential benefits. The time when a thrombolytic agent should be administered to maximize benefit as well as how one defines a dose response relationship using intravenous critical care medicines were discussed as important clinical trial issues. The benefit versus risk data on currently available thrombolytic agents was reviewed and the potential roles for adjunctive agents addressed. Overall strategies regarding post- x thrombolytic care and relationships to sudden cardiac death were also detailed. The panel discussion sections provided a comprehensive view of the current thinking of the various participating groups in this symposium. Sudden cardiac death remains the number one cause of mortality in western industrialized societies.

A critical review of the most up-to-date research on purines and myocardial protection. The role of purines in reversible `myocardial stunning' and irreversible (myocardial infarction) ischemic injury, ventricular arrhythmias, and ischemic preconditioning is discussed in detail, by experts. All reviews address recent and rather controversial issues on purines and myocardial protection. Mechanisms of cardioprotection of exogenous versus endogenous purines are discussed in detail. The contribution of internationally recognized experts in the field of purines and cardiovascular physiology and in myocardial protection makes this a unique and interesting book for clinicians, basic scientists and students.

It is quite natural that literature related to car­ heart disease, cardiomyopathy, pulmonary and diac structure, function, pathology, and patho­ pulmonary vascular disease, trauma, acquired valvular disease, congenital disease, and surgi­ physiology has emphasized the left heart and systemic circulation. The relative lack of im­ cal considerations. The pathologic and clinical relevance of myocardial infarction of the right portance of the right ventricle was supported by studies performed in the 1940s and 1950s ventricle has only been documented over the which suggested that the right ventricular free last 15 years. The chapter on right ventricular wall could be effectively destroyed in an animal infarction integrates clinical, functional, patho­ model without detectable untoward hemody­ physiologic, and pathologic observations to pro­ namic consequences. The relative inadequacy vide the reader with a thorough review, equally of noninvasive tools to study right ventricular relevant to the clinician and investigator. The contribution on dilated cardiomyopathy pro­ structure and function obviated detailed and systematic investigation. However, over the vides novel insight into the impact of right ventricular performance on the functional in­ past 15 years there has been a resurgence of interest in the right ventricle by a variety of capacity accompanying left heart failure. A book dealing with the right ventricle would investigators. The skeptic would argue that this renewed interest resulted from an exhaustion be incomplete without at least cursory reference we have of clinically-related observations that could be to the pulmonary circulation.

There are few techniques that have influenced therapeutic strategies in modem cardiology to a similar extent as coronary arteriography. Bypass surgery as well as transluminal coronary angioplasty would not have been possible without coronary angiography serving as a 'midwife' in their evolu­ tion. Despite the widespread and long-standing use in clinical practice, however, the interpretation of coronary angiograms has not changed very much since the early days. Most angiogr~s are still reviewed in a visual and semi-quantitative and thus often very subjective way. In the face of an almost exploding field for interventional catheterization including thrombolysis, balloon dilatation, and other rapidly evolving techniques for transluminal revascularization or recanalization, a more detailed and quantitative analysis of coronary arteriograms is urgently required. In addition to the delineation of coronary morphology, we need dynamic and functional information about flow and perfusion to understand the physiological significance of anatomic abnormalities. Coronary arteriography contains and can provide most of this information. With the application of appropriate techniques, it can be made available in the catheterization laboratory even during the patient's investiga­ tion, thus facilitating and improving clinical decision making. Objective and reproducible analysis will furthermore enhance our understanding about the pathophysiology of coronary disease.

Hypertension is the major cause of left ventricular hypertrophy. While the electrocardiogram is an extremely insensitive measure of anatomic left ven­ tricular hypertrophy, it provides a time-tested important marker of an adverse cardiovascular outcome. There has been a recent temporal decrease in the incidence of electrocardiographic evidence of L VH even within the hyperten­ sive population; no doubt this is the result of large antihypertensive treatment experts. Anatomical evidence of left ventricular hypertrophy is best docu­ mented pre-morbidly using echocardiographic techniques. It therefore ap­ pears that between 20 and 50 percent of the hypertensive population has left ventricular hypertrophy by echo cardiographic techniques. The prognostic significance of the echocardiographically determined increase in left ventric­ ular mass is just beginning to be evaluated. Early information suggests that there is an increased rate of cardi~)Vascular morbidity in patients with echo car­ diographic evidence of increased left ventricular mass. However, this in­ formation is only preliminary, and as yet only a limited number of events have been reported. Far more supporting information will be required before the full impact of echocardiographically-detected left ventricular hypertrophy can be determined. Nevertheless, it must be stated that the electrocardiogram still has the greatest predictive value of cardiovascular morbid and mortal events when the pattern of left ventricular hypertrophy plus repolarization abnormal­ ities are present.

The Symposium on New Drugs provides for an annual forum for academic investigators, research and development personnel from the pharmaceutical and related health care industries, and members of the Food and Drug Administration to discuss important clinical research issues. The Tenth Annual Symposium on New Drugs addressed the problem of whether it was still appropriate to approve antihypertensive agents soley on the endpoint of lowering cuff blood pressure. The initial discussions at this symposium related to the approaches and methods to studying antihypertensive agents. Dr. William Frishman provided a detailed list of the new approaches to the treatment of hypertension and pointed out the many new concepts that are currently active in the development of many new antihypertensive agents. Dr. William White detailed the growing importance of ambulatory blood pressure monitoring to define hypertension and to determine the change in blood pressure due to pharmacologically active agents. Dr. Jay Cohn pointed out the flaws in using cuff blood pressure and detailed the potential virtues of using vascular compliance to identify patients requiring treatment for hypertension. Dr. Thomas Pickering also discussed the potential value of evaluating changes in left ventricular hypertrophy a finding which identifies high risk patients who need to be included in clinical trials. Dr. Michael Weber detailed the issues and suggested refinements in the approaches to clinical trial designs for antihypertensive agents and Dr. Raymond Lipicky discussed the definition of dose-duration and the role of non-Mem and Peak/Through measurements in defining an antihypertensive drug effect.

Research at the molecular and the cellular level has greatly enhanced our understanding of the pathogenesis and management of heart disease. Valuable contributions, towards this end, have been made by scientists from different dis­ ciplines including biochemistry, physiology, pathology, molecular biology and biophysics. We felt that it would be of interest and value to bring together ex­ perts from diverse specialities to present their work and to discuss the common problems encountered in their endeavours. In accordance, a symposium was organised in February 1988 at the Postgraduate Institute of Medical Education & Research, Chandigarh. It was held during the annual meeting of the Indian section of the International Society for Heart Research. This book is a compila­ tion of some of the papers presented at the symposium. The symposium was sponsored by the Council on Cardiac Metabolism of the International Society and Federation of Cardiology. A number of Indian or­ ganisations gave generous financial help. These included the National Academy of Medical Sciences, Indian Council of Medical Research, Council of Scientific and Industrial Research and Department of Science and Technology. Desktop publishing was used to prepare this volume. In doing so we came to appreciate the remarkable qualities, skills and help rendered by Professor Dharam Vir. For typing the manuscripts and for other secretarial assistance we gratefully acknowledge the help of Ravinder and Sawtantar. PATHOPHYSIOLOGY AND PHARMACOLOGY OF HEART DISEASE 1 THE NEWBORN PIG HEART, A SUPERIOR ANIMAL MODEL OF CARDIAC HYPERTROPHY Howard E.

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.

The Stressed Heart is truly unique in concept and will provide an eXCItmg adventure to the reader no matter what his or her field of expertise and interest. The title, although quite appropriate, does not adequately indicate the range of topics considered or the rational interrelationships among them. Indeed, perhaps the most important point to be learned from the book is that a serious consideration of the response of the heart to mechanical overload, ischemia, or excessive humoral stimuli must include evaluation of each of the topics in the table of contents. The heart responds to stress through alterations in both structure and function. How these changes are brought about is the subject of the initial chapters. These consider first the normal regulation of gene expression in the heart, the rapid response to mechanical overload that leads to both quantitative and qualitative changes in the contractile proteins, and our current understand­ ing of the signals that might be elicited by stress and alter gene expression. One chapter emphasizes the fact that, regardless of the nature of the stress, the common denominator is a discrepancy between energy requirements and expenditure. The central role of cellular acidosis in initiating the sequence of responses to stress and the possible roles of peptide regulators of transcription and protein regulators of translation are considered in detail.

These Proceedings are from the Fifth Annual Meeting of the American Section of the International Society for Heart Research held at Hilton Head Island, South Carolina, September 21-24, 1983. The program and abstracts were published in the Journal of Molecular and Cellular Cardiology, Vol. 15, Supplement 4, September 1983, Academic Press. This Symposium Proceedings consists of three sections. Section I deals with the mechanical factors and their i'nfluence on coronary blood flow in the normal and failing heart. Section II is developed around the area of vascular smooth muscle and the factors that may control it which ultimately play such an important role in the regulation of coronary blood flow. Section III is primarily devoted to the mechanical aspects of the function of the heart in both hypertrophy and failure including the molecular changes in the myocyte, alterations in neural control, and in inotropic responsiveness of the hypertrophied and failing heart. The editors hope that these three areas encompass a significant body of new and ongoing information that will be helpful to those who work in these areas as well as those who treat patients with varying degrees of myocardial failure or with compromised coronary circulations. The editors express their appreciation to all the contributors and to Ms. Jeri B. McClain for assisting in the organization and compiling of this volume. Francis L. Abel, M. D. , Ph. D. Walter H. Newman, Ph. D.

The ATP-sensitive potassium channel (KATP) was discovered in 1983. Since then, an enormous amount of research has been undertaken to characterize it in detail. This volume consolidates both the current knowledge and most recent advances on the subject, and its relationship to myocardial protection. To this end, the editors have assembled investigators at the forefront of ongoing basic and clinical research to provide scholarly and candid comments concerning each of the pertinent issues, including: a comprehensive review of the biology of the channel with respect to the structure-activity relationship as well as overall chemistry of the channel; the role of opening this channel and its effect on smooth muscle (covering both the effects on myocardial stunning and its ability to protect against myocardial infarction); the relationship of KATP channel opening and the protection to the myocardium afforded by the phenomenon of ischemic preconditioning; the relationship between the KATP channel and electrophysiological consequences with specific reference to arrhythmogenicity; and the clinical implications of the use of agents that mimic the opening of this channel, with reference to its protective nature and its use in the treatment of angina. Audience: Clinicians and basic scientists who have a direct interest in the KATP channel as well as those groups who are interested in the entire concept of myocardial protection and its relationship to academic and clinical medicine.

In 1628 William Harvey published his discovery of the existence of the microcirculation which he deduced from careful anatomical and physiological study. Thirty-three years later, Malpighi confirmed the presence of capillaries through direct microscopical observation. Subsequent scientific advance has been slow, and in view of the fact that microvascular in the genesis and expression of many pathophysiology may be implicated diseases, our know ledge of human microvascular function is surprisingly limited. This ignorance attests to the difficulty of studying something that is both minute and inaccessible without disturbing the quantity that is being measured. In the last fifteen years, however, direct techniques have been developed for studying human microvascular pressure, flow and permeability. These methods have provided new insights into human microvascular function in health and disease. At the same time there has been a steady growth of new indirect techniques based on a w ide range of physical principles that reflect some or other aspect of microvascular function.

In summary, there are many animal models that are useful in selecting new antiarrhythmic drugs. The selection of which model is most idea depends upon precisely what question is being asked. The large number of experimental models used to evaluate antiarrhythmic compounds points out the inability of anyone model to define the probability of antiarrhythmic efficacy in man. It has therefore become standard practice to utilize a batter of animal models for the evaluation of new antiarrhythmic agents. Each model has its own advantages and disadvantages and it is necessary to understand each model fully in oder to evaluate experimental findings and apply them to clinical settings. We believe that the availability of the chronic myocardial infarction ventricular tachyarrhythmia model provides 1) an excellent opportunity to more precisely understand arrhythmia mechanisms, 2) to develop new techniques such as signal averaging for evaluating late low level potentials identifying hearts at high risk of sudden death 3) to identify new antifibrillatory drugs versus drugs that are effective primarily against PVC's and ventricular tachycardia 4) to identify new surgical techniques to eliminate VT/VF, and 5) to evaluate new pacing modalities including implantable cardioverters. Although all animal models are wrong, many are very useful in furthering our knowledge directed at decreasing the distressingly high mortality from heart disease. NORMAL HtART TACHYCMDIA HtART , .. '" \ I I I I I I I I I .

After a certain age, one is elderly, aged, venerable, and patriarchal. Or just plain old. When I became old, I did not know it. I do know it now because of a syndrome of which I had previously been unaware. It is quite simple-when it hurts, it works; when it doesn't hurt, it doesn't work! Writing about the old is a preoccupation of the young, and that is as it should be because it is the young who must carry the burden of the old. I don't know the average age of the contributors to Franz Messerli's book, but I would guess it to be less than 50, which to me is positively pubescent! For many years I thought geriatric medicine was nonsense, and today I still think some of it is. What changes with age are principally the attitude and purposes of the individual and how much energy he or she has to carry out those purposes. It isn't so much that the goals, ambitions, and desire to alter or improve the world disappear; they just diminish along with what it takes to accomplish them. Which brings me to one particular aspect of aging, that is, the cardiovascular system. The first evidence of the cardiovascular system's aging is the failure of the heart to respond to the demands placed on it.

In Harch of 1980, we organized the first symposium on how to evaluate new antiarrhythmic agents in which the participants included members of the Cardio-Renal Division of the Food and Drug Administration, academic investigators from the United States and Abroad and directors and imple­ mentors of pharmacological research representing the pharmaceutical industry. By bringing together all three elements, it was hoped that better communication and under­ standing would ensue to more rapidly bring new cardiac agents to the American public. This goal was important since a rather limited number of antiarrhythmic agents were and are currently available to treat patients with such disorders in the United States. These agents are needed not only for the treatment of patients with sustained ventricular tachyarrhythmias which produce life-threatening hemodynamic consequences but also and in fact more potentially important as a prophylactic measure in the high risk patient subject to sudden cardiac death. This book represents the proceedings of the third of these Symposiums whose purpose was to evaluate the clinical research methodology and models used in the evaluation of ne" antiarrhythmic agents for not only acute therapeutic inter­ vention but also for the prophylaxis of sudden cardiac death. In addition, new devices have evolved over the past few years that can detect and treat life-threatening cardiac arrhythmias and the evaluation of efficacy and safety of these devices is detailed.

The first Taurine Symposium organized by Dr. Ryan Huxtable and the late Dr. Andre Barbeau was held in Tucson, Arizona, in 1975. Since that auspici­ ous event, nine international symposia on the role of taurine in biology have taken place. The locations for these meetings have been Tucson (two times), Rome, Philadelphia, Tokyo, Vancouver, Mexico City, Helsinki, and Florence. In 1977, due to the large number of scientists in Japan who were interested in the role of this unique amino acid in biological systems, we organized the Japanese Research Society on Sulfur Amino Acids with the encouragement and financial assistance of the Taisho Pharmaceutical Co., Ltd (Tokyo). Annual meetings have been held, and the membership has expanded from 78 to 414 in 1987; the number of presentations has increased during this time span from 29 to 74. The symposium in Tokyo in 1982, "Sulfur Amino Acids, Biochemical and Clinical Aspects" [1], was held to celebrate the 5th Annual Meeting of our Society. I would like to emphasize that in Japan we have an active Research Society especially directed to the study of sulfur amino acids. We have published our own semi-annual journal entitled Sulfur Amino Acids. Our society is an inter­ disciplinary research society since taurine is a highly diversified compound that interconnects physiology, biochemistry, pharmacology, nutrition, and medicine. One exciting fringe benefit of taurine research and the society has been the fostering of contacts with distinguished scientists from many varied medical fields.

Although some investigators have questioned the importance and even the existence of silent myocardial ischemia, documentation presented at this two day symposium leaves little doubt about its existence and importance. It has been estimated that about 3 million of the estimated 4 million angina sufferers in the United states have frequent episodes of silent myocardial ischemia. Although it is not possible to define how many Americans die due to silent ischemia, it has been suggested that the mortality rate may exceed hundreds of thousands of victims annually. Unfortunately, there still remains a lack of definitive information as to why some ischemic events are painless. Some suggest the concept that the location and size of the myocardium at jeopardy relates to pain, that the pain threshold varies from patient to patient or that there are neurological deficits in the myocardium of some patients with silent ischemia. Abnormalities in myocardial perfusion and function can occur without pain. An interesting observation presented by several investigators has been that when a coronary artery is occluded in man, no ischemic pain is perceived for the first 30 seconds. Only after a 30 second period or so of occlusion does angina occur. An even more confusing observation is that some 30 second periods of occlusion of the same vessel in the same patient results in angina while the next occlusion can be a totally silent event.

Although the remarks that follow are based can be induced in a completely healthy heart by a relatively minor perturbation, on my reading not of the volume itself, but on my reading of the table of contents and namely, an electrical stimulus delivered in the vulnerable period. On the other hand, it of the editors' comments on each of the main sections of the book, it is clear that this is a very rare event, since during a lifetime synthesis is a timely one that shows how of 70 years, the average human heart con­ much we have learned in the past 30 years tracts and relaxes some 2. 5 billion times about tachyarrhythmias. This book also sets without developing persistent ventricular the stage for further research. New insights fibrillation. That an event so easily induced into the cellular basis for the generation of in a normal heart should occur so rarely is arrhythmias, new studies of fibrillation, an intriguing fact that seems worth bearing deeper investigations of the role of the ner­ in mind as we continue to investigate this fascinating phenomenon.

Focuses primarily on aortic and mitral valve disease.Special attention devoted to optimal timing and the role of echocardiography to assess prosthetic valve function and dysfunction.Discusses techniques for aortic valve surgery and choosing valve replacement devices.Part of the series: Developments in Cardiovascular Medicine

The VIth World Symposium on Cardiac Pacing in Montreal 1979 opened with a course, meant to be an introduction for newcomers and an updating re­ fresher and link between the various fields of knowledge needed by experienced persons for cardiac pacing. Invited guest lecturers were selected for their world recognized expertise in the individual subjects. This book is a collection of the various presentations on historical, clinical, electrophysiological and technical aspects of cardiac pacing. Together they cover the fundamentals of cardiac stimulation. We hope that this book may become an introductory guide to the field of cardiac pacing and that it may contribute to a better understanding of the pacemaker system and a better treatment of the pacemaker patient. Claude C. Meere Hilbert J. Th. Thalen ACKNOWLEDGEMENT The editors of 'Fundamentals on Cardiac Pacing' acknowledge the under­ standing and support of their families, during the long nocturnal hours and weekends during which this book was prepared. A special note of appreciation is extended to our secretaries, especially Mrs. Carolyn Gaarenstroom-Arriens and Miss Katrien Schuurman for their 'emergency typing' and Miss Lynn Bacon and Mr. Boudewijn Commandeur from Martinus Nijhoff Publishers, who succeeded in completing the book in time for the Montreal meeting. Only those involved are able to realize the importance of their contribution. CONTRIBUTORS David L. Bowers, B.S.E.E., Vitarel Inc. San Diego, California, U.S.A. Guy Fontaine, M.D., Groupe Hospitalier, Pitie-Salpetriere, Paris, France.