Bøger i Developments in Cardiovascular serien

The hemodynamic mechanisms of hypertension are often limited to the study of three dominant parameters: blood pressure, cardiac output and vascular resis­ tance. Accordingly, the development of hypertension is usually analyzed in terms of a 'struggle' between cardiac output and vascular resistance, resulting in the classical pattern of normal cardiac output and increased vascular resistance, thus indicating a reduction in the caliber of small arteries. However, during the past years, the clinical management of hypertension has largely modified these simple views. While an adequate control of blood pressure may be obtained with antihypertensive drugs, arterial complications may occur, involving mainly the coronary circulation and suggesting that several parts of the cardiovascular system are altered in hypertension. Indeed, disturbances in the arterial and the venous system had already been noticed in animal hypertension. The basic assumption in this book is that the overall cardiovascular system is involved in the mechanisms of the elevated blood pressure in patients with hypertension: not only the heart and small arteries, but also the large arteries and the venous system. For that reason, the following points are emphasized. First, the cardiovascular system in hypertension must be studied not only in terms of steady flow but also by taking into account the pulsatile components of the heart and the arterial systems. Second, arterial and venous compliances are altered in hypertension and probably reflect intrinsic alterations of the vascular wall.

In recent years considerable progress and new developments in diagnostic and interventional cardiology have been observed, such as balloon angioplasty of coronary artery stenoses, reperfusion techniques in acute myocardial infarction, new pacing, and cardioversion-defibrillation techniques in ventricular tachyar­ rhythmias. On 5-8 May, 1985, an international symposium on 'Invasive Cardio­ vascular Therapy' was held in Cologne, which provided a survey on the experi­ ment~l and routine therapeutic measures presently available and practiced in cardiovascular medicine. This volume is based on the oral presentations given during the symposium. In five chapters the most important traditional and new interventional techniques are discussed by experts in the field. Chapter I contains a description of results from catheter palliation of congeni­ tal shunt disorders or relief of congenital pulmonary or aortic valve stenoses as well as the recent experience with surgical repair of single ventricle, Fallot's tetralogy and tricuspid atresia. Chapter II presents the surgical results of valve replacement with different valve prostheses in acquired valvular disease, the surgical management of bacte­ rial endocarditis, as well as the various techniques of partial transient left heart support devices and of cardiac transplantation. In chapter III, the invasive management of chronic coronary heart disease, peripheral vascular disease by balloon catheter or laser techniques, and the surgical approach to coronary heart disease are discussed.

Over the past twenty years, technical advances in coronary arteriography have contributed to our understanding of the pathophysiologic aspects and natural history of coronary artery disease. Probably more than 700. 000 coronary arterio­ grams are performed annually throughout the world. Usually, these arteriograms are interpreted visually to determine the morphologic extent and severity of coronary artery disease. These subjective determinations, which are hampered . by relatively large intra- and interobserver variations, are used as a basis for critically important therapeutic decisions: Which arteries are to be revascular­ ized, which lesions are suitable for coronary bypass surgery or for percutaneous coronary angioplasty? To improve on this clinical decision making, on the treat­ ment and follow-up of such patients, new, objective and reproducible techniques for the assessment of the extent and severity of coronary artery disease, both in terms of anatomy and functional significance of the lesions, must be made widely available. With such new procedures and technologies the efficacy of new thera­ peutic procedures, the effects of vasodilating and constricting drugs, and the results of long-term studies on the regression and progression of atherosclerotic plaque can be determined in an objective and cost-effective manner.

The introduction of quantitative Doppler echocardiography gave rise to explo­ sive interest in the application of this method in clinical cardiology. However, before cardiologists could fully validate its clinical utility, they were confronted with a further development, namely color-coded Doppler flow imaging. This new technique allows a comprehensive study of the direction, velocity, uniformity and timing of intracardiac blood flow, while simultaneously revealing cardiac struc­ tures and their movement. 'Color Doppler' facilitates the diagnosis of a variety of cardiac conditions, and an overwhelming amount of information is available at any instant. Interpretation of these fascinating images requires a substantial experience and theoretical background. This monograph updates the application of color Doppler to both congenital and acquired heart disease. The work comprises 15 chapters written by authorities in the field, each of whom presents his most recent experience in the field. In addition, further advantages in the clinical use of pulsed and continuous wave Doppler in pediatric and adult cardiol­ ogy are presented. This book contains, of course, many color plates. 1. Roelandt, M. D. VII Contents Preface V List of contributors IX 1. Technical aspects and physical principles revisited Structure and performances of mono- and bidimensional pulsed Doppler systems 3 P. Peronneau, B. Diebold, J. P. Guglielmi, O. Lanusel, R. Bele, J. Souquet Estimation of transvalvular pressure drops hy Doppler echocardiography: the Bernoulli equation revisited 19 H. Rijsterborgh, 1. Roelandt Factors influencing fluid velocity measurements in valvular regurgitation 29 B. Wranne, P. Ask, D.

The ultrasound velocity tomography allows measurement of cardiac geometries for various phases in the cardiac cycle. The present tomograph makes reconstruc­ tions at intervals of 20 ms. Because of a lack of clear (intramural) landmarks (except the roots of the papillairy muscle), it is difficult to pinpoint spatial trajectories of particular points in the heart. Therefore, a second method was developed of injecting radiopaque markers in the heart and following their motion patterns during the cardiac cycle with help of a biplane X-ray equipment. The data obtained with both methods can be implemented in our finite element model of the heart to compute intramural stresses and strains. The results obtained sofar with the extended Darcy equation to account for the interaction of blood rheology and tissue mechanics look promising. Further testing with more sophisticated subjects than mentioned in Figure 9 is required before it will be implemented in our finite element model of the heart. We conclude that analysis of regional cardiac function, including regional myocardial blood flow, requires still a major research effort but the results obtained sofar justify, to our opinion, a continuation in this direction. Acknowledgement The authors acknowledge Dr. C. Borst and coworkers for doing the animal experiments and prof. Van Campen and dr. Grootenboer for their participation is some aspects of this work.

2 The free internal Ca+ concentration in human red cells is set according to the leak­ 2 and-pump principle: There is a finite passive Ca+ influx at the physiological 2 2 Ca+ -gradient across the membrane which is compensated by Ca+ pumping in the outward direction with a rate given by the degree of saturation of the A TP-fuelled Ca­ 2 pump at the steady-state internal Ca+ concentration. Simons (1982) recently devised a method allowing the measurement of the steady­ 2 2 state internal Ca+ concentration. Cells are suspended in media of different Ca+ con­ 2 2 tent whose Ca+ concentration is monitored by a Ca+ -selective electrode. When the cells are lysed (by digitonin) there is an upward or downward deflection of the elec­ 2 trode signal. At the point of zero deflection, the cellular Ca+ concentration equals that 2 of the medium. The result is, that in fresh human red blood cells the Ca+ concentra­ tion is ;;;; O.4,uM (this is an upper estimate; the true value may be considerably lower).

The fundamental fault in hypertension is unknown. Calling it a fundamental fault, indeed, tacitly begs the question: Is there one fundamental fault, or are there several that are interlinked or interdependent? A simple yes or no answer cannot be offered. This volume is not designed to survey the up-to-date recent advances in research on hypertension, nor intended to provide provisional an­ swers to the so many unknowns in this topic. It is, in fact, an attempt to articulate questions that are worth asking, given the license of an unhibited, albeit disci­ plined, inquiry. The range of expression varies from dogmatic opinion to a declared speculation. Is the primary abnormality an excessive sodium and reduced potassium intake over generations? Or is it hormonal excess, deficiency, imbalance or altered synthesis of abnormal forms? Does the nervous system playa role of active initiation or only of passive maintenance in the genesis of hypertension? Is the heart only a pump acting in concert with the happenings to the vasculature trying to provide adequate flow in the face of vasconstriction induced by neural or humoral factors, or does it sometimes become the culprit by pumping blood flow in excess of demand and thus initiating hypertrophic changes in blood vessels, or by assuming the role of an endocrine organ and being the source of a hormone with influence on cellular transport of sodium and on vasomotor tone? Is an elusive and mysterious fault in the kidney, the primary basis of all of the above

In the thirty years since the advent of efTective pharmacologic treatment for hypertension, the world ofthe hypertensive has been transformed beyond recog­ nition. The first change involved only malignant hypertensives with enough residual renal parenchyma to survive. Such a hypertensive could trade inevitable renal failure - unless an intracerebral bleed occurred first - for a rigid regimen which prevented his blood pressure from destroying him but which was asso­ ciated with nearly intolerable side effects. Over the next 20 years, increasing numbers of patients with hypertension of decreasing severity were treated with drugs that had fewer and fewer side effects. In 1970, with the medical world finally ready to accept the concept, the well-known Veterans Administration Study demonstrated that morbidity and mortality could be diminished in mode­ rately hypertensive patients by antihypertensive therapy that had minimal side effects. As a result there has been a major attempt to bring everyone with elevated blood pressure under lifelong pharmacologic control. It is difficult, however, to know what levels ofblood pressure deserve treatment; many who, when therapy first became available, would not have even been considered hypertensive are now candidates for treatment. The lower the pressure, the larger the potential population to be treated, but the smaller the individual risk and hence the smaller the possible benefit. The point where decades of diminished quaiity of life from treatment begins to outweigh a possible late-life complication is yet to be de­ termined.

It is not often that one one writes the foreword for a book based on a conference which contributed so much to our knowledge in the field of hypertension. During my close association with the International Society of Hypertension from 1978-1982, numerous satellite symposia were held in connection with five interna­ tional meetings. The specific topics addressed in this volume, the quality of the contributions, and the superb expertise of the contributors make this monograph one of the most outstanding publications that the International Society of Hyper­ tension has sponsored. Satellite symposia such as the present one serve useful and important functions for our society. They provide a mechanism of getting together the outstanding experts on special subjects for presentation of new data and for a free interchange of ideas. This type of endeavor is one of the most uniquely effective ways of accumulating new knowledge, because the data presented are subjected to critical review and discussion. No textbook or publication in journals can provide the type of critically evaluated information that comes from a small group­ is a mechanism for scientists to become meeting of this type. Furthermore, it acquainted or better acquainted with one another. All of this is, of course, very provocative and supportive of high quality research, one of the trademarks of the International Society of Hypertension. The conference for this book publication was organized by Drs.

This book is a comprehensive overview of electrocardiography and the major effects of current cardiac pharmacological therapy on electrocardiography. The text is based on work presented at the International Symposium on Non-invasive Cardiovascular Diagnosis and Therapy, held in May, 1987 at the University of Cologne. The theme of the book is to review, in broad clinical perspective the current state-of-the-art of electrocardiography as it pertains to standard electrocar­ diograms, exercise testing, ambulatory electrocardiography, electrocardiographic telemetry, and high resolution electrocardiography. Furthermore, advance!, in cardiac drug therapy in relation to diuretics, beta blocking drugs, antiarrhythmic agents and thrombolytic agents are reviewed. The emphasis of the conference and this book is to review the clinical state-of-the-art information and applications in this regard. In the initial section on electrocardiography, Dr. Spodick reviews our present day physiologic and pathophysiologic understanding of systolic time intervals, and how they are affected by a variety of cardiac disease states and pharmacologic agents. Dr. Ellestad examines problems and provides pragmatic tips on exercise testing in the diagnosis of coronary artery disease, and advances in exercise scores and computer analysis. Dr. Graboys reviews the value of exercise testing in the diagnosis and management of patients with serious ventricular arrhythmias. Dr. Kellermann presents the complimentary role that exercise testing plays in com­ prehensive follow-up therapy of the cardiac patient, and the use of exercise for work and physical training. Detailed information concerning the interaction of cardiac rehabilitation and ventricular arrhythmias are examined.

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.

World-wide, the fibre optics communications market is estimated to reach 8.3 billion dollars annually by 1998. The full exploitation of this enormous potential in science, engineering and other applications requires the precise characterisation of optical fibres and their associated systems and components, based on effective and accurate measurements supported by reliable measuring standards and good practice in measurement and calibration. Furthermore, it is necessary to have in place permanent intercomparison practices, both horizontal and vertical. With this aim in view, Trends in Optical Fibre Metrology and Standards covers optical fibres and materials; optical fibre components; optical sources; optical fibre amplifiers; optical fibre characterisation; calibration and standards; instrumentation; optical communications systems; optical sensors; and future trends. An unparalleled coverage of a topic of acute commercial and scientific interest.

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.

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.

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.

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.

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.

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.

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.

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 .

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 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.

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.

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.