Bøger i Developments in Cardiovascular serien

In recent years there have been major advances in the fields of cardiovascular nuclear medicine and cardiac magnetic resonance imaging. In nuclear cardiology more adequate tomographic systems have been designed for routine cardiac use, as well as new or improved quantitative analytic software packages both for planar and tomographic studies implemented on modern state-of-the-art workstations. In addition, artificial intelligence techniques are being applied to these images in attempts to interpret the nuclear studies in a more objective and reproducible manner. Various new radiotracers have been developed, such as antimyosin, labeled isonitriles, metabolic compounds, etc. Furthermore, alternative stress testing with dipyridamole and dobutamine has received much attention in clinical cardiac practice. Magnetic resonance imaging is a relative newcomer in cardiology and has already shown its merits, not only for anatomical information but increasingly for the functional aspects of cardiac performance. This book covers almost every aspect of quantitative cardiovascular nuclear medicine and magnetic resonance imaging. It will assist the nuclear medicine physician, the radiologist, the physicist/image processing specialist and the clinical cardiologist in understanding the nuclear medicine techniques used in cardiovascular medicine, and in increasing our knowledge of cardiac magnetic resonance imaging.

1. Platelet activation and aggregation: rationale for combining antithrombotic drugs.- 2. Role of nitric oxide in endothelial cell - platelet interactions.- 3. Platelets and megakaryocytes in vascular disease.- 4. Thrombosis in relation to atherosclerosis.- 5. Pharmacological inhibition of the ADP-GP IIb/IIIa-fibrinogen pathway of platelet aggregation.- 6. Calcium fluxes in platelets and endothelial cells, mechanisms and functional significance.- 7. Inhibition of platelet function by cyclic nucleotides and cyclic nucleotide-dependent protein kinases.- 8. Pharmacological modification of platelet-derived cyclooxygenase product formation and its consequences for platelet-vessel wall interactions.- 9. Antithrombotics and the lipoxygenase pathway.- 10. Pathological expressions of platelet-vessel wall interactions: implications of serotonin.- 11. The involvement of PAF in thrombotic events.- 12. Prostaglandins and -analogs in the treatment of platelet-vessel wall interaction.- 13. Adjuvant agents to enhance and sustain reperfusion with t-PA: studies in experimental dog models.- 14. Effect of dietary marine lipids on (anti-)thrombotic mechanisms.

One: Pathophysiological considerations.- 1. The cell biology of atherosclerosis.- 2. The pathology of atherosclerosis.- Two: Occult carotid and cerebrovascular disease.- 3. The natural history of asymptomatic carotid artery disease.- 4. Techniques of screening, diagnosis and assessment of occult carotid and cerebrovascular disease.- 5. The diagnosis and management of occult atherosclerotic disease of the extra-cranial carotid artery.- Three: Occult coronary artery disease.- 6. Risk factors and epidemiology in the pathogenesis and clinical progress of occult coronary artery disease.- 7. ECG and stress testing in the diagnosis of occult atherosclerotic disease of the coronary arteries.- 8. Use of Holier monitoring in occult coronary artery disease.- 9. Radionuclide techniques in the diagnosis and assessment of occult coronary artery disease.- 10. Echocardiography in the diagnosis and assessment of occult coronary artery disease.- 11. Doppler ultrasound in the diagnosis and assessment of occult coronary artery disease.- 12. Prognosis and management of occult coronary artery disease.- 13. Occult myocardial infarction.- Four: Occult atherosclerotic disease of the aorta and arteries of the lower limbs.- 14. Epidemiology of occult atherosclerosis in the lower limbs.- 15. Occult aortic aneurysm.- 16. Occult atherosclerotic disease of arteries of the lower limb - incidence, pathophysiology, diagnosis and assessment.- 17. The detection of occult peripheral arterial disease using the one-minute exercise test.- 18. The management of occult atherosclerosis in arteries of the lower limbs.- Five: Occult atherosderotic disease of the renal and mesenteric arteries.- 19. Occult atherosclerotic involvement of the renal vasculature-pathophysiology, clinical manifestations and investigations contributing to management.- 20. Investigations of mesenteric and renal arteriosclerotic disease.- Six: New techniques, combined lesions and prevention.- 21. Use of DNA technology in the diagnosis of occult atherosclerotic disease.- 22. Occult cardiovascular atherosderotic disease in the diabetic.- 23. Who should be investigated for occult atherosderotic disease?.- 24. Prevention of occult atherosderotic disease.

1. The controlled clinical trial - a model for the intricate relationships between clinical medicine and drug research.- 1.1. Introduction.- 1.2. The evolution of the controlled clinical trial (CCT).- 1.3 The implementation of the controlled clinical trial in drug research.- 1.4. Criticism of the classical view of the controlled clinical trial.- 1.5. Conclusions.- 2. The architecture of drug discovery.- 2.1. Introduction.- 1. The discovery process.- 2.2. Current views of drug discovery.- 2.2.1. Basic concepts in drug discovery.- 2.2.2. Basic epistemologies in drug discovery.- 2.3. Scientific discovery from the viewpoint of cognitive science.- 2.4. The drug discovery process revisited.- 2. The representation of knowledge about drugs and diseases.- 2.5. An epistemological analysis of the concept of drug and disease profiles.- 2.5.1. Introduction.- 2.5.2. The concept of drug profile.- 2.5.2.1..The classification of drugs.- 2.5.2.2. Incursion of drug profiles into disease profiles.- 2.5.2.3. The nature of drug characteristics.- 2.5.3. The concept of disease profile.- 2.5.3.1. Disease profiles as pigeon holes of medical knowledge.- 2.5.3.2. The fundamental basis of taxonomy in medicine.- 2.5.3.3. Convergent and divergent forces in clinical taxonomy.- 2.5.3.4. The translation of everyday medical language into the structure of profiles.- 2.5.4. Conclusions.- 3. A set-theoretical model of drug discovery.- 2.6. A definition of the concept of profile in terms of set theory.- 2.6.1. Introduction.- 2.6.2. The first aspect of a profile: membership.- 2.6.3. The second aspect of the concept of profile: values of the disease characteristics.- 2.6.4. The third aspect of the concept of profile: ranking order of characteristics.- 2.6.5. Conclusions.- 2.7. The drug discovery process - a set-theoretical model.- 2.7.1. Introduction.- 2.7.2. A naive definition.- 2.7.3. First adjustment of the naive defenition: structural and functional characteristics of drugs.- 2.7.4. Second adjustment of the naive defenition: disease characteristics.- 2.7.5. The improvement of toxic effects of drugs: positive and negative aspects and their judgment.- 2.7.6. Conclusions.- 3.Experimental and therapeutic profiling in drug innovation: the early history of the beta blockers.- 3.1. Introduction.- 3.2. Historical overview of the development of the beta blockers.- 3.3. From Dale to Ahlquist: a new methodology in pharmacology.- 3.4. Change in the concepts of agonist and antagonist.- 3.5. Experimental and therapeutic profiling in drug innovation.- 3.5.1. Cardiac arrhythmias.- 3.5.2. Angina pectoris.- 3.6. Conclusions.- 4. Industrial research and beta blockade.- 4.1. Introduction.- 4.2. Beta blocker research at Imperial Chemical Industries (ICI).- 4.2.1. The early phase.- 4.2.2. The birth of pronethalol.- 4.2.3. The demise of pronethalol.- 4.2.4. The development of propranolol.- 4.2.4.1. A "clean" drug.- 4.2.4.2. The rapid expansion of a successful drug.- 4.2.4.3. Endangered drug.- 4.2.5. The development of practolol.- 4.2.5.1. Practolol: a tool in industrial research.- 4.2.5.2. Selectivity in industrial and academic research.- 4.2.5.3. The therapeutic interest.- 4.3. The beta blocker project of Eli Lilly & Co..- 4.4. The beta blocker project of Mead Johnson.- 4.5. The beta blocker project of AB Hässle.- 4.5.1. The early phase.- 4.5.2. Intrinsic sympathomimetic activity of alprenolol.- 4.5.3. The profiling of alprenolol.- 4.5.4. Selective beta blockade.- 4.6. The beta blocker project at CIBA.- 4.7. Conclusions.- 5. Verapamil: dying drug or sleeping beauty?.- 5.1 Introduction.- 5.2 The early history of verapamil.- 5.3 Verapamil: a coronary vasodilator?.- 5.4 Verapamil: a beta blocker?.- 5.5. Verapamil: a calcium antagonist! - The elucidation of verapamil's mechanism of action by Fleckenstein.- 5.6. Citation analysis of the concept of calcium antagonism elaborated by Fleckenstein.- 5.7. The application of the theory of drug and disease profiles.- 5.7.1. Changing views on the

1. From hemodynamic principles to clinical management.- 2. The clinical use and accuracy of echo-Doppler techniques for assessing severity of disease in valvular stenotic lesions.- 3. Proper timing of valve replacement in aortic stenosis.- 4. Optimal timing of surgery for volume overload hypertrophy in mitral and aortic regurgitation.- 5. Acute effects of myocardial ischemia on left ventricular function: How to differentiate myocardial infarction, stunned myocardium, and hibernating myocardium.- 6. Effects of coronary reperfusion on left ventricular function and survival: Some remaining problems.- 7. Effects of revascularization on left ventricular function in the stunned and hibernating myocardium.- 8. Heart failure: Newer concepts and origin of symptoms.- 9. Guidelines for the evaluation of treatment in congestive heart failure.- 10. Management of patients with hypertrophic cardiomyopathy.- 11. Antiarrhytmic therapy in heart failure.- 12. Non-invasive evaluation of cardiomyopathies.- 13. Can ultrasound reliably predict acute rejection in heart transplant recipients?.- 14. Cardiac transplantation.

Bound and Referential Pronouns.- Logical Form and Barriers in Navajo.- Towards a Modular Theory of Coreference.- Head Government in LF-Representations.- Logical Structure in Syntactic Structure: The Case of Hungarian.- In Defense of the Correspondence Hypothesis: Island Effects and Parasitic Constructions in Logical Form.- Construing WH.- Two Properties of Clitics in Clitic-Doubled Constructions.- LF Movement in Iraqi Arabic.- List of Contributors.

One Introduction.- One Anatomy of the Heart and of the Large Vessels.- Internal anatomy.- A. The ventricles.- B. The atria.- C. The coronary vessels.- D. The pericardium.- E. The anatomy of the large vessels.- 1. The main pulmonary artery.- 2. The aorta.- 3. The pulmonary veins.- 4. The vena cava system.- Two Principles of Cardiac Mr Imaging.- I: Basic physical principles of nuclear magnetic resonance.- I-1. Nuclei - Magnetic dipolar moment - Small magnet.- I-2. Spin and gyromagnetic ratio.- I-3. Static magnetic fields.- I-4. Precession - Resonant frequency - Longitudinal and transverse components.- I-5. Energy states and net magnetization vector.- I-6. Electromagnetic radiations - Resonance conditions.- I-7. Radiofrequency pulses.- I-8. Relaxation mechanisms - Relaxation times.- I-9. Detection of the NMR resonance signal - FID.- I-10. NMR Spectrum - Fourier transform - Chemical shift.- I-11. Experimental T2 times.- II: Advances imaging topics.- II-1. Spin-echo (SE) pulse sequence - Echo time (TE) and repetition time (TR) - Weightings.- II-2. Image contrast - Contrast weighting.- II-3. Image reconstruction.- II-4. Acquisition times - Scan time.- III: Special topics.- III-1. Fast imaging methods - Gradient echoes sequences.- III-2. Ultra fast imaging - The close future.- III-3. Flow phenomena.- III-4. Image quality.- III-5. Artefacts.- IV: References.- IV-1. Textbooks.- IV-2. Books chapters.- IV-3. Review articles.- Two Cardiac MR Imaging.- One MRI Slices of the Heart.- Transverse slices 1-13.- Sagittal slices 1-10.- Coronal slices 1-7.- LAO equivalent slices 1-10.- RAO equivalent slices 1-6.- Two Dynamic and Functional Studies.- Long axis views.- Short axis views.- Double angulation views.- End systole and end diastole.- Comprehensive Bibliography.- 1. Textbooks.- 2. Book chapters.- 3. Review articles.- 4. Technical considerations.- 5. Normal anatomy and MR-imaging planes of the heart.- 6. Ventricular function.- 7. Congenital heart disease.- 8. Valvular heart diseases.- 9. Chest, mediastinum and pulmonary hila.- 10. Myocardial ischemia and infarction.- 11. Cardiomyopathies.- 12. Contrast agents.- 13. Various heart diseases.- 14. Cardiac and paracardiac masses.- 15. Pericardium.- 16. Thoracic great vessels.- 17. Coronary arteries and grafts.- 18. Cardiac transplantation.- Anatomical Index.

The extension of conventional M-mode to two-dimensional echocardiography has been a major advance for the evaluation and management of cardiac disease. Their combined use is optimal for a comprehensive analysis of anatomy and structure function and thus best serving the patient. This book critically examines the validity of the applications of these ultra­ sound techniques in common cardiac disorders. In addition to the clinical value of contrast and Doppler echocardiography, several chapters are devoted to problems related to quantitation of both M-mode and two-dimensional echocardiography. This volume is specifically aimed at the practicing cardiologist and provides an in-depth appreciation of most recent echocardiographic advances. J. ROELANDT LIST OF CONTRIBUTORS Anliker, M., MD, Department of Cardiology, University Hospital Zurich, R!imistrasse 100, 8091 Zurich, SWITZERLAND. Carroll, J.D., MD, Department of Cardiology, University Hospital of ZUrich, R!imistrasse 100, 8091 Zurich, SWITZERLAND. Cate, F.J. ten, MD, Harbour Hospital, Haringvliet 2, 3011 TD Rotterdam, THE NETHERLANDS. Cikes, I., MD, Institute of Cardiovascular Disease, School of Medicine, University of Zagreb, Kispaticeva 12, 41000 Zagreb, YUGOSLAVIA. Domburg, R.T. van, PhD, Thoraxcenter, Academic Hospital Dijkzigt and Erasmus University, P.O. Box 1738, 3000 DR Rotterdam, THE NETHERLANDS. Ernst, A., MD, Institute of Cardiovascular Disease, School of Medicine, University of Zagreb, Kispaticeva 12, 41000 Zagreb, YUGOSLAVIA. Hanrath, P., MD, Department of Cardiology, University Hospital Hamburg-Eppendorf, Mar­ tinistrasse 52, 2000 Hamburg 20, BRD. Hess, D.M., MD, Department of Cardiology, University Hospital Zurich, R!imistrasse 100, 8091 ZUrich, SWITZERLAND.

This volume contains most of the invited lectures presented at the second "Interna­ tional Symposium on the Evaluation of Cardiac Dynamics by Ultrasound" which was held on May 27-28, 1982, in Hamburg. Main topics of the symposium dealt with new echocardiographic technologies such as the transesophageal technique and digital image processing of echocardio­ grams, as well as with latest clinical and experimental results in the fields of contrast and Doppler echocardiography, tissue characterization and analysis of left ventricular function. We are greatly indebted to all participants who kept a very tight schedule in order to have these proceedings available at the time of the meeting. We cordially thank Dr. M. Schluter for his editorial assistance, Mrs. B. Kratzenberg for her secretarial help, and the Pharma-Schwarz Company for their generous financial support. Hamburg, May 1982 The Editors CONTRIBUTORS ABE, A., First Department of Medicine, Osaka University Medical School, 1-1-50, Fukushi­ ma, Fukushima-ku, Osaka 553, Japan. BACKS, B., Medizinische Universitiitsklinik Bonn, Abteilung fUr Kardiologie, 5300 Bonn, BRO. BAKER, D.W., Ph.D., Squibb Medical Systems International, 2100 124th Avenue NE, Bellevue, WA 98005, USA. BIAMINO, G., M.D., Klinikum Steglitz, Kardiologische Abteilung, Hindenburgdamm 30, 1000 Berlin 20, BRO. BLEIFELD, W., M.D., Abteilung fiir Kardiologie, Universitiitskrankenhaus Eppendorf, Martini­ strasse 52, 2000 Hamburg 20, BRO. BOM, K., Ph.D., Thorax Center, Erasmus University, P.O. Box 1738, 3000 DR Rotterdam, The Netherlands.

With the beginning of the 1980's it was becoming increasingly evident that the lack of approval of new cardiovascular agents for use by clinicians in the United States for the treatment of cardiovascular disorders was becoming a problem. Patients requiring medical therapy for hypertension, angina pectoris, arrhythmias, congestive heart failure, and vasospastic disorders of the coronary arteries could receive in the United States only a small number of the drugs available to physicians in the rest of the world. In fact, as the 1980's began, there was only one available beta blocking agent released by The Food and Drug Administration; and even as of this writing, no oral calcium antagonist agent. This lag, in part, has been due to the confusion of proper and expeditious methods to define safety and efficacy of such agents so that the United States regulatory agency (Food and Drug Administration) could approve the use of such agents by clinicians. The vast number of new beta blocker and calcium antagonist agents being developed, as well as the long-term use abroad of many new drugs, has raised important questions as to how relative safety and efficacy of such agents can be determined to facilitate availability in the United States.

In the denervated state the mammalian heart, both in vivo and in vitro, is excited at very regular intervals, the coefficient of variance of the interbeat intervals not exceeding 2%. The pacemaker that is the source of this regular ex­ citation is localised normally within the sinus node (" sino-atrial node " node of Keith and Flack), a most intriguing small piece of tissue in the caval corner of the right atrium. A small portion of this node containing a group of probably only a few thousands of cells fires spontaneously, that means without any exter­ nal influence to trigger their activity. The so called pacemaker cells do this by letting their membrane potential fall to the level where an action potential will start which subsequently activates surrounding cells to fire an action po­ tential. The first question which is tackled in this book is which processes underly this spontaneous diastolic depolarization. This is discussed in section I, concerning the fundamental properties of pacemaker cells with special refer­ ence to ionic membrane currents. Although views still quite differ about the exact nature of the membrane processes that cause the automatic pacemaker dis­ charge there is agreement that diastolic depolarization is brought about by the interaction of a number of ionic current systems, including both inward and out­ ward going currents.

Hypertension is a major world-wide health problem. With high blood pressure there is a greater risk of stroke, heart attack, heart failure, kidney disease and renal failure. Far too few people realize what the risks are and what can be done to prevent these risks even in the countries where pro­ grams in hypertension research are active and the full significance of hyper­ tension is best understood. Some studies of the known hypertensive popu­ lation indicate that one-half or less are receiving adequate treatment, and, of those on therapy, only half have their high blood pressure satisfactorily controlled. These realizations emphasize the need to inform all segments of society throughout the world on the importance of detection and control of high blood pressure. The great incidence of hypertension makes it of para­ mount importance that all practicing physicians have available the latest information on diagnosis and treatment of hypertensive cardiovascular dis­ ease. This treatise on hypertension arrives at a time when there is an increasing recognition the world over of the importance of detecting and treating high blood pressure. The book has been edited by Dr. A. Amery and his asso­ ciates in the University of Leuven. Professor Amery is one of the leaders in the field of hypertension and serves on the Council of the International Society of Hypertension.

Why a book on contrast echocardiography? Over the past dozen years enough experience has accumulated to warrant a more extensive treatment of this method. Furthermore, there are new developments that suggest increased clinical utility for contrast echocardiography in the future. This book aims to summarize the "state of the art" for those interested in echocardiography - presumably mainly cardiologists, but here and there those of a more technical bent will find useful information as well. We feel that a more basic understanding of microbubble dynamics is necessary to advance research for such applications as transmission through the lungs, videodensitometric quantitation of cardiac output, intracardiac shunts, etc. All of these topics are extensively dealt with. The reader will note that many of the clinical chapters are written by pediatric cardiologists. This is only natural, since shunt detection and analysis of flow relationships are relatively more important in congenital heart diseases, and cur­ rently represent the most important uses for contrast echo cardiography in day-to­ day practice.

Patients currently experiencing acute myocardial infarcts are the beneficiaries of information gathered during the 80 years since this clinical phenomenon was described and the 20 years since treatment in coronary care units was introduced. Physicians have gained the ability to minimize inhospital mortality from rhythm disturbances and have gained insight into the importance of optimizing both left ventricular fIlling pressure and outflow resistance in the management of myocar­ dial failure. Understanding of the pathophysiology of acute myocardial infarcts has matured sufficiently so that now it is possible to consider whether an infarct must evolve to a predetermined size or whether the size could be limited by implementing one or more clinically feasible strategies. Concurrently, it has become evident that patients with acute infarcts are not as 'fragile' as previously supposed, and that they may undergo procedures such as coronary angiography and coronary bypass surgery with acceptable risks. Clinical trials are currently in progress to assess the possible benefit of various interventions for limiting myocardial infarct size. The outcome of these studies may be used to formulate strategies for clinical care of future patients. If the results are positive, community hospitals may undergo changes even more exten­ sive than those required when they established coronary care units. If the inter­ ventions are not proven to provide significant advantages over the course of nature, the current concepts of coronary care may be retained. However, such conclusions will be only as valid as the techniques used to measure infarct size.

This symposium is the fourth of a series of scientific meetings in the field of echocardiology, held at the Erasmus University, Rotterdam.* The series was initiated by Klaas Born, who organized the first two meetings, and was continued by Charles Lancee. These previous symposia met with great success. These proceedings comprise most of the invited lectures and free commu­ nications which had their' live performance' during the 4th Symposium on Echocardiology. We decided, again, to maintain one ofthe most striking features of the last meetings: having the proceedings available at the time of the meeting. As a consequence, the authors-to-be were confronted with a very tight schedule. The editing time was also limited and therefore neither terminology nor units have been completely standardized. However, as a result, these proceedings do reflect the 'state of the art' in echocardiology. This is not a textbook on echocardiology, but cardiologists and techni­ cians, with experience in the field of echocardiology, will certainly appreciate the educational features of this book. This symposium was organized in association with Interuniversity Institute of Cardiology, Amsterdam, the Netherlands. Dutch Society of Ultrasound in Medicine and Biology Dutch Heart Foundation, The Hague, the Netherlands European Society of Cardiology Financial support was given by Interuniversity Institute of Cardiology, Amsterdam, the Netherlands University-fund Rotterdam Foundation, Rotterdam, the Netherlands Dutch Heart Foundation, The Hague, the Netherlands.

Thus, there are now several chronic canine myocardial infarction­ ventricular tachyarrhythmia models which are available for the evaluation of new antiarrhythmic drugs (Table I). The available models fulfill many, but not all of the requirements for an ideal chronic arrhythmia model (Table 11). The sustained arrhythmias initiated in these models using programmed pacing presumably have the same localized reentrant mechanism that characterizes chronic human myocardial infarction and chronic coronary 26 artery disease. However, these models are not suitable for determining whether a new drug will abolish spontaneous ly-occurring PVCs. In addition, these models are of unproven value in the study of acute spontaneously­ occurring sudden death; although recently initiated, provocative work may shed further light on this subject. Most importantly, the available models do seem well-suited to the evaluation of new drugs intended for use in chronic coronary artery disease patients at risk for sustained reentrant ventricular tachycardia or VF. Notably, the results of preliminary electropharmacologic studies in these canine models parallel closely those findings reported in human patients with sustained life-threatening ventricu­ lar tachyarrhythmias (Table Ill). Therefore, increased use of these chronic models for new antiarrhythmic drug testing is strongly recommended. TABLE II Ideal vs Available Chronic Canine - Arrhythmia Models Ideal Available 1. (a) Arrhythmia mechanism comparable to Yes patients with chronic CAD: Reentry (b) Pathophysiology similar (e. g. , atherogenic CAD) No 2. Susceptible to: (a) spontaneous PVCs No l No (b) spontaneous VT/VF (c) inducible VT/VF Yes 3.

Noninvasive visualization of myocardial infarction using radionuclides dates back over eighteen years. Edward A. Carr and William H. Beierwaltes were first to report (1962) successful external imaging of myocardial infarcts in dogs and in man using an Anger scintillation camera. They demonstrated that after intravenous administration of 86Rb or l3ICS an infarct was visualized as a "cold spot", while 203Hg-labeled-chlormeridin resulted in a "hot-spot" image of the infarct. Since then, there have been major developmental improvements in avail­ able radionuclides, scintillation cameras and computer processing capabilities. In particular, the development of mobile gamma cameras opened the possi­ bility to obtain high quality images even at the bedside of critically ill patients. Since the development in 1974 of a new radiopharmaceutical, 20lTI and the application of 99mTc-pyrophosphate for myocardial imaging, these imaging agents are widely used for the detection of acute myocardial infarction. However, for practical application, frequently there appears to be uncertainty or even confusion concerning the relative merits of each method.

Hypertension is a major health problem and contrary to ischemic heart disease, which occurs only in Western countries, its distribution is almost universal. It is this universality that has prompted us to gather, in this book, data on arterial blood pressure obtained in different parts of the world. Moreover, cerebrovascular mortality, which is the commonest cause of death from hypertension, is decreasing in most Western countries and in Japan, and the reasons for this are still far from clear. A major problem in comparing blood pressure values from different centers is the standardization of the measurement. Complete standardization will never be achieved if one takes into account the numerous factors that may influence blood pressure in epidemiological studies. Whether blood pressures are measured by doctors or by technicians, are recorded at home, in the working place or in a hospital, in sitting, standing or supine position, and is taken during the same examination-all of these whether a blood sample factors can influence blood pressure measurement. But meals, time of day (blood pressure being higher in the evening), heart rate, cuff size, stethoscope used, digit preference, month of year, temperature, etc., can equally influence the measurement. Home reading of arterial blood pressure at standardized times is probably the best answer to all of these problems and has been used with gratifying results in a comparative study between Belgium and Korea.

Over the last ten years, it has become increasingly obvious that sudden death represents the major challenge confronting cardiology in the last part of the XXth Century. Careful epidemiologic studies have established the magnitude of this overall important problem of public health. The frequent association of sudden death with coronary artery disease has been demonstrated. Some of the electrophysiologic mechanisms underlying lethal arrhythmias have been unveiled. In addition, clinical markers permitting identifica­ tion of high risk individuals have emerged. Finally, different studies have raised some hope as to the ability of therapeutic interventions to protect these patients against a premature and possibly evitable demise. Over the years, a sizable amount of new and relevant information, both basic and clinical, has become available. We felt therefore that a conference on sudden death might be timely. It was decided to organize a small gathering during which experts from different disciplines in cardiology could sit together in a quiet retreat to share their knowledge and discuss issues pertaining to research and therapy that might be of benefit to patients. The conference was held in Liege, on May 7, 8 and 9, 1979. This three day meeting in which re­ presentatives from seven different countries participated was extremely stimulating. The discussions were very lively and sometimes reflected the divergence of opinion which may persist on some topics.

Cardiac Dynamics is the name of a relatively young field of study, born from the fruitful interaction between branches of two different disciplines: medicine and physics. "Dynamics" is the branch of physics which deals with the action of forces on bodies or particles in motion or at rest. "Cardiac" relates to the clinical field of cardiology but also to cardiophysiology, both of which are specialized branches of medicine. Narrower than the well­ established field of Hemodynamics, Cardiac Dynamics is restricted to dynamic phenomena occurring in and around the heart. The mathematical treatment of such phenomena, however, is vastly more complex because of the intricate nature of the mechanisms involved in the cardiac action. Thus, whereas hemodynamics is concerned with predominantly passive (visco-) elastic structures - vessels - containing time-variant flow of viscous flui- blood -, the mechanical study of the heart requires additional con­ siderations such as: active elastic components representing the contractile mechanism of cardiac muscle, complex geometry and fiber structure in the myocardial wall, autoregulatory mechanisms, and intricate flow patterns associated with valve motion. Viewed in this light it is not surprising that attempts to describe ventricular pump function and to quantify contractile performance have not reached the level of sophistication which is common in e. g. arterial hemodynamics. For the same reason, many of the often simplified approaches to describe ventricular mechanics failed to stand up to more rigorous theoretical, experimental or clinical testing.

This Symposium is the third of a series of scientific meetings in the field of echocardiology, held at the Erasmus University Rotterdam. * The series was initiated by Klaas Born, who organized the first two meetings with great success. These followed the procedure of two days of parallel sessions with invited speakers only. This time, we decided to broaden the basis of the meeting and have a three-day program of parallel sessions, combining invited papers, free com­ munications and posters. We decided, however, to maintain one of the most striking features of the last meeting- having the complete proceedings available at the time of the meeting. We confronted the authors-to-be with a very tight schedule in order to make the book a true reflection of the state of the art in echocardiology. As a 'result, editing time was also very limited and neither terminology nor units have been completely standardized. This book has three main parts. The first, and largest, part consists of contributions on echocardiology in adults, and is divided into four sections. The first section is a general survey of various applications, whereas the remaining three centre round specific applications, i.e. ischemic disease, left ventricular function and cardiac valves, respectively. The second part con­ tains applications in pediatric cardiology; due to the wide variety of topics covered, no particular subdivision has been made. The last part of the book is devoted to instrumentation, methods and new developments.

Therapy in cardiology has advanced enormously in recent years. This has resulted in the organization of many meetings and the publication of numerous books dedicated to examining the latest aspects of, for instance, pharmacolog­ ic, electrical and surgical treatment. However, only a few of these meetings and publications have attempted to present an overall review of all advances that have taken place in the field of therapy. In the last years the Spanish Society of Cardiology has shown a great interest in the continuous medical education in cardiology. The Society has organized various meetings and has published several books on the above-mentioned topics. Consequently, the Society has decided to publish this book, an update of the therapeutics in cardiology, of which a Spanish version is also available. World renowned experts and outstanding Spanish cardiologists were invited to review all aspects of therapy in cardiology. We would like to thank the Spanish Society of Cardiology and the Catalan Cardiac Society for the generous assistance they have given us during all stages of book preparation. We also would like to express our appreciation to all the authors for their valuable contributions. Their combined efforts enable us to put this volume in the hands of the reader.

The rhythm of the heart, its normal functioning and pathologic disturbances, has been a favored subject of investigation by clinical and basic scientists in recent decades. This heightened interest and attention was stimulated by the somber and surprising revelations from epidemiologists and pathologists of the enormity of the number of sudden arrhythmic deaths in the Western world, and the concurrent advancement of technology for recording and control of electrical activity of the heart. Technological advancements have included the recording of intracellular potentials from cardiac cells, the recording of intracardiac extra­ cellular potentials generated by specific cardiac structures, simultaneous record­ ings from numerous sites with computer processing for spatial mapping of activa­ tion or potential variations with time, high gain, high resolution recordings with signal averaging for detecting potentials of low amplitudes, complex stimulation protocols, various high energy stimulation modes, intracellular voltage control of multicellular preparations and single cardiac cells, and the isolation of single cardiac cells for electrophysiological study. The interest and technology have produced an increasing bounty of information and understanding, acceptable solutions to some clinical problems, and definite progress toward solutions to other problems. Progress in research in electrophysiology and arrhythmias has been reviewed and highlighted in various meetings and books in recent years. Because the body of information has become so large, general overviews of the field have neces­ sarily been superficial in certain aspects or have contained gaps.

depolarization in cardiac muscle involve quantities, such as Vmax' that are not directly descriptive of the underlying mechanisms of propagation.