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Coronary Thrombolysis and the New Biology

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Coronary Thrombolysis and the New Biology CORE Metadata, citation and similar papers at core.ac.uk Provided by Elsevier - Publisher Connector 850 JACC Vol. 14, No. 4 October 1989:850-60 PLENARY LECTURE Coronary Thrombolysis and the New Biology BURTON E. SOBEL, MD, FACC St. Louis, Missouri Remarkable progress in the treatment of heart disease is patients with acute evolving infarction, and DeWood and chronicled by the remarks of the distinguished plenary coworkers convincingly documented a high prevalence of session speakers who have addressed the College during the coronary thrombosis in patients with transmural infarction. past 10 years (Table 1). Recently, fibrinolysis has proved to In concert, these observations lent impetus to the burgeon- be a particularly powerful means of treating patients with ing enthusiasm for coronary thrombolysis-an enthusiasm acute myocardial infarction. Accordingly, in this year’s fed also by rapid progress in molecular biology (3). address, it is a privilege to discuss some of the novel and Until recently, the revolution in molecular biology that significant contributions of molecular biology to the progress has had such a profound impact on medicine in general has in coronary thrombolysis. been felt only peripherally in our cardiovascular subspe- Results from Washington University that will be presented cialty. However, the harnessing of genetic engineering to reflect vigorous efforts by many colleagues. In addition, we produce thrombolytic drugs with promising properties now have had extensive help from numerous talented and gracious benefits patients with heart disease (4). Several practical collaborators from centers throughout the world, such as pharmacologic targets can be approached by genetic engi- Desire Cohen at the University of Leuven. To paraphrase neering in the design of even more powerful thrombolytic John Zinman, a director of the Wills Physics Laboratory of agents. They include relative clot selectivity, increased the University of Bristol, they have made our activities in the efficacy of recanalization, increased safety, lack of antige- molecular biology and biochemistry of coronary thrombolysis nicity, altered half-life in the circulation and therapeutic a joyful experience in the tradition of research he described as synergistic interactions. “a romance of discovery-a creative enterprise in which the The history of coronary thrombolysis has been punctu- only enemy is ignorance” (I). ated by several milestones pertinent to products of the new Coronary thrombolysis is a long-standing concept. Liq- biology. Elucidation of the biochemical structure and mech- uefaction of the blood has been recognized for more than a anisms of action of activators, purification of tissue-type century. The fibrinolytic properties of streptokinase were plasminogen activators (t-PA), cloning of the t-PA gene and identified more than 50 years ago. Thus, we must ask, why angiographic documentation of recanalization in pilot studies has enthusiasm been delayed until relatively recently? Sev- set the stage for multicenter large scale efforts involving eral paradigm shifts have punctuated the change. Working literally thousands of investigators during the past several with Eugene Braunwald and colleagues at the University of years. California at San Diego, who demonstrated that infarct size could be reduced by diminution of myocardial oxygen re- quirements and that infarction was a dynamic process, we and others (2) showed that the extent of infarction was an Coronary Thrombolysis important determinant of prognosis. In elucidating the phe- Theoretical Considerations nomenon of coronary spasm, Attilio Maseri and coworkers First generation thromholytic agents. Clot lysis occurs showed that coronary angiography was safe, even in patients when plasminogen, a circulating protein that associates with an acute coronary syndrome. Soon after, Rentrop and avidly with thrombi, is converted to plasmin, a proteolytic colleagues documented recanalization after streptokinase in enzyme that hydrolyzes fibrin. Physiologically, the conver- sion is mediated by t-PA elaborated from endothelial cells juxtaposed to intravascular clots. Early efforts to induce From the Cardiovascular Division, Washington University School of thrombolysis utilized streptokinase and urokinase, so-called Medicine, St. Louis, Missouri. This report was presented as the Plenary Address at the 38th Annual Meeting of the American College of Cardiology, first generation thrombolytic agents. These activators con- Anaheim, California, March 20, 1989. vert circulating as well as thrombus-associated plasminogen Manuscript received March 20, 1989;accepted April I, 1989. to plasmin with equal alacrity. Physiologic modulation of the Address for remint$: Burton E. Sobel, MD, Director, Cardiovascular Division, Washington University School of Medicine, 660 S. Euclid Ave., fibrinolytic system relies on inhibitors such as alpha-2 anti- Campus Box 8086, St. Louis, hiissouri 63110. plasmin and fast-acting plasminogen activator inhibitor type 01989 by the American College of Cardiology 0735-1097/89/$3.50 JACC Vol. 14. No. 4 SOBEL 851 October 1989:85tiO CORONARY THROMBOLYSIS AND THE NEW BIOLOGY Table 1. American College of Cardiology Opening Plenary Fluid (Plasma) Phase Addresses During the Past Decade Plasminogen ?? t-PA + [Pg - t-PA] ---?- Plasmin + I-PA Year Speaker Address A m k., Ik, -K, - 65 PM 1979 H.J.C. Swan Impedance Reduction and Heart Failure 1980 Harriet P. Dustan Hypertension 1981 Eugene A. Stead The Cardiologist and Society 1982 Alexander S. Nadas Pulmonary Hypertension Fibrin Domain (Thrombus) 1983 John Ross. Jr. Ventricular Function and Contractility v 1984 Edgar Haber Antibodies in Cardiology kl kz Pfasminogen * t-PA - Pg - I-PA M t-PA + Plasmin ?? Fibrinolysis 1985 Edmond H. Sonnenblick The Treatment of Heart Failure T I [ ‘fibrin’ 1 1986 Stephen E. Epstein Hypertrophic Cardiomyopathy k.,/k, -K, - .14pM 1987 Norman E. Shumway Heart and Heart-Lung Transplantation 1988 Douglas P. Zipes Cardiac Electrophysiology Figure 1. The hypothesis of competition. Equilibrium between plasminogen in the fluid (plasma) phase and plasminogen (Pg) associated with clots can hypothetically result in depletion of clot-associated plasminogen when the concentration of plasminogen 1 (PA&l) that attenuate fibrinolytic activity by diverse in plasma declines. First generation agents invariably diminish circulating plasminogen markedly. In contrast. second generation mechanisms. agents such as tissue-type plasminogen activators (t-PA) interact Second generation thromholytic agents. After t-PA had much more avidly with plasminogen associated with fibrin, as been isolated and purified in pharmacologic quantities by reflected by the lower K, value shown for fibrin domain interactions Collen et al. (5), it became clear that second generation compared with interactions between t-PA and plasminogen in thrombolytic agents differed markedly from first generation plasma. Accordingly, depletion of plasminogen from plasma by t-PA is much less marked than is the case with first generation agents and, agents. When thrombolysis is induced with a first generation consequently. the likelihood of depletion of plasminogen from the agent, circulating plasminogen is converted to plasmin, with fibrin domain is diminished substantially. As a result, plasminogen consequent degradation of circulating proteins, such as remains available for activation to form plasmin in the fibrin domain, fibrinogen and plasminogen, as well as degradation of pro- with consequent persistence of intense fibrinolysis. k,, kk, and kz coagulants involved in the defense against systemic bleed- are unidirectional rate constants. ing. In contrast. second generation agents preferentially convert plasminogen associated with thrombi to plasmin, Results of Initial Studies With Second hence inducing clot lysis without plasminemia and with Generation Agents relative sparing of fibrinogen, as well as avoidance of degra- dation of circulating proteins including procoagulants re- In initial studies of naturally occurring human t-PA given quired for hemostasis (6). to dogs with induced coronary thrombi, which we performed Clot selectivity. The implications of preferential conver- with Desire Collen in 1983 (7), prompt lysis of the coronary sion of clot-associated compared with circulating plasmino- clots, reperfusion of myocardium and restoration of inter- gen to plasmin by second generation agents are striking. Clot mediary metabolism delineated by positron emission tomog- selectivity may confer protection against systemic bleeding raphy were documented. Sparing of fibrinogen and plasmi- by precluding marked elevation of concentrations of circu- nogen was evident in contrast to the case with equieffective lating fibrinogen degradation products and marked degrada- doses of urokinase. Subsequently, we obtained similar re- tion of procoagulants required for hemostasis. In addition, sults in dogs given t-PA produced by recombinant DNA the property of relative clot selectivity may result in an technology (8). increased incidence of recanalization. Initial human studies of coronary thrombolysis. In our Plasminogen in plasma is in equilibrium with plasminogen initial study (9) of patients with myocardial infarction given in the domain of fibrin (Fig. 1). Accordingly, a first genera- naturally occurring t-PA, prompt coronary thrombolysis was tion agent such as streptokinase that markedly consumes seen in more than 80%. The agent used was melanoma cell, plasma plasminogen may
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