Development and Pathophysiological Basis of Thrombolytic Therapy in Acute Myocardial Infarction Part I. 1912–1977 The Controversy Over the Pathogenetic Role of Thrombus in Acute Myocardial Infarction

Abstract

Although acute myocardial infarction (MI) was among the indications of Fletcher's 1959 safety study of thrombolytic therapy, this indication was not pursued in subsequent U.S. trials. The 1977 FDA approval of thrombolytic therapy did not include acute MI. The view that coronary thrombus, due to rupture of the underlying plaque and frequently associated with dissecting hemorrhage from the lumen into the plaque causes MI, had lost its dominance. Branwood had concluded that coronary thrombosis was not the cause but the consequence of MI, occurring in a minority of patients. Paterson had ascribed plaque hemorrhage to rupture of capillaries within the plaque. Autopsy studies in the mid‐1960s provided fresh evidence that coronary thrombi were common in acute MI and that intimal fissuring caused both intraluminal thrombosis and plaque hemorrhage. Despite this, Robert's view that plaque fissures were artifacts resulting from sectioning arteries, and that coronary thrombosis resulted from a prolonged low output state associated with large infarcts, prevailed. Meanwhile, European investigators continued to explore thrombolysis in acute MI, although they believed that the lysis time for a coronary thrombus exceeded the time limit of myocardial tolerance of anoxia. They hoped to improve collateral flow and microcirculation by lysing microthrombi in capillaries and venules within and around the infarct zone. The reduction in blood viscosity associated with fibrinolytic therapy was expected to further improve collateral flow and to decrease myocardial oxygen demand by reducing afterload. The discussion about the pathogenesis of acute MI was limited by the inherent selection bias of autopsy studies and a paucity of in vivo angiographic data.