UNSTABLE ANGINA-PECTORIS AND THE PROGRESSION TO ACUTE MYOCARDIAL-INFARCTION - ROLE OF PLATELETS AND PLATELET-DERIVED MEDIATORS

The conversion from stable to unstable angina and the further progression to myocardial infarction are usually associated with atherosclerotic plaque fissuring or ulceration at sites of coronary artery stenosis and subsequent development of a thrombus. This thrombus formation is initiated by platelet adhesion and aggregation; these, in turn, are promoted by the local release and accumulation of thromboxane A2 and serotonin. This accumulation and the resulting platelet aggregation at sites of endothelial injury cause dynamic vasoconstriction. With time, the platelet-initiated thrombus expands to include white and red blood cells in a fibrin mesh. Thus, a fully occlusive coronary thrombus may develop and cause the progression from unstable angina to acute myocardial infarction, often Q-wave myocardial infarction. We believe that the connection between unstable angina and acute myocardial infarction is a continuum relative to the processes of coronary artery thrombosis and vasoconstriction. When the period of platelet aggregation or dynamic vasoconstriction at sites of endothelial injury and coronary stenosis lasts only a few minutes and is repetitive, unstable angina or non-Q wave myocardial infarction occurs. However, when complete coronary artery occlusion lasts for longer than 4 hours, a transmural or Q-wave myocardial infarction results. Recently, in experimental animal models with mechanically induced coronary artery stenoses and endothelial injury, we have found that other mediators, including adenosine diphosphate and thrombin, also contribute to coronary artery thrombosis. Moreover, in humans with limiting angina, we have identified spontaneous coronary blood flow variations in a pattern similar to the variations caused by alternating platelet attachment and dislodgement in experimental canine modes. In this review, we add information to our previous observations in order to present the possible mechanisms of conversion from chronic to acute coronary heart disease syndromes

ROLE OF NEW ANTIPLATELET AGENTS AS ADJUNCTIVE THERAPIES IN THROMBOLYSIS

Coronary thrombolysis is the treatment of choice for patients with acute Q-wave myocardial infarcts who have no contraindications to such therapy. However, the time required for thrombolysis and the possibility of reocclusion of th infarct-related artery remain problematic. Herein are described experimental animal studies and clinical evaluations in which attempts have been made to develop adjunctive therapies that, when coupled with available thrombolytic interventions, might shorten the time to thrombolysis and delay or prevent reocclusion. From the studies conducted to date, it is clear that a combined thromboxane synthesis inhibitor and receptor antagonist with a serotonin receptor antagonist and heparin shorten the time to thrombolysis and delay or prevent coronary artery reocclusion in experimental canine models with copper coil-induced coronary artery thrombi. A monoclonal antibody to the platelet glycoprotein IIb/IIIa receptor coupled with tissue plasminogen activator (t-PA) and heparin also shortens the time to thrombolysis and delays or prevents reocclusion in experimental canine models. Thrombin inhibitors, including heparin and synthetic inhibitors, given with t-PA and aspirin, appear to shorten the time to thrombolysis and delay or prevent coronary artery reocclusion in experimental canine models. Aspirin coupled with intravenous streptokinase reduces mortality in patients with presumed acute myocardial infarction, and a combination of heparin and t-PA results in infarct-artery patency more frequently than t-PA without heparin. Data from these studies are encouraging with regard to the possibility of developing effective and relatively safe thrombolytic regimens that shorten the time to thrombolysis and delay or prevent coronary artery reocclusion