Ischemic heart disease is the direct cause of 700,000 deaths each year in the United States alone. Coronary thrombosis is considered a prime cause of myocardial ischemia. Although extensive evidence indicates platelet activation and aggregation does occur, the effects of anti-platelet drugs in reducing myocardial injury, preventing coronary vasospasm and improving long-term prognosis for re-infarction or sudden death, have been disappointing. We recently found that the invasion of leukocytes is central to the process of tissue damage. We propose that platelets per se are not an important determinant of myocardial damage, but that interactions between platelets and leukocytes promote ischemia-induced myocardial injury by the generation of pro-inflammatory mediators, such as lipoxygenase metabolites of arachidonic acid (AA), platelet-activating factor and superoxide. Interactions between platelets, leukocytes and vascular tissue will be studied in vitro, by determining changes in AA metabolism, superoxide generation and cell aggregation. The formation and release of pro-inflammatory mediators will be assessed in isolated perfused rabbit hearts following either coronary occlusion in vivo or global ischemia in vitro, and compared to the profile of mediators produced upon addition of platelets and/or leukocytes to the perfusate. Inhibition of mediator release, myocardial injury and cell accumulation in the myocardium will also be examined in this model using a variety of anti-platelet and anti-leukocyte drugs. The vascular and cardiac effects of identified mediators, and their interactions, will be examined in the coronary circulation of the dog in vivo, comparing effects on a vascular bed damaged by ischemia to a normal vascular bed; on isolated rings of coronary arteries taken from these two areas; and isolated perfused hearts of rabbits. Effects on leukocyte and platelet aggregation will also be assessed. Longitudinal changes in vascular AA metabolism will be elucidated by comparing metabolism in major coronary arteries, microvessels and veins, and assessing differences in vessels taken from normal or ischemic regions of the heart. Finally, the contribution of platelet-leukocyte interactions to myocardial ischemia in vivo will be studied using specific anti-platelet and anti-neutrophil antisera, a selective thromboxane synthetase inhibitor benzylimidazole, and nafazatrom, a new anti-platelet drug. The study of platelet-leukocyte interactions in myocardial ischemia may promote a better understanding of the events leading to myocardial injury and open new avenues of prospective therapy.
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