Recent clinical observations on coronary artery spasm have generated renewed interest that vasomotion might be involved in the etiology of angina pectoris and myocardial infarction. At the same time, post myocardial infarction thrombolytic therapy has proven to be very successful: a result which supports the view of an occlusive thrombus within the coronary artery as the cause for myocardial infarction. Rather than viewing coronary vasomotion and thrombus formation as two completely separate entities, this grant proposal presents the hypothesis that in the presence of coronary artery stenosis, coronary vasomotion can critically narrow the stenosis and result in the eventual formation of an occlusive thrombus. This grant proposal will analyze different aspects of this hypothesis. In addition to canine and porcine studies, human coronary arteries will be studied. The first section will examine clinically relevant amplifiers of arterial vasoconstriction, denudation and cholesterol in the presence of an arterial stenosis. This section will determine if this amplified vasoconstriction can cause greater flow decreases at lower concentrations of agonist. Such increased sensitivity could be involved in coronary artery spasm. The second section will examine platelet: accumulation, the precursor of clot formation, in an arterial stenosis. In particular, effects of blood flow velocity and/or percent stenosis and denudation on platelet accumulation will be studied. Continuous monitoring of radioactive Indium-lll will enable quantitative determination of platelet: deposition within the stenosis, while morphological analysis will determine exact stenotic size and flow velocity. Relation between blood flow velocity and efficacy of platelet inhibiting agents will also be studied. Conceivably, increased blood flow velocity through arterial stenoses may reduce the efficacy of these agents. Conversely, relation between flow velocity and platelet stimulating agents will be analyzed. The last section will examine the interaction of platelet accumulation and vasoconstriction. Since most human coronary stenoses are capable of vasomotion, it is imperative to analyze effect of platelet accumulation in a stenosis capable of vasomotion. The information gained in this grant proposal will provide new insight into the pathogenesis of angina pectoris, ventricular fibrillation, myocardial infarction, and cerebral vascular accidents. This new knowledge will be of vital importance to millions of Americans suffering from coronary heart disease and may help to interpret clinical data and shape future therapy.
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