Coronary vasospasm and thrombosis may lead to myocardial injury, but the pathogenesis of these events is poorly understood. Although there has been intense interest in vasoactive substances, little attention has been directed to the coronary arterial wall, and even less to its vascular supply. This study will test the hypothesis that local proliferation of coronary vasa vasorum contributes to vasospasm and thrombosis. Vasa vasorum are not easily recognized. Previous studies of the vasa vasorum, which are limited, have concentrated on the aorta; little is known regarding the coronary vasa vasorum. Our hypothesis will be tested by addressing the following questions: 1) What is the distribution of coronary vasa vasorum in non-atherosclerotic coronary arteries, and is it age dependent? 2) How is the development, distribution, and density of vasa vasorum modified in areas of atherosclerotic disease? 3) What is the distribution and density of coronary vasa vasorum in areas of thrombosis? 4) What is the distribution and density of coronary vasa vasorum in areas of vasospasm? 5) Is proliferation of vasa vasorum associated with changes in the composition of the coronary arterial wall? These questions will be studied using a special method of fixing, clearing, and injecting the post-mortem heart which permits direct visualization of atherosclerotic plaque, as well as the pathway of flow in vasa vasorum. Histologic analysis will be performed using plastic embedded, giemsa-stained one-micron sections, which offer several advantages over routine light microscopy, and are particularly suited for analysis of the vasculature and endothelial cells. These two techniques are mutually reinforcing: the injection technique will pinpoint the areas most likely to provide maximum histologic information. We will apply these injection techniques to post-mortem human hearts, as well as to three populations of rabbits: 1) New Zealand rabbits fed a regular diet; 2) New Zealand rabbits fed a high cholesterol, high fat diet to produce arterial lesions of a foam cell type; and 3) An animal model of human familial hypercholesterolemia: Watanabe heritable hyperlipidemic rabbits, that spontaneously develop disease very similar to man. The proposed project is an essential first step to define the contribution of vasa vasorum to coronary vasospasm and thrombosis.
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