MICROVASCULAR DETERMINANTS OF FOCAL MYOCARDIAL NECROSIS

The ultimate determinant of myocardial cell death or survival in ischemia is the availability of oxygenated substrate at the microvascular level. Despite this, there has been little interest in the anatomy or pathophysiology of the myocardial microcirculation. Recently, in preliminary studies in dogs, we embolized 25 micron microspheres into the the coronary arteries. Subsequent histological evaluation revealed multiple foci of discrete contraction band necrosis associated with the microemboli. Because of the similarity of these foci to necrosis in the cardiomyopathic Syrian hamster, where we have evidence that microvascular spasm contributes to the pathogenesis of these lesions, we attempted alpha adrenergic blockade with phentolamine prior to embolization. In treated animals, the necrotic foci were prevented, suggesting that simple obstruction of the microcirculation by microspheres was not the cause of necrosis. We also observed that the necrotic lesions were not homogeneously distributed across the ventricular wall. There was increased necrosis in the midwall layer, despite the fact that more microspheres were deposited in the subendocardium. We believe that the microembolization model can provide significant information about the anatomy and pathophysiology of the cardiac microcirculation. Many interrelated questions may be answered by the proposed studies. These include, the amount of myocardium supplied by the microcirculation, i.e., a microvascular unit; localization of microvascular anastomoses; mechanisms by which alpha adrenergic blockade prevents necrosis and the value of other vasodilators; the time course of acute micronecrosis; the intra or extra cardiac control of sympathetic microvascular tone and its transmural variability; and whether microvascular spasm can be directly visualized. We also will study the effects of microembolization with and without treatment on the skeletal muscle and brain since these tissues will be embolized secondary to our cardiac studies; although not specifically the objective of this proposal, these studies are particularly relevant because of skeletal muscle involvement in hamster cardiomyopathy. The concepts to be tested are unique in that they are aimed at understanding the dynamic function of the microcirculation and its role in disease.