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.