Many patients with coronary artery disease have chronically reduced regional myocardial function distal to severe stenoses or in collateral dependent myocardium in the absence of subjective signs of ischemia or a history of prior myocardial infarction. While some of these dysfunctional states reflect the delayed recovery of function following an cute episode of ischemia or """"""""stunning"""""""", others occur without subjective signs of recent ischemia. These dysfunctional regions are associated with relative reductions in resting flow that are stable for long periods of time and are called """"""""hibernating myocardium"""""""" which is distinguished from irreversible injury by its improvement following revascularization. Despite a substantial knowledge base regarding physiological and molecular mechanisms involved in the myocardial response to acute ischemia, advances in our understanding of chronic adaptations to ischemia have been limited by the inability to reproduce the clinical state of hibernation or chronic stunning experimentally. Our laboratory has recently developed a model that can reproduce the salient features of clinically defined hibernation in pigs instrumented with a proximal coronary artery stenosis for 3 months. Using this, we propose to test the overall hypothesis that hibernation is an intrinsic myocardial adaptation to frequent episodes of reversible ischemia that maintains tissue viability at the expense of a reduced contractile function by down-regulating regional energy requirements. Furthermore, the adaptations associated with hibernation are accompanied by changes in gene expression that are distinct from those associated with myocardial stunning. An integrative approach will employ physiological studies in intact chronically instrumented animals with studied to examine molecular mechanisms using Northern and Western analysis.
Three specific aims are proposed. In the first aim, physiological studies will compare chronic adaptations in regional flow, function, metabolism and 18FDG uptake in models of hibernating myocardium vs. chronic stunning. These will be complimented with studies to compare the expression of candidate genes for stress proteins, calcium regulatory proteins and glucose transporters. Genes that are uniquely expressed in hibernating myocardium will be identified by RNA fingerprinting using differential display PCR.
The second aim will characterize the functional and metabolic responses of chronic hibernation to changes in myocardial metabolic demand.
The third aim will determine whether changes in regional expression of heat shock proteins or myocardial antioxidants are accompanied by physiological evidence of a state of chronic preconditioning. New information will come forth that leads to a better understanding of the intrinsic myocardial adaptations involved in chronic ischemic heart disease that could lead to new strategies to induce protection from irreversible injury.
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