OPTIMIZING CORONARY FLOW TO REDUCE MYOCARDIAL STUNNING

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The myocardium becomes ischemic and is reperfused under pathological conditions, such as coronary vasospasm, and also in the course of treatments such as coronary angioplasty and various cardiothoracic surgical procedures. After such a period of ischemia, the contractile function of the myocardium may be impaired for hours or days, although there is no evidence of infarction, and the myocardium does eventually recover normal function. The pilot research project proposed here is designed to test the hypothesis that this myocardial stunning is mediated, at least in part, by delivery of excess blood flow to the myocardium during reperfusion, due to impairment of coronary vascular smooth muscle function. Experiments will be performed with Langendorff perfused isolated rat hearts, under both conditions of controlled flow, and conditions of controlled perfusion pressure. The specific aims are (1) to define a protocol for producing consistent and severe myocardial stunning, (2) to identify reperfusion protocols that reduce stunning, (3) to test possible mechanisms by which excess blood flow mediates myocardial stunning, and (4) to test possible coronary vascular mechanisms responsible for excess delivery of flow to the myocardium during reperfusion. Mechanisms that will be considered, for both the changes in myocardial functions and the changes in coronary vascular function, include (1) generation of harmful quantities of oxygen-derived free radicals, 92) acid-based derangements secondary to inappropriate accumulation or washout of carbon dioxide, and (3) impairment of Ca/++-transport by the myocytes or vascular smooth muscle cells, secondary to changes in electrochemical gradients. An understanding of the mechanisms by which excess is delivered to the myocardium, and the mechanisms by which excess flow promoters myocardial stunning is fundamental to the development of clinically applicable procedures for preventing or reversing myocardial stunning, as well as to basic understanding of coronary and myocardial function.