Transient myocardial ischemia in man, if sufficiently brief, is generally regarded as a reversible insult from which recovery is rapid and complete. Brief coronary artery occlusion in animal models, however, has shown that regional abnormalities of myocardial contraction can be prolonged, well beyond the period of ischemia. A preliminary investigation has demonstrated that repeated brief coronary occlusions can produce progressive and significant regional ventricular dysfunction without evidence of permanent cellular injury. Since recurrent brief episodes of ischemia are known to occur in man and may be frequent and without symptoms, it is important to define the consequences of these episodes on myocardial function. This proposal will examine abnormal mechanical function in a chronic dog model following repeated brief coronary occlusions. Regional function will be measured with implanted ultrasonic time transit gauges; myocardial blood flow will be quantitated from injections of radioactively labeled microspheres; and evidence of cellular damage will be determined from histochemical stains and histology. The degree and duration of mechanical impairment will be examined as a function of the number, frequency, and duration of ischemic episodes. An attempt will be made to determine the underlying pathophysiologic mechanism by quantitative measurements of adenine neucleotides, mitochondrial respiration, and sarcoplasmic reticulum calcium uptake. Finally, therapeutic strategies to reverse or prevent the mechanical dysfunction will be examined. These studies will define the functional significance of recurrent brief episodes of ischemia and may lead to new insight into the mechanism and therapy of ischemic cardiomyopathy.
