The proposed research is intended to provide a more thorough understanding of the process of myocardial ischemia, the nation's leading cause of morbidity and mortality. The relationship between coronary physiology and cardiac function will be investigated in a variety of animal models which are designed to assess the physiologic significance of coronary artery obstruction nd the consequences of abnormal circulatory physiology. Particular attention will be paid to the time-oriented nature of the myocardial ischemic process, with the goal being the identification of interventions having appropriate timing and direction to amefiomte the functional effects of coronary insufficiency. Two basic model systems will be investigated. The first model system involves the assessment of regional and global myocardial ischemia using models of regional and global dynamic left ventricular geometry in the setting of reversible ischemic injury. The inotropic state of the involved myocardium will be critically assessed during ischemia and reperfusion. Interventions, such as the temporal dissociation of regional afterload by pacing the ischemic region and controlled metabolic reperfusion, will be tested as methods to ameliorate the ischemic process. The second model system is devoted to the direct assessment of regional myocardial perfusion using 2-dimensional echocardiography and a new perfusion contrast agent. These studies are designed to assess the transmural nature of regional myocardial perfusion as it is influenced by regional perturbations in coronary anatomy. In a model simulating both coronary artery stenosis and surgical myocardial revascularization, these techniques will be applied and validated using radioactive tracer microspheres. The nature of these methods will permit the establishment of visually determinable, transmural border zones of perfusion, thus enabling an accurate definition of the degree of coronary stenosis (or combination of coronary stenoses) that are required to create the condition of coronary insufficiency. In addition, these methods are non-destructive and thus applicable to the study of human coronary disease. They will be employed during coronary artery bypass surgery and, with peripheral venous injections, in the long-term follow up of patients after coronary artery bypass surgery.
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