Normally, blood flow and contractile function are closely coupled in the myocardium. As a result, one of the most rapid and striking consequences of myocardial ischemia is development of regional dysfunction. Not all regional dysfunction, however, is restricted to ischemic myocardium. At the lateral and epicardial margins of ischemic areas, nonischemic dysfunction may be present that extends the zone of mechanical dysfunction, potentially amplifying the global impact of regional ischemia. In similar fashion, nonischemic dysfunction can characterize reperfused but stunned myocardium. Therefore, the specific aspect of regional myocardial function that serves as a theme for the proposal is nonischemic dysfunction. Consistent with the previous proposals, the functional border zone (the transition area at the lateral boundary between ischemic and nonischemic myocardium defined in terms of systolic contractile function) will continue to be part of the project.
The Specific Aims have been expanded, however, to focus on acute and chronic changes in contractile function across the myocardial wall within an ischemic, reperfused or infarcted area, as well. Particular attention is concentrated on normally or near normally perfused subepicardial muscle overlying ischemic or infarcted subendocardial layers. The studies will be conducted in dogs. Regional function will be measured with sonomicrometers arrayed to measure wall thickness and microspheres will be used to measure myocardial blood flow. In collaboration with Dr. Daniel Remick (Dept. of Pathology), studies relating infarct and scar distribution to changes in regional function will be performed. In collaboration with Dr. Markus Schwaiger (Div. of Nuclear Medicine), studies on glucose uptake are also proposed to integrate aspects of metabolism, perfusion, and mechanical performance into a more comprehensive analysis of regional function.
The Specific Aims are: 1. Define the relationship between changes in blood flow, wall thickening, and glucose utilization during regional ischemia. 2. Determine the effects of ischemia and reperfusion on transmural differences in regional function (inner and outer wall thickening). 3. Determine the effects of acute ischemia and reperfusion on regional function at the lateral margins of an ischemic area. 4. Determine serial changes in lateral border zone function that occur with time after permanent occlusion of the left anterior descending occlusion or circumflex artery. 5. Determine serial changes that take place in viable epicardial layers overlying a subendocardial infarction after permanent coronary occlusion or 3.0 hour occlusions followed by reperfusion.
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