description): The proposed research will address the regulation of myocardial oxidative phosphorylation at maximal energy expenditure rates (induced by inotropic stimulation) in hearts with severe post-infarction left ventricular remodeling (LVR). The primary focus is to study the role of oxygen and carbon substrate delivery by blood flow, along with creatine levels and activities of creatine kinase isoforms, in regulating oxidative phosphorylation and the energy charge of the myocyte. The applicant will perform experimental measurements of the progression of LVR with a unique combination of MRS and MRI in the closed chest pig model, with each study culminating in acute studies on the open chest pig to determine the bioenergetics and tissue oxygenation levels across the LV wall, along with more traditional measurements of regional blood flow with radiolabeled, tracer microspheres and metabolic parameters with biochemical an immunoassay methods. The applicant proposes this approach to test six hypotheses: The first is that oxygen delivery to mitochondria is not limiting oxygen consumption rate and, as such, does not limit ATP turnover at maximal workloads. The second is that at very high workstates, carbon substrate delivery by blood flow is limiting the rate of oxygen consumption, but that carbon substrate metabolism becomes a controlling factor in determining mitochondrial NADH production. Part of this hypothesis is also that hearts with LVR are more vulnerable to high workstate stress. The third hypothesis is that in the failing heart, inotropic response to elevated cAMP impairs energy reserve. The fourth is that mitochondrial uncoupling causes increased MVO2 in normal hearts, but fails to increase MVO2 in failing hearts, reflecting exhaustion of myocardial energy reserve. The fifth hypothesis is that reduced myocardial creatine levels may contribute to reduced PCr levels and creatine kinase flux in LVR, which contribute to bioenergetic and functional abnormalities. The applicant hypothesizes that chronic creatine supplementation will increase PCr levels and CK flux as a beneficial effect on the remodeling process. The final hypothesis is that late reopening of the infarct-related coronary artery has beneficial effects that are associated with amelioration of bioenergetic abnormalities that result from reduced LV wall stresses.
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