The major objective of the proposed project is to continue the development of MRS into a tool for exploring in vivo myocardial bioenergetics. Two major hypotheses will be addressed. 1) The effects of acute and chronic volume overload on myocardial energetics can be predicted by MRS determination of heart phosphocreatine (PCr) concentration as estimated by the ratio of PCr to adenosine triphosphate (PCr/ATP) or to inorganic phosphate (PCr/Pi). These parameters can then be used to estimate adenosine diphosphate (ADP) and phosphorylation potential, respectively. 2) Heart work and bioenergetics are related by Michaelis-Menten Kinetics, and metabolic instability and thus mechanical instability can be predicted by a change in the slope of curves relating heart work t substrate utilization. In exploring these hypotheses, MRS parameters will be related to measures of O2 availability and use, NADH redox state and heart work parameters (heart rate x blood pressure, cardiac output, pressure-volume work). MRS data will also be compared to measurements of heart metabolites obtained with routine analytical biochemical techniques to evaluate the sensitivity and reproducibility of MRS measurements compared to traditional methods. The acute studies will be performed on anesthetized dogs and cats, and the chronic studies will be performed on anesthetized dogs. All animals will be intubated, mechanically ventilated, and instrumented for physiological monitoring. Two types of experiments will be done: 1) acute volume overload will be created via surgical placement of cannulae between the abdominal aorta and vena cava. After control studies are done, the shunts will be opened and workload related to energy metabolism. After the animal has stabilized (no change in PCr/ATP or PCr/Pi ratio), pressure loading will be added to the volume load with norephinephrine (NE) to determine the metabolic stability of an acutely volume loaded heart. 2) A chronic volume overload condition will be created via surgical anastomosis of the abdominal aorta to vena cava. These animals will be studied monthly for 2-12 months to determine the effects of chronic volume overload on myocardial energetics. After control studies are done for each time period, the heart will be pressure loaded with norephinephrine to increase heart work to determine whether chronic volume loading effects a change in myocardial energetics. These combined data will be used to determine whether volume loading is associated with energetic changes, a question heretofore, not answered.
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