DYNAMICS OF CARDIAC ENERGY METABOLISM

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The goal of this project is to understand the dynamic regulation of cardiac energy metabolism and its effects on heart function in cardiac disease, especially during hypertrophy culminating in heart failure and during myocardial stunning. The time constant of the phosphate metabolites determined with NMR spectroscopy during heart rate steps (3 s) was shorter than the time constant of oxygen consumption (11 s) in the same hearts. We hypothesized that this was due to transitory glycolytic ATP production which delays transport and explains the gap between the 3 and 11 s time constants and retards the transfer of the energetic signal between sites of ATP consumption and the mitochondria. Indeed, when glycolysis was inhibited and bypassed by giving pyruvate as exogenous substrate both time constants became short and the time constant of oxygen consumption was not significantly different from the time constant of inorganic phosphate and phosphocreatine. The time constant of oxygen consumption in response to heart rate steps was also shortened when creatine kinase was inhibited, suggesting that energetic buffering, not only by glycolysis, but also by creatine kinase delays the energetic signal between the sites of ATP consumption and the mitochondria. At 37 degrees Celsius 15 min of ischemia or hypoxia did lead to a substantial increase in the mitochondrial time constant, indicating that energy transfer and/or signaling between energy-consuming sites and mitochondria is deteriorated in stunned myocardium. Reducing the mitochondrial aerobic capacity by selective partial inhibition with oligomycin did not lead to a slower response of oxidative phosphorylation to heart rate steps, suggesting that transcytosolic energy transport rather than mitochondrial processes determine the adaptation speed of oxidative phosphorylation. We found that modest arterial pressure overload for six weeks did not lead to a significant increase in the response time of oxygen consumption, suggesting that energy signaling between sites of ATP consumption and the mitochondria is not yet impaired during mild cardiac hypertrophy.