REGIONAL FDG UPTAKE IN STUNNED VS HIBERNATING MYOCARDIUM

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Myocardial "hibernation" refers to LV dysfunction in response to chronic hypoperfusion. Although there is minimal experimental evidence that it exists, patients with severe CAD show improved function with revascularization. Myocardial "stunning" refers to reversible dysfunction following severe ischemia and reperfusion. Clinically and experimentally, it is not clear whether the two entities are distinct. This proposal presents 2 models which typify both situations. Stunning will be induced by temporarily occluding the LAD for 20 min and reperfusing for 24 hours and hibernation will be induced by placing a fixed constrictor around the LAD which limits perfusion as the animal enlarges. PET and appropriate tracers will be used to measure serial changes in myocardial blood flow and metabolism. Firstly, we hypothesize that both models will induce regional dysfunction in the absence of significant necrosis. We postulate that regional glucose uptake is increased relative to perfusion in both models. However, we speculate that enhanced glucose uptake signals a broad adaptive process in hibernation which balances energy supply with demand. Secondly, we hypothesize that within chronically hypoperfused myocardium, myocardium retains the capacity to regenerate high energy phosphates and glycogen stores. Using NMR techniques, we have shown that rapid pacing causes a reduction in transmural ATP in hibernation, suggesting that the myocardium adapts to a new level of energy-supply balance, albeit on the threshold of ischemia. We speculate that energy supply differs from that of chronically reperfused myocardium at a time that function is depressed and glucose uptake is increased (24 hours post-ischemia). Thirdly, we postulate that the myocardium adapts to chronic hypoperfusion by "down-regulating" total energy expenditure. Therefore, we expect that regional MVO2 will be depressed as hibernation evolves. Whereas stunning is associated with enhanced MVO2 relative to function, hibernation is efficient related to O2 supply and demand. Fourthly, we will determine whether measurable flow reserve is present within hibernating myocardium. If so, this would support the notion that resistance vessels remodel during chronic reductions in flow. The study would also allow us to make serial measures in flow reserve during evolution of the model. The corollary to this study is that flow reserve in reperfused myocardium is normal. If so, this would be consistent with our studies in acutely stunned myocardium. Fifthly, we propose that unlike stunned myocardium, hibernating regions will become more dependent upon carbohydrate substrate utilization such as glucose for energy production. Administration of intravenous 2 deoxyglucose has been shown to block glycolysis by >75%. Under euglycemic conditions, we will test whether blocking glycolysis will alter NMR estimates of transmural ATP either at rest or during a modest pacing stress. If true, the findings would suggest that glucose metabolism plays an important role in the adaptive process of hibernation. In parallel experiments, we will assess whether GLUT4 protein is translocated to the plasma membrane in hibernating hearts. Preliminary data in stunning suggests that GLUT4, the major insulin-dependent transporter of glucose is not upregulated. Finally, we postulate that adenosine may play an important role in altering glucose uptake via A1 receptor stimulation. PET and Fick estimates of glucose uptake will be determined to test whether the accuracy of PET measurements are reliable under circumstances in which tissue levels of adenosine are increased.