Improving the recovery of aerobic myocardial metabolism following cardioplegic arrest

grantor: University of Toronto'Background'. Cardiovascular disease remains an important cause of morbidity and mortality in North America. Surgical treatment of cardiovascular disorders has emerged over the past 40 years and is now a proven, effective therapy. Cardioplegic arrest of the heart enables surgeons to operate on a motionless field, but is associated with a degree of perioperative injury. Sensitive measures of myocardial metabolism and function reveal a delayed recovery following surgery which may lead to postoperative morbidity and mortality. These series of investigations were designed to evaluate the recovery of aerobic myocardial metabolism following cardioplegic arrest. We believe that improving the transition from anaerobic to aerobic metabolism may result in enhanced functional recovery and improved patient outcomes following cardiac surgery. We hypothesized that insulin would stimulate myocardial pyruvate dehydrogenase activity and lead to improved metabolic recovery following simulated ischemia and reperfusion. 'Methods'. We employed isolated, cultured human ventricular cardiomyocytes to examine the effects of ischemia and reperfusion on myocardial metabolism. We measured the degree of cellular injury, intracellular lactate accumulation, extracellular lactate and pyruvate release, intracellular high energy phosphate levels and the activity of mitochondrial pyruvate dehydrogenase (PDH). We investigated the effect of preischemic exposure to insulin on the recovery of myocardial metabolism following ischemia and reperfusion. 'Results'. Preischemic exposure to insulin (10 IU/L) was found to confer protection against ischemia. Insulin was found to stimulate mitochondrial PDH during stabilization and preserved the activity of PDH following ischemia and reperfusion. Insulin exposure reduced extracellular lactate release and improved the preservation of high energy phosphates. The mechanism of insulin' effect on myocardial PDH was found to be mediated by Protein Kinase C-Ã stimulation of the PDH phosphatase subunit. 'Conclusions'. Preischemic exposure to insulin improved human cardiomyocyte tolerance to ischemia and reperfusion. These investigations provide the first direct evidence that insulin can stimulate human myocardial pyruvate dehydrogenase and lead to improved metabolic recovery following ischemia. Novel strategies of myocardial protection can be developed to exploit the beneficial metabolic effects of pyruvate dehydrogenase stimulation.Ph.D