This grant is directed at the study of myocardial metabolism under conditions of surgical stress related to myocardial hypothermic preservation during cardiac bypass, low flow normothermic ischemia, and hyperdynamic sepsis. Studies are underway in evaluating the myocardial utilization of various substrates during the period of hypothermic cardiac preservation and in the immediate post perfusion rewarming period when the myocardium must take over circulatory demands and preliminary studies are being initiated in the other two areas. This study of myocardial metabolism has been developed experimentally in a myocardial pedicle system which enables complete control of arterial inflow and coronary venous outflow in a segment of the intact working left ventricle of a dog from which all collaterals have been excluded. Techniques also have been developed for the study of substrate metabolism using 13C labeled glucose which permits tracing of the metabolic byproducts of glucose through Krebs cycle of into ketone and fat metabolism. The regulation of glucose metabolsim under conditions of hypothermic preservation and during rewarm reperfusion during low flow ischemia, and in sepsis are being studied. The effects of various substrate mixtures is deing correlated with the degree of return of effective myocardial electrical activity in a coherent transmural propagation velocity sequence as an indicator of myocardial arrhythmogenic potential. These techniques are designed so as to be applicable to human studies. Thus, they involve the use of non radioactive 13C labeled substrates which can be ascertained by GC-mass spectrometry techniques in a 50 mg biopsy taken during cardiopulmonary bypass and electrical measurements which can be made with a very fine gauge needle electrode containing multiple ECG sensor tips. Studies of human myocardial metabolism are planned in cardiac surgical patients undergoing cardiopulmonary bypass and the clinical effect of various substrate mixtures with and without K+ cardioplegia will be evaluated in the setting of intrinsic myocardial disease. Finally, a non invasive method of the detection of focal areas of aberrant or delayed transmural conduction form body surface electrodes is being developed, which can be applied in man as a guide to the detection of abnormal areas of metabolic and electrical recovery from injury. These techniques will be used to study the use of alternative metabolic fuels in the management of acute myocardial failure states.
