The overall aim of this Program Project application is to identify physiological, biochemical and molecular mechanisms which are fundamental to the progression of ischemic heart disease and its progression to heart failure. This aim will be accomplished by utilizing a combined approach of integrative and basic scientists. There are four projects and four cores, with major interactions among projects and cores. The projects range from cellular and molecular studies (Projects 1-4) to integrative whole animal physiology (Projects 1-4). This Program Project application relies heavily on the integrative approach. Even the cellular/molecular projects have a strong link to in vivo models. Project 1 utilizes a combined noel approach to determining the alteration in genes and proteins in stunned myocardium. Whereas most other studies in this field employ rodent models, one unique feature of this project is the use of the large mammalian model. Genomics elated to cell survival, Ca2+ regulation, sarcomeric proteins, and previously undescribed genes will be examined. Project 2 represents a continuation of the work in Dr. S. Vatner's laboratory using four different models of hibernating myocardium to understand the regulation of blood flow and function in the most physiological models of hibernating myocardium to understand the regulation of blood flow and function in the most physiological models of short-term, chronic and true hibernation. The first is a model of short-term hibernation, 90-minute coronary stenosis with 4 days reperfusion. The second is a model of hibernating myocardium that will be derived from repetitive bouts of stunning using the model of 90- minute coronary and 12 hour reperfusion. The third involves another model of hibernating myocardium, which is induced in pigs with chronic ameroid constriction on a coronary artery. The fourth model is one of true hibernation in hibernating woodchucks. As related to Project 2, two novel aspects of myocardial metabolism will be investigated using NMR spectroscopy focusing on the role of nitric oxide in mediating a potential beneficial effect on metabolism during the effect of myocardial ischemia, and reperfusion. Project 3 is directed at examining cellular and molecular signaling mechanisms mediating apoptosis. In Project 3, the predominant animal models are murine, although studies in pigs will be carried out as well. Project 4 is another project that also uses large animal models, similar to Project 2, i.e., the pig, but concentrates on the cellular mechanisms of abnormalities in electrophysiological function and arrhythmias. There are several novel features of this projects as well. These studies represent the first model of myocardial stunning with parallel experiments of mechanical and electrophysiological function in isolated myocytes.