Following myocardial infarction a prolonged period of stable LV remodeling may be followed by myocardial exhaustion with the development of congestive heart failure (CHF). Hearts with stable remodeling or CHF have abnormal bioenergetic characteristics but whether limitations in the ATP synthetic or transport processes actually contribute to the transition from hemodynamic stability to CHF is unclear. The overall goals of the current proposal are: i. to determine whether functionally significant limitations of ATP synthetic capacity are present in compensated and CHF associated remodeled hearts and, ii. whether a metabolic therapeutic intervention can attenuate the remodeling process. This study will be carried out in a pig model of post-infarction left ventricular remodeling in which a significant portion of the infarcted animals develop CHF. The relationships between the severity of pump dysfunction and severity of alterations in myocyte oxygenation, myocardial bioenergetics (including ATP synthetic capacity), and regional myocardial blood flow will be determined. One major objective is to determine whether stable or failing remodeled hearts can be driven to workstates where oxygen or substrate availability limit function. Because CHF hearts have decreased responsiveness to catecholamine stimulation as a consequence of down regulation of the beta-adrenergic receptors, increases of cyclic AMP will be produced by direct stimulation of adenylyl cyclase with forskolin or by inhibition of phosphodiesterase with milrinone in addition to catecholamine infusion. In vivo mitochondrial respiration capacity will be examined with a mitochondrial uncoupling agent 2,4-dinitrophenol (DNP) which decreases the proton gradient in the mitochondrial membrane and drives MVO2 to levels above those dictated by the rates of ATP utilization. A third acute intervention will be the infusion of pyruvate and butyrate, substrates which bypass the rate limiting steps in generation of mitochondrial acetyl CoA. These interventions will allow determination of whether the maximum capacity for mitochondrial oxidative phosphorylation is limiting in the failing heart and, if so, whether the abnormality is in the ability of mitochondria of the CHF hearts to generate a proton gradient or whether ATP synthase or subsequent processes involved in ATP transport are at fault. The relationships and time-course of pump dysfunction and the alterations in myocardial energetics during the evolution of CHF will be examined by magnetic resonance imaging/spectroscopy. To examine whether limitations of long chain fatty acid metabolism alter myocardial CP/ATP or limit the maximal rate of ATP synthesis in the failing heart, animals will receive carnitine supplementation to compensate for the rate limiting step in long chain fatty acid metabolism and/or other abnormalities in intermediary metabolism. Taken together, the results of these studies will establish whether the ATP synthetic capacity: i. ultimately restricts myocardial maximal MVO2 in hearts with LV remodeling and failure, ii. contributes to the transition between stable remodeling and CHF and, iii. Whether a metabolic intervention can attenuate the remodeling response and the transition from stable remodeling to CHF.
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