The primary focus of cardiac research in this laboratory has ben the development of progressively more powerful magnetic resonance methodologies and their application to the investigation of myocardial bioenergetics and metabolism. The current proposal continues this strategy and is centered around the use of 1h NMR techniques to evaluate myocardial myoglobin deoxygenation in vivo for the first time, combined with 31 P NMR measurements of high energy phosphate compound levels using spatial localization to differentiation layers across the left ventricular wall. The latter is a necessary capability because of the well recognized transmural gradients of wall-stress, O2 utilization, and biochemical composition. The general biological questions to be examined concern the mechanisms of regulation of oxidative phosphorylation in normal myocardium in vivo at very high levels of energy expenditure, and the effect of post- ischemic myocardial stunning on this regulation. Specifically, we propose to establish the 1H NMR capability to monitor deoxy- and oxy-myoglobin in and across the left ventricular wall in situ by means of non-localized and transmurally localized differentiation in an open chest, instrumented canine model. Previous 1h NMR studies of myocardial myoglobin oxygenation have been performed in perfused rodent heart models. In vivo studies are crucial if physiologic regulation of O2 supply by the vasculature is to be taken into account and to permit proper interpretation of 31P NMR data obtained during physiological or pharmacological interventions. The transmurally differentiated Mb detection will be used together with our already well established, transmurally localized 31P spectroscopy approach to examine the specific biological questions of whether i) maximal workloads and myocardial oxygen consumptions rate attainable by normal in situ cardiac muscle are dictated by a limitation of oxygen and/or carbon substrate delivery to the mitochondria, and ii) such a limitation may be exacerbated by a transient ischemic result.
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