In a steady state, the rate of myocardial energy conversion (ATP production) must equal the rate of work (ATP hydrolysis or ATP consumption). During 60 minutes of steady mild myocardial ischemia, a new balance between the rate of ATP consumption and blood-flow-limited ATP production is achieved at the expense of reduced regional contractile function. These adaptations to mild ischemia appear to define the pathophysiology of the hibernating myocardium. The goal of this grant is to define the cellular regulation of mitochondrial ATP production (ADP, inorganic phosphate, phosphorylation potential, redox state, magnesium, myoglobin oxygenation, F1-F0-ATP synthase activity) and myocardial ATP consumption (myofibrillar work, intracellular calcium metabolism) as metabolic adaptations to mild ischemia develop. We will use a combination of in vivo 31P NMR spectroscopy, 1H magnetic resonance imaging, optical spectroscopy, and myocardial biopsy techniques. This will require further development and validation for rapid magnetic resonance imaging techniques of myocardial oxygenation. The assessment of calcium transient amplitudes and myocardial energetics will test the hypothesis that myocardial calcium levels regulate both regional contractile function and ATP production during prolonged mild ischemia. The effects of a new class of inotropic agents (typified by EMD 57033) should help delineate the role of calcium in the pathophysiology of hibernating myocardium as well as the metabolic and functional consequences of these agents on ischemic myocardium. The effects of adenosine on myocardial ATP content will help define the balance between ATP production and consumption during mild ischemia. The application of these state-of-the-art methodologies should enhance our understanding of clinically common states of myocardial hypoperfusion such as the hibernating myocardium.
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| Arai, A E; Gaither 3rd, C C; Epstein, F H et al. (1999) Myocardial velocity gradient imaging by phase contrast MRI with application to regional function in myocardial ischemia. Magn Reson Med 42:98-109 |
