The overall aim of this proposal is the further investigation of the biochemical markers of reversible and irreversible cellular damage in myocardial ischemia. Phosphorus-31 and carbon-13 nuclear magnetic resonance (NMR) techniques will be employed to obtain serial, non-invasive, flow-independent measurements of tissue high energy phosphate levels and substrate metabolism during global ischemia and reflow in a perfused guinea pig heart model. In addition, saturation transfer and inversion transfer NMR techniques will be utilized to study substrate and creatine kinase kinetics during reperfusion following ischemic periods of various lengths. The metabolite concentrations and kinetic information obtained in this manner will be correlated with functional data and evidence of irreversible cell damage as defined by ultrastructural changes and membrane permeability changes to lanthanum. Similar studies will be performed in a model of regional ischemia in perfused hearts with spatially localized metabolic information obtained using surface coil and topical magnetic resonance methods. Using the experience gained in these studies, the techniques will be applied to an in vivo open-chest model of regional ischemia in rabbits and small dogs. Specific points to be addressed include: (1) Is severe ATP depletion as measured by NMR a reliable predictor of irreversible cellular injury as referenced to histopathologic and membrane permeability changes? (2) Is NAD depletion a more specific marker of irreversible damage than ATP depletion? (3) Are the changes in phospholipid and fatty acid metabolites which may play a major role in membrane damage detectable by carbon-13 NMR? (4) How are creatine kinase and substrate kinetics affected by varying periods of ischemia? (5) During reflow are there alterations in substrate and creatine kinase kinetics which may make the cell vulnerable to further damage or play a role in the slow recovery of performance following ischemia? This work is expected to extend the utility of NMR techniques in establishing the exact nature and degree of metabolic damage incurred during an ischemic episode. The long term potential for this research lies in that it will allow one to better assess the metabolic integrity of the myocardial cell compromised by ischemia. With this knowledge one may be able to design more specific therapy to improve recovery.
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