Despite meticulous adherence to myocardial protection principles, reperfusion injury (Rl) following surgically induced ischemia continues to occur and is related to the operative mortality subsequent to cardiac operations that are adequately performed. With aging of the U.S. population, an increased operative mortality has been noted in elderly patients undergoing open heart surgery. Despite a small but increasing data base on the aging heart, myoprotective regimens used successfully in the past with children and middle aged adults are used for the aged. We propose to study systematically the biology of surgically induced ischemia and RI on the senescent myocardium as compared to the infant and mature heart in order to develop new myoprotective strategies that are specific for the aging patient. Recovery after ischemic arrest involves: 1) resumption of normal oxidative metabolism, and restoration of contractility; 2) reversal of disrupted transmembrane gradients, particularly the accumulation of cytosolic calcium (Ca2+); 3) restoration of altered coronary vascular resistance regulation and 4) repair of damaged organelles. Sexually mature and aged sheep, rats and rabbits will be used to study the effects of ischemia and reperfusion using the following biologic markers to measure RI: (1) Myocardial muscle mechanics and energetic changes as a function of aging using sonomicrometry techniques will validate hypothesized differences in chemomechanical transduction, define alterations in descriptors of contractility, evaluate internal and external work efficiency and analyze changes in ventriculoarterial coupling; (2) Citosolic Ca2+ as a probe to evaluate age related changes in the disruption of transmembrane ionic gradients and correlate the onset of contracture and ATP changes with the rise in cytosolic Ca2+ associated with RI; (3) Changes in Coronary Vascular Resistance Regulation and Regional Perfusion with a specific emphasis on endothelial cell relaxing and contracting factors and (4) Morphologic Studies using morphometric analysis. These methods will be used to validate varying myoprotective methodologies involving the use of acellular and blood cardioplegia, hypothermia, substrate enchancement, buffers, anti-oxidants, Ca2+ blocking and chelating agents, as well as continous blood cardioplegia in order to develop a regimen that will be specific for the senescent heart. As a consequence of these studies, we hope to contribute new information regarding the response of the aging heart to surgical ischemia and as a consequence reduce the mortality related to cardiac surgery in the aged.
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