Despite meticulous adherence to myocardial protection principles, reperfusion injury following surgically induced ischemia continues to occur and is related to the operative mortality subsequent to cardiac operations performed in a technically adequate manner. With aging of the U.S. population, an increased operative mortality has been noted in elderly patients undergoing open heart surgery. Despite an increasing database on the aging heart, myocardial protective regimens used successfully in the past for children and middle-aged adults continue to be used for the aged. The investigator proposes to study systematically the biology of surgically-induced ischemia in the senescent myocardium, as compared to the mature heart. 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+]i; and 3) repair of damaged organelles. In previous studies, they have shown that the senescent heart experiences greater dysfunction following ischemia compared to mature hearts and that this phenomenon is accompanied by increased [Ca2+]i, nuclear calcium and mitochondrial calcium with increased DNA fragmentation and decreased mitochondria cytochrome oxidase I (COXI) mRNA levels in the aged heart. Magnesium supplemented potassium cardioplegia modulated but did not reverse these changes. They hypothesize that the mechanism leading to decreased functional recovery following ischemia in the aged heart is the result of the progressive accumulation of genetic damage (not necessarily mutation or deletion) exceeding the capacity of cellular mechanisms for repair, renewal and removal of damaged genomic molecules. Using metabolic and molecular probes in ischemic, sexually mature and senescent rabbit hearts, they plan to study the effects of increased [Ca2+]i on changes in high energy phosphate moieties, on mitochondrial genomic function and on nuclear homeostasis and to isolate and identify RNA transcripts (nuclear and/or mitochondrial) associated with enhanced functional recovery to allow for the development of new myocardial protective strategies. As a consequence of these studies, the investigator hopes to contribute new information regarding the response of the aged heart to surgical ischemia and, as a corollary, reduce mortality related to cardiac surgery in the elderly.
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