A body of work now exists to suggest that mitochondrial DNA defects occurring either through inherited or acquired pathways are associated with cardiovascular abnormalities. Previously, the investigator have shown that mitochondrial calcium ([Ca2+]mt) accumulation and mitochondrial gene expression are altered during surgically induced global ischemia and reperfusion and that these alterations are associated with decreased post-ischemic functional recovery in the aged but not the mature heart. They have also shown that increased [Ca2+]mt accumulation in the aged heart was associated with decreased mitochondrial gene expression and enzyme activity. These phenomena were shown to be related to decreased preservation and resynthesis of high energy phosphates during ischemia and reperfusion in the aged myocardium. In preliminary investigations using a novel polymerase chain reaction methodology, the PI showed that in the rabbit heart the prevalence of the mtDNA7, 436 deletion is increased during global ischemia and reperfusion and that these alterations are associated with decreased pot ischemic functional recovery in the aged but not the mature heart. In a parallel study using atrial appendage tissues from human patients undergoing cardiac surgery, similar results have been obtained indicated that ischemia-reperfusion increases the prevalence of the mtDNA, 436 deletion. The pathophysiology leading to these alterations in mtDNA and their relationship to myocardial dysfunction remain to be elucidated, however, preliminary investigation would suggest that AT-rich sequences flanking the mtDNA7,436 deletions in the rabbit and human heart may be of significance. The investigators plan to investigate the relevance of mtDNA deletions in a clinically relevant animal model and in human atrial tissue samples from cardiac surgery patients to determine the mechanisms leading to increased prevalence of mtDNA deletions during ischemia and/or reperfusion and to determine the identity and relative contribution of mtDNA deletions to post-ischemia functional recovery in the cardiac surgical patient. These studies will provide insight as to: the prevalence of mtDNA deletions in the cardiac patient; the effect of myocardial aging; and the effect of mtDNA deletions on surgical outcome. In addition, these investigation will provide information which will allow for the development of alternative myoprotective surgical procedures to optimize potential outcome in cardiac surgical patients.
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