PRECONDITIONING THE AGED HEART: EFFICACY AND MECHANISMS

Brief episodes of nonlethal myocardial ischemia protect or "precondition" the heart and profoundly limit infarct size caused by a later sustained period of coronary artery occlusion. Evidence of this paradoxical, ischemia-induced reduction of infarct size has been documented in all species and models evaluated to date and, although the mechanisms responsible for this protection remain poorly resolved, an ever-increasing body of data has implicated G-protein-coupled signal transduction (specifically, activation of protein kinase C and/or alterations in inositol 1,4,5-triphosphate release), initiated during the brief preconditioning stimulus, as important cellular mediators of this phenomenon. Despite the intensive effort devoted to ischemic preconditioning during the past decade, it is perhaps remarkable that cardioprotection with preconditioning has, to this point, almost exclusively been investigated using juvenile or adult animals. An obvious question is whether brief antecedent ischemia effectively protects the aged or senescent heart against subsequent infarction. However, this issue is virtually unexplored and, among the handful of currently published studies, discrepant results have been obtained. Thus, the primary aim of this pilot proposal is to definitively determine whether infarct size reduction with preconditioning is manifest in the aged heart. Experiments will be conducted using the isolated buffer- perfused rabbit heart model of regional ischemia, with infarct size delineated by tetrazolium staining. Second, we will begin to evaluate and compare G-protein-mediated signal transduction initiated by brief preconditioning ischemia in aged versus adult myocardium, again in rabbit heart, with inositol trisphosphate content and subcellular protein kinase C activities quantified using commercially available assays. It is hoped that knowledge obtained from the study of ischemic preconditioning may ultimately lead to the design of novel therapeutic strategies to protect the human heart against infarction. In this regard, the question of whether the senescent heart is amenable to preconditioning-induced protection is of fundamental importance, as the aged cohort is precisely the clinical population in which myocardial infarction is most prevalent and, thus, cardioprotection is most relevant.