The objective of this proposal is to test the hypothesis that preconditioning reduces infarct size and improves recovery of regional function in conscious, chronically instrumented dogs and pigs. Preconditioning is defined as the process induced by brief episodes of ischemia that render the myocardium more resistant to irreversible damage produced by subsequent prolonged occlusions. Identified in this manner, preconditioning has proven to be remarkably effective in reducing infarct size (by 75% or more) in anesthetized, open-chest dogs, pigs, and rabbits. At face value, the concept of preconditioning the myocardium with ischemia appears interesting but not particularly practical. The broader implications of precondition, however, are striking. The existence of a preconditioning effect implies that the myocardium is capable of """"""""adjusting"""""""" itself very rapidly in a manner that changes tolerance for ischemic and/or reperfusion injury. Before concentrating resources on delineating the mechanisms of preconditioning, however, we propose that a critical question must be answered: Does preconditioning also work in conscious, chronically-instrumented animals? Addressing this question is the main objective of the proposal. Many interventions have been used to reduce infarct size and improve regional function in open-chest, anesthetized animals. Of the relatively few interventions also tested in the more physiologic conditions provided by use of chronically-instrumented animals, most have filed to show any benefit and some have been detrimental. Accordingly, we contend that conscious animals provide a more rigorous setting in which to test the efficacy of preconditioning. Studies in chronically-instrumented animals are demanding, but the effort is warranted in the case of preconditioning because it is a potentially important type and model of acute cardiac adaptation. Until the effects of preconditioning are evaluated in conscious animals, the reservation that it is a phenomenon unique to open- chest conditions can not be eliminated. The proposed studies will be conducted in conditioned dogs and pigs (Minipigs, Charles Rivers Laboratories).
The Specific Aims are: 1). TEst the hypothesis that preconditioning is effective in reducing infarct size produced by occlusion of a major coronary artery in chronically-instrumented, conscious dogs and pigs. 2). Determine the effects of preconditioning on short and long term recovery of regional contractile function measured as wall thickening with sonomicrometers.
