Much evidence supports the hypothesis that accumulation of noxious metabolites in the ischemic heart contributes to electrical instability and sudden death following myocardial infarction. Recent evidence strongly suggests that long-chain acylcarnitines accumulated in the sarcolemma of hypoxic myocytes and play a significant role in the genesis of arrhythmias. The objective of the proposed work is to further elucidate the role of long-chain acylcarnitines in arrythmogenesis. This study will utilize a combination of biochemical and intracellular recording techniques in a cultrued rat neonatal myocyte preparation subjected to hypoxic perfusion. Experiments are planned to identify the biochemcial mechanisms responsible for long-chain acylcarnitine accumulation and to delineate factors that modulate their metabolism. Common anti-arrhythmic drugs will be tested for their ability to inhibit long-chain acylarnitine elevation. Preferential extraction of long-chain acylcarnitines from sarcolemma will be attempted and cells will be monitored electrophysiologically. The ultimate goal is to develop methods that inhibit elevation or prevent the effects of long-chain acylcarnitines in hypoxic tissue and offer promise for protection of the ischemic heart against potentially fatal arrhythmias.
