Abstract 095: Uncoupling The Mitochondria Facilitates Alternans Formation In The Isolated Rabbit Heart

Abstract

Alternans of action potential duration (APD) and intracellular calcium ([Ca 2+ ] i ) transients in the whole heart are thought to be markers of increased propensity to ventricular fibrillation during ischemia reperfusion injuries. During ischemia, ATP production is affected and the mitochondria become uncoupled. This uncoupling may play an important role in alternans formation in the heart. The aim of our study was to investigate the role of mitochondrial depolarization on the formation of APD and [Ca 2+ ] i alternans in the isolated rabbit heart. We performed dual voltage and [Ca 2+ ] i optical mapping of isolated rabbit hearts under control conditions, global no-flow ischemia (n=6), and after treatment with 50 nM of the mitochondrial uncoupler FCCP (n=6). We investigated the formation of alternans of APD, [Ca 2+ ] i amplitude (CaA), and [Ca 2+ ] i duration (CaD) in the heart, under different rates of pacing. We found that treatment with FCCP leads to the early occurrence of APD (192 ± 18 ms vs 136 ± 6 ms, p<0.05), CaD (182 ± 20 ms vs 133 ± 6 ms, p<0.05), and CaA (152 ± 5 ms vs 141 ± 3 ms, p<0.05) alternans, and an increase of intraventricular APD (0.44 ± 0.02 vs 0.2 ± 0.05, p<0.05) but not CaD (0.20 ± 0.03 vs 0.16 ± 0.03, p=N/S) heterogeneity, when compared to control. On the other hand, FCCP does not affect the conduction velocity in the heart (0.95 ± 0.06 m/s vs 1.05 ± 0.11 m/s, p=N/S). Furthermore, we demonstrated that FCCP and global ischemia have similar effects on the prolongation of [Ca 2+ ] i transients, whereas ischemia induces a significantly larger reduction of APD compared to FCCP treatment. Our results demonstrate that uncoupling of mitochondria leads to earlier occurrence of alternans in the heart. Thus, in conditions of mitochondrial stress, as seen during myocardial ischemia, uncoupled mitochondria may be responsible for the formation of both APD and [Ca 2+ ] i alternans in the heart, which in turn creates a substrate conducive to formation of ventricular arrhythmias.