Epicardial border zone overexpression of skeletal muscle sodium channel SkM1 normalizes activation, preserves conduction, and suppresses ventricular arrhythmia an in silico, in vivo, in vitro study

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Abstract

Background-In depolarized myocardial infarct epicardial border zones, the cardiac sodium channel (SCN5A) is largely inactivated, contributing to low action potential upstroke velocity (V max), slow conduction, and reentry. We hypothesized that a fast inward current such as the skeletal muscle sodium channel (SkM1) operating more effectively at depolarized membrane potentials might restore fast conduction in epicardial border zones and be antiarrhythmic. Methods and Results-Computer simulations were done with a modified Hund-Rudy model. Canine myocardial infarcts were created by coronary ligation. Adenovirus expressing SkM1 and green fluorescent protein or green fluorescent protein alone (sham) was injected into epicardial border zones. After 5 to 7 days, dogs were studied with epicardial mapping, programmed premature stimulation in vivo, and cellular electrophysiology in vitro. Infarct size was determined, and tissues were immunostained for SkMl and green fluorescent protein. In the computational model, modest SkM1 expression preserved fast conduction at potentials as positive as -60 mV; overexpression of SCN5A did not. In vivo epicardial border zone electrograms were broad and fragmented in shams (31.5±2.3 ms) and narrower in SkMl (22.6±2.8 ms; P=0.03). Premature stimulation induced ventricular tachyarrhythmia/ fibrillation >60 seconds in 6 of 8 shams versus 2 of 12 SkMl (P=0.02). Microelectrode studies of epicardial border zones from SkMl showed membrane potentials equal to that of shams and V̇ max greater than that of shams as membrane potential depolarized (P<0.01). Infarct sizes were similar (sham, 30±2.8%; SkM1, 30±2.6%; P=0.86). SkMl expression in injected epicardium was confirmed immunohistochemically. Conclusions-SkMl increases V̇ max of depolarized myocardium and reduces the incidence of inducible sustained ventricular tachyarrhythmia/fibrillation in canine infarcts. Gene therapy to normalize activation by increasing V̇ max at depolarized potentials may be a promising antiarrhythmic strategy. (Circulation. © 2009 American Heart Association, Inc.

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Lau, D. H., Clausen, C., Sosunov, E. A., Shlapakova, I. N., Anyukhovsky, E. P., Danilo, P., … Rosen, M. R. (2009). Epicardial border zone overexpression of skeletal muscle sodium channel SkM1 normalizes activation, preserves conduction, and suppresses ventricular arrhythmia an in silico, in vivo, in vitro study. Circulation, 119(1), 19–27. https://doi.org/10.1161/CIRCULATIONAHA.108.809301

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