Antiarrhythmic Gene Therapy for Depressed Conduction in Myocardial Infarction

Background: In depolarized myocardial of infarct epicardial border zones (EBZ), the cardiac sodium channel (SCN5A) is largely inactivated, contributing to low action potential upstroke velocity (Vmax), slow conduction, and reentry. We hypothesized the skeletal muscle sodium channel (SkM1) would operate more effectively at depolarized membrane potentials to restore fast conduction in EBZ and be antiarrhythmic. Methods and Results: Adenovirus expressing SkM1 and green fluorescent protein (GFP) or GFP alone (sham) was injected into EBZ of canine hearts post-coronary ligation. Immunohistochemical confirmation of expression was obtained. Dogs were studied with epicardial mapping, programmed premature stimulation in vivo, and cellular electrophysiology in vitro on days 5-7. In vivo EBZ electrograms were broad and fragmented in shams (32± 2ms) and narrower in SkM1 (23±3ms; P<.03). Longitudinal conduction velocity (CV) was larger in SkM1 than in GFP (p<.05) while transverse CV did not differ between groups. Premature stimulation induced ventricular tachycardia/fibrillation (VT/VF) in 6 of 8 shams vs. 2 of 12 SkM1 (P<.02). Microelectrode studies of EBZ showed SkM1 membrane potentials equalled shams and Vmax in SkM1>sham (P<.01). Infarct sizes were similar across groups (approximately 30%, P>.05). Conclusions: SkM1 increases Vmax of depolarized myocardium, increases longitudinal CV and reduces induced VT/VF in canine infarcts. Gene therapy to normalize activation by increasing Vmax at depolarized potentials is antiarrhythmic.