Abstract 5333: 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
Introduction: Reentry accounts for the majority of serious arrhythmias complicating ischemic heart disease. In the depolarized infarct epicardial border zone (EBZ), the cardiac sodium channel (SCN5a) is largely inactivated and contributes to the low action potential (AP) upstroke velocity (Vmax), slow conduction and reentry. We hypothesized that a fast inward current operating more effectively at depolarized membrane potentials such as that of the skeletal muscle sodium channel (SkM1) whose V1/2 for inactivation=−62mV (vs −84mV for SCN5a) may restore fast conduction in the border zone and be antiarrhythmic.
Methods: Computer simulations were done with the modified Hund-Rudy model describing AP in ventricular myocytes. Myocardial infarcts were created by LAD ligation in adult male mongrel dogs. Adenovirus expressing SkM1+GFP or GFP alone (6x1010 ffu) was injected into the EBZ (7 SkM1/GFP, 7 GFP controls). After 1 week, dogs were studied by epicardial mapping, programmed premature stimulation in vivo and cellular electrophysiology in vitro. Infarct size was determined by tetrazolium red staining and injection site tissues were immunostained for SkM1 and GFP.
Results: In a computational model, modest expression of SkM1 preserved fast conduction at potentials as positive as −60mV while overexpression of SCN5a did not. EBZ electrograms were broad and fragmented in controls (31.5±2.3 ms) and narrower in SkM1 (22.6±2.8 ms, P<.05). Premature stimulation induced VT/VF >60 sec in 6/7 controls versus 2/7 in SkM1 (P=0.05). Microelectrode maps of EBZ slabs from controls exhibited similar distribution of isochrones (22.1 +/−1.4 msec) as SkM1 tissues (24.0 +/−1.3 msec, P>.05) in 4mM K Tyrode’s solution. At K=7mM, maps were preserved in SkM1 (19.2 +/−1.3 msec) versus controls (11.3 +/−1.4 msec, P<.05). Infarct sizes were similar (Control 26±4% SkM1 28±9%, P>.05). SkM1 expression in injected epicardium was confirmed immunohistochemically.
Conclusions: SkM1 normalizes activation and reduces incidence of inducible sustained VT/VF in canine infarcts. Gene therapy to normalize activation via increasing Vmax at depolarized potentials may be a promising antiarrhythmic strategy.