Expression of skeletal but not cardiac Na+ channel isoform preserves normal conduction in a depolarized cardiac syncytium

Abstract

Expression of SkM1 but not Nav1.5 preserves AP upstroke and CV in a K(+)-depolarized syncytium. The higher AV and shorter excitable gap observed during reentry excitation around a void in SkM1 cultures would be expected to facilitate reentry self-termination. SkM1 Na(+) channel expression represents a novel gene therapy for the treatment of reentrant arrhythmias.

The past, present, and future of pacemaker therapies

“…In vitro studies indicated that overexpressing the cardiac Na + -channel (SCN5A) has only a minor effect on cardiac myocyte Na + -channel availability 35 because there is a large endogenous pool of Na + -channels whose availability is primarily limited by the kinetics of inactivation. Thus, overexpressing SCN5A should have only a minor effect on the AP threshold.…”

“…In contrast, the skeletal muscle Na + -channel (SkM1) has inactivation kinetics 10-15 mV more positive than SCN5A. 35 Moreover, microelectrode recordings on isolated myocardial bundles showed that SkM1 overexpression hyperpolarizes the AP threshold potential ( Figure 3A). In the presence of an unchanged maximum diastolic potential, the net result was that membrane potential was now closer to threshold.…”

Gene Therapy for Restoring Heart Rhythm

“…These cells express adenovirus and lentivirus carrying genes with high efficiency and also can be transfected with reasonable efficiency by electroporation. [38][39][40] This latter trait permits candidate genes to be prescreened for efficacy before a viral vector is prepared. The automaticity of these cultures derives in part from relatively low background potassium current (I K1 ).…”

“…In NBRV, SkM1 but not SCN5a is able to ''rescue'' the action potential upstroke from the depressing effect of potassium depolarization (10 mmol/L). 39 In the next section, we discuss the efficacy of SkM1 coexpressed with HCN2 in the canine heart as a biological pacemaker.…”

Biological Therapies for Cardiac Arrhythmias

“…98 Together with gap-junctional modification, these studies begin to develop a novel toolkit for altering electric conduction by focal gene transfer.…”