Overexpression of a human potassium channel suppresses cardiac hyperexcitability in rabbit ventricular myocytes

The high incidence of sudden death in heart failure may reflect abnormaliti es of repolarization and heightened susceptibility to arrhyhmogenic early a fterdepolarizations (EADs). We hypothesized that overexpression of the huma n K+ channel HERG (human ether-a-go-go-related gene) could enhance repolari zation and suppress EADs. Adult rabbit ventricular myocytes were maintained in primary culture, which suffices to prolong action potentials and predis poses to EADs. To achieve efficient gene transfer, we created AdHERG, a rec ombinant adenovirus containing the HERG gene driven by a Rous sarcoma virus (RSV) promoter. The virally expressed HERG current exhibited pharmacologic and kinetic properties like those of native I-Kr. Transient outward curren ts in AdHERG-infected myocytes were similar in magnitude to those in contro l cells, while stimulated action potentials (0.2 Hz, 37 degrees C) were abb reviated compared with controls. The occurrence of EADs during a train of a ction potentials was reduced by more than fourfold, and the relative refrac tory period was increased in AdHERG-infected myocytes compared with control cells. Gene transfer of delayed rectifier potassium channels represents a novel and effective strategy to suppress arrhythmias caused by unstable rep olarization.