Overexpression of a human potassium channel suppresses cardiac hyperexcitability in rabbit ventricular myocytes
H. Bradley Nuss, … , Eduardo Marbán, David C. Johns
H. Bradley Nuss, … , Eduardo Marbán, David C. Johns
Published March 15, 1999
Citation Information: J Clin Invest. 1999;103(6):889-896. https://doi.org/10.1172/JCI5073.
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Article

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

Abstract

The high incidence of sudden death in heart failure may reflect abnormalities of repolarization and heightened susceptibility to arrhythmogenic early afterdepolarizations (EADs). We hypothesized that overexpression of the human K+ channel HERG (human ether-a-go-go-related gene) could enhance repolarization and suppress EADs. Adult rabbit ventricular myocytes were maintained in primary culture, which suffices to prolong action potentials and predisposes to EADs. To achieve efficient gene transfer, we created AdHERG, a recombinant 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 IKr. Transient outward currents in AdHERG-infected myocytes were similar in magnitude to those in control cells, while stimulated action potentials (0.2 Hz, 37°C) were abbreviated compared with controls. The occurrence of EADs during a train of action potentials was reduced by more than fourfold, and the relative refractory 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 repolarization.

Authors

H. Bradley Nuss, Eduardo Marbán, David C. Johns

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HERG overexpression increases refractory period. The refractory period w...
HERG overexpression increases refractory period. The refractory period was determined by interposing premature suprathreshold stimuli (115% of threshold) at varying intervals during periods of continuous AP stimulation. (a) In noninfected and AdGFP-infected myocytes, a second AP could be elicited before final repolarization to resting potential was complete. (b) An obvious refractory period persisted in AdHERG-infected myocytes after the membrane voltage returned to resting potential. To quantify the refractory period independent of differences in APD between groups, refractory period was measured from the APD90 of the first AP to the next stimulus that elicited a second normal AP. The refractory period increased by 82% because of HERG overexpression (n = 4, P = 0.02) compared with noninfected and AdGFP-infected controls (n = 3).