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

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

Research output: Contribution to journalArticle

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 I(Kr). 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.

Original languageEnglish (US)
Pages (from-to)889-896
Number of pages8
JournalJournal of Clinical Investigation
Volume103
Issue number6
StatePublished - Mar 1999

Fingerprint

Potassium Channels
Muscle Cells
Action Potentials
Rabbits
Genes
Delayed Rectifier Potassium Channels
Rous sarcoma virus
Sudden Death
Adenoviridae
Ether
Cardiac Arrhythmias
Heart Failure
Incidence

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Overexpression of a human potassium channel suppresses cardiac hyperexcitability in rabbit ventricular myocytes. / Nuss, H. Bradley; Marbán, Eduardo; Johns, David C.

In: Journal of Clinical Investigation, Vol. 103, No. 6, 03.1999, p. 889-896.

Research output: Contribution to journalArticle

Nuss, H. Bradley ; Marbán, Eduardo ; Johns, David C. / Overexpression of a human potassium channel suppresses cardiac hyperexcitability in rabbit ventricular myocytes. In: Journal of Clinical Investigation. 1999 ; Vol. 103, No. 6. pp. 889-896.
@article{fabd1641ddcd4c8d94ccd11f5d7429df,
title = "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 I(Kr). 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.",
author = "Nuss, {H. Bradley} and Eduardo Marb{\'a}n and Johns, {David C.}",
year = "1999",
month = "3",
language = "English (US)",
volume = "103",
pages = "889--896",
journal = "Journal of Clinical Investigation",
issn = "0021-9738",
publisher = "The American Society for Clinical Investigation",
number = "6",

}

TY - JOUR

T1 - Overexpression of a human potassium channel suppresses cardiac hyperexcitability in rabbit ventricular myocytes

AU - Nuss, H. Bradley

AU - Marbán, Eduardo

AU - Johns, David C.

PY - 1999/3

Y1 - 1999/3

N2 - 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 I(Kr). 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.

AB - 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 I(Kr). 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.

UR - http://www.scopus.com/inward/record.url?scp=0033559392&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0033559392&partnerID=8YFLogxK

M3 - Article

C2 - 10079110

AN - SCOPUS:0033559392

VL - 103

SP - 889

EP - 896

JO - Journal of Clinical Investigation

JF - Journal of Clinical Investigation

SN - 0021-9738

IS - 6

ER -