Reversal of potassium channel deficiency in cells from failing hearts by adenoviral gene transfer: A prototype for gene therapy for disorders of cardiac excitability and contractility

H. B. Nuss, D. C. Johns, S. Kääb, G. F. Tomaselli, D. Kass, J. H. Lawrence, E. Marban

Research output: Contribution to journalArticle

55 Scopus citations

Abstract

Heart failure is a common, often lethal disorder in which conventional pharmacologic strategies have achieved limited success. Failing hearts exhibit a delay of electrical repolarization which predisposes to fatal arrhythmias. To explore the feasibility of gene therapy for this condition, we isolated myocytes from normal and failing dog hearts and quantified electrophysiologic and contractile parameters in primary culture. Action potentials were prolonged in failing cells as a result of diminished potassium currents. Exposure to AdShK, an adenovirus that overexpresses potassium channels, reversed the action potential prolongation of failing cells. The precise phenotype varied as a function of the density of expressed channels; modest increases in potassium current sufficed to mimic the non-diseased state most faithfully, while more robust expression of the transgene excessively abbreviated excitation and contraction. Our results demonstrate that viral gene transfer can modify the electrical properties of adult mammalian heart cells in a manner appropriate to reverse a fundamental disorder of excitability. Realistic application of this form of therapy will need to include a sensitive mechanism for control of the level and distribution of transgene expression.

Original languageEnglish (US)
Pages (from-to)900-912
Number of pages13
JournalGene Therapy
Volume3
Issue number10
StatePublished - Oct 30 1996
Externally publishedYes

Keywords

  • Action potential
  • Adenovirus
  • Cardiac myocyte
  • Gene transfer
  • Heart failure
  • Ion channel

ASJC Scopus subject areas

  • Molecular Medicine
  • Molecular Biology
  • Genetics

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