In vivo gene transfer of Kv1.5 normalizes action potential duration and shortens QT interval in mice with long QT phenotype

Am J Physiol Heart Circ Physiol. 2003 Jul;285(1):H194-203. doi: 10.1152/ajpheart.00971.2002.

Abstract

Mutations in cardiac voltage-gated K+ channels cause long QT syndrome (LQTS) and sudden death. We created a transgenic mouse with a long QT phenotype (Kv1DN) by overexpression of a truncated K+ channel in the heart and investigated whether the dominant negative effect of the transgene would be overcome by the direct injection of adenoviral vectors expressing wild-type Kv1.5 (AV-Kv1.5) into the myocardium. End points at 3-10 days included electrophysiology in isolated cardiomyocytes, surface ECG, programmed stimulation of the right ventricle, and in vivo optical mapping of action potentials and repolarization gradients in Langendorff-perfused hearts. Overexpression of Kv1.5 reconstituted a 4-aminopyridine-sensitive outward K+ current, shortened the action potential duration, eliminated early afterdepolarizations, shortened the QT interval, decreased dispersion of repolarization, and increased the heart rate. Each of these changes is consistent with a physiologically significant primary effect of adenoviral expression of Kv1.5 on ventricular repolarization of Kv1DN mice.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • 4-Aminopyridine / pharmacology
  • Action Potentials / physiology
  • Adenoviridae / genetics
  • Animals
  • Blotting, Western
  • Cells, Cultured
  • Cloning, Molecular
  • Electrocardiography
  • Electrophysiology
  • Gene Transfer Techniques
  • Kv1.5 Potassium Channel
  • Long QT Syndrome / genetics
  • Long QT Syndrome / physiopathology*
  • Mice
  • Muscle Cells / drug effects
  • Muscle Cells / metabolism
  • Myocardium / cytology
  • Myocardium / metabolism
  • Patch-Clamp Techniques
  • Phenotype
  • Potassium Channel Blockers / pharmacology
  • Potassium Channels / drug effects
  • Potassium Channels / genetics*
  • Potassium Channels, Voltage-Gated*

Substances

  • Kcna5 protein, mouse
  • Kv1.5 Potassium Channel
  • Potassium Channel Blockers
  • Potassium Channels
  • Potassium Channels, Voltage-Gated
  • 4-Aminopyridine