Improving Cardiac Conduction With a Skeletal Muscle Sodium Channel by Gene and Cell Therapy

J Cardiovasc Pharmacol. 2012 Jul;60(1):88-99. doi: 10.1097/FJC.0b013e3182588b00.

Abstract

The voltage-gated Na+ channel is a critical determinant of the action potential (AP) upstroke. Increasing Na+ conductance may speed AP propagation. In this study, we propose use of the skeletal muscle Na+ channel SkM1 as a more favorable gene than the cardiac isoform SCN5A to enhance conduction velocity in depolarized cardiac tissue. We used cells that electrically coupled with cardiac myocytes as a delivery platform to introduce the Na+ channels. Human embryonic kidney 293 cells were stably transfected with SkM1 or SCN5A. SkM1 had a more depolarized (18 mV shift) inactivation curve than SCN5A. We also found that SkM1 recovered faster from inactivation than SCN5A. When coupled with SkM1 expressing cells, cultured myocytes showed an increase in the dV/dtmax of the AP. Expression of SCN5A had no such effect. In an in vitro cardiac syncytium, coculture of neonatal cardiac myocytes with SkM1 expressing but not SCN5A expressing cells significantly increased the conduction velocity under both normal and depolarized conditions. In an in vitro reentry model induced by high-frequency stimulation, expression of SkM1 also enhanced angular velocity of the induced reentry. These results suggest that cells carrying a Na+ channel with a more depolarized inactivation curve can improve cardiac excitability and conduction in depolarized tissues.

Publication types

  • Comparative Study
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Action Potentials
  • Animals
  • Animals, Newborn
  • Cell- and Tissue-Based Therapy / methods
  • Dogs
  • Female
  • Genetic Therapy / methods
  • HEK293 Cells
  • Heart Conduction System / metabolism
  • Humans
  • Male
  • Muscle, Skeletal / metabolism*
  • Myocytes, Cardiac / metabolism*
  • NAV1.4 Voltage-Gated Sodium Channel / genetics*
  • NAV1.4 Voltage-Gated Sodium Channel / metabolism
  • NAV1.5 Voltage-Gated Sodium Channel / genetics*
  • Rats
  • Rats, Sprague-Dawley
  • Time Factors
  • Transfection

Substances

  • NAV1.4 Voltage-Gated Sodium Channel
  • NAV1.5 Voltage-Gated Sodium Channel
  • SCN4A protein, human