Ionic mechanisms of cellular electrical and mechanical abnormalities in Brugada syndrome

  • Dong M
  • Niklewski P
  • Wang H
  • 2

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Abstract

The Brugada syndrome (BrS) is a right ventricular (RV) arrhythmia that is responsible for up to 12% of sudden cardiac deaths. The aims of our study were to determine the cellular mechanisms of the electrical abnormality in BrS and the potential basis of the RV contractile abnormality observed in the syndrome. Tetrodotoxin was used to reduce cardiac Na + current (I Na ) to mimic a BrS-like setting in canine ventricular myocytes. Moderate reduction ( < 50%) of I Na with tetrodotoxin resulted in all-or-none repolarization in a fraction of RV epicardial myocytes. Dynamic clamp and modeling show that reduction of I Na shifts the action potential (AP) duration-transient outward current (I to ) density curve to the left and has a biphasic effect on AP duration. In the presence of a large I to , I Na reduction either prolongs or collapses the AP, depending on the exact density of I to . These repolarization changes reduce Ca 2+ influx and sarcoplasmic reticulum load, resulting in marked attenuation of myocyte contraction and Ca 2+ transient in RV epicardial myocytes. We conclude that I Na reduction alters repolarization by reducing the threshold for I to -induced all-or-none repolarization. These cellular electrical changes suppress myocyte excitation-contraction coupling and contraction and may be a contributing factor to the contractile abnormality of the RV wall in BrS. Copyright © 2011 the American Physiological Society.

Author-supplied keywords

  • Action potential
  • Cardiac myocyte
  • Dynamic clamp
  • Excitation-contraction coupling

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Authors

  • M. Dong

  • P.J. Niklewski

  • H.-S. Wang

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