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Short communication: flecainide exerts an antiarrhythmic effect in a mouse model of catecholaminergic polymorphic

Nian Liu1, Marco Denegri, Yanfei Ruan

  • 1Cardiovascular Genetics Program, Leon H. Charney Division of Cardiology, New York University School of Medicine, 522 First Ave, New York, NY 10016, USA.

Circulation Research
|June 18, 2011
PubMed
Abstract

Insights

Flecainide prevents catecholamine-induced arrhythmias in a mouse model of CPVT. The drug acts extracellularly by blocking sodium channels, not by affecting intracellular calcium handling.

Area of Science:

  • Cardiology
  • Molecular Cardiology
  • Pharmacology

Background:

  • Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a life-threatening arrhythmia.
  • Flecainide is used to treat CPVT, but its antiarrhythmic mechanism is not fully understood.
  • Previous studies suggested flecainide might affect the cardiac ryanodine receptor (RyR2), but its hydrophilic nature implies an extracellular action.

Purpose of the Study:

  • To elucidate the antiarrhythmic mechanism of flecainide in a RyR2(R4496C+/-) knock-in mouse model of CPVT.
  • To investigate flecainide's effects on intracellular calcium handling and arrhythmogenesis.

Main Methods:

  • Utilized a RyR2(R4496C+/-) knock-in mouse model exhibiting CPVT.
  • Performed cellular studies on isolated RyR2(R4496C+/-) myocytes.
  • Assessed flecainide's impact on isoproterenol-induced Ca(2+) transients, sparks, and triggered activity.

Main Results:

  • Flecainide effectively prevented catecholamine-induced sustained ventricular tachycardia in the CPVT mouse model.
  • Flecainide did not alter intracellular Ca(2+) transients, sarcoplasmic reticulum Ca(2+) content, or spontaneous Ca(2+) sparks.
  • Flecainide significantly increased the threshold for action potential induction, suggesting an extracellular mechanism.

Conclusions:

  • Flecainide prevents CPVT in RyR2(R4496C+/-) mice through an extracellular mechanism.
  • Contrary to prior reports, flecainide showed minimal impact on intracellular Ca(2+) homeostasis.
  • The antiarrhythmic effect is attributed to reduced Na(+) channel availability and an elevated threshold for triggered activity.

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