Short communication: Flecainide exerts an antiarrhythmic effect in a mouse model of catecholaminergic polymorphic ventricular tachycardia by increasing the threshold for triggered activity

Nian Liu, Marco Denegri, Yanfei Ruan, José Everardo Avelino-Cruz, Andrea Perissi, Sara Negri, Carlo Napolitano, William A. Coetzee, Penelope A. Boyden, Silvia G. Priori

Research output: Contribution to journalArticle

Abstract

Rationale: Flecainide prevents arrhythmias in catecholaminergic polymorphic ventricular tachycardia, but the antiarrhythmic mechanism remains unresolved. It is possible for flecainide to directly affect the cardiac ryanodine receptor (RyR2); however, an extracellular site of action is suggested because of the hydrophilic nature of flecainide. Objective: To investigate the mechanism for the antiarrhythmic action of flecainide in a RyR2R4496C-/- knock-in mouse model of catecholaminergic polymorphic ventricular tachycardia. Methods and Results: Flecainide prevented catecholamine-induced sustained ventricular tachycardia in RyR2R4496C-/- mice. Cellular studies were performed with isolated RyR2R4496C-/- myocytes. Isoproterenol caused the appearance of spontaneous Ca2+ transients, which were unaffected by flecainide (6 μmol/L). Flecainide did not affect Ca2+ transient amplitude, decay, or sarcoplasmic reticulum Ca2+ content. Moreover, it did not affect the frequency of spontaneous Ca2+ sparks in permeabilized myocytes. In contrast, flecainide effectively prevented triggered activity induced by isoproterenol. The threshold for action potential induction was increased significantly (P+ channel blockade. Conclusions: Flecainide prevents catecholaminergic polymorphic ventricular tachycardia in RyR2R4496C-/- mice; however, at variance with previous reports, we observed minimal effects on intracellular Ca2+ homeostasis. Our data suggest that the antiarrhythmic activity of the drug is caused by reduction of Na+ channel availability and by an increase in the threshold for triggered activity.

Original languageEnglish
Pages (from-to)291-295
Number of pages5
JournalCirculation Research
Volume109
Issue number3
DOIs
Publication statusPublished - Jul 22 2011

Fingerprint

Flecainide
Communication
Ryanodine Receptor Calcium Release Channel
Isoproterenol
Muscle Cells
Polymorphic catecholergic ventricular tachycardia
Anti-Arrhythmia Agents
Sarcoplasmic Reticulum
Ventricular Tachycardia
Action Potentials
Catecholamines
Cardiac Arrhythmias
Homeostasis

Keywords

  • genetics
  • ryanodine receptor
  • sodium channel
  • ventricular tachycardia

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine

Cite this

Short communication : Flecainide exerts an antiarrhythmic effect in a mouse model of catecholaminergic polymorphic ventricular tachycardia by increasing the threshold for triggered activity. / Liu, Nian; Denegri, Marco; Ruan, Yanfei; Avelino-Cruz, José Everardo; Perissi, Andrea; Negri, Sara; Napolitano, Carlo; Coetzee, William A.; Boyden, Penelope A.; Priori, Silvia G.

In: Circulation Research, Vol. 109, No. 3, 22.07.2011, p. 291-295.

Research output: Contribution to journalArticle

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AU - Avelino-Cruz, José Everardo

AU - Perissi, Andrea

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AU - Napolitano, Carlo

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