title: Short communication: flecainide exerts an antiarrhythmic effect in a mouse model of catecholaminergic polymorphic ventricular tachycardia by increasing the threshold for triggered activity.
abstract: BACKGROUND
  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 RyR2(R4496C+/-) knock-in mouse model of catecholaminergic polymorphic ventricular tachycardia.
  
  
  RESULTS
  Flecainide prevented catecholamine-induced sustained ventricular tachycardia in RyR2(R4496C+/-) mice. Cellular studies were performed with isolated RyR2(R4496C+/-) myocytes. Isoproterenol caused the appearance of spontaneous Ca(2+) transients, which were unaffected by flecainide (6 μmol/L). Flecainide did not affect Ca(2+) transient amplitude, decay, or sarcoplasmic reticulum Ca(2+) content. Moreover, it did not affect the frequency of spontaneous Ca(2+) sparks in permeabilized myocytes. In contrast, flecainide effectively prevented triggered activity induced by isoproterenol. The threshold for action potential induction was increased significantly (P<0.01), which suggests a primary extracellular antiarrhythmic effect mediated by Na(+) channel blockade.
  
  
  CONCLUSIONS
  Flecainide prevents catecholaminergic polymorphic ventricular tachycardia in RyR2(R4496C+/-) mice; however, at variance with previous reports, we observed minimal effects on intracellular Ca(2+) 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.
authors.affiliation: Cardiovascular Genetics Program, Leon H. Charney Division of Cardiology, New York University School of Medicine, 522 First Ave, New York, NY 10016, USA.
authors.forename: Nian
authors.initials: N
authors.lastname: Liu
authors.forename: Marco
authors.initials: M
authors.lastname: Denegri
authors.forename: Yanfei
authors.initials: Y
authors.lastname: Ruan
authors.forename: José Everardo
authors.initials: JE
authors.lastname: Avelino-Cruz
authors.forename: Andrea
authors.initials: A
authors.lastname: Perissi
authors.forename: Sara
authors.initials: S
authors.lastname: Negri
authors.forename: Carlo
authors.initials: C
authors.lastname: Napolitano
authors.forename: William A
authors.initials: WA
authors.lastname: Coetzee
authors.forename: Penelope A
authors.initials: PA
authors.lastname: Boyden
authors.forename: Silvia G
authors.initials: SG
authors.lastname: Priori
mesh_terms: D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology*; D020013:Calcium Signaling / Q000187:drug effects / Q000502:physiology; D004195:Disease Models, Animal; D005110:Extracellular Space / Q000187:drug effects / Q000502:physiology; D005424:Flecainide / Q000494:pharmacology*; D055879:Gene Knock-In Techniques; D007545:Isoproterenol / Q000494:pharmacology; D051379:Mice; D008817:Mice, Mutant Strains; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000502:physiology; D018408:Patch-Clamp Techniques; D019837:Ryanodine Receptor Calcium Release Channel / Q000235:genetics / Q000502:physiology*; D012519:Sarcoplasmic Reticulum / Q000187:drug effects / Q000502:physiology; D015222:Sodium Channels / Q000502:physiology; D013566:Sympathomimetics / Q000494:pharmacology; D017180:Tachycardia, Ventricular / Q000188:drug therapy* / Q000235:genetics / Q000517:prevention & control*; D000098850:Polymorphic Catecholaminergic Ventricular Tachycardia
chemical_list: D000889:Anti-Arrhythmia Agents; D019837:Ryanodine Receptor Calcium Release Channel; D015222:Sodium Channels; D013566:Sympathomimetics; D005424:Flecainide; D007545:Isoproterenol