title: Flecainide exerts paradoxical effects on sodium currents and atrial arrhythmia in murine RyR2-P2328S hearts.
abstract: OBJECTIVE
  Cardiac ryanodine receptor mutations are associated with catecholaminergic polymorphic ventricular tachycardia (CPVT), and some, including RyR2-P2328S, also predispose to atrial fibrillation. Recent work associates reduced atrial Nav 1.5 currents in homozygous RyR2-P2328S (RyR2(S/S) ) mice with slowed conduction and increased arrhythmogenicity. Yet clinically, and in murine models, the Nav 1.5 blocker flecainide reduces ventricular arrhythmogenicity in CPVT. We aimed to determine whether, and how, flecainide influences atrial arrhythmogenicity in RyR2(S/S) mice and their wild-type (WT) littermates.
  
  
  METHODS
  We explored effects of 1 μm flecainide on WT and RyR2(S/S) atria. Arrhythmic incidence, action potential (AP) conduction velocity (CV), atrial effective refractory period (AERP) and AP wavelength (λ = CV × AERP) were measured using multi-electrode array recordings in Langendorff-perfused hearts; Na(+) currents (INa ) were recorded using loose patch clamping of superfused atria.
  
  
  RESULTS
  RyR2(S/S) showed more frequent atrial arrhythmias, slower CV, reduced INa and unchanged AERP compared to WT. Flecainide was anti-arrhythmic in RyR2(S/S) but pro-arrhythmic in WT. It increased INa in RyR2(S/S) atria, whereas it reduced INa as expected in WT. It increased AERP while sparing CV in RyR2(S/S) , but reduced CV while sparing AERP in WT. Thus, RyR2(S/S) hearts have low λ relative to WT; flecainide then increases λ in RyR2(S/S) but decreases λ in WT.
  
  
  CONCLUSIONS
  Flecainide (1 μm) rescues the RyR2-P2328S atrial arrhythmogenic phenotype by restoring compromised INa and λ, changes recently attributed to increased sarcoplasmic reticular Ca(2+) release. This contrasts with the increased arrhythmic incidence and reduced INa and λ with flecainide in WT.
authors: Physiological Laboratory, University of Cambridge, Cambridge, UK.
authors: S C
authors: SC
authors: Salvage
authors: Physiological Laboratory, University of Cambridge, Cambridge, UK.
authors: J H
authors: JH
authors: King
authors: Physiological Laboratory, University of Cambridge, Cambridge, UK.
authors: K H
authors: KH
authors: Chandrasekharan
authors: Physiological Laboratory, University of Cambridge, Cambridge, UK.
authors: D I G
authors: DI
authors: Jafferji
authors: Department of Biochemistry, University of Cambridge, Cambridge, UK.
authors: L
authors: L
authors: Guzadhur
authors: Physiological Laboratory, University of Cambridge, Cambridge, UK.
authors: H R
authors: HR
authors: Matthews
authors: Physiological Laboratory, University of Cambridge, Cambridge, UK.|Department of Biochemistry, University of Cambridge, Cambridge, UK.
authors: C L-H
authors: CL
authors: Huang
authors: Physiological Laboratory, University of Cambridge, Cambridge, UK.
authors: J A
authors: JA
authors: Fraser
mesh_terms: D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000008:administration & dosage; D001281:Atrial Fibrillation / Q000175:diagnosis / Q000378:metabolism*; D005424:Flecainide / Q000008:administration & dosage*; D015640:Ion Channel Gating / Q000187:drug effects; D008564:Membrane Potentials / Q000187:drug effects*; D051379:Mice; D009154:Mutation; D062554:NAV1.5 Voltage-Gated Sodium Channel / Q000187:drug effects*; D019837:Ryanodine Receptor Calcium Release Channel / Q000235:genetics*; D012964:Sodium / Q000378:metabolism*; D016896:Treatment Outcome; D061567:Voltage-Gated Sodium Channel Blockers / Q000008:administration & dosage
chemical_list: D000889:Anti-Arrhythmia Agents; D062554:NAV1.5 Voltage-Gated Sodium Channel; D019837:Ryanodine Receptor Calcium Release Channel; C568321:Scn5a protein, mouse; D061567:Voltage-Gated Sodium Channel Blockers; C000592748:ryanodine receptor 2. mouse; D012964:Sodium; D005424:Flecainide
keywords: CPVT; Na+ currents; atrial arrhythmia; conduction velocity; flecainide; ryanodine receptor