Flecainide exerts paradoxical effects on sodium currents and atrial arrhythmia in murine R yR2‐P2328S hearts

Aims 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 Na v 1.5 currents in homozygous RyR2‐P2328S ( RyR2 S/S ) mice with slowed conduction and increased arrhythmogenicity. Yet clinically, and in murine models, the Na v 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  μ m 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 ( I Na ) were recorded using loose patch clamping of superfused atria. Results RyR2 S/S showed more frequent atrial arrhythmias, slower CV , reduced I Na and unchanged AERP compared to WT . Flecainide was anti‐arrhythmic in RyR2 S/S but pro‐arrhythmic in WT . It increased I Na in RyR2 S/S atria, whereas it reduced I Na 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  μ m ) rescues the RyR2‐P2328S atrial arrhythmogenic phenotype by restoring compromised I Na and λ , changes recently attributed to increased sarcoplasmic reticular Ca 2+ release. This contrasts with the increased arrhythmic incidence and reduced I Na and λ with flecainide in WT .