Atrial fibrillation (AF), is the commonest cardiac arrhythmia and is associated with increased morbidity and mortality (1). Yet its underlying mechanisms are incompletely understood. Cardiac ryanodine receptor (RyR2) gain-of-function mutations predispose to catecholaminergic polymorphic ventricular tachycardia (CPVT) (2) and in some cases, including RyR2-P2328S (RyR2s/s), atrial arrhythmia (3). Recently, an anti-arrhythmic effect of flecainide (flec) was reported in CPVT (4). However, the effect of flec on RyR2-related atrial arrhythmias has not been studied.We explored the effects of flec (1 µM) on arrhythmic incidence, action potential conduction velocity (CV), refractory period (RP), wavelength (λ = CV x RP) and Na+ current activation and inactivation, in wild-type (WT) and RyR2s/s hearts. WT and RyR2s/s mice (3-11 months) were killed in accordance with the UK Animals (Scientific Procedures) Act (1986). Hearts were Langendorff-perfused and paced at 8 Hz (S1) with interposed S2 stimuli at progressively shorter S1-S2 intervals (3). Left atrial epicardial excitation was recorded by a 32 pin multi-electrode array (MEA). CV was determined using velocity vector analysis, while RP was quantified as the last non-refractory S1-S2 interval. Loose patch-clamp experiments determined Na+ current properties in superfused atrial preparations as previously described (5). Data are expressed as means ± SEM. Statistical significance (to p<0.05) was tested using two-way ANOVA or paired t-tests as appropriate.Arrhythmic score in RyR2s/s (2.65±0.38, n=17) was higher than that of WT (1.10±0.22, n=10) (Fig. 1). Flec increased arrhythmic score in WT (2.65±0.38, n=9) but decreased it in RyR2s/s (1.59±0.39, n=17). Flec slowed CV in WT from 0.38±0.024 m s-1, n=14 to 0.22±0.02 m s-1, n=10, p<0.001, and did not influence RP (control: 24.6±1.5 ms; flec: 27.7±3 ms, n=9). In contrast, flec did not alter CV in RyR2s/s (control: 0.28±0.02 m s-1, n=14; flec: 0.29±0.02 m s-1, n=10), but increased RP from 23±1.8 ms to 34±3.9 ms, n=17, p<0.001. Thus, flec decreased λ in WT (8.69±0.72 to 6.72±0.86 mm, n=8, p<0.05) but increased it in RyR2s/s (6.27±0.78 to 7.38±0.83 mm, n=10, p<0.05). Activation and inactivation studies revealed smaller Na+ currents in RyR2s/s than WT. Flec increased Na+ currents in RyR2s/s yet reduced them in WT. This suggests that the expected inhibition of Na+ channels by flec was opposed by concurrent inhibition of RyR2-mediated release of SR Ca2+, previously shown to reduce Na+ channel function (3,5).These findings demonstrate that flec decreases atrial arrhythmia with increased λ and Na+current in RyR2s/s, yet increases atrial arrhythmia with decreased λ and Na+ current in WT.