Oral Presentation 2014 International Biophysics Congress

Contrasting effects of flecainide on atrial arrhythmia in wild-type and RyR2-P2328S mice (#189)

Samantha C. Salvage 1 , James H. King 1 , Karthik H. Chandrasekharan 1 , Dan Jafferji 1 , Laila Guzadhur 2 , Hugh R. Matthews 1 , Christopher L.-H. Huang 1 2 , Fraser A. James 1
  1. Department of Physiology, Development and Neuroscience, University of Cambridge, Cambridge, UK
  2. Department of Biochemistry, University of Cambridge, Cambridge, UK

Background. The RyR2-P2328S mutation is associated with atrial fibrillation and catecholaminergic polymorphic ventricular tachycardia (CPVT) 1–3. Recently an anti-arrhythmic effect of flecainide was reported in CPVT 4. However, the effect of flecainide on RyR2-related atrial arrhythmias has not been studied.

Methods and Results. Atrial arrhythmic incidence, Na+ current, action potential conduction velocities (CV), atrial effective refractory periods (AERP), and wavelength (λ = CV ´ AERP) were measured in murine wild-type (WT) and homozygotic, RyR2-P2328S (RyR2s/s) hearts before and following flecainide administration. Multi-electrode array recordings in Langendorff-perfused hearts demonstrated more frequent atrial arrhythmias, reduced CV and similar AERP in RyR2s/s as in WT. Flecainide (1 µM) reduced arrhythmogenicity in RyRs/s but increased it in WT, whilst reducing excitability in both genotypes at 5 µM. Flecainide increased AERP while sparing CV in RyR2s/s, whereas it slowed CV whilst sparing AERP in WT. Thus, λ was reduced in RyR2s/s hearts relative to WT, but flecainide contrastingly increased λ in RyR2s/swhile decreasing λ in WT. Loose-patch clamp studies of Na+ current (INa) activation and inactivation in superfused atrial preparations demonstrated reduced INa in RyR2s/s compared to WT. Flecainide (1 µM) increased INa in RyR2s/s yet reduced INa in WT.

Conclusions. Flecainide decreases atrial arrhythmogenicity while increasing INa and λ in RyR2s/s, yet increases arrhythmogenicity while reducing INa and λ in WT hearts. The findings suggest a dual effect of flecainide in both directly inhibiting INa and rescuing the SR Ca2+ leak previously implicated in the reduced INa observed in RyR2s/s hearts 5.

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