Abstract 2726: Atrial Fibrillation in Two Mouse Models With Human CPVT Ryanodine Receptor Mutations
Atrial fibrillation (AF) is the most commonly occurring cardiac arrhythmia in humans. Multiple mechanisms potentially induce AF, but the role of altered atrial Ca2+ cycling in AF etiology is unclear. The cardiac ryanodine receptor (RyR2) is the major Ca2+ release channel in myocytes and controls the release of Ca2+ from the sarcoplasmic reticulum during contraction. RyR2 mutations are implicated in catecholaminergic polymorphic ventricular tachycardia (CPVT), but it is unknown whether RyR2 dysfunction is involved in AF. CPVT patients are known to exhibit atrial arrhythmias, indicating that altered RyR2 function may play a role in the development of AF. We generated two “knock-in” mouse models of human CPVT, RyR2-R2474S and RyR2-N2386I. We used an intra-esophageal burst pacing protocol to examine the inducibility of AF in these two human CPVT mouse models. Both mutant mice exhibited AF after burst pacing (R2474S, 50%, n = 10; N2386I, 50%, n = 10) in contrast to wild-type (WT) littermates (0%, n = 10, P < 0.05 vs. R2474S and N2386I). We also examined the effects of isoproterenol (ISO) on AF inducibility. ISO (0.5μg/kg) increased pacing induced AF incidence (WT, 20%; R2474S, 100%; N2386I, 80%, n = 10 for all groups, P < 0.05 for both RyR2 mutant groups vs. WT). Treatment of RyR2-R2474S mice with metoprolol (30 mg/kg/day, 2 weeks, n = 5) failed to prevent AF in CPVT mice. However, S107 (150 mg/kg/day, in the drinking water, for 2 weeks), a member of a novel class of calcium release channel stabilizers or rycals (1,4-benzothiazepine derivative) that inhibits SR Ca2+ leak via RyR2 channels, reduced pacing induced AF in CPVT mice (R2474S, 0%, n = 10; N2386I, 14%, n = 7, P < 0.05 vs. vehicle treatment in R2474S) and in ISO (0.5 μg/kg) treated CPVT mice (R2474S, 20%, n = 10; N2386IS, 29%, n = 7, P < 0.05 vs. vehicle treatment in R2474S).
CONCLUSIONS: Mice with CPVT-linked RyR2 mutations exhibit pacing induced AF and inhibiting SR Ca2+ leak via mutant RyR2 with a rycal, S107, decreased burst pacing-stimulated AF in CPVT mice.