Accelerated Sinus Rhythm Prevents Catecholaminergic Polymorphic Ventricular Tachycardia in Mice and in Patients

RATIONALE:Catecholaminergic polymorphic ventricular tachycardia (CPVT) is caused by mutations in cardiac ryanodine receptor (RyR2) or calsequestrin (Casq2) genes. Sinoatrial node dysfunction associated with CPVT may increase the risk for ventricular arrhythmia (VA). OBJECTIVE:To test the hypothesis that CPVT is suppressed by supraventricular overdrive stimulation. METHODS AND RESULTS:Using CPVT mouse models (Casq2 and RyR2 mice), the effect of increasing sinus heart rate was tested by pretreatment with atropine and by atrial overdrive pacing. Increasing intrinsic sinus rate with atropine before catecholamine challenge suppressed ventricular tachycardia in 86% of Casq2 mice (6/7) and significantly reduced the VA score (atropine0.6±0.2 versus vehicle1.7±0.3; P