複数のRyR2変異マウスモデル系統を用いたカテコラミン誘発性多型性心室頻拍（CPVT）に対する抗不整脈薬の評価

抄録

Gain-of-function mutations in type 2 ryanodine receptors (RyR2) are known to cause severe arrhythmias such as catecholaminergic polymorphic ventricular tachycardia (CPVT). Conventional antiarrhythmic drugs are sometimes insufficient to suppress these arrhythmias. To seek more effective drugs, we aimed to provide a basis for quantitative evaluation of the two important effects of antiarrhythmic drugs, i.e., prevention and treatment/stopping of arrhythmia, using multiple RyR2 mutant mouse lines (R420W, I4093V and K4750Q) with varying degrees of enhanced Ca²⁺ release activity. Short term ECG was recorded from the limb leads under isoflurane anesthesia, and arrhythmia was induced by administration of adrenaline alone or adrenaline/caffeine mixture. For monitoring basal arrhythmia during everyday activities, long range ECG was recorded by telemetry system. The R420W mice having moderately activated channels showed little basal arrhythmia but exhibited severe ventricular arrhythmias by adrenaline/caffeine induction. On the contrary, the RyR2-I4093V and K4750Q strains having highly activated channels showed frequent basal arrhythmia without adrenergic induction. Na channel blockers, Ca channel blockers and beta blockers suppressed the induced arrhythmia and basal arrhythmia to varying degrees. Interestingly, the preventive effect and the stopping effect seemed to differ depending on their mechanism of action. The usage of multiple lines of mice with different degrees of activity are useful for the evaluation of therapies for CPVT.