A knock-in mouse model of N-terminal R420W mutation of cardiac ryanodine receptor exhibits arrhythmogenesis with abnormal calcium dynamics in cardiomyocytes

Cardiac ryanodine receptor gene (RyR2) mutations cause fatal arrhythmogenic diseases such as catecholaminergic polymorphic ventricular tachycardia and arrhythmogenic right ventricular cardiomyopathy. The N-terminal region of RyR2 is one of the hot spots for mutations. In this study, we investigated cardiac phenotypes of a knock-in mouse model carrying R420W mutation of RyR2. The N-terminal R420W mutation has already been found in juvenile sudden death cadavers of unrelated families. The depolarization-induced Ca2+ transient amplitude was significantly lower in cardiomyocytes from RyR2R420W/R420W mice compared with wild-type mice. The time to peak of the Ca2+ transient was significantly increased in RyR2R420W/R420W mice. Furthermore, the prolonged decay time from the peak of the Ca2+ transient was detected in RyR2R420W/R420W mice. ECG telemetry revealed that various types of arrhythmias were induced in RyR2R420W/R420W mice in response to administration of caffeine and adrenaline. The mutant mice showed high occurrences of arrhythmias in response to heart stimulants compared with wild-type mice. These findings suggest that R420W mutation impairs depolarization-induced Ca2+ oscillation in cardiomyocytes, which possibly results in sudden death due to stress-induced arrhythmias.