Hence, we suggest that the RyR2-R2474S mutation induces a metabolic burden in cardiomyocytes through excess ROS generation, especially after β-adrenergic stimulation, tipping the balance from a compensated to a high energetic cost and acutely increased diastolic Ca2+ leak, a multifactorial process, which may acutely contribute to the development of the arrhythmogenic CPVT phenotype as proposed for calsequestrin2-null mice previously (Hamilton et al., 2020). This evidence concerns the gene RYR2 and catecholaminergic polymorphic ventricular tachycardia.