Using specific compounds and genome editing, the critical roles of CaMKII-dependent re-entry and CaMKII-dependent phosphorylation at Ser2814 in RyR2 were shown to be deleterious for the first time in the two human engineered tissue models of CPVT, harboring the RyR2-D358N and RyR2-R4651I mutations, respectively. Here, RYR2 is linked to catecholaminergic polymorphic ventricular tachycardia.