Objective A naturally-occurring mutation in cardiac calsequestrin (CASQ2) at amino acid 307 was discovered in a highly inbred family and hypothesized to cause Catecholaminergic Polymorphic Ventricular Tachycardia (CPVT). The goal of this study was to establish a causal link between CASQ2^D307H and the CPVT phenotype using an in vivo model.

Methods and results Cardiac-specific expression of the CASQ2^D307H transgene was achieved using the α-MHC promoter. Multiple transgenic (TG) mouse lines expressing CASQ2^D307H from 2- to 6-fold possess structurally normal hearts without any sign of hypertrophy. The hearts displayed normal ventricular function. Myocytes isolated from TG mice had diminished I_Ca-induced Ca²⁺ transient amplitude and duration, as well as increased Ca²⁺ spark frequency. These myocytes, when exposed to isoproterenol and caffeine, displayed disturbances in their rhythmic Ca²⁺ oscillations and membrane potential, and delayed afterdepolarizations. ECG monitoring revealed that TG mice challenged with isoproterenol and caffeine developed complex ventricular arrhythmias, including non-sustained polymorphic ventricular tachycardia.

Conclusions The findings of the present study demonstrate that expression of mutant CASQ2^D307H in the mouse heart results in abnormal myocyte Ca²⁺ handling and predisposes to complex ventricular arrhythmias similar to the CPVT phenotype observed in human patients.