Expression of mutant CASQ2(D307H) in the mouse heart resulted in abnormal myocyte Ca2+ handling and predisposed to complex ventricular arrhythmias similar to human CPVT.
The CASQ2(D307H) mutation causes abnormal calcium handling and predisposes to complex ventricular arrhythmias in a mouse model, establishing a causal link to the human Catecholaminergic Polymorphic Ventricular Tachycardia (CPVT) phenotype.
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 alpha-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.
Dirksen et al. (Tue,) conducted a other in Catecholaminergic Polymorphic Ventricular Tachycardia (CPVT). CASQ2(D307H) transgene expression was evaluated on Development of complex ventricular arrhythmias and abnormal myocyte Ca2+ handling. Expression of mutant CASQ2(D307H) in the mouse heart resulted in abnormal myocyte Ca2+ handling and predisposed to complex ventricular arrhythmias similar to human CPVT.