Catecholaminergic polymorphic ventricular tachycardia (CPVT) is an inherited disease manifested as syncope or sudden death in children and young adults. The ryanodine receptor (RyR2) R420Q mutation was identified in a 14-year-old boy who died suddenly. We generated human induced pluripotent (h-iPS) derived cardiomyocytes from two sisters. As most of sudden death occurs in males, we had the hypothesis that there might be some sex-dependent differences.

We aim to elucidate the key role of [Ca²⁺]_i in the genesis of cardiac arrhythmia in female RyR2^R420Q CPVT patients. We generated hiPSC-CM from two sisters, one carrier and the other non-carrier. We assessed intracellular [Ca²⁺]_i handling both spontaneous and during electrical pacing at 1Hz by confocal microscopy. For SR Ca²⁺ load quantification, h-iPS-CMs were rapidly perfused with 10mmol/L caffeine. To induce β-adrenergic activation, 100nM isoproterenol (ISO) was added in some experiments. All confocal Ca²⁺ images were analysed by homemade routines using IDL software.

First, we found that woman CPVT h-iPS-CMs presented longer cycle length than wt cells, correlating with the bradycardia observed in CPVT patients. The amplitude of the Ca²⁺ transients were significantly higher for CPVT h-iPS-CMs compared to wt; however Ca²⁺ transients did not change in CPVT h-iPS-CMs, after ISO perfusion. SR Ca²⁺ load presented no differences between groups but the time decay constant of the caffeine-evoked Ca²⁺ transients were faster in CPVT h-iPS-CMs whereas it became slower after ISO perfusion. Moreover, Ca²⁺ pro-arrhythmogenic events were significantly higher in CPVT h-iPS-CMs compared to wt h-iPS-CMs whereas similar values were observed in CPVT cells after ISO perfusion. Although pro-arrythmogenic events were similarly higher in both male and female hiPSC-CM, the Ca²⁺ handling characteristics were slightly different.

The RyR2R420Q mutation in woman CPVT h-iPS-CMs provides a reliable model to study CPVT in human context.