Slowed depolarization and irregular repolarization in catecholaminergic polymorphic ventricular tachycardia: a study from cellular Ca2+ transients and action potentials to clinical monophasic action potentials and electrocardiography

Spontaneous Ca2+ release leads to afterdepolarizations and triggered arrhythmia in catecholaminergic polymorphic ventricular tachycardia (CPVT). Irregular Ca2+ release is hypothesized to manifest as slowed depolarization and irregular repolarization. Our goal was to study depolarization and repolarization abnormalities in CPVT, as they remain largely uninvestigated. We studied intracellular Ca2+ handling and action potentials (APs) in an induced pluripotent stem cell (iPSC) model of CPVT. Induced pluripotent stem cell cardiomyocytes from a RyR2-P2328S patient showed increased non-alternating variability of Ca2+ transients in response to isoproterenol. beta-Agonists decreased AP upslope velocity in CPVT cells and in monophasic AP recordings of CPVT patients. We compared 24 h electrocardiograms (ECGs) of 19 CPVT patients carrying RyR2 mutations and 19 healthy controls. Short-term variability (STV) of the QT interval was 6.9 +/- 0.5 ms in CPVT patients vs. 5.5 +/- 0.4 ms in controls (P < 0.05) and associated with a history of arrhythmic events. Mean T-wave alternans (TWA) was 25 +/- 1.4 A mu V in CPVT patients vs. 31 +/- 2.0 A mu V in controls (P < 0.05). Older CPVT patients showed lower maximal upslope velocity of the ECG R-spike than control patients. Catecholaminergic polymorphic ventricular tachycardia patients show higher STV of repolarization but lower TWA on the 24 h ECG than control patients, which is likely to reflect increased non-alternating variability of Ca2+ release by mutant RyR2s as observed in vitro. beta-Agonists slow depolarization in RyR2-mutant cells and in CPVT patients. These findings may constitute a marker of arrhythmogenicity.