Background: Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a disease related to altered ryanodine receptor (RyR) mediated SR Ca²⁺ leak and associated with sudden cardiac death in young adults. We recently identified a family with a mixed phenotype of CPVT and long-QT-syndrome (CPVT3*) related to a novel mutation in the trans-2.3-enyol-CoA reductase-like (TECRL) gene. Ventricular arrhythmia burden varies greatly between individual CPVT3* patients.

Methods/Results: We generated human induced pluripotent stem cell derived cardiomyocytes (iPSc-CM) from a control and CPVT3* patient to explore underlying mechanisms and individualize pharmacological treatment. iPSc-CM were studied using confocal Ca²⁺ imaging (fluo-4). Ca²⁺ signaling during excitation-contraction coupling was studied in the presence of different clinically available modulators of RyR mediated SR Ca²⁺ leak. In particular, cardiomyocyte function and arrythmias were tested upon addition of the class Ic antiarrhythmic flecainide (10µM), the RyR stabilizer dantrolene (1µM), the betablocker R-Carvedilol (1µM), the kinase inhibitor Rimacalib (10 µM) and the RyR-Calstabin interaction stabilizer S107 (10µM). Under baseline conditions, CPVT3* iPSc-CM showed significantly decreased Ca²⁺ transient (CaT) amplitudes and increased CaT duration. Altered SR Ca²⁺ content was associated with increased L-type Ca²⁺ currents. Upon addition of the beta-agonist isoproterenol (ISO, 100nM), CaT amplitudes and pro-arrhythmogenic Ca²⁺ release (i.e. Ca²⁺ sparks) significantly increased in CPVT3* as compared to control. All pharmaceuticals altered Ca²⁺ signaling in CPVT3* in a substance dependent manner and pro-arrhythmogenic Ca²⁺ release was particularly mitigated upon addition of flecainide. Flecainide preferentially decreased L-type Ca²⁺ currents in CPVT as compared to WT. Treatment of the CPVT3* patient with flecainide significantly reduced ventricular premature beats as determined by 24 hour holter-ECG monitoring.

Conclusion: We quantitatively assessed drugs targeting RyR mediated SR Ca²⁺ leak in a CPVT3* patient with a novel TECRL mutation using iPSc-CM. Favorable in-vitro results of flecainide were mirrored in a significant reduction of ventricular arrhythmia in-vivo. Our results underscore the potential of iPSc-CM for the development of patient-tailored treatment in genetic arrhythmia syndromes.