Abstract Coordinated release of calcium (Ca 2+ ) from the sarcoplasmic reticulum (SR) through cardiac ryanodine receptor (RYR2) channels is essential for cardiomyocyte function. In catecholaminergic polymorphic ventricular tachycardia (CPVT), an inherited disease characterized by stress‐induced ventricular arrhythmias in young patients with structurally normal hearts, autosomal dominant mutations in RYR2 or recessive mutations in calsequestrin lead to aberrant diastolic Ca 2+ release from the SR causing arrhythmogenic delayed after depolarizations (DADs). Here, we report the generation of induced pluripotent stem cells (iPSCs) from a CPVT patient carrying a novel RYR2 S406L mutation. In patient iPSC‐derived cardiomyocytes, catecholaminergic stress led to elevated diastolic Ca 2+ concentrations, a reduced SR Ca 2+ content and an increased susceptibility to DADs and arrhythmia as compared to control myocytes. This was due to increased frequency and duration of elementary Ca 2+ release events (Ca 2+ sparks). Dantrolene, a drug effective on malignant hyperthermia, restored normal Ca 2+ spark properties and rescued the arrhythmogenic phenotype. This suggests defective inter‐domain interactions within the RYR2 channel as the pathomechanism of the S406L mutation. Our work provides a new in vitro model to study the pathogenesis of human cardiac arrhythmias and develop novel therapies for CPVT.

Dantrolene rescues arrhythmogenic RYR2 defect in a patient‐specific stem cell model of catecholaminergic polymorphic ventricular tachycardia