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

作者：Jung Christian B; Moretti Alessandra; Mederos Y Schnitzler Michael; Iop Laura; Storch Ursula; Bellin Milena; Dorn Tatjana; Ruppenthal Sandra; Pfeiffer Sarah; Goedel Alexander; Dirschinger Ralf J; Seyfarth Melchior; Lam Jason T; Sinnecker Daniel; Gudermann Thomas; Lipp Peter; Laugwitz Karl Ludwig^*

来源：EMBO Molecular Medicine, 2012, 4(3): 180-191.

DOI：10.1002/emmm.201100194

• CPVT
• dantrolene
• disease modelling
• induced pluripotent stem cells
• ryanodine receptor 2

Coordinated release of calcium (Ca2+) 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 Ca2+ 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 Ca2+ concentrations, a reduced SR Ca2+ content and an increased susceptibility to DADs and arrhythmia as compared to control myocytes. This was due to increased frequency and duration of elementary Ca2+ release events (Ca2+ sparks). Dantrolene, a drug effective on malignant hyperthermia, restored normal Ca2+ 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.

• 出版日期2012-3