Dantrolene rescues arrhythmogenic RYR2 defect in a patient-specific stem cell model of catecholaminergic polymorphic ventricular tachycardia.
Bottom Line: 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.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.
Affiliation: Klinikum rechts der Isar, Technische Universität München, I. Medizinische Klinik, Kardiologie, München, Germany.Show MeSH
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Mentions: Since in CPVT patients tachycardia is restricted to the ventricles under stress condition, it might be expected that CPVT is a disease of ventricular cardiomyocytes. Our cardiac differentiation protocol leads to the generation of all three subtypes of cardiomyocytes, namely ventricular-like, atrial-like and nodal-like cells, which can be distinguished by the expression of specific myocytic lineage markers and by the shape of the action potential (Moretti et al, 2010b). Immunohistochemical analysis for ventricular and atrial myosin light chain 2 (MLC2v and MLC2a) proteins and electrophysiological measurements of action potentials in single iPSC-derived myocytes demonstrated that the ventricular subtype is largely predominant, accounting for 70–80% of all myocytes similarly in both control and CPVT groups (Fig 5A). To assess whether Ca2+ spark properties were specifically altered only in ventricular cells, we stained the cells with an antibody against MLC2v retrospectively and analysed spark data from ventricular (MLC2v+ cells) and non-ventricular (MLC2v− cells) myocytes separately. The observed differences in Ca2+ spark properties between control and CPVT cells persisted in the ventricular and non-ventricular subpopulations (Fig 5B), indicating that the mutated S406L-RYR2 channels are dysfunctional in all myocytes.
Affiliation: Klinikum rechts der Isar, Technische Universität München, I. Medizinische Klinik, Kardiologie, München, Germany.