title: Dantrolene rescues arrhythmogenic RYR2 defect in a patient-specific stem cell model of catecholaminergic polymorphic ventricular tachycardia.
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.
authors.affiliation: Klinikum rechts der Isar, Technische Universität München, I. Medizinische Klinik, Kardiologie, München, Germany.
authors.forename: Christian B
authors.initials: CB
authors.lastname: Jung
authors.forename: Alessandra
authors.initials: A
authors.lastname: Moretti
authors.forename: Michael
authors.initials: M
authors.lastname: Mederos y Schnitzler
authors.forename: Laura
authors.initials: L
authors.lastname: Iop
authors.forename: Ursula
authors.initials: U
authors.lastname: Storch
authors.forename: Milena
authors.initials: M
authors.lastname: Bellin
authors.forename: Tatjana
authors.initials: T
authors.lastname: Dorn
authors.forename: Sandra
authors.initials: S
authors.lastname: Ruppenthal
authors.forename: Sarah
authors.initials: S
authors.lastname: Pfeiffer
authors.forename: Alexander
authors.initials: A
authors.lastname: Goedel
authors.forename: Ralf J
authors.initials: RJ
authors.lastname: Dirschinger
authors.forename: Melchior
authors.initials: M
authors.lastname: Seyfarth
authors.forename: Jason T
authors.initials: JT
authors.lastname: Lam
authors.forename: Daniel
authors.initials: D
authors.lastname: Sinnecker
authors.forename: Thomas
authors.initials: T
authors.lastname: Gudermann
authors.forename: Peter
authors.initials: P
authors.lastname: Lipp
authors.forename: Karl-Ludwig
authors.initials: KL
authors.lastname: Laugwitz
mesh_terms: D000328:Adult; D002118:Calcium / Q000378:metabolism; D002478:Cells, Cultured; D003620:Dantrolene / Q000494:pharmacology*; D005260:Female; D006801:Humans; D057026:Induced Pluripotent Stem Cells / Q000187:drug effects / Q000378:metabolism*; D017136:Ion Transport / Q000187:drug effects; D008954:Models, Biological; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism; D019837:Ryanodine Receptor Calcium Release Channel / Q000235:genetics / Q000378:metabolism*; D012519:Sarcoplasmic Reticulum / Q000187:drug effects / Q000378:metabolism; D017180:Tachycardia, Ventricular / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism*; D000098850:Polymorphic Catecholaminergic Ventricular Tachycardia
chemical_list: D019837:Ryanodine Receptor Calcium Release Channel; D003620:Dantrolene; D002118:Calcium