title: Antiarrhythmic Effects of Dantrolene in Patients with Catecholaminergic Polymorphic Ventricular Tachycardia and Replication of the Responses Using iPSC Models.
abstract: Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a highly malignant inherited arrhythmogenic disorder. Type 1 CPVT (CPVT1) is caused by cardiac ryanodine receptor (RyR2) gene mutations resulting in abnormal calcium release from sarcoplasmic reticulum. Dantrolene, an inhibitor of sarcoplasmic Ca(2+) release, has been shown to rescue this abnormal Ca(2+) release in vitro. We assessed the antiarrhythmic efficacy of dantrolene in six patients carrying various RyR2 mutations causing CPVT. The patients underwent exercise stress test before and after dantrolene infusion. Dantrolene reduced the number of premature ventricular complexes (PVCs) on average by 74% (range 33-97) in four patients with N-terminal or central mutations in the cytosolic region of the RyR2 protein, while dantrolene had no effect in two patients with mutations in or near the transmembrane domain. Induced pluripotent stem cells (iPSCs) were generated from all the patients and differentiated into spontaneously beating cardiomyocytes (CMs). The antiarrhythmic effect of dantrolene was studied in CMs after adrenaline stimulation by Ca(2+) imaging. In iPSC derived CMs with RyR2 mutations in the N-terminal or central region, dantrolene suppressed the Ca(2+) cycling abnormalities in 80% (range 65-97) of cells while with mutations in or near the transmembrane domain only in 23 or 32% of cells. In conclusion, we demonstrate that dantrolene given intravenously shows antiarrhythmic effects in a portion of CPVT1 patients and that iPSC derived CM models replicate these individual drug responses. These findings illustrate the potential of iPSC models to individualize drug therapy of inherited diseases.Trial Registration: EudraCT Clinical Trial Registry 2012-005292-14.
authors.affiliation: BioMediTech, University of Tampere, Tampere, Finland; School of Medicine, University of Tampere, Tampere, Finland.
authors.forename: Kirsi
authors.initials: K
authors.lastname: Penttinen
authors.affiliation: Heart and Lung Center, Helsinki University Hospital, Helsinki, Finland.
authors.forename: Heikki
authors.initials: H
authors.lastname: Swan
authors.affiliation: Heart Hospital, Tampere University Hospital, Tampere, Finland.
authors.forename: Sari
authors.initials: S
authors.lastname: Vanninen
authors.affiliation: Minerva Foundation Institute for Medical Research, Helsinki, Finland.
authors.forename: Jere
authors.initials: J
authors.lastname: Paavola
authors.affiliation: Department of Medicine, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.
authors.forename: Annukka M
authors.initials: AM
authors.lastname: Lahtinen
authors.affiliation: Department of Medicine, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.
authors.forename: Kimmo
authors.initials: K
authors.lastname: Kontula
authors.affiliation: BioMediTech, University of Tampere, Tampere, Finland; School of Medicine, University of Tampere, Tampere, Finland; Heart Hospital, Tampere University Hospital, Tampere, Finland.
authors.forename: Katriina
authors.initials: K
authors.lastname: Aalto-Setälä
mesh_terms: D000328:Adult; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000008:administration & dosage*; D001145:Arrhythmias, Cardiac / Q000188:drug therapy / Q000235:genetics; D002118:Calcium / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects; D003620:Dantrolene / Q000008:administration & dosage*; D004837:Epinephrine / Q000378:metabolism; D005260:Female; D006801:Humans; D057026:Induced Pluripotent Stem Cells; D008875:Middle Aged; D009154:Mutation; D032383:Myocytes, Cardiac / Q000187:drug effects* / Q000473:pathology; D019837:Ryanodine Receptor Calcium Release Channel / Q000235:genetics; D017180:Tachycardia, Ventricular / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D000098850:Polymorphic Catecholaminergic Ventricular Tachycardia
chemical_list: D000889:Anti-Arrhythmia Agents; D019837:Ryanodine Receptor Calcium Release Channel; D003620:Dantrolene; D002118:Calcium; D004837:Epinephrine