title: A human pluripotent stem cell model of catecholaminergic polymorphic ventricular tachycardia recapitulates patient-specific drug responses.
abstract: Although β-blockers can be used to eliminate stress-induced ventricular arrhythmias in patients with catecholaminergic polymorphic ventricular tachycardia (CPVT), this treatment is unsuccessful in ∼25% of cases. Induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) generated from these patients have potential for use in investigating the phenomenon, but it remains unknown whether they can recapitulate patient-specific drug responses to β-blockers. This study assessed whether the inadequacy of β-blocker therapy in an individual can be observed in vitro using patient-derived CPVT iPSC-CMs. An individual with CPVT harboring a novel mutation in the type 2 cardiac ryanodine receptor (RyR2) was identified whose persistent ventricular arrhythmias during β-blockade with nadolol were abolished during flecainide treatment. iPSC-CMs generated from this patient and two control individuals expressed comparable levels of excitation-contraction genes, but assessment of the sarcoplasmic reticulum Ca(2+) leak and load relationship revealed intracellular Ca(2+) homeostasis was altered in the CPVT iPSC-CMs. β-adrenergic stimulation potentiated spontaneous Ca(2+) waves and unduly frequent, large and prolonged Ca(2+) sparks in CPVT compared with control iPSC-CMs, validating the disease phenotype. Pursuant to the patient's in vivo responses, nadolol treatment during β-adrenergic stimulation achieved negligible reduction of Ca(2+) wave frequency and failed to rescue Ca(2+) spark defects in CPVT iPSC-CMs. In contrast, flecainide reduced both frequency and amplitude of Ca(2+) waves and restored the frequency, width and duration of Ca(2+) sparks to baseline levels. By recapitulating the improved response of an individual with CPVT to flecainide compared with β-blocker therapy in vitro, these data provide new evidence that iPSC-CMs can capture basic components of patient-specific drug responses.
authors.affiliation: Division of Pediatric Cardiology, Department of Pediatrics, Emory University School of Medicine and Children's Healthcare of Atlanta, Atlanta, GA 30322, USA Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology and Emory University, Atlanta, GA 30322, USA.
authors.forename: Marcela K
authors.initials: MK
authors.lastname: Preininger
authors.affiliation: Division of Pediatric Cardiology, Department of Pediatrics, Emory University School of Medicine and Children's Healthcare of Atlanta, Atlanta, GA 30322, USA.
authors.forename: Rajneesh
authors.initials: R
authors.lastname: Jha
authors.affiliation: Division of Pediatric Cardiology, Department of Pediatrics, Emory University School of Medicine and Children's Healthcare of Atlanta, Atlanta, GA 30322, USA Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology and Emory University, Atlanta, GA 30322, USA.
authors.forename: Joshua T
authors.initials: JT
authors.lastname: Maxwell
authors.affiliation: Division of Pediatric Cardiology, Department of Pediatrics, Emory University School of Medicine and Children's Healthcare of Atlanta, Atlanta, GA 30322, USA Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology and Emory University, Atlanta, GA 30322, USA.
authors.forename: Qingling
authors.initials: Q
authors.lastname: Wu
authors.affiliation: Division of Pediatric Cardiology, Department of Pediatrics, Emory University School of Medicine and Children's Healthcare of Atlanta, Atlanta, GA 30322, USA.
authors.forename: Monalisa
authors.initials: M
authors.lastname: Singh
authors.affiliation: Division of Pediatric Cardiology, Department of Pediatrics, Emory University School of Medicine and Children's Healthcare of Atlanta, Atlanta, GA 30322, USA.
authors.forename: Bo
authors.identifier: 0000-0003-0673-6548
authors.initials: B
authors.lastname: Wang
authors.affiliation: Division of Pediatric Cardiology, Department of Pediatrics, Emory University School of Medicine and Children's Healthcare of Atlanta, Atlanta, GA 30322, USA.
authors.forename: Aarti
authors.initials: A
authors.lastname: Dalal
authors.affiliation: Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology and Emory University, Atlanta, GA 30322, USA Department of Cell Biology, Emory University School of Medicine, Atlanta, GA 30322, USA Laboratory of Translational Cell Biology, Emory University School of Medicine, Atlanta, GA 30322, USA.
authors.forename: Zachary T
authors.initials: ZT
authors.lastname: Mceachin
authors.affiliation: Department of Cell Biology, Emory University School of Medicine, Atlanta, GA 30322, USA Laboratory of Translational Cell Biology, Emory University School of Medicine, Atlanta, GA 30322, USA.
authors.forename: Wilfried
authors.initials: W
authors.lastname: Rossoll
authors.affiliation: Department of Neurology, Emory University School of Medicine, Atlanta, GA 30322, USA.
authors.forename: Chadwick M
authors.initials: CM
authors.lastname: Hales
authors.affiliation: Division of Pediatric Cardiology, Department of Pediatrics, Emory University School of Medicine and Children's Healthcare of Atlanta, Atlanta, GA 30322, USA.
authors.forename: Peter S
authors.initials: PS
authors.lastname: Fischbach
authors.affiliation: Division of Pediatric Cardiology, Department of Pediatrics, Emory University School of Medicine and Children's Healthcare of Atlanta, Atlanta, GA 30322, USA Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology and Emory University, Atlanta, GA 30322, USA.
authors.forename: Mary B
authors.initials: MB
authors.lastname: Wagner
authors.affiliation: Division of Pediatric Cardiology, Department of Pediatrics, Emory University School of Medicine and Children's Healthcare of Atlanta, Atlanta, GA 30322, USA Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology and Emory University, Atlanta, GA 30322, USA chunhui.xu@emory.edu.
authors.forename: Chunhui
authors.identifier: 0000-0003-1748-0648
authors.initials: C
authors.lastname: Xu
mesh_terms: D000319:Adrenergic beta-Antagonists / Q000494:pharmacology / Q000627:therapeutic use; D001145:Arrhythmias, Cardiac / Q000188:drug therapy / Q000503:physiopathology; D015415:Biomarkers / Q000378:metabolism; D002118:Calcium / Q000378:metabolism; D020013:Calcium Signaling / Q000187:drug effects; D002395:Catecholamines / Q000378:metabolism*; D002454:Cell Differentiation / Q000187:drug effects; D019070:Cell Lineage / Q000187:drug effects; D055724:Electrophysiological Phenomena / Q000187:drug effects; D005260:Female; D005424:Flecainide / Q000494:pharmacology / Q000627:therapeutic use; D006706:Homeostasis / Q000187:drug effects; D006801:Humans; D057026:Induced Pluripotent Stem Cells / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D008954:Models, Biological; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D010375:Pedigree; D011943:Receptors, Adrenergic, beta / Q000378:metabolism; D017180:Tachycardia, Ventricular / Q000188:drug therapy* / Q000473:pathology* / Q000503:physiopathology; D000098850:Polymorphic Catecholaminergic Ventricular Tachycardia
chemical_list: D000319:Adrenergic beta-Antagonists; D015415:Biomarkers; D002395:Catecholamines; D011943:Receptors, Adrenergic, beta; D005424:Flecainide; D002118:Calcium
keywords: Arrhythmia models; CPVT; Ca2+ handling; Cardiomyocytes; iPSCs