title: Patient-Specific Human Induced Pluripotent Stem Cell Model Assessed with Electrical Pacing Validates S107 as a Potential Therapeutic Agent for Catecholaminergic Polymorphic Ventricular Tachycardia.
abstract: BACKGROUND
  Human induced pluripotent stem cells (hiPSCs) offer a unique opportunity for disease modeling. However, it is not invariably successful to recapitulate the disease phenotype because of the immaturity of hiPSC-derived cardiomyocytes (hiPSC-CMs). The purpose of this study was to establish and analyze iPSC-based model of catecholaminergic polymorphic ventricular tachycardia (CPVT), which is characterized by adrenergically mediated lethal arrhythmias, more precisely using electrical pacing that could promote the development of new pharmacotherapies.
  
  
  RESULTS
  We generated hiPSCs from a 37-year-old CPVT patient and differentiated them into cardiomyocytes. Under spontaneous beating conditions, no significant difference was found in the timing irregularity of spontaneous Ca2+ transients between control- and CPVT-hiPSC-CMs. Using Ca2+ imaging at 1 Hz electrical field stimulation, isoproterenol induced an abnormal diastolic Ca2+ increase more frequently in CPVT- than in control-hiPSC-CMs (control 12% vs. CPVT 43%, p<0.05). Action potential recordings of spontaneous beating hiPSC-CMs revealed no significant difference in the frequency of delayed afterdepolarizations (DADs) between control and CPVT cells. After isoproterenol application with pacing at 1 Hz, 87.5% of CPVT-hiPSC-CMs developed DADs, compared to 30% of control-hiPSC-CMs (p<0.05). Pre-incubation with 10 μM S107, which stabilizes the closed state of the ryanodine receptor 2, significantly decreased the percentage of CPVT-hiPSC-CMs presenting DADs to 25% (p<0.05).
  
  
  CONCLUSIONS
  We recapitulated the electrophysiological features of CPVT-derived hiPSC-CMs using electrical pacing. The development of DADs in the presence of isoproterenol was significantly suppressed by S107. Our model provides a promising platform to study disease mechanisms and screen drugs.
authors.affiliation: Department of Cardiovascular Medicine, Kyoto University Graduate School of Medicine, Kyoto, Japan.
authors.forename: Kenichi
authors.initials: K
authors.lastname: Sasaki
authors.affiliation: Department of Cardiovascular Medicine, Kyoto University Graduate School of Medicine, Kyoto, Japan.
authors.forename: Takeru
authors.initials: T
authors.lastname: Makiyama
authors.affiliation: Kyoto University iPS Cell Research and Application, Kyoto, Japan.
authors.forename: Yoshinori
authors.initials: Y
authors.lastname: Yoshida
authors.affiliation: Department of Cardiovascular Medicine, Kyoto University Graduate School of Medicine, Kyoto, Japan.|Department of Cardiovascular and Respiratory Medicine, Shiga University of Medical Science, Otsu, Japan.
authors.forename: Yimin
authors.initials: Y
authors.lastname: Wuriyanghai
authors.affiliation: Department of Cardiovascular Medicine, Kyoto University Graduate School of Medicine, Kyoto, Japan.
authors.forename: Tsukasa
authors.initials: T
authors.lastname: Kamakura
authors.affiliation: Department of Cardiovascular Medicine, Kyoto University Graduate School of Medicine, Kyoto, Japan.
authors.forename: Suguru
authors.initials: S
authors.lastname: Nishiuchi
authors.affiliation: Department of Cardiovascular Medicine, Kyoto University Graduate School of Medicine, Kyoto, Japan.
authors.forename: Mamoru
authors.initials: M
authors.lastname: Hayano
authors.affiliation: Department of Cardiovascular Medicine, Kyoto University Graduate School of Medicine, Kyoto, Japan.
authors.forename: Takeshi
authors.initials: T
authors.lastname: Harita
authors.affiliation: Department of Cardiovascular Medicine, Kyoto University Graduate School of Medicine, Kyoto, Japan.
authors.forename: Yuta
authors.initials: Y
authors.lastname: Yamamoto
authors.affiliation: Department of Cardiovascular Medicine, Kyoto University Graduate School of Medicine, Kyoto, Japan.
authors.forename: Hirohiko
authors.initials: H
authors.lastname: Kohjitani
authors.affiliation: Department of Cardiovascular Medicine, Kyoto University Graduate School of Medicine, Kyoto, Japan.
authors.forename: Sayako
authors.initials: S
authors.lastname: Hirose
authors.affiliation: Department of Cardiovascular Medicine, Kyoto University Graduate School of Medicine, Kyoto, Japan.
authors.forename: Jiarong
authors.initials: J
authors.lastname: Chen
authors.affiliation: Department of Cardiovascular and Respiratory Medicine, Shiga University of Medical Science, Otsu, Japan.
authors.forename: Mihoko
authors.initials: M
authors.lastname: Kawamura
authors.affiliation: Department of Cardiovascular and Respiratory Medicine, Shiga University of Medical Science, Otsu, Japan.
authors.forename: Seiko
authors.initials: S
authors.lastname: Ohno
authors.affiliation: Department of Cardiovascular and Respiratory Medicine, Shiga University of Medical Science, Otsu, Japan.
authors.forename: Hideki
authors.initials: H
authors.lastname: Itoh
authors.affiliation: Department of Integrative and Systems Physiology, Faculty of Medical Sciences, University of Fukui, Fukui, Japan.
authors.forename: Ayako
authors.initials: A
authors.lastname: Takeuchi
authors.affiliation: Department of Integrative and Systems Physiology, Faculty of Medical Sciences, University of Fukui, Fukui, Japan.
authors.forename: Satoshi
authors.initials: S
authors.lastname: Matsuoka
authors.affiliation: Division of Cardiology, Tokyo Metropolitan Children's Medical Center, Tokyo, Japan.
authors.forename: Masaru
authors.initials: M
authors.lastname: Miura
authors.affiliation: Department of Pediatric Cardiology, Saitama Medical University International Medical Center, Saitama, Japan.
authors.forename: Naokata
authors.initials: N
authors.lastname: Sumitomo
authors.affiliation: Department of Cardiovascular and Respiratory Medicine, Shiga University of Medical Science, Otsu, Japan.
authors.forename: Minoru
authors.initials: M
authors.lastname: Horie
authors.affiliation: Kyoto University iPS Cell Research and Application, Kyoto, Japan.
authors.forename: Shinya
authors.initials: S
authors.lastname: Yamanaka
authors.affiliation: Department of Cardiovascular Medicine, Kyoto University Graduate School of Medicine, Kyoto, Japan.
authors.forename: Takeshi
authors.initials: T
authors.lastname: Kimura
mesh_terms: D000200:Action Potentials / Q000187:drug effects*; D000328:Adult; D000818:Animals; D018927:Anti-Asthmatic Agents / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D002118:Calcium / Q000378:metabolism; D037282:Calreticulin / Q000235:genetics / Q000378:metabolism; D002155:Calsequestrin / Q000235:genetics / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects; D002478:Cells, Cultured; D004558:Electric Stimulation; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism; D006801:Humans; D057026:Induced Pluripotent Stem Cells / Q000166:cytology / Q000378:metabolism; D007545:Isoproterenol / Q000494:pharmacology; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D008954:Models, Biological; D032383:Myocytes, Cardiac / Q000166:cytology / Q000187:drug effects / Q000637:transplantation; D012433:Ryanodine / Q000494:pharmacology; D019837:Ryanodine Receptor Calcium Release Channel / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases / Q000235:genetics / Q000378:metabolism; D017180:Tachycardia, Ventricular / Q000188:drug therapy / Q000473:pathology* / Q000628:therapy*; D013841:Thiazepines / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D014183:Transplantation, Heterologous; D000098850:Polymorphic Catecholaminergic Ventricular Tachycardia
chemical_list: D018927:Anti-Asthmatic Agents; C443109:CASQ2 protein, human; D037282:Calreticulin; D002155:Calsequestrin; D019837:Ryanodine Receptor Calcium Release Channel; C540746:S-107 compound; D013841:Thiazepines; D012433:Ryanodine; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases; C506946:ATP2A2 protein, human; D007545:Isoproterenol; D002118:Calcium