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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
Authors: Sasaki, Kenichi
Makiyama, Takeru  kyouindb  KAKEN_id
Yoshida, Yoshinori  kyouindb  KAKEN_id  orcid (unconfirmed)
Wuriyanghai, Yimin
Kamakura, Tsukasa
Nishiuchi, Suguru
Hayano, Mamoru
Harita, Takeshi
Yamamoto, Yuta
Kohjitani, Hirohiko
Hirose, Sayako
Chen, Jiarong
Kawamura, Mihoko
Ohno, Seiko
Itoh, Hideki
Takeuchi, Ayako
Matsuoka, Satoshi
Miura, Masaru
Sumitomo, Naokata
Horie, Minoru
Yamanaka, Shinya  kyouindb  KAKEN_id
Kimura, Takeshi  kyouindb  KAKEN_id
Author's alias: 牧山, 武
吉田, 善紀
Issue Date: 20-Oct-2016
Publisher: Public Library of Science
Journal title: PLOS ONE
Volume: 11
Issue: 10
Thesis number: e0164795
Abstract: Introduction 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. Method and 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-hiPSCCMs. 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-hiPSCCMs (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.
Rights: © 2016 Sasaki et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
DOI(Published Version): 10.1371/journal.pone.0164795
PubMed ID: 27764147
Appears in Collections:Journal Articles

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