Patient-Specific Human Induced Pluripotent Stem Cell Model Assessed with Electrical Pacing Validates S107 as a Potential Therapeutic Agent for Catecholaminergic Polymorphic Ventricular Tachycardia

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 establis...

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Detalles Bibliográficos
Autores principales: Sasaki, Kenichi, Makiyama, Takeru, Yoshida, Yoshinori, 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, Kimura, Takeshi
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2016
Materias:
Research Article
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5072719/
https://www.ncbi.nlm.nih.gov/pubmed/27764147
http://dx.doi.org/10.1371/journal.pone.0164795
Descripción
Sumario: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 Ca(2+) transients between control- and CPVT-hiPSC-CMs. Using Ca(2+) imaging at 1 Hz electrical field stimulation, isoproterenol induced an abnormal diastolic Ca(2+) 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.

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