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

Kenichi Sasaki; Takeru Makiyama; Yoshinori Yoshida; Yimin Wuriyanghai; Tsukasa Kamakura; Suguru Nishiuchi; Mamoru Hayano; Takeshi Harita; Yuta Yamamoto; Hirohiko Kohjitani; Sayako Hirose; Jiarong Chen; Mihoko Kawamura; Seiko Ohno; Hideki Itoh; Ayako Takeuchi; Satoshi Matsuoka; Masaru Miura; Naokata Sumitomo; Minoru Horie; Shinya Yamanaka; Takeshi Kimura

doi:10.1371/journal.pone.0164795

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

PLoS One. 2016 Oct 20;11(10):e0164795. doi: 10.1371/journal.pone.0164795. eCollection 2016.

Authors

Kenichi Sasaki¹, Takeru Makiyama¹, Yoshinori Yoshida², Yimin Wuriyanghai^{1

3}, Tsukasa Kamakura¹, Suguru Nishiuchi¹, Mamoru Hayano¹, Takeshi Harita¹, Yuta Yamamoto¹, Hirohiko Kohjitani¹, Sayako Hirose¹, Jiarong Chen¹, Mihoko Kawamura³, Seiko Ohno³, Hideki Itoh³, Ayako Takeuchi⁴, Satoshi Matsuoka⁴, Masaru Miura⁵, Naokata Sumitomo⁶, Minoru Horie³, Shinya Yamanaka², Takeshi Kimura¹

Affiliations

¹ Department of Cardiovascular Medicine, Kyoto University Graduate School of Medicine, Kyoto, Japan.
² Kyoto University iPS Cell Research and Application, Kyoto, Japan.
³ Department of Cardiovascular and Respiratory Medicine, Shiga University of Medical Science, Otsu, Japan.
⁴ Department of Integrative and Systems Physiology, Faculty of Medical Sciences, University of Fukui, Fukui, Japan.
⁵ Division of Cardiology, Tokyo Metropolitan Children's Medical Center, Tokyo, Japan.
⁶ Department of Pediatric Cardiology, Saitama Medical University International Medical Center, Saitama, Japan.

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-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.

MeSH terms

Action Potentials / drug effects*
Adult
Animals
Anti-Asthmatic Agents / chemistry
Anti-Asthmatic Agents / pharmacology
Anti-Asthmatic Agents / therapeutic use
Calcium / metabolism
Calreticulin / genetics
Calreticulin / metabolism
Calsequestrin / genetics
Calsequestrin / metabolism
Cell Differentiation / drug effects
Cells, Cultured
Electric Stimulation*
Fibroblasts / cytology
Fibroblasts / metabolism
Humans
Induced Pluripotent Stem Cells / cytology
Induced Pluripotent Stem Cells / metabolism
Isoproterenol / pharmacology
Mice
Mice, Inbred NOD
Mice, SCID
Models, Biological*
Myocytes, Cardiac / cytology
Myocytes, Cardiac / drug effects
Myocytes, Cardiac / transplantation
Ryanodine / pharmacology
Ryanodine Receptor Calcium Release Channel / chemistry
Ryanodine Receptor Calcium Release Channel / genetics
Ryanodine Receptor Calcium Release Channel / metabolism
Sarcoplasmic Reticulum Calcium-Transporting ATPases / genetics
Sarcoplasmic Reticulum Calcium-Transporting ATPases / metabolism
Tachycardia, Ventricular / drug therapy
Tachycardia, Ventricular / pathology*
Tachycardia, Ventricular / therapy*
Thiazepines / chemistry
Thiazepines / pharmacology*
Thiazepines / therapeutic use
Transplantation, Heterologous

Substances

Anti-Asthmatic Agents
CASQ2 protein, human
Calreticulin
Calsequestrin
Ryanodine Receptor Calcium Release Channel
S-107 compound
Thiazepines
Ryanodine
Sarcoplasmic Reticulum Calcium-Transporting ATPases
ATP2A2 protein, human
Isoproterenol
Calcium

Supplementary concepts

Polymorphic catecholergic ventricular tachycardia

Grants and funding

This work was supported by Japan Society for the Promotion of Science KAKENHI Grant Number 25461054 and Suzuken Memorial Foundation Grant Number 10-097. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.