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.

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

Grant support

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.