Modeling polymorphic ventricular tachycardia at rest using patient-specific induced pluripotent stem cell-derived cardiomyocytes

EBioMedicine. 2020 Oct:60:103024. doi: 10.1016/j.ebiom.2020.103024. Epub 2020 Sep 24.


Background: While mutations in the cardiac type 2 ryanodine receptor (RyR2) have been linked to exercise-induced or catecholaminergic polymorphic ventricular tachycardia (CPVT), its association with polymorphic ventricular tachycardia (PMVT) occurring at rest is unclear. We aimed at constructing a patient-specific human-induced pluripotent stem cell (hiPSC) model of PMVT occurring at rest linked to a single point mutation in RyR2.

Methods: Blood samples were obtained from a patient with PMVT at rest due to a heterozygous RyR2-H29D mutation. Patient-specific hiPSCs were generated from the blood samples, and the hiPSC-derived cardiomyocytes (CMs) were generated via directed differentiation. Using CRIPSR/Cas9 technology, isogenic controls were generated by correcting the RyR2-H29D mutation. Using patch-clamp, fluorescent confocal microscopy and video-image-based analysis, the molecular and functional properties of RyR2-H29D hiPSCCMs and control hiPSCCMs were compared.

Findings: RyR2-H29D hiPSCCMs exhibit intracellular sarcoplasmic reticulum (SR) Ca2+ leak through RyR2 under physiological pacing. RyR2-H29D enhances the contribution of inositol 1,4,5-trisphosphate receptors to excitation-contraction coupling (ECC) that exacerbates abnormal Ca2+ release in RyR2-H29D hiPSCCMs. RyR2-H29D hiPSCCMs exhibit shorter action potentials, delayed afterdepolarizations, arrhythmias and aberrant contractile properties compared to isogenic controls. The RyR2-H29D mutation causes post-translational remodeling that is fully reversed with isogenic controls.

Interpretation: To conclude, in a model based on a RyR2 point mutation that is associated with short-coupled PMVT at rest, RyR2-H29D hiPSCCMs exhibited aberrant intracellular Ca2+ homeostasis, shortened action potentials, arrhythmias and abnormal contractile properties.

Funding: French Muscular Dystrophy Association (AFM; project 16,073, MNM2 2012 and 20,225), "Fondation de la Recherche Médicale" (FRM; SPF20130526710), "Institut National pour la Santé et la Recherche Médicale" (INSERM), National Institutes of Health (ARM; R01 HL145473) and New York State Department of Health (NYSTEM C029156).

Keywords: Calcium handling; Contractile properties; PMVT; Ryanodine receptor; hiPSC-derived cardiomyocytes.

MeSH terms

  • Alleles
  • CRISPR-Cas Systems
  • Calcium / metabolism
  • Calcium Signaling
  • Cell Differentiation*
  • Genotype
  • Homeostasis
  • Humans
  • Immunohistochemistry
  • Induced Pluripotent Stem Cells / cytology*
  • Models, Biological*
  • Mutation
  • Myocytes, Cardiac / cytology*
  • Myocytes, Cardiac / metabolism*
  • Protein Processing, Post-Translational
  • Stem Cell Transplantation
  • Tachycardia, Ventricular / diagnosis*
  • Tachycardia, Ventricular / etiology
  • Tachycardia, Ventricular / therapy*


  • Calcium