Modeling polymorphic ventricular tachycardia at rest using patient-specific induced pluripotent stem cell-derived cardiomyocytes
Yvonne Sleiman,
Monia Souidi,
Ritu Kumar,
Ellen Yang,
Fabrice Jaffré,
Ting Zhou,
Albin Bernardin,
Steve Reiken,
Olivier Cazorla,
Andrey V. Kajava,
Adrien Moreau,
Jean-Luc Pasquié,
Andrew R. Marks,
Bruce B. Lerman,
Shuibing Chen,
Jim W. Cheung,
Todd Evans,
Alain Lacampagne,
Albano C. Meli
Affiliations
Yvonne Sleiman
PhyMedExp, Inserm, CNRS, University of Montpellier, Montpellier, France
Monia Souidi
PhyMedExp, Inserm, CNRS, University of Montpellier, Montpellier, France
Ritu Kumar
Department of Surgery, Weill Cornell Medical College, New York, NY, United States
Ellen Yang
Department of Surgery, Weill Cornell Medical College, New York, NY, United States
Fabrice Jaffré
Department of Surgery, Weill Cornell Medical College, New York, NY, United States
Ting Zhou
Department of Surgery, Weill Cornell Medical College, New York, NY, United States
Albin Bernardin
PhyMedExp, Inserm, CNRS, University of Montpellier, Montpellier, France
Steve Reiken
Department of Physiology and Cellular Biophysics, Clyde and Helen Wu Center for Molecular Cardiology, Columbia University College of Physicians and Surgeons, New York, NY, United States
Olivier Cazorla
PhyMedExp, Inserm, CNRS, University of Montpellier, Montpellier, France
Andrey V. Kajava
CRBM, CNRS, University of Montpellier, Montpellier, France
Adrien Moreau
PhyMedExp, Inserm, CNRS, University of Montpellier, Montpellier, France
Jean-Luc Pasquié
PhyMedExp, Inserm, CNRS, University of Montpellier, Montpellier, France; Department of Cardiology, CHU of Montpellier, Montpellier, France
Andrew R. Marks
Department of Physiology and Cellular Biophysics, Clyde and Helen Wu Center for Molecular Cardiology, Columbia University College of Physicians and Surgeons, New York, NY, United States
Bruce B. Lerman
Division of Cardiology, Weill Cornell Medical College, New York, NY, United States
Shuibing Chen
Department of Surgery, Weill Cornell Medical College, New York, NY, United States
Jim W. Cheung
Division of Cardiology, Weill Cornell Medical College, New York, NY, United States
Todd Evans
Department of Surgery, Weill Cornell Medical College, New York, NY, United States
Alain Lacampagne
PhyMedExp, Inserm, CNRS, University of Montpellier, Montpellier, France
Albano C. Meli
PhyMedExp, Inserm, CNRS, University of Montpellier, Montpellier, France; To whom correspondence should be addressed: Albano C. Meli, Ph.D., PhyMedExp, INSERM U1046, CNRS UMR9214, University of Montpellier, CHU Arnaud de Villeneuve, 371 Avenue du Doyen G. Giraud, 34295, Montpellier cedex 5, France.
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).
