Modeling of Catecholaminergic Polymorphic Ventricular Tachycardia With Patient-Specific Human-Induced Pluripotent Stem Cells

Study Questions:

Can skin fibroblasts from affected patients be used to study inherited cardiac arrhythmias?


Dermal fibroblasts were obtained from a patient with catecholaminergic polymorphic ventricular tachycardia (CPVT) due to a mutation in the ryanodine receptor gene (RYR2) and then reprogrammed to generate CPVT-human-induced pluripotent stem cells (hiPSCs). The patient-specific hiPSCs were differentiated into the cardiac lineage and compared with healthy control hiPSCs-derived cardiomyocytes (CMs).


Intracellular electrophysiology recordings demonstrated the development of delayed afterdepolarizations (DADs) in 69% of the CPVT-hiPSCs-CMs compared with 11% in healthy control CMs. Adrenergic stimulation by isoproterenol or forskolin increased the frequency and magnitude of ADs and also led to development of triggered activity in the CPVT-hiPSCs-CMs. In contrast, flecainide and thapsigargin eliminated all DADs in these cells, suggesting an important role for internal Ca2+ stores in the pathogenesis of delayed DADs. Ca2+ imaging revealed significant whole-cell [Ca2+] transient irregularities in the CPVT CMs that worsened with adrenergic stimulation and Ca2+ overload and improved with beta-blockers.


The authors concluded that this study demonstrates potential of hiPSCs for studying inherited arrhythmogenic syndromes and represents a promising paradigm to study disease mechanisms, optimize patient care, and aid in the development of new therapies.


hiPSCs are pluripotent stem cells derived from nonpluripotent cells (adult somatic cells in this study) by forced expression of certain genes (Oct4, Sox2, Klf4, and then valproic acid treatment in this study). The potential applications of these techniques are enormous, including the development of patient-specific mutant cell lines that show the disease phenotype in vitro. This study demonstrates that these techniques can be used to study genetic arrhythmia syndromes. In addition to elucidation of mechanisms related to these diseases, these cells will also enable drug screening.

Clinical Topics: Arrhythmias and Clinical EP, Implantable Devices, SCD/Ventricular Arrhythmias, Atrial Fibrillation/Supraventricular Arrhythmias

Keywords: Mutation, Pluripotent Stem Cells, Electrophysiology, Tachycardia, Ventricular, Fibroblasts

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