Modeling of catecholaminergic polymorphic ventricular tachycardia with patient-specific human-induced pluripotent stem cells

Ilanit Itzhaki, Leonid Maizels, Irit Huber, Amira Gepstein, Gil Arbel, Oren Caspi, Liron Miller, Bernard Belhassen, Eyal Nof, Michael Glikson, Lior Gepstein*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

178 Scopus citations


Objectives: The goal of this study was to establish a patient-specific human-induced pluripotent stem cells (hiPSCs) model of catecholaminergic polymorphic ventricular tachycardia (CPVT). Background: CPVT is a familial arrhythmogenic syndrome characterized by abnormal calcium (Ca 2+) handling, ventricular arrhythmias, and sudden cardiac death. Methods: Dermal fibroblasts were obtained from a CPVT patient due to the M4109R heterozygous point RYR2 mutation and reprogrammed to generate the CPVT-hiPSCs. The patient-specific hiPSCs were coaxed to differentiate into the cardiac lineage and compared with healthy control hiPSCs-derived cardiomyocytes (hiPSCs-CMs). Results: Intracellular electrophysiological recordings demonstrated the development of delayed afterdepolarizations in 69% of the CPVT-hiPSCs-CMs compared with 11% in healthy control cardiomyocytes. Adrenergic stimulation by isoproterenol (1 μM) or forskolin (5 μM) increased the frequency and magnitude of afterdepolarizations and also led to development of triggered activity in the CPVT-hiPSCs-CMs. In contrast, flecainide (10 μM) and thapsigargin (10 μM) eliminated all afterdepolarizations in these cells. The latter finding suggests an important role for internal Ca 2+ stores in the pathogenesis of delayed afterdepolarizations. Laser-confocal Ca 2+ imaging revealed significant whole-cell [Ca 2+] transient irregularities (frequent local and large-storage Ca 2+-release events, broad and double-humped transients, and triggered activity) in the CPVT cardiomyocytes that worsened with adrenergic stimulation and Ca 2+ overload and improved with beta-blockers. Store-overload-induced Ca 2+ release was also identified in the hiPSCs-CMs and the threshold for such events was significantly reduced in the CPVT cells. Conclusions: This study highlights the potential of hiPSCs for studying inherited arrhythmogenic syndromes, in general, and CPVT specifically. As such, it represents a promising paradigm to study disease mechanisms, optimize patient care, and aid in the development of new therapies.

Original languageEnglish
Pages (from-to)990-1000
Number of pages11
JournalJournal of the American College of Cardiology
Issue number11
StatePublished - 11 Sep 2012


FundersFunder number
Seventh Framework Programme260830


    • arrhythmia
    • genetics
    • ryanodine receptor
    • stem cells


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