Clinical Research
Heart Rhythm Disorders
Modeling of Catecholaminergic Polymorphic Ventricular Tachycardia With Patient-Specific Human-Induced Pluripotent Stem Cells

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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 (Ca2+) 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 Ca2+ stores in the pathogenesis of delayed afterdepolarizations. Laser-confocal Ca2+ imaging revealed significant whole-cell [Ca2+] transient irregularities (frequent local and large-storage Ca2+-release events, broad and double-humped transients, and triggered activity) in the CPVT cardiomyocytes that worsened with adrenergic stimulation and Ca2+ overload and improved with beta-blockers. Store-overload–induced Ca2+ 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.

Key Words

arrhythmia
genetics
ryanodine receptor
stem cells

Abbreviations and Acronyms

AP
action potential
CASQ2
cardiac calsequestrin isoform 2
CPVT
catecholaminergic polymorphic ventricular tachycardia
DADs
delayed afterdepolarizations
EB
embryoid body
hiPSC
human-induced pluripotent stem cell
hiPSCs-CMs
human-induced pluripotent stem cells–derived cardiomyocytes
PCR
polymerase chain reaction
RT-PCR
real-time polymerase chain reaction
RyR2
ryanodine receptor isoform 2
SOICR
store-overload–induced Ca2+ release
SR
sarcoplasmic reticulum

Cited by (0)

This study was funded by the European Research Council Ideas program (ERC-2010-StG-260830-Cardio-iPS) and by the Nancy and Stephen Grand philanthropic fund. The authors have reported that they have no relationships relevant to the contents of this paper to disclose. The first two authors contributed equally to this work.