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.