Sudden cardiac death caused by ventricular arrhythmias is a disastrous event, 
especially when it occurs in young individuals. Among the five major 
arrhythmogenic disorders occurring in the absence of a structural heart disease 
is catecholaminergic polymorphic ventricular tachycardia (CPVT), which is a 
highly lethal form of inherited arrhythmias. Our study focuses on the autosomal 
recessive form of the disease caused by the missense mutation D307H in the 
cardiac calsequestrin gene, CASQ2. Because CASQ2 is a key player in excitation 
contraction coupling, the derangements in intracellular Ca(2+) handling may 
cause delayed afterdepolarizations (DADs), which constitute the mechanism 
underlying CPVT. To investigate catecholamine-induced arrhythmias in the CASQ2 
mutated cells, we generated for the first time CPVT-derived induced pluripotent 
stem cells (iPSCs) by reprogramming fibroblasts from skin biopsies of two 
patients, and demonstrated that the iPSCs carry the CASQ2 mutation. Next, iPSCs 
were differentiated to cardiomyocytes (iPSCs-CMs), which expressed the mutant 
CASQ2 protein. The major findings were that the β-adrenergic agonist 
isoproterenol caused in CPVT iPSCs-CMs (but not in the control cardiomyocytes) 
DADs, oscillatory arrhythmic prepotentials, after-contractions and diastolic 
[Ca(2+) ](i) rise. Electron microscopy analysis revealed that compared with 
control iPSCs-CMs, CPVT iPSCs-CMs displayed a more immature phenotype with less 
organized myofibrils, enlarged sarcoplasmic reticulum cisternae and reduced 
number of caveolae. In summary, our results demonstrate that the 
patient-specific mutated cardiomyocytes can be used to study the 
electrophysiological mechanisms underlying CPVT.