29 This process of reprogramming occurs by the introduction of a defined and Buparlisib mw limited set of transcription factors and by culturing these cells under embryonic stem cell conditions. Somatic cell reprogramming by the induction of four ectopic genes (OCT3/4, SOX2, C-MYC, and

KLF4) by retroviral insertion was first described in mouse cells,30 and later on in human cells,31 by Yamanaka’s group. Inhibitors,research,lifescience,medical This new technology allows us to investigate cardiac disorders in vitro and opens new opportunities for investigating the diseases’ mechanism in vitro, developing new drugs, predicting their toxicity, and optimizing current treatment strategies (Figure 3). Recently, several groups reported on the generation of patient-specific iPSC of the inherited arrhythmias—LEOPARD syndrome,32 Inhibitors,research,lifescience,medical long-QT1,33

long-QT2,34,35 and Timothy syndrome36—and demonstrated the capacity of these cells to give rise to functional cardiomyocytes that display the electrophysiological characteristics of the disorder. In the last year, three groups reported on the generation of iPSC-derived cardiomyocytes from CPVT237 and CPVT138,39 patients. In this regard, our group was the first to generate cardiomyocytes from CPVT patients Inhibitors,research,lifescience,medical carrying the missense D307H in the CASQ2 gene, which in response to β-adrenergic stimulation generated DADs and triggered activity.37 Specifically, Novak et al. reported on the generation of cardiomyocytes from two CPVT2 patients: Inhibitors,research,lifescience,medical a 12-year-old boy and a 30-year-old woman carrying the missense mutation D307H Inhibitors,research,lifescience,medical in the CASQ2 gene, which exhibited the key features of catecholaminergic-mediated arrhythmogenesis.37 The D307H mutation (associated with a change from a negatively charged aspartic acid to a positively charged histidine) causes reduced affinity of the mutant CASQ2 to Ca2+, thereby

resulting in Ca2+ spillover during adrenergic stress.4 To decipher the cellular mechanisms of CPVT we performed patch clamp and intracellular Ca2+ and contraction measurements from iPSC cardiomyocytes generated from healthy and diseased individuals. In agreement with previous studies reporting Phosphoprotein phosphatase a lower resting heart rate among CPVT patients,40,41 we found that the mean spontaneous beating rate of CPVT iPSC cardiomyocytes was slower by 34% than control cardiomyocytes. These findings still need to be established in a larger number of cells from different clones. The adrenergically mediated arrhythmogenic features of CPVT2 cardiomyocytes were demonstrated by exposing the cells to the β-adrenergic agonist isoproterenol.