title: Modeling of catecholaminergic polymorphic ventricular tachycardia with patient-specific human-induced pluripotent stem cells.
abstract: OBJECTIVE
  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.
authors: The Sohnis Family Laboratory for Cardiac Electrophysiology and Regenerative Medicine, Rappaport Faculty of Medicine and Research Institute, Technion-Israel Institute of Technology, Haifa, Israel.
authors: Ilanit
authors: I
authors: Itzhaki
authors: Leonid
authors: L
authors: Maizels
authors: Irit
authors: I
authors: Huber
authors: Amira
authors: A
authors: Gepstein
authors: Gil
authors: G
authors: Arbel
authors: Oren
authors: O
authors: Caspi
authors: Liron
authors: L
authors: Miller
authors: Bernard
authors: B
authors: Belhassen
authors: Eyal
authors: E
authors: Nof
authors: Michael
authors: M
authors: Glikson
authors: Lior
authors: L
authors: Gepstein
mesh_terms: D001145:Arrhythmias, Cardiac / Q000235:genetics; D002118:Calcium / Q000378:metabolism; D022062:Electrophysiologic Techniques, Cardiac; D015870:Gene Expression; D006801:Humans; D057026:Induced Pluripotent Stem Cells; D008955:Models, Cardiovascular; D032383:Myocytes, Cardiac / Q000378:metabolism*; D019837:Ryanodine Receptor Calcium Release Channel / Q000235:genetics*; D017180:Tachycardia, Ventricular / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology*; D000098850:Polymorphic Catecholaminergic Ventricular Tachycardia
chemical_list: D019837:Ryanodine Receptor Calcium Release Channel; D002118:Calcium