|Ph.D Student||Barad Lili|
|Subject||Cellular and Molecular Mechanisms of Inherited Ventricular|
Arrhythmias in Cardiomyocytes Generated from
Induced Pluripotent Stem Cells (iPSC)
Derived from Affected indiv..
|Department||Department of Medicine||Supervisor||PROFESSOR EMERITUS Ofer Binah|
|Full Thesis text|
Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a familial arrhythmogenic disorder characterized by episodic syncope and sudden death occurring during exercise or acute emotion in individuals without structural cardiac abnormalities. The disease is caused by abnormal Ca2 handling resulting from mutations in the RYR2 or the CASQ2 genes. The present study had three main aims: (1) investigate the electrophysiological properties of cardiomyocytes (CM) derived from induced Pluripotent Stem Cells (iPSC) generated from dermal fibroblasts obtained from CPVT1 patients carrying the heterozygous R420Q mutation in the RYR2 gene (CPVT1-CM). (2) Investigate the electrophysiological properties of CM derived from iPSC generated from dermal fibroblasts obtained from CPVT2 patients carrying the homozygote D307H mutation in the CASQ2 gene (CPVT2-CM) (3) Investigate the responsiveness of CPVT1-CM and CPVT2-CM to β-adrenergic stimulation. Our major findings were: (1) Both CPVT1-CM and CPVT2-CM exhibit the disease specific characteristics responsible for the arrhythmogenic phenotype in CPVT such as delayed afterdepolarizations (DADs), oscillatory prepotentials and triggered activity. (2) The spontaneous beating rate of CPVT1-CM and CPVT2-CM was significantly lower than the spontaneous beating rate of control-CM. (3) While none the control cells (n=14) exhibited arrhythmogenic features in response to β-adrenergic stimulation, 75% of CPVT2-CM and 50% of CPVT1-CM exhibited DADs and/or oscillatory prepotentials and/or triggered arrhythmia in response to β-adrenergic stimulation. (4) 2APB, an IP3R blocker, drastically reduced the presence of DADs in CPVT1-CM, rescuing the arrhythmic phenotype observed in CPVT1-CM in baseline conditions. Our results highlight the potential of iPSC 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.