Patient specific induced Pluripotent Stem Cell-derived cardiomyocytes for drug development and screening in Catecholaminergic Polymorphic Ventricular Tachycardia

摘要

Catecholaminergic polymorphic ventricular tachycardia (CPVT), an inherited arrhythmia often leading to sudden cardiac death in children and young adults, is characterized by polymorphic/bidirectional ventricular tachycardia induced by adrenergic stimulation associated with emotionally stress or physical exercise. There are two forms of CPVT: (1) CPVT1 is caused by mutations in the RYR2 gene, encoding for ryanodine receptor type 2. CPVT1 is the most common form of CPVT in the population, and is inherited by a dominant mechanism. (2) CPVT2 is caused by mutations in the CASQ2 gene, encoding for cardiac calsequestrin 2 and is inherited by recessive mechanism. Patient-specific induced Pluripotent Stem Cells (iPSC) have the ability to differentiate into cardiomyocytes carrying the patient's genome including CPVT-linked mutations and expressing the disease phenotype in vitro at the cellular level. The potency for in vitro modeling using iPSC-derived cardiomyocytes (iPSC-CMs) has been exploited to investigate a variety of inherited diseases including cardiac arrhythmias such as CPVT. In this review we attempted to cover the majority of CPVT patient specific iPSC researches previously published. CPVT patient-specific iPSC model enables the in vitro investigation of the molecular and cellular disease-mechanisms by the means of electrophysiologycal and Ca+2 imaging methodologies. Furthermore, this in vitro model allows the screening of various antiarrhythmic drugs, specifically for each patient, also known as "personalized medicine".