Patient-Specific Drug Screening Using a Human Induced Pluripotent Stem Cell Model of Catecholaminergic Polymorphic Ventricular Tachycardia Type 2

被引:43
作者
Maizels, Leonid [1 ,2 ]
Huber, Irit [1 ,2 ]
Arbel, Gil [1 ,2 ]
Tijsen, Anke J. [1 ,2 ]
Gepstein, Amira [1 ,2 ]
Khoury, Asaad [3 ]
Gepstein, Lior [1 ,2 ,3 ]
机构
[1] Technion Israel Inst Technol, Rappaport Fac Med, Haifa, Israel
[2] Technion Israel Inst Technol, Res Inst, Haifa, Israel
[3] Technion Israel Inst Technol, Rambam Hlth Care Campus, Haifa, Israel
基金
欧洲研究理事会;
关键词
drug therapy; induced pluripotent stem cells; myocytes; cardiac; stem cell; tachycardia; ventricular; LONG-QT SYNDROME; INDUCED CA2+ RELEASE; HEART-FAILURE; CARDIOMYOCYTES; FLECAINIDE; CPVT; MUTATIONS; MICE; RYR2; MECHANISM;
D O I
10.1161/CIRCEP.116.004725
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
Background-Catecholaminergic polymorphic ventricular tachycardia type 2 (CPVT2) results from autosomal recessive CASQ2 mutations, causing abnormal Ca2+-handling and malignant ventricular arrhythmias. We aimed to establish a patient-specific human induced pluripotent stem cell (hiPSC) model of CPVT2 and to use the generated hiPSC-derived cardiomyocytes to gain insights into patient-specific disease mechanism and pharmacotherapy. Methods and Results-hiPSC cardiomyocytes were derived from a CPVT2 patient (D307H-CASQ2 mutation) and from healthy controls. Laser-confocal Ca2+ and voltage imaging showed significant Ca2+-transient irregularities, marked arrhythmogenicity manifested by early afterdepolarizations and triggered arrhythmias, and reduced threshold for store overload-induced Ca2+-release events in the CPVT2-hiPSC cardiomyocytes when compared with healthy control cells. Pharmacological studies revealed the prevention of adrenergic-induced arrhythmias by beta-blockers (propranolol and carvedilol), flecainide, and the neuronal sodium-channel blocker riluzole; a direct antiarrhythmic action of carvedilol (independent of its alpha/beta-adrenergic blocking activity), flecainide, and riluzole; and suppression of abnormal Ca2+ cycling by the ryanodine stabilizer JTV-519 and carvedilol. Mechanistic insights were gained on the different antiarrhythmic actions of the aforementioned drugs, with carvedilol and JTV-519 (but not flecainide or riluzole) acting primarily through sarcoplasmic reticulum stabilization. Finally, comparable outcomes were found between flecainide and labetalol antiarrhythmic effects in vitro and the clinical results in the same patient. Conclusions-These results demonstrate the ability of hiPSCs cardiomyocytes to recapitulate CPVT2 disease phenotype and drug response in the culture dish, to provide novel insights into disease and drug therapy mechanisms, and potentially to tailor patient-specific drug therapy.
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页数:14
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