Functional abnormalities in iPSC‐derived cardiomyocytes generated from CPVT1 and CPVT2 patients carrying ryanodine or calsequestrin mutations

Journal of Cellular and Molecular Medicine

Atara Novak⁵  Lili Barad⁵  Avraham Lorber¹  Mihaela Gherghiceanu³  Irina Reiter⁵  Binyamin Eisen⁵  Liron Eldor⁶  Joseph Itskovitz-Eldor⁴  Michael Eldar²  Michael Arad² 

[1] Ruth & Bruce Rappaport Faculty of Medicine, Technion, Haifa, Israel;Leviev Heart Center, Sheba Medical Center, Tel Hashomer and Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel;‘Victor Babes’ National Institute of Pathology, Bucharest, Romania;The Rappaport Institute for Research in the Medical Sciences, Technion, Haifa, Israel;Department of Physiology, Technion, Haifa, Israel;Department of Plastic Surgery, Rambam Health Care Campus, Haifa, Israel

关键词: catacholaminergic polymorphic ventricular tachycardia;    Induced pluripotent stem cells;    arrhythmias;    cardiomyocytes;    Ca2+ transients;   

DOI  :  10.1111/jcmm.12581

来源: Wiley

【 摘 要 】

Abstract

Catecholaminergic polymorphic ventricular tachycardia (CPVT) is an inherited arrhythmia characterized by syncope and sudden death occurring during exercise or acute emotion. CPVT is caused by abnormal intracellular Ca²⁺ handling resulting from mutations in the RyR2 or CASQ2 genes. Because CASQ2 and RyR2 are involved in different aspects of the excitation-contraction coupling process, we hypothesized that these mutations are associated with different functional and intracellular Ca²⁺ abnormalities. To test the hypothesis we generated induced Pluripotent Stem Cell-derived cardiomyocytes (iPSC-CM) from CPVT1 and CPVT2 patients carrying the RyR2^R420Q and CASQ2^D307H mutations, respectively, and investigated in CPVT1 and CPVT2 iPSC-CM (compared to control): (i) The ultrastructural features; (ii) the effects of isoproterenol, caffeine and ryanodine on the [Ca²⁺]_i transient characteristics. Our major findings were: (i) Ultrastructurally, CASQ2 and RyR2 mutated cardiomyocytes were less developed than control cardiomyocytes. (ii) While in control iPSC-CM isoproterenol caused positive inotropic and lusitropic effects, in the mutated cardiomyocytes isoproterenol was either ineffective, caused arrhythmias, or markedly increased diastolic [Ca²⁺]_i. Importantly, positive inotropic and lusitropic effects were not induced in mutated cardiomyocytes. (iii) The effects of caffeine and ryanodine in mutated cardiomyocytes differed from control cardiomyocytes. Our results show that iPSC-CM are useful for investigating the similarities/differences in the pathophysiological consequences of RyR2 versus CASQ2 mutations underlying CPVT1 and CPVT2 syndromes.

【 授权许可】

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© 2015 The Authors. Journal of Cellular and Molecular Medicine published by John Wiley & Sons Ltd and Foundation for Cellular and Molecular Medicine.

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