Functional abnormalities in iPSC‐derived cardiomyocytes generated from CPVT1 and CPVT2 patients carrying ryanodine or calsequestrin mutations |
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Authors: | Atara Novak Lili Barad Avraham Lorber Mihaela Gherghiceanu Irina Reiter Binyamin Eisen Liron Eldor Joseph Itskovitz‐Eldor Michael Eldar Michael Arad Ofer Binah |
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Institution: | 1. Department of Physiology, Technion, Haifa, Israel;2. The Rappaport Institute for Research in the Medical Sciences, Technion, Haifa, Israel;3. Ruth & Bruce Rappaport Faculty of Medicine, Technion, Haifa, Israel;4. Department of Pediatric Cardiology, Rambam Health Care Campus, Haifa, Israel;5. ‘Victor Babes’ National Institute of Pathology, Bucharest, Romania;6. Department of Plastic Surgery, Rambam Health Care Campus, Haifa, Israel;7. Leviev Heart Center, Sheba Medical Center, Tel Hashomer and Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel |
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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 RyR2R420Q and CASQ2D307H 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. |
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Keywords: | catacholaminergic polymorphic ventricular tachycardia Induced pluripotent stem cells arrhythmias cardiomyocytes Ca2+ transients |
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