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

Atara Novak, Lili Barad, Avraham Lorber, Mihaela Gherghiceanu, Irina Reiter, Binyamin Eisen, Liron Eldor, Joseph Itskovitz-Eldor, Michael Eldar, Michael Arad, Ofer Binah

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish
Pages (from-to)2006-2018
Number of pages13
JournalJournal of Cellular and Molecular Medicine
Volume19
Issue number8
DOIs
StatePublished - 1 Aug 2015

Keywords

  • Arrhythmias
  • Ca transients
  • Cardiomyocytes
  • Catacholaminergic polymorphic ventricular tachycardia
  • Induced pluripotent stem cells

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