TRPC3 Inhibitor Pyr3 Corrects the Disease-specific Phenotype of the Induced Pluripotent Stem Cell-derived Cardiomyocytes from the Patients with Infantile Hypertrophic Cardiomyopathy

[Speaker] Atsuhiko T. Naito:1
[Co-author] Taku Sakai:2, Hiroko Izumi-Nakaseko:1, Kentaro Ando:1, Mihoko Hagiwara-Nagasawa:1, Yuji Nakamura:1, Atsushi Sugiyama:1
1:Department of Pharmacology, Toho University Faculty of Medicine, Japan, 2:Department of Cardiovascular Medicine, Osaka University Graduate School of Medicine, Japan

Introduction: Hypertrophic cardiomyopathy (HCM) is a genetic disorder that is characterized by hypertrophy of the myocardium. Most of the patients with HCM show the symptoms and are diagnosed at adolescents or adults but some of the patients develop HCM at infancies. The etiologies of these infantile HCM include syndromic HCM and the prognosis of the infantile HCM, especially those diagnosed before 1-year-old, is worse compared with general HCM. Nevertheless, pathophysiology of the infantile HCM, including the similarity and difference between general HCM, remains largely unknown.
Methods and Results: We generated induced pluripotent stem cells (iPSCs) from two patients with infantile HCM: one with Noonan syndrome and the other with idiopathic HCM. We found that the cell size of iPSC-derived cardiomyocytes (iPSC-CMs) from both patients were significantly larger than that from healthy subjects. Diastolic intracellular calcium concentration was also elevated in iPSC-CMs from the idiopathic HCM patient. Unlike iPSC-CMs from the adolescent/adult HCM patient, spontaneous beating rhythm was regular and the arrhythmia was not observed in the iPSC-CMs from both infantile HCM patients. Phenotypic screening revealed that Pyr3, a TRPC channel inhibitor, decreased both the cell size and diastolic intracellular calcium concentration in the iPSC-CMs from both Noonan syndrome and idiopathic infantile HCM patients. However, another TRPC channel inhibitor, Btp2, did not show any effect on the phenotype of iPSC-CMs.
Conclusions: iPSC-CMs from 2 patients of infantile HCM with distinct etiology exhibited disease-specific cellular phenotype with both similarity and difference between iPSC-CMs from adolescent/adult HCM. Pyr3 was identified as a compound that could normalize the disease-specific phenotype of iPSC-CMs. Investigating the novel target of Pyr3 may unveil the novel molecule that is essential in the pathogenesis of HCM. Moreover, testing the therapeutic effect of Pyr3 in other HCM iPSC-CMs and in animal model of HCM may lead to clinical development of Pyr3 or its derivative in the treatment of HCM.

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