Disease Phenotypes and Mechanisms of iPSC-Derived Cardiomyocytes From Brugada Syndrome Patients With a Loss-of-Function SCN5A Mutation

Wener Li; Michael Stauske; Xiaojing Luo; Stefan Wagner; Meike Vollrath; Carola S Mehnert; Mario Schubert; Lukas Cyganek; Simin Chen; Sayed-Mohammad Hasheminasab; Gerald Wulf; Ali El-Armouche; Lars S Maier; Gerd Hasenfuss; Kaomei Guan

doi:10.3389/fcell.2020.592893

Disease Phenotypes and Mechanisms of iPSC-Derived Cardiomyocytes From Brugada Syndrome Patients With a Loss-of-Function SCN5A Mutation

Front Cell Dev Biol. 2020 Oct 22:8:592893. doi: 10.3389/fcell.2020.592893. eCollection 2020.

Authors

Wener Li¹, Michael Stauske^{2

3}, Xiaojing Luo¹, Stefan Wagner^{2

4}, Meike Vollrath¹, Carola S Mehnert¹, Mario Schubert¹, Lukas Cyganek^{2

3}, Simin Chen³, Sayed-Mohammad Hasheminasab^{5

6}, Gerald Wulf⁴, Ali El-Armouche¹, Lars S Maier^{2

7}, Gerd Hasenfuss^{2

3}, Kaomei Guan^{1

2

3}

Affiliations

¹ Institute of Pharmacology and Toxicology, Technische Universität Dresden, Dresden, Germany.
² Department of Cardiology and Pneumology, University Medical Center Göttingen, Göttingen, Germany.
³ German Center for Cardiovascular Research (DZHK), Partner site Göttingen, Göttingen, Germany.
⁴ Department of Hematology and Oncology, University Medical Center Göttingen, Göttingen, Germany.
⁵ Department of Dermatology, Venereology and Allergy, Charité - Universitätsmedizin Berlin, Berlin, Germany.
⁶ CCU Translational Radiation Oncology, German Cancer Consortium Core-Center Heidelberg, National Center for Tumor Diseases, Heidelberg University Hospital (UKHD) and German Cancer Research Center (DKFZ), Heidelberg, Germany.
⁷ Clinic for Internal Medicine II, University Hospital Regensburg, Regensburg, Germany.

Abstract

Brugada syndrome (BrS) is one of the major causes of sudden cardiac death in young people, while the underlying mechanisms are not completely understood. Here, we investigated the pathophysiological phenotypes and mechanisms using induced pluripotent stem cell (iPSC)-derived cardiomyocytes (CMs) from two BrS patients (BrS-CMs) carrying a heterozygous SCN5A mutation p.S1812X. Compared to CMs derived from healthy controls (Ctrl-CMs), BrS-CMs displayed a 50% reduction of I _Na density, a 69.5% reduction of Na_V1.5 expression, and the impaired localization of Na_V1.5 and connexin 43 (Cx43) at the cell surface. BrS-CMs exhibited reduced action potential (AP) upstroke velocity and conduction slowing. The I _to in BrS-CMs was significantly augmented, and the I _CaL window current probability was increased. Our data indicate that the electrophysiological mechanisms underlying arrhythmia in BrS-CMs may involve both depolarization and repolarization disorders. Cilostazol and milrinone showed dramatic inhibitions of I _to in BrS-CMs and alleviated the arrhythmic activity, suggesting their therapeutic potential for BrS patients.

Keywords: Brugada syndrome; SCN5A mutation; depolarization; disease modeling; induced pluripotent stem cells; repolarization.