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

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

JOURNAL=Frontiers in Cell and Developmental Biology

VOLUME=8

YEAR=2020

URL=https://www.frontiersin.org/journals/cell-and-developmental-biology/articles/10.3389/fcell.2020.592893

DOI=10.3389/fcell.2020.592893

ISSN=2296-634X

ABSTRACT=<p>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 <italic>SCN5A</italic> mutation p.S1812X. Compared to CMs derived from healthy controls (Ctrl-CMs), BrS-CMs displayed a 50% reduction of <italic>I</italic><sub>Na</sub> density, a 69.5% reduction of Na<sub>V</sub>1.5 expression, and the impaired localization of Na<sub>V</sub>1.5 and connexin 43 (Cx43) at the cell surface. BrS-CMs exhibited reduced action potential (AP) upstroke velocity and conduction slowing. The <italic>I</italic><sub>to</sub> in BrS-CMs was significantly augmented, and the <italic>I</italic><sub>CaL</sub> 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 <italic>I</italic><sub>to</sub> in BrS-CMs and alleviated the arrhythmic activity, suggesting their therapeutic potential for BrS patients.</p>