1. Disease Phenotypes and Mechanisms of iPSC-Derived Cardiomyocytes from Brugada Syndrome Patients with a Loss-of-Function SCN5A Mutation
- Author
-
Wener Li, Stefan Wagner, Michael Stauske, Simin Chen, Lars S. Maier, Ali El-Armouche, Carola S. Mehnert, Lukas Cyganek, Gerd Hasenfuss, Xiaojing Luo, Sayed-Mohammad Hasheminasab, Gerald Wulf, Meike Vollrath, and Kaomei Guan
- Subjects
0303 health sciences ,medicine.medical_specialty ,business.industry ,fungi ,Connexin ,Depolarization ,030204 cardiovascular system & hematology ,medicine.disease ,Sudden cardiac death ,03 medical and health sciences ,0302 clinical medicine ,Endocrinology ,health services administration ,Internal medicine ,medicine ,Repolarization ,Milrinone ,Induced pluripotent stem cell ,business ,health care economics and organizations ,Loss function ,030304 developmental biology ,Brugada syndrome ,medicine.drug - 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-derived cardiomyocytes from two BrS patients (BrS-CMs) carrying a heterozygous SCN5A mutation p.S1812X. Compared to cardiomyocytes derived from healthy controls (Ctrl-CMs), BrS-CMs displayed a 50% reduction of INa density, a 69.5% reduction of NaV1.5 expression, and the impaired localization of NaV1.5 and connexin 43 at the cell surface. BrS-CMs exhibited reduced action potential upstroke velocity and conduction slowing. The Ito in BrS-CMs was significantly augmented, and the ICaL 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 Ito in BrS-CMs and alleviated the arrhythmic activity, suggesting their therapeutic potential for BrS patients.
- Published
- 2020