A cellular model of Brugada syndrome with SCN10A variants using human-induced pluripotent stem cell-derived cardiomyocytes.
Action Potentials
/ drug effects
Ajmaline
/ pharmacology
Brugada Syndrome
/ genetics
Cardiotonic Agents
/ pharmacology
Case-Control Studies
Cellular Reprogramming Techniques
Cnidarian Venoms
/ pharmacology
Death, Sudden, Cardiac
Humans
Induced Pluripotent Stem Cells
Loss of Function Mutation
Male
Middle Aged
Morpholines
/ pharmacology
Mutation
Myocytes, Cardiac
/ drug effects
NAV1.8 Voltage-Gated Sodium Channel
/ genetics
Niacinamide
/ analogs & derivatives
Patch-Clamp Techniques
Phenotype
Tachycardia, Ventricular
Voltage-Gated Sodium Channel Blockers
/ pharmacology
Brugada syndrome
Cellular phenotype
SCN10A
Stem cells
Journal
Europace : European pacing, arrhythmias, and cardiac electrophysiology : journal of the working groups on cardiac pacing, arrhythmias, and cardiac cellular electrophysiology of the European Society of Cardiology
ISSN: 1532-2092
Titre abrégé: Europace
Pays: England
ID NLM: 100883649
Informations de publication
Date de publication:
01 Sep 2019
01 Sep 2019
Historique:
received:
16
10
2018
accepted:
03
04
2019
pubmed:
21
5
2019
medline:
15
12
2020
entrez:
21
5
2019
Statut:
ppublish
Résumé
Brugada syndrome (BrS) is associated with a pronounced risk to develop sudden cardiac death (SCD). Up to 21% of patients are related to mutations in SCN5A. Studies identified SCN10A as a contributor of BrS. However, the investigation of the human cellular phenotype of BrS in the presence of SCN10A mutations remains lacking. The objective of this study was to establish a cellular model of BrS in presence of SCN10A mutations using human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs). Dermal fibroblasts obtained from a BrS patient suffering from SCD harbouring the SCN10A double variants (c.3803G>A and c.3749G>A) and three independent healthy control subjects were reprogrammed to hiPSCs. Human-induced pluripotent stem cells were differentiated into cardiomyocytes (hiPSC-CMs).The hiPSC-CMs from the BrS patient showed a significantly reduced peak sodium channel current (INa) and a significantly reduced ATX II (sea anemone toxin, an enhancer of late INa) sensitive as well as A-887826 (a blocker of SCN10A channel) sensitive late sodium channel current (INa) when compared with the healthy control hiPSC-CMs, indicating loss-of-function of sodium channels. Consistent with reduced INa the action potential amplitude and upstroke velocity (Vmax) were significantly reduced, which may contribute to arrhythmogenesis of BrS. Moreover, Ajmaline effects on action potentials were stronger in BrS-hiPSC-CMs than in healthy control cells. This is in agreement with the higher susceptibility of patients to sodium channel blocking drugs in unmasking BrS. Patient-specific hiPSC-CMs are able to recapitulate single-cell phenotype features of BrS with SCN10A mutations and may provide novel opportunities to further elucidate the cellular disease mechanism.
Identifiants
pubmed: 31106349
pii: 5491508
doi: 10.1093/europace/euz122
doi:
Substances chimiques
5-(4-butoxy-3-chlorophenyl)-N-((2-morpholinopyridin-3-yl)methyl)nicotinamide
0
Cardiotonic Agents
0
Cnidarian Venoms
0
Morpholines
0
NAV1.8 Voltage-Gated Sodium Channel
0
SCN10A protein, human
0
Voltage-Gated Sodium Channel Blockers
0
Ajmaline
1PON08459R
Niacinamide
25X51I8RD4
toxin II (Anemonia sulcata)
60748-45-0
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
1410-1421Commentaires et corrections
Type : CommentIn
Type : CommentIn
Informations de copyright
Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2019. For permissions, please email: journals.permissions@oup.com.