scholarly journals Sodium channel current loss of function in induced pluripotent stem cell-derived cardiomyocytes from a Brugada syndrome patient

2018 ◽  
Vol 114 ◽  
pp. 10-19 ◽  
Author(s):  
Elisabet Selga ◽  
Franziska Sendfeld ◽  
Rebecca Martinez-Moreno ◽  
Claire N. Medine ◽  
Olga Tura-Ceide ◽  
...  
Keyword(s):  
Stem Cell ◽  
Sodium Channel ◽  
Brugada Syndrome ◽  
Pluripotent Stem Cell ◽  
Induced Pluripotent Stem Cell ◽  
Syndrome Patient ◽  
Loss Of Function ◽  
Current Loss ◽  
Channel Current ◽  
Induced Pluripotent

A cellular model of Brugada syndrome with SCN10A variants using human-induced pluripotent stem cell-derived cardiomyocytes

EP Europace ◽  
2019 ◽  
Vol 21 (9) ◽  
pp. 1410-1421 ◽  
Author(s):  
Ibrahim El-Battrawy ◽  
Sebastian Albers ◽  
Lukas Cyganek ◽  
Zhihan Zhao ◽  
Huan Lan ◽  
...  
Keyword(s):  
Stem Cell ◽  
Sodium Channel ◽  
Brugada Syndrome ◽  
Pluripotent Stem Cell ◽  
Induced Pluripotent Stem Cell ◽  
Dermal Fibroblasts ◽  
Cellular Model ◽  
Channel Current ◽  
Healthy Control ◽  
Induced Pluripotent

Abstract Aims 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). Methods and results 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. Conclusion 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.

scholarly journals Establishment of a Beals syndrome patient-derived human induced pluripotent stem cell line HELPi001-A

2019 ◽  
Vol 40 ◽  
pp. 101535
Author(s):  
Hao Liu ◽  
Yatping Tsui ◽  
Jiaxian Wang ◽  
Chen Su ◽  
Rui Zheng ◽  
...  
Keyword(s):  
Stem Cell ◽  
Cell Line ◽  
Pluripotent Stem Cell ◽  
Induced Pluripotent Stem Cell ◽  
Syndrome Patient ◽  
Stem Cell Line ◽  
Induced Pluripotent ◽  
Beals Syndrome

scholarly journals Hyperthermia Influences the Effects of Sodium Channel Blocking Drugs in Human-Induced Pluripotent Stem Cell-Derived Cardiomyocytes

PLoS ONE ◽  
2016 ◽  
Vol 11 (11) ◽  
pp. e0166143 ◽  
Author(s):  
Ibrahim El-Battrawy ◽  
Siegfried Lang ◽  
Zhihan Zhao ◽  
Ibrahim Akin ◽  
Gökhan Yücel ◽  
...  
Keyword(s):  
Stem Cell ◽  
Sodium Channel ◽  
Pluripotent Stem Cell ◽  
Induced Pluripotent Stem Cell ◽  
Channel Blocking ◽  
Induced Pluripotent

scholarly journals GS-967 and Eleclazine Block Sodium Channels in Human Induced Pluripotent Stem Cell-derived Cardiomyocytes

2020 ◽  
Author(s):  
Franck Potet ◽  
Defne E. Egecioglu ◽  
Paul W. Burridge ◽  
Alfred L. George
Keyword(s):  
Stem Cell ◽  
Sodium Channel ◽  
Sodium Channels ◽  
Pluripotent Stem Cell ◽  
Sodium Current ◽  
Induced Pluripotent Stem Cell ◽  
Slow Inactivation ◽  
Molecular Pharmacology ◽  
Recovery From Inactivation ◽  
Induced Pluripotent

ABSTRACTGS-967 and eleclazine (GS-6615) are novel sodium channel inhibitors exhibiting antiarrhythmic effects in various in vitro and in vivo models. The antiarrhythmic mechanism has been attributed to preferential suppression of late sodium current (INaL). Here, we took advantage of a throughput automated electrophysiology platform (SyncroPatch 768PE) to investigate the molecular pharmacology of GS-967 and eleclazine on peak sodium current (INaP) recorded from human induced pluripotent stem cell (hiPSC)-derived cardiomyocytes. We compared GS-967 and eleclazine to the antiarrhythmic drug lidocaine, the prototype INaL inhibitor ranolazine, and the slow inactivation enhancing drug lacosamide. In human induced pluripotent stem cell-derived cardiomyocytes, GS-967 and eleclazine caused a reduction of INaP in a frequency-dependent manner consistent with use-dependent block (UDB). GS-967 and eleclazine had similar efficacy but evoked more potent UDB of INaP (IC50=0.07 and 0.6 μM, respectively) than ranolazine (7.8 μM), lidocaine (133.5 μM) and lacosamide (158.5 μM). In addition, GS-967 and eleclazine exerted more potent effects on slow inactivation and recovery from inactivation compared to the other sodium channel blocking drugs we tested. The greater UDB potency of GS-967 and eleclazine was attributed to the significantly higher association rates (KON) and moderate unbinding rate (KOFF) of these two compounds with sodium channels. We propose that substantial UDB contributes to the observed antiarrhythmic efficacy of GS-967 and eleclazine.SIGNIFICANCE STATEMENTWe investigated the molecular pharmacology of GS-967 and eleclazine on sodium channels in human induced pluripotent stem cell derived cardiomyocytes using a high throughput automated electrophysiology platform. Sodium channel inhibition by GS-967 and eleclazine has unique features including accelerating the onset of slow inactivation and impairing recovery from inactivation. These effects combined with rapid binding and moderate unbinding kinetics explain potent use-dependent block, which we propose contributes to their observed antiarrhythmic efficacy.

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