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Effects of Antiarrhythmic Drugs on hERG Gating in Human-Induced Pluripotent Stem Cell-Derived Cardiomyocytes From a Patient With Short QT Syndrome Type 1

Aims: The short QT syndrome type 1 (SQT1) is linked to hERG channel mutations (e.g., N588K). Drug effects on hERG channel gating kinetics in SQT1-cells have not been investigated. Methods: This study used hiPSC-CMs of a healthy donor and a SQT1-patient carrying the N588K mutation and patch clamp to...

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Autores principales: Huang, Mengying, Liao, Zhenxing, Li, Xin, Yang, Zhen, Fan, Xuehui, Li, Yingrui, Zhao, Zhihan, Lang, Siegfried, Cyganek, Lukas, Zhou, Xiaobo, Akin, Ibrahim, Borggrefe, Martin, El-Battrawy, Ibrahim
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8138577/
https://www.ncbi.nlm.nih.gov/pubmed/34025432
http://dx.doi.org/10.3389/fphar.2021.675003
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author Huang, Mengying
Liao, Zhenxing
Li, Xin
Yang, Zhen
Fan, Xuehui
Li, Yingrui
Zhao, Zhihan
Lang, Siegfried
Cyganek, Lukas
Zhou, Xiaobo
Akin, Ibrahim
Borggrefe, Martin
El-Battrawy, Ibrahim
author_facet Huang, Mengying
Liao, Zhenxing
Li, Xin
Yang, Zhen
Fan, Xuehui
Li, Yingrui
Zhao, Zhihan
Lang, Siegfried
Cyganek, Lukas
Zhou, Xiaobo
Akin, Ibrahim
Borggrefe, Martin
El-Battrawy, Ibrahim
author_sort Huang, Mengying
collection PubMed
description Aims: The short QT syndrome type 1 (SQT1) is linked to hERG channel mutations (e.g., N588K). Drug effects on hERG channel gating kinetics in SQT1-cells have not been investigated. Methods: This study used hiPSC-CMs of a healthy donor and a SQT1-patient carrying the N588K mutation and patch clamp to examine the drug effects on hERG channel gating kinetics. Results: Ajmaline, amiodarone, ivabradine, flecainide, quinidine, mexiletine and ranolazine inhibited the hERG channel current (I(Kr)) less strongly in hiPSC-CMs from the SQTS1-patient (SQT1-hiPSC-CMs) comparing with cells from the healthy donor (donor-hiPSC-CMs). Quinidine and mexiletine reduced, but ajmaline, amiodarone, ivabradine and ranolazine increased the time to peak of I(Kr) similarly in SQT1-hiPSC-CMs and donor-hiPSC-CMs. Although regarding the shift of activation and inactivation curves, tested drugs showed differential effects in donor- and SQT1-hiPSC-CMs, quinidine, ajmaline, ivabradine and mexiletine but not amiodarone, flecainide and ranolazine reduced the window current in SQT1-hiPSC-CMs. Quinidine, ajmaline, ivabradine and mexiletine differentially changed the time constant of recovery from inactivation, but all of them increased the time constant of deactivation in SQT1-hiPSC-CMs. Conclusion: The window current-reducing and deactivation-slowing effects may be important for the antiarrhythmic effect of ajmaline, ivabradine, quinidine and mexiletine in SQT1-cells. This information may be helpful for selecting drugs for treating SQT1-patients with hERG channel mutation.
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spelling pubmed-81385772021-05-22 Effects of Antiarrhythmic Drugs on hERG Gating in Human-Induced Pluripotent Stem Cell-Derived Cardiomyocytes From a Patient With Short QT Syndrome Type 1 Huang, Mengying Liao, Zhenxing Li, Xin Yang, Zhen Fan, Xuehui Li, Yingrui Zhao, Zhihan Lang, Siegfried Cyganek, Lukas Zhou, Xiaobo Akin, Ibrahim Borggrefe, Martin El-Battrawy, Ibrahim Front Pharmacol Pharmacology Aims: The short QT syndrome type 1 (SQT1) is linked to hERG channel mutations (e.g., N588K). Drug effects on hERG channel gating kinetics in SQT1-cells have not been investigated. Methods: This study used hiPSC-CMs of a healthy donor and a SQT1-patient carrying the N588K mutation and patch clamp to examine the drug effects on hERG channel gating kinetics. Results: Ajmaline, amiodarone, ivabradine, flecainide, quinidine, mexiletine and ranolazine inhibited the hERG channel current (I(Kr)) less strongly in hiPSC-CMs from the SQTS1-patient (SQT1-hiPSC-CMs) comparing with cells from the healthy donor (donor-hiPSC-CMs). Quinidine and mexiletine reduced, but ajmaline, amiodarone, ivabradine and ranolazine increased the time to peak of I(Kr) similarly in SQT1-hiPSC-CMs and donor-hiPSC-CMs. Although regarding the shift of activation and inactivation curves, tested drugs showed differential effects in donor- and SQT1-hiPSC-CMs, quinidine, ajmaline, ivabradine and mexiletine but not amiodarone, flecainide and ranolazine reduced the window current in SQT1-hiPSC-CMs. Quinidine, ajmaline, ivabradine and mexiletine differentially changed the time constant of recovery from inactivation, but all of them increased the time constant of deactivation in SQT1-hiPSC-CMs. Conclusion: The window current-reducing and deactivation-slowing effects may be important for the antiarrhythmic effect of ajmaline, ivabradine, quinidine and mexiletine in SQT1-cells. This information may be helpful for selecting drugs for treating SQT1-patients with hERG channel mutation. Frontiers Media S.A. 2021-05-07 /pmc/articles/PMC8138577/ /pubmed/34025432 http://dx.doi.org/10.3389/fphar.2021.675003 Text en Copyright © 2021 Huang, Liao, Li, Yang, Fan, Li, Zhao, Lang, Cyganek, Zhou, Akin, Borggrefe and El-Battrawy. https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Pharmacology
Huang, Mengying
Liao, Zhenxing
Li, Xin
Yang, Zhen
Fan, Xuehui
Li, Yingrui
Zhao, Zhihan
Lang, Siegfried
Cyganek, Lukas
Zhou, Xiaobo
Akin, Ibrahim
Borggrefe, Martin
El-Battrawy, Ibrahim
Effects of Antiarrhythmic Drugs on hERG Gating in Human-Induced Pluripotent Stem Cell-Derived Cardiomyocytes From a Patient With Short QT Syndrome Type 1
title Effects of Antiarrhythmic Drugs on hERG Gating in Human-Induced Pluripotent Stem Cell-Derived Cardiomyocytes From a Patient With Short QT Syndrome Type 1
title_full Effects of Antiarrhythmic Drugs on hERG Gating in Human-Induced Pluripotent Stem Cell-Derived Cardiomyocytes From a Patient With Short QT Syndrome Type 1
title_fullStr Effects of Antiarrhythmic Drugs on hERG Gating in Human-Induced Pluripotent Stem Cell-Derived Cardiomyocytes From a Patient With Short QT Syndrome Type 1
title_full_unstemmed Effects of Antiarrhythmic Drugs on hERG Gating in Human-Induced Pluripotent Stem Cell-Derived Cardiomyocytes From a Patient With Short QT Syndrome Type 1
title_short Effects of Antiarrhythmic Drugs on hERG Gating in Human-Induced Pluripotent Stem Cell-Derived Cardiomyocytes From a Patient With Short QT Syndrome Type 1
title_sort effects of antiarrhythmic drugs on herg gating in human-induced pluripotent stem cell-derived cardiomyocytes from a patient with short qt syndrome type 1
topic Pharmacology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8138577/
https://www.ncbi.nlm.nih.gov/pubmed/34025432
http://dx.doi.org/10.3389/fphar.2021.675003
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