In silico investigation of a KCNQ1 mutation associated with short QT syndrome

Abstract Short QT syndrome (SQTS) is a rare condition characterized by abnormally ‘short’ QT intervals on the ECG and increased susceptibility to cardiac arrhythmias and sudden death. This simulation study investigated arrhythmia dynamics in multi-scale human ventricle models associated with the SQT...

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Autores principales:	Ismail Adeniran, Dominic G. Whittaker, Aziza El Harchi, Jules C. Hancox, Henggui Zhang
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2017
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/044b8cefebd34de7b1efa223d20e618e
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spelling	oai:doaj.org-article:044b8cefebd34de7b1efa223d20e618e2021-12-02T15:05:21ZIn silico investigation of a KCNQ1 mutation associated with short QT syndrome10.1038/s41598-017-08367-22045-2322https://doaj.org/article/044b8cefebd34de7b1efa223d20e618e2017-08-01T00:00:00Zhttps://doi.org/10.1038/s41598-017-08367-2https://doaj.org/toc/2045-2322Abstract Short QT syndrome (SQTS) is a rare condition characterized by abnormally ‘short’ QT intervals on the ECG and increased susceptibility to cardiac arrhythmias and sudden death. This simulation study investigated arrhythmia dynamics in multi-scale human ventricle models associated with the SQT2-related V307L KCNQ1 ‘gain-of-function’ mutation, which increases slow-delayed rectifier potassium current (IKs). A Markov chain (MC) model recapitulating wild type (WT) and V307L mutant IKs kinetics was incorporated into a model of the human ventricular action potential (AP) for investigation of QT interval changes and arrhythmia substrates. In addition, the degree of simulated IKs inhibition necessary to normalize the QT interval and terminate re-entry in SQT2 conditions was quantified. The developed MC model accurately reproduced AP shortening and reduced effective refractory period associated with altered IKs kinetics in homozygous (V307L) and heterozygous (WT-V307L) mutation conditions, which increased the lifespan and dominant frequency of re-entry in 3D human ventricle models. IKs reductions of 58% and 65% were sufficient to terminate re-entry in WT-V307L and V307L conditions, respectively. This study further substantiates a causal link between the V307L KCNQ1 mutation and pro-arrhythmia in human ventricles, and establishes partial inhibition of IKs as a potential anti-arrhythmic strategy in SQT2.Ismail AdeniranDominic G. WhittakerAziza El HarchiJules C. HancoxHenggui ZhangNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 7, Iss 1, Pp 1-14 (2017)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Ismail Adeniran Dominic G. Whittaker Aziza El Harchi Jules C. Hancox Henggui Zhang In silico investigation of a KCNQ1 mutation associated with short QT syndrome
description	Abstract Short QT syndrome (SQTS) is a rare condition characterized by abnormally ‘short’ QT intervals on the ECG and increased susceptibility to cardiac arrhythmias and sudden death. This simulation study investigated arrhythmia dynamics in multi-scale human ventricle models associated with the SQT2-related V307L KCNQ1 ‘gain-of-function’ mutation, which increases slow-delayed rectifier potassium current (IKs). A Markov chain (MC) model recapitulating wild type (WT) and V307L mutant IKs kinetics was incorporated into a model of the human ventricular action potential (AP) for investigation of QT interval changes and arrhythmia substrates. In addition, the degree of simulated IKs inhibition necessary to normalize the QT interval and terminate re-entry in SQT2 conditions was quantified. The developed MC model accurately reproduced AP shortening and reduced effective refractory period associated with altered IKs kinetics in homozygous (V307L) and heterozygous (WT-V307L) mutation conditions, which increased the lifespan and dominant frequency of re-entry in 3D human ventricle models. IKs reductions of 58% and 65% were sufficient to terminate re-entry in WT-V307L and V307L conditions, respectively. This study further substantiates a causal link between the V307L KCNQ1 mutation and pro-arrhythmia in human ventricles, and establishes partial inhibition of IKs as a potential anti-arrhythmic strategy in SQT2.
format	article
author	Ismail Adeniran Dominic G. Whittaker Aziza El Harchi Jules C. Hancox Henggui Zhang
author_facet	Ismail Adeniran Dominic G. Whittaker Aziza El Harchi Jules C. Hancox Henggui Zhang
author_sort	Ismail Adeniran
title	In silico investigation of a KCNQ1 mutation associated with short QT syndrome
title_short	In silico investigation of a KCNQ1 mutation associated with short QT syndrome
title_full	In silico investigation of a KCNQ1 mutation associated with short QT syndrome
title_fullStr	In silico investigation of a KCNQ1 mutation associated with short QT syndrome
title_full_unstemmed	In silico investigation of a KCNQ1 mutation associated with short QT syndrome
title_sort	in silico investigation of a kcnq1 mutation associated with short qt syndrome
publisher	Nature Portfolio
publishDate	2017
url	https://doaj.org/article/044b8cefebd34de7b1efa223d20e618e
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In silico investigation of a KCNQ1 mutation associated with short QT syndrome

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