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The effects of ageing and adrenergic challenge on electrocardiographic phenotypes in a murine model of long QT syndrome type 3

Chadda, K, Ahmad, S, Valli, H, den Uijl, Ingrid, Al-Hadithi, A, Salvage, S, Grace, A, Huang, C and Jeevaratnam, Kamalan (2017) The effects of ageing and adrenergic challenge on electrocardiographic phenotypes in a murine model of long QT syndrome type 3 Scientific Reports, 7, 11070.

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Abstract

Long QT Syndrome 3 (LQTS3) arises from gain-of-function Nav1.5 mutations, prolonging action potential repolarisation and electrocardiographic (ECG) QT interval, associated with increased agedependent risk for major arrhythmic events, and paradoxical responses to β-adrenergic agents. We investigated for independent and interacting efects of age and Scn5a+/ΔKPQ genotype in anaesthetised mice modelling LQTS3 on ECG phenotypes before and following β-agonist challenge, and upon fbrotic change. Prolonged ventricular recovery was independently associated with Scn5a+/ΔKPQ and age. Ventricular activation was prolonged in old Scn5a+/ΔKPQ mice (p=0.03). We associated Scn5a+/ΔKPQ with increased atrial and ventricular fbrosis (both: p<0.001). Ventricles also showed increased fbrosis with age (p<0.001). Age and Scn5a+/ΔKPQ interacted in increasing incidences of repolarisation alternans (p=0.02). Dobutamine increased ventricular rate (p<0.001) and reduced both atrioventricular conduction (PR segment-p=0.02; PR interval-p=0.02) and incidences of repolarisation alternans (p<0.001) in all mice. However, in Scn5a+/ΔKPQ mice, dobutamine delayed the changes in ventricular repolarisation following corresponding increases in ventricular rate. The present fndings implicate interactions between age and Scn5a+/ΔKPQ in prolonging ventricular activation, correlating them with fbrotic change for the frst time, adding activation abnormalities to established recovery abnormalities in LQTS3. These fndings, together with dynamic electrophysiological responses to β-adrenergic challenge, have therapeutic implications for ageing LQTS patients.

Item Type: Article
Divisions : Faculty of Health and Medical Sciences > School of Veterinary Medicine
Authors :
NameEmailORCID
Chadda, K
Ahmad, S
Valli, H
den Uijl, Ingridi.denuijl@surrey.ac.uk
Al-Hadithi, A
Salvage, S
Grace, A
Huang, C
Jeevaratnam, Kamalank.jeevaratnam@surrey.ac.uk
Date : 11 September 2017
Identification Number : 10.1038/s41598-017-11210-3
Copyright Disclaimer : © The Author(s) 2017. This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. Te images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
Depositing User : Melanie Hughes
Date Deposited : 27 Feb 2018 17:14
Last Modified : 30 May 2018 10:53
URI: http://epubs.surrey.ac.uk/id/eprint/845906

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