Normal interventricular differences in tissue architecture underlie right ventricular susceptibility to conduction abnormalities in a mouse model of Brugada syndrome

Kelly, A., Salerno, S., Connolly, A., Bishop, M., Charpentier, F., Stølen, T. and Smith, G. L. (2018) Normal interventricular differences in tissue architecture underlie right ventricular susceptibility to conduction abnormalities in a mouse model of Brugada syndrome. Cardiovascular Research, 114(5), pp. 724-736. (doi:10.1093/cvr/cvx244) (PMID:29267949)

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Abstract

AIMS Loss-of-function of the cardiac sodium channel NaV1.5 is a common feature of Brugada syndrome. Arrhythmias arise preferentially from the right ventricle (RV) despite equivalent NaV1.5 downregulation in the left ventricle (LV). The reasons for increased RV sensitivity to NaV1.5 loss-of-function mutations remains unclear. Because ventricular electrical activation occurs predominantly in the transmural axis, we compare RV and LV transmural electrophysiology to determine the underlying cause of the asymmetrical conduction abnormalities in Scn5a haploinsufficient mice (Scn5a+/-). METHODS AND RESULTS Optical mapping and two-photon microscopy in isolated-perfused mouse hearts demonstrated equivalent depression of transmural conduction velocity in the LV and RV of Scn5a+/- vs wild type littermates. Only RV transmural conduction was further impaired when challenged with increased pacing frequencies. Epicardial dispersion of activation and beat-to-beat variation in activation time were increased only in the RV of Scn5a+/- hearts. Analysis of confocal and histological images revealed larger intramural clefts between cardiomyocyte layers in the RV vs LV, independent of genotype. Acute sodium current inhibition in wild type hearts using TTX reproduced beat-to-beat activation variability and frequency-dependent conduction velocity slowing in the RV only, with the LV unaffected. The influence of clefts on conduction was examined using a two-dimensional monodomain computational model. When peak sodium channel conductance was reduced to 50% of normal the presence of clefts between cardiomyocyte layers reproduced the activation variability and conduction phenotype observed experimentally. CONCLUSION Normal structural heterogeneities present in the RV are responsible for increased vulnerability to conduction slowing in the presence of reduced sodium channel function. Heterogeneous conduction slowing seen in the RV will predispose to functional block and the initiation of re-entrant ventricular arrhythmias.

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Smith, Professor Godfrey and Kelly, Dr Allen
Authors: Kelly, A., Salerno, S., Connolly, A., Bishop, M., Charpentier, F., Stølen, T., and Smith, G. L.
College/School:College of Medical Veterinary and Life Sciences > Institute of Cardiovascular and Medical Sciences
Journal Name:Cardiovascular Research
Publisher:Oxford University Press
ISSN:0008-6363
ISSN (Online):1755-3245
Published Online:18 December 2017
Copyright Holders:Copyright © 2017 The Authors
First Published:First published in Cardiovascular Research 114(5): 724-736
Publisher Policy:Reproduced under a Creative Commons License

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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
665411Investigating the mechanisms of low-voltage defibrillation and its application to the human ventricle to facilitate its translation into the clinicGodfrey SmithBritish Heart Foundation (BHF)PG/14/66/30927RI CARDIOVASCULAR & MEDICAL SCIENCES