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Fibrosis, Connexin-43, and Conduction Abnormalities in the Brugada Syndrome.

Nademanee, K; Raju, H; de Noronha, SV; Papadakis, M; Robinson, L; Rothery, S; Makita, N; Kowase, S; Boonmee, N; Vitayakritsirikul, V; et al. Nademanee, K; Raju, H; de Noronha, SV; Papadakis, M; Robinson, L; Rothery, S; Makita, N; Kowase, S; Boonmee, N; Vitayakritsirikul, V; Ratanarapee, S; Sharma, S; van der Wal, AC; Christiansen, M; Tan, HL; Wilde, AA; Nogami, A; Sheppard, MN; Veerakul, G; Behr, ER (2015) Fibrosis, Connexin-43, and Conduction Abnormalities in the Brugada Syndrome. Journal of The American College of Cardiology, 66 (18). pp. 1976-1986. https://doi.org/10.1016/j.jacc.2015.08.862
SGUL Authors: Behr, Elijah Raphael Raju, Hariharan Sharma, Sanjay de Noronha, Sofia Victoria Fenster Calheiros Sheppard, Mary Noelle

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Abstract

BACKGROUND: The right ventricular outflow tract (RVOT) is acknowledged to be responsible for arrhythmogenesis in Brugada syndrome (BrS), but the pathophysiology remains controversial. OBJECTIVES: This study assessed the substrate underlying BrS at post-mortem and in vivo, and the role for open thoracotomy ablation. METHODS: Six whole hearts from male post-mortem cases of unexplained sudden death (mean age 23.2 years) with negative specialist cardiac autopsy and familial BrS were used and matched to 6 homograft control hearts by sex and age (within 3 years) by random risk set sampling. Cardiac autopsy sections from cases and control hearts were stained with picrosirius red for collagen. The RVOT was evaluated in detail, including immunofluorescent stain for connexin-43 (Cx43). Collagen and Cx43 were quantified digitally and compared. An in vivo study was undertaken on 6 consecutive BrS patients (mean age 39.8 years, all men) during epicardial RVOT ablation for arrhythmia via thoracotomy. Abnormal late and fractionated potentials indicative of slowed conduction were identified, and biopsies were taken before ablation. RESULTS: Collagen was increased in BrS autopsy cases compared with control hearts (odds ratio [OR]: 1.42; p = 0.026). Fibrosis was greatest in the RVOT (OR: 1.98; p = 0.003) and the epicardium (OR: 2.00; p = 0.001). The Cx43 signal was reduced in BrS RVOT (OR: 0.59; p = 0.001). Autopsy and in vivo RVOT samples identified epicardial and interstitial fibrosis. This was collocated with abnormal potentials in vivo that, when ablated, abolished the type 1 Brugada electrocardiogram without ventricular arrhythmia over 24.6 ± 9.7 months. CONCLUSIONS: BrS is associated with epicardial surface and interstitial fibrosis and reduced gap junction expression in the RVOT. This collocates to abnormal potentials, and their ablation abolishes the BrS phenotype and life-threatening arrhythmias. BrS is also associated with increased collagen throughout the heart. Abnormal myocardial structure and conduction are therefore responsible for BrS.

Item Type: Article
Additional Information: © 2015 by the American College of Cardiology Foundation. Published by Elsevier Inc. This is an open access article under the CC BY license (http://creativecommons.org/ licenses/by/4.0/).
Keywords: gap junction, myocardial fibrosis, right ventricular outflow tract, sudden arrhythmic death syndrome, sudden unexpected death, Ablation Techniques, Adult, Brugada Syndrome, Collagen, Connexin 43, Death, Sudden, Cardiac, Electrocardiography, Fibrosis, Gap Junctions, Heart Conduction System, Humans, Male, Myocardium, Pericardium, Thoracotomy, Ventricular Outflow Obstruction, Myocardium, Heart Conduction System, Pericardium, Gap Junctions, Humans, Death, Sudden, Cardiac, Ventricular Outflow Obstruction, Fibrosis, Collagen, Connexin 43, Electrocardiography, Thoracotomy, Adult, Male, Brugada Syndrome, Ablation Techniques, gap junction, myocardial fibrosis, right ventricular outflow tract, sudden arrhythmic death syndrome, sudden unexpected death, Cardiovascular System & Hematology, 1102 Cardiovascular Medicine And Haematology, 1117 Public Health And Health Services
SGUL Research Institute / Research Centre: Academic Structure > Molecular and Clinical Sciences Research Institute (MCS)
Academic Structure > Molecular and Clinical Sciences Research Institute (MCS) > Cardiac (INCCCA)
Journal or Publication Title: Journal of The American College of Cardiology
Language: eng
Dates:
DateEvent
3 November 2015Published
Publisher License: Creative Commons: Attribution 4.0
Projects:
Project IDFunderFunder ID
FS/11/71/28918British Heart Foundationhttp://dx.doi.org/10.13039/501100000274
PubMed ID: 26516000
Web of Science ID: WOS:000363868600005
Go to PubMed abstract
URI: https://openaccess.sgul.ac.uk/id/eprint/107605
Publisher's version: https://doi.org/10.1016/j.jacc.2015.08.862

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