Fibrosis, connexin-43, and conduction abnormalities in the Brugada syndrome

Koonlawee Nademanee, Hariharan Raju, Sofia V. De Noronha, Michael Papadakis, Laurence Robinson, Stephen Rothery, Naomasa Makita, Shinya Kowase, Nakorn Boonmee, Vorapot Vitayakritsirikul, Samrerng Ratanarapee, Sanjay Sharma, Allard C. Van Der Wal, Michael Christiansen, Hanno L. Tan, Arthur A. Wilde, Akihiko Nogami, Mary N. Sheppard, Gumpanart Veerakul, Elijah R. Behr*

*Corresponding author for this work

Research output: Contribution to journalArticle

165 Citations (Scopus)
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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.

Original languageEnglish
Pages (from-to)1976-1986
Number of pages11
JournalJournal of the American College of Cardiology
Volume66
Issue number18
DOIs
Publication statusPublished - 3 Nov 2015
Externally publishedYes

Bibliographical note

Copyright the Author(s) 2015. Version archived for private and non-commercial use with the permission of the author/s and according to publisher conditions. For further rights please contact the publisher.

Keywords

  • gap junction
  • myocardial fibrosis
  • right ventricular outflow tract
  • sudden arrhythmic death syndrome
  • sudden unexpected death

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