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Title: Fibrosis, connexin-43, and conduction abnormalities in the Brugada syndrome
Authors: 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
Pacific Rim Electrophysiology Research Institute
St George's University of London
Hammersmith Hospital
Nagasaki University
Yokohama Rosai Hospital
Royal Thai Air Force
Mahidol University
Academic Medical Centre, University of Amsterdam
Statens Serum Institut
Princess Al-Jawhara Al-Brahim Centre of Excellence in Research of Hereditary Disorders
University of Tsukuba
Keywords: Medicine
Issue Date: 3-Nov-2015
Citation: Journal of the American College of Cardiology. Vol.66, No.18 (2015), 1976-1986
Abstract: © 2015 American College of Cardiology Foundation. 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.
ISSN: 15583597
Appears in Collections:Scopus 2011-2015

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