title: Fibrosis, Connexin-43, and Conduction Abnormalities in the Brugada Syndrome.
abstract: BACKGROUND
  The right ventricular outflow tract (RVOT) is acknowledged to be responsible for arrhythmogenesis in Brugada syndrome (BrS), but the pathophysiology remains controversial.
  
  
  OBJECTIVE
  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.
authors.affiliation: Pacific Rim Electrophysiology Research Institute, Los Angeles, California.
authors.forename: Koonlawee
authors.initials: K
authors.lastname: Nademanee
authors.affiliation: Cardiovascular Sciences, St. George's, University of London, London, United Kingdom.
authors.forename: Hariharan
authors.initials: H
authors.lastname: Raju
authors.affiliation: Cardiovascular Sciences, St. George's, University of London, London, United Kingdom.
authors.forename: Sofia V
authors.initials: SV
authors.lastname: de Noronha
authors.affiliation: Cardiovascular Sciences, St. George's, University of London, London, United Kingdom.
authors.forename: Michael
authors.initials: M
authors.lastname: Papadakis
authors.affiliation: Cardiovascular Sciences, St. George's, University of London, London, United Kingdom.
authors.forename: Laurence
authors.initials: L
authors.lastname: Robinson
authors.affiliation: Centre for Translational & Experimental Medicine, Imperial College London and Hammersmith Hospital, London, United Kingdom.
authors.forename: Stephen
authors.initials: S
authors.lastname: Rothery
authors.affiliation: Department of Molecular Physiology, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan.
authors.forename: Naomasa
authors.initials: N
authors.lastname: Makita
authors.affiliation: Department of Heart Rhythm Management, Yokohama Rosai Hospital, Yokohama City, Japan.
authors.forename: Shinya
authors.initials: S
authors.lastname: Kowase
authors.affiliation: Bhumibol Adulyadej Air Force Hospital, Royal Thai Air Force, Bangkok, Thailand.
authors.forename: Nakorn
authors.initials: N
authors.lastname: Boonmee
authors.affiliation: Bhumibol Adulyadej Air Force Hospital, Royal Thai Air Force, Bangkok, Thailand.
authors.forename: Vorapot
authors.initials: V
authors.lastname: Vitayakritsirikul
authors.affiliation: Department of Pathology, Siriraj Hospital, Mahidol University, Bangkok, Thailand.
authors.forename: Samrerng
authors.initials: S
authors.lastname: Ratanarapee
authors.affiliation: Cardiovascular Sciences, St. George's, University of London, London, United Kingdom.
authors.forename: Sanjay
authors.initials: S
authors.lastname: Sharma
authors.affiliation: Heart Centre, Academic Medical Centre, Amsterdam, the Netherlands.
authors.forename: Allard C
authors.initials: AC
authors.lastname: van der Wal
authors.affiliation: Clinical Biochemistry, Statens Serum Institute, Copenhagen, Denmark.
authors.forename: Michael
authors.initials: M
authors.lastname: Christiansen
authors.affiliation: Heart Centre, Academic Medical Centre, Amsterdam, the Netherlands.
authors.forename: Hanno L
authors.initials: HL
authors.lastname: Tan
authors.affiliation: Heart Centre, Academic Medical Centre, Amsterdam, the Netherlands; Princess Al-Jawhara Al-Brahim Centre of Excellence in Research of Hereditary Disorders, Jeddah, Saudi Arabia.
authors.forename: Arthur A
authors.initials: AA
authors.lastname: Wilde
authors.affiliation: Cardiovascular Division, Faculty of Medicine, University of Tsukuba, Tsukuba, Japan.
authors.forename: Akihiko
authors.initials: A
authors.lastname: Nogami
authors.affiliation: Cardiovascular Sciences, St. George's, University of London, London, United Kingdom.
authors.forename: Mary N
authors.initials: MN
authors.lastname: Sheppard
authors.affiliation: Bhumibol Adulyadej Air Force Hospital, Royal Thai Air Force, Bangkok, Thailand.
authors.forename: Gumpanart
authors.initials: G
authors.lastname: Veerakul
authors.affiliation: Cardiovascular Sciences, St. George's, University of London, London, United Kingdom. Electronic address: ebehr@sgul.ac.uk.
authors.forename: Elijah R
authors.initials: ER
authors.lastname: Behr
mesh_terms: D055011:Ablation Techniques / Q000379:methods; D000328:Adult; D053840:Brugada Syndrome / Q000150:complications / Q000175:diagnosis / Q000601:surgery; D003094:Collagen / Q000378:metabolism*; D018031:Connexin 43 / Q000378:metabolism*; D016757:Death, Sudden, Cardiac / Q000209:etiology / Q000473:pathology; D004562:Electrocardiography; D005355:Fibrosis; D017629:Gap Junctions / Q000473:pathology; D006329:Heart Conduction System / Q000378:metabolism / Q000473:pathology; D006801:Humans; D008297:Male; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D010496:Pericardium / Q000378:metabolism / Q000473:pathology; D013908:Thoracotomy / Q000379:methods; D014694:Ventricular Outflow Obstruction / Q000209:etiology / Q000378:metabolism / Q000473:pathology / Q000601:surgery
chemical_list: D018031:Connexin 43; D003094:Collagen
keywords: gap junction; myocardial fibrosis; right ventricular outflow tract; sudden arrhythmic death syndrome; sudden unexpected death