TY - JOUR
T1 - Fibrosis, connexin-43, and conduction abnormalities in the Brugada syndrome
AU - Nademanee, Koonlawee
AU - Raju, Hariharan
AU - De Noronha, Sofia V.
AU - Papadakis, Michael
AU - Robinson, Laurence
AU - Rothery, Stephen
AU - Makita, Naomasa
AU - Kowase, Shinya
AU - Boonmee, Nakorn
AU - Vitayakritsirikul, Vorapot
AU - Ratanarapee, Samrerng
AU - Sharma, Sanjay
AU - Van Der Wal, Allard C.
AU - Christiansen, Michael
AU - Tan, Hanno L.
AU - Wilde, Arthur A.
AU - Nogami, Akihiko
AU - Sheppard, Mary N.
AU - Veerakul, Gumpanart
AU - Behr, Elijah R.
N1 - 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.
PY - 2015/11/3
Y1 - 2015/11/3
N2 - 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.
AB - 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.
KW - gap junction
KW - myocardial fibrosis
KW - right ventricular outflow tract
KW - sudden arrhythmic death syndrome
KW - sudden unexpected death
UR - http://www.scopus.com/inward/record.url?scp=84945296649&partnerID=8YFLogxK
U2 - 10.1016/j.jacc.2015.08.862
DO - 10.1016/j.jacc.2015.08.862
M3 - Article
C2 - 26516000
AN - SCOPUS:84945296649
SN - 0735-1097
VL - 66
SP - 1976
EP - 1986
JO - Journal of the American College of Cardiology
JF - Journal of the American College of Cardiology
IS - 18
ER -