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

JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY

卷:66

Article

Nademanee, Koonlawee¹  Raju, Hariharan²  de Noronha, Sofia V.²  Papadakis, Michael²  Robinson, Laurence²  Rothery, Stephen^2,3,4  Makita, Naomasa⁵  Kowase, Shinya⁶  Boonmee, Nakorn⁷  Vitayakritsirikul, Vorapot⁷  Ratanarapee, Samrerng⁸  Sharma, Sanjay²  van der Wal, Allard C.⁹  Christiansen, Michael¹⁰  Tan, Hanno L.⁹  Wilde, Arthur A.^9,11  Nogami, Akihiko¹²  Sheppard, Mary N.²  Veerakul, Gumpanart⁷  Behr, Elijah R.² 

[1] Pacific Rim Elect Res Inst, Los Angeles, CA USA

[2] St Georges Univ London, Cardiovasc Sci Res Ctr, London SW17 0RE, England

[3] Univ London Imperial Coll Sci Technol & Med, Ctr Translat & Expt Med, London, England

[4] Hammersmith Hosp, London, England

[5] Nagasaki Univ, Grad Sch Biomed Sci, Dept Mol Physiol, Nagasaki 852, Japan

[6] Yokohama Rosai Hosp, Dept Heart Rhythm Management, Yokohama, Kanagawa, Japan

[7] Royal Thai Air Force, Bhumibol Adulyadej Air Force Hosp, Bangkok, Thailand

[8] Mahidol Univ, Siriraj Hosp, Dept Pathol, Bangkok 10700, Thailand

[9] Univ Amsterdam, Acad Med Ctr, Ctr Heart, NL-1105 AZ Amsterdam, Netherlands

[10] Statens Serum Inst, Clin Biochem, DK-2300 Copenhagen, Denmark

[11] Princess Al Jawhara Al Brahim Ctr Excellence Res, Jeddah, Saudi Arabia

[12] Univ Tsukuba, Fac Med, Cardiovasc Div, Tsukuba, Ibaraki, Japan

关键词: gap junction;    myocardial fibrosis;    right ventricular outflow tract;    sudden arrhythmic death syndrome;    sudden unexpected death;   

DOI  :  10.1016/j.jacc.2015.08.862

来源: Elsevier

【 摘 要 】

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. (C) 2015 by the American College of Cardiology Foundation.

【 授权许可】

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