Fibrosis, Connexin-43, and Conduction Abnormalities in the Brugada Syndrome.
Fibrosis, Connexin-43, and Conduction Abnormalities in the Brugada Syndrome.
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Brugada综合征的纤维化，连接蛋白43和传导异常。
DOI：
10.1016/j.jacc.2015.08.862
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发表时间：
2015-11-03
影响因子：
24
通讯作者：
Behr ER
中科院分区：
文献类型：
--
作者：
Nademanee K;Raju H;de Noronha SV;Papadakis M;Robinson L;Rothery S;Makita N;Kowase S;Boonmee N;Vitayakritsirikul V;Ratanarapee S;Sharma S;van der Wal AC;Christiansen M;Tan HL;Wilde AA;Nogami A;Sheppard MN;Veerakul G;Behr ER
Brugada综合征（BrS）患者右室流出道（RVOT）是其发生的主要原因，但其病理生理机制仍存在争议。本研究评估了死后和体内BrS的基础底物，以及开胸消融术的作用。使用6个来自男性死因不明的猝死（平均年龄23.2岁）的尸检病例的完整心脏，这些病例的专家心脏尸检结果和家族性BrS均为阴性，并通过随机风险集抽样，按性别和年龄（3年内）与6个同种移植对照心脏相匹配。将病例和对照心脏的心脏尸检切片用天狼星红染色以检测胶原蛋白。详细评价RVOT，包括连接蛋白43（Cx43）的免疫荧光染色。胶原蛋白和Cx43进行数字化定量并进行比较。对6名连续BrS患者（平均年龄39.8岁，均为男性）进行了体内研究，这些患者在通过开胸术进行心外膜RVOT消融治疗心律失常期间。发现异常晚电位和碎裂电位提示传导减慢，并在消融前进行活检。与对照组相比，BrS尸检病例的胶原蛋白增加（比值比[OR]：1.42; p = 0.026）。RVOT（OR：1.98; p = 0.003）和心外膜（OR：2.00; p = 0.001）的纤维化最严重。BrS RVOT中Cx43信号降低（OR：0.59; p = 0.001）。尸检和体内RVOT样本确定了心外膜和间质纤维化。这与体内异常电位共存，消融时，在24.6 ± 9.7个月内消除了1型Brugada心电图，无室性心律失常。BrS与心外膜表面和间质纤维化以及RVOT中间隙连接表达减少相关。这与异常电位并置，并且它们的消融消除了BrS表型和危及生命的心律失常。BrS还与整个心脏的胶原蛋白增加有关。因此，异常的心肌结构和传导是BrS的原因。
The right ventricular outflow tract (RVOT) is acknowledged to be responsible for arrhythmogenesis in Brugada syndrome (BrS), but the pathophysiology remains controversial. This study assessed the substrate underlying BrS at post-mortem and in vivo, and the role for open thoracotomy ablation. 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. 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. 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.