临床特征.

Brugada综合征的临床特点是可导致猝死的心脏传导异常（心电图V₁-V₃ 导联ST段异常和室性心律失常高发风险）。 Brugada综合征主要成年发病，婴儿期至老年期都可能诊断本病，猝死的平均年龄约为40岁。其临床表现还可包括婴儿期猝死综合征（SIDS；1岁以 内婴儿不明原因死亡）和夜间猝死综合征（SUNDS），后者是东南亚患病个体的典型表现。其他传导异常包括一度房室传导阻滞，心室内传导延迟，右束支传 导阻滞和病态窦房结综合征。

诊断/检测.

诊断基于临床表现和/或在下列23个基因中检测出一个杂合（或在男性患者中检测出KCNE5基因半合子）致病变异：ABCC9、 CACNA1C、CACNA2D1、CACNB2、FGF12、GPD1L、HCN4、KCND2、KCND3、KCNE5、KCNE3、KCNH2、 KCNJ8、PKP2、RANGRF、SCN1B、SCN2B、SCN3B、SCN5A、 SCN10A、SEMA3A、SLMAP和TRPM4。

治疗.

对症治疗：对于既往有晕厥或心脏骤停史的患者可植入埋藏式心脏复律除颤器（ICD）；应用异丙肾上腺素治疗电风暴。

预防主要表现：奎尼丁（每日1-2g）。无症状个体是否需治疗仍有争议。

预防并发症：Brugada综合征患者在手术期和术后恢复期应进行心电图监测。

监测：对于有Brugada综合征家族史或携带已知致病变异等可导致Brugada综合征患病风险的个体，应每1至2年进行心电图监测。

应避免的情况和药物：高热、麻醉药、抗抑郁药以及具有钠通道阻滞作用的抗精神药物；IC类抗心律失常药物（如氟卡尼、普罗帕酮）和IA类抗心律失常药物（如普鲁卡因胺、丙吡胺）。

亲属风险评估：使用心电图或分子遗传检查（如家系中致病变异已知）可发现有患病风险的亲属，可使用预防措施和避免服用可诱发室性心律失常的药物。

遗传咨询.

多数情况下，Brugada综合征以常染色体显性方式遗传；KCNE5基因变异所致的Brugada综合征例外，其以X-连锁方式遗传。大多数诊断为Brugada综合征的患者父母都患病。约1%的病例由新发致病变异引起。常染色体显性遗传Brugada综合征患者的每个子女均有50%的概率遗传该致病变异。如家系中致病变异已知，妊娠时疾病再现风险增加，可对孕妇进行产前诊断。

确诊

 先证者具有下列临床发现并检测出表1a和1b中列出基因的杂合(或男性中KCNE5基因半合子) 致病变异，则可确诊为Brugada综合征（见备注）。

• 1型心电图 在使用或不使用钠通道阻滞剂（如氟卡尼、比西卡因、阿义马林或普鲁卡因胺）的情况下，一个以上右胸导联(V₁-V₃) J波抬高≥2mm，伴随T波倒置，并 ST 段呈“穹隆型”和下斜型* (见 图1) 

  ^* 当排外其他因素，应考虑为心电图异常。

• 下列表现中至少一项：

  • 有记录的心室纤维性颤动

  • 可自行终止的多形性室性心动过速

  • 心源性猝死家族史

  • 家系成员“穹隆型”心电图

  • 心电生理检查可诱发

  • 晕厥或夜间濒死样呼吸

备注： 约75%患有Brugada综合征的患者是基于临床病史和心电图结果作出诊断的。分子遗传检测有助于确诊，并可作为临床检查的补充[Benito et al 2009]。

图2 为Brugada综合征诊断流程。

图 2.

Brugada综合征诊断流程。来自Berne & Brugada [2012]，已获准使用。

分子遗传检测方法包括候选单基因检测, 多基因panel检测, 和更全面的基因组检测。

• 候选单基因检测可考虑先从SCN5A开始检测，杂合致病变异约占15%-30%。或者说，如临床表现、实验室检查和家系等因素都提示某一特定基因可能性大，则可以考虑候选单基因检测。

  首先应进行相关候选基因测序，如未发现致病变异，随后应行基因缺失/重复检测。

•  多基因panel检测包含所有目前已知与Brugada综合征相关的基因（见鉴别诊断），也应考虑。备注：（1）不同实验室的panel中包含的基因以及多基因panel的敏感性都不一致，并随时间推移更新变化。（2）有些多基因panel可能包括的基因与GeneReview中的疾病不相关；因此，临床医师需要权衡决定哪个多基因panel能以最合理的成本提供检测出疾病遗传病因的最佳可能。（3）panel中使用的方法可能包括测序、 缺失/重复检测和/或其他非测序检测。

• 如在具有Brugada综合征特征的个体中，使用候选单基因检测和/或多基因panel检测未找到遗传病因确诊时，可考虑更全面的基因组检测 (当可行时)，包括全外显子组测序和全基因组测序。这类检测可能提供或建议之前未考虑的诊断（例如可导致相似临床表型的其他基因突变）。关于基因组检查的结果解读中需要考虑的问题，请单击此处。

 表1a中列出了最常见的致病基因（此表中任一基因的致病变异占Brugada综合征病因的>1% ）和表1b中列出了较罕见的致病基因（此表中任一基因的致病变异仅在少数家系中报道过）。

表1a.

Brugada综合征的分子遗传学：最常见的致病基因

此表中任一基因的致病变异占Brugada综合征病因的>1%。

1.

关于染色体位置和蛋白质，参见 表A. 基因和数据库 。

2.

关于检测的致病等位基因变异信息，参见分子遗传学 。

3.

测序检测变异分为五类：良性、可能良性、意义不明 、可能致病或致病。致病变异可包括基因内小的缺失/重复、错义、无义和剪切位点变异；通常不能检测外显子或全基因的缺失/重复。关于测序结果解读需要考虑的问题，请单击此处。

4.

基因缺失/重复检测可发现基因内的缺失或重复序列。具体方法包括：定量 PCR、长片段PCR、多重连接探针扩增(MLPA)和设计用于检测单个外显子缺失或重复的基因靶向微阵列。

5.

Kapplinger et al [2010]

6.

Eastaugh et al [2011]，Hertz et al [2015]

表1b.

Brugada综合征的分子遗传学：较罕见的致病基因

此表中任一基因的致病变异仅在少数家系中报道过（在Brugada综合征中比例＜1%）

1.

基因按首字母顺序列出。

2.

关于染色体位置和蛋白质，参见表A. 基因和数据库 。

3.

分子遗传学部分未详细描述的基因，可参阅此处 (pdf)。

临床表现

确诊年龄. Brugada综合征主要于成年发病，猝死平均年龄约为40岁。确诊此综合征的个体最小为2天龄，最大为85岁[Huang & Marcus 2004]。

性别差异. 虽然Brugada综合征好发于男性，但女性也可患病，并且两种性别都具有室性心律失常和猝死的高风险[Hong et al 2004b]。

表现. 目前，本病最常见的表现是在40岁之前出现恶性室性心律失常以及既往晕厥发作史。晕厥是一种常见的主要症状。[Mills et al 2005， Benito & Brugada 2006， Karaca & Dinckal 2006]。

容易诱发持续性室性心律失常和自发异常心电图的患病个体，在生存期间的任何时间发生心律失常事件的可能性为45% [Benito et al 2009]。电风暴（也称为心律失常风暴）是在短时间内多次发作室性心律失常，在Brugada综合征中是恶性并且罕见的表现。持续室性心动过速（VT）是指持续长达数小时的血液动力学稳定的室性心动过速。

Brugada综合征可并发传导系统疾病， Brugada综合征中合并出现一度房室传导阻滞、室内传导延迟、右束支传导阻滞和病态窦房结综合征并不少见[Smits et al 2005]。

Brugada综合征的临床表型还可包括婴儿期猝死综合征（SIDS；1岁以 内婴儿不明原因死亡）[Priori et al 2000a, Antzelevitch 2001, Skinner et al 2005, Van Norstrand et al 2007] 和夜间猝死综合征（SUNDS）[Vatta et al 2002]，后者是一种见于东南亚年轻人不明原因心脏骤停的综合征。在患有Brugada综合征和SUNDS的患者中都检测出相同的SCN5A致病变异，因此支持两者是相同疾病的假设[Hong et al 2004a].

Brugada心电图波形和心源性猝死综合征的诱因包括发热、使用可卡因、电解质紊乱以及使用 I 类抗心律失常药物和许多非心脏病药物[Francis & Antzelevitch 2005]。最重要的是，有些人（通常是年轻人）中出现可诱发的Brugada心电图波形与心源性猝死相关。这种关联背后的病理生理机制在很大程度上仍未知。

预测恶性心律失常风险. 已明确的发生恶性心律失常危险分层的几个参数 (见图3)。

图三.

Brugada综合征患者推荐的危险分层和植入ICD推荐。来自Berne & Brugada [2012]，已获准使用。 

• 电生理学检查 (EPS) 的可诱导性是 目前用于临床决策的唯一参数。此检查使用心脏内导管对心脏进行电刺激。尽管无症状个体行EPS时诱发出心律失常高度预示着随后会出现恶性事件（心律失常和 心源性猝死），但此数据仍有争议。有数个小组不使用EPS对无症状个体进行危险分层，然而目前也没有其他可用的危险分层参数[Nunn et al 2010]。因此，决定何时植入ICD，不同的医师和研究的观点不同[Eckardt et al 2005, Glatter et al 2005, Ikeda et al 2005, Al-Khatib 2006, Delise et al 2006, Gehi et al 2006, Imaki et al 2006, Ito et al 2006, Ott & Marcus 2006, Tatsumi et al 2006, Benito et al 2009]。

• 基因型已被提出作为危险分层的附加参数。Meregalli [2009]等发现，在含有SCN5A致病变异的个体中，往往更多表现为心电图中传导减慢，这一表现支持了由SCN5A功能丧失型致病变异介导传导减慢的概念，这是Brugada综合征的关键病理生理机制。这项有限的研究表明，将来有可能在危险分层中使用基因型信息；然而目前仍有待研究。

• 病理生理学. 钠离子通道疾病引起的Brugada综合征与年龄相关的进行性传导异常，如心电图中PQ、QRS和HV间期延长相关[Smits et al 2002, Yokokawa et al 2007]。钠电流功能障碍引起心外膜中的局部传导阻滞，导致QRS波群出现切迹，并触发心房颤动和心室纤维性颤动[Morita et al 2008]。

  钠离子通道病表现为典型的Brugada样心电图和心动过缓时频繁发生心律失常[Makiyama et al 2005]；奎尼丁和异丙肾上腺素可使抬高的J-ST回归基线并防止心律失常发生。

  基因型-表型关联

  只有少数研究了基因型-表型的关联性。

  关于SCN5A:

• 在含有或不含有SCN5A杂合致病变异 的Brugada综合征患者中，ST段抬高程度和心律失常发生率是相似的[Morita et al 2009].   

• 通常，功能获得型SCN5A致病变异可导致LQT3 (见长QT 综合征) ，功能丧失型则导致Brugada 综合征和进行性传导系统疾病；然而已有报道表明，同一家系中的致病变异与两种疾病都相关。

• 常见的SCN5A变异p.His558Arg通过恢复（至少部分）钠电流异常，来调节SCN5A 杂合致病变异导致的表型[Lizotte et al 2009]，如 p.Thr512Ile，可导致临床显著的心脏传导障碍[Viswanathan et al 2003]，以及 p.Arg282His可导致Brugada综合征[Poelzing et al 2006]。

• 外显率

  在含有SCN5A致病变异的个体中：

• 约20%-30% 个体具有Brugada综合征的心电图诊断。

• 当使用钠通道阻滞剂（阿义马林）激发时，约80% 个体表现为特征性心电图改变[Hong et al 2004b, Benito et al 2009]。

• 命名

  Vatta et al [2002]和Hong et al [2004a]的研究表明，夜间猝死综合征(SUNDS) 和 Brugada综合征在表型、基因型和功能方面是同一疾病。SUNDS最初源自对东南亚个体的描述。SUNDS的其他名称还包括突发意外死亡综合征(SUDS)、 bangungut (菲律宾)、 non-lai tai (老挝)、lai-tai (泰国)和 pokkuri (日本)。

  流行病学

  Brugada综合征在近年来才被提出，因此很难确定其患病率和人群分布情况。此外，由于其心电图是动态变化的且可表现正常，诊断困难，这给在总人群中估计Brugada综合征的真实患病率带来了困难。

  数据表明Brugada综合征在世界各地发生。在流行地区，这种疾病的患病率约为1：2000人。在夜间猝死综合征（SUNDS）高发的东南亚国家，它是40岁以下男性死亡的第二原因（排在事故后）。

  已发表的研究数据表明，Brugada综合征导致了4%-12%的意外猝死，并且在心脏明显正常的个体猝死中比例高达20%。

  随着未来对Brugada综合征认识的深入，预计可发现的病例数量将会大幅增加。

  一项纳入成年日本人口（22,027人）的前瞻性研究显示，12人（0.05%的患病率）的心电图符合Brugada综合征[Tohyou et al 1995]。

  对Awa (日本)成人的另一项研究显示为0.6% 的患病率(66:10,420 人) [Namiki et al 1995]。

  相比之下，纳入日本儿童的第三项研究显示，仅0.0006% (1:163,110) 的心电图符合Brugada综合征[Hata et al 1997]。因此，在没有症状和/或SCN5A基因分子遗传检测的情况下，这些研究估计了所研究的群体中Brugada综合征ECG波形（不是Brugada综合征）的发生率。 结果表明，Brugada综合征主要于成年期出现，这与猝死的平均年龄（35-40岁）的发现一致。

  
  

初步诊断后评估

为了确定诊断为Brugada综合征患者的疾病程度，推荐进行以下评估：

• 心电图

• 在表现为2型或3型心电图以及怀疑本病的患者中使用钠通道阻滞剂（阿义马林、普鲁卡因胺、吡西卡尼和氟卡尼）

• 使用电生理检查来评估心源性猝死风险。尽管目前数据有争议，但暂无其他危险分层参数可用于无症状个体[Nunn et al 2010]。

• 咨询临床遗传学家和/或遗传咨询师

对症治疗

Brugada综合征以V₁ - V₃ 导联ST段抬高为特征。植入埋藏式心脏复律除颤器（ICDs）是目前已知在既往有晕厥或心脏骤停史的Brugada综合征患者中唯一有效的治疗方法[Brugada et al 1999, Wilde et al 2002]。关于Brugada综合征患者ICD植入的危险分层和推荐，参见图3 。

异丙肾上腺素(1-3 µg/min)输注作为先于其他抗心律失常药物的一线治疗，对电风暴效果良好[Maury et al 2004]。

重要的是:

• 避免/治疗药物/情况，如发热、可卡因使用、电解质紊乱以及使用I类抗心律失常药物和其他可引起急性心律失常的非心脏病药物；

  和

• 住院病人至少待心电图波形恢复正常。

关于无症状个体的治疗存在争议，推荐各不相同[Benito et al 2009, Escárcega et al 2009, Nunn et al 2010]，包括以下内容 ：

• 观察，直到出现首发症状（首发症状也可以是心源性猝死）

• 如心源性猝死家族史为阳性，则需植入ICD

• 通过电生理检查（EPS）来明确那些最有可能发生心律失常的患者，从而最大限度地受益于ICD植入

预防主要表现

奎尼丁（每日1-2g）已证实可使ST段抬高恢复，并降低心律失常的发生率 [Belhassen et al 2004, Hermida et al 2004, Probst et al 2006]。

预防并发症

Brugada综合征患者在手术期和术后恢复期应进行心电图检测。

监测

有Brugada综合征家族史或已知致病变异的有风险的个体应该从出生开始每隔一至两年进行心电图检查[Oe et al 2005]。I型心电图波形改变应该进行进一步检查。

应避免的药物/情况

下列情况可诱发Brugada综合征心电图 [Antzelevitch et al 2002]：

• 发热状态

• 安眠药物

• α-肾上腺受体激动剂[Miyazaki et al 1996]

• β-肾上腺受体拮抗剂

• 三环类抗抑郁药

• 第一代抗组胺药 (曲拉明)

• 可卡因中毒

下列情况应该避免[Antzelevitch et al 2003]：

• 1C类抗心律失常药物，包括氟卡尼和普罗帕酮

• 1A类抗心律失常药物，包括普鲁卡因胺和丙吡胺

亲属风险评估

如在已经患病的家庭成员中检测到，应当对有风险的亲属进行分子遗传检测，因为：

• 心电图变化在用于确诊时灵敏度低 [Priori et al 2003]；

• 识别有患病风险的个体，以采取预防措施，例如避免使用可诱发室性心律失常的药物；

• 可以只监测已明确鉴定携带致病变异的家系成员[Benito et al 2009, Escárcega et al 2009, Nunn et al 2010]。

如在家系中未检测出致病变异，亲属应行心电图筛查。如检查出I型心电图，则必须进一步检查。

关于针对有患病风险的亲属检查进行遗传咨询的目的的相关问题，请参阅遗传咨询。

妊娠管理

怀孕期间的激素变化可引发患有Brugada综合征的妇女出现心律失常事件。低剂量静脉输注异丙肾上腺素后，口服奎尼丁可抑制快速性室性心律失常反复发作，并使心电图波形恢复正常[Sharif-Kazemi et al 2011]。

奎尼丁对于发育中的胎儿是否致畸目前是未知的，它是治疗妊娠期心律失常的优选药物。关于怀孕期间药物使用的更多信息，请访问www.mothertobaby.org。

正在研究的治疗方法

搜索ClinicalTrials.gov获取关于各种疾病的临床研究信息。注意：本疾病可能没有临床试验。

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推荐阅读

• Antzelevitch C, Brugada P, Borggrefe M, Brugada J, Brugada R, Corrado D, Gussak I, LeMarec H, Nademanee K, Perez Riera AR, Shimizu W, Schulze-Bahr E, Tan H, Wilde A. Brugada syndrome: report of the second consensus conference. Heart Rhythm. 2005;2:429 - 40. [PubMed: 15898165]
• Brugada P, Brugada R, Brugada J. Should patients with an asymptomatic Brugada electrocardiogram undergo pharmacological and electrophysiological testing? Circulation. 2005;112:279 - 92. [PubMed: 16009809]
• Brugada R, Brugada P, Brugada J. Electrocardiogram interpretation and class I blocker challenge in Brugada syndrome. J Electrocardiol. 2006;39:S115 - 8. [PubMed: 16934827]
• Keating MT, Sanguinetti MC. Familial cardiac arrhythmias. In: Valle D, Beaudet AL, Vogelstein B, Kinzler KW, Antonarakis SE, Ballabio A, Gibson K, Mitchell G, eds. The Metabolic and Molecular Bases of Inherited Disease (OMMBID). Chap 203. McGraw-Hill. Available online.
• Morita H, Nagase S, Miura D, Miura A, Hiramatsu S, Tada T, Murakami M, Nishii N, Nakamura K, Morita ST, Oka T, Kusano KF, Ohe T. Differential effects of cardiac sodium channel mutations on initiation of ventricular arrhythmias in patients with Brugada syndrome. Heart Rhythm. 2009;6:487 - 92. [PubMed: 19324308]
• Morita H, Zipes DP, Morita ST, Lopshire JC, Wu J. Epicardial ablation eliminates ventricular arrhythmias in an experimental model of Brugada syndrome. Heart Rhythm. 2009;6:665 - 71. [PubMed: 19328041]
• Morita H, Zipes DP, Morita ST, Wu J. Genotype-phenotype correlation in tissue models of Brugada syndrome simulating patients with sodium and calcium channelopathies. Heart Rhythm. 2010;7:820 - 7. [PubMed: 20206324]
• Sarquella-Brugada G, Campuzano O, Arbelo E, Brugada J, Brugada R. Brugada syndrome: clinical and genetic findings. Genet Med. 2016;18:3 - 12. [PubMed: 25905440]

作者注释

Gencardio
Cardiovascular Genetics Center, University of Girona
Institut d'Investigacions Biomèdiques de Girona (IDIBGI)
C/ Dr Castany s/n, Parc Hospitalari Martí i Julià (Mancomunitat-2) 17190
Salt -Girona- (Spain)

Ramon Brugada博士是心脏病学教授（Girona大学医学院教授），心血管遗传中心主任以及Girona Josep Trueta医院的心脏病专家。

• 临床领域. 作为临床和非介入心脏病学家，Brugada教授对遗传性心脏病患者的临床管理有一定造诣。   

• 研究领域. Brugada教授的研究领域集中在心血管疾病的分子遗传学，侧重于心律失常的遗传学研究。他的研究成果包括鉴定10q22家族性房颤的染色体基因座，家族性特发性心室颤动（Brugada综合征）和短QT综合征的基因。

• 2016年11月17日 (ma) 全面更新发布到网站

• 2014年4月10日 (me) 全面更新发布到网站

• 2012年8月16日 (cd) 修订：可应用针对Brugada综合征和心源性猝死的多基因 panels 

• 2012年1月12日 (cd) 修订：CACNB2 和 HCN4 基因突变的临床检测被列入GeneTests™ 实验室的目录； SCN5A基因大片段缺失被报道[Eastaugh et al 2011]

• 2011年9月8日 (me) 全面更新发布到网站

• 2009年8月11日 (cd) 修订：SCN5A的产前诊断可用于临床

• 2007年12月7日 (me) 全面更新发布到网站

• 2005年3月31日 (me) 综述发布到网站

• 2004年3月11日 (rb) 原始提交

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