[SCD-FORUM] 10—17 EXPERT ASK AND EXPERT ANSER: Question by Dr. Terushi Tanabe, from Japan

[SCD Symposium]

10—17 EXPERT ASK AND EXPERT ANSER: Question by Dr. Terushi Tanabe,  
from Japan

  日本的Terushi Tanabe 医生提问：

Brugada综合征因其可能导致心脏猝死而成为目前关注 
的焦点。Brugada综合征患者是否会因地域、国家、种 
族的不同而呈现不同的表现型？出现这种现象的原因 
又是什么呢?

Dr. Pedro Brugada和Dr. Andrea Sarkozyr回答：

Tanabe医生，您提的问题很好，很有实际意义。现有的 
临床研究已经强有力证实不同地域的Brugada综合征患 
者心脏猝死的发生率和其他临床特征确有不同。

1．人类学研究发现，亚洲（日本）人心电图无症状 
性穹隆样Brugada波的阳性率明显高于高加索人种 
(0.1-0.4%比 0-0.1%)。 简而言之，Brugada综合征患者猝死 
的发生率在东南亚较高，其次为高加索地区。在泰 
国， Brugada综合征是青壮年自然死亡的第一位死因。

2. 不明原因的猝死综合征(SUNDS)首先是在美国的移民 
中被诊断的，但实际上，许多年前在东南亚地区，尤 
其是泰国、日本和菲律宾，该病就已经被发现。该病 
主要发生于健康男性，多在夜间出现不明原因的猝 
死。60%患者静息时心电图即可呈现Brugada波。新近研 
究发现10例SUNDS患者中3例出现SCN5A基因突变。该突变 
导致钠离子通道“功能缺失”样改变。该研究结果提 
示：无论从表型、基因型还是功能改变而言， Brugada 
综合征和SUNDS均属同种疾病。然而，该病在南亚和高 
加索地区存在地域差异；发病率的男女性别比例分别 
为 8:1及3:1，后者的数据来源于3个欧洲注册调查。亚 
洲患者几乎毫无例外的均在夜间出现症状，而高加索 
患者有在白天发生猝死的记录。

现有研究并不能很好的解释该差异出现的原因，但实 
际出现的差异不得不引发我们的思考：

1. 2002年，Splawski等证实SCN5A单核苷所多态性能够影响 
心律失常的易感性。大约13.2%的非洲人携带该等位基 
因，后者可产生亚临床型的基因功能修饰从而导致心 
律失常易感性增加。因此推测，在某些情况下如低 
钾、服用某些药物、器质性心脏病时，这些异常等位 
基因携带者发生心律失常的危险性明显增高。

2. 2004年，Ackerman等在829例健康个体中检出39例SCN5A基 
因编码区出现缺失改变的患者（包括4个普通的单核 
苷酸多态性患者），出现频率最高（等位基因频率 
 >0.5%）的8个SNP位点中有2个呈现明显的种族特异性； 
R1193Q单核苷酸多态性在亚洲人中的发生率为8%，而在 
白色人种中出现率仅为3%（在西班牙人和黑色人种中 
几乎完全没有）。与之不同的是，H558R单核苷酸多态 
性在亚洲人中的发生率为9%，而在白色人种中出现率 
却高达20%（在西班牙人种的出现率为23%，黑色人种中 
的出现率为29%）。

3．近来Bezzina等人报道了在SCN5A启动子区域同样存在 
SNP的种族特异性现象。其中有6个SNP位点（表现为单 
倍体变异）仅在亚洲人出现（等位基因频率为22%）， 
而其他人种没有这种改变。这种单倍体变异可导致钠 
离子通道蛋白表达和功能下降。

需要指出的是，这种单倍体变异本身不会影响Brugada 
综合征的表型，并且在Brugada综合征中的出现率也很 
低，但却会造成传导速度的减慢即PR间期和QRS波群时 
限的延长。另外，近几年有研究发现，在因基因突变 
而导致Brugada综合征的患者中若存在某些SCN5A单核苷酸 
多态性改变，这些SNP就可能助于产生Brugada综合征的 
临床表现并进一步影响基因突变的表达，对钠通道功 
能的影响可表现为正反两方面。

综上，Keating 在长QT 综合征中提及的“multi-hit” 理论 
可能是对您提出的问题最好的解释：亚洲人与高加索 
人种的基因背景不同，这其中包括种族特异性的SCN5A 
（或其他影响离子通道功能的基因）单核苷酸多态 
性， 这些SNP能够在亚临床水平影响钠通道的功能和/ 
或表达，降低许多无症状患者的“抗颤”储备能力。 
这些患者如果同时合并有其他的基因突变或类似的使 
离子通道功能降低的SNP，在应用钠通道阻滞剂后或在 
特定的环境因素（发热、性别）下，离子通道的功能 
更易被降低，从而导致瞬时动作电位的改变进而出现 
心电图异常，引发临床心律失常的出现。



1.              Antzelevitch C et al: Brugada syndrome. Report of the  
second consensus conference Circ 2005;111:659-70

2.              Nademanee K et al: Arrhythmogenic marker for the  
sudden unexplained death syndrome in Thai men Circ 1997;96:2595-600

3.              Watta M et al: Genetic and biophysical basis of  
sudden unexplained nocturnal death syndrome (SUNDS), a disease  
allelic to Brugada syndrome Hum Mol Gen 2002;11:337-45

4.              Ackerman MJ et al: Spectrum and prevalence of cardiac  
sodium channel variants among black, white, Asian and Hispanic  
individuals: Implications for arrhythmogenic susceptibility and  
Brugada/long QT syndrome genetic testing Heart Rhythm 2004;1:600-7

5.              Bezzina CR et al: Common sodium channel promoter  
haplotype in Asian subjects underlies variability in cardiac  
conduction Circ 2006;113:338-44

6.              Splawski I et al: Variant of SCN5A sodium channel  
implicated in risk of cardiac arrhythmia Science 2002;297:1333-6

7.              Keating MT, Sanguinetti MC: Molecular and cellular  
mechanisms of cardiac arrhythmias Cell 2001;104:569-80





董颖雪译 王玲洁校



原文：

Question by Dr. Terushi Tanabe, from Japan

- Sudden cardiac death is most serious in patients with Brugada  
syndrome and the number one concern.  However, there are differences  
in incidence of Brugada syndrome between race and country or  
regions?  Why do you think this occurs?


Dear Dr Tanabe
Thank you for your actual and excellent question. The intriguing  
differences between the incidence and perhaps other characteristics  
of Brugada syndrome between the different geographical regions have  
been supported by the strong clinical evidence;
1, Population studies revealed that the incidence of the diagnostic  
coved Brugada ECG pattern in the general asymptomatic Asian  
(Japanese) population is much more frequent than in the Caucasian  
population (0.1-0.4% vs. 0-0.1%). Similarly, sudden death due to  
Brugada syndrome is also much more frequent in the south East Asian  
population, then in the Caucasian; the syndrome is the leading  
natural cause of death in young Thai men (1). 2, Sudden Unexplained  
Death Syndrome (SUNDS) , first described in US immigrants, is a  
disorder that had been prevalent for many years in south-east Asia,  
particularly Thailand, Japan and the Phillipines. SUNDS is  
characterized by sudden unexpected death at night in apparently  
healthy men. 60% of the patients have the characteristics Brugada ECG  
pattern on the baseline ECG (2). Recently, SCN5A mutations have been  
identified in 3 of 10 patients with SUNDS. The gene mutation resulted  
in similar ‘loss-of-function’ channel function alterations as in  
Brugada syndrome. This data suggest that SUNDS and Brugada syndrome  
are phenotypically, genetically and functionally the same disorder (3).
However, there are differences between the Brugada syndrome in the  
southeast Asian (SUNDS) and Caucasian patient populations; the man:  
female ratio is much higher in the Asian patient population (8:1 in  
SUNDS vs. 3:1 in the 3 European registries); the Asian patients die  
almost exclusively during sleep while the Caucasian patients  
sometimes die suddenly daytime.
Evidence based explanation is missing to account for these  
differences, however some recent data might allow some speculations;
1, In 2002, Splawski et al provided evidence that single nucleotide  
common polymorphisms of the SCN5A gene can influence arrhythmia  
susceptibility (6). About 13.2% of African Americans carried this  
allele. The allele had a subtle effect on arrhythmia risk due to  
subclinical sodium channel function modification. It was proposed  
that in the presence of additional acquired risk factors, such as  
medications, hypokalemia and structural heart disease, the  
individuals with the allele have increased risk of arrhythmia.
2, Ackerman et al in 2004 described in 829 healthy subjects  
altogether 39 distinct missense variants of the SCN5A coding region,  
including the previously described known 4 common single nucleotid  
polymorphisms (SNP). Interestingly, 2 of the 8 most frequent  
polymorphisms (allelic frequency >0.5%) showed a largely ethnic  
specific distribution; the R1193Q single nucleotide polymorphism  
occurred in 8% of the Asian vs. 0.3% of the white population (and was  
entirely missing in the Hispanic and black population), in contrast  
to the H558R polymorphism which occurred in 20% of the white (29% of  
the black and 23% of the Hispanic population) vs. in 9% of the Asian  
population ( (4).
3, Recently, Bezzina et al described a similar ethnic specific  
distribution in SNP distributions but in the SCN5A promoter region. A  
certain combination of 6 single nucleotid polymorphisms (designated  
as haplotype B variant) only occurred in Asian subjects (at an allele  
frequency of 22%) and was absent in the other ethnic groups. This  
haplotype variant resulted in decreased sodium channel expression and  
function. Although it should be underlined that this haplotype  
variant neither caused Brugada phenotype nor was more frequent in the  
Brugada syndrome population, it clearly influenced conduction  
velocities and was responsible for longer PR and QRS intervals (5).
Additionally, in the last years several case reports proved that  
certain SCN5A polymorphism in the presence of a Brugada syndrome  
causing SCN5A mutation can influence the clinical phenotype and thus  
clinical consequences of the mutation; the polymorphism can rescue  
and restore or in contrast can further worsen the sodium channel  
function.
Putting these pieces of evidence together in one picture, it is  
possible that the currently best theory to answer your question is  
the expansion of the multi-hit theory in long QT syndrome described  
by Keating et al (7). The Asian population, as compared to the  
Caucasian population, might have a different genetic background  
consisting of ethnic specific SCN5A (or other ion channel function  
influencing genes) polymorphisms. These polymorphisms influence  
sodium channel function and/or expression, but only in a subclinical  
manner; “decreasing the antifibrillatory reserves” in a large  
normally asymptomatic population. However, in these individuals, in  
the setting of either another mutation or similar function decreasing  
polymorphism (on the SCN5A or other ion channel genes) or sodium  
channel blocking agents or other environmental factors (gender, fever  
etc), the ion channel function is much more easily depressed under  
the critical level to cause transient action potential, and  
subsequent ECG abnormalities, provoking clinical arrhythmias.


--
Dr. Sergio Dubner
President of Scientific Committee

Dr. Edgardo Schapachnik
President of Steering Committee