[SCD-FORUM] EXPERTS ASK, EXPERTS ANSWER

[SCD Symposium]

Dr. Teruhisa Tanabe from Japan asks

- 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?


Dr. Andrea Sarkozy and Dr. Pedro Brugada from Belgium answer

- 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.


(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


--
Dr. Sergio Dubner
President of Scientific Committee

Dr. Edgardo Schapachnik
President of Steering Committee




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