<HTML><BODY style="word-wrap: break-word; -khtml-nbsp-mode: space; -khtml-line-break: after-white-space; "><FONT class="Apple-style-span" face="Arial">Dr. Teruhisa Tanabe from Japan asks</FONT><DIV><FONT class="Apple-style-span" face="Arial"><BR class="khtml-block-placeholder"></FONT></DIV><DIV><DIV><DIV><DIV class="MsoNormal"><FONT class="Apple-style-span" face="Arial">- 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?</FONT></DIV></DIV><DIV><DIV class="MsoNormal"><FONT class="Apple-style-span" face="Arial"><BR class="khtml-block-placeholder"></FONT></DIV><DIV class="MsoNormal"><FONT class="Apple-style-span" face="Arial"><BR class="khtml-block-placeholder"></FONT></DIV><DIV class="MsoNormal"><FONT class="Apple-style-span" face="Arial">Dr. Andrea Sarkozy and Dr. Pedro Brugada from Belgium answer</FONT></DIV><DIV class="MsoNormal"><FONT class="Apple-style-span" face="Arial"><BR class="khtml-block-placeholder"></FONT></DIV><DIV class="MsoNormal"><FONT class="Apple-style-span" face="Arial">- Dear Dr Tanabe</FONT></DIV><DIV class="MsoNormal"><FONT class="Apple-style-span" face="Arial">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;</FONT></DIV><DIV class="MsoNormal"><FONT class="Apple-style-span" face="Arial">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).</FONT></DIV><DIV class="MsoNormal"><FONT class="Apple-style-span" face="Arial">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.</FONT></DIV><DIV class="MsoNormal"><FONT class="Apple-style-span" face="Arial">Evidence based explanation is missing to account for these differences, however some recent data might allow some speculations;</FONT></DIV><DIV class="MsoNormal"><FONT class="Apple-style-span" face="Arial">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. </FONT></DIV><DIV class="MsoNormal"><FONT class="Apple-style-span" face="Arial">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). </FONT></DIV><DIV class="MsoNormal"><FONT class="Apple-style-span" face="Arial">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). </FONT></DIV><DIV class="MsoNormal"><FONT class="Apple-style-span" face="Arial">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.</FONT></DIV><DIV class="MsoNormal"><FONT class="Apple-style-span" face="Arial">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.</FONT></DIV><DIV class="MsoNormal"><FONT class="Apple-style-span" face="Arial"> </FONT></DIV><DIV class="MsoNormal"><FONT class="Apple-style-span" face="Arial"> </FONT></DIV><DIV><FONT class="Apple-style-span" face="Arial">(1) Antzelevitch C et al: Brugada syndrome. Report of the second consensus conference Circ 2005;111:659-70</FONT></DIV><DIV><FONT class="Apple-style-span" face="Arial">(2) Nademanee K et al: Arrhythmogenic marker for the sudden unexplained death syndrome in Thai men Circ 1997;96:2595-600</FONT></DIV><DIV><FONT class="Apple-style-span" face="Arial">(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</FONT></DIV><DIV><FONT class="Apple-style-span" face="Arial">(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 </FONT></DIV><DIV><FONT class="Apple-style-span" face="Arial">(5) Bezzina CR et al: Common sodium channel promoter haplotype in Asian subjects underlies variability in cardiac conduction Circ 2006;113:338-44 </FONT></DIV><DIV><FONT class="Apple-style-span" face="Arial">(6) Splawski I et al: Variant of SCN5A sodium channel implicated in risk of cardiac arrhythmia Science 2002;297:1333-6 </FONT></DIV><DIV><FONT class="Apple-style-span" face="Arial">(7) Keating MT, Sanguinetti MC: Molecular and cellular mechanisms of cardiac arrhythmias Cell 2001;104:569-80 </FONT></DIV><DIV class="MsoNormal"><FONT class="Apple-style-span" face="Arial"> </FONT></DIV></DIV></DIV><FONT class="Apple-style-span" face="Arial"><BR></FONT><DIV> <DIV><FONT class="Apple-style-span" face="Arial">--</FONT></DIV><DIV><FONT class="Apple-style-span" face="Arial">Dr. Sergio Dubner</FONT></DIV><DIV><FONT class="Apple-style-span" face="Arial">President of Scientific Committee</FONT></DIV><DIV><FONT class="Apple-style-span" face="Arial"><BR></FONT></DIV><DIV><FONT class="Apple-style-span" face="Arial">Dr. Edgardo Schapachnik</FONT></DIV><DIV><FONT class="Apple-style-span" face="Arial">President of Steering Committee</FONT></DIV><DIV><FONT class="Apple-style-span" face="Arial"><BR class="khtml-block-placeholder"></FONT></DIV><DIV><FONT class="Apple-style-span" face="Arial"><BR class="khtml-block-placeholder"></FONT></DIV><FONT class="Apple-style-span" face="Arial"><BR class="Apple-interchange-newline"> </FONT></DIV><FONT class="Apple-style-span" face="Arial" size="3"><SPAN class="Apple-style-span" style="font-size: 13px;"><BR></SPAN></FONT></DIV></BODY></HTML>