<HTML><BODY style="word-wrap: break-word; -khtml-nbsp-mode: space; -khtml-line-break: after-white-space; "><DIV><FONT class="Apple-style-span" face="Arial">Dear Teruhisa Tanabe from Japan: here Andrés Ricardo Pérez Riera from Sao Paulo Brazil. Indeed there are differences in incidence of Brugada syndrome( BrS) among races, countries and regions because the chanelopathy eventually has a genetic component. BrS is genetically determined in a dominant autosomal mode in approximately 20% of the cases and is caused by mutations in the SCN5A gene on chromosome 3p21-23, encoding the cardiac sodium channel (1).</FONT></DIV><DIV><FONT class="Apple-style-span" face="Arial"><BR></FONT></DIV><DIV><FONT class="Apple-style-span" face="Arial">Most cardiac channelopathies are inherited as autosomal dominant disorders. This means that any person with an inherited cardiac channelopathy has a 50% chance of passing it on to each of his or her children. The channelopaties that affect the SCN5A gene are allelic with BrS ((Any one of a series of two or more different genes that occupy the same position (locus) on a chromosome.) The majority of these mutations are missense. However, other types such as deletions, insertions, frame shifts, nonsense and splice-donor errors have also been reported.(2)</FONT></DIV><DIV><FONT class="Apple-style-span" face="Arial"><BR></FONT></DIV><DIV><FONT class="Apple-style-span" face="Arial">We think that we must divided Brugada entities in (3):</FONT></DIV><DIV><FONT class="Apple-style-span" face="Arial"><BR></FONT></DIV><DIV><FONT class="Apple-style-span" face="Arial">1) Familial cases (»17%): true Brugada disease. .We proposes that this entity should be promoted to the category of disease, since it has a characteristic set of signs and symptoms, and an identified genetic defect. (4);</FONT></DIV><DIV><FONT class="Apple-style-span" face="Arial"><BR></FONT></DIV><DIV><FONT class="Apple-style-span" face="Arial">(2) Sporadic cases (»63%): Brugada syndrome (5)</FONT></DIV><DIV><FONT class="Apple-style-span" face="Arial"><BR></FONT></DIV><DIV><FONT class="Apple-style-span" face="Arial">(3) Acquired forms: those entities or clinical pharmacological conditions, where the Brugada phenotype or Brugada-type ECG may be found as a consequence of promoting increase in Ito channel function in the ventricular epicardium or decrease in the slow calcium channel.</FONT></DIV><DIV><FONT class="Apple-style-span" face="Arial"><BR></FONT></DIV><DIV><FONT class="Apple-style-span" face="Arial">Because the ECG pattern can be dynamic and is often concealed, it is difficult to estimate the true prevalence of the disease in the general population.</FONT></DIV><DIV><FONT class="Apple-style-span" face="Arial"><BR></FONT></DIV><DIV><FONT class="Apple-style-span" face="Arial">BrS causes 4 to 10 SCD per 10,000 inhabitants per year in areas like Thailand and Laos (Southeast Asia). It is particularly frequent among young men (under the age of 40) of Asian origin. In these countries, the disease represents the leading cause of death in young adult men (6) BrS deaths are second only to automobile accidents as a cause of death among young adults men in some countries around the world. The annual mortality rate in Thailand for this subgroup the. prevalence of the disease was estimated to be 26 to 38 deaths per 100,000 inhabitants(7)</FONT></DIV><DIV><FONT class="Apple-style-span" face="Arial"><BR></FONT></DIV><DIV><FONT class="Apple-style-span" face="Arial">The prevalence, incidence and prognostic value of the Brugada-type ECG has been studied in a general adult Japanese population. The 4,788 subjects (1,956 men and 2,832 women) were under 50 years of age in 1958 and had undergone biannual health examinations, including ECG, through 1999. There were a total of 32 Brugada-type ECG cases. The prevalence and incidence were 146.2 in 100,000 persons and 14.2 persons per 100,000 person-years, respectively. The incidence was nine times higher among men than women, and the average age at presentation was 45 +/- 10.5 years. The Brugada-type ECG appeared intermittently in most cases and was found in 26% of subjects who died unexpectedly. Cox survival analysis revealed that mortality from unexpected death was significantly higher in subjects with a Brugada-type ECG than in control subjects (p < 0.01). Unexpected deaths were more frequent among subjects with the Brugada-type ECG who had a history of syncope (p < 0.05). The Brugada-type ECG is not a very rare condition in the adult Japanese population. Subjects with a Brugada-type ECG have an increased risk of unexpected death (8).</FONT></DIV><DIV><FONT class="Apple-style-span" face="Arial"><BR></FONT></DIV><DIV><FONT class="Apple-style-span" face="Arial">The Brugada-type ECG was found in 0.70% of 13,929 study subjects (98 cases) in a community-based population in Japan, predominantly in men. The typical coved-type ST-T morphology with the RBBB pattern-an rsR' pattern in the V1 lead ("typical" Brugada-type 1)-was found in 0.12% of all subjects.</FONT></DIV><DIV><FONT class="Apple-style-span" face="Arial"><BR></FONT></DIV><DIV><FONT class="Apple-style-span" face="Arial">The prevalence of cardiac events among male subjects with a Brugada-type ECG (81%) was significantly higher than it was for those without it.</FONT></DIV><DIV><FONT class="Apple-style-span" face="Arial"><BR></FONT></DIV><DIV><FONT class="Apple-style-span" face="Arial">The Brugada-type ECG was found in 2.14% of male subjects, and the "typical" Brugada-type 1 was found in 0.38%. After 2.6 +/- 0.3 years of follow-up, there was one death of a subject with the Brugada-type ECG, whereas there were 139 deaths of those without the Brugada-type ECG (p = 0.9943, log-rank test). The total mortality of subjects with the Brugada-type ECG did not differ from the mortality of those without the Brugada-type ECG (9).</FONT></DIV><DIV><FONT class="Apple-style-span" face="Arial"><BR></FONT></DIV><DIV><FONT class="Apple-style-span" face="Arial">From about 12,000 non-selected and non-cardiac patients in just one University Hospital, collected prospectively for a period of two years, there were 52 cases with the typical ECG pattern, i.e., with Brugada sign(10).</FONT></DIV><DIV><FONT class="Apple-style-span" face="Arial"><BR></FONT></DIV><DIV><FONT class="Apple-style-span" face="Arial">In France have shown a prevalence of Brugada pattern of ECG in 1 per 1,000 normal asymptomatic individuals (11).</FONT></DIV><DIV><FONT class="Apple-style-span" face="Arial"><BR></FONT></DIV><DIV><FONT class="Apple-style-span" face="Arial">The prevalence, incidence, and prognosis of the Brugada-type ECG were analyzed in the general population of Japan, based on a study of four decades. Thus, from a group of 4788 individuals, 32 Brugada-type ECGs were detected, the prevalence and incidence being 146.2 in 100,000 people and 14.2 per 100,000 individuals/year, respectively. This incidence was nine times higher in men than in women; the intermittence of the Brugada-type ECG was found in 26% of cases of those who underwent SCD, and the Cox survival analysis showed that unexpected mortality was significantly higher in subjects with the Brugada-type ECG than in control subjects(12).</FONT></DIV><DIV><FONT class="Apple-style-span" face="Arial"><BR></FONT></DIV><DIV><FONT class="Apple-style-span" face="Arial">Monroe and Littmann (2000), in 12,000 consecutive ECG in non-cardiac patients, during two years, they found Brugada pattern in 52 ECGs showing a higher prevalence than thought before(13).</FONT></DIV><DIV><FONT class="Apple-style-span" face="Arial"><BR></FONT></DIV><DIV><FONT class="Apple-style-span" face="Arial">BrS is believed to be responsible for 4-12% of all SCD and around 20% of deaths in patients with apparently structurally normal hearts(14).</FONT></DIV><DIV><FONT class="Apple-style-span" face="Arial"><BR></FONT></DIV><DIV><FONT class="Apple-style-span" face="Arial">Prevalence and prognosis of subjects with Brugada-type ECG pattern was studied in 2479 healthy young male Air Force applicants age 18-30 years) and in 542 healthy middle-aged subjects age between 40-60 years Finnish population. Fifteen (0.61%) subjects in the first population and three subjects in the second population (0.55%) fulfilled the ECG criteria for Type 1 or 2 Brugada syndrome pattern. They had J-point elevation and a saddleback-type ST-segment configuration in the right precordial leads. Type 1 Brugada ECG pattern (coved ST-segment elevation) was not seen in any subject. The benign natural course of the patients with the "Brugada sign" suggests that in asymptomatic subjects without a family history of SCD, Type 2 or 3 Brugada ECG pattern is a normal variant rather than a specific predictor of life-threatening ventricular arrhythmias(15).</FONT></DIV><DIV><FONT class="Apple-style-span" face="Arial"><BR></FONT></DIV><DIV><FONT class="Apple-style-span" face="Arial">The prevalence of typical drug-induced Brugada syndrome ECGs was 5 of the 1,000 patients. This value was fivefold greater than the reported prevalence of spontaneous BrS ECGs in the healthy population(16)</FONT></DIV><DIV><FONT class="Apple-style-span" face="Arial"><BR></FONT></DIV><DIV><FONT class="Apple-style-span" face="Arial">Blangy et al studdied the prevalence of BrS among 35,309 inhabitants of Lorraine (France) screened at preventive medicine center. ECGs of 35,309 individuals (mean age = 37.2 years, 47% men) recorded over a 1-year period were reviewed and classified as (1) typical, (2) suspicious, and (3) negative. Subjects whose ECG was suspicious were offered a provocative test with flecainide, 2 mg/kg, i.v., and individuals whose ECG was typical were advised to undergo Programmed Ventricular Stimulation (PVS). In 14 men and 6 women between the ages of 24 and 77 years (mean =47.5), ECGs were typical (n=6) or suspicious (n=14). Among 6 subjects with typical ECGs, 3 underwent PVS, which was positive in 1, who received an ICD. Among 14 subjects whose ECGs were suspicious, 5 declined further investigations and 5 developed typical ECG characteristics of BrS after flecainide administration. PVS was negative in 4 subjects who consented to the procedure. Overall, among 35,309 individuals screened, 11 had ECG findings consistent with BrS and, over a follow-up of 30 months, all had remained free of adverse cardiac event. The authors estimated a prevalence of BrS of 0.3% in Lorraine. A single patient received an ICD for inducible VT during PVS, representing a potential 30 per million asymptomatic adult rate of ICD implantation for this indication(17)</FONT></DIV><DIV><FONT class="Apple-style-span" face="Arial"><BR></FONT></DIV><DIV><FONT class="Apple-style-span" face="Arial">Shin SC et al (18) studied the prevalence of Brugada-type ECG changes from a total of 225 healthy Korean male subjects with a mean age of 44+/-13 (20-69) years with no syncope or family history of SCD. ECGs were taken from 4th, 3rd, and 2nd intercostals spaces and examined for Brugada-type ECG changes. There were none on the routine 12-lead ECGs, but 3 (1.3%) of the 225 subjects had a Brugada-type ECG recorded from the higher intercostals spaces and 1 of them had a Brugada-type ECG recorded at both the 2nd and 3rd intercostals spaces. The prevalence of the Brugada-type ECG was 1.3% at the 3rd intercostals space, 0.4% at the 2nd intercostals space. All were type 2. The authors conclude that some healthy Korean males with normal routine ECGs show Brugada-type 2 changes on ECGs recorded from higher intercostals spaces.</FONT></DIV><DIV><FONT class="Apple-style-span" face="Arial"><BR></FONT></DIV><DIV><FONT class="Apple-style-span" face="Arial">References</FONT></DIV><DIV><FONT class="Apple-style-span" face="Arial"><BR></FONT></DIV><DIV><FONT class="Apple-style-span" face="Arial">1) Napolitano C, Priori S. Brugada syndrome. Orphanet J Rare Dis. 2006;135;</FONT></DIV><DIV><FONT class="Apple-style-span" face="Arial"><BR></FONT></DIV><DIV><FONT class="Apple-style-span" face="Arial">2) Moric E, Herbert E, Trusz-Gluza M, Filipecki A, Mazurek U, Wilczok T. The implications of genetic mutations in the sodium channel gene (SCN5A). Europace. 2003; 5:325-334</FONT></DIV><DIV><FONT class="Apple-style-span" face="Arial"><BR></FONT></DIV><DIV><FONT class="Apple-style-span" face="Arial">3) de Souza D, Riera AR, Bombig MT, et al. Electrocardiographic changes by accidental hypothermia in an urban and a tropical region. J Electrocardiol. 2006 Oct 4; [Epub ahead of print]</FONT></DIV><DIV><FONT class="Apple-style-span" face="Arial"><BR></FONT></DIV><DIV><FONT class="Apple-style-span" face="Arial">4) Riera AR, Schapachnik E, Ferreira C. Brugada disease: chronology of discovery and paternity. Preliminary observations and historical aspects. Indian Pacing Electrophysiol J. 2003;3:253-260;</FONT></DIV><DIV><FONT class="Apple-style-span" face="Arial"><BR></FONT></DIV><DIV><FONT class="Apple-style-span" face="Arial">5) Schulze-Bahr E, Eckardt L, Breithardt G, Sodium channel gene (SCN5A) mutations in 44 index patients with Brugada syndrome: different incidences in familial and sporadic disease. Hum Mutat. 2003; 21:651-652.</FONT></DIV><DIV><FONT class="Apple-style-span" face="Arial"><BR></FONT></DIV><DIV><FONT class="Apple-style-span" face="Arial">6) Brugada J, Brugada P, Brugada R. The syndrome of right bundle branch block ST segment elevation in V1 to V3 and sudden death-the Brugada syndrome. Europace 1999; 1:156-66.</FONT></DIV><DIV><FONT class="Apple-style-span" face="Arial"><BR></FONT></DIV><DIV><FONT class="Apple-style-span" face="Arial">7) Nademanee KK, Veerakul G, Nimmannit, S, et.al. Arrhytmogenic marker for the sudden unexplained death syndrome in Thai men. Circulation. 1997; 96:2595-2600.</FONT></DIV><DIV><FONT class="Apple-style-span" face="Arial"><BR></FONT></DIV><DIV><FONT class="Apple-style-span" face="Arial">8) Matsuo K, Akahoshi M, Nakashima E, et. al. The prevalence, incidence and prognostic value of the Brugada-type electrocardiogram: a population-based study of four decades. J Am Coll Cardiol 2001;38:765-770</FONT></DIV><DIV><FONT class="Apple-style-span" face="Arial"><BR></FONT></DIV><DIV><FONT class="Apple-style-span" face="Arial"><BR></FONT></DIV><DIV><FONT class="Apple-style-span" face="Arial">9) Miyasaka Y, Tsuji H, Yamada K, et al. Prevalence and mortality of the Brugada-type electrocardiogram in one city in Japan. J Am Coll Cardiol 2001; 38:771-774.</FONT></DIV><DIV><FONT class="Apple-style-span" face="Arial"><BR></FONT></DIV><DIV><FONT class="Apple-style-span" face="Arial">10) Monroe MH, Littmann L. Two-year case collection of the Brugada syndrome electrocardiogram pattern at a large teaching hospital. Clin Cardiol. 2000;23:849-851.</FONT></DIV><DIV><FONT class="Apple-style-span" face="Arial"><BR></FONT></DIV><DIV><FONT class="Apple-style-span" face="Arial">11) Hermida J, Lemoine J, Aoun FB, et al.: Prevalence of the Brugada syndrome in an apparently healthy population. Am J Cardiol; 2000; 86:91-94.</FONT></DIV><DIV><FONT class="Apple-style-span" face="Arial"><BR></FONT></DIV><DIV><FONT class="Apple-style-span" face="Arial">12) Matsuo K, Akahoshi M, Nakashima E, et al. The prevalence, incidence and prognostic value of the Brugada-type electrocardiogram: a population-based study of four decades. J Am Coll Cardiol 2001; 38:765-770.</FONT></DIV><DIV><FONT class="Apple-style-span" face="Arial"><BR></FONT></DIV><DIV><FONT class="Apple-style-span" face="Arial">13) Monroe MH, Littmann L. Two-year case collection of the Brugada syndrome electrocardiogram pattern at a large teaching hospital. Clin Cardiol. 2000; 23:849-851.</FONT></DIV><DIV><FONT class="Apple-style-span" face="Arial"><BR></FONT></DIV><DIV><FONT class="Apple-style-span" face="Arial">14) Juang JM, Huang SK.Brugada syndrome--an under-recognized electrical disease in patients with sudden cardiac death.Cardiology. 2004; 101:157-169.</FONT></DIV><DIV><FONT class="Apple-style-span" face="Arial"><BR></FONT></DIV><DIV><FONT class="Apple-style-span" face="Arial">15) Junttila MJ, Raatikainen MJ, Karjalainen J, Kauma H, Kesaniemi YA, Huikuri HV. Prevalence and prognosis of subjects with Brugada-type ECG pattern in a young and middle-aged Finnish population. Eur Heart J. 2004; 25:874-878.</FONT></DIV><DIV><FONT class="Apple-style-span" face="Arial"><BR></FONT></DIV><DIV><FONT class="Apple-style-span" face="Arial">16) Hermida JS, Jandaud S, Lemoine JL, Rodriguez-Lafrasse C, Delonca J, Bertrand C, Jarry G, Rochette J, Rey JL. Prevalence of drug-induced electrocardiographic pattern of the Brugada syndrome in a healthy population. Am J Cardiol. 2004; 94:230-233.</FONT></DIV><DIV><FONT class="Apple-style-span" face="Arial"><BR></FONT></DIV><DIV><FONT class="Apple-style-span" face="Arial">17) Blangy H, Sadoul N, Coutelour JM, et al. Prevalence of Brugada syndrome among 35,309 inhabitants of Lorraine screened at preventive medicine center Arch Mal Coeur Vaiss. 2005; 98:175-180.</FONT></DIV><DIV><FONT class="Apple-style-span" face="Arial"><BR></FONT></DIV><DIV><FONT class="Apple-style-span" face="Arial">18) Shin SC, Ryu HM, Lee JH, et al. Prevalence of the Brugada-Type ECG Recorded From Higher Intercostal Spaces in Healthy Korean Males. Circ J. 2005; 69:1064-1067.</FONT></DIV><DIV><FONT class="Apple-style-span" face="Arial"><BR></FONT></DIV><DIV><FONT class="Apple-style-span" face="Arial">All the best</FONT></DIV><DIV><FONT class="Apple-style-span" face="Arial"><BR></FONT></DIV><DIV><FONT class="Apple-style-span" face="Arial">Andrés Ricardo Pérez Riera</FONT></DIV><DIV><FONT class="Apple-style-span" face="Arial"><BR></FONT></DIV><DIV><FONT class="Apple-style-span" face="Arial">Chief of Electro-Vectocardiology Sector of the Discipline of Cardiology,</FONT></DIV><DIV><FONT class="Apple-style-span" face="Arial"><BR></FONT></DIV><DIV><FONT class="Apple-style-span" face="Arial">ABC Faculty of Medicine (FMABC), Foundation of ABC (FUABC)</FONT></DIV><DIV><FONT class="Apple-style-span" face="Arial"><BR></FONT></DIV><DIV><FONT class="Apple-style-span" face="Arial">- Santo André - Sao Paulo - Brazil.</FONT></DIV><DIV><FONT class="Apple-style-span" face="Arial"><BR></FONT></DIV><DIV><FONT class="Apple-style-span" face="Arial">Rua Sebastião Afonso 885 - Zip Code: 044417-100- Jardim Miriam S.P Brazil-</FONT></DIV><DIV><FONT class="Apple-style-span" face="Arial"><BR></FONT></DIV><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><DIV><BLOCKQUOTE type="cite"><DIV><FONT class="Apple-style-span" face="Arial"><BR></FONT></DIV> <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><BR class="khtml-block-placeholder"><FONT class="Apple-style-span" face="Arial"></FONT></DIV></BLOCKQUOTE></DIV></BODY></HTML>