[SCD-FORUM] EXPERTS ASK, EXPERTS ANSWER. Dr. Perez Riera

[SCD Symposium]

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).

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)

We think that we must divided Brugada entities in (3):

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);

(2) Sporadic cases (»63%): Brugada syndrome (5)

(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.

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.

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)

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).

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.

The prevalence of cardiac events among male subjects with a Brugada- 
type ECG (81%) was significantly higher than it was for those without  
it.

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).

 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).

In France have shown a prevalence of Brugada pattern of ECG in 1 per  
1,000 normal asymptomatic individuals (11).

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).

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).

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).

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).

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)

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)

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.

References

1)      Napolitano C, Priori S. Brugada syndrome. Orphanet J Rare  
Dis. 2006;135;

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

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]

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;

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.

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.

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.

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


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.

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.

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.

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.

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.

14)   Juang JM, Huang SK.Brugada syndrome--an under-recognized  
electrical disease in patients with sudden cardiac death.Cardiology.  
2004; 101:157-169.

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.

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.

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.

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.

All the best

Andrés Ricardo Pérez Riera

Chief of Electro-Vectocardiology Sector of the Discipline of Cardiology,

ABC Faculty of Medicine (FMABC), Foundation of ABC (FUABC)

- Santo André -  Sao Paulo - Brazil.

Rua Sebastião Afonso  885 - Zip Code: 044417-100- Jardim Miriam  S.P  
Brazil-

--
Dr. Sergio Dubner
President of Scientific Committee

Dr. Edgardo Schapachnik
President of Steering Committee

>
> 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
>
>
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