Europace Advance Access published online on April 18, 2007
Europace, doi:10.1093/europace/eum053
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Homozygous SCN5A mutation in Brugada syndrome with monomorphic ventricular tachycardia and structural heart abnormalities
1 Department of Cardio-Thoracic and Vascular Sciences, University of Padua Medical School, Padua, Italy; 2 Department of Biology, University of Padua Medical School, Padua, Italy; 3 Cardiovascular Unit, S. Martino Hospital, Belluno, Italy; 4 Cardiovascular Unit, Boldrini Hospital, Thiene, Italy
Manuscript submitted 7 December 2006. Accepted after revision 5 March 2007.
* Corresponding author. Tel: +39 049 8762176; fax: +39 049 8762176. E-mail address: andrea.nava{at}unipd.it
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Abstract |
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Aims To describe a patient showing monomorphic ventricular tachycardia, ECG aspect of Brugada syndrome, and structural heart abnormalities due to a homozygous missense mutation in SCN5A.
Methods and results Thirteen subjects (six males, seven females, mean age 46 ± 22 years) belonging to the same family underwent physical examination, basal biochemical marker detection, 12-lead ECG, Holter ECG, signal-averaged ECG, echocardiogram and genetic analysis. The proband underwent a stress test together with left and right ventricular angiography and electrophysiological study. Three subjects (the proband, his mother, and one brother) showed on ECG an ST-segment elevation in the right precordial leads with coved type aspect. Moreover, the proband presented a sustained monomorphic ventricular tachycardia (left bundle branch block aspect with superior axis), whereas all other family members were asymptomatic. Imaging techniques documented right ventricular structural abnormalities only in the proband. Mutation screening in SCN5A gene was performed in the proband and in available family members. The proband carries a novel SCN5A mutation, R814Q, in homozygous, whereas the parents and four siblings were heterozygous carriers of the same mutation.
Conclusion This study provides the first evidence of a homozygous missense mutation in SCN5A associated with atypical ventricular arrhythmias and right structural abnormalities.
Key Words: Brugada syndrome, SCN5A gene, Ventricular tachycardia, Right ventricular abnormalities
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Introduction |
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In 1989, Martini et al.1
described a peculiar ECG pattern characterized by right bundle branch block and ST-segment elevation in patients with localized heart structural abnormalities survived of cardiac arrest. Some years later, Brugada and Brugada2 defined this ECG pattern due to a new distinctive syndrome, called Brugada syndrome (BS) characterized by the high incidence of sudden death in the absence of cardiac pathology.3 In 1998, BS was found to be linked to mutations in SCN5A gene,4 encoding for the alpha-subunit of the cardiac sodium channel gene; about 18–30% of subjects with BS were found to carry a SCN5A gene mutation with autosomal dominant inheritance.3 Thus in the remaining 70–75%, other causes and/or other genes could be involved. In addition, the presence of concealed structural cardiac abnormalities, as part of the phenotype of the BS previously suggested by some authors,5,6 was later confirmed, at least, in a part of the affected patients.7–10
Moreover, mutations of SCN5A gene have been found to be associated also with other arrhythmic disorders (long-QT syndrome and atrioventricular block)11–15 and even with cardiomyopathies.16,17
Patients with BS usually present with polymorphic ventricular tachycardia or ventricular fibrillation. Rarely, a monomorphic ventricular tachycardia has been described.18–25 Genetic test, when performed,21,24,25 showed heterozygous mutation in SCN5A gene.25
We describe here a patient with BS and monomorphic ventricular tachycardia who, different from previously reported studies, showed a SCN5A mutation in homozygous status associated with heart structural abnormalities.
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Clinical data
A family composed of 13 subjects (six males, seven females, mean age 46 ± 22 years) underwent physical examination, basal biochemical marker detection, 12-lead ECG, signal-averaged ECG with time-domain analysis (SAECG), 24-h Holter ECG, echocardiogram, and genetic screening for the SCN5A mutation. The family was studied after the investigation of the proband (25-year-old man) admitted to the hospital due to the onset of a sustained monomorphic ventricular tachycardia and in whom baseline ECG showed ST-segment elevation in V1–V2 (coved type) and right bundle branch block, compatible with BS. The proband underwent an exercise stress test and invasive cardiac evaluation with right ventricular angiography and electrophysiological study.26
,27 The presence of symptoms such as syncope or presyncope, family history of syncopal episodes, and/or sudden death were carefully investigated.
Mutation analysis
Blood samples were obtained after written informed consent. Genomic DNA was isolated from peripheral blood lymphocytes by standard procedures.
Previously published primer pairs were used to amplify all exons of SCN5A gene from genomic DNA.28 PCR amplicons were screened by direct sequencing, using the Big Dye Terminator chemistry and analysed on an ABI Prism 3730XL DNA sequencer (Applied Biosystems, Foster city, CA). CHROMAS software (release 1.5; Technelsium) and the LASERGENE software package (DNASTAR) were used to edit and assemble sequences. A control group of 200 healthy and unrelated subjects (400 alleles) from the Italian population was used to exclude that the detected mutation could be a common DNA polymorphism. Mutation screening of genes known to be more frequently involved in arrhythmogenic right ventricular cardiomyopathy [desmoplakin (DSP), plakophilin-2 (PKP2), and desmoglein-2 (DSG2)] was performed as previously described.29–31
Haplotype analysis
The Genethon microsatellite markers D3S1260 and D3S3521 and the additional markers EF077480
[GenBank]
, EF077481
[GenBank]
, EF077482
[GenBank]
, and EF077483
[GenBank]
were PCR-amplified using forward primers labelled with different florochromes, and migrated on an ABI3730XL automated sequencer. Results were analysed by the Genotyper software (Applied Biosystems).
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Proband
The proband (III,3 Figure 1A) was a 25-year-old man admitted to the hospital due to a sustained monomorphic ventricular tachycardia with left bundle branch block morphology and superior axis (Figure 2) terminated with DC shock. Electrocardiogram showed sinus rhythm, prolonged PQ and QRS intervals (right bundle branch block), and ST-segment elevation in V1–V2 close to 2 mm, coved type (Figure 3). The patient refused the Flecainide test. Biochemical markers and chest X-ray were under normal limits.
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SAECG demonstrated the presence of late potentials at 40 Hz filter-setting (Figure 4) and bicycle stress test performed at submaximal exercise (85% of age-predicted maximum heart rate) did not show significant ventricular arrhythmias, whereas it induced an increasing of ST-segment elevation (Figure 5).
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Two-dimensional echocardiogram demontrated normal left ventricular dimensions and kinetics with the absence of a valve disease. The right ventricle was mildly enlarged (end-diastolic volume: 67 mL/m2) with localized kinetic alterations on the posterior subtricuspid wall (akinetic bulging) and at the apex (mild dilatation and akinesia). These findings were confirmed by angiographic study, mainly with right anterior oblique and left lateral views (Figure 6A and B).
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Electrophysiological investigation proved an involvement of the main conduction system with a prolonged HV interval (65 ms).32
The triple extrastimuli technique performed in the infundibular and apical regions of the right ventricle did not induce sustained ventricular arrhythmias. The patient refused the implantation of a cardioverter defibrillator; therefore he started a therapy with a beta-blocker (Atenolol 100 mg daily). Continuous ECG monitoring performed during antiarrhythmic therapy documented rare and isolated premature ventricular beats, while 24-h ambulatory ECG showed sinus rhythm with sporadic polymorphic ventricular beats. The patient was discharged with beta-blocker therapy and a 6-month clinical and instrumental follow-up was planned. During the follow-up (3 years), the patient remained asymptomatic with sporadic premature ventricular beats.
Mutation screening was performed on genomic DNA in the coding sequences and splicing sites of SCN5A, DSP, PKP2, and DSG2 genes by direct sequencing and DHPLC analysis. No pathogenic mutations have been detected in DSP, PKP2, and DSG2 genes. Sequence analysis of exon 16 of SCN5A gene revealed a G-to-A base substitution in homozygous at nucleotide 2441, leading to an amino acid substitution of an arginine by a glutamine at codon 814 (R814Q) (Figure 1B). The R814Q mutation lies on the fourth transmembrane segment of domain II (DIIS4), the electrically charged segment that probably is the voltage-sensing region of the domain, characterized by a series of positively charged amino acids at every third position.33 The detected nucleotide change was absent in 200 control individuals (400 chromosomes).
Family members
Family history reported an unexplained juvenile death (a female cousin of subject II,6 who died suddenly at the age of 20). No clinical or autoptic data were available.
All family members were asymptomatic with normal physical examination and biochemical markers.
The proband's mother (II,6 Figure 1A) and one brother (III,2 Figure 1A) showed ECG features characterized by ST-segment elevation in right precordial leads and right bundle branch block suggestive for BS (Figure 7A and B, respectively). The mother's ECG features were enhanced with Flecainide test. SAECG demonstrated the presence of late potentials at 40 Hz filter setting only in the brother (III, 2) (Figure 7C).
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Subjects II, 3 and II, 4 (65 and 72 years old, respectively) were found to be affected by a coronary heart disease with localized left ventricular kinetic alterations in the site of previous myocardial infarction.
The remaining family members had normal baseline ECG, SAECG, ambulatory ECG, and 2D-echocardiogram.
Family members (II,1; II,2; II,3), the parents and the siblings (III,1; III,2; III,4; III,5) were heterozygous for the same SCN5A mutation (R814Q) previously found in the proband. Then, we looked for a founder effect by performing haplotype analysis on chromosome 3 containing the SCN5A locus with six microsatellite markers. The same haplotype was transmitted by the parents to the proband, which was homozygous for all the microsatellite markers (Figure 1A). As the intragenic haplotype is the same, this result suggests a founder effect.
The conduction values at baseline ECG of heterozygous carriers (PQ: 0.20 ± 0.02, QRS: 0.12 ± 0.01 ms) were compared with those of non-carriers (PQ: 0.16 ± 0.01, QRS: 0.10 ± 0.01), and the P-values were 0.08 and 0.05, respectively.
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Heterozygous mutations of SCN5A gene are involved in several cardiac diseases, such as BS, LQT3, isolated cardiac conduction defects, and dilated cardiomyopathy.34
In the present study, we describe a novel SCN5A missense mutation, R814Q, in the S4 transmembrane segment, identified at the homozygous state in a symptomatic male with sustained monomorphic ventricular tachycardia.
The mutation reported in the present study involves a residue located within a highly conserved domain and consists of a glutamine substitution for the third basic residue in S4 of the second domain (D2), counting from the extracellular (amino) end of S4. The highly charged S4 segments in each domain are postulated voltage sensors for gating. Chen et al.35 made a series of charge-neutralizing or reversing substitutions for basic residues in the S4 segments of each domain of human SCN5A and examined their consequences on the gating of the channel in Xenopus oocytes. One of the examined substitutions was R814Q and its effect was a reduction of the net positive charge of the D2 domain and a significant decrease in the voltage dependence of the activation. Moreover, R814Q mutant gave alteration in the slopes and mid-points of steady-state inactivation. These results indicate effects on both activation and inactivation of Na+ channel potentially leading to reduced sodium channel current. The differences in phenotype among family members seem to be in favour of a more important effect on the gating of the channel in the homozygote status compared with the heterozygote. The proband carrying the mutation in homozygosis showed the ECG alteration typical of the BS, a sustained monomorphic ventricular tachycardia with left bundle branch block morphology and a cardiac pathology of the right ventricle. However, no mutations in known ARVC genes where identified. The other family members carrying the mutation in heterozygosis were asymptomatic and did not show any structural cardiac alterations. The analysis of conduction parameters at baseline ECG showed minor abnormalities (prolonged PQ and QRS intervals) in heterozygote carriers compared with non-carriers, due to reduction of sodium current for the heterozygous status. Nevertheless, within the carriers, only two individuals showed ECG abnormalities characterized by ST-segment elevation with coved type aspect in right precordial leads.
The proband of the family presented a sustained monomorphic ventricular tachycardia with left bundle branch block morphology, that could be in keeping with the re-entrant circuit due to the presence of an organic substrate characterized by the contiguity of areas of myocardium with normal conduction and areas with low conduction. It is noteworthy that this arrhythmia was different from the typical polymorphic ventricular arrhythmias usually detected in BS patients. Moreover, exercise stress test provoked an increase of the ST-segment. The response to exercise of the ST elevation in the BS is variable, even if usually the exercise decreases the amplitude of ST-segment.36 The increase of the ST-segment during exercise has been already described.37 Bezzina et al.12 reported an inherited C-terminal SCN5A mutation (1795insD) causing QT-interval prolongation at slow heart rates and distinctive ST-segment elevation with exercise in affected individuals. Veldkamp et al.38 showed that the mutation altered both the fast and slow components of inactivation. In particular, it induces depolarized Na+ channels to undergo excessive slow inactivation during the sustained depolarization period intrinsic to the cardiac action potential. This abnormal behaviour reduces Na+ channel availability primarly at rapid heart rates and underlies the pronounced ST-segment elevation seen in carriers during exercise.
It is noteworthy that the mutation in the same amino acid (R814) was reported by Olson et al.,39 leading to dilated cardiomyopathy and atrial fibrillation. This was a de novo mutation (R814W) identified in a young woman with dilated cardiomyopathy, atrial flutter, and short runs of sustained ventricular tachycardia. Cardiac biopsy revealed mild-to-moderate myocellular hypertrophy and mild interstitial fibrosis.
Up to now, only one homozygous SCN5A gene mutation (V1777M) has been described, linked with long-QT syndrome and functional two-to-one atrioventricular block (2:1 A-V block).40 The proband presented an homozygote status, whereas the parents and two siblings were heterozygote carriers. Functional studies demonstrated that residual sodium current was more important in the homozygote model compared with the heterozygote model. Long-QT with 2:1 A-V block conduction has been reported often in infants or young children with a major QTc prolongation, but without any positive family history.
Bezzina et al.41 described a case with two sodium channel abnormalities (compound heterozygosity), also leading to a severe cardiac phenotype. In particular, conduction was affected and structural abnormalities have been demonstrated.
The mechanisms by which similar or identical SCN5A mutations lead to variable expression of heart disease remain unknown. Indeed, it has been shown that the same mutation can cause either isolated cardiac conduction defect or BS within the same family.15
As far as the therapeutic strategy is concerned, in our study, asymptomatic family members with diagnostic ECG did not use any drug. On the contrary, in the proband, we suggested an implantable cardioverter defibrillator that was refused by the patient. Thus, he started a beta-blocker therapy that seems to be effective so far, even if the follow-up is still too short to evaluate its efficacy.
In conclusion, this study suggests that homozygous mutations in SCN5A gene may be associated with an atypical BS phenotype showing monomorphic ventricular tachycardia and structural heart abnormalities.
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This study was supported by TELETHON, Rome; VENETO REGION, Venice; MURST, Rome; Fondazione Cassa di Risparmio, Padova e Rovigo, Italy.
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[1] Martini B, Nava A, Thiene G, Buja GF, Canciani B, Scognamiglio R, et al. Ventricular fibrillation without apparent heart disease: description of six cases. Am Heart J 1989; 118: 1203–9.[CrossRef][Web of Science][Medline]
[2] Brugada P and Brugada J. Right bundle branch block, persistent ST segment elevation and sudden death: a distinct clinical and electrocardiographic syndrome. A multicenter report. J Am Coll Cardiol 1992; 20: 1391–6.[Abstract]
[3] Antzelevitch C, Brugada P, Borggrefe M, Brugada J, Brugada R, Corrado D, et al. Brugada Syndrome. Report of the Second Consensus Conference. Circulation 2005; 111: 659–70.
[4] Chen Q, Kirsch GE, Zhang D, Brugada R, Brugada J, Brugada P, et al. Genetic basis and molecular mechanisms for idiopathic ventricular fibrillation. Nature 1998; 392: 293–6.[CrossRef][Medline]
[5] Martini B, Corrado D, Nava A, Thiene G. Syndrome of right bundle branch block, ST segment elevation and sudden death. Evidence of an organic substrate. 1997; In Nava A, Rossi L, Thiene G (Eds.). Amsterdam Elsevier 438–53.
[6] Martini B and Nava A. 1988–2003. Fifteen years after the first Italian description by Nava-Martini-Thiene and colleagues of a new sindrome (different from the Brugada syndrome?) in the Giornale Italiano di Cardiologia: do we really know everything on this entity? Ital Heart J 2004; 5: 53–60.[Medline]
[7] Takagi M, Aihara N, Kuribayashi S, Taguchi A, Shimizu W, Kurita T, et al. Localized right ventricular morphological abnormalities detected by electron-beam computed tomography represent arrhythmogenic substrates in patients with the Brugada syndrome. Eur Heart J 2001; 22: 1032–41.
[8] Papavassiliu T, Wolpert C, Flüchter S, Schimpf R, Neff W, Haase KK, et al. Magnetic resonance imaging findings in patients with Brugada syndrome. J Cardiovasc Electrophysiol 2004; 15: 1133–38.[CrossRef][Web of Science][Medline]
[9] Coronel R, Casini S, Koopmann TT, Wilms-Schopman FJG, Verkerk AO, de Groot JR, et al. Right ventricular fibrosis and condution delay in a patient with clinical signs of Brugada syndrome. A combined electrophysiological, genetic, histopathologic, and computational study. Circulation 2005; 112: 2769–77.
[10] Frustaci A, Priori SG, Pieroni M, Chimenti C, Napoletano C, Rivolta I, et al. Cardiac Histological substrate in patients with clinical phenotype of Brugada syndrome. Circulation 2005; 112: 3680–87.
[11] Wang DW, Viswanathan PC, Balser JR, George AL, Benson DW. Clinical, genetic and biophysical characterization of SCN5A mutations associated with atrioventricular conduction block. Circulation 2002; 105: 341–6.
[12] Bezzina C, Weldkamp MW, van den Berg M, Postma AV, Rook MB, Viersma J-W, et al. A single Na+ channel mutation causing both long-QT and Brugada syndromes. Circ Res 1999; 85: 1206–13.
[13] Splawski I, Timothy K, Tateyama M, Clancy CE, Malhotra A, Beggs AH, et al. Variant of SCN5A sodium channel implicated in risk of cardiac arrhythmia. Science 2002; 297: 1333–6.
[14] Priori SG, Napolitano C, Schwartz PJ, Bloise R, Clotti R, Ronchetti E. The elusive link between LQT3 and Brugada syndrome. The role of flecainide challenge. Circulation 2000; 102: 945–7.
[15] Kyndt F, Probst V, Potet F, Demolombe S, Chevallier JC, Baro I, et al. Novel SCN5A mutation leading either to isolated cardiac conduction defect or Brugada syndrome in a large French family. Circulation 2001; 104: 3081–6.
[16] McNair WP, Ku L, Taylor MRG, Fain PR, Dao D, Wolfel E, et al. SCN5A mutation associated with dilated cardiomyopathy, conduction disorder, and arrhythmia. Circulation 2004; 110: 2163–67.
[17] Kim H, Cho Y, Park Y, Lee H, Kang H, Nah D-Y, et al. Underlying cardiomyopathy in patients with ST-segment elevation in the right precordial leads. Circ J 2006; 70: 719–25.[CrossRef][Web of Science][Medline]
[18] Shimada M, Miyazaki T, Miyoshi S, Soejima K, Hori S, Mitamura H, et al. Sustained monomorphic ventricular tachicardia in a patient with Brugada syndrome. Jpn Circ J 1996; 60: 364–70.[CrossRef][Medline]
[19] Pinar Bermudez E, Garcia-Alberola A, Martinez Sanchez J, Sanchez Munoz JJ, Valdes Chiavarri M. Spontaneous sustained monomorphic ventricular tachycardia after administration of ajmaline in a patient with Brugada syndrome. PACE 2000; 23: 407–9.[Medline]
[20] Sastry BSK, Narasimhan C, Soma Raju B. Brugada syndrome with monomorphic ventricular tachycardia in a one-year-old child. Indian Heart J 2001; 53: 203–5.[Medline]
[21] Boersma LVA, Jaarsma W, Jessurun ER, Van Hemel NH, Wever EF. Brugada syndrome: a case report of monomorphic ventricular tachycardia. PACE 2001; 24: 112–5.[Medline]
[22] Ogawa M, Kumagai K, Saku K. Spontaneous right ventricular outflow tract tachycardia in a patient with Brugada syndrome. J Cardiovasc Electrophysiol 2001; 12: 838–40.[CrossRef][Web of Science][Medline]
[23] Dinckal MH, Davutoglu V, Akdemir I, Soydinc S, Kirilmaz A, Aksoy M. Incessant monomorphic ventricular tachicardia during febbrile illness in a patient with Brugada syndrome: fatal electrical storm. Europace 2003; 5: 257–61.
[24] Mok N-S and Chan N-Y. Brugada syndrome presenting with sustained monomorphic ventricular tachycardia. Int J Cardiol 2004; 97: 307–09.[CrossRef][Web of Science][Medline]
[25] Probst V, Evain S, Gournay V, Marie A, Schott JJ, Boisseau P, et al. Monomorphic ventricular tachycardia due to Brugada syndrome successfully treated by hydroquinidine therapy in a 3-year-old child. J Cardiovasc Electrophysiol 2006; 17: 97–100.[CrossRef][Web of Science][Medline]
[26] Daliento L, Rizzoli G, Thiene G, Nava A, Rinuncini M, Chioin R, et al. Diagnostic accuracy of right ventriculography in arrhythmogenic right ventricular cardiomyopathy. Am J Cardiol 1990; 66: 741–5.[CrossRef][Web of Science][Medline]
[27] Wilde AAM, Antzelevitch C, Borggrefe M, Brugada J, Brugada R, Brugada P, et al. Proposed diagnostic criteria for the Brugada syndrome. Consensus Report. Circulation 2002; 106: 2514–19.
[28] Wang Q, Shen J, Splawski I, Atkinson D, Li Z, Robinson JL, et al. SCN5A mutations associated with an inherited cardiac arrhythmia, long QT syndrome. Cell 1995; 80: 805–11.[CrossRef][Web of Science][Medline]
[29] Rampazzo A, Nava A, Malacrida S, Beffagna G, Bauce B, Rossi V, et al. Mutation in human desmoplakin domain binding to plakoglobin causes a dominant form of arrhythmogenic right ventricular cardiomyopathy. Am J Hum Genet 2002; 71: 1200–6.[CrossRef][Web of Science][Medline]
[30] Gerull B, Heuser A, Wichter T, Paul M, Basson CT, McDermott DA, et al. Mutations in the desmosomal protein plakophilin-2 are common in arrhythmogenic right ventricular cardiomyopathy. Nat Genet 2004; 36: 1162–4.[CrossRef][Web of Science][Medline]
[31] Pilichou K, Nava A, Basso C, Beffagna G, Bauce B, Lorenzon A, et al. Mutations in desmoglein-2 gene are associated with arrhythmogenic right ventricular cardiomyopathy. Circulation 2006; 113: 1171–9.
[32] Kupersmith J, Krongrad E, Waldo A. Conduction intervals and conduction velocity in the human cardiac conduction system. Studies during open-heart surgery. Circulation 1973; 47: 776–85.
[33] Gellens ME, George AL Jr, Chen LQ, Chahine M, Horn R, Barchi RL, et al. Primary structure and functional expression of the human cardiac tetrodotoxin-insensitive voltage-dependent sodium channel. Proc Natl Acad Sci USA 1992; 89: 554–8.
[34] Bezzina C, Rook M, Wilde A. Cardiac sodium channel and inherited arrhythmia syndromes. Cardiovasc Res 2001; 49: 257–71.
[35] Chen LQ, Santarelli V, Horn R, Kallen RG. A unique role for the S4 segment of domain 4 in the inactivation sodium channels. J Gen Physiol 1996; 108: 549–56.
[36] Francisa J and Antzelevitch C. Brugada syndrome. Int J Cardiol 2005; 101: 173–8.[CrossRef][Web of Science][Medline]
[37] Furuhashi M, Uno K, Tsuchihashi K, Nagahara D, Hyakukoku M, Ohtomo T, et al. Prevalence of asymptomatic ST segment elevation in right precordial leads with right bundle branch block (Brugada-type ST shift) among the general Japanese population. Heart 2001; 86: 161–6.
[38] Veldkamp MW, Viswanathan PC, Bezzina C, Baartscheer A, Wilde AA, Balser JR. Two distinct congenital arrhythmias evoked by a multidysfunctional Na(+) channel. Circ Res 2000; 86: e91–7.
[39] Olson TM, Michels VV, Ballew JD, Reyna SP, Karst ML, Herron KJ, et al. Sodium channel mutations and susceptibility to heart failure and atrial fibrillation. JAMA 2005; 293: 447–54.
[40] Lupoglazoff JM, Cheav T, Baroudi G, Berthet M, Denjoy I, Cauchemez B, et al. Homozygous SCN5A mutation in long-QT syndrome with functional two-to-one atrioventricular block. Circ Res 2001; 89: e16–21.
[41] Bezzina CR, Rook MB, Groenewegen WA, Herfst LJ, van der Wal AC, Lam J, et al. Compound heterozygosity for mutations (W156X and R225W) in SCN5Aassociated with severe cardiac conduction disturbances and degenerative changes in the conduction system. Circ Res 2003; 92: 159–68.
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