Copyright © 2003 by the European Society of Cardiology.
Letter to the Editor
The continuing story: The aetiology of Brugada syndrome: functional or structural basis?
a Academic Medical Center, Amsterdam, The Netherlands
b Masonic Medical Research Laboratory, Utica, USA
* Correspondence to: Dr A. A. M. Wilde, Department of Clinical and Experimental Cardiology, Academic Medical Center, PO Box 22700, 1100 DE Amsterdam, The Netherlands. Tel: +31 20 5663265; fax: +31 20 6975458
E-mail address: a.a.wilde{at}amc.uva.nl
In response to our consensus report on Brugada syndrome,1Dr Martini once again draws attention to the controversy as to whether the typical ECG pattern is based on structural or on functional alterations. Dr. Martini has raised this subject repeatedly in letters to the editors of various journals and the issue has been discussed at great length in previous responses.2,3Accordingly, our comments will be brief.
The consensus report was meant to come to a uniform set of diagnostic criteria, which should facilitate future knowledge on this entity, and not to settle its aetiology. Indeed, the functional theory lacked and still lacks direct proof and the causal involvement of SCN5a, also identified in a subset of SUDS victims,4does not exclude the presence of structural alterations in all cases. Indeed, recent evidence has been presented suggesting that SCN5a mutations could lead to degenerative changes in the cardiac conduction system.5However, these changes have not been observed in all patients with right precordial ST-segment elevation, including a patient with meticulous post-mortem investigation, described by the Padua group (see 2 for references). Since wall motion abnormalities and late potentials can have functional explanations,6it cannot be regarded as definite proof for an anatomical substrate.
It is to be expected that the awaited identification of other causal genes will further clarify the aetiology of this intriguing syndrome. One of these is found in the region where the causal gene for ARVD4 resides,7and may turn out to be the same gene. If this proves to be the case, it will serve as an example of how structural alterations could cause the ECG pattern of the Brugada syndrome, as previously demonstrated by Corrado and co-workers.8However, at present it seems fair to conclude that despite the fact that SCN5a mutations might lead to structural changes, right precordial ST-elevation is also observed in patients with no evidence for structural changes whatsoever. As far as the consensus document is concerned: it concluded with ‘... that the proposed criteria are based on currently available data and that it is work in-progress that is awaiting confirmatory molecular, patho-anatomical, and prospective clinical data’. Evidence-based data available to date indicate that structural or morphological defects are associated with a Brugada-like ECG in a small minority of patients. Further delineation and definition of these relationships awaits the results of prospective clinical trials.
References
- Wilde AAM, Antzelevitch C, Borggrefe M et al. Diagnostic criteria for the Brugada Syndrome. A consensus report. Eur Heart J. 2002;23:1648–1654.
[Free Full Text] - Wilde AAM, Remme CA, Derksen R et al. Brugada syndrome (Letter to the editor). Eur Heart J. 2002;23:675–676.
[Free Full Text] - Antzelevitch C. Brugada syndrome: historical perspectives and observations. Eur Heart J. 2002;23:676–678.
[Free Full Text] - Vatta M, Dumaine R, Varghese G et al. Genetic and biophysical basis of sudden unexplained nocturnal death syndrome (SUNDS), a disease allelic to Brugada syndrome. Hum Mol Genet. 2002;11:337–345.
[Abstract/Free Full Text] - Bezzina CR, Rook MB, Groenewegen A et al. Compound heterozygosity for mutations (W156X and R225W) in SCN5A associated with severe cardiac conduction disturbances and degenerative changes in the conduction system. Circ Res. 2003;92:159–168.
[Abstract/Free Full Text] - Antzelevitch C, Brugada P, Brugada J et al. Brugada syndrome: 1992–2002. A historical perspective. J Am Coll Cardiol. 2003;41:1665–1671.
[Abstract/Free Full Text] - Weiss R, Barmada MM, Nguyen T et al. Clinical and molecular heterogeneity in the Brugada Syndrome. A novel gene locus on chromosome 3. Circulation. 2002;105:707–713.
[Abstract/Free Full Text] - Corrado D, Basso C, Buja G et al. Right bundle branch block, right precordial ST-segment elevation, and sudden death in young people. Circulation. 2001;103:710–717.
[Abstract/Free Full Text]
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