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European Heart Journal Advance Access published online on November 23, 2008
European Heart Journal, doi:10.1093/eurheartj/ehn520
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Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2008. For permissions please email: journals.permissions@oxfordjournals.org

Transcriptional profiling of ion channel genes in Brugada syndrome and other right ventricular arrhythmogenic diseases

Nathalie Gaborit1,2,3,{dagger}, Thomas Wichter4,5,{dagger}, Andras Varro6,7, Viktoria Szuts7, Guillaume Lamirault1,2, Lars Eckardt4, Matthias Paul4, Günter Breithardt4, Eric Schulze-Bahr4, Denis Escande1,2,3, Stanley Nattel8 and Sophie Demolombe1,2,3,*

1 INSERM, UMR915, l'institut du thorax, Nantes F-44000, France
2 CNRS, ERL3147, Nantes F-44000, France
3 Université de Nantes, Nantes F-44000, France
4 Department of Cardiology and Angiology, Hospital of the University of Münster and Leibniz Institute for Arteriosclerosis Research (LIFA), Münster, Germany
5 Department of Internal Medicine and Cardiology, Marienhospital Osnabrück, Osnabrück, Germany
6 Department of Pharmacology and Pharmacotherapy, University of Szeged, Szeged, Hungary
7 Division for Cardiovascular Pharmacology, Hungarian Academy of Sciences, Szeged, Hungary
8 Department of Medicine and Research Center, Montreal Heart Institute and Université de Montréal, Montréal, Quebec, Canada

Received 3 April 2008; revised 30 September 2008; accepted 23 October 2008.

* Corresponding author: INSERM UMR915, 1, rue G. Veil, 44035 Nantes cedex, France. Tel: +33 240 41 11 11, Fax: +33 240 41 29 50, Email: sophie.demolombe{at}nantes.inserm.fr

Aims: Brugada syndrome is an inherited sudden-death arrhythmia syndrome. Na+-current dysfunction is central, but mutations in the SCN5A gene (encoding the cardiac Na+-channel Nav1.5) are present in only 20% of probands. This study addressed the possibility that Brugada patients display specific expression patterns for ion-channels regulating cardiac conduction, excitability, and repolarization.

Methods and results: Transcriptional profiling was performed on right-ventricular endomyocardial biopsies from 10 unrelated Brugada probands, 11 non-diseased organ-donors, seven heart-transplant recipients, 10 with arrhythmogenic right-ventricular cardiomyopathy, and nine with idiopathic right-ventricular outflow-tract tachycardia. Brugada patients showed distinct clustering differences vs. the two control and two other ventricular-tachyarrhythmia groups, including 14 of 77 genes encoding important ion-channel/ion-transporter subunits. Nav1.5 and K+-channels Kv4.3 and Kir3.4 were more weakly expressed, whereas the Na+-channel Nav2.1 and the K+-channel TWIK1 were more strongly expressed, in Brugada syndrome. Differences were also seen in Ca2+-homeostasis transcripts, including stronger expression of RYR2 and NCX1. The molecular profile of Brugada patients with SCN5A mutations did not differ from Brugada patients without SCN5A mutations.

Conclusion: Brugada patients exhibit a common ion-channel molecular expression signature, irrespective of the culprit gene. This finding has potentially important implications for our understanding of the pathophysiology of Brugada syndrome, with possible therapeutic and diagnostic consequences.

Key Words: Gene expression • Humans • Ion channels • Ventricular tachycardia

{dagger} These authors contributed equally.


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