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(Circulation. 2005;112:471-481.)
© 2005 American Heart Association, Inc.

Arrhythmia/Electrophysiology

Human Atrial Ion Channel and Transporter Subunit Gene-Expression Remodeling Associated With Valvular Heart Disease and Atrial Fibrillation

Nathalie Gaborit, MSc^*; Marja Steenman, PhD^*; Guillaume Lamirault, MD; Nolwenn Le Meur, MSc; Sabrina Le Bouter, PhD; Gilles Lande, MD; Jean Léger, PhD; Flavien Charpentier, PhD; Torsten Christ, MD; Dobromir Dobrev, MD; Denis Escande, MD, PhD; Stanley Nattel, MD; Sophie Demolombe, PhD

From l’Institut du Thorax, INSERM U533, Faculté de Médecine, Nantes, France (N.G., M.S., G. Lamirault, N.L.M., S.L.B., G. Lande, J.L., F.C., D.E., S.D.); the Montreal Heart Institute and University of Montreal, Montreal, Canada (S.N.); and Institut für Pharmakologie und Toxikologie, Dresden, Germany (T.C., D.D.).

Correspondence to Sophie Demolombe, PhD, INSERM U533, Faculté de Médecine, 1 rue G. Veil, 44035 Nantes cedex, France. E-mail sophie.demolombe{at}nantes.inserm.fr

Received September 14, 2004; revision received April 7, 2005; accepted April 14, 2005.

Background— Valvular heart disease (VHD), which often leads to atrial fibrillation (AF), and AF both cause ion-channel remodeling. We evaluated the ion-channel gene expression profile of VHD patients, in permanent AF (AF-VHD) or in sinus rhythm (SR-VHD), in comparison with patients without AF or VHD, respectively.

Methods and Results— We used microarrays containing probes for human ion-channel and Ca²⁺-regulator genes to quantify mRNA expression in atrial tissues from 7 SR-VHD patients and 11 AF-VHD patients relative to 11 control patients in SR without structural heart disease (SR-CAD). From the data set, we selected for detailed analysis 59 transcripts expressed in the human heart. SR-VHD patients differentially expressed 24/59 ion-channel and Ca²⁺-regulator transcripts. There was significant overlap between VHD groups, with 66% of genes altered in SR-VHD patients being similarly modified in AF-VHD. Statistical differences between the AF- and SR-VHD groups identified the specific molecular portrait of AF, which involved 12 genes that were further confirmed by real-time reverse transcription–polymerase chain reaction. For example, phospholamban, the ß-subunit MinK (KCNE1) and MIRP2 (KCNE3), and the 2-pore potassium channel TWIK-1 were upregulated in AF-VHD compared with SR-VHD, whereas the T-type calcium-channel Cav3.1 and the transient-outward potassium channel Kv4.3 were downregulated. Two-way hierarchical clustering separated SR-VHD from AF-VHD patients. AF-related changes in L-type Ca²⁺-current and inward-rectifier current were confirmed at protein and functional levels. Finally, for 13 selected genes, SR restoration reversed ion-channel remodeling.

Conclusions— VHD extensively remodels cardiac ion-channel and transporter expression, and AF alters ion-channel expression in VHD patients.

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