Human atrial ion channel and transporter subunit gene-expression remodeling associated with valvular heart disease and atrial fibrillation.
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.


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 beta-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.
Gaborit
Nathalie
N
Institut du Thorax, INSERM U533, Faculté de Médecine, Nantes, France.
Steenman
Marja
M
Lamirault
Guillaume
G
Le Meur
Nolwenn
N
Le Bouter
Sabrina
S
Lande
Gilles
G
Léger
Jean
J
Charpentier
Flavien
F
Christ
Torsten
T
Dobrev
Dobromir
D
Escande
Denis
D
Nattel
Stanley
S
Demolombe
Sophie
S
D001281:Atrial Fibrillation / Q000378:metabolism*; D015153:Blotting, Western; D020746:Calcium Channels, L-Type / Q000235:genetics; D017630:Connexins / Q000235:genetics; D020869:Gene Expression Profiling; D006325:Heart Atria / Q000378:metabolism*; D006349:Heart Valve Diseases / Q000378:metabolism*; D006801:Humans; D007473:Ion Channels / Q000235:genetics*; D026901:Membrane Transport Proteins / Q000235:genetics; D024661:Potassium Channels, Inwardly Rectifying / Q000235:genetics; D021122:Protein Subunits; D020133:Reverse Transcriptase Polymerase Chain Reaction; D051672:Shal Potassium Channels / Q000235:genetics; D000097003:Gap Junction alpha-5 Protein
D020746:Calcium Channels, L-Type; D017630:Connexins; D007473:Ion Channels; D026901:Membrane Transport Proteins; D024661:Potassium Channels, Inwardly Rectifying; D021122:Protein Subunits; D051672:Shal Potassium Channels; D000097003:Gap Junction alpha-5 Protein; C489457:KCNJ2 protein, human; C419385:L-type calcium channel alpha(1C)