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(Circulation Research. 2007;100:425.)
© 2007 American Heart Association, Inc.

Integrative Physiology

Contrasting Gene Expression Profiles in Two Canine Models of Atrial Fibrillation

Sophie Cardin^*, Eric Libby^*, Patricia Pelletier, Sabrina Le Bouter, Akiko Shiroshita-Takeshita, Nolwenn Le Meur, Jean Léger, Sophie Demolombe, André Ponton, Leon Glass, Stanley Nattel

From the From Department of Medicine and Research Center (S.C., P.P., S.L.B., A.S.-T., S.N.), Montreal Heart Institute and Université de Montréal, Departments of Pharmacology (S.C., S.N.) and Physiology (E.L., L.G.), McGill University, Montreal, McGill University and Genome Quebec Innovation Centre (A.P.) and INSERM U533-Institut du Thorax (N.L.M., J.L., S.D.), Nantes, France.

Correspondence to Stanley Nattel, Montreal Heart Institute, 5000 Belanger St. E., Montreal, Quebec, Canada, H1T 1C8. E-mail stanley.nattel{at}icm-mhi.org

Gene-expression changes in atrial fibrillation patients reflect both underlying heart-disease substrates and changes because of atrial fibrillation-induced atrial-tachycardia remodeling. These are difficult to separate in clinical investigations. This study assessed time-dependent mRNA expression-changes in canine models of atrial-tachycardia remodeling and congestive heart failure. Five experimental groups (5 dogs/group) were submitted to atrial (ATP, 400 bpm x24 hours, 1 or 6 weeks) or ventricular (VTP, 240 bpm x24 hours or 2 weeks) tachypacing. The expression of 21,700 transcripts was analyzed by microarray in isolated left-atrial cardiomyocytes and (for 18 genes) by real-time RT-PCR. Protein-expression changes were assessed by Western blot. In VTP, a large number of significant mRNA-expression changes occurred after both 24 hours (2209) and 2 weeks (2720). In ATP, fewer changes occurred at 24 hours (242) and fewer still (87) at 1 week, with no statistically-significant alterations at 6 weeks. Expression changes in VTP varied over time in complex ways. Extracellular matrix-related transcripts were strongly upregulated by VTP consistent with its pathophysiology, with 8 collagen-genes upregulated >10-fold, fibrillin-1 8-fold and MMP2 4.5-fold at 2 weeks (time of fibrosis) but unchanged at 24 hours. Other extracellular matrix genes (eg, fibronectin, lysine oxidase-like 2) increased at both time-points (10, 5-fold respectively). In ATP, mRNA-changes almost exclusively represented downregulation and were quantitatively smaller. This study shows that VTP-induced congestive heart failure and ATP produce qualitatively different temporally-evolving patterns of gene-expression change, and that specific transcriptomal responses associated with atrial fibrillation versus underlying heart disease substrates must be considered in assessing gene-expression changes in man.

Key Words: arrhythmia • remodeling • genomic

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