Original article Marked differences between atrial and ventricular gene-expression remodeling in dogs with experimental heart failure Sophie Cardin a,c,1 , Patricia Pelletier a,b,1 , Eric Libby d , Sabrina Le Bouter a , Ling Xiao c , Stefan Kääb e , Sophie Demolombe f,g,h , Leon Glass d , Stanley Nattel a,b,c, ⁎ a Research Center and Department of Medicine, Montreal Heart Institute and Université de Montréal, Canada b Department of Pharmacology, Université de Montréal, Canada c Department of Pharmacology, McGill University, Montreal, Canada d Department of Physiology, McGill University, Montreal, Canada e Medical Hospital I, University of Munich, Germany f INSERM, UMR915, l'Institut du Thorax, France g CNRS, ERL3147, France h Université de Nantes, Nantes, F-44000, France abstract article info Article history: Received 26 June 2008 Received in revised form 12 August 2008 Accepted 12 August 2008 Available online 30 August 2008 Keywords: Heart failure Arrhythmias Remodeling Gene-expression Metabolism Fibrosis Congestive heart failure (CHF) causes arrhythmogenic, structural and contractile remodeling, with important atrial–ventricular differences: atria show faster and greater inflammation, cell-death and fibrosis. The present study assessed time-dependent left atrial (LA) and ventricular (LV) gene-expression changes in CHF. Groups of dogs were submitted to ventricular tachypacing (VTP, 240 bpm) for 24 h or 2 weeks, and compared to sham- instrumented animals. RNA from isolated LA and LV cardiomyocytes of each dog was analyzed by canine- specific microarrays (N 21,700 probe-sets). LA showed dramatic gene-expression changes, with 4785 transcripts significantly-altered (Q b 5) at 24-hour and 6284 at 2-week VTP. LV gene-changes were more limited, with 52 significantly-altered at 24-hour and 130 at 2-week VTP. Particularly marked differences were seen in ECM genes, with 153 changed in LA (e.g. ~65-fold increase in collagen-1) at 2-week VTP versus 2 in LV; DNA/RNA genes (LA =358, LV=7); protein biosynthesis (LA=327, LV =14); membrane transport (LA =230, LV = 8); cell structure and mobility (LA= 159, LV=6) and coagulation/inflammation (LA=147, LV= 1). Noteworthy changes in LV were genes involved in metabolism (35 genes; creatine-kinase B increased 8-fold at 2-week VTP) and Ca 2+ -signalling. LA versus LV differential gene-expression decreased over time: 1567 genes were differentially expressed (Q b 1) at baseline, 1499 at 24-hour and 897 at 2-week VTP. Pathway analysis revealed particularly-important changes in LA for mitogen-activated protein-kinase, apoptotic, and ubiquitin/ proteasome systems, and LV for Krebs cycle and electron-transfer complex I/II genes. VTP-induced CHF causes dramatically more gene-expression changes in LA than LV, dynamically altering the LA–LV differential gene- expression pattern. These results are relevant to understanding chamber-specific remodeling in CHF. © 2008 Elsevier Inc. All rights reserved. 1. Introduction Congestive heart failure (CHF) is a leading cause of hospital admis- sion and presently affects over 5 million Americans [1]. It is also one of the most important causes of atrial fibrillation (AF), the most common sustained cardiac arrhythmia [2]. Both pathologies are associated with important structural, electrophysiological, biochemical and molecular remodeling [3]. There are significant atrial–ventricular gene-expres- sion differences [4], as well as differences between atrial and ven- tricular remodeling [5]. Ventricular gene-expression changes have been studied in dogs with terminal CHF caused by ventricular tachypacing (VTP) [6]. The VTP model of CHF produces a substrate for AF that reproduces many features observed in patients [7]. As in CHF patients, ventricular- tachypaced CHF dogs show time-dependent development of fibrosis, atrial and ventricular dilatation, and impaired ventricular and atrial function, as well as time-dependent electrophysiological remodeling manifested as ion-channel alterations and AF promotion [5,8–11]. In view of the different phenotypic features of atrial versus ventricular remodeling with the development of VTP-induced CHF [5], it is rea- sonable to consider the possibility that there may be chamber-specific patterns of gene-expression alterations. Furthermore, Barth et al. have shown that the atrial gene-expression pattern is changed in AF patients, becoming more similar to the ventricular gene-expression pattern [12]. Whether similar changes in chamber-specific gene- Journal of Molecular and Cellular Cardiology 45 (2008) 821–831 * Corresponding author. Montreal Heart Institute, 5000 Belanger St. E., Montreal, Quebec, Canada, H1T 1C8. Tel.: +1514 376 3330; fax: +1514 376 1355. E-mail address: stanley.nattel@icm-mhi.org (S. Nattel). 1 S.C. and P.P. contributed equally to this study and share first authorship. 0022-2828/$ – see front matter © 2008 Elsevier Inc. All rights reserved. doi:10.1016/j.yjmcc.2008.08.007 Contents lists available at ScienceDirect Journal of Molecular and Cellular Cardiology journal homepage: www.elsevier.com/locate/yjmcc