title: Contrasting gene expression profiles in two canine models of atrial fibrillation.
abstract: 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 x 24 hours, 1 or 6 weeks) or ventricular (VTP, 240 bpm x 24 hours or 2 weeks) tachypacing. The expression of approximately 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 ( approximately 10, approximately 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.
authors.affiliation: Department of Medicine and Research Center, Montreal Heart Institute and Université de Montréal, Montreal, Quebec, Canada.
authors.forename: Sophie
authors.initials: S
authors.lastname: Cardin
authors.forename: Eric
authors.initials: E
authors.lastname: Libby
authors.forename: Patricia
authors.initials: P
authors.lastname: Pelletier
authors.forename: Sabrina
authors.initials: S
authors.lastname: Le Bouter
authors.forename: Akiko
authors.initials: A
authors.lastname: Shiroshita-Takeshita
authors.forename: Nolwenn
authors.initials: N
authors.lastname: Le Meur
authors.forename: Jean
authors.initials: J
authors.lastname: Léger
authors.forename: Sophie
authors.initials: S
authors.lastname: Demolombe
authors.forename: André
authors.initials: A
authors.lastname: Ponton
authors.forename: Leon
authors.initials: L
authors.lastname: Glass
authors.forename: Stanley
authors.initials: S
authors.lastname: Nattel
mesh_terms: D000818:Animals; D001281:Atrial Fibrillation / Q000150:complications / Q000235:genetics* / Q000378:metabolism; D015153:Blotting, Western; D002304:Cardiac Pacing, Artificial; D002478:Cells, Cultured; D003199:Computer Systems; D004195:Disease Models, Animal; D004285:Dogs; D016326:Extracellular Matrix Proteins / Q000096:biosynthesis / Q000235:genetics; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D006333:Heart Failure / Q000209:etiology / Q000235:genetics*; D008297:Male; D032383:Myocytes, Cardiac / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis; D012333:RNA, Messenger / Q000096:biosynthesis; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013382:Subtraction Technique; D017180:Tachycardia, Ventricular / Q000235:genetics / Q000378:metabolism; D020257:Ventricular Remodeling / Q000235:genetics*
chemical_list: D016326:Extracellular Matrix Proteins; D012333:RNA, Messenger