Contrasting gene expression profiles in two canine models of atrial fibrillation.
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.
Cardin
Sophie
S
Department of Medicine and Research Center, Montreal Heart Institute and Université de Montréal, Montreal, Quebec, Canada.
Libby
Eric
E
Pelletier
Patricia
P
Le Bouter
Sabrina
S
Shiroshita-Takeshita
Akiko
A
Le Meur
Nolwenn
N
Léger
Jean
J
Demolombe
Sophie
S
Ponton
André
A
Glass
Leon
L
Nattel
Stanley
S
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*
D016326:Extracellular Matrix Proteins; D012333:RNA, Messenger