Marked differences between atrial and ventricular gene-expression remodeling in dogs with experimental heart failure.
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 (>21,700 probe-sets). LA showed dramatic gene-expression changes, with 4785 transcripts significantly-altered (Q<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. approximately 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<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.
Cardin
Sophie
S
Research Center and Department of Medicine, Montreal Heart Institute and Université de Montréal, Montreal, Quebec, Canada.
Pelletier
Patricia
P
Libby
Eric
E
Le Bouter
Sabrina
S
Xiao
Ling
L
Kääb
Stefan
S
Demolombe
Sophie
S
Glass
Leon
L
Nattel
Stanley
S
D000818:Animals; D016923:Cell Death; D004285:Dogs; D005260:Female; D005355:Fibrosis; D005786:Gene Expression Regulation; D006325:Heart Atria / Q000378:metabolism / Q000473:pathology; D006333:Heart Failure / Q000378:metabolism* / Q000473:pathology; D006352:Heart Ventricles / Q000378:metabolism / Q000473:pathology; D008297:Male; D009124:Muscle Proteins / Q000096:biosynthesis*; D009206:Myocardium / Q000378:metabolism* / Q000473:pathology
D009124:Muscle Proteins