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. ∼ 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 Ca2+-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.