Abstract 11679: Ivabradine Reverses the Extracellular Matrix Changes in Heart Failure
In the failing heart, the extracellular matrix (ECM) undergoes structural remodelling characterised by changes in the accumulation and organisation of collagen. Ivabradine (IVA) an inhibitor of the pacemaker current has been shown to have beneficial effects in heart failure (HF) with multiple actions on the structure and function of the myocardium, including the reduction of myocardial fibrosis. However, whether IVA prevents further collagen deposition during the progression of the disease or reverses the process in unknown. In addition, the cellular and molecular effects on the ECM have not been studied. HF was induced in rats by coronary artery ligation. Sham-operated animals (S) were used as controls. After 12 weeks, HF animals (ejection fraction<40%) were treated either with IVA (HF-IVA) (10mg/kg/day) or saline (HF-S) for a further 4 weeks. Fibrosis was assessed in paraffin-embedded sections using picrosirius red. HF-IVA had significantly reduced fibrosis compared with HF at 12 weeks suggesting that IVA not only prevents further collagen deposition but reverses this process (HF: 5.11±0.41%; HF-S: 7.46±0.39%; HF-IVA: 2.83±0.25%; p<0.001). Using immunofluorescence and confocal microscopy, sections were studied for specific ECM proteins and the percentage area fraction was quantified on 8-10 fields per heart (3-4 hearts per group) using ImageJ software. IVA significantly reduced the levels of Collagen I (S: 2.76±0.35%; HF-S: 5.16±0.38%; HF-IVA: 1.53±0.22%; p<0.05), Collagen III (S: 0.31.5±0.06%; HF-S: 4.99±0.51%; HF-IVA: 2.51±0.23%; p<0.001) and Elastin (S: 0.51±0.11%; HF-S: 3.17±0.60%; HF-IVA: 0.63±0.16%; p<0.001). The sections were also stained for vimentin as a marker for cardiac fibroblasts. IVA reduced the area positive for vimentin observed in HF-S to sham levels (S: 1.04±0.13%; HF-S: 2.00±0.19%; HF-IVA: 0.70±0.08%; p<0.05). Further, no change in von Willebrand factor staining was observed suggesting that endothelial cell number was not affected. Our results suggest that IVA reverses the accumulation of several components of the ECM and reduces fibroblast numbers.
- © 2012 by American Heart Association, Inc.