Progression of matrixin and cardiokine expression patterns in an ovine model of heart failure and recovery

•This is a reversible large animal model for studying heart failure and recovery at the molecular and functional levels.•The duration of the study was 150 weeks which is comparable to the disease course occurring in human.•The work identified MMP-1,2,3, VEGF, FGF, sCD40L and IFN-alpha-2 as players in the development of the disease.•The above allows for the development of new therapeutic targets.

BackgroundThe molecular mechanisms underlying the geometrical changes of the left ventricle during the progression to heart failure and recovery are not well defined.ObjectiveHere we investigate the involvement of matrixins and cardiokines in an ovine model of pressure-induced left ventricular failure (LVF).MethodsFifteen sheep underwent supracoronary aortic banding with an inflatable cuff. A controlled and progressive increase of LV pressure was monitored echocardiographically. Endomyocardial biopsies were collected throughout the development of LVF and subsequent recovery after pressure unloading.ResultsThirteen sheep developed LVF with a subsequent recovery. Peak left ventricular hypertrophy (LVH) and dilatation (LVD) occurred at 31.5 ± 1.6 weeks and 102.7 ± 2.2 weeks post-banding respectively, with an increase in LV internal diameter in diastole (LVIDd 5.11 ± 0.12 compared to the control 3.37 ± 0.07 cm, p < 0.001), with preserved LV ejection fraction (LVEF). Reduced LVEF became evident 116.5 ± 2.7 weeks post-banding. Clinical and echocardiographic improvements were observed following deflation of the aortic banding cuff. By 138.1 ± 3.1 weeks cardiac performance recovered with restoration of LVEF. Significant changes in the expression of matrix metalloproteinases (MMP)-1, -2, -3, vascular endothelial cell growth factor (VEGF), fibroblast growth factor (FGF)-2, interferon (INF)-α-2 and soluble CD40 ligand (sCD40L) were observed throughout the progression to failure and recovery.ConclusionsWe used an ovine model to study reversible LV remodelling without interruption and found significant changes in matrixin and cardiokine expression during LV progression to failure and recovery.