Heart failure with normal ejection fraction (HFNEF) is characterized by diastolic dysfunction and no cardiac dilation compared to patients with heart failure and reduced ejection fraction (HFREF). Here we investigate the differences between both heart failure types in regard to changes in the gene expression of ECM proteins and matrix metalloproteinases in cardiac fibroblasts from these patients.Methods
Endomyocardial biopsies were used to obtain cardiac fibroblasts from patients with heart failure and normal EF as well as reduced EF. This human cardiac fibroblast cell culture system from these patients was used to investigate the basal expression pattern in regard to different matrix regulation in both groups. Moreover, the response of the fibroblasts to different stress stimuli known in heart failure was investigated.Results
In cardiac fibroblasts derived from endomyocardial biopsies of HFNEF patients higher expression of ECM proteins were detected compared to the HFREF group. The level of collagen I and collagen III was significantly higher in fibroblasts from HFNEF compared to HFREF patients. Importantly for LV dilation, the gene expression of the major human collagenase matrix metalloproteinases-1 (MMP-1) was differently expressed when we compared the expression in fibroblasts from HFNEF to HFREF patients. It was significantly higher expressed in patients with HFREF compared to HFNEF fibroblasts. Furthermore, the stimulation with TGF-beta resulted in the transdifferentiation of fibroblasts to myofibroblasts (activated fibroblasts) in which an increased expression of collagen and alpha-smooth-muscle action was determined. Moreover, after stimulation with TGF-beta, MMP-1 expression in patients with HFREF (2 fold) increased compared to baseline. This could not be documented in fibroblasts from HFNEF patients, which did not respond with an increment of MMP-1 expression at all.Conclusions
The matrix metalloproteinase-1 was higher expressed and could be further increased by TGF-beta stimulation in fibroblasts from patients with HFREF compared to HFNEF. The increment of the major human collagenase MMP-1 is important for the destabilisation of the structural integrity of the extracellular matrix in patients with HFREF and therefore triggers cardiac dilation compared to HFNEF patients where no up regulation of MMP-1 as well as no cardiac dilation could be documented. This different gene expression between both heart failure types might be one mechanism explaining the differences in the development of HFNEF as well as HFREF and might be one future target for treatment.