Fibrosis progression in a non-inflammatory small animal model of liver congestion
Objectives: Congestive heart failure ultimately leads to cardiac cirrhosis, a poorly understood hepatopathy which can be monitored by elevated liver stiffness (LS). We here study a small animal model of liver congestion to simulate congestive heart failure and to learn more about fibrosis progression and LS under conditions of increased central venous pressure.
Methods: The caval vein was subphrenically clamped in male Wistar rats for 1 day, or 1, 4, 8 and 16 weeks. Altogether 70 animals were studied (clamps = 30, sham operated = 26, controls = 14). LS was measured invasively using the novel µFibroscan platform (Echosens, Paris) with the following parameters: 15 Hz, 1.5 – 3.3 mm, IQR 30%. In addition, liver histology (semiquantitative Chevallier fibrosis score), hepatic mRNA expression of fibrosis-relates genes, blood count and serum laboratory tests were performed. Data were analyzed using paired T-Test, Spearman rank correlation.
Results: Congestion significantly and immediately increased LS from mean 6.0 to 10.7 kPa (P < 10E-12). LS only slightly and non-significantly increased to 11.4 kPa over 4 months. No apparent inflammation or necrosis was seen wether histologically or in serum tests. In contrast to humans, no elevation of GGT was observed. Starting from week 8, a significantly increased histological fibrosis score (P < 0.05) was seen. Increased LS was highly associated with alphaSMA (P < 0.00005), TGF-beta (P < 0.0005) and collagen3 and MMP14 (P < 0.001). Fibrosis resolution could not be studied due to irreversible partial occlusion of the caval vein.
Conclusion: Our findings indicate that increased venous pressure and liver stiffness are associated with a pronounced profibrogenic response and histological fibrosis progression in the absence of inflammation. Pressure and mechanic stimulation of hepatic stellate cells could be an important hitherto underestimated factor in the development of matrix deposition.