Effect of Rosuvastatin on Inflammatory Cytokines during Murine DVT Resolution

Background: Statins, inhibitors of HMG-CoA reductase, are commonly prescribed lipid lowering agents that also have pleiotropic anti-inflammatory properties. Among this class of medications is rosuvastatin which was shown to reduce hsCRP and cardiovascular mortality in the JUPITER trial. After acute DVT, inflammatory markers are significantly elevated and have been shown to persist for years afterwards. Prior studies in mice have suggested that statin therapy accelerated venous thrombus resolution. We hypothesize that statins may have beneficial effects by reducing the chronic inflammation that may lead to post thrombotic syndrome. The purpose of this study is to evaluate the impact of rosuvastatin on venous thrombus resolution in a mouse model of DVT induced by ligation of the infra-renal inferior vena cava (IVC).

Methods: Wildtype CD1 mice were treated with either a regular chow diet (control group) or 1 mg/kg rosuvastatin diet (treatment group) for one week prior to surgical creation of a venous thrombus by IVC ligation. Respective diets were continued after surgery until euthanasia. There were a total of 15 control mice and 8 rosuvastatin mice. The mice were evaluated on post-operative days 3 and 7 to assess thrombus weights to evaluate thrombus formation and resolution. Additionally, plasma was collected for luminex multiplex analysis (MHSTCMAG-70K, Millipore) to evaluate for low levels of cytokine and chemokine biomarkers.

Results: Thrombus weights were equivalent in the rosuvastatin treated mice compared to the control mice both on both day 3 (1.17 mg/kg +/- 0.25 vs 1.34 mg/kg +/- 0.35, Student t-test p = 0.58) and day 7(1.04 mg/kg +/- 0.48 vs 0.97 mg/kg +/- 0.25, Student t-test p = 0.73). On day 3, plasma analysis of rosuvastatin treated mice demonstrated decreased levels of MCP-1 (8.20 +/- 4.07 vs 17.37 +/- 3.26, Student t-test p = 0.04) and TNF-alpha (2.42 +/- 0.42 vs 4.74 +/- 0.91, Student t-test p = 0.02) in comparison to control mice. However, on day 7, plasma analysis of rosuvastatin treated mice demonstrated increased levels of IFN-gamma (4.22 +/- 5.02 vs 0.49 +/- 0.01, Student t-test p = 0.04) in comparison to the control mice.

Conclusion: In contrast to prior studies, we found that rosuvastatin did not accelerate thrombus resolution nor did it affect thrombus formation. Rosuvastatin appears to decrease inflammatory cytokines during thrombus formation and increase an anti-inflammatory cytokine in early thrombus resolution. Further research is needed to study whether modulation of the inflammatory profile during DVT may be helpful in reducing harmful chronic inflammation that can lead to PTS.

No relevant conflicts of interest to declare.