Abstract 11400: Targeting Coagulation Factor Xa With Rivaroxaban Reduces the Onset and Progression of Atherosclerosis and Enhances Plaque Stability in ApoE Null Mice
Objective: Atherosclerosis is a progressive chronic inflammatory vascular disease, complicated by plaque rupture and subsequent thrombus formation. In vitro studies indicate that coagulation proteases such as thrombin and factor Xa (FXa) may contribute to pro-atherosclerotic mechanisms mediated through activation of protease-activated receptors (PARs). Whereas experimental thrombin inhibition reduced development and progression of atherosclerosis, the contribution of FXa to atherogenesis has not been elucidated. To assess the involvement of FXa in atherosclerosis, we investigated the effects of direct FXa inhibition by rivaroxaban on experimental atherosclerosis.
Approach and Results: Female ApoE-/- mice (age 8-9weeks) received high-fat diet (HFD) or HFD supplemented with rivaroxaban for 8 or 14 weeks (n=10/group). In the second arm, ApoE-/- mice received HFD for 14 weeks, followed by either continuation with HFD or switched to HFD supplemented with rivaroxaban for 6 weeks (n=10/group). Inhibition of FXa decreased the onset of atherosclerosis in the aortic arch after 8 weeks (-36.92%, p<0.05) and 14 weeks (-46.47%, p<0.05) as well as in the carotid artery; 8 weeks (-38.14%, p<0.05) and 14 weeks (-23.38%, p<0.05). Furthermore, progression of pre-existing plaque after 14 weeks was reduced in the aortic arch (-20.85%, p<0.05) and carotid artery (-30.26%, p<0.05). Immunohistochemical staining revealed reduced plaque vulnerability, as reflected by diminished macrophage infiltration (-38.28%, p<0.05), enhanced collagen (+45.30%, p<0.05) and reduced necrotic core (-37.49%, p<0.05). These findings were associated with elevated collagen-producing vascular smooth muscle cells and reduced collagen degradation proteins MMPs. The qualitative and quantitative improvements were accompanied by reduced expression of PARs and their activators, thrombin and FXa.
Conclusions: Pharmacological inhibition of FXa with rivaroxaban impedes the onset and progression of atherosclerosis and increased plaque stability, which is possibly mediated through reduced activation of PARs. These data suggest that direct targeting of FXa may be beneficial in treatment of atherosclerosis; to demonstrate clinical relevance further studies are required.
Author Disclosures: J. Posthuma: None. J. Posma: None. R. van Oerle: None. L. Schurgers: None. S. Heitmeier: None. H. ten Cate: None. H. Spronk: None.
- © 2016 by American Heart Association, Inc.