title: Evaluation of plaque stability of advanced atherosclerotic lesions in apo E-deficient mice after treatment with the oral factor Xa inhibitor rivaroxaban.
abstract: OBJECTIVE
  Thrombin not only plays a central role in thrombus formation and platelet activation, but also in induction of inflammatory processes. Activated factor X (FXa) is traditionally known as an important player in the coagulation cascade responsible for thrombin generation. We assessed the hypothesis that rivaroxaban, a direct FXa inhibitor, attenuates plaque progression and promotes stability of advanced atherosclerotic lesions in an in vivo model.
  
  
  RESULTS
  Rivaroxaban (1 or 5 mg/kg body weight/day) or standard chow diet was administered for 26 weeks to apolipoprotein E-deficient mice (n = 20 per group) with already established atherosclerotic lesions. There was a nonsignificant reduction of lesion progression in the high-concentration group, compared to control mice. FXa inhibition with 5 mg Rivaroxaban/kg/day resulted in increased thickness of the protective fibrous caps (12.3 ± 3.8 μm versus 10.1 ± 2.7 μm; P < .05), as well as in fewer medial erosions and fewer lateral xanthomas, indicating plaque stabilizing properties. Real time-PCR from thoracic aortas revealed that rivaroxaban (5 mg/kg/day) treatment reduced mRNA expression of inflammatory mediators, such of IL-6, TNF-α, MCP-1, and Egr-1 (P < .05).
  
  
  CONCLUSIONS
  Chronic administration of rivaroxaban does not affect lesion progression but downregulates expression of inflammatory mediators and promotes lesion stability in apolipoprotein E-deficient mice.
authors.affiliation: Department of Internal Medicine III, University of Heidelberg, 69120 Heidelberg, Germany.
authors.forename: Qianxing
authors.initials: Q
authors.lastname: Zhou
authors.forename: Florian
authors.initials: F
authors.lastname: Bea
authors.forename: Michael
authors.initials: M
authors.lastname: Preusch
authors.forename: Hongjie
authors.initials: H
authors.lastname: Wang
authors.forename: Berend
authors.initials: B
authors.lastname: Isermann
authors.forename: Khurrum
authors.initials: K
authors.lastname: Shahzad
authors.forename: Hugo A
authors.initials: HA
authors.lastname: Katus
authors.forename: Erwin
authors.initials: E
authors.lastname: Blessing
mesh_terms: D000818:Animals; D000925:Anticoagulants / Q000627:therapeutic use*; D001057:Apolipoproteins E / Q000235:genetics / Q000378:metabolism*; D050197:Atherosclerosis / Q000188:drug therapy* / Q000473:pathology*; D065427:Factor Xa Inhibitors; D005260:Female; D006801:Humans; D008055:Lipids / Q000097:blood; D051379:Mice; D018345:Mice, Knockout; D009025:Morpholines / Q000627:therapeutic use*; D058226:Plaque, Atherosclerotic / Q000188:drug therapy* / Q000473:pathology*; D011897:Random Allocation; D000069552:Rivaroxaban; D013876:Thiophenes / Q000627:therapeutic use*
chemical_list: D000925:Anticoagulants; D001057:Apolipoproteins E; D065427:Factor Xa Inhibitors; D008055:Lipids; D009025:Morpholines; D013876:Thiophenes; D000069552:Rivaroxaban