Inhibition of coagulation factor Xa improves myocardial function during CVB3-induced myocarditis

Cardiovasc Ther. 2014 Jun;32(3):113-9. doi: 10.1111/1755-5922.12069.

Abstract

Introduction: Myocarditis is induced by coxsackievirus B3 (CVB3). Myocardial inflammation is tied to the activation of coagulation. Coagulation factor (F) Xa, a central player in coagulation, activates matrix metalloproteinases (MMP), which modulate the remodeling.

Aims: In this study, we investigated the effects of pharmacological FXa inhibition on myocardial function, inflammation, and remodeling during a CVB3-induced myocarditis.

Methods and results: Immune cells and matrix proteins were detected by immunohistochemistry. The expression of cytokines was measured by real-time PCR and the activity of MMP-2 by zymography. Left ventricular function was analyzed using microconductance pressure catheter. Treatment with the FXa inhibitor fondaparinux led to an improved left ventricular function in CVB3-induced mice compared to saline-treated controls (dPdtmax: fondaparinux 4632 ± 499.6 vs. saline 3131 ± 374.0 [mmHg/s], P = 0.0503; SV: fondaparinux 33.19 ± 4.893 vs. saline 19.32 ± 2.236 [μL], P < 0.118; CO: fondaparinux 15124 ± 2183 vs. saline 8088 ± 1035 [μL/min], P < 0.05). Therapy with fondaparinux reduced the activity of MMP-2 (fondaparinux 1.208 ± 0.1247 vs. saline 1.565 ± 0.05476, P < 0.05). The collagen type I/III ratio as well as the expression of TIMP-1 was comparable in both infection groups postinfectionem (p.i.), despite an increased infiltration of macrophages into the hearts of mice treated with fondaparinux 8 days p.i. (CD68+: fondaparinux 494.2 ± 64.73 vs. saline 306.9 ± 43.73 [cells/mm(2) ], P < 0.05). Anti-inflammatory CD206-positive M2-type macrophages were increased in the infected hearts after fondaparinux treatment (CD206+: fondaparinux 182.1 ± 18.18 vs. saline 111.6 ± 21.07 [cells/mm(2) ], P < 0.05), whereas CD80-positive M1-type macrophages were comparable in both groups.

Conclusion: In conclusion, selective inhibition of FXa improves the left ventricular function during CVB3-induced myocarditis and seems to be associated with an improved myocardial remodeling.

Keywords: Factor Xa; Fondaparinux; Inflammation; Myocarditis; Remodeling.

MeSH terms

  • Animals
  • Coxsackievirus Infections / blood
  • Coxsackievirus Infections / drug therapy*
  • Coxsackievirus Infections / physiopathology
  • Coxsackievirus Infections / virology
  • Cytokines / genetics
  • Cytokines / metabolism
  • Disease Models, Animal
  • Enterovirus B, Human / pathogenicity*
  • Factor Xa / metabolism*
  • Factor Xa Inhibitors / pharmacology*
  • Fondaparinux
  • Inflammation Mediators / metabolism
  • Male
  • Matrix Metalloproteinase 2 / metabolism
  • Mice, Inbred C57BL
  • Myocarditis / blood
  • Myocarditis / drug therapy*
  • Myocarditis / physiopathology
  • Myocarditis / virology
  • Polysaccharides / pharmacology*
  • RNA, Messenger / metabolism
  • Ventricular Function, Left / drug effects*
  • Ventricular Remodeling / drug effects*
  • Viral Load

Substances

  • Cytokines
  • Factor Xa Inhibitors
  • Inflammation Mediators
  • Polysaccharides
  • RNA, Messenger
  • Factor Xa
  • Matrix Metalloproteinase 2
  • Mmp2 protein, mouse
  • Fondaparinux