The factor Xa inhibitor rivaroxaban reduces cardiac dysfunction in a mouse model of myocardial infarction

Michael F Bode; Alyson C Auriemma; Steven P Grover; Yohei Hisada; Alex Rennie; Weeranun D Bode; Rashi Vora; Saravanan Subramaniam; Brian Cooley; Patricia Andrade-Gordon; Silvio Antoniak; Nigel Mackman

doi:10.1016/j.thromres.2018.05.015

The factor Xa inhibitor rivaroxaban reduces cardiac dysfunction in a mouse model of myocardial infarction

Thromb Res. 2018 Jul:167:128-134. doi: 10.1016/j.thromres.2018.05.015. Epub 2018 May 17.

Authors

Affiliations

¹ Division of Cardiology, Department of Medicine, McAllister Heart Institute, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
² Division of Hematology and Oncology, McAllister Heart Institute, Department of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
³ Department of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
⁴ Division of Hematology and Oncology, McAllister Heart Institute, Department of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA; Department of Pathology and Laboratory Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
⁵ Department of Pathology and Laboratory Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
⁶ Janssen Research and Development, LLC, Spring House, PA, USA.
⁷ Division of Hematology and Oncology, McAllister Heart Institute, Department of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA; Department of Pathology and Laboratory Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA. Electronic address: nmackman@med.unc.edu.

PMID: 29843086
DOI: 10.1016/j.thromres.2018.05.015

Abstract

Introduction: Rivaroxaban selectively inhibits factor Xa (FXa), which plays a central role in blood coagulation. In addition, FXa activates protease-activated receptor-2 (PAR-2). We have shown that PAR-2^-/- mice exhibit less cardiac dysfunction after cardiac injury.

Material and methods: Wild-type (WT) and PAR-2^-/- mice were subjected to left anterior descending artery (LAD) ligation to induce cardiac injury and heart failure. Mice received either placebo or rivaroxaban chow either starting at the time of surgery or 3 days after surgery and continued up to 28 days. Cardiac function was measured by echocardiography pre-surgery and 3, 7 and 28 days after LAD ligation. We also measured anticoagulation, intravascular thrombi, infarct size, cardiac hypertrophy and inflammation at various times.

Results: Rivaroxaban increased the prothrombin time and inhibited the formation of intravascular thrombi in mice subjected to LAD ligation. WT mice receiving rivaroxaban immediately after surgery had similar infarct sizes at day 1 as controls but exhibited significantly less impairment of cardiac function at day 3 and beyond compared to the placebo group. Rivaroxaban also inhibited the expansion of the infarct at day 28. Rivaroxaban did not significantly affect the expression of inflammatory mediators or a neutrophil marker at day 2 after LAD ligation. Delaying the start of rivaroxaban administration until 3 days after surgery failed to preserve cardiac function. In addition, rivaroxaban did not reduce cardiac dysfunction in PAR-2^-/- mice.

Conclusions: Early administration of rivaroxaban preserves cardiac function in mice after LAD ligation.

Keywords: Cardiac remodeling; Coagulation; Factor Xa; Myocardial infarction; Protease-activated receptor; Rivaroxaban.

MeSH terms

Animals
Disease Models, Animal
Factor Xa Inhibitors / pharmacology
Factor Xa Inhibitors / therapeutic use*
Heart Diseases / drug therapy*
Humans
Mice
Myocardial Infarction / prevention & control*
Rivaroxaban / pharmacology
Rivaroxaban / therapeutic use*

Substances

Factor Xa Inhibitors
Rivaroxaban