Abstract 20024: Rivaroxaban Attenuates Pressure Overload-Induced Vulnerability to Atrial Fibrillation via the Suppresion of Protease Activated Receptor-2 Activation by Factor Xa
Introduction: Coagulation factor Xa not only promotes thrombus formation, but also exacerbates inflammation via activation of protease activated receptor-2 (PAR-2).
Hypothesis: We tested the hypotheses whether oral administration of RVX would attenuate transverse aortic constriction (TAC)-induced atrial inflammatory fibrosis and vulnerability to AF in mice.
Methods: Six-week old male CL57/B6 mice were divided into Sham-operation (CNT) group and TAC-surgery group. Furthermore these two groups were then subdivided into vehicle (VEH) group and RVX treatment group (30mg/kg/day). By using rat cultured cells, PAR-2 expression in response to TAC-related stimulation were assessed.
Results: We observed followings. 1) Tail vein bleeding time and prothrombin time by two hours after RVX administration were significantly prolonged in RVX treatment groups. 2) TAC-induced left atrial thrombi were not observed in TAC-RVX group (62.5% vs. 0%, p<0.05). 3) Cardiac PAR-2 upregulation was observed in both TAC groups. In the quantitative analysis of the mRNA levels, the cardiac PAR-2 upregulation tended to be attenuated in TAC-RVX group compared to TAC-VEH group (P=0.042). 4) In histological evaluation, TAC+VEH group showed cardiac inhomogeneous interstitial fibrosis and abundant infiltration of macrophages, which were attenuated by RVX administration (p<0.05). 5) Electrophysiological study revealed that AF duration induced by TAC was shortened by RVX administration (P<0.05). 6) TAC-induced mRNA overexpression of tumor necrosis factor-α, monocyte chemoattractant protein-1, interleukin-1β and interleukin-6 in the left atrium tended to be suppressed by RVX treatment. 7) Addition of isoproterenol and persistent intermittent stretch upregulated PAR-2 in cardiac fibroblasts. 8) RVX suppressed PAR-2 upregulation induced by addition of isoproterenol and persistent intermittent stretch in cardiac fibroblasts (P=0.036), while PAR-2 inhibitor significantly suppressed the upregulation.
Conclusions: These observations demonstrated that rivaroxaban may have the cardio-protective effect against pressure overload-induced atrial remodeling.
Author Disclosures: M. Haraguchi: None. H. Kondo: None. N. Takahashi: None.
- © 2016 by American Heart Association, Inc.