Abstract 18040: Activated Factor X Signaling Pathway via Protease-Activated Receptor-2 is a Novel Therapeutic Target to Prevent Atrial Fibrillation

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Background: Atrial fibrillation (AF) is the most common type of arrhythmia seen in clinical practice. Recent studies have suggested that inflammation contributes to the pathogenesis of AF. On the other hand, accumulating evidence suggests that activated factor X (FXa), which plays a key role in the coagulation cascade, contributes to the pathophysiology of chronic inflammation via protease-activated receptor-2 (PAR-2). Recently, the direct FXa inhibitor, rivaroxaban, has been reported to have anti-inflammatory action in addition to anticoagulant effect. Furthermore, we have recently reported that rivaroxaban attenuates atherosclerotic plaque progression and destabilization in apolipoprotein E-deficient mice. This study aimed to assess whether PAR-2 signaling contributes to the AF arrhythmogenesis and whether rivaroxaban ameliorates atrial inflammation and prevents AF.

Methods: In study 1, PAR-2 deficient (PAR2-/-) and wild-type mice were infused with angiotensin II (Ang II) or vehicle via an osmotic minipump for 2 weeks. In study 2, spontaneously hypertensive rats (SHR) were treated with rivaroxaban, warfarin, and vehicle for two weeks after 8-hour right atrial rapidly pacing. Then, we examined AF inducibility by intracardiac electrophysiological study and the inflammation-induced atrial remodeling by biochemical analysis in both studies.

Results: Ang II-treated PAR2-/- mice showed lower incidence of AF and less mRNA expressions of collagen-1 and -3 in atrium compared with wild-type mice treated with Ang II. Administration of rivaroxaban significantly reduced AF inducibility compared with warfarin or vehicle. In SHR treated with vehicle, rapid atrial pacing promoted the gene expression of inflammatory and fibrosis-related biomarkers (TNF-α, MCP-1, collagen-1 and -3) in atrium. Rivaroxaban, but not warfarin, significantly reduced these gene expression levels.

Conclusions: FXa-PAR-2 signaling pathway might contribute to the AF arrhythmogenesis associated with atrial inflammation. A direct FXa inhibitor, rivaroxaban, could prevent atrial inflammation and reduce AF inducibility probably by inhibiting pro-inflammatory activation.

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