Inhibitory Effect of Rivaroxaban on Atrial Arrhythmogenesis via Protease-Activated Receptor 2 Pathway

Anticoagulants are used to prevent cerebrovascular events in patients with atrial fibrillation (AF). Accumulating clinical evidence has proved that direct oral anticoagulants (DOACs), in addition to warfarin, can reduce the occurrence of cerebrovascular events in patients with non-valvular AF.^1–3 Rivaroxaban is used in AF and venous thrombosis and exerts its anticoagulant properties by inhibiting activated Factor X (FXa).^3,4 It has been reported that combination therapies that include low-dose rivaroxaban may be effective in the secondary prevention of acute coronary syndrome,⁵ which suggests that rivaroxaban is effective not only for stroke prevention in AF and venous thrombosis, but also coronary artery thrombosis.

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Conversely, coagulation proteases such as FXa have been shown to play a pivotal role not only in the activation of thrombus formation, but also in proinflammatory responses via protease-activated receptor (PAR) signaling pathways in several cell types.⁶ Therefore, it is of considerable interest to understand the roles of coagulation proteases and their cell signaling effects in the development of vascular and tissue inflammation. PARs are a family of protease-mediated G-protein-coupled 7-transmembrane receptors; thus far, 4 PARs (PAR1, PAR2, PAR3, and PAR4) have been identified.⁷ Of these, PAR2 is activated by FXa, whereas PAR1 is activated by both FXa and thrombin.⁸ In arteriosclerosis models, rivaroxaban exhibits anti-inflammatory properties by ameliorating PAR1 and PAR2.^9,10 In addition, basic in vivo and in vitro studies have examined in detail the relationship between PARs and cardiac remodeling.^11,12 A recent study showed that the cardiac remodeling process after myocardial infarction was improved following the administration of rivaroxaban by inhibition of PARs.¹³ However, little is known about the relationship between the inhibition of the FXa/PAR2 pathway by rivaroxaban and atrial arrhythmogenesis.

In this issue of the Journal, Matsuura et al report the significance of PAR2 signaling in AF arrhythmogenesis and the beneficial effects of rivaroxaban treatment on AF prevention through amelioration of PAR2-mediated atrial inflammation.¹⁴ Matsuura et al showed that angiotensin (Ang) II-treated PAR2-deficient mice had a lower incidence of AF and decreased mRNA expression of collagens 1 and 3 in the atrium compared with AngII-treated wild-type mice, and that rivaroxaban reduced AF inducibility compared with warfarin or vehicle by reducing the gene expression of inflammatory and fibrosis-related biomarkers in the atrium.¹⁴ This is an important report showing the significance of the FXa/PAR2 signaling pathway in AF arrhythmogenesis associated with atrial inflammation.

The most important and impressive finding in the study of Matsuura et al was the dual effect of rivaroxaban, a DOACs, that may contribute not only to stroke prevention in non-valvular AF but also to inhibition of AF arrhythmogenesis. Although the detailed molecular mechanism(s) in the prevention of AF arrhythmogenesis may be complicated, the Matsuura et al focused on the relationship between the FXa/PAR2 signaling pathway and atrial remodeling by using PAR2-deficient mice.¹⁴ Matsuura et al showed that PAR2 deficiency contributed to lower AF inducibility via suppression of atrial fibrosis in AngII-treated PAR2-deficient mice,¹⁴ findings that are supported by previous experimental studies.^12,15 Although several cascades may contribute to the atrial fibrotic process leading to the development of AF, the FXa/PAR2 cascade may be one of the therapeutic targets to inhibit AF inducibility.

Matsuura et al also showed that the rivaroxaban administration significantly reduced AF inducibility compared with warfarin or vehicle in spontaneously hypertensive rats (SHRs).¹⁴ Furthermore, they showed that rivaroxaban, but not warfarin, significantly reduced the gene expression of PAR1, PAR2, inflammatory and that of fibrosis-related biomarkers, such as tumor necrosis factor-α, monocyte chemoattractant protein-1, transforming growth factor-β, and collagens 1 and 3, in the atrium.¹⁴ These results suggest that rivaroxaban may be a therapeutic option for improving atrial remodeling by inhibiting the proinflammatory response via the PAR2 signaling pathway. However, it is unclear how much the suppression of the PAR2 signaling pathway is associated with the beneficial effects of inhibiting AF arrhythmogenesis compared with other signaling pathways, including PAR1 (Figure). Further experimental studies and clinical multicenter studies in a large patient cohort would be needed to support and strengthen the findings of Matsuura et al.

Figure.

Dual inhibitory effects of rivaroxaban on thrombus formation and arrhythmogenesis in atrial fibrillation. Rivaroxaban exerts its anticoagulant properties by inhibiting Factor X (FXa) and regulating; it also reduces protease-activated receptor (PAR) 1, PAR2, and inflammatory and fibrosis-related biomarkers (e.g., tumor necrosis factor [TNF]-α, monocyte chemoattractant protein-1 [MCP1], transforming growth factor [TGF]-β, and collagens 1 and 3) in the atrium, leading to the inhibition of atrial arrhythmogenesis. II, prothrombin; IIa, thrombin.

Hopefully, rivaroxaban can be used for both stroke prevention in non-valvular AF and the inhibition of AF arrhythmogenesis.

Disclosures

K. Kaikita has received grants and honoraria from Bayer Yakuhin, Ltd., and Daiichi-Sankyo Co., Ltd.

K. Tsujita is a member of Circulation Journal’s Editorial Team, and has received honoraria from Bayer Yakuhin, Ltd., Daiichi Sankyo Co., Ltd., Kowa Pharmaceutical Co., Ltd., MSD K.K., Sanofi K.K., and Takeda Pharmaceutical Co., Ltd.; trust research/joint research funds from AstraZeneca K.K., Sugi Bee Garden, and Japan Medical Device Technology Co., Ltd.; and grants from ITI Co., Ltd., Astellas Pharma Inc., Abbott Vascular Japan Co., Ltd., Otsuka Pharmaceutical Co., Ltd., Kaneka Medix Co., Ltd., Goodman Co., Ltd., GM Medical Co., Ltd., Daiichi Sankyo Co., Ltd., Takeda Pharmaceutical Co., Ltd., Mitsubishi Tanabe Pharma, Chugai Pharmaceutical Co., Ltd., TERUMO Co., Ltd., Boehringer Ingelheim Japan, Medtronic Japan Co., Ltd., Japan Lifeline Co., Ltd., Novartis Pharma K.K., Fides-One, Inc., Bristol-Myers K.K., Boston Scientific Japan K.K., Cardinal Health Japan, and MSD K.K.

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