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  • Paroxysmal or sustained atrial fibrillations profoundly acti

    2021-09-22

    Paroxysmal or sustained atrial fibrillations profoundly activate platelets and induce coagulation factors in the heart (Choudhury and Lip, 2003). Accumulating factor Xa and downstream thrombin in the fibrillating left atrium activate PAR1 and/or PAR2 signaling to modulate electrical characteristics of PV myocardial sleeves (Spronk et al., 2014). Factor Xa is a serine protease and plays a central role in the coagulation cascade linking the extrinsic and intrinsic pathways. Factor Xa in association with activated factor V and phospholipids forms the prothrombinase complex and activates prothrombin to thrombin (Spronk et al., 2014). To reduce thromboembolic complications with atrial fibrillation, several new antithrombotic agents were developed with non-inferior/superior antithrombotic effects and fewer hemorrhagic complications than the traditional vitamin K antagonist. Edoxaban and rivaroxaban are both direct oral factor Xa inhibitors approved to prevent thromboembolic stroke in patients with atrial fibrillation (Patel et al., 2011, Lip and Agnelli, 2014). These novel oral anticoagulants (NOACs) inhibit free factor Xa and prothrombinase-bound and clot-associated factor Xa in a concentration-dependent manner, and reduce the production of thrombin and resultant thrombogenesis and PAR signaling (Patel et al., 2011, Lip and Agnelli, 2014). In the heart, both PAR1 and PAR2 are present and are expressed by cardiomyocytes, endothelial cells, and smooth muscle cells. Receptor desensitization studies and experiments with PAR-blocking normally indicated that factor Xa signaling is generally mediated by both PAR1 and PAR2 (Kawabata and Kawao, 2005, Chang et al., 2012, Spronk et al., 2014). Although factor Xa and thrombin signal through PARs, PAR1-induced responses differ according to the nature of the ligand, whereas PAR2 serves mainly as a receptor for factor Xa but not for thrombin (Kawabata and Kawao, 2005, Chang et al., 2012, Spronk et al., 2014). The proteolytic cleavage of PARs by factor Xa or thrombin results in subsequent cell-specific events, which may occur in both normal and distinct pathophysiological conditions. Thus, the contribution of factor Xa to myocardial modulation may occur either directly via binding and activation of PAR1 and/or PAR2 or indirectly through the generation of thrombin. In this study, in the presence of a PAR1 blocker (BMS200261), both edoxaban and rivaroxaban lost their electrical effects on PVs, which suggests that factor Xa inhibitors modulate PV electrical activity mainly through PAR1 signaling. In this study, similar to the previous report, inhibition of INa-late reduced PV spontaneous beating rates (Lu et al., 2012). In addition, inhibition of INa-late attenuated the effects of edoxaban and rivaroxaban on PV electrical activity, which suggests the important role of INa-late in the effects of factor Xa inhibitors on PV arrhythmogenesis. The INa-late was found to be present in atrial myocytes hominoid undergo diastolic depolarization (Pinet et al., 2008; Moreno and Clancy, 2012). A critical role for the INa-late in pace-making was highlighted by a recent study which demonstrated that atrial automaticity can be modulated by INa-late enhancers and inhibitors (Pinet et al., 2008; Moreno and Clancy, 2012). We herein demonstrated that factor Xa inhibitors, in a supra-physiological concentration, reduced SAN spontaneous rates, which possibly could be attributed to INa-late inhibition. The INa-late plays an important role in PV electrical activity as well. An increase in the normally INa-late contributes to intracellular Na+ and Ca2+ loading, leading to arrhythmogenesis (Wu et al., 2008, Huang et al., 2016). Inhibition of the INa-late was shown to improve function and reduce arrhythmogenic activity (Wu et al., 2008, Huang et al., 2016). Thus, reducing the INa-late by blocking factor Xa-PAR signaling provides a new pharmacological target and herein was evidenced in the patch clamp study of PV myocytes. We found that both edoxaban and rivaroxaban reduced PV electrical activities, which was blocked by BMS200261 and ranolazine, suggesting that factor Xa blockers might reduce PV arrhythmogenesis through PAR1 inhibition and INa-late reduction. There seemed dose-dependent effect of factor Xa inhibitors in decreasing beating rates of PV and SAN tissue preparations, but the effect on INa-late was not dose-dependent in PV cardiomyocytes. The different pharmacological effects of factor Xa inhibitors on PV spontaneous activity and INa-late may be caused by the differences between tissue and single cell experiments, whereas the tissue experiments allow a longer drug administration. In addition, the PV electrical activity may be modulated by multiple cell interactions (smooth muscle, fibrocytes, adipocytes and endothelial cells) and cytokines in tissue preparations. Since PVs play a critical role in genesis and maintenance of atrial fibrillation, our findings suggest that factor Xa inhibitors might further reduce thromboembolic events in patients with paroxysmal atrial fibrillation through reducing the burden of atrial fibrillation in addition to their anticoagulant activity.