Archives

  • 2018-07
  • 2019-04
  • 2019-05
  • 2019-06
  • 2019-07
  • 2019-08
  • 2019-09
  • 2019-10
  • 2019-11
  • 2019-12
  • 2020-01
  • 2020-02
  • 2020-03
  • 2020-04
  • 2020-05
  • 2020-06
  • 2020-07
  • 2020-08
  • 2020-09
  • 2020-10
  • 2020-11
  • 2020-12
  • 2021-01
  • 2021-02
  • 2021-03
  • 2021-04
  • 2021-05
  • 2021-06
  • 2021-07
  • 2021-08
  • 2021-09
  • 2021-10
  • 2021-11
  • 2021-12
  • 2022-01
  • 2022-02
  • 2022-03
  • 2022-04
  • 2022-05
  • 2022-06
  • 2022-07
  • 2022-08
  • 2022-09
  • 2022-10
  • 2022-11
  • 2022-12
  • 2023-01
  • 2023-02
  • 2023-03
  • 2023-04
  • 2023-05
  • 2023-06
  • 2023-07
  • 2023-08
  • 2023-09
  • 2023-10
  • 2023-11
  • 2023-12
  • 2024-01
  • 2024-02
  • 2024-03
  • br Introduction Atrial fibrillation is the most

    2022-06-24


    Introduction Atrial fibrillation is the most common cardiac arrhythmia (Benjamin et al., 1998). Pulmonary vein (PV) sleeves contain a mixture of working myocardium and potential arrhythmogenic pacemaker Sodium Phenylbutyrate behaving as an ectopic trigger of atrial fibrillation (Haissaguerre et al., 1998, Chen et al., 1999). Atrial fibrillation activates prothrombotic factors which are mainly activated factor X (factor Xa) and downstream thrombin (Chang et al., 2016). A lot of evidence shows that factor Xa and thrombin act as signaling molecules that mediate cellular responses by activating diverse protease-activated receptors (PARs) in addition to their roles in the coagulation cascade (Rana et al., 2012). PARs were detected in human autopsied hearts, and its expression levels were higher in left atrial tissue compared to left ventricular tissue (Rana et al., 2012). Activation of PAR type 1 (PAR1) increased the persistent sodium current and intracellular sodium with resulting sodium/calcium exchanger activation, which favors triggered activity in human atrial cardiomyocytes (Bollensdorff et al., 2004). Since factor Xa plays a role in the electrical remodeling of fibrillating atria via PAR1 activation, we suggest that specific coagulation inhibitors might prevent arrhythmogenic changes in fibrillating PVs. Our previous study had demonstrated that thrombin enhanced arrhythmogenesis by reducing the spontaneous beating rate, inducing delayed afterdepolarizations and burst firings in rabbit PVs preparations (Chang et al., 2012). This suggests that a direct thrombin inhibitor might disrupt the “atrial fibrillation begets atrial fibrillation” by blocking PAR1 signaling. Treatment with a direct thrombin inhibitor causes both attenuated coagulation and a portion of PAR1 signaling but does not alter the signaling capacity of PARs for factor Xa (Kawabata and Kawao, 2005). Therefore, the use of a factor Xa inhibitor could alter both factor Xa- and thrombin-induced coagulation and PAR signaling, which provides extensive electrophysiological consequences than the use of direct thrombin inhibitor alone. There is evidence that factor Xa inhibitor (rivaroxaban) modulates the electromechanical characteristics of left atrial preparations (Chang et al., 2013), but the effects of a factor Xa inhibitor on PVs are still unclear. One study demonstrated that activation of PARs by the SFLLR-NH2 peptide induced a rapid and dramatic elevation in intracellular sodium ([Na+]i) (Bollensdorff et al., 2004). The increase in [Na+]i could contribute to myocyte injury during ischemia as the result of an intracellular calcium overload and activation of calcium-dependent signaling cascades (Karpinski et al., 2014). This hypothesis was supported by a recent finding of cardioprotective and antiarrhythmic effects of the late Na+ current (INa-late) inhibitor, ranolazine (Undrovinas et al., 2006). We therefore tested whether a factor Xa inhibitor could attenuate PVs spontaneous activity through the blockage of PAR1 and reduction of the INa-late, which may underlie the antiarrhythmic benefits in patients with atrial fibrillation beyond stroke prevention. Edoxaban and rivaroxaban, both of which are approved worldwide as selective factor Xa inhibitors, decrease thrombin formation and prevent thromboembolic events in AF patients (Patel et al., 2011, Lip and Agnelli, 2014). However, it is not clear whether edoxaban and rivaroxaban share the classic electrophysiological effects on the ectopic trigger (PVs) and pace-making site (sinoatrial node, SAN). The purposes of this study were to investigate the effects of edoxaban and rivaroxaban on PVs and SAN tissue preparations and the roles of PAR1 and the Sodium Phenylbutyrate INa-late in underscoring factor Xa inhibition in isolated PV myocytes.
    Materials and methods
    Results
    Discussion We found that factor Xa inhibitors effectively reduced the spontaneous beating rate of PVs at physiological concentrations (0.3 μM edoxaban and 0.1 μM rivaroxaban) but inhibited the automaticity of the SAN at supra-physiological concentrations (1 μM edoxaban and 0.3 μM rivaroxaban). Trough and peak plasma concentrations of edoxaban (0.05 and 0.34 μM) and rivaroxaban (0.06 and 0.29 μM) for references were measured after oral administration of a single oral dose in healthy volunteers (Patel et al., 2011, Lip and Agnelli, 2014). Both edoxaban (0.3 and 1 μM) and rivaroxaban (0.1 and 0.3 μM) could effectively reduce the INa-late in PV myocytes. Furthermore, edoxaban (1 μM) and rivaroxaban (0.3 μM) could not reduce PV spontaneous beating rates in the presence of 1 μM BMS200261 (a PAR1 blocker) or 10 μM ranolazine (an INa-late inhibitor). BMS200261 didn’t significantly affect the electrical activity in the PVs. The previous study has shown that PAR1 inhibitor reduced the effects of thrombin on coagulation and PAR1 signaling in part (Matthew et al., 2017). However, PAR1 inhibitor incompletely prohibited the effects of factor Xa on PAR signaling (Kawabata and Kawao, 2005). These findings suggest that a PAR1 inhibitor (BMS200261) partially attenuated the effect of factor Xa because factor Xa activated both PAR1 and PAR2. Moreover, PAR1 may be less activated in a non-coagulative (non-fibrillating) status, thus the PAR1 exerted little effect at baseline. Our data herein provides an antiarrhythmogenic property of factor Xa inhibitors in PVs beyond their innate anticoagulative function and demonstrates that these two factor Xa inhibitors shared the classical electrophysiological effect in PV myocardial sleeves.