Rivaroxaban prevents prothrombogenic remodelling of human atrial myocardium

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Andreas-Goette

By Andreas Goette

Stroke is one of the major problems in patients with atrial fibrillation (AF). Recent studies have clearly elucidated the pathophysiology of atrial thrombus formation in AF. Endocardial changes in the left atrium appear of particular importance in the process of clot formation.1 Novel oral anticoagulants like rivaroxaban (Xarelto, Bayer Healthcare) have been shown to reduce atrial thrombogenesis in AF. In addition, low dose of rivaroxaban proved to reduce cardiovascular events in patients with acute coronary syndromes. Thus, inhibition of clotting factor X might have beneficial effects in the vascular circulation.

The activated coagulation factor X plays a central role in the coagulation cascade linking the extrinsic and intrinsic coagulation pathway. In addition, evidence shows that factor X acts as a signalling molecule mediating cellular responses by activating protease-activated receptors (PARs) inducing inflammatory and thrombogenic activity.

A recent study by our group in Germany provides evidence that factor X acts as mediator of inflammatory signalling via activation of protease-activated receptors 1 and 2 in human atrial tissue.2 Most importantly, the synergistic action of factor X and simulated atrial tachyarrhythmia results in a potentiated response involving the increase of inflammatory and oxidative stress molecules, which create an inflammatory, prothrombotic status in atrial tissue.

In detail, we could show that factor X application to human atrial myocardium resulted in the 1.7 fold upregulation of PAR2-mRNA, activation of MAP kinases (ERK1/2) and NF-κB signalling. Furthermore, factor X increased the expression of adhesion molecule ICAM-1, chemokine IL-8, as well as prothrombotic molecule PAI-1. The combination of rapid pacing and factor X caused significant upregulation of PAR1, PAR2, ICAM-1, IL-8, LOX-1, and PAI-1 at the mRNA level. Rivaroxaban prevented upregulation of PARs, ICAM-1, LOX-1, IL-8, and activation of MAP kinases.

Thus, our study provides evidence that in human atrial tissue, factor X acts a mediator of inflammatory signalling via specific receptors. Most importantly, the synergistic action of factor X and simulated atrial tachyarrhythmia results in a potentiated response involving the increase of inflammatory and oxidative stress molecules, which create an inflammatory, prothrombotic status in atrial tissue. Importantly, the factor X induced inflammatory signalling can be substantially attenuated by factor X antagonist, rivaroxaban. Thus, factor X and protease-activated receptors appear as novel therapeutic targets to reduce prothrombogenic atrial remodelling.


References

 

1. Schotten U, Verheule S, Kirchhof P, Goette A. Pathophysiological mechanisms of atrial fibrillation: a translational appraisal. Physiol Rev. 2011;91(1):265–325.

2. Bukowska et al. Coagulation factor Xa induces an inflammatory signalling by activation of protease-activated receptors in human atrial tissue. Eur J Pharmacol. 2013;718:114–123


Andreas Goette is director of Cardiology and Intensive Care Medicine, St Vincenz Hospital, Paderborn, Germany, and head of Working Group Molecular Electrophysiology, University Hospital Magdeburg, Germany

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