Hypercoagulability and atrial fibrillation: a two-way road?

This editorial refers to ‘Hypercoagulability causes atrial fibrosis and promotes atrial fibrillation’†, by H.M.H. Spronk et al., on page 38. Atrial fibrillation (AF) is one of the most relevant cardiac disturbances requiring close monitoring due to its direct association with thrombo-embolic complications, such as cardio-embolic stroke or even sudden death, and heart failure.1,2 The crucial role of hypercoagulability as the direct mechanism behind this high-risk scenario has been widely studied.3,4 Indeed, several reports have shown that AF occurs together with platelet and coagulation activation5,6 and abnormal fibrinolysis.7,8 Therefore, the presence of haemostatic alterations as a consequence of AF is widely accepted. However, until now it has been unclear whether the existence of an altered haemostatic balance could promote and/or exacerbate AF development. Spronk et al. in an experimental study have now demonstrated that the association between AF and hypercoagulability could be a two-way street (Figure 1) in which the hypercoagulable state could induce atrial fibrosis, further enhancing AF.9 These authors examined, by using three complementary approaches, whether AF-related hypercoagulability promotes structural remodelling in the atria, contributing to the development of a substrate for AF. First, the authors demonstrate a thrombin-induced activation of protease-activated receptor (PAR) signalling pathways, mainly PAR1 but to some extent also PAR2 and PAR3, in adult rat atrial fibroblasts by the phosphorylation of several molecules such as Akt, Erk, and p38. In addition, they show that thrombin co-ordinately induces the expression of key profibrotic molecules such as αSMA (α smooth muscle actin) and TGFβ1 (transforming growth factor β1), and several proinflammatory effectors such as interleukin-6 (IL-6) and monocyte chemoattractant protein-1 (MCP-1). In fact, previous studies have related increased plasma levels of inflammatory markers, specifically IL-6 and C-reactive protein (CRP), with a higher risk of vascular death and the composite of thrombo-embolic events independent of clinical risk factors in AF patients.10 Interestingly, the authors show that these thrombin-induced effects can be attenuated by in vitro dabigatran treatment of atrial fibroblasts. Additionally, the authors prove the association between a hypercoagulable phenotype and the appearance of AF episodes by analysing the occurrence and the duration of burst pacing-evoked episodes of AF in transgenic mice carrying a mutation in the thrombomodulin gene (TMpro/pro) in comparison with wild-type animals. TMpro/pro mice had a larger proportion of AF episodes lasting longer than 1 s, being the duration of the longest AF episode significantly longer in mice with the hypercoagulable phenotype. Finally, and in order to prove the potential clinical implication of their findings, Spronk et al. demonstrate that nadroparin treatment, targeting Factor Xa (FXa)-mediated thrombin generation, in goats with AF was associated with a reduction in cell–cell distances and a lower number of αSMA-positive myofibroblasts compared with non-treated animals, indicating that the attenuation of a hypercoagulable state prevents atrial fibrosis.