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- Title
Hypercoagulability causes atrial fibrosis and promotes atrial fibrillation.
- Authors
Spronk, Henri M. H.; De Jong, Anne Margreet; Verheule, Sander; De Boer, Hetty C.; Maass, Alexander H.; Lau, Dennis H.; Rienstra, Michiel; van Hunnik, Arne; Kuiper, Marion; Lumeij, Stijn; Zeemering, Stef; Linz, Dominik; Kamphuisen, Pieter Willem; ten Cate, Hugo; Crijns, Harry J.; Van Gelder, Isabelle C.; van Zonneveld, Anton Jan; Schotten, Ulrich
- Abstract
Aims Atrial fibrillation (AF) produces a hypercoagulable state. Stimulation of protease-activated receptors by coagulation factors provokes pro-fibrotic, pro-hypertrophic, and pro-inflammatory responses in a variety of tissues. We studied the effects of thrombin on atrial fibroblasts and tested the hypothesis that hypercoagulability contributes to the development of a substrate for AF. Methods and results In isolated rat atrial fibroblasts, thrombin enhanced the phosphorylation of the pro-fibrotic signalling molecules Akt and Erk and increased the expression of transforming growth factor β1 (2.7-fold) and the pro-inflammatory factor monocyte chemoattractant protein-1 (6.1-fold). Thrombin also increased the incorporation of 3H-proline, suggesting enhanced collagen synthesis by fibroblasts (2.5-fold). All effects could be attenuated by the thrombin inhibitor dabigatran. In transgenic mice with a pro-coagulant phenotype (TMpro/pro), the inducibility of AF episodes lasting >1 s was higher (7 out of 12 vs. 1 out of 10 in wild type) and duration of AF episodes was longer compared with wild type mice (maximum episode duration 42.8 ± 68.4 vs. 0.23 ± 0.39 s). In six goats with persistent AF treated with nadroparin, targeting Factor Xa-mediated thrombin generation, the complexity of the AF substrate was less pronounced than in control animals (LA maximal activation time differences 23.3 ± 3.1 ms in control vs. 15.7 ± 2.1 ms in nadroparin, P < 0.05). In the treated animals, AF-induced α-smooth muscle actin expression was lower and endomysial fibrosis was less pronounced. Conclusion The hypercoagulable state during AF causes pro-fibrotic and pro-inflammatory responses in adult atrial fibroblasts. Hypercoagulability promotes the development of a substrate for AF in transgenic mice and in goats with persistent AF. In AF goats, nadroparin attenuates atrial fibrosis and the complexity of the AF substrate. Inhibition of coagulation may not only prevent strokes but also inhibit the development of a substrate for AF.
- Publication
European Heart Journal, 2017, Vol 38, Issue 1, p38
- ISSN
0195-668X
- Publication type
Article
- DOI
10.1093/eurheartj/ehw119