title: Hypercoagulability causes atrial fibrosis and promotes atrial fibrillation.
abstract: 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.
  
  
  
  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 of3H-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.
  
  
  
  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.
authors.affiliation: Department of Biochemistry, Maastricht University, Maastricht, The Netherlands.|Department of Internal Medicine, Maastricht University, Maastricht, The Netherlands.
authors.forename: Henri M H
authors.initials: HM
authors.lastname: Spronk
authors.affiliation: Department of Cardiology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
authors.forename: Anne Margreet
authors.initials: AM
authors.lastname: De Jong
authors.affiliation: Department of Physiology, Maastricht University, PO Box 616, 6200 MD Maastricht, The Netherlands.
authors.forename: Sander
authors.initials: S
authors.lastname: Verheule
authors.affiliation: Department of Nephrology and the Einthoven Laboratory for Experimental Vascular Medicine, Leiden University Medical Centre, Leiden, The Netherlands.
authors.forename: Hetty C
authors.initials: HC
authors.lastname: De Boer
authors.affiliation: Department of Cardiology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
authors.forename: Alexander H
authors.initials: AH
authors.lastname: Maass
authors.affiliation: Department of Physiology, Maastricht University, PO Box 616, 6200 MD Maastricht, The Netherlands.
authors.forename: Dennis H
authors.initials: DH
authors.lastname: Lau
authors.affiliation: Department of Cardiology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
authors.forename: Michiel
authors.initials: M
authors.lastname: Rienstra
authors.affiliation: Department of Physiology, Maastricht University, PO Box 616, 6200 MD Maastricht, The Netherlands.
authors.forename: Arne
authors.initials: A
authors.lastname: van Hunnik
authors.affiliation: Department of Physiology, Maastricht University, PO Box 616, 6200 MD Maastricht, The Netherlands.
authors.forename: Marion
authors.initials: M
authors.lastname: Kuiper
authors.affiliation: Department of Physiology, Maastricht University, PO Box 616, 6200 MD Maastricht, The Netherlands.
authors.forename: Stijn
authors.initials: S
authors.lastname: Lumeij
authors.affiliation: Department of Physiology, Maastricht University, PO Box 616, 6200 MD Maastricht, The Netherlands.
authors.forename: Stef
authors.initials: S
authors.lastname: Zeemering
authors.affiliation: Klinik für Innere Medizin III, Universitätsklinikum des Saarlandes, Homburg, Germany.
authors.forename: Dominik
authors.initials: D
authors.lastname: Linz
authors.affiliation: Department of Vascular Medicine, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
authors.forename: Pieter Willem
authors.initials: PW
authors.lastname: Kamphuisen
authors.affiliation: Department of Biochemistry, Maastricht University, Maastricht, The Netherlands.|Department of Internal Medicine, Maastricht University, Maastricht, The Netherlands.
authors.forename: Hugo
authors.initials: H
authors.lastname: Ten Cate
authors.affiliation: Department of Cardiology, Academic Hospital Maastricht, Maastricht University, Maastricht, The Netherlands.
authors.forename: Harry J
authors.initials: HJ
authors.lastname: Crijns
authors.affiliation: Department of Cardiology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
authors.forename: Isabelle C
authors.initials: IC
authors.lastname: Van Gelder
authors.affiliation: Department of Nephrology and the Einthoven Laboratory for Experimental Vascular Medicine, Leiden University Medical Centre, Leiden, The Netherlands.
authors.forename: Anton Jan
authors.initials: AJ
authors.lastname: van Zonneveld
authors.affiliation: Department of Physiology, Maastricht University, PO Box 616, 6200 MD Maastricht, The Netherlands schotten@maastrichtuniversity.nl.
authors.forename: Ulrich
authors.initials: U
authors.lastname: Schotten
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D000991:Antithrombins / Q000494:pharmacology; D001281:Atrial Fibrillation / Q000209:etiology*; D049109:Cell Proliferation / Q000187:drug effects; D000069604:Dabigatran / Q000494:pharmacology; D005260:Female; D005343:Fibrinolytic Agents / Q000494:pharmacology; D005347:Fibroblasts / Q000187:drug effects; D005355:Fibrosis / Q000209:etiology; D006041:Goats; D006325:Heart Atria / Q000473:pathology; D007191:Indazoles / Q000494:pharmacology; D008822:Mice, Transgenic; D017762:Nadroparin / Q000494:pharmacology; D010447:Peptide Hydrolases / Q000187:drug effects; D011758:Pyrroles / Q000493:pharmacokinetics; D011799:Quinazolines / Q000493:pharmacokinetics; D051381:Rats; D018179:Receptors, Thrombin / Q000187:drug effects*; D013917:Thrombin / Q000494:pharmacology*; D019851:Thrombophilia / Q000503:physiopathology*; D014508:Urea / Q000031:analogs & derivatives / Q000494:pharmacology
chemical_list: D000991:Antithrombins; D005343:Fibrinolytic Agents; D007191:Indazoles; C415424:N3-cyclopropyl-7-((4-(1-methylethyl)phenyl)methyl)-7H-pyrrolo(3, 2-f)quinazoline-1,3-diamine; D017762:Nadroparin; D011758:Pyrroles; D011799:Quinazolines; C435606:RWJ-56110; D018179:Receptors, Thrombin; D014508:Urea; D010447:Peptide Hydrolases; D013917:Thrombin; D000069604:Dabigatran
keywords: Atrial fibrillation; Atrial fibrosis; Direct thrombin inhibitors; Hypercoagulability; Protease-activated receptors; Stroke