{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,20]],"date-time":"2026-01-20T15:05:45Z","timestamp":1768921545880,"version":"3.49.0"},"reference-count":53,"publisher":"Georg Thieme Verlag KG","license":[{"start":{"date-parts":[[2026,1,8]],"date-time":"2026-01-08T00:00:00Z","timestamp":1767830400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100000780","name":"European Union","doi-asserted-by":"crossref","award":["633196,860974,952166,965286"],"award-info":[{"award-number":["633196,860974,952166,965286"]}],"id":[{"id":"10.13039\/501100000780","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100001674","name":"Fondation Leducq","doi-asserted-by":"crossref","id":[{"id":"10.13039\/501100001674","id-type":"DOI","asserted-by":"crossref"}]},{"name":"Netherlands Heart Foundation","award":["01-002-2022-0118,CVON2014-09"],"award-info":[{"award-number":["01-002-2022-0118,CVON2014-09"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Thromb Haemost"],"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Atrial fibrillation (AF) is associated with an increased risk of stroke and hypercoagulability. Coagulation factors mediate remodeling processes via protease-activated receptors (PARs) in various organs.<\/jats:p>\n                  <jats:p>We evaluated whether inhibition of factor Xa (FXa) via rivaroxaban protects against atrial structural remodeling in goats with persistent AF and explored FXa and thrombin hypertrophic effect on human iPSC-derived cardiomyocytes (hiPSC-CMs).<\/jats:p>\n                  <jats:p>Three groups of goats were tested: CTRL AF (control AF, n\u2009=\u200910), RIVA AF (rivaroxaban treatment during AF, n\u2009=\u200911), and SHAM (no AF, n\u2009=\u200910). Pacing-induced AF was maintained for 16 weeks. AF stability, hemodynamics, and AF complexity were assessed. Atrial samples were collected for histological and gene expression analyses. hiPSC-CM were stimulated with PAR-1 agonist TRAP14, FXa, or thrombin with and without their inhibitors. Pro-hypertrophic and pro-inflammatory gene expression was assessed by qRT-PCR after 24\u2009hours.<\/jats:p>\n                  <jats:p>Rivaroxaban inhibited thrombin generation in RIVA AF goats (baseline: 249\u2009\u00b1\u200942\u2009nM vs. final: 69\u2009\u00b1\u200933\u2009nM). Sixteen weeks of AF induced atrial myocyte hypertrophy in CTRL AF (13.5\u2009\u00b5m [95% CI: 12.9, 14.0] vs. SHAM: 12.5\u2009\u00b5m [95% CI: 12.0, 13.0]) and pro-hypertrophic (NPPA: fourfold; NPPB: 22-fold) and pro-fibrotic (COL1A1: threefold) gene expression. Rivaroxaban fully prevented hypertrophy (12.2\u2009\u00b5m [95% CI: 11.7, 12.7]) and downregulated inflammatory signaling without altering hemodynamics and AF stability. In hiPSC-CM, thrombin and TRAP14 induced overexpression of the pro-hypertrophic genes NPPA and NPPB. The PAR1 antagonist, SCH79797, prevented thrombin-induced NPPA and NPPB upregulation.<\/jats:p>\n                  <jats:p>Prolonged rivaroxaban treatment reduces thrombin generation, preventing AF-induced atrial myocyte hypertrophy through inhibition of PAR-1 signaling.<\/jats:p>","DOI":"10.1055\/a-2761-6106","type":"journal-article","created":{"date-parts":[[2026,1,9]],"date-time":"2026-01-09T00:55:36Z","timestamp":1767920136000},"source":"Crossref","is-referenced-by-count":0,"title":["Rivaroxaban Treatment Prevents Atrial Myocyte Hypertrophy in Goats with Persistent Atrial Fibrillation by Inhibition of Protease-Activated Receptor-1"],"prefix":"10.1055","author":[{"given":"Elisa","family":"D'Alessandro","sequence":"additional","affiliation":[{"name":"Department of Physiology, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University Medical Center (MUMC), Maastricht, The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Billy","family":"Scaf","sequence":"additional","affiliation":[{"name":"Department of Physiology, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University Medical Center (MUMC), Maastricht, The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Dragan","family":"Opa\u010di\u0107","sequence":"additional","affiliation":[{"name":"Department of Physiology, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University Medical Center (MUMC), Maastricht, The Netherlands"},{"name":"Clinic for Thoracic- and Cardiovascular Surgery, Heart and Diabetes Center North Rhine-Westphalia, Bad Oeynhausen, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Arne","family":"van Hunnik","sequence":"additional","affiliation":[{"name":"Department of Physiology, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University Medical Center (MUMC), Maastricht, The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Vladim\u00edr","family":"Sobota","sequence":"additional","affiliation":[{"name":"Department of Physiology, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University Medical Center (MUMC), Maastricht, The Netherlands"},{"name":"Department of Physiology, Faculty of Medicine, Masaryk University, Brno, Czech Republic"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Marion","family":"Kuiper","sequence":"additional","affiliation":[{"name":"Department of Physiology, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University Medical Center (MUMC), Maastricht, The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Marian","family":"Viola","sequence":"additional","affiliation":[{"name":"Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Thomas","family":"Hutschalik","sequence":"additional","affiliation":[{"name":"Department of Physiology, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University Medical Center (MUMC), Maastricht, The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Marianna","family":"Langione","sequence":"additional","affiliation":[{"name":"Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jos\u00e8 M.","family":"Pioner","sequence":"additional","affiliation":[{"name":"Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Chantal","family":"Munts","sequence":"additional","affiliation":[{"name":"Department of Physiology, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University Medical Center (MUMC), Maastricht, The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jorik","family":"Simons","sequence":"additional","affiliation":[{"name":"Department of Physiology, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University Medical Center (MUMC), Maastricht, The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Joris","family":"Winters","sequence":"additional","affiliation":[{"name":"Department of Physiology, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University Medical Center (MUMC), Maastricht, The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Aaron","family":"Isaacs","sequence":"additional","affiliation":[{"name":"Department of Physiology, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University Medical Center (MUMC), Maastricht, The Netherlands"},{"name":"Maastricht Centre for Systems Biology (MaCSBio), Maastricht University, Maastricht, The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Stefan","family":"Heitmeier","sequence":"additional","affiliation":[{"name":"Bayer AG, Wuppertal, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Monika","family":"Stoll","sequence":"additional","affiliation":[{"name":"Institute of Human Genetics, University of M\u00fcnster, M\u00fcnster, Germany"},{"name":"Departments of Biochemistry and Internal Medicine, CARIM, MUMC, Maastricht, The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ren\u00e9","family":"van Oerle","sequence":"additional","affiliation":[{"name":"Departments of Biochemistry and Internal Medicine, CARIM, MUMC, Maastricht, The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7796-4463","authenticated-orcid":false,"given":"Hugo","family":"ten Cate","sequence":"additional","affiliation":[{"name":"Departments of Biochemistry and Internal Medicine, CARIM, MUMC, Maastricht, The Netherlands"},{"name":"Center for Thrombosis and Hemostasis, Gutenberg University Medical Center, Mainz, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Henri M. H.","family":"Spronk","sequence":"additional","affiliation":[{"name":"Departments of Biochemistry and Internal Medicine, CARIM, MUMC, Maastricht, The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sander","family":"Verheule","sequence":"additional","affiliation":[{"name":"Department of Physiology, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University Medical Center (MUMC), Maastricht, The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Frans A.","family":"van Nieuwenhoven","sequence":"additional","affiliation":[{"name":"Department of Physiology, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University Medical Center (MUMC), Maastricht, The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ulrich","family":"Schotten","sequence":"additional","affiliation":[{"name":"Department of Physiology, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University Medical Center (MUMC), Maastricht, The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"194","published-online":{"date-parts":[[2026,1,19]]},"reference":[{"issue":"08","key":"ref1","doi-asserted-by":"crossref","first-page":"983","DOI":"10.1161\/01.STR.22.8.983","article-title":"Atrial fibrillation as an independent risk factor for stroke: the Framingham Study","volume":"22","author":"P A Wolf","year":"1991","journal-title":"Stroke"},{"issue":"18","key":"ref2","doi-asserted-by":"crossref","first-page":"2370","DOI":"10.1001\/jama.285.18.2370","article-title":"Prevalence of diagnosed atrial fibrillation in adults: national implications for rhythm management and stroke prevention: the anticoagulation and risk factors in atrial fibrillation (ATRIA) study","volume":"285","author":"A S Go","year":"2001","journal-title":"JAMA"},{"issue":"09","key":"ref3","doi-asserted-by":"crossref","first-page":"1042","DOI":"10.1161\/01.CIR.0000140263.20897.42","article-title":"Lifetime risk for development of atrial fibrillation: the Framingham Heart Study","volume":"110","author":"D M Lloyd-Jones","year":"2004","journal-title":"Circulation"},{"issue":"08","key":"ref4","doi-asserted-by":"crossref","first-page":"949","DOI":"10.1093\/eurheartj\/ehi825","article-title":"Prevalence, incidence and lifetime risk of atrial fibrillation: the Rotterdam study","volume":"27","author":"J Heeringa","year":"2006","journal-title":"Eur Heart J"},{"issue":"11","key":"ref5","doi-asserted-by":"crossref","first-page":"3103","DOI":"10.1161\/STROKEAHA.113.002329","article-title":"Atrial fibrillation, stroke risk, and warfarin therapy revisited: a population-based study","volume":"44","author":"S Bj\u00f6rck","year":"2013","journal-title":"Stroke"},{"issue":"01","key":"ref6","doi-asserted-by":"crossref","first-page":"47","DOI":"10.1161\/01.STR.21.1.47","article-title":"Coagulation factors and the increased risk of stroke in nonvalvular atrial fibrillation","volume":"21","author":"C Gustafsson","year":"1990","journal-title":"Stroke"},{"issue":"03","key":"ref7","doi-asserted-by":"crossref","first-page":"425","DOI":"10.1161\/01.CIR.94.3.425","article-title":"Fibrin D-dimer and beta-thromboglobulin as markers of thrombogenesis and platelet activation in atrial fibrillation. 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