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CC BY 4.0 · Thromb Haemost
DOI: 10.1055/a-2761-6106
Original Article: Coagulation and Fibrinolysis

Rivaroxaban Treatment Prevents Atrial Myocyte Hypertrophy in Goats with Persistent Atrial Fibrillation by Inhibition of Protease-Activated Receptor-1

Authors

  • Elisa D'Alessandro

    1   Department of Physiology, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University Medical Center (MUMC), Maastricht, The Netherlands

  • Billy Scaf

    1   Department of Physiology, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University Medical Center (MUMC), Maastricht, The Netherlands

  • Dragan Opačić

    1   Department of Physiology, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University Medical Center (MUMC), Maastricht, The Netherlands
    2   Clinic for Thoracic- and Cardiovascular Surgery, Heart and Diabetes Center North Rhine-Westphalia, Bad Oeynhausen, Germany

  • Arne van Hunnik

    1   Department of Physiology, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University Medical Center (MUMC), Maastricht, The Netherlands

  • Vladimír Sobota

    1   Department of Physiology, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University Medical Center (MUMC), Maastricht, The Netherlands
    3   Department of Physiology, Faculty of Medicine, Masaryk University, Brno, Czech Republic

  • Marion Kuiper

    1   Department of Physiology, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University Medical Center (MUMC), Maastricht, The Netherlands

  • Marian Viola

    4   Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy

  • Thomas Hutschalik

    1   Department of Physiology, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University Medical Center (MUMC), Maastricht, The Netherlands

  • Marianna Langione

    4   Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy

  • Josè M. Pioner

    4   Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy

  • Chantal Munts

    1   Department of Physiology, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University Medical Center (MUMC), Maastricht, The Netherlands

  • Jorik Simons

    1   Department of Physiology, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University Medical Center (MUMC), Maastricht, The Netherlands

  • Joris Winters

    1   Department of Physiology, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University Medical Center (MUMC), Maastricht, The Netherlands

  • Aaron Isaacs

    1   Department of Physiology, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University Medical Center (MUMC), Maastricht, The Netherlands
    5   Maastricht Centre for Systems Biology (MaCSBio), Maastricht University, Maastricht, The Netherlands

  • Stefan Heitmeier

    6   Bayer AG, Wuppertal, Germany

  • Monika Stoll

    7   Institute of Human Genetics, University of Münster, Münster, Germany
    8   Departments of Biochemistry and Internal Medicine, CARIM, MUMC, Maastricht, The Netherlands

  • René van Oerle

    8   Departments of Biochemistry and Internal Medicine, CARIM, MUMC, Maastricht, The Netherlands

  • Hugo ten Cate 

    8   Departments of Biochemistry and Internal Medicine, CARIM, MUMC, Maastricht, The Netherlands
    9   Center for Thrombosis and Hemostasis, Gutenberg University Medical Center, Mainz, Germany

  • Henri M. H. Spronk

    8   Departments of Biochemistry and Internal Medicine, CARIM, MUMC, Maastricht, The Netherlands

  • Sander Verheule

    1   Department of Physiology, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University Medical Center (MUMC), Maastricht, The Netherlands

  • Frans A. van Nieuwenhoven

    1   Department of Physiology, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University Medical Center (MUMC), Maastricht, The Netherlands

  • Ulrich Schotten

    1   Department of Physiology, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University Medical Center (MUMC), Maastricht, The Netherlands

Funding Information This work was supported by grants of the Netherlands Heart Foundation (CVON2014-09, RACE V Reappraisal of Atrial Fibrillation: Interaction between Hypercoagulability, Electrical remodeling, and Vascular Destabilisation in the Progression of AF, and grant number: 01-002-2022-0118, EmbRACE: Electro-Molecular Basis and the Rapeutic Management of Atrial Cardiomyopathy, Fibrillation, and Associated Outcomes) and the European Union (ITN Network Personalize AF: Personalized Therapies for Atrial Fibrillation: A Translational Network, grant number: 860974; CATCH ME: Characterizing Atrial fibrillation by Translating its Causes into Health Modifiers in the Elderly, grant number: 633196; MAESTRIA: Machine Learning Artificial Intelligence Early Detection Stroke Atrial Fibrillation, grant number: 965286; REPAIR: Restoring Cardiac Mechanical Function by Polymeric Artificial Muscular Tissue, grant number: 952166), and by the Leducq Foundation (2024, Immune Targets of Atrial Fibrillation).
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Graphical Abstract

Abstract

Background

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.

Objective

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).

Methods

Three groups of goats were tested: CTRL AF (control AF, n = 10), RIVA AF (rivaroxaban treatment during AF, n = 11), and SHAM (no AF, n = 10). 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 hours.

Results

Rivaroxaban inhibited thrombin generation in RIVA AF goats (baseline: 249 ± 42 nM vs. final: 69 ± 33 nM). Sixteen weeks of AF induced atrial myocyte hypertrophy in CTRL AF (13.5 µm [95% CI: 12.9, 14.0] vs. SHAM: 12.5 µm [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 µm [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.

Conclusion

Prolonged rivaroxaban treatment reduces thrombin generation, preventing AF-induced atrial myocyte hypertrophy through inhibition of PAR-1 signaling.

Keywords

atrial fibrillation - activated coagulation factors - protease-activated receptor-1 - atrial myocyte hypertrophy - rivaroxaban

Note

Portions of this manuscript are based on the doctoral dissertation of Scaf and D'Alessandro.[23]


Supplementary Material



Publication History

Received: 16 September 2025

Accepted after revision: 02 December 2025

Accepted Manuscript online:
08 January 2026

Article published online:
19 January 2026

© 2026. The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution License, permitting unrestricted use, distribution, and reproduction so long as the original work is properly cited. (https://creativecommons.org/licenses/by/4.0/)

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