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

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

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