Rivaroxaban treatment prevents atrial myocyte hypertrophy in goats with persistent atrial fibrillation by inhibition of protease-activated receptor-1

: Background Atrial fibrillation (AF) is associated with an increased risk of stroke and hypercoagulability. Coagulation factors mediate remodelling processes via protease-activated receptors (PARs) in various organs. Objectives We evaluated whether inhibition of Factor Xa (FXa) via rivaroxaban protects against atrial structural remodelling 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 ± 42nM vs. final: 69 ± 33nM). 16 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: 4-fold; NPPB: 22-fold) and pro-fibrotic (COL1A1: 3-fold) gene expression. Rivaroxaban fully prevented hypertrophy (12.2 µm [95%CI: 11.7, 12.7]) and downregulated inflammatory signalling 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 signalling.