| Summary: | Background: Atrial myopathy and atrial fibrillation (AF) accompany thrombo-inflammation. This facilitates disease progression and promotes major adverse cardiovascular events (MACEs). Thrombin receptor (protease-activated receptor 1, PAR1) signalling is central in mediating thrombo-inflammation. We hypothesised that PAR1 signalling links coagulation and inflammation through cytotoxic CD8<sup>+</sup> T lymphocytes in patients presenting with first-diagnosed AF (FDAF). Methods: A total of 210 patients were studied. We included data and blood samples from patients presenting with FDAF (<i>n</i> = 160), cardiac tissue from patients with paroxysmal AF (<i>n</i> = 32) and 20 controls. Results: During early AF, a pro-inflammatory and cytotoxic subset of T lymphocytes (CD8<sup>+</sup>) circulated more frequently when compared to patients with chronic cardiovascular disease but without AF, accompanied by elevated plasma levels of CD8<sup>+</sup> effector molecules, which corresponded to biomarkers of adverse cardiac remodelling and atrial dysfunction. Activation of tissue factor (TF) and PAR1 was associated with pro-inflammatory and cytotoxic effector functions. PAR1-related CD8<sup>+</sup> cell activation was more frequent in FDAF patients that experienced a MACE. Conclusions: In patients with FDAF, the TF-factor Xa-factor IIa-axis contributes to thrombo-inflammation via PAR1 in CD8<sup>+</sup> T cells. Intervening in this cascade might be a promising synergistic approach to reducing disease progression and the vascular complications of AF.
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