Thrombin receptor protease-activated receptor 1 (PAR1) related cytotoxic CD8+ T cell activity is associated with atrial myopathy and pro-inflammatory immune response in early atrial fibrillation

Abstract Background and aims Cytotoxic CD8+ T cells mediate myocardial damage in patients with virus induced myocarditis, plaque erosion during acute coronary syndrome, promote adverse post-ischemic cardiac remodeling. There is emerging evidence to support a link between inflammation atrial fibrillation (AF). Protease-activated receptor 1 (PAR1) the thrombin expressed on platelets, but it also endothelial cells, vascular smooth muscle fibroblasts, cells. The role of PAR1 myopathy early AF have not been studied. Methods In 80 non-anticoagulated first documented episode AF, 20 control subjects without comparable cardiovascular risk profile (e.g. SCORE2, CHA2DS2-VASc, p>0.05), we studied PAR1-related cytotoxic cell activity hours (up 24 h) clinical manifestation. Apolipoprotein E–knock out (ApoEko) mouse commonly used model metabolic syndrome that develops (structural correlate AF). ApoEko male mice (Apoetm1Unc C57BL/6 genetic background) were fed for six weeks standard chew, western-type diet (high fat high sucrose = WD) ± specific inhibitor vorapaxar. Results High levels circulating, activated (CD8+CD57+ pro-inflammatory properties) present (flow cytometry). Stimulation PAR1, isolated from new onset released cytokines IFN-γ, TNF-α). Enhanced was suggested by elevated plasma effector molecules granulysin granzyme). WD, as structural paralleled increased expression associated (like perforin, granzyme A, B, IFN-γ). disrupted release potective natriuretic peptide, ANP, signaling pathways fibrosis TGF-β, cTGF, TGF-β receptor). inhibitor, vorapaxar, reduced inflammatory activity, transcription fibrotic mediators, reconstituted ANP secretion atria mice. Conclusions Targeting FXa/FIIa-PAR1-CD8+ axis might be promising approach reduce inflammation. Funding Acknowledgement Type funding sources: Public grant(s) – National budget only. Main source(s): BIH Charité Clinician Scientist Program