POAF occurs in 30% of patients undergoing cardiac surgery and increases short- and long-term morbidity and mortality. Generally a transient phenomenon, POAF incidence peaks 48-72h after surgery. The underlying mechanisms are incompletely understood, and clinical management remains challenging. Pre-existing Ca²⁺-handling abnormalities and NLRP3-inflammasome/CaMKII signaling have been identified as molecular substrates sensitizing atrial cardiomyocytes to the proarrhythmic influence of inflammatory mediators. Cardiopulmonary bypass leads to acute and substantial increases in the activation of thrombin, which elicits coagulation-independent pro-inflammatory actions via protease-activated receptors (PAR). The role of PAR in the context of POAF is unknown.

Right atrial appendages (RAA) of patients with no history of AF and low pre-operative plasma C-reactive protein were collected prior to cardiac surgery. RAA from patients who subsequently developed POAF exhibited higher abundance of thrombin receptors PAR1 and PAR4 in whole tissue lysates and at the cardiomyocyte level, compared to RAA from patients remaining in sinus rhythm.

Exposure of HL-1 atrial cardiomyocytes to physiological levels of thrombin (1 U/mL) increased expression and proteolytic activation of the NLRP3 inflammasome effector caspase-1, the caspase-1 maturation product IL-1β, and the pyroptotic pore protein gasdermin D. IL-1β secretion from HL-1 cells was significantly stimulated by PAR4-activating peptide (AP) but not PAR1-AP. PAR4-AP additionally increased phosphorylation of CamKII as well as AKT, mTOR and P70S6K in HL-1 cells. Atria from PAR4^-/- mice expressed lower levels of activated caspase-1, IL-1β and total and phospho-mTOR compared to atria from wild-type littermates. Atria from mice subjected to sham hepatectomy, as a model of vascular surgery, showed transient post-operative upregulation of PAR4, coinciding with elevated CamKII, IL-1β and total and phosphorylated mTOR.

Taken together, upregulated thrombin receptor PAR4 may contributes to the molecular substrate predisposing to POAF, mediating pro-arrhythmic signaling through AKT/mTOR, CamKII and the NLRP3 inflammasome in atrial cardiomyocytes. The emerging PAR4 antagonists provide a therapeutic perspective to improve clinical management of POAF.