Atrial endothelial impairment through Toll-like receptor 4 signaling causes atrial thrombogenesis

Low-grade inflammation associated with heart failure (HF) is known to deteriorate cardioembolic stroke in patients with atrial fibrillation (AF). Little is known about the relationship between atrial endothelial impairment induced by innate immunity and thrombus formation. We examined whether atrial endothelial impairment through Toll-like receptor (TLR) 4 signaling causes atrial thrombogenesis. TLR4, heat shock protein 60, and vascular cell adhesion molecule (VCAM)-1 expression were higher in the atrium of AF patients who underwent valve replacement surgery with HF compared with those without it (p < 0.05). We created thoracic transverse aortic constriction (TAC) in TLR4 knock-out (KO) and wild-type (WT) mice. Atrial thrombosis was observed less frequently in TLR4 KO mice (4/15) than in WT mice (16/20) 4 weeks after TAC despite similar severity of heart failure. The decrease in endothelial nitric oxide synthase (eNOS) phosphorylation and increase in VCAM-1 and plasminogen activator inhibitor (PAI)-1 expression, observed in the atrium of WT mice following TAC, were significantly attenuated in TLR4 KO mice (p < 0.05). Nuclear factor-κB (NF-κB) activation after TAC was attenuated in TLR4 KO mice compared with WT mice. Activation of mitogen-activated protein kinase p38 (p38) after TAC was also attenuated in TLR4 KO mice (p < 0.05). Thus, increased VCAM-1 and PAI-1, and decreased eNOS phosphorylation through the TLR4/NFκB/p38 pathway, may be associated with atrial thrombogenesis in the heart failure mice model. Atrial endothelial impairment through the TLR4 signaling may play a role in atrial thrombogenesis in AF patients with HF.