Toll-like receptor 4 activation modulates pericardium-myocardium interactions in lipopolysaccharide-induced atrial arrhythmogenesis

Aims Inflammation plays a role in the pathogenesis of atrial fibrillation (AF). Pericarditis enhanced atrial arrhythmogenesis, but the role of the pericardium remains unclear in AF. Activation of the toll-like receptor 4 (TLR4) by binding to lipopolysaccharide (LPS) promotes cardiac electrical remodelling. In this study, we hypothesized that pericarditis may induce atrial arrhythmogenesis via pericardium-myocardium interactions by TLR4 signalling. Methods and results Pericarditis was induced in rabbits by injecting LPS (1-2mg/kg) into the pericardium. Conventional microelectrodes were used to record the action potentials of left atrial (LA) posterior walls (LAPWs) and LA appendages (LAAs) with and without attached pericardium in the control or pericarditis-induced rabbits. Cytokine array was used to measure the expression levels of proinflammatory cytokines in control and LPS-treated pericardium. Compared with the controls, the LPS-treated pericardium had higher expressions of IL-1 alpha, IL-8, and MIP-1 beta. Rapid atrial pacing-induced burst firing in LPS-treated LAPWs and LAAs, and in control LAPWs (but not in LAAs). The incidence of pacing-induced spontaneous activity and burst firing was increased by LPS-treated pericardium but was attenuated by the control pericardium. Moreover, burst firing induced by LPS-treated pericardium was blocked upon administration of the TLR4 inhibitor, TAK-242 (100ng/mL), ryanodine receptor inhibitor (ryanodine, 3 mu M), or calmodulin kinase II inhibitor (KN-93, 1 mu M). Conclusions Healthy and inflamed pericardium differently modulate LPS-induced atrial arrhythmogenesis. Targeting pericardium via TLR4 signalling may be a novel therapeutic strategy for AF.

Automated summary

Pericarditis induced by lipopolysaccharide activates TLR4 signaling, leading to atrial arrhythmogenesis. Targeting pericardium via TLR4 signaling may be a novel therapeutic strategy for atrial fibrillation.