α-adrenoceptor-mediated enhanced inducibility of atrial fibrillation in a canine system inflammation model

Abstract

The exact mechanism associated with inflammation and atrial fibrillation (AF) remains unknown. The aim of the present study was to investigate the roles of connexin 43 (Cx43) and a1‑adrenergic receptor (α1‑AR) activation in the pathogenesis of system inflammation‑induced AF. A canine model of chronic low‑grade system inflammation was established by administrating a low dose of lipopolysaccharide (LPS; 0.1 µg/kg) for 2 weeks. Programmed stimulation was applied on the right atrial appendage to determine the effective refractory periods (ERP) and the window of vulnerability (WOV). Tumor necrosis factor α (TNF‑α) and interleukin 6 (IL‑6) levels in plasma and atrial tissue were measured by ELISA. Cx43, Toll‑like receptor 4 (TLR4) and nuclear factor κB (NF‑κB) proteins were analyzed using western blotting or immunohistochemistry. Administration of LPS for 2 weeks increased the concentration of TNF‑α and IL‑6 in the plasma and right atrium. ERP was markedly shortened and cumulative WOV was significantly widened in the LPS group. Following treatment with LPS, the amount of Cx43 protein in the area of intercalated disk increased. In addition, a high‑density of Cx43 in the lateral connection was identified. LPS also induced the activation of NF‑κB in the canine atrium. Administration with the α1‑AR blocker doxazosin prevented the production of LPS‑induced inflammatory cytokine and reversed the enhanced vulnerability to atrial fibrillation. Doxazosin inhibited the LPS‑induced increase in Cx43 protein and heterogeneous distribution, and prevented the activation of NF‑κB. These results indicated that chronic low‑grade system inflammation may increase the inducibility of AF in a canine model. The underlying mechanism may be involved in the LPS‑induced activation of NF‑κB, and the increase in Cx43 expression and lateral distribution via an α1-AR-dependent pathway.

Gut microbiota, dysbiosis and atrial fibrillation. Arrhythmogenic mechanisms and potential clinical implications

“…56 In a canine model, administration of LPS increases the atrial concentration of pro-inflammatory cytokines, thereby increasing connexin 43 expression and causing connexin lateralization. 57 LPS down-regulates the expression of L-type calcium channels (a1C and b2 subunits) and abbreviates the effective refractory period. 58 Abnormal calcium handling and connexin modulation are potential mechanisms underlying inducible AF.…”

Muscarinic receptor regulation of chronic pain-induced atrial fibrillation

“…The noradrenergic might contribute to AF vulnerability in CCI chronic pain mice, as shown in our research β-receptor blocker propranolol preventing TEB induction AF occurrence in one mouse, although these data failed to reach statistical significance. α1 receptor is a G-protein-coupled receptor and causes Ca 2+ release from SR by generating IP3 and DAD, which thought may contribute to atrial fibrillation ( 20 , 38 , 39 ). There was no effect on the AF occurrence between the two groups by pretreatment of α-blocker phentolamine.…”

Sugar Fructose Triggers Gut Dysbiosis and Metabolic Inflammation with Cardiac Arrhythmogenesis

“…The administration of LPS in a canine model caused increases in the levels of TNF-α and IL-6 in circulation and the right atrium [90]. The underlying mechanism may involve the LPS-induced activation of NF-κB and an increase in both connexin 43 expression and lateral distribution through the α1-adrenergic receptor-dependent pathway that promotes AF inducibility in LPS-induced systemic inflammation [90]. Moreover, the LPS-TLR4 axis mediates NLRP3 inflammasome activation and induces the secretion of IL-1β/IL-18, which promotes cardiac inflammation [91].…”

“…In patients with AF, serum LPS levels predicted the occurrence of major adverse cardiovascular events and were inversely associated with adherence to a Mediterranean diet (Med-diet) [71]. The administration of LPS in a canine model caused increases in the levels of TNF-α and IL-6 in circulation and the right atrium [90]. The underlying mechanism may involve the LPS-induced activation of NF-κB and an increase in both connexin 43 expression and lateral distribution through the α1-adrenergic receptor-dependent pathway that promotes AF inducibility in LPS-induced systemic inflammation [90].…”