Department of Cardiology, Shanghai General Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China; Department of Cardiology, First Affiliated Hospital of Soochow University, Suzhou City, Jiangsu Province, China.
Department of Cardiology, Shanghai General Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
Heart Rhythm. 2023 Dec;20(12):1759-1770. doi: 10.1016/j.hrthm.2023.08.026. Epub 2023 Aug 25.
Atrial fibrillation (AF) has been accepted as an inflammatory atrial myopathy. Interleukin 6 (IL-6)-dependent inflammatory signaling pathways take context-dependent effects on cardiovascular diseases. IL-6 trans-signaling is predominantly pro-inflammatory. However, its effect on AF is unclear.
The purpose of this study was to investigate the role of IL-6 trans-signaling in AF.
Circulating levels of IL-6, soluble IL-6 receptor, and soluble glycoprotein 130 (sgp130) in patients with AF and controls were measured to estimate the activation of IL-6 trans-signaling. A mouse model of AF was established by transverse aortic constriction surgery. Sgp130Fc administration was used for the selective blockade of IL-6 trans-signaling. Studies were conducted to evaluate the effects and underlying mechanisms of sgp130Fc on AF inducibility and atrial conduction abnormalities and structural remodeling.
In patients, the elevation of IL-6 trans-signaling level was positively associated with AF occurrence. IL-6 trans-signaling activation was recapitulated in the mouse model of AF. In transverse aortic constriction-challenged mice, the selective blockade of IL-6 trans-signaling with sgp130Fc attenuated AF inducibility, which was attributable to the amelioration of slow conduction and conduction heterogeneity induced by atrial dilation, fibrosis, and reduction in connexin 40 and redistribution of connexin 43. Sgp130Fc administration also reduced immune cell infiltration and oxidative stress in the mouse atrium and abrogated IL-6 trans-signaling activation-mediated connexin dysregulation and reactive oxygen species production in atrial myocytes.
IL-6 trans-signaling activation contributes to AF development, and its selective blockade may promise a novel therapeutic strategy.
心房颤动（AF）已被认为是一种炎症性心房心肌病。白细胞介素 6（IL-6）依赖性炎症信号通路对心血管疾病具有上下文依赖性影响。IL-6 转信号主要是促炎的。然而，其对 AF 的影响尚不清楚。
本研究旨在探讨 IL-6 转信号在 AF 中的作用。
测量 AF 患者和对照组患者循环中 IL-6、可溶性 IL-6 受体和可溶性糖蛋白 130（sgp130）的水平，以评估 IL-6 转信号的激活情况。通过横主动脉缩窄手术建立 AF 小鼠模型。sgp130Fc 给药用于选择性阻断 IL-6 转信号。进行研究以评估 sgp130Fc 对 AF 易感性、心房传导异常和结构重塑的影响及其潜在机制。
在患者中，IL-6 转信号水平的升高与 AF 的发生呈正相关。AF 小鼠模型中重现了 IL-6 转信号的激活。在横主动脉缩窄挑战的小鼠中，sgp130Fc 选择性阻断 IL-6 转信号可减轻 AF 的易感性，这归因于心房扩张、纤维化、连接蛋白 40 减少和连接蛋白 43 重新分布引起的缓慢传导和传导异质性的改善。sgp130Fc 给药还减少了小鼠心房中的免疫细胞浸润和氧化应激，并阻断了 IL-6 转信号激活介导的连接蛋白失调和心房肌细胞中活性氧的产生。
IL-6 转信号的激活有助于 AF 的发展，其选择性阻断可能提供一种新的治疗策略。
