Interactions between metabolism regulator adiponectin and intrinsic cardiac autonomic nervous system: A potential treatment target for atrial fibrillation

• Published in: International journal of cardiology Vol. 302; pp. 59 - 66
• Main Authors: Zhou, Zhen, Li, Shuyan, Sheng, Xia, Liu, Zhihao, Lai, Yanqiu, Wang, Menglong, Wang, Zhenya, Zhou, Liping, Meng, Guannan, Chen, Hu, Zhou, Huixin, Zhou, Xiaoya, Jiang, Hong
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 01.03.2020
• Subjects: Adiponectin; Adiponectin - metabolism; Animals; Atrial fibrillation; Atrial Fibrillation - metabolism; Atrial Fibrillation - physiopathology; Atrial Fibrillation - therapy; Atrial Remodeling; Autonomic nervous system; Autonomic Nervous System - metabolism; Autonomic Nervous System - physiopathology; Biomarkers - metabolism; Cardiac Pacing, Artificial - methods; Disease Models, Animal; Dogs; Ganglionated plexi; Heart Atria - physiopathology; Heart Conduction System - physiopathology; Male; Proinflammatory cytokine; Autonomic nervous system; Ganglionated plexi; Atrial fibrillation; Proinflammatory cytokine; Adiponectin
• ISSN: 0167-5273; 1874-1754
• DOI: 10.1016/j.ijcard.2019.12.031

Previous studies indicated that inhibiting the cardiac autonomic nervous system (CANS) suppressed atrial fibrillation (AF). Clinical research revealed serum adiponectin (APN) exerted a beneficial influence on sympathetic and vagal tone in patients with type 2 diabetes. However, the effects of APN on CANS is unknown. This study aims to investigate whether APN could regulate CANS and suppress rapid atrial pacing (RAP)-induced AF. Eighteen beagles were divided into the control group (saline plus sham RAP, N = 6), the RAP group (saline plus RAP, N = 6) and the APN + RAP group (APN plus RAP, N = 6). APN (10 μg, 0.1 μg/μL) or saline was microinjected into 4 major ganglionated plexi (GP) prior to RAP. Atrial electrophysiological parameters, anterior right GP (ARGP) function, neural activity and GP tissues were detected. Compared with the control treatment, RAP shortened effective refractory period (ERP) values at all sites and increased cumulative window of vulnerability (ΣWOV), ARGP function and neural activity, whereas APN injection reversed these changes. Mechanistically, APN ameliorated RAP-induced inflammatory response and down-regulated the expression of c-fos protein and nerve growth factor. Moreover, the APN receptors 1 and APN receptors 2 were detected both in neurons and in non-neuronal cells. APN pretreatment activated downstream adenosine monophosphate-activated protein kinase (AMPK) signaling, inhibited nuclear factor-kappa B signaling and promoted macrophage phenotype switching from proinflammatory to anti-inflammatory state. This study demonstrates that administration of APN into GP can suppress RAP-induced AF by regulating the CANS. APN signaling may provide a potential therapeutic target to AF. Schematic diagram illustrating how adiponectin exerted anti-atrial fibrillation effect. Rapid atrial pacing (RAP) at the left atrial appendage activated the intrinsic cardiac autonomic system, resulted in the atrial ganglionated plexi (GP) remodeling, and increased the expression of proinflammatory cytokines in GP fat pads. However, Local injection of adiponectin inhibited the GP activity and decreased the atrial fibrillation inducibility via two different pathways. In the direct pathway, adiponectin directly acted on the GP neurons via adiponectin receptors (AdipoRs) and downstream pathway, ameliorated RAP induced neural remodeling. In the indirect pathway, adiponectin switched the macrophages around the GP to an anti-inflammatory phenotype, which further attenuated neuroinflammation in the GP fat pads and decreased GP activity, subsequently decreased atrial fibrillation inducibility. [Display omitted] •Adiponectin directly regulated cardiac ganglionated plexi activity and inhibited rapid pacing-induced atrial fibrillation.•Adiponectin is the link between epicardial adipose tissue and atrial fibrillation.•Pharmaceutical agents targeting adiponectin or its receptors signaling may work in patients with atrial fibrillation.