The Role Of Adiponectin In Atrial Fibrillation And The Autonomic Mechanism

Background The autonomic nervous system is closely related to atrial fibrillation(known as atrial fibrillation for short).Modulating cardiac autonomic nervous system can exert an anti-atrial fibrillation effect.Anatomical evidence shows that the cardiac autonomic ganglion plexi(GP)is surrounded by epicardial adipose tissue,and the volume of adipose tissue is significantly positively related to the incidence of atrial fibrillation.Adipose tissue is not only an thermogenic organ,but also an endocrine organ.It can secrete a variety of adipokines,such as leptin,adiponectin,resistin and so on.As an important adipokine,adiponectin has various physiological functions such as regulating glucose and lipid metabolism,anti-inflammatory,anti-oxidative stress,and anti-atherosclerosis.Recent clinical studies have shown that serum adiponectin plays a beneficial role in the regulation of sympathetic and vagus nerve tone in patients with type 2 diabetes.But the effect of adiponectin on cardiac autonomic nerve and atrial fibrillation remains unclear.Aim The purpose of this study was to investigate whether adiponectin can regulate cardiac autonomic nervous system activity,and to further explore the effect of adiponectin on rapid atrial pacing(RAP)-induced atrial fibrillation and its neural mechanism.Methods In this study,the beagles underwent bilateral thoracotomy after general anesthesia with 3% sodium pentobarbital.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).adiponectin(10 μg,0.1 mg/m L)or saline was microinjected into 4 major ganglionated plexi(GP)prior to RAP.Atrial electrophysiological parameters,anterior right GP(ARGP)function and neural activity were measured at the baseline level.During measurements,two tungsten microelectrodes were inserted into the atrial fat pad to record the frequency and amplitude of ARGP neuron discharge to reflect the cardiac autonomic nervous system.The multi-electrode catheter was fixed to the ARGP fat pad.And the degree(percent)of sinus rate reduction caused by voltage-increasing high-frequency electrical stimulation of ARGP reflected ARGP function.A multi-electrode catheter was fixed on the atria and pulmonary veins while measuring atrial electrophysiological parameters(the effective refractory period(ERP)of the atrial and pulmonary veins sites,the cumulative vulnerability window of atrial fibrillation(ΣWOV))at different timepoints.Subsequently,saline(Control group and RAP group)or adiponectin(APN + RAP group)were microinjected into four main atrial ganglionated plexi: the inferior right ganglionated plexi(IRGP),the superior left ganglionated plexi(SLGP),inferior left ganglionated plexi(ILGP).The indicators above were then measured again at the end of the 3-hour RAP.After the experiment,the beagles were euthanized.And GP tissues were retained for western blot(WB)analysis,real-time polymerase chain reaction(RT-PCR),and histopathological staining.Results Compared with the control treatment,RAP shortened effective refractory period(ERP)values at all sites(P <0.05)and increased cumulative window of vulnerability(ΣWOV)(P <0.05),whereas adiponectin injection reversed these changes.In addition,adiponectin administration before RAP significantly inhibited ARGP function and neural activity(P <0.05)in the AF model.Mechanistically,the APN receptors 1 and adiponectin receptors 2 were detected both in neurons and in non-neuronal cells.Adiponectin microinjection down-regulated the expression of c-fos protein and nerve growth factor in the GP fat pad.Moreover,adiponectin 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.Conclusion This study shows that local injection of adiponectin into GP fat pads could inhibit RAP-induced atrial fibrillation.The mechanism may be that adiponectin activates the Adipo R / AMPK / NF-κB signaling pathway and promotes the macrophage phenotype in the GP fat pads converting to an anti-inflammatory state,which alleviated the GP inflammatory response.The results of this study indicate that adiponectin and its receptor signaling may be a potential targets for AF treatment.