The Role Of Sigma-1 Receptor On Stress-related Atrial Fibrillation

BackgroundAtrial fibrillation is the most common tachyarrhythmia,with a prevalence rate of 0.77%,its complications,including stroke and heart failure,affecting the quality of life of patients,increase the risk of death,has become the heavy burden of medical care in the world.Psychological stress,which results from stressful events,has recently been shown to be an important risk factor for atrial fibrillation,which is closely related to the outcome of atrial fibrillation,but the underlying mechanism is unknown.Sigma-1 recepter(?1R),an endoplasmic reticulum molecular chaperone,play an important role in psychological stress,cardiovascular disease,and arrhythmia.Thus,81R may be an important molecular target with psychological stress and atrial fibrillation.In this study,we investigated the role and mechanism of 81R in psychological stress related atrial fibrillation by using psychological stress models,cardiac electrophysiological techniques,confocal laser scanning microscopy and molecular biology techniques.ObjectiveThe aim of this study was to elucidate the effects of psychological stress on atrial electrophysiological activity and susceptibility to atrial fibrillation,and to investigate the role of ?1R in psychological stress related atrial fibrillation.MethodsPart 1:Adult male Wistar rates(220-250g)were subjected to chronic uncontrollable mild stress for 4 weeks.The experimental animals were divided into four groups:control group(n=20),psychological stress group(n=20),psychological stress +fluoxetine treatment group(n=20)and psychological stress + recovery group(n=20).The behavior was evaluated with the sucrose preference test,open field test,and weight change.The atrial effective refractory period(ERP),alternans(ALT),and inducible rate of atrial fibrillation were measured in vivo electrophysiological experiments.The activation mapping and conduction velocity were tested with the MEA microelectrode array system in the isolated heart.The Western Blot was used to measure the expression of ?1R.Part 2:The models of psychological stress were generated by chronic uncontrollable mild stress.The animals was subjected to treated with specific agonist of?1R(PER084,1nM/d)and specific inhibitor of ?1R(BD-1047,0.5nM/d)for 2 weeks.Atrial electrical activity and atrial fibrillation susceptibility was evaluated in vivo and in vitro electrophysiological experiments.Atrial fibrosis was detected by using Sirius red staining level,and the expression level of atrial ?1R with Western Blot.Ca2+ transients and sarcoplasmic reticulum(SR)Ca2+ load were detected with confocal system.The expression level of calcium operation related proteins were measured with Western Blot.ResultsPart 1:Four-weeks psychological stress significantly reduced sugar consumption,increase the immobility time,and delay the weight gain,there were statistically significant difference compared with the control group(P<0.01).The psychological stress group showed decreased atrial ERP,increased ALT threshold,atrial electric conduction disturbance,slow conduction velocity,with statistically significant difference compared with the control group(P<0.01).The vulnerability to AF was significantly higher in the psychological stress group than the control group(8/8 vs.0/8,P<0.01).Furthermore,the expression of atrial ?1R downregulted with 46%in the psychological stress group(P<0.01 vs control group).Interestingly,fluoxetine treatment and 2-weeks recovery only partly reversed atrial electrical remodeling,and the inducible rate of atrial fibrillation was significantly higher in those group than that of the control group(all P<0.01).Part 2:The activation of ?1R significantly improved the behavior,reversed the changes of ERP and ALT,and reduced atrial fibrillation susceptibility,which induced by the 4-weeks psychological stress,with statistically significant difference compared with the psychological stress group(all P<0.01),but there were no statistical difference compared with the control group(all P<0.01).In addition,the inhibition of SIR increased atrial electrical activity disorder,decreased ERP,increased ALT threshold,increased susceptibility to atrial fibrillation,with statistically significant differences compared with the psychological stress group(all P<0.01).Likely,the expression of atrial ?1R was up-regulated after activating ?1R,and was down-regulated after inhibited 81R in animals of psychological stress(P<0.01).Four-weeks psychological stress significantly reduced sarcoplasmic reticulum Ca2+ concentration,increased time 50%decay,increase the proportion of spontaneous activity in atrial myocytes,with statistically significant compared with the control group(all P<0.01).The expression of calcium-handling related proteins were changed in psychological stress group,there were statistically significant compared with the control group(all P<0.01).Activation of?1R reversed the disorders of calcium handling and expression of calcium-handling related proteins;however,inhibition of ?1R worsened the above indicators,and there was a statistically significant difference compared with the psychological stress group(P<0.01).Conclusion1.The behavioral abnormalities,atrial electrical activity disorder,increased atrial susceptibility,down-regulated atrial 1R expression was showed in rats of psychological stress.2.Activation of ?1R has a therapeutic effect on psychological stress related atrial fibrillation.?1R activation could reverse the disturbance of atrial electrical activity and atrial fibrillation susceptibility induced by psychological stress,while inhibition of ?1R aggravated the above changes.The therapeutic effect of?1R is associated with calcium handling in atrial myocytes...