Regulating Effect Of Spinal Cord In The Occurrence And Development Of Atrial Fibrillation

Part I Effects of extrinsic cardiac nerve stimulation on atrial fibrilla-tion inducibility:The regulatory role of the spinal cordObjective:To investigate the effect of the mutual regulation of the extrinsic cardiac nerves on atrial electrophysiology and atrial fibrillation(AF)vulnerability.Methods and results:Fourteen dogs were randomly divided into 2 groups:spinal cord stimulation(SCS)group(n=7)and spinal cord block(SCB)group(n=7).SCS was performed with 90%of the threshold voltage stimulating the T1-T2 spinal level,while SCB was performed by injecting 2%lidocaine into the epidural space at the T2-3 level.The effective refractory period(ERP),ERP dispersion,and AF inducibility were measured during atrial pacing combined with different extrinsic cardiac nerve stimulation.ERPs were decreased in the atrium and pulmonary veins and ERP dispersion was increased from baseline during left cervical vagus nerve stimulation(VNS)or left stellate ganglion stimulation(SGS)in the two groups.When combined with SCS,VNS resulted in diminished ERPs at all recording sites,longer ERP dispersion and more episodes of AF than were observed during VNS,whereas ERPs were greater and correspondingly fewer episodes of AF occurred during SCS combined with SGS than SGS.In the SCB group,ERPs were shortened,ERP dispersion was lengthened,and episodes of AF were increased during SGS after SCB.SCS enhanced the activity of the left vagus nerve but attenuated the left stellate ganglion and superior left ganglionated plexus.Conclusion:SCS modulates extrinsic and intrinsic cardiac nerve activity among the vagus nerve,stellate ganglion and ganglionated plexus.SCS facilitates the effect of VNS and attenuates the effect of SGS on atrial electrophysiology.Part II Effects of spinal cord stimulation on atrial electrophysiology and atrial fibrillation vulnerability in paroxysmal atrial fibrillation dogsObjective:To investigate the effect of spinal cord stimulation on atrial electrophy-siology and AF vulnerability in paroxysmal AF dogsMethods:Thirty mongrel dogs were implanted with a high-frequency cardiac pacemaker with a transvenous lead inserted into the right atrial appendage.The dogs were randomly divided into four groups:a sham-operated group(n=6),the SCS group 1(n=8),the SCS group 2(n=8)and the SCS group 3(n=8).Sham-operated group dogs were only implanted with pacemakers without pacing;SCS group 1 were implanted with pacemakers with intermittent atrial pacing for 8 hours a day and a total of 8 weeks.After 8 weeks,the dogs experienced low-level SCS for 3 hours;SCS group 2 underwent bilateral vagotomy and SCS group 3 underwent bilateral stellate neurotomy,and then also received low-level SCS.Atrial electrophysiology and atrial fibrillation vulnerability were measured in all the animals after 8 weeks of pacing and at the end of each hour of SCS.Results:Compared with the sham-operated group,ERPs were decreased in the atrium and pulmonary veins,ERP dispersion was increased,and episodes and duration of AF were increased from baseline after 8 weeks of pacing in SCS group 1,2 and 3.SCS resulted in prolonged ERPs at all recording sites,shorter ERP dispersion and few episodes of AF than before SCS with the prolongation of stimulation time in SCS group 1 and 3(SCS group 1:ERP dispersion from 37.3±4.2 ms of Oh,29.9±3.6ms of 1h,22.3±4.4 ms of 2h to 15.1 ±2.7 ms of 3h;AF-Duration from 126.3±12.3 s of 0h,98.7±10.8soflh,68.4±11.9 s of 2h to 40.3±13.6 s of 3h.SCS group 3:ERP dispersion from 40.5±5.7 ms of Oh,31.2±4.4 ms of 1h,25.3±3.4 ms of 2h to 18.9±2.8 ms of 3h;AF-Duration from 118.4±13.5 s of Oh,93.5±14.6 s of lh,59.7 ± 12.5 s of 2h to 36.6 ± 10.7 s of 3h).More interesting,the AF cycle length was longer and longer with the prolongation of stimulation time in SCS group 1 and 3(SCS group 1:AF cycle length from 90.4±2.5 ms of 0h,95.3±2.2 ms of 1h,104.6±3.0 ms of 2h to 112.5 ±4.0 ms of 3h;SCS group 3:AF cycle length from 88.2 ±2.8 ms of 0h,94.6±2.1 ms of 1h,102.7±3.2 ms of 2h to 114.6±3.8 ms of 3h).In the SCS2 group,there was no significant change in atrial electrophysiological characteristics and AF vulnerability with the stimulation time.Conclusion:SCS could effectively reverse the atrial electrical remodeling and reduce the induction of AF in paroxysmal AF dogs,which is closely related to vagus nerve.Part Ⅲ Mechanisms of spinal cord stimulation suppressing atrial fibrillationObjectives:To investigate the mechanisms of spinal cord stimulation(SCS)suppressing AF.Methods:Custom cardiac pacemakers were implanted in 30 dogs to induce right atrial pacing(RAP)for 8 hours per day.After 8 weeks of RAP,the SCS1 dogs experienced low-level SCS for 3 hours;The SCS2 underwent bilateral vagotomy and the SCS4 had methyllycaconitine applied to the main ganglionated plexus,and then also received low-level SCS.Venous blood were collected at baseline and before and after SCS.Finally,atrial tissues were excised for western-blot.Results:All the dogs had significantly higher plasma levels of IL-6 and TNF-α and lower level of ACH after long-term intermittent RAP compared with the baseline(both P<0.01).After SCS for 3 hours,the plasma levels of IL-6 and TNF-a sharply decreased(IL-6:548.6±30.5 pg/mL vs 363.3±26.3 pg/mL,P<0.01;TNF-a:260.3±29.2 pg/mL vs 184.1±28.2 pg/mL,P<0.01),and the ACH level increased from 22.4±4.8 μg/mL to 52.3±9.3 μg/mL in SCS group 1(P<0.01).The same trend of the levels of IL-6,TNF-a and ACH were observed in SCS group 4.However,no significant changes were detected before and after SCS in SCS group 2.The expression of a7nAchR in atrial tissues was significantly higher in SCS group 1(P<0.01)than any other group.However,the expression of IL-6 and TNF-a and the phosphorylation of IKKβ and P65 were significantly lower in SCS group 1 than in any other group.There were no significant changes in expression of the above listed proteins among the control group,SCS group 2 and SCS group 4.Conclusions:SCS can significantly reduce the levels of TNF-and IL-6 in the plasma and atrial tissues in paroxysmal AF dogs,which may be related to the activation of the cholinergic anti-inflammatory pathway mediated by the vagus nerve.