Using Selective Nerve Stimulation To Reduce Cardiac Sympathetic Tone

The purpose of the present study was to test the hypothesis that vagal nerve stimulation(VNS)and subcutaneous nerve stimulation(SCNS)could reduce sympathetic activities and suppress cardiac neural remodeling through damaging the central and peripheral autonomic nervous system(ANS)and that excitotoxicity could underlie the mechanisms of stellate ganglion(SG)damage induced by SCNS,which could also reduce cardiac arrhythmias through reducing cardiac sympathetic tone after myocardial infarction(MI).In this study,the experiments mainly included the following four parts:Part ?: Test the hypothesis that VNS affects atrial neural remodeling and controls heart rate in atrial fibrillation animals.Part ?: Test the hypothesis that different sites of SCNS,respectively,could reduce left stellate ganglion nerve activity,LSGNA),as well as HR in animals.Besides,spontaneous paroxysmal atrial tachycardia would also be suppressed,both for frequency and duration.Part ?: Test that calcium-dependent excitotoxicity could be one of the mechanism of sympathetic outflow reduce function of SCNS by injecting dantrolene into left stellate ganglion(LSG)directly.Part ?: Test the hypothesis that SCNS reduce cardiac sympathetic tone after myocardial infarction and then reduce post-myocardial infarction arrhythmia through damaging both central and peripheral autonomic nervous system structures.From this study,we drew the conclusions as:(1)Atrial neural remodeling plays an important role in the initiation and maintaienance of AF.Modulating autonomic nerve function with VNS can contribute to AF control.(2)SCNS at three different sites could reduce SGNA and HR,as well as frequency and duration of spontaneous PAT.Histological study showed visible damaged region in bilateral SG.The percentage of TH(-)cells and TUNEL(+)cells were significantly increase compared with that of normal dogs.(3)Dantrolene injection cut down the impaction of SCNS on sympathetic outflow.Histological study showed the damaged region was smaller in Dantrolene group.The percentage of TH(-)and TUNEL(+)cells were lower than that of normal saline intervened group.(4)SGNA was significantly increased after MI created compared to baseline.Left lateral thoracic nerve stimulation(LLTNS)could efficiently suppress LSGNA after MI and reduce HR.PAT after MI,both frequency and duration,were significantly reduced after LLTNS.Part ?:Vagal nerve stimulation affects atrial neural remodeling and reduces atrial fibrillation inducibilityObjective: The effects of vagal nerve stimulation(VNS)on atrial neural remodeling during atrial fibrillation(AF)remain unclear.In this part,we would test the hypothesis that VNS could affects atrial neural remodeling and reduces AF inducibility.Methods: Twenty rabbits were randomly divided into two groups: rapid atrial pacing group(RAP group)and rapid atrial pacing and VNS group(VNS group).Rapid pacing at 600 bpm was used to induce AF in all animals,while VNS was also performed in VNS group.AF inducibility studies and atrial histologic analysis were performed after 4 weeks of pacing.Results: In RAP group,5 rabbits(5/10)developed sustained AF after 4 weeks of rapid pacing.None of rabbits in VNS group(0/10)had developed AF.The incidence of sustained AF in VNS group was significant lower than that in RAP group(P<0.01).Treatment with VNS resulted in a significant reduction in atrial neural remodeling and AF duration(P<0.01).Conclusion: Atrial neural remodeling plays an important role in the initiation and maintenance of AF.Modulation automonic nerve function with VNS can contribute to AF control.Part ?:Subcutaneous nerve stimulation reduces cardiac sympathetic toneObjective: Stellate ganglion is an important sympathetic nerve structure that plays critical role in cardiac arrhythmogenesis.Therapeutic approaches that either reduce the sympathetic outflow or reduce the end-effects of sympathetic action on the myocardium are both potentially beneficial in arrhythmia control.Besides,more and more neuromodulation methods are being tested now.However,the mechanism is still unknown.The objective of this part is to test the hypothesis that subcutaneous nerve stimulation at three different sites can reduce cardiac sympathetic tone in canine.Methods: A total of 10 mongrel dogs(21-30kg)were studied.A radiotransmitter with 3 bipolar recording electrodes was implanted to record left stellate ganglion nerve activity(SGNA),vagal nerve activity(VNA),and subcutaneous nerve activity(SCNA).After 2 weeks of post-operation recovery,DSI was turned on and baseline of nerve activities and ECG were recorded.In Group A and B,neurostimulator was turned on and subcutaneous nerve stimulation(SCNS)was started after baseline record.In Group C,baseline recording was prolonged to 6 weeks before SCNS was started.Results: All the groups showed a reduced i SGNA after 2 weeks of SCNS of 3.5m A(from 1.78 m V-s,95% CI 1.50-2.06 at baseline to 1,45 m V-s,CI 1,16-1,75,P=0.028),with the HR reduced from 89 bpm,95% CI 80-98 at baseline to 83 bpm,CI 76-90,P=0.007).i VNA and i SCNA didn't changed significantly.During the 6 weeks of baseline recording in Group C,no spontaneous reduction showed in SGNA.ECG analysis showed the frequency and duration of PAT were both reduced in all three groups.TH staining showed visible damaged region in bilateral SG of three groups with TH(-)cell percentage increased.TUNEL staining showed a significantly increased number of staining positive ganglion cells.Conclusions: Subcutaneous nerve stimulation reduces stellate ganglion nerve activity through damaging stellate ganglion cells,and controls heart rate and arrhythmia.Part ?:Effect of calcium channel blockers on subcutaneous nerve stimulation and sympathetic toneObjective: The aim of this part is to test the hypothesis the possible mechanism of subcutaneous nerve stimulation(SCNS)is term excitotoxicity by sarcoplasmic reticulum calcium release.Dantrolene can partly weaken the effect of SCNS.Methods: A total of 6 mongrel dogs(22-31kg)were studied.A radiotransmitter with 3 bipolar recording electrodes was implanted to record left stellate ganglion nerve activity(SGNA),vagal nerve activity(VNA),and left lateral thoracic nerve activity(LLNA).Meanwhile,an Alzet osmotic pump was implanted to LSG for continuous infusion.And a neurostimulator was implanted with the electrode cuffed around the left lateral thoracic nerve in between the two electrodes of the third pair of DSI.After 2 weeks of post-operation recovery,baseline was recorded.Then the SCNS started with dantrolene(1mg/kg/day)continuous infusion in experimental group while the same volume of normal saline was given in control group.TH staining and TUNEL staining were performed in all samples.A group of SGs from normal dogs were studied simultaneously.Results: After 4 weeks of SCNS,control group showed a reduced SGNA compared to baseline while SGNA of experimental group didn't changed significantly.Histological study showed compared to the normal group,the percentage of TH(-)cells and TUNEL(+)cells were both increased in control group but did not show a significant change in experimental group.Conclusions: One of the possible mechanism of SCNS reduces SGNA is calcium overload depended excitotoxcity.Dantrolene which can block Ryanodine calcium channel on sarcoplasmic reticulum can reduce the effect of SCNS through protecting ganglion cell term excitotoxicity.Part ?:Using subcutaneous nerve stimulation to reduce sympathetic tone after myocardial infarction and control post-myocardial infarction arrhythmiaObjective: Nerve sprouting and myocardial hyperinnervation may occur after myocardial infarction(MI)and the presence of heterogeneous myocardial innervation is associated with the occurrence of cardiac arrhythmias and sudden death.The aim of this part is to test the hypothesis that SCNS reduces post-MI cardiac arrhythmias through reducing cardiac sympathetic tone after MI.Methods: A total of 12 mongrel dogs(25-32kg)were studied.Before surgery,18FDG-PET/MRI was performed in all animals.During the first survival surgery,a radiotransmitter with 3 bipolar recording electrodes and a neurostimulator were implanted.After baseline was recorded,4 weeks after the first surgery,MI model was created.Then the activities and ECG of post-MI was recorded and 18FDG-PET/MRI was repeated.Then the animal was divided into two groups randomly.In experimental group,SCNS was start of 0.5m A output then increased to 3.5m A gradually.In sham group,the output was 0m A.Results: After MI was created,SGNA was significantly increased with a rapid heart rate and obvious cardiac arrhythmias of various types.Most of the ventricular arrhythmias disappeared 2 weeks after acute myocardial infarction expect four from sham group,one of them showed PVC until the end of the experiment.Both frequency and duration increased significantly after MI occurred.After 4 weeks of SCNS,SGNA was reduced as well as heart rate and PAT frequency and duration(P<0.05).The percentage of TH(-)and TUNEL(+)cells were increased significantly in experimental group.But in sham group,TH(-)ganglion cells was even less than that of normal dogs.In addition,the TUNEL staining of brainstem also showed positive neurons.18FDG-PET/MRI analysis showed a decreased blood perfusion after SCNS.Conclusions:(1)Subcutaneous nerve stimulation reduces post-myocardial infarction in canine;(2)The possible mechanism of SCNS reducing cardiac sympathetic tone is damaging both central and peripheral nervous structure.