The Role And Mechanism Of Neuromodulation In The Prevention Of Sudden Cardiac Death

Part ? Median Nerve Stimulation Reduces Ventricular Arrhythmias Induced by Dorsomedial Hypothalamic StimulationBackground:This study tested the hypothesis that median nerve stimulation(MNS)prevents ventricular arrhythmias(VAs)induced by dorsomedial hypothalamus stimulation(DMHS)and investigated the electrophysiological mechanisms underlying the anti-arrhythmic effects of MNS by recording left stellate ganglion activity(LSGA).Methods:Twenty-one rabbits were anesthetized,the median nerve was anchored by stimulating electrodes,and a bipolar electrode was implanted into the LSG to record nerve activity.The DMH was stimulated to induce arrhythmia.All animals underwent six repetitions of DMHS(30 s).The 21 rabbits were divided into the following 3 groups:a control group,which underwent only DMHS(n = 7);an MNS group,which underwent MNS during both the third and fourth DMHS repetitions(n = 7);and an LSGA-recording group,for which LSGA was recorded at baseline,immediately following DMHS and again immediately following MNS and DMHS(n = 7).Results:Repeated DMHS-induced multiple VAs,in the rabbits.Compared with the DMHS-only group,the concurrent administration of MNS during DMHS significantly reduced the incidence of VAs(7 ± 3 and 9 ± 2 beats for the third and fourth DMHS +MNS repetitions vs.29 ± 8 and 27 ± 9 beats for the first two DMHS repetitions,p<0.05).The total duration of the abnormal discharges of the LSG(ADLSG)following MNS and DMHS was significantly reduced compared with that of the DMHS-only group(40 ± 18 vs.14 ± 6 s,p<0.05).Conclusion:MNS reduced VAs induced by DMHS,which is thought to be mediated through suppressing of ADLSG.New and noteworthy Median nerve electrical stimulation prevented ventricular arrhythmias induced by DMHS through the mechanism of suppressing abnormal discharges of left stellate ganglion.Part II The Effect of Low-level Left Vagus Nerve Stimulation on Ventricular Arrhythmias and the Mechanisms Involved in Dogs with Acute Myocardial InfarctionBackground:Vagus nerve stimulation(VNS)has been widely studied for the treatment of ventricular arrhythmias(VAs)and heart failure.VNS applied in most of previous studies were before or during ischemia.However,in clinical reality,patients suffering from myocardial infarction(MI)are less likely treated before or during MI.The aim of this study was to evaluate if low-level left vagus nerve stimulation(LLVNS)applied 120min after MI without changing heart rate could be an effective therapeutic strategy for preventing VAs and to investigate the underlying mechanisms in canine postinfarcted heart.Methods:After implanted with implantable cardioverter defibrillators(ICD)and left-cervical vagal stimulators,17 dogs were randomly divided into three groups:MI(n=7),MI+LLVNS(n=5),and sham operation(n=5).In the LLVNS+MI group,stimulators were turned on at 120min after MI.The stimulators implanted in the MI and sham operation groups remained off.VAs and T-wave alternans were detected by ICDs.Gene expression profile was documented by using affymetrix genechip canine genome 2.0 array and real time-PCR;the immunohistochemical staining for tyrosine hydroxylase(TH),growth-associated protein 43(GAP 43),neurofilament(NF)and connexin43(Cx43)were performed to assessed the density of sympathetic nerve,new axonal growth,nerve fibrils and changes of connexin protein of gap junction,respectively.Left ventricular ejection fraction(LVEF)and left ventricular end-diastolic dimension(LVEDD)were measured to assess cardiac function;the level of interleukin-6(IL-6)and tumor necrosis factor-a(TNF-a)were measured with Elisa.Results:Three weeks after MI,compared with the MI group,dogs in MI+LLVNS group had a lower incidence of ventricular fibrillation(0.25±0.21 vs,1 ±0.44,p<0.05)and ventricular tachycardia(12.3±5.4 vs.74.7±7.5,p<0.05).The microarray analysis identified 206 genes that were significantly altered by at least 1.5-fold between the two groups(p<0.05).Among them,the levels of 151 and 55 genes were decreased and increased,respectively,in the MI+LLVNS group compared with MI group.The differentially expressed genes(DEGs)involved in various pathway such as Toll-like receptor signaling,JAK-STAT,NF-?B,TNF,MAPK,AGE-RAGE,protein processing in endoplasmic reticulum and complement and coagulation cascades.LVEF in the MI+LLVNS group was significantly increased(44.5±0.4 vs.26.3±7.5,p<0.05)and the LVEDD was significantly reduced(4.2±0.9 vs.3.4±0.2,p<0.05)when compared with the MI group.LLVNS inhibited the excessive sympathetic nerve sprouting,decreased the density of TH-positive,GAP43-positive and NF-positive nerve(p<0.05).LLVNS increased the density of Cx43(p<0.05).ELISA results showed a reduction of IL-6 and TNF-a(p<0.05).Compared with the MI group,dogs in the MI+VNS group had lower TWA amplitude(8.7±4.6 vs.13.8±7.8 ?V,p<0.001)and K score(1.3±2.4 vs.3.0±4.4,p=0.017).Conclusions:The main findings of the present study include:(1)LLVNS applied 120min after MI significantly reduced VAs without changing heart rate during the follow-up period;(2)LLVNS caused 206 cardiac DEGs compared with the MI group;(3)the mechanism of of the reduction in VAs by LLVNS is likely associated with tissue reverse remodeling,less cardiac neuronal sprouting,decreased inflammation reaction,improved ventricular electric stability and these changes were correlated with the pattern of gene expressions.Part III Association between Implantable Cardioverter-defibrillator and Cardiac Resynchronization Therapy-defibrillator Home Monitoring Data and Sudden Cardiac Death1.The role of variability in night-time mean heart rate on the prediction of ventricular arrhythmias and all-cause mortality in implantable cardioverter defibrillator patientsAims:This study was to use implantable cardioverter-defibrillator(ICD)Home Monitoring(HM)feature to evaluate the role of mean night-time heart rate(MNHR)in the occurrence of ventricular arrhythmias(VAs)and mortality.Methods:This study retrospectively analyzed clinical and ICD device data in 318 ICD patients.Data of the first 30-day MNHR(recorded 02:00-06:00 am)by HM were collected.The average and standard deviation of the 30-day MNHR(AVHR and SDHR,respectively)were then determined in each patient.The primary endpoint was appropriate ICD treatment of VAs.The secondary endpoint was all-cause mortality.Results:During a mean follow-up period of 32±10 months,179 of the 318 patients(56.3%)experienced VAs,123 patients(38.7%)were treated by ICD shocks and 37 patients(11.6%)died.The overall SDHR in this study cohort was 4.5±3.0 bpm.Based on the receiver operating characteristic curve,the cut-off value of SDHR=3.685 bpm was identified to predict VAs.In the Kaplan-Meier survival,SDHR?3.685 bpm was associated with increased VAs[Hazard ratio(HR)=1.885;95%confidence interval(CI)=1.362-2.609;p<0.001],shock events(HR=1.637;CI=1.11-2.414;p=0.013),all-cause mortality(HR=2.42;CI=1.266-4.627;p=0.008)and the combined endpoints(HR=1.872;CI=1.365-2.567;p<0.001).In univar:iate and multivariate Cox model(adjusting for clinical factors),SDHR?3.685 bpm was still an independent predictor for all endpoints.Conclusion:In ICD population,SDHR?3.685 bpm was an independent predictor for VAs and all-cause mortality.Part III Association between Implantable Cardioverter-defibrillator and Cardiac Resynchronization Therapy-defibrillator Home Monitoring Data and Sudden Cardiac Death2.Association of Patient Activity and long-term Cardiac Death in Patients with Implantable Cardioverter-defibrillator and Cardiac Resynchronization Therapy-defibrillatorBackground:Patient activity(PA)have been demonstrated could predict all-cause mortality.However,the associations of PA and to what extent it could predict cardiac death are unclear.Aims:The aim of this study is to evaluate if PA could predict cardiac death and what's the cut-off of PA to discriminate cardiac death,and the underlying mechanism in patients with home monitoring.Methods:This study retrospectively analyzed the clinical and implantable cardioverter-defibrillator(ICD)/cardiac resynchronisation therapy defibrillator(CRT-D)device data in 845 patients.Data of PA and PP variability during the first 30-60 days recording by home monitoring were collected and calculated an average in each patient.The primary endpoint was cardiac death and the second endpoint was all-cause mortality.Results:The mean PA was 11±5.8%.Based on the receiver operating characteristic curve,the cut-off value of PA=7.84%(113 min)was identified to predict cardiac death.During a mean follow-up period of 31.1±12.9 months(range from 3 to 60 months),PA<7.84%was associated with increased risk of cardiac death and all-cause mortality in an unadjusted analysis,after adjusting in a multivariate Cox model,these relationships remained significant between PA<7.84%and cardiac death(HR=3.639,95%CI=2.42-5.471,p<0.001)or PA<7.84%and all-cause mortality(HR=3.677,95%CI=2.535-5.334,p<0.001).A significant correlation was observed between PA and PP variability(r=0.6012,p<0.001).Conclusions:Baseline PA<7.84%have a higher risk of cardiac death and all-cause mortality in patients who survived more than 3 months after ICD/CRT-D implanted.PA had a sizable effect on heart rate variability,reflecting autonomic function.