Stellate Ganglion Nerve Activity Research Articles

The Mechanism of Cardiac Sympathetic Activity Assessment Methods: Current Knowledge.

This review has summarized the methods currently available for cardiac sympathetic assessment in clinical or under research, with emphasis on the principles behind these methodologies. Heart rate variability (HRV) and other methods based on heart rate pattern analysis can reflect the dominance of sympathetic nerve to sinoatrial node function and indirectly show the average activity level of cardiac sympathetic nerve in a period of time. Sympathetic neurotransmitters play a key role of signal transduction after sympathetic nerve discharges. Plasma or local sympathetic neurotransmitter detection can mediately display sympathetic nerve activity. Given cardiac sympathetic nerve innervation, i.e., the distribution of stellate ganglion and its nerve fibers, stellate ganglion activity can be recorded either directly or subcutaneously, or through the surface of the skin using a neurophysiological approach. Stellate ganglion nerve activity (SGNA), subcutaneous nerve activity (SCNA), and skin sympathetic nerve activity (SKNA) can reflect immediate stellate ganglion discharge activity, i.e., cardiac sympathetic nerve activity. These cardiac sympathetic activity assessment methods are all based on the anatomy and physiology of the heart, especially the sympathetic innervation and the sympathetic regulation of the heart. Technological advances, discipline overlapping, and more understanding of the sympathetic innervation and sympathetic regulation of the heart will promote the development of cardiac sympathetic activity assessment methods.

The frequency spectrum of sympathetic nerve activity and arrhythmogenicity in ambulatory dogs

Sympathetic nerve activity, heart rate (HR), and blood pressure (BP) all have very low frequency (VLF), low frequency (LF), and high frequency (HF) oscillations. The purpose of this study was to test the hypothesis that the frequency spectra of subcutaneous nerve activity (ScNA), stellate ganglion nerve activity (SGNA), HR, and BP are important to cardiac arrhythmogenesis. We used radiotransmitters to record SGNA, ScNA, HR, and BP in 6 ambulatory dogs and determined the dominant frequency and paroxysmal atrial tachyarrhythmias (PATs) episodes in 3-minute windows over a 24-hour period. The frequency spectra determined in ScNA reflected that in SGNA. HF oscillations were present in both ScNA and SGNA at all time but could be overshadowed by the much larger LF and VLF burst activities. The dominant frequency could occur in any of the 3 frequency bands. There were circadian variations with more frequent occurrences of HF oscillations at night. HF oscillations in HR and BP matched HF oscillations in SGNA and ScNA. PATs occurred only when dominant frequencies of SGNA and ScNA were in the LF and VLF bands. HF oscillations in BP and HR correlate with HF oscillations in sympathetic nerve activity and are present at all time. HF oscillations can be overshadowed by the much larger LF and VLF burst activities. PATs occur only when LF or VLF, but not when HF, is the dominant frequency. The frequency spectra determined in ScNA reflect that in SGNA.

Effects of subcutaneous nerve stimulation with blindly inserted electrodes on ventricular rate control in a canine model of persistent atrial fibrillation

Subcutaneous nerve stimulation (ScNS) delivered directly to large subcutaneous nerves can be either antiarrhythmic or proarrhythmic, depending on the stimulus output. The purpose of this study was to perform a prospective randomized study in a canine model of persistent AF to test the hypothesis that high-output ScNS using blindly inserted subcutaneous electrodes can reduce ventricular rate (VR) during persistent atrial fibrillation (AF) whereas low-output ScNS would have opposite effects. We prospectively randomized 16 male and 15 female dogs with sustained AF (>48 hours) induced by rapid atrial pacing into 3 groups (sham, 0.25 mA, 3.5 mA) for 4 weeks of ScNS (10 Hz, alternating 20-seconds ON and 60-seconds OFF). ScNS at 3.5 mA, but not 0.25 mA or sham, significantly reduced VR and stellate ganglion nerve activity (SGNA), leading to improvement of left ventricular ejection fraction (LVEF). No differences were found between the 0.25-mA and sham groups. Histologic studies showed a significant reduction of bilateral atrial fibrosis in the 3.5-mA group compared with sham controls. Only 3.5-mA ScNS had significant fibrosis in bilateral stellate ganglions. The growth-associated protein 43 (GAP43) staining of stellate ganglions indicated the suppression of GAP43 protein expression in the 3.5-mA group. There were no significant differences of nerve sprouting among all groups. There was no interaction between sex and ScNS effects on reduction of VR and SGNA, LVEF improvement, or results of histologic studies. We conclude that 3.5-mA ScNS with blindly inserted electrodes can improve VR control, reduce atrial fibrosis, and partially improve LVEF in a canine model of persistent AF.

Subcutaneous nerve stimulation reduces sympathetic nerve activity in ambulatory dogs with myocardial infarction

Subcutaneous nerve stimulation (ScNS) remodels the stellate ganglion and reduces stellate ganglion nerve activity (SGNA) in dogs. Acute myocardial infarction (MI) increases SGNA through nerve sprouting. The purpose of this study was to test the hypothesis that ScNS remodels the stellate ganglion and reduces SGNA in ambulatory dogs with acute MI. In the experimental group, a radio transmitter was implanted during the first sterile surgery to record nerve activity and an electrocardiogram, followed by a second sterile surgery to create MI. Dogs then underwent ScNS for 2 months. The average SGNA (aSGNA) was compared with that in a historical control group (n = 9), with acute MI monitored for 2 months without ScNS. In the experimental group, the baseline aSGNA and heart rate were 4.08±0.35 μV and 98±12 beats/min, respectively. They increased within 1 week after MI to 6.91±1.91 μV (P=.007) and 107±10 beats/min (P=.028), respectively. ScNS reduced aSGNA to 3.46±0.44 μV (P<.039) and 2.14±0.50 μV (P<.001) at 4 and 8 weeks, respectively, after MI. In comparison, aSGNA at 4 and 8 weeks in dogs with MI but no ScNS was 8.26±6.31 μV(P=.005) and 10.82±7.86 μV (P=0002), respectively. Immunostaining showed confluent areas of remodeling in bilateral stellate ganglia and a high percentage of tyrosine hydroxylase-negative ganglion cells. Terminal deoxynucleotidyl transferase dUTP nick end labeling was positive in 26.61%±11.54% of ganglion cells in the left stellate ganglion and 15.94%±3.62% of ganglion cells in the right stellate ganglion. ScNS remodels the stellate ganglion, reduces SGNA, and suppresses cardiac nerve sprouting after acute MI.

P6347Wireless optogenetic inhibition of cardiac sympathetic nerve activity to improve cardiac function and remodeling in chronic post-infarction canines

Abstract Background Our previous study has shown that optogenetic modulation of left stellate ganglion (LSG) nerve activity suppresses ventricular arrhythmia (VA) after acute myocardial infarction (MI). Objective This study introduced a fully implantable, battery-free wireless optogenetic neuromodulation system to investigate whether chronic optogenetic inhibition of LSG nerve activity could reduce myocardial infarct size and improve left ventricular (LV) function and remodeling in a post-MI canine model. Methods Eighteen beagles were randomized into the normal control group (saline injection without MI, n=6), the MI group (AAV2/9-CAG-GFP injection plus MI, n=6) and the optogenetics group (AAV2/9-CAG-ArchT-GFP injection plus MI, n=6). Four weeks after AAV/saline microinjection into LSG, MI was induced and LED device (Figure 1A) was implanted (Figure 1B, C) to perform illumination (565nm) for optogenetic modulation 1h per day for 4 weeks. Results Chronic optogenetic modulation significantly attenuated LSG function and neural activity as compared to the MI group. Chronic optogenetic modulation significantly reduced myocardial infarction size and improved LV function (LV ejection fraction: 53±1.3% vs. 45.9±1.8%, P&lt;0.05) as compared to the MI group. Furthermore, chronic optogenetic modulation suppressed MI-induced LSG sympathetic remodeling and LV fibrosis. Figure 1 Conclusion Chronic optogenetic modulation using this fully implantable, battery-free wireless optogenetic system significantly inhibited LSG nerve activity, reduced myocardial infarction size, improved LV function and remodeling in a post-MI canine model (Figure 1D).

Effects of anesthetic and sedative agents on sympathetic nerve activity

The effects of sedative and anesthetic agents on sympathetic nerve activity (SNA) are poorly understood. The purpose of this study was to determine the effects of commonly used sedative and anesthetic agents on SNA in ambulatory dogs and humans. We implanted radiotransmitters in 6 dogs to record stellate ganglion nerve activity (SGNA), subcutaneous nerve activity (ScNA), and blood pressure (BP). After recovery, we injected dexmedetomidine (3 μg/kg), morphine (0.1 mg/kg), hydromorphone (0.05 mg/kg), and midazolam (0.1 mg/kg) on different days. We also studied 12 human patients (10 male; age 68.0 ± 9.1 years old) undergoing cardioversion for atrial fibrillation with propofol (0.77 ± 0.18 mg/kg) or methohexital (0.65 mg/kg) anesthesia. Skin sympathetic nerve activity (SKNA) and electrocardiogram were recorded during the study. SGNA and ScNA were significantly suppressed immediately after administration of dexmedetomidine (P = .000 and P= .000, respectively), morphine (P = .011 and P = .014, respectively), and hydromorphone (P = .000 and P = .012, respectively), along with decreased BP and heart rate (HR) (P <.001 for each). Midazolam had no significant effect on SGNA and ScNA (P = .248 and P = .149, respectively) but increased HR (P = .015) and decreased BP (P = .004) in ambulatory dogs. In patients undergoing cardioversion, bolus propofol administration significantly suppressed SKNA (from 1.11 ± 0.25 μV to 0.77 ± 0.15 μV; P=.001), and the effects lasted for at least 10 minutes after the final cardioversion shock. Methohexital decreased chest SKNA from 1.59 ± 0.45 μV to 1.22 ± 0.58 μV (P = .000) and arm SKNA from 0.76 ± 0.43 μV to 0.55 ± 0.07 μV (P = .001). The effects lasted for at least 10 minutes after the cardioversion shock. Propofol, methohexital, dexmedetomidine, morphine, and hydromorphone suppressed, but midazolam had no significant effects on, SNA.

Subcutaneous nerve stimulation for rate control in ambulatory dogs with persistent atrial fibrillation

Subcutaneous nerve stimulation (ScNS) damages the stellate ganglion and improves rhythm control of atrial fibrillation (AF) in ambulatory dogs. The purpose of this study was to test the hypothesis that thoracic ScNS can improve rate control in persistent AF. We created persistent AF in 13 dogs and randomly assigned them to ScNS (n = 6) and sham control (n = 7) groups. 18F-2-Fluoro-2-deoxyglucose positron emission tomography/magnetic resonance imaging of the brain stem was performed at baseline and at the end of the study. The average stellate ganglion nerve activity reduced from 4.00 ± 1.68 μV after the induction of persistent AF to 1.72 ± 0.42 μV (P = .032) after ScNS. In contrast, the average stellate ganglion nerve activity increased from 3.01 ± 1.26 μV during AF to 5.52 ± 2.69 μV after sham stimulation (P = .023). The mean ventricular rate during persistent AF reduced from 149 ± 36 to 84 ± 16 beats/min (P = .011) in the ScNS group, but no changes were observed in the sham control group. The left ventricular ejection fraction remained unchanged in the ScNS group but reduced significantly in the sham control group. Immunostaining showed damaged ganglion cells in bilateral stellate ganglia and increased brain stem glial cell reaction in the ScNS group but not in the control group. The 18F-2-fluoro-2-deoxyglucose uptake in the pons and medulla was significantly (P = .011) higher in the ScNS group than the sham control group at the end of the study. Thoracic ScNS causes neural remodeling in the brain stem and stellate ganglia, controls the ventricular rate, and preserves the left ventricular ejection fraction in ambulatory dogs with persistent AF.

Antiarrhythmic effects of stimulating the left dorsal branch of the thoracic nerve in a canine model of paroxysmal atrial tachyarrhythmias

Stellate ganglion nerve activity (SGNA) precedes paroxysmal atrial tachyarrhythmia (PAT) episodes in dogs with intermittent rapid left atrial (LA) pacing. The left dorsal branch of the thoracic nerve (LDTN) contains sympathetic nerves originating from the stellate ganglia. The purpose of this study was to test the hypothesis that high-frequency electrical stimulation of the LDTN can cause stellate ganglia damage and suppress PATs. We performed long-term LDTN stimulation in 6 dogs with and 2 dogs without intermittent rapid LA pacing while monitoring SGNA. LDTN stimulation reduced average SGNA from 4.36 μV (95% confidence interval [CI] 4.10-4.62 μV) at baseline to 3.22 μV (95% CI 3.04-3.40 μV) after 2 weeks (P = .028) and completely suppressed all PAT episodes in all dogs studied. Tyrosine hydroxylase staining showed large damaged regions in both stellate ganglia, with increased percentages of tyrosine hydroxylase-negative cells. The terminal deoxynucleotidyl transferase dUTP nick end labeling assay showed that 23.36% (95% CI 18.74%-27.98%) of ganglion cells in the left stellate ganglia and 11.15% (95% CI 9.34%-12.96%) ganglion cells in the right stellate ganglia were positive, indicating extensive cell death. A reduction of both SGNA and heart rate was also observed in dogs with LDTN stimulation but without rapid LA pacing. Histological studies in the 2 dogs without intermittent rapid LA pacing confirmed the presence of extensive stellate ganglia damage, along with a high percentage of terminal deoxynucleotidyl transferase dUTP nick end labeling-positive cells. LDTN stimulation damages both left and right stellate ganglia, reduces left SGNA, and is antiarrhythmic in this canine model of PAT.

Oscillatory behavior of P wave duration and PR interval in experimental congestive heart failure: a preliminary study

Objective: The relationship between the autonomic nervous system (ANS) modulation of the sinus node and heart rate variability has been extensively investigated. The current study sought to evaluate, in an animal experimental model of pacing-induced tachycardia congestive heart failure (CHF), a possible ANS influence on the P wave duration and PR interval oscillations. Approach: Short-term (5 min) time and frequency domain analysis has been obtained in six dogs for the following electrocardiographic intervals: P wave duration (P), from the onset to peak of P wave (Pp), from the onset of P wave to the q onset (PR) and from the end of P wave to the onset of q wave (PeR). Direct vagal nerve activity (VNA), stellate ganglion nerve activity (SGNA) and electrocardiogram (ECG) intervals have been evaluated contextually by implantation of three bipolar recording leads. Main results: At the baseline, multiple regression analysis pointed out that VNA was strongly positively associated with the standard deviation of PP and PeR intervals (r2:0.997, p < 0.05). The same variable was also positively associated with high-frequency (HF) of P expressed in normalized units, of Pp, and of PeR (b: 0.001) (r2: 0.993; p < 0.05). During CHF, most of the time and frequency domain variability significantly decreased from 20% to 50% in comparison to the baseline values (p < 0.05) and SGNA correlated inversely with the low frequency (LF) obtained from PeR (p < 0.05) and PR (p < 0.05) (r2:0.899, p < 0.05). LF components, expressed in absolute and normalized power, obtained from all studied intervals, were reduced significantly during CHF. Any difference between the RR and PP spectral components was observed. Significance: The data showed a significant relationship between ANS and atrial ECG variables, independent of the cycle duration. In particular, the oscillations were vagal mediated at the baseline, while sympathetic mediated during CHF. Whereas P wave variability might have a clinical utility in CHF management, it needs to be addressed in specific studies.

CHRONIC OPTOGENETIC INHIBITION OF CARDIAC SYMPATHETIC NERVE ACTIVITY REDUCES CARDIAC REMODELING AND VENTRICULAR ARRHYTHMIA INDUCIBILITY IN A POST-INFARCTION CANINE MODEL

Our previous study showed that optogenetics could inhibit left stellate ganglion (LSG) nerve activity and suppress ventricular arrhythmia (VA) after acute myocardial infarction (MI). This study investigated whether chronic optogenetic inhibition of LSG nerve activity could reduce VA and cardiac

Abstract 20949: Impact of Renal Denervation on Autonomic Nerve Activity

Introduction: Recent studies reported potential antiarrhythmic effect of catheter-based renal denervation (RDN). We sought to evaluate impacts of RDN on cardiac autonomic nerve activity in ambulatory canine model. Methods: Telemetry devices (D70-EEE, DSI) were implanted in 17 mongrel dogs to record ambulatory nerve activity simultaneously from left stellate ganglion (SG), superior left ganglionated plexus (SLGP), and left renal nerve. After 1 week of baseline nerve activity recording, RDN was performed at both renal arteries using a specialized catheter (Symplicity TM , Medtronic) (n=10). A control animals underwent autonomic nerve recording operation but with sham procedure (n=3). Bilateral surgical stripping of the renal nerve adventitia was performed in 4 dogs (n=4, surgical RDN). One-minute integrated nerve activities were quantified and compared among groups up to 2 weeks. Results: Renal nerve acvitivity (RNA) decreased after catheter RDN (-6.7±13.4% from baseline), while RNA increased after sham operation by 7.4±9.5% (p=0.103). After surgical RDN, no RNA was observed. In contrast to the increased SG nerve activity (SGNA) after sham operation (+2.2±11.4%), SGNA decreased after catheter RDN (-2.1±10.8%, p=0.073) and surgical RDN (-10.6±13.1%, p=0.061 vs. control). SLGP nerve activity (SLGPNA) also increased by 7.1±3.1% after sham operation, while SLGPNA decreased after catheter-based (-8.1±13.9%, p=0.008), and surgical RDN (-6.3±10.2%, p=0.073 vs. control). Immunohistochemistry showed increment of TH (tyrosine hydroxylase)-negative cells in SG after RDN (% of TH-negative cells: control=1.8%, catheter RDN=5.5% [p=0.058 vs. control], surgical RDN=7.35% [p=0.039, vs. control]). Conclusions: The response of renal nerve and cardiac autonomic nerve activity to catheter based RDN was diverse. Renal denervation decreased SGNA and SLGPNA, with neural remodeling at SG. These results may support anti-arrhythmic effects of RDN.

A proposal for a noninvasive monitoring of sympathetic nerve activity in patients with takotsubo syndrome

The pathophysiology of takotsubo syndrome (TTS) is still elusive; many hypotheses of its cause have been proposed with a heightened activity of the peripheral autonomic sympathetic nervous system (PASNS) via local norepinephrine release, and direct cardiomyocyte toxicity mediated by blood-borne catecholamines, being among the most currently entertained. Monitoring of PASNS during hospitalization will provide a metric which could be of immense value in unraveling of the pathophysiology and aiding in the management of the patients with TTS by predicting in-hospital complications, long-term outcome, and its recurrence. Recent work with noninvasive monitoring of skin sympathetic nerve activity (SKNA), via conventional electrodes used for the recording of the electrocardiogram have shown that the filtered signals >500 Hz originate in the cervical and stellate ganglia, which also innervate the heart, and thus they provide an estimate of stellate ganglion nerve activity. Such information may prove invaluable for the management of patients with TTS.

Left cervical vagal nerve stimulation reduces skin sympathetic nerve activity in patients with drug resistant epilepsy

We recently reported that skin sympathetic nerve activity (SKNA) can be used to estimate sympathetic tone in humans. In animal models, vagal nerve stimulation (VNS) can damage the stellate ganglion, reduce stellate ganglion nerve activity, and suppress cardiac arrhythmia. Whether VNS can suppress sympathetic tone in humans remains unclear. The purpose of this study was to test the hypothesis that VNS suppresses SKNA in patients with drug-resistant epilepsy. ECG patch electrodes were used to continuously record SKNA in 26 patients with drug-resistant epilepsy who were admitted for video electroencephalographic monitoring. Among them, 6(2men, age 40 ± 11 years) were previously treated with VNS and 20 (7 men, age 37 ± 8 years) were not. The signals from ECG leads I and II were filtered to detect SKNA. VNS had an on-time of 30 seconds and off-time of 158 ± 72 seconds, with output of 1.92 ± 0.42 mA at 24.17 ± 2.01 Hz. Average SKNA during VNS off-time was 1.06 μV (95% confidence interval [CI] 0.93-1.18) in lead I and 1.13 μV (95% CI 0.99-1.27) in lead II, which was significantly lower than 1.38 μV (95% CI 1.01-1.75; P = .036) and 1.38 μV (95% CI 0.98-1.78; P = .035) in the control group, respectively. Heart rate was 65 bpm (95% CI 59-71) in the VNS group, which was significantly lower than 77 bpm (95% CI 71-83) in the control group. Patients with VNS had significantly lower SKNA than those without VNS.

Median nerve stimulation prevents atrial electrical remodelling and inflammation in a canine model with rapid atrial pacing.

Studies have shown that stellate ganglion nerve activity has association with atrial electrical remodelling and atrial fibrillation (AF) inducibility, while median nerve stimulation (MNS) decreases cardiac sympathetic drive. In this study, we tested the hypothesis that MNS suppresses atrial electrical remodelling and AF vulnerability. The atrial effective refractory period (AERP) and AF inducibility at baseline and after 3 h of rapid atrial pacing were determined in dogs undergoing MNS (n = 7), MNS+ application of methyllycaconitine (n = 7) or sham procedure (n = 6). Then, the levels of tumour necrosis factor-alpha (TNF-a), interleukin-6 (IL-6), and acetylcholine (Ach) in the plasma and atrial tissues were measured. The control dogs (n = 4) were assigned to measure atrial inflammation cytokines. Short-term rapid atrial pacing induced shortening of the AERP, an increase in AERP dispersion, and an increase AF vulnerability in the sham dogs, which were all suppressed by MNS. Levels of TNF-a and IL-6 were higher, and Ach levels were lower in the left and the right atrium in the sham dogs than in the MNS dogs. Methyllycaconitine blunted the effects of MNS on the AERP, AERP dispersion, the AF vulnerability, and TNF-a and IL-6 levels in the atrium, but had no impact on the levels of Ach. The effects of MNS on atrial electrical remodelling and AF inducibility might be associated with the cholinergic anti-inflammatory pathway.

Renal sympathetic stimulation and ablation affect ventricular arrhythmia by modulating autonomic activity in a cesium-induced long QT canine model

Our previous studies showed that renal sympathetic stimulation (RS) may facilitate ischemic ventricular arrhythmia (VA) by increasing left stellate ganglion (LSG) nerve activity, whereas renal sympathetic ablation (RA) may suppress VA. The purpose of this study was to investigate whether renal sympathetic interventions also can affect VA by modulating LSG activity in a cesium-induced long QT canine model. Twenty-four dogs were randomly divided into RS group (n = 8), RA group (n = 8), or control group (n = 8). Serum norepinephrine, LSG function, and LSG neural activity were measured before and 3 hours after RS or RA. Increasing doses of cesium chloride then were administered until a "threshold dose" produced sustained ventricular tachycardia or ventricular fibrillation. Early afterdepolarization amplitude, VA prevalence, and tachycardia threshold dose were compared among these groups. Nerve growth factor and c-fos protein expressed in the LSG also were examined. Serum norepinephrine, LSG function, and LSG neural activity were all significantly increased after 3 hours of RS and all were decreased 3 hours after RA. In addition, RS significantly decreased the tachycardia threshold dose, increased the early afterdepolarization amplitude, facilitated the incidence of VAs, and increased the expression of nerve growth factor and c-fos protein. In contrast, RA induced the opposite effects. RS promotes, whereas RA suppresses, the incidence of VAs in a canine model of cesium-induced long QT. Modulation of LSG neural activity by RS and RA may be responsible for these different effects.

Effects of renal sympathetic denervation on the stellate ganglion and brain stem in dogs

Renal sympathetic denervation (RD) is a promising method of neuromodulation for the management of cardiac arrhythmia. We tested the hypothesis that RD is antiarrhythmic in ambulatory dogs because it reduces the stellate ganglion nerve activity (SGNA) by remodeling the stellate ganglion (SG) and brain stem. We implanted a radiotransmitter to record SGNA and electrocardiogram in 9 ambulatory dogs for 2 weeks, followed by a second surgery for RD and 2 months SGNA recording. Cell death was probed by terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay. Integrated SGNA at baseline and 1 and 2 months after RD were 14.0 ± 4.0, 9.3 ± 2.8, and 9.6 ± 2.0 μV, respectively (P = .042). The SG from RD but not normal control dogs (n = 5) showed confluent damage. An average of 41% ± 10% and 40% ± 16% of ganglion cells in the left and right SG, respectively, were TUNEL positive in RD dogs compared with 0% in controls dogs (P = .005 for both). The left and right SG from RD dogs had more tyrosine hydroxylase-negative ganglion cells than did the left SG of control dogs (P = .028 and P = .047, respectively). Extensive TUNEL-positive neurons and glial cells were also noted in the medulla, associated with strongly positive glial fibrillary acidic protein staining. The distribution was heterogeneous, with more cell death in the medial than lateral aspects of the medulla. Bilateral RD caused significant central and peripheral sympathetic nerve remodeling and reduced SGNA in ambulatory dogs. These findings may in part explain the antiarrhythmic effects of RD.

Intermittent left cervical vagal nerve stimulation damages the stellate ganglia and reduces the ventricular rate during sustained atrial fibrillation in ambulatory dogs

The effects of intermittent open-loop vagal nerve stimulation (VNS) on the ventricular rate (VR) during atrial fibrillation (AF) remain unclear. The purpose of this study was to test the hypothesis that VNS damages the stellate ganglion (SG) and improves VR control during persistent AF. We performed left cervical VNS in ambulatory dogs while recording the left SG nerve activity (SGNA) and vagal nerve activity. Tyrosine hydroxylase (TH) staining and terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) staining were used to assess neuronal cell death in the SG. We induced persistent AF by atrial pacing in 6 dogs, followed by intermittent VNS with short ON-time (14 seconds) and long OFF-time (66 seconds). The integrated SGNA and VR during AF were 4.84 mV·s (95% confidence interval [CI] 3.08-6.60 mV·s) and 142 beats/min (95% CI 116-168 beats/min), respectively. During AF, VNS reduced the integrated SGNA and VR, respectively, to 3.74 mV·s (95% CI 2.27-5.20 mV·s; P = .021) and 115 beats/min (95% CI 96-134 beats/min; P = .016) during 66-second OFF-time and to 4.07 mV·s (95% CI 2.42-5.72 mV·s; P = .037) and 114 beats/min (95% CI 83-146 beats/min; P = .039) during 3-minute OFF-time. VNS increased the frequencies of prolonged (>3 seconds) pauses during AF. TH staining showed large confluent areas of damage in the left SG, characterized by pyknotic nuclei, reduced TH staining, increased percentage of TH-negative ganglion cells, and positive TUNEL staining. Occasional TUNEL-positive ganglion cells were also observed in the right SG. VNS damaged the SG, leading to reduced SGNA and better rate control during persistent AF.

Abstract 16255: Left Cervical Vagal Nerve Stimulation Suppresses Cardiac Sympathetic Tone

Background: In ambulatory dogs, the left cervical vagal nerve stimulation (VNS) reduces stellate ganglion nerve activity (SGNA) and heart rate, while upper thoracic skin sympathetic nerve activity (SKNA) has been shown to be a surrogate of SGNA to measure sympathetic tone. Objective: To test the hypothesis that VNS suppresses SKNA in human. Methods: We used conventional electrocardiogram (ECG) patches to continuously record SKNA in 12 patients who were admitted for video electroencephalographic monitoring. The ECG patches were placed under the right subclavian and left subclavian areas to form Lead I. The signals were band pass filtered between 200 to 1000 Hz to reveal SKNA. All antiepileptic medications were withdrawn. No patients had known organic heart diseases. No seizures occurred during the recording period. Nerve activity was quantified by integrating (iSKNA) the absolute value of the filtered signal over a 1 min window at intervals of 2 min, 20 min, and 40 min past each hour between 6 AM and 1 PM. Heart rate was determined by calculating the R-R intervals. Results: Six patients (2 men, age 40±5 years ) received chronic left cervical VNS (VNS group) and 6 (1 man, age 44±7 years) had no VNS pacing (control group). The admission diagnoses were generalized seizure (N=1) and partial seizure (N=5) in VNS group; generalized seizure (N=2) and partial seizure (N=4) in control group. The VNS pacing was continuous with an ON-time of 30 s and OFF-time of 158±72 s. The output was 1.92±0.42 mA with a frequency of 24.17±2.01 Hz. Fast Fourier Transform of the signals showed only physiologic activity between 200-1000 Hz. The iSKNA during VNS OFF-time was 13.77 mV-s [95% confidence interval, CI, 11.09 to 16.45], which was significantly lower than 20.75 mV-s [95% CI, 16.34 to 25.16, p=0.006] of the control Group. The heart rate was 67 bpm [95% CI, 60 to 74] in VNS group, significantly lower than 73 bpm [95% CI, 63 to 84] in control group. Conclusion: Patients with left cervical VNS had lower heart rate and iSKNA than patients without VNS. These findings are consistent with those observed in ambulatory canines, and suggest that chronic intermittent VNS can suppress cardiac sympathetic tone in human.

Subcutaneous nerve activity is more accurate than heart rate variability in estimating cardiac sympathetic tone in ambulatory dogs with myocardial infarction.

We recently reported that subcutaneous nerve activity (SCNA) can be used to estimate sympathetic tone. The purpose of this study was to test the hypothesis that left thoracic SCNA is more accurate than heart rate variability (HRV) in estimating cardiac sympathetic tone in ambulatory dogs with myocardial infarction (MI). We used an implanted radiotransmitter to study left stellate ganglion nerve activity (SGNA), vagal nerve activity (VNA), and thoracic SCNA in 9 dogs at baseline and up to 8 weeks after MI. HRV was determined based on time-domain, frequency-domain, and nonlinear analyses. The correlation coefficients between integrated SGNA and SCNA averaged 0.74 (95% confidence interval [CI] 0.41-1.06) at baseline and 0.82 (95% CI, 0.63-1.01) after MI (P <.05 for both). The absolute values of the correlation coefficients were significantly larger than that between SGNA and HRV analysis based on time-domain, frequency-domain, and nonlinear analyses, respectively, at baseline (P <.05 for all) and after MI (P <.05 for all). There was a clear increment of SGNA and SCNA at 2, 4, 6, and 8 weeks after MI, whereas HRV parameters showed no significant changes. Significant circadian variations were noted in SCNA, SGNA, and all HRV parameters at baseline and after MI, respectively. Atrial tachycardia (AT) episodes were invariably preceded by SCNA and SGNA, which were progressively increased from 120th, 90th, 60th, to 30th seconds before AT onset. No such changes of HRV parameters were observed before AT onset. SCNA is more accurate than HRV in estimating cardiac sympathetic tone in ambulatory dogs with MI.

Using skin sympathetic nerve activity to estimate stellate ganglion nerve activity in dogs.

Stellate ganglion nerve activity (SGNA) is important in cardiac arrhythmogenesis. However, direct recording of SGNA requires access to the thoracic cavity. Skin of upper thorax is innervated by sympathetic nerve fibers originating from the stellate ganglia and is easily accessible. The purpose of this study was to test the hypothesis that thoracic skin nerve activity (SKNA) can be used to estimate SGNA. We recorded SGNA and SKNAs using surface electrocardiogram leads in 5 anesthetized and 4 ambulatory dogs. Apamin injected into the right stellate ganglion abruptly increased both right SGNA and SKNA in 5 anesthetized dogs. We integrated nerve activities and averaged heart rate in each 1-minure window over 10 minutes. We implanted a radiotransmitter to record left SGNA in 4 ambulatory dogs (2 normal, 1 with myocardial infarction, 1 with intermittent rapid atrial pacing). After 2 weeks of recovery, we simultaneously recorded the SKNA and left SGNA continuously for 30 minutes when the dogs were ambulatory. There was a positive correlation [average r = 0.877, 95% confidence interval (CI) 0.732-1.000, P <.05 for each dog] between integrated skin nerve activity (iSKNA) and SGNA (iSGNA) and between iSKNA and heart rate (average r = 0.837, 95% CI 0.752-0.923, P <.05). Similar to that found in the anesthetized dogs, there was a positive correlation (average r = 0.746, 95% CI 0.527-0.964, P <.05) between iSKNA and iSGNA and between iSKNA and heart rate (average r = 0.706, 95% CI 0.484-0.927, P <.05). SKNAs can be used to estimate SGNA in dogs.