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Chronic orthostatic intolerance (OI) is characterized by the development of tachycardia and other symptoms when assuming an upright body position.The purpose of this study was to test the hypothesis that skin sympathetic nerve activity (SKNA) bursts are specific symptomatic biomarkers in patients with chronic OI.We used an electrocardiogram monitor with a built-in triaxial accelerometer to simultaneously record SKNA and posture in ambulatory participants. Study 1 compared chronic OI (14 women and 2 men; mean age 35 ± 10 years) with reference control participants (14 women; mean age 31 ± 6 years). Study 2 included 17 participants with chronic OI (15 women and 2 men; mean age 39 ± 12 years) not yet treated with ivabradine, pyridostigmine, or β-blockers.In study 1, there were 124 episodes (8 ± 4 per participant) of postural changes, with 11 episodes (8.9%) associated with symptoms. In comparison, 0 of 104 postural changes (7 ± 3 per participant) in controls were symptomatic (P = .0011). In participants with chronic OI, the SKNA bursts associated with symptoms had higher burst frequencies, longer burst durations, and larger mean burst areas than did bursts during asymptomatic periods. However, SKNA bursts and tachycardia were asymptomatic in controls. We analyzed 110 symptomatic episodes in study 2 (6 ± 5 per participant). Among them, 98 (89.1%) followed at least 1 SKNA burst. In comparison, only 41 (37.3%) had heart rate exceed 100 beats/min 1 minute before symptom onset (P.0001).SKNA bursts are a highly specific, albeit insensitive, symptomatic biomarker for chronic OI.

Background Subcutaneous nerve stimulation (ScNS) damages the stellate ganglion and improves rhythm control of atrial fibrillation (AF) in ambulatory dogs. Objective The purpose of this study was to test the hypothesis that thoracic ScNS can improve rate control in persistent AF. Methods 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. Results 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. Conclusion 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.

Background Sympathetic nerve activity, heart rate (HR), and blood pressure (BP) all have very low frequency (VLF), low frequency (LF), and high frequency (HF) oscillations. Objective 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. Methods 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. Results 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. Conclusion 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.

Background Reducing sympathetic efferent outflow from the stellate ganglia (SG) may be antiarrhythmic. Objective The purpose of this study was to test the hypothesis that chronic thoracic subcutaneous nerve stimulation (ScNS) could reduce SG nerve activity (SGNA) and control paroxysmal atrial tachycardia (PAT). Methods Thoracic ScNS was performed in 8 dogs while SGNA, vagal nerve activity (VNA), and subcutaneous nerve activity (ScNA) were monitored. An additional 3 dogs were used for sham stimulation as controls. Results Xinshu ScNS and left lateral thoracic nerve ScNS reduced heart rate (HR). Xinshu ScNS at 3.5 mA for 2 weeks reduced mean average SGNA from 5.32 μV (95% confidence interval [CI] 3.89-6.75) at baseline to 3.24 μV (95% CI 2.16-4.31; P = .015) and mean HR from 89 bpm (95% CI 80-98) at baseline to 83 bpm (95% CI 76-90; P = .007). Bilateral SG showed regions of decreased tyrosine hydroxylase staining with increased terminal deoxynucleotidyl transferase dUTP nick-end labeling-positive nuclei in 18.47% (95% CI 9.68-46.62) of all ganglion cells, indicating cell death. Spontaneous PAT episodes were reduced from 9.83 per day (95% CI 5.77-13.89) in controls to 3.00 per day (95% CI 0.11-5.89) after ScNS (P = .027). Left lateral thoracic nerve ScNS also led to significant bilateral SG neuronal death and significantly reduced average SGNA and HR in dogs. Conclusion ScNS at 2 different sites in the thorax led to SG cell death, reduced SGNA, and suppressed PAT in ambulatory dogs.

Intrinsic cardiac nerve activity (ICNA) and skin nerve activity (SKNA) are both associated with cardiac arrhythmias in dogs.The purpose of this study was to test the hypothesis that ICNA and SKNA correlate with postoperative cardiac arrhythmias in humans.Eleven patients (mean age 60 ± 13 years; 4 women) were enrolled in this study. Electrical signals were simultaneously recorded from electrocardiogram (ECG) patch electrodes on the chest wall and from 2 temporary pacing wires placed during open heart surgery on the left atrial epicardial fat pad. The signals were filtered to display SKNA and ICNA. Premature atrial contractions (PACs) and premature ventricular contractions were determined manually. The SKNA and ICNA of the first 300 minutes of each patient were calculated minute by minute to determine baseline average amplitudes of nerve activities and to determine their correlation with arrhythmia burden.We processed 1365 ± 973 minutes of recording per patient. Low-amplitude SKNA and ICNA were present at all time, while the burst discharges were observed much less frequently. Both SKNA and burst ICNA were significantly associated with the onset of PACs and premature ventricular contractions. Baseline average ICNA (aICNA), but not average SKNA, had a significant association with PAC burden. The correlation coefficient (r) between aICNA and PAC burden was 0.78 (P.01). A patient with the greatest aICNA developed postoperative atrial fibrillation.ICNA and SKNA can be recorded from human patients in the postoperative period. The baseline magnitude of ICNA correlates with PAC burden and development of postoperative atrial fibrillation.

Background Renal sympathetic denervation (RD) is a promising method of neuromodulation for the management of cardiac arrhythmia. Objective 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. Methods 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. Results 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. Conclusion 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.

BackgroundSympathetic nerve activity is important to cardiac arrhythmogenesis.ObjectiveThe purpose of this study was to develop a method for simultaneous noninvasive recording of skin sympathetic nerve activity (SKNA) and electrocardiogram (ECG) using conventional ECG electrodes. This method (neuECG) can be used to adequately estimate sympathetic tone.MethodsWe recorded neuECG signals from the skin of 56 human subjects. The signals were low-pass filtered to show the ECG and high-pass filtered to show nerve activity. Protocol 1 included 12 healthy volunteers who underwent cold water pressor test and Valsalva maneuver. Protocol 2 included 19 inpatients with epilepsy but without known heart diseases monitored for 24 hours. Protocol 3 included 22 patients admitted with electrical storm and monitored for 39.0 ± 28.2 hours. Protocol 4 included 3 patients who underwent bilateral stellate ganglion blockade with lidocaine injection.ResultsIn patients without heart diseases, spontaneous nerve discharges were frequently observed at baseline and were associated with heart rate acceleration. SKNA recorded from chest leads (V1-V6) during cold water pressor test and Valsalva maneuver (protocol 1) was invariably higher than during baseline and recovery periods (P < .001). In protocol 2, the average SKNA correlated with heart rate acceleration (r = 0.73 ± 0.14, P < .05) and shortening of QT interval (P < .001). Among 146 spontaneous ventricular tachycardia episodes recorded in 9 patients of protocol 3, 106 episodes (73%) were preceded by SKNA within 30 seconds of onset. Protocol 4 showed that bilateral stellate ganglia blockade by lidocaine inhibited SKNA.ConclusionSKNA is detectable using conventional ECG electrodes in humans and may be useful in estimating sympathetic tone.

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.

Background 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. Objective The purpose of this study was to test the hypothesis that VNS suppresses SKNA in patients with drug-resistant epilepsy. Methods 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 (2 men, 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. Results 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. Conclusion Patients with VNS had significantly lower SKNA than those without VNS.

Skin sympathetic nerve activity (SKNA) is useful for estimating sympathetic tone in humans.The purpose of this study was to test the hypotheses that (1) increased SKNA is associated with the onset and termination of paroxysmal atrial tachycardia (AT) and atrial fibrillation (AF) and (2) sinoatrial node response to SKNA is reduced in patients with more frequent AT or AF episodes.SKNA and electrocardiogram were recorded in 11 patients (4 men and 7 women; average age 66 ± 10 years), including 3 patients with AT (11 ± 18 episodes per patient) and 8 patients with AF (24 ± 26 episodes per patient).The average SKNA (aSKNA) 10 seconds before AT onset was 1.07 ± 0.10 μV and 10 seconds after termination was 1.27 ± 0.10 μV; both were significantly (P = .032 and P.0001) higher than that during sinus rhythm (0.97 ± 0.09 μV). The aSKNA 10 seconds before AF onset was 1.34 ± 0.07 μV and 10 seconds after termination was 1.31 ± 0.07 μV; both were significantly (P .0001) higher than that during sinus rhythm (1.04 ± 0.07 μV). The aSKNA before onset (P.0001) and after termination (P = .0011) was higher in AF than in AT. The sinus rate correlated (P.0001) with aSKNA in each patient (average r = 0.74; 95% confidence interval 0.65-0.84). The r value in each patient negatively correlated with the number of AT and AF episodes (r = -0.6493; 95% confidence interval -0.8990 to -0.08073; P = .0306).Increased SKNA was observed both at the onset and termination of AT and AF. Patients with more frequent AT and AF episodes had a weak correlation between sinus rate and aSKNA, suggesting sinoatrial node remodeling by tachycardia.

Evidence from a canine experimental acute myocardial infarction (MI) model shows that until the seventh week after MI, the relationship between stellate ganglion nerve activity (SGNA) and vagal nerve activity (VNA) progressively increases.The purpose of this study was to evaluate how autonomic nervous system activity influences temporal myocardial repolarization dispersion at this period.We analyzed autonomic nerve activity as well as QT and RR variability from recordings previously obtained in nine dogs. From a total of 48 short-term ECG segments, 24 recorded before and 24 recorded 7 weeks after experimentally-induced MI, we obtained three indices of temporal myocardial repolarization dispersion: QTe (from Q-wave to T-wave end), QTp (from Q-wave to T-wave peak), and Te (from T-wave peak to T-wave end) variability index (QTeVI, QTpVI, TeVI). We also performed heart rate variability power spectral analysis on the same segments.After MI, all the QT variables increased QTeVI (median [interquartile range]) (from -1.76[0.82] to -1.32[0.68]), QTeVI (from -1.90[1.01] to -1.45[0.78]), and TeVI (from -0.72[0.67] to -0.22[1.00]), whereas all RR spectral indices decreased (P.001 for all). Distinct circadian rhythms in QTeVI (P.05,) QTpVI (P.001) and TeVI (P.05) appeared after MI with circadian variations resembling that of SGNA/VNA. The morning QTpVI and TeVI acrophases approached the SGNA/VNA acrophase. Conversely, the evening QTeVI acrophase coincided with another SGNA/VNA peak. After MI, regression analysis detected a positive relationship between SGNA/VNA and TeVI (R(2): 0.077; β: 0.278; p0.001).Temporal myocardial repolarization dispersion shows a circadian variation after MI reaching its peak at a time when sympathetic is highest and vagal activity lowest.

Small conductance calcium-activated potassium (SK) channels are responsible for afterhyperpolarization that suppresses nerve discharges.To test the hypothesis that low-level vagus nerve stimulation (LL-VNS) leads to the upregulation of SK2 proteins in the left stellate ganglion.Six dogs (group 1) underwent 1-week LL-VNS of the left cervical vagus nerve. Five normal dogs (group 2) were used as controls. SK2 protein levels were examined by using Western blotting. The ratio between SK2 and glyceraldehydes-3-phosphate-dehydrogenase levels was used as an arbitrary unit (AU).We found higher SK2 expression in group 1 (0.124 ± 0.049 AU) than in group 2 (0.085 ± 0.031 AU; P.05). Immunostaining showed that the density of nerve structures stained with SK2 antibody was also higher in group 1 (11,546 ± 7,271 μm(2)/mm(2)) than in group 2 (5321 ± 3164 μm(2)/mm(2); P.05). There were significantly more ganglion cells without immunoreactivity to tyrosine hydroxylase (TH) in group 1 (11.4%±2.3%) than in group 2 (4.9% ± 0.7%; P.05). The TH-negative ganglion cells mostly stained positive for choline acetyltransferase (95.9% ± 2.8% in group 1 and 86.1% ± 4.4% in group 2; P = .10). Immunofluorescence confocal microscopy revealed a significant decrease in the SK2 staining in the cytosol but an increase in the SK2 staining on the membrane of the ganglion cells in group 1 compared to group 2.Left LL-VNS results in the upregulation of SK2 proteins, increased SK2 protein expression in the cell membrane, and increased TH-negative (mostly choline acetyltransferase-positive) ganglion cells in the left stellate ganglion. These changes may underlie the antiarrhythmic efficacy of LL-VNS in ambulatory dogs.

Background There is a lack of understanding of the substrate for microreentrant circuits and triggered activity of the pulmonary vein (PV) muscle sleeves and atria in patients with atrial fibrillation (AF). Objective This study sought to examine the histological substrate of patients with chronic AF. Methods We stained 23 biopsies taken from the PV-left atrium (LA) junction and right atrial appendage from 5 chronic AF patients and 3 sinus rhythm (SR) patients undergoing mitral valve surgery using periodic acid-Schiff (PAS) test, and antibodies to hyperpolarization-activated cyclic nucleotide-gated potassium channel 4 (HCN4), CD117/c-kit, myoglobin, tyrosine hydroxylase (TH), growth-associated protein 43, cholineacetyltransferase, and synaptophysin, as well as trichrome. Results As opposed to being clustered together in the subendocardial layer in SR patients, PAS-positive cells were separated from each other by inflammatory infiltrate and collagen fibers in AF patients. These cells stained positively for HCN4 and myoglobin, indicating they were cardiomyocytes that might have a potential pacemaking function, but different from CD117/c-kit-positive interstitial Cajal-like cells (ICLC). In AF patients, the intercellular space was occupied by a lymphomononuclear infiltrate (100% vs 33% in SR patients, P = .002), and a greater amount of interstitial fibrosis (37% ± 5.6% vs 7.4% ± 2.8%, P = .009). Nerve densities did not differ between AF and SR patients. However, the density of sympathetic nerve twigs in AF patients was significantly greater as compared to the others nerves ( P = .03). Conclusion HCN4-/PAS-positive cardiomyocytes and CD117/c-kit-positive ICLC scattered among abundant inflammatory infiltrate, fibrous tissue, and sympathetic nerve structures in the atria and at the PV–LA junctions might be a substrate for the maintenance of chronic AF.

Background Little information is available on the temporal relationship between instantaneous sympathetic nerve activity and ventricular arrhythmia in ambulatory animals. Objective The purpose of this study was to determine if increased sympathetic nerve activity precedes the onset of ventricular arrhythmia. Methods Simultaneous continuous long-term recording of left stellate ganglion (LSG) nerve activity and electrocardiography was performed in eight dogs with nerve growth factor infusion to the LSG, atrioventricular block, and myocardial infarction (experimental group) and in six normal dogs (control group). Results LSG nerve activity included low-amplitude burst discharge activity (LABDA) and high-amplitude spike discharge activity (HASDA). Both LABDA and HASDA accelerated heart rate. In the experimental group, most ventricular tachycardia (86.3%) and sudden cardiac death were preceded within 15 seconds by either LABDA or HASDA. The closer to onset of ventricular tachycardia, the higher the nerve activity. The majority of HASDA was followed immediately by either ventricular arrhythmia (21%) or QRS morphology changes (65%). HASDA occurred in a circadian pattern. HASDA occurred twice as often in the experimental group than in the control group. Electrical stimulation of LSG increased transmural heterogeneity of repolarization (Tpeak-end intervals) and induced either ventricular tachycardia or fibrillation in the experimental group but not in the control group. Immunohistochemical studies revealed increased synaptogenesis and nerve sprouting in the LSG in the experimental group. Conclusion Two distinct types of LSG nerve activity (HASDA and LABDA) are present in the LSG of ambulatory dogs. The majority of malignant ventricular arrhythmias are preceded by either HASDA or LABDA, with HASDA particularly arrhythmogenic.

Rapid repetitive activities arising from pulmonary veins may initiate atrial fibrillation. The basis of these rapid repetitive activities remains unclear, but recent evidence suggests that the autonomic nervous system plays an important role in their formation. Pulmonary veins and the adjoining left atrium are highly innervated structures. This review summarizes recent developments in the understanding of the anatomy of autonomic nerves in and around pulmonary veins and their implications for atrial fibrillation.

Background The effects of intermittent open-loop vagal nerve stimulation (VNS) on the ventricular rate (VR) during atrial fibrillation (AF) remain unclear. Objective The purpose of this study was to test the hypothesis that VNS damages the stellate ganglion (SG) and improves VR control during persistent AF. Methods 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. Results 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. Conclusion VNS damaged the SG, leading to reduced SGNA and better rate control during persistent AF.

Objectives The purpose of this study was to test the hypothesis that radiofrequency (RF) catheter ablation results in cardiac nerve sprouting. Background Nerve sprouting plays a role in cardiac arrhythmogenesis. Whether or not nerve sprouting occurs after RF catheter ablation is unclear. Methods We performed RF catheter ablation in the right atrium (RA) and right ventricle (RV) in 10 dogs, which then were sacrificed in 2 hours (acute group, n=5) or 1 month (chronic group, n=5). Seven normal dogs were used as control. Immunohistochemical staining for growth-associated protein 43 (GAP-43) was performed to measure growing (sprouting) nerves. Results A significant increase of GAP-43 immunoreactive nerve fiber density was observed at the RA ablation sites in 2 hours (4,410 ± 1,379 μm 2 /mm 2 ) and in 1 month (2,948 ± 666 μm 2 /mm 2 ) after ablation compared to controls (1,377 ± 471 μm 2 /mm 2 , P = .0001). At remote sites (>2 cm away from ablation sites) of RA, RF ablation also resulted in robust nerve sprouting in both the acute group (5,846 ± 3241μm 2 /mm 2 ) and the chronic group (6,030 ± 2226 μm 2 /mm 2 ). RF ablation in the RV did not increase nerve density at the ablation sites, but nerve density was increased at remote sites in 2 hours (1,345 ± 451 μm 2 /mm 2 , P = .0136) that was reduced down to the normal control level (722 ± 337 μm 2 /mm 2 ) in 1 month. Conclusions Nerve sprouting occurred within 2 hours after RF ablation in both the RA and RV and persisted for at least 1 month in the RA but not the RV. The increased GAP-43 + nerve densities developed at both the ablation and the remote sites.

Stellate ganglion nerve activity (SGNA) is important in ventricular arrhythmogenesis. However, because thoracotomy is needed to access the stellate ganglion, it is difficult to use SGNA for risk stratification.The purpose of this study was to test the hypothesis that subcutaneous nerve activity (SCNA) in canines can be used to estimate SGNA and predict ventricular arrhythmia.We implanted radiotransmitters to continuously monitor left stellate ganglion and subcutaneous electrical activities in 7 ambulatory dogs with myocardial infarction, complete heart block, and nerve growth factor infusion to the left stellate ganglion.Spontaneous ventricular tachycardia (VT) or ventricular fibrillation (VF) was documented in each dog. SCNA preceded a combined 61 episodes of VT and VF, 61 frequent bigeminy or couplets, and 61 premature ventricular contractions within 15 seconds in 70%, 59%, and 61% of arrhythmias, respectively. Similar incidence of 75%, 69%, and 62% was noted for SGNA. Progressive increase in SCNA [48.9 (95% confidence interval [CI] 39.3-58.5) vs 61.8 (95% CI 45.9-77.6) vs 75.1 (95% CI 57.5-92.7) mV-s] and SGNA [48.6 (95% CI 40.9-56.3) vs 58.5 (95% CI 47.5-69.4) vs 69.0 (95% CI 53.8-84.2) mV-s] integrated over 20-second intervals was demonstrated 60 seconds, 40 seconds, and 20 seconds before VT/VF (P.05), respectively. The Pearson correlation coefficient for integrated SCNA and SGNA was 0.73 ± 0.18 (P.0001 for all dogs, n = 5). Both SCNA and SGNA exhibited circadian variation.SCNA can be used as an estimate of SGNA to predict susceptibility to VT and VF in a canine model of ventricular arrhythmia and sudden cardiac death.

Cardiac innervation comes from both extrinsic and intrinsic sources. The extrinsic sympathetic innervation arises from the stellate ganglia and paravertebral sympathetic ganglia. The vagal nerves are sources of extrinsic parasympathetic nerves that innervate the heart. In addition to the extrinsic cardiac nervous system, there is also an extensive intrinsic cardiac nervous system1 that includes collections of ganglionated plexuses (or “ganglionated plexi”, or GP). Each GP contains both sympathetic and parasympathetic neurons that are associated with complex synaptology. In addition to efferent nerves, the GP also contains afferent nerves. While GP at different locations of the heart have different specialized functions (such as controlling sinoatrial node, atrioventricular node etc), they are also known to communicate among each other and with the extrinsic nervous system.

Myocardial infarction results in denervation, followed by neural remodeling characterized by nerve sprouting and heterogeneous sympathetic hyperinnervation throughout the myocardium. There is an association between the density of sympathetic nerves and occurrence of cardiac arrhythmia in humans. Autonomic nerve recording in ambulatory dogs showed a close association between autonomic nerve activity and paroxysmal atrial and ventricular arrhythmias. Cryoablation of the stellate ganglion prevented paroxysmal atrial tachycardia and atrial fibrillation in canine models. Further studies are needed to determine if these same methods can be used to control atrial arrhythmias in humans.

The presence of circadian variations in sympathetic outflow from the stellate ganglia is unclear.The purpose of this study was to continuously record stellate ganglion nerve activity (SGNA) in ambulatory dogs.We performed continuous 24-hour left (N = 3) or bilateral (N = 3) SGNA recordings in normal ambulatory dogs using implanted Data Sciences International transmitters. We also performed simultaneous ECG recording (n = 5) or simultaneous ECG and blood pressure recordings (n = 1).The total duration of continuous ambulatory recording averaged 41.5 +/- 16.6 days. Five dogs had persistent stable recording, and one dog developed hardware malfunction in week 3. SGNA was followed immediately (1 second) by heart rate and blood pressure elevation and a reduced standard deviation of consecutive activation cycle length (SDNN) from 236 +/- 93 ms to 121 +/- 51 ms (P = 0.007). Heart rate correlated significantly with SGNA. When there was a sudden increase of SGNA, the sudden increase occurred bilaterally in 90% of the episodes. Both heart rate and SGNA showed statistically significant (P.01) circadian variation. Nadolol (20 mg/day for 5 days) reduced average heart rate from 99 +/- 8 bpm at baseline to 88 +/- 9 bpm (N = 6, P = .001) but did not significantly alter SGNA. Immunohistochemical staining of the stellate ganglia showed tyrosine hydroxylase-positive ganglion cells and nerves at the recording site.There is a circadian variation in sympathetic outflow from canine stellate ganglia. Circadian variation of SGNA is an important cause of circadian variations of cardiac sympathetic tone.

Background Nerve growth factor (NGF) infusion into the right stellate ganglion (RSG) is antiarrhythmic, while NGF infusion into the left stellate ganglion (LSG) is proarrhythmic in dogs with myocardial infarction (MI) and complete atrioventricular block (CAVB). This functional asymmetry suggests differential neural remodeling. Objectives To test the hypothesis that NGF infusion into the RSG and the LSG can lead to differential β-adrenoceptor (β-AR) expression in dogs with MI and CAVB. Methods and Results We performed immunostaining to quantify β 1 -AR and β 3 -AR immunoreactivity in six dogs with MI and CAVB, nine dogs with MI, CAVB, and NGF infusion to the LSG, six dogs with MI, CAVB, and NGF infusion to the RSG, and six normal dogs. There was significantly increased β 3 -AR immunoreactivity in dogs with NGF infusion into the LSG and significantly decreased β 3 -AR immunoreactivity in dogs with NGF infusion into the RSG compared with controls and with the MI and CAVB group. There were no significant differences in β 1 -AR immunoreactivity among these four groups. To determine protein and mRNA expression of β-ARs, we created MI and CAVB and infused NGF into the LSG in six additional dogs. The noninfarcted left ventricle free wall was harvested 1 week later. The protein level and receptor density of β 3 -AR (but not β 1 - or β 2 -AR) significantly increased in these six dogs compared with normal controls. Conclusions We conclude that NGF infusion into the RSG and the LSG in dogs with MI and CAVB induced differential β 3 -AR expression in the left ventricular myocardium.