Role of the autonomic nervous system in atrial fibrillation: pathophysiology and therapy.

Autonomic nervous system activation can induce significant and heterogeneous changes of atrial electrophysiology and induce atrial tachyarrhythmias, including atrial tachycardia and atrial fibrillation (AF). The importance of the autonomic nervous system in atrial arrhythmogenesis is also supported by circadian variation in the incidence of symptomatic AF in humans. Methods that reduce autonomic innervation or outflow have been shown to reduce the incidence of spontaneous or induced atrial arrhythmias, suggesting that neuromodulation may be helpful in controlling AF. In this review, we focus on the relationship between the autonomic nervous system and the pathophysiology of AF and the potential benefit and limitations of neuromodulation in the management of this arrhythmia. We conclude that autonomic nerve activity plays an important role in the initiation and maintenance of AF, and modulating autonomic nerve function may contribute to AF control. Potential therapeutic applications include ganglionated plexus ablation, renal sympathetic denervation, cervical vagal nerve stimulation, baroreflex stimulation, cutaneous stimulation, novel drug approaches, and biological therapies. Although the role of the autonomic nervous system has long been recognized, new science and new technologies promise exciting prospects for the future.

Estimating sympathetic tone by recording subcutaneous nerve activity in ambulatory dogs.

INTRODUCTION: We tested the hypothesis that subcutaneous nerve activity (SCNA) of the thorax correlates with the stellate ganglion nerve activity (SGNA) and can be used to estimate the sympathetic tone. METHODS AND RESULTS: We implanted radio transmitters in 11 ambulatory dogs to record left SGNA, left thoracic vagal nerve activity (VNA), and left thoracic SCNA, including 3 with simultaneous video monitoring and nerve recording. Two additional dogs were studied under general anesthesia with apamin injected into the right stellate ganglion while the right SGNA and the right SCNA were recorded. There was a significant positive correlation between integrated SGNA (iSGNA) and integrated SCNA (iSCNA) in the first 7 ambulatory dogs, with correlation coefficient of 0.70 (95% confidence interval [CI] 0.61-0.84, P < 0.05 for each dog). Tachycardia episodes (heart rate exceeding 150 bpm for ≥3 seconds) were invariably preceded by SGNA and SCNA. There was circadian variation of both SCNA and SGNA. Crosstalk was ruled out because SGNA, VNA, and SCNA bursts had different timing and activation patterns. In an eighth dog, closely spaced bipolar subcutaneous electrodes also recorded SCNA, but with reduced signal to noise ratio. Video monitoring in additional 3 dogs showed that movement was not a cause of high frequency SCNA. The right SGNA correlated strongly with right SCNA and heart rate in 2 anesthetized dogs after apamin injection into the right stellate ganglion. CONCLUSIONS: SCNA recorded by bipolar subcutaneous electrodes correlates with the SGNA and can be used to estimate the sympathetic tone.

Sympathetic toggled paroxysmal atrial fibrillation and recurrent premature atrial contractions in ambulatory patients.

BACKGROUND: Autonomic nerve activity is important in the mechanisms of paroxysmal atrial fibrillation (PAF). OBJECTIVE: The purpose of this study was to test the hypothesis that a single burst of skin sympathetic nerve activity (SKNA) can toggle on and off PAF or premature atrial contraction (PAC) clusters. METHODS: Simultaneous recording of SKNA and electrocardiogram (neuECG) recording was performed over 7 days in patients with PAF. RESULTS: In study 1, 8 patients (7 men and 1 woman; age 62 ± 8 years) had 124 episodes of PAF. An SKNA burst toggled both on and off PAF in 8 episodes (6.5%) (type 1), toggled on but not off in 12 episodes (9.7%) (type 2), and toggled on a PAC cluster followed by PAF in 4 episodes (3.2%) (type 3). The duration of these PAF episodes was <10 minutes. The remaining 100 episodes (80.6%) were associated with active SKNA bursts throughout PAF (type 4) and lasted longer than type 1 (P = .0185) and type 2 (P = .0027) PAF. There were 47 PAC clusters. Among them, 24 (51.1%) were toggled on and off, and 23 (48.9%) were toggled on but not off by an SKNA burst. In study 2, 17 patients (9 men and 8 women; age 58 ± 12 years) had <10 minutes of PAF (4, 8, 0, and 31 of types 1, 2, 3, and 4, respectively). There were significant circadian variations of all types of PAF. CONCLUSION: A single SKNA burst can toggle short-duration PAF and PAC cluster episodes on and off. The absence of continued SKNA after the onset might have affected the maintenance of these arrhythmias.

Autonomic Modulation of Atrial Fibrillation.

The autonomic nervous system plays a vital role in cardiac arrhythmias, including atrial fibrillation (AF). Therefore, reducing the sympathetic tone via neuromodulation methods may be helpful in AF control. Myocardial ischemia is associated with increased sympathetic tone and incidence of AF. It is an excellent disease model to understand the neural mechanisms of AF and the effects of neuromodulation. This review summarizes the relationship between autonomic nervous system and AF and reviews methods and mechanisms of neuromodulation. This review proposes that noninvasive or minimally invasive neuromodulation methods will be most useful in the future management of AF.

Skin sympathetic nerve activity and nocturnal blood pressure nondipping in patients with postural orthostatic tachycardia syndrome.

OBJECTIVE: Postural orthostatic tachycardia syndrome (POTS) is associated with abnormal blood pressure (BP) regulation and increased prevalence of nocturnal nondipping. We hypothesized that nocturnal nondipping of BP is associated with elevated skin sympathetic nerve activity (SKNA) in POTS. METHOD: We used an ambulatory monitor to record SKNA and electrocardiogram from 79 participants with POTS (36 ±â€Š11 years, 72 women), including 67 with simultaneous 24-h ambulatory BP monitoring. RESULTS: Nocturnal nondipping of BP was present in 19 of 67 (28%) participants. The nondipping group had a higher average SKNA (aSKNA) from midnight of day 1 to 0100 h on day 2 than the dipping group ( P  = 0.016, P  = 0.030, respectively). The differences (Δ) of aSKNA and mean BP between daytime and night-time were more significant in the dipping group compared with the nondipping group (ΔaSKNA 0.160 ±â€Š0.103 vs. 0.095 ±â€Š0.099 µV, P  = 0.021, and Δmean BP 15.0 ±â€Š5.2 vs. 4.9 ±â€Š4.2 mmHg, P  < 0.001, respectively). There were positive correlations between ΔaSKNA and standing norepinephrine (NE) (r = 0.421, P  = 0.013) and the differences between standing and supine NE levels ( r  = 0.411, P  = 0.016). There were 53 (79%) patients with SBP less than 90 mmHg and 61 patients (91%) with DBP less than 60 mmHg. These hypotensive episodes were associated with aSKNA of 0.936 ±â€Š0.081 and 0.936 ±â€Š0.080 µV, respectively, which were both significantly lower than the nonhypotensive aSKNA (1.034 ±â€Š0.087 µV, P  < 0.001 for both) in the same patient. CONCLUSION: POTS patients with nocturnal nondipping have elevated nocturnal sympathetic tone and blunted reduction of SKNA between day and night. Hypotensive episodes were associated with reduced aSKNA.

Continuous low-level vagus nerve stimulation reduces stellate ganglion nerve activity and paroxysmal atrial tachyarrhythmias in ambulatory canines.

BACKGROUND: We hypothesize that left-sided low-level vagus nerve stimulation (LL-VNS) can suppress sympathetic outflow and reduce atrial tachyarrhythmias in ambulatory dogs. METHODS AND RESULTS: We implanted a neurostimulator in 12 dogs to stimulate the left cervical vagus nerve and a radiotransmitter for continuous recording of left stellate ganglion nerve activity, vagal nerve activities, and ECGs. Group 1 dogs (N=6) underwent 1 week of continuous LL-VNS. Group 2 dogs (N=6) underwent intermittent rapid atrial pacing followed by active or sham LL-VNS on alternate weeks. Integrated stellate ganglion nerve activity was significantly reduced during LL-VNS (7.8 mV/s; 95% confidence interval [CI] 6.94 to 8.66 versus 9.4 mV/s [95% CI, 8.5 to 10.3] at baseline; P=0.033) in group 1. The reduction was most apparent at 8 am, along with a significantly reduced heart rate (P=0.008). Left-sided low-level vagus nerve stimulation did not change vagal nerve activity. The density of tyrosine hydroxylase-positive nerves in the left stellate ganglion 1 week after cessation of LL-VNS were 99 684 µm(2)/mm(2) (95% CI, 28 850 to 170 517) in LL-VNS dogs and 186 561 µm(2)/mm(2) (95% CI, 154 956 to 218 166; P=0.008) in normal dogs. In group 2, the frequencies of paroxysmal atrial fibrillation and tachycardia during active LL-VNS were 1.4/d (95% CI, 0.5 to 5.1) and 8.0/d (95% CI, 5.3 to 12.0), respectively, significantly lower than during sham stimulation (9.2/d [95% CI, 5.3 to 13.1]; P=0.001 and 22.0/d [95% CI, 19.1 to 25.5], P<0.001, respectively). CONCLUSIONS: Left-sided low-level vagus nerve stimulation suppresses stellate ganglion nerve activities and reduces the incidences of paroxysmal atrial tachyarrhythmias in ambulatory dogs. Significant neural remodeling of the left stellate ganglion is evident 1 week after cessation of continuous LL-VNS.

Neural mechanisms of atrial fibrillation.

PURPOSE OF REVIEW: The autonomic nerve system is a potentially potent modulator of the initiation and perpetuation of atrial fibrillation. This review will briefly summarize the neural mechanisms of atrial fibrillation. RECENT FINDINGS: Complex interactions exist between the sympathetic and parasympathetic nervous system on the atrial electrophysiologic properties. Direct autonomic recordings in canine models demonstrated simultaneous sympathovagal discharges are the most common triggers of paroxysmal atrial tachycardia and paroxysmal atrial fibrillation. Also, intrinsic cardiac autonomic nerve can serve as a sole triggering factor for the initiation of atrial fibrillation. Modulation of autonomic nervous system (ANS) by electrical stimulation has been tried as a treatment strategy clinically and experimentally. Recent studies showed that autonomic nervous system modulation can suppress the stellate ganglion nerve activity and reduce the incidence of paroxysmal atrial tachyarrhythmias in ambulatory dogs. SUMMARY: The autonomic nerve system influences the initiation and perpetuation of atrial fibrillation. Scientific advances toward a better understanding of the complex interrelationships of the various components of the ANS will hopefully lead to improvement of treatments for this common arrhythmia.

Skin sympathetic nerve activity in patients with chronic orthostatic intolerance.

BACKGROUND: Chronic orthostatic intolerance (OI) is characterized by the development of tachycardia and other symptoms when assuming an upright body position. OBJECTIVE: 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. METHODS: 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 ß-blockers. RESULTS: 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). CONCLUSION: SKNA bursts are a highly specific, albeit insensitive, symptomatic biomarker for chronic OI.

Sympathetic toggled sinus rate acceleration as a mechanism of sustained sinus tachycardia in chronic orthostatic intolerance syndrome.

BACKGROUND: The role of sympathetic nerve activity to maintain sinus rate acceleration remains unclear. OBJECTIVE: The purpose of this study was to test the hypothesis that sustained (>30 seconds) sinus rate acceleration can be associated with either a sympathetic driven or a sympathetic toggled mechanism. METHODS: We used a patch monitor to record skin sympathetic nerve activity (SKNA) and electrocardiogram over 24 hours. Study 1 included chronic orthostatic intolerance (OI) (n = 18), atrial fibrillation (n = 7), and asymptomatic normal control (n = 19) groups. Study 2 included 17 participants with chronic OI not treated with ivabradine, pyridostigmine, or ß-blockers. RESULTS: While a majority of sinus rate acceleration was driven by persistent SKNA in study 1, some episodes were toggled on and off by SKNA bursts without persistent SKNA elevation. The sympathetic toggled sinus rate acceleration episodes were found in 7 of 18 participants with chronic OI (39%), 2 of 7 participants with atrial fibrillation (29%), and 6 of 19 normal control participants (32%) (P = .847) and were faster and longer in the chronic OI group than in other groups. In study 2, there were a total of 11 episodes of sinus rate acceleration that persisted for >200 seconds. Among these episodes, 6 (35%) were toggled on and off by SKNA bursts. CONCLUSION: Sustained sinus rate acceleration (may be toggled on or off) is associated with SKNA bursts in participants with chronic OI, participants with atrial fibrillation, and normal controls. Patients with OI had more frequent and longer episodes than did other groups.

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

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.

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

BACKGROUND: 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. OBJECTIVE: 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. METHODS: 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. RESULTS: 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. CONCLUSION: ScNS remodels the stellate ganglion, reduces SGNA, and suppresses cardiac nerve sprouting after acute MI.

Simultaneous noninvasive recording of electrocardiogram and skin sympathetic nerve activity (neuECG).

neuECG, the simultaneous noninvasive recording of ECG and skin sympathetic nerve activity (SKNA), directly records sympathetic nerve activity over a long period of time. It can be used to measure sympathetic tone in healthy subjects and in subjects with non-cardiovascular diseases. The electrical activity that can be measured on the surface of the skin originates from the heart, the muscle or nerve structures. Because the frequency content of nerve activity falls in a higher frequency range than that of the ECG and myopotential, it is possible to use high-pass or band-pass filtering to specifically isolate the SKNA. neuECG is voltage calibrated and does not require invasive procedures to impale electrodes in nerves and thus has advantages over microneurography. Here, we present a protocol that takes <10 min to set up. The neuECG can be continuously recorded over a 24-h period or longer. We also describe methods to efficiently analyze neuECG from humans using commercially available hardware and software to facilitate adoption of this technology in clinical research.

Neural mechanisms of paroxysmal atrial fibrillation and paroxysmal atrial tachycardia in ambulatory canines.

BACKGROUND: The relationship between autonomic activation and the mechanisms of paroxysmal atrial fibrillation remains unclear. METHODS AND RESULTS: We implanted a pacemaker and a radio transmitter in 7 dogs (group 1). After baseline recording, we paced the left atrium at 20 Hz for 1 week and then monitored left stellate ganglion nerve activity, left vagal nerve activity, and left atrial electrogram without pacing for 24 hours. This protocol repeated itself until sustained atrial fibrillation (>48 hours) was induced in 3+/-1 weeks. In another 6 dogs (group 2), we cryoablated left and right stellate ganglia and the cardiac branch of the left vagal nerve during the first surgery and then repeated the same pacing protocol until sustained atrial fibrillation was induced in 7+/-4 weeks (P=0.01). There were 4+/-2 episodes of paroxysmal atrial fibrillation per day and 10+/-3 episodes of paroxysmal atrial tachycardia per day in group 1. Simultaneous sympathovagal discharges were observed to immediately precede the onset of atrial arrhythmias in 73% of episodes. In comparison, group 2 dogs had no paroxysmal atrial fibrillation (P=0.046) or paroxysmal atrial tachycardia (P<0.001) episodes. Nerve sprouting, sympathetic hyperinnervation, and a massive elevation of transcardiac norepinephrine levels occurred in both groups. CONCLUSIONS: Intermittent rapid left atrial pacing results in sympathetic hyperinnervation, paroxysmal atrial fibrillation, and paroxysmal atrial tachycardia. Simultaneous sympathovagal discharges are common triggers of these arrhythmias. Cryoablation of extrinsic sympathovagal nerves eliminated paroxysmal atrial fibrillation and paroxysmal atrial tachycardia, which suggests that simultaneous sympathovagal discharges and these arrhythmias are causally related. Because cryoablation only delayed but did not prevent sustained atrial fibrillation, autonomic nerve activity is not the only factor that determines atrial fibrillation maintenance.

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

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.

Antiarrhythmic effects of beta3-adrenergic receptor stimulation in a canine model of ventricular tachycardia.

BACKGROUND: Beta3-adrenergic receptor (beta3-AR) stimulation inhibits cardiac contractility. OBJECTIVE: This study sought to test the hypothesis that beta3-AR stimulation is antiarrhythmic. METHODS: We implanted a radio transmitter for continuous electrocardiogram monitoring in 18 dogs with a tendency for high incidence of spontaneous ventricular tachycardia (VT). Ten of 18 had subcutaneous continuous BRL37344 (beta3-AR agonist) infusion (experimental group) for 1 month. The other dogs were controls. Western blotting studies were performed on tissues sampled from the noninfarcted left ventricular free wall of all dogs that survived the 60-day follow-up period. RESULTS: Phase 2 VT appeared significantly later in the experimental group than in the control group (P <.05). The number of VT episodes in the experimental group was significantly lower than in the control group during both the first month (0.5 +/- 0.95 episodes/day vs. 2.6 +/- 2.3 episodes/day) and the second month (0.2 +/- 0.2 episode/day vs. 1.2 +/- 1.1 episodes/day, P <.05 for both). The experimental group had shorter QTc than control (P <.002). The experimental group had decreased protein levels for sodium calcium exchanger and dihydropyridine receptor, increased beta3-AR expression, without changes in beta1-AR, beta2-AR. The average heart weight and the left ventricular free wall thickness in the experimental group (226 +/- 17 g and 15.1 +/- 1.2 mm, respectively) was significantly lower than in the control group (265 +/- 21 g and 17.4 +/- 2.5 mm, respectively, P <.05 for both). There was no difference in the incidences of sudden cardiac death in these 2 groups of dogs. CONCLUSION: Beta3-AR stimulation significantly reduces the occurrence of ventricular tachycardia.

Spontaneous stellate ganglion nerve activity and ventricular arrhythmia in a canine model of sudden death.

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.

Atrial sympathetic and parasympathetic nerve sprouting and hyperinnervation induced by subthreshold electrical stimulation of the left stellate ganglion in normal dogs.

BACKGROUND: Subthreshold electrical stimulation of the left stellate ganglion (LSG) can induce nerve sprouting and sympathetic hyperinnervation in canine ventricles. It is unclear whether a similar neural plasticity involving both sympathetic and parasympathetic innervation also exists in the atria. METHODS AND RESULTS: We applied subthreshold electrical stimulation at 20 Hz (0.45 ms pulse width) or 5 Hz (1.9 ms pulse width) to the LSG in 6 normal mongrel dogs. After 41+/-9 days, the hearts were harvested and the right and left atrium stained for synaptophysin (SYN), growth-associated protein 43 (GAP43), sympathetic nerve markers tyrosine hydroxylase (TH), and parasympathetic marker choline acetyltransferase (ChAT). Tissues from 6 additional healthy dogs were used as controls. The hearts from dogs with LSG electrical stimulation had a higher density of nerve structures immunopositive to the SYN, GAP43, TH, and ChAT (P<.01) in both right and left atria. Nerve density was equal in right and left atria. There were more TH-positive nerve structures than ChAT-positive nerve structures (P<.01) for both right and left atria. No atrial arrhythmia was observed at the second surgery. CONCLUSIONS: Continuous subthreshold electrical stimulation to the LSG induces both sympathetic and parasympathetic hyperinnervation in both right and left atria in normal dogs.

Anti-phospholipid antibodies in cerebrospinal fluid but not serum from a boy with psychosis.

A 12-year-old African American boy with mental retardation and Asperger's disorder presented with acute psychosis. Antiphospholipid antibody testing with enzyme-linked immunosorbent assay showed increased levels of immunoglobulin G anticardiolipin antibodies in the cerebrospinal fluid, but not in the serum. Although antiphospholipid antibodies have been reported in the serum of patients with thrombotic and neurologic disorders, there are only a few reports of these antibodies in cerebrospinal fluid. This finding is consistent with a recent report of antiphospholipid antibodies found in the cerebrospinal fluid of adults with acute psychosis.

Long-term intermittent high-amplitude subcutaneous nerve stimulation reduces sympathetic tone in ambulatory dogs.

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.

Effects of Vagal Nerve Stimulation on Ganglionated Plexi Nerve Activity and Ventricular Rate in Ambulatory Dogs With Persistent Atrial Fibrillation.

OBJECTIVES: This study was designed to test the hypothesis that low-level vagal nerve stimulation (VNS) reduces the ventricular rate (VR) during atrial fibrillation (AF) through the activation of the inferior vena cava (IVC)-inferior atrial ganglionated plexus nerve activity (IAGPNA). BACKGROUND: Increased IVC-IAGPNA can suppress atrioventricular node conduction and slow VR in canine models of AF. METHODS: Persistent AF was induced in 6 dogs and the IVC-IAGPNA, right vagal nerve activity, left vagal nerve activity, and an electrocardiogram were recorded. After persistent AF was documented, VNS was programed to 14 s "on" and 1.1 min "off." After 1 week, the VNS was reprogramed to 3 min off and stimulation continued for another week. Neural remodeling of the stellate ganglion (SG) was assessed with tyrosine hydroxylase staining and terminal deoxynucleotidyl transferase deoxyuridine triphosphate nick-end labeling staining. RESULTS: Average IVC-IAGPNA was increased during both VNS 1.1 min off (8.20 ± 2.25 µV [95% confidence interval (CI): 6.33 to 9.53 µV]; p = 0.002) and 3 min off (7.96 ± 2.03 µV [95% CI: 6.30 to 9.27 µV]; p = 0.001) versus baseline (7.14 ± 2.20 µV [95% CI: 5.35 to 8.52 µV]). VR was reduced during both VNS 1.1 min off (123.29 ± 6.29 beats/min [95% CI: 116.69 to 129.89 beats/min]; p = 0.001) and 3 min off (120.01 ± 4.93 beats/min [95% CI: 114.84 to 125.18 beats/min]; p = 0.001) compared to baseline (142.04 ± 7.93 bpm [95% CI: 133.72 to 150.37]). Abnormal regions were observed in the left SG, but not in the right SG. Terminal deoxynucleotidyl transferase deoxyuridine triphosphate nick-end labeling-positive neurons were found in 22.2 ± 17.2% [95% CI: 0.9% to 43.5%] of left SG cells and 12.8 ± 8.4% [95% CI: 2.4% to 23.2%] of right SG cells. CONCLUSIONS: Chronic low-level VNS increases IVC-IAGPNA and damages bilateral stellate ganglia. Both mechanisms could contribute to the underlying mechanism of VR control during AF.