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.

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.

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.

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

BACKGROUND: We recently reported that subcutaneous nerve activity (SCNA) can be used to estimate sympathetic tone. OBJECTIVE: 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). METHODS: 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. RESULTS: 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. CONCLUSION: SCNA is more accurate than HRV in estimating cardiac sympathetic tone in ambulatory dogs with MI.

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.

Effects of simvastatin on cardiac neural and electrophysiologic remodeling in rabbits with hypercholesterolemia.

BACKGROUND: Significant cardiac neural and electrophysiologic remodeling occurs with hypercholesterolemia (HC). Whether simvastatin can reverse HC-induced remodeling is unclear. OBJECTIVE: The purpose of this study was to determine the mechanisms underlying the antiarrhythmic effects of statins. METHODS: Rabbits (N = 38) were fed HC chow (HC), standard chow (Control), HC chow followed by standard chow (Withdrawal), or HC chow and simvastatin (Statin) for 8 weeks. The hearts then were Langendorff-perfused for electrophysiologic studies. Nerves were identified by immunostaining of growth-associated protein-43 (GAP43) and tyrosine hydroxylase (TH). Action potential duration (APD) restitution in normal hearts with (N = 5) and without (N = 5) simvastatin therapy also was studied. RESULTS: Serum cholesterol levels (mg/dL) were 1,855 +/- 533 in HC, 50 +/- 21 in Control, 570 +/- 115 in Withdrawal, and 873 +/- 112 in Statin groups (P <.001). Compared with HC (16,700 +/- 5,342; 12,200 +/- 3,878 microm(2)/mm(2)), the Statin group had significantly reduced GAP43-positive (10,289 +/- 3,393 microm(2)/mm(2), P = .03) and TH-positive (7,685 +/- 2,959 microm(2)/mm(2), P = .04) nerve density, respectively. APD was longer in HC rabbits than in controls (192 +/- 20 ms vs 174 +/- 17 ms; P <.03). Withdrawal and Statin groups had less APD prolongation than HC group. Statin group has less repolarization heterogeneity than HC group (P <.01). Statin therapy flattened the slope of APD restitution in normal hearts. Ventricular fibrillation was either induced or occurred spontaneously in 79% of hearts in HC, 20% in Control, and 66% in Withdrawal groups. However, there was no VF in hearts of Statin group (P <.001). CONCLUSION: Simvastatin significantly reduced vulnerability to ventricular fibrillation via the mechanism of reduction of HC-induced neural and electrophysiologic remodeling.

Altered atrial electrical restitution and heterogeneous sympathetic hyperinnervation in hearts with chronic left ventricular myocardial infarction: implications for atrial fibrillation.

BACKGROUND: The substrates for the increased incidence of atrial fibrillation (AF) in hearts with chronic left ventricular myocardial infarction (MI) remain poorly defined. We hypothesized that chronic MI is associated with atrial electrical and neural remodeling that enhances AF vulnerability. METHODS AND RESULTS: We created MI in 8 dogs by permanent occlusion of the left anterior descending (LAD) coronary artery. Seven dogs (3 with thoracotomy) that had no LAD occlusion served as controls. Eight weeks after surgery, the incidence and duration of pacing-induced AF in the open chest anesthetized state were significantly (P<0.05) higher in the MI than in control dogs. Multisite biatrial monophasic action potential (MAP) recordings showed increased heterogeneity of MAP duration (MAPD) and MAPD restitution slope. AF in the MI groups was preceded by significantly higher MAPD (P<0.01) and MAP amplitude (P<0.05) alternans in both atria compared with controls. Epicardial mapping using 1792 bipolar electrodes (1-mm spatial resolution) showed multisite wavebreaks of the paced wavefronts leading to AF in MI but not in control dogs. Multiple wavelets in MI dogs were associated with significantly higher incidence and longer duration of AF compared with control. The density of biatrial tyrosine hydroxylase (TH) and growth-associated protein43 (GAP43) nerves were 5- to 8-fold higher and were more heterogeneous in MI compared with control dogs. CONCLUSIONS: Chronic ventricular MI with no atrial involvement causes heterogeneous alteration of atrial electrical restitution and atrial sympathetic hyperinnervation that might provide important substrates for the observed increased AF vulnerability.

Sympathetic nerve sprouting, electrical remodeling, and increased vulnerability to ventricular fibrillation in hypercholesterolemic rabbits.

Whether hypercholesterolemia (HC) can induce proarrhythmic neural and electrophysiological remodeling is unclear. We fed rabbits with either high cholesterol (HC, n=10) or standard (S, n=10) chows for 12 weeks (protocol 1), and with HC (n=12) or S (n=10) chows for 8 weeks (protocol 2). In protocol 3, 10 rabbits were fed with various protocols to observe the effects of different serum cholesterol levels. Results showed that the serum cholesterol levels were 2097+/-288 mg/dL in HC group and 59+/-9 mg/dL in S group for protocol 1 and were 1889+/-577 mg/dL in HC group and 50+/-21 mg/dL in S group for protocol 2. Density of growth-associated protein 43- (GAP43) and tyrosine hydroxylase- (TH) positive nerves in the heart was significantly higher in HC than S in protocol 1. Compared with S, HC rabbits had longer QTc intervals, more QTc dispersion, longer action potential duration, increased heterogeneity of repolarization and higher peak calcium current (ICa) density (14.0+/-3.1 versus 9.1+/-3.4 pA/pF; P<0.01) in protocol 1 and 2. Ventricular fibrillation was either induced or occurred spontaneously in 9/12 of hearts of HC group and 2/10 of hearts in S group in protocol 2. Protocol 3 showed a strong correlation between serum cholesterol level and nerve density for GAP43 (R2=0.94; P<0.001) and TH (R2=0.91; P<0.001). We conclude that HC resulted in nerve sprouting, sympathetic hyperinnervation, and increased ICa. The neural and electrophysiological remodeling was associated with prolonged action potential duration, longer QTc intervals, increased repolarization dispersion, and increased ventricular vulnerability to fibrillation.