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.

Antiarrhythmic and proarrhythmic effects of subcutaneous nerve stimulation in ambulatory dogs.

BACKGROUND: High output subcutaneous nerve stimulation (ScNS) remodels the stellate ganglia and suppresses cardiac arrhythmia. OBJECTIVE: The purpose of this study was to test the hypothesis that long duration low output ScNS causes cardiac nerve sprouting and increases plasma norepinephrine concentration and the duration of paroxysmal atrial tachycardia (PAT) in ambulatory dogs. METHODS: We prospectively randomized 22 dogs (11 males and 11 females) into 5 different output groups for 2 months of ScNS: 0 mA (sham) (n = 6), 0.25 mA (n = 4), 1.5 mA (n = 4), 2.5 mA (n = 4), and 3.5 mA (n = 4). RESULTS: As compared with baseline, the changes in the durations of PAT episodes per 48 hours were significantly different among different groups (sham, -5.0 ± 9.5 seconds; 0.25 mA, 95.5 ± 71.0 seconds; 1.5 mA, -99.3 ± 39.6 seconds; 2.5 mA, -155.3 ± 87.8 seconds; and 3.5 mA, -76.3 ± 44.8 seconds; P < .001). The 3.5 mA group had a greater reduction in sinus heart rate than did the sham group (-29.8 ± 15.0 beats/min vs -14.5 ± 3.0 beats/min; P = .038). Immunohistochemical studies showed that the 0.25 mA group had a significantly increased while 2.5 mA and 3.5 mA stimulation had significantly reduced growth-associated protein 43 nerve densities in both atria and ventricles. The plasma norepinephrine concentrations in the 0.25 mA group was 5063.0 ± 4366.0 pg/mL, which was significantly higher than that in the other groups of dogs (739.3 ± 946.3; P = .009). There were no significant differences in the effects of simulation between males and females. CONCLUSION: In ambulatory dogs, low output ScNS causes cardiac nerve sprouting and increases plasma norepinephrine concentration and the duration of PAT episodes while high output ScNS is antiarrhythmic.

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

BACKGROUND: 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. OBJECTIVE: 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. METHODS: We performed long-term LDTN stimulation in 6 dogs with and 2 dogs without intermittent rapid LA pacing while monitoring SGNA. RESULTS: 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. CONCLUSION: LDTN stimulation damages both left and right stellate ganglia, reduces left SGNA, and is antiarrhythmic in this canine model of PAT.

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 atrial fibrillation substrate and spatiotemporal organization on atrial defibrillation thresholds.

BACKGROUND: We previously showed that canine models of atrial fibrillation (AF) have different substrates (either structural or electrical) that lead to differences in AF characteristics. OBJECTIVE: The purpose of this study was to determine whether the differences in AF characteristics also would lead to differences in atrial defibrillation thresholds (ADFTs). METHODS: Dogs were divided into five groups: control; MR-mitral regurgitation for 5 weeks; CHF-congestive heart failure for 4 weeks; RAP-rapid atrial pacing for 6 weeks; and METH-acetyl-beta-methylcholine acutely administered. A cross-sectional area of the left atrium was calculated, and AF was induced with rapid atrial pacing. Biphasic shocks with a pulse width of 3/3 ms were delivered through specially constructed shocking catheters with a surface area of 3.7 cm(2) that were placed in the right and left atria. An up-down-up protocol was used to determine the 50% ADFT threshold (ADFT(50)). A wide-bipole AF signal was digitally filtered, and a fast Fourier transform was calculated over a 2-second window every 1 second. The dominant frequency was determined, and the organization index was calculated as the ratio of the area under the dominant peak and its harmonics to the total area of the spectrum. RESULTS: For left atrial size, the CHF and MR groups had a significantly larger atria than did control. ADFT(50) for control, MR, CHF, RAP, and METH groups were 160 +/- 30 V, 120 +/- 50 V, 132 +/- 20 V, 668 +/- 205 V, and 593 +/- 128 V, respectively (analysis of variance, P <.0001). Dominant frequencies were significantly higher and organization indexes significantly lower in the RAP and METH models compared with the other models. CONCLUSION: RAP and METH canine models had a significantly higher ADFT(50) compared with the other AF models. The increase in ADFT(50) in these models corresponded with higher global dominant frequencies and lower measured organization indexes.

Intracellular chloride accumulation and subcellular elemental distribution during atrial fibrillation.

BACKGROUND: Ion channel remodeling occurs during atrial fibrillation (AF); however, the extent of alteration in the subcellular distribution of elements (Na, K, Cl, Ca, Mg, P) is unknown. Electron probe microanalysis was used to determine the total (free+bound) in vivo subcellular concentration of these elements during AF. METHODS AND RESULTS: The left atrial appendage (LAA) was snap-frozen in situ after pacing (640 bpm) for 3 minutes (n=5 dogs), 30 minutes (n=3), or 48 hours (n=5). Dogs in sinus rhythm (n=3) served as controls. Whole-cell, cytosolic, and mitochondrial elemental concentrations were measured in cryosections. LAA effective refractory period (ERP) was measured before and after pacing. LAA ERP decreased significantly after 48 hours (116+/-3 to 88+/-10 ms, P=0.02). Whole-cell Cl increased by 9.0 mmol/L and 17 mmol/L after 3 and 30 minutes of pacing, respectively (P<0.0001), without a concomitant increase in Na. However, at 48 hours, whole-cell Na was reduced by 51% (P<0.01). Cytosolic Ca increased by 1.1 mmol/kg dry wt after 3 minutes (P<0.005), but mitochondrial Ca remained low and unchanged. Cell size measured in transverse cryosections increased after 3 minutes of pacing (75+/-5 to 109+/-11 microm2, P=0.007) but returned to baseline by 30 minutes (66+/-5 microm2). CONCLUSIONS: Intracellular Cl accumulation induced by rapid pacing is a novel finding and may play a role in AF pathogenesis by causing resting membrane depolarization and ERP reduction. There was no evidence of cellular or mitochondrial Ca overload despite the development of electrical remodeling and transient increase in cytoplasmic Ca.

Effect of electrical and structural remodeling on spatiotemporal organization in acute and persistent atrial fibrillation.

INTRODUCTION: Atrial fibrillation (AF) may originate from discrete sites of periodic activity. We studied the effect of structural and electrical remodeling on spatiotemporal organization in acute and persistent AF. METHODS AND RESULTS: Atrial effective refractory periods (AERPs) were recorded from five different sites at baseline and after pacing in acute AF (n = 8 dogs) and persistent AF (n = 8). Four persistent AF dogs subsequently were cardioverted to sinus rhythm to allow AERP recovery. Periodicity was quantified by calculating power spectra on left atrial electrograms obtained from a 64-electrode basket catheter. Left atrial size was measured by intracardiac echocardiography and structural changes were assessed by electron microscopy. Mean AERPs decreased after pacing in acute (128 +/- 16 msec to 108 +/- 29 msec, P < 0.001) and persistent AF (135 +/- 16 msec to 104 +/- 24 msec, P < 0.0001). AERP recovery was established after 7 days of sinus rhythm. Structural changes were mild in acute AF, severe in persistent AF, and remained severe after AERP recovery. A single dominant frequency was identified in 94% of acute AF bipoles, 57% in persistent AF, and 76% after AERP recovery. Average correlation coefficient was 0.82 among acute AF bipoles, 0.63 in persistent AF, and 0.73 after AERP recovery. CONCLUSION: Transition from acute to persistent AF is associated with loss of spatiotemporal organization. A single dominant frequency recruits the majority of the left atrium in acute AF. Persistent AF, however, is associated with structural remodeling and dominant frequency dispersion. Recovery of refractoriness only partially restores spatiotemporal organization, indicating a major role for structural remodeling in the maintenance of persistent AF.

Use of global atrial fibrillation organization to optimize the success of burst pace termination.

OBJECTIVES: The purpose of this study was to determine if burst atrial pacing would have an effect on terminating atrial fibrillation. BACKGROUND: We hypothesized that frequency domain analysis of a filtered wide bipolar atrial electrogram describes the global organization of atrial fibrillation (AF) and should vary over time. Timing burst pacing to periods of high organization of AF should promote regional atrial conduction block and terminate AF. METHODS: Nine dogs were conditioned with rapid atrial pacing for 48 h. Electrogram recordings were made from a wide right atrium (RA) to left atrium (LA) bipole and digitally filtered. A fast-Fourier transform was performed every 0.5 s on a sliding 2-s window, and the organization index (OI) was calculated as a ratio of the area of the first four harmonic peaks to the total power of the spectrum. Organization indexes >0.5 indicated more organized AF activity. Right atrium and LA burst pacing (burst) (cycle length 50 ms, 9.9 ms, 9.9 mA, 1 to 4 s) was performed through decapolar catheters. Burst was either random or synchronized to OI >0.5. RESULTS: Burst termination was attempted 1,814 times (889 OI sync, 925 random) and succeeded in seven of nine dogs. Burst had an overall success rate of 11.1% versus 6.3% for random (p < 0.0003). Biatrial pacing had the highest efficacy for terminating AF, with a success rate of 16.5% for OI sync versus 8.2% for random (p < 0.0001). CONCLUSIONS: Timing the delivery of the burst pace when the OI is >0.5 increases the efficacy of burst pace termination of AF. Biatrial pacing is more effective than either RA or LA pacing alone.