Stellate Ganglion Stimulation Research Articles

PO-02-152 EFFECTS OF SYMPATHETIC STIMULATION ON REPOLARIZATION AND ARRHYTHMOGENESIS DURING LEFT LATERAL MYOCARDIAL ISCHEMIA

Left stellate ganglion stimulation (LSGS) is arrhythmogenic during acute myocardial ischemia of the anterior wall of the left ventricle. We hypothesized, as a counterpart, that right stellate ganglion stimulation (RSGS) is proarrhythmic when ischemia is produced by occlusion of the circumflex coronary artery. In 7 anesthetized female open-chested pigs, ventricular repolarization was measured in unipolar electrograms from 128 epicardial sites on the left lateral ventricular wall in an electrode grid of 14x30 mm (interelectrode distance 2 mm). Seven subsequent episodes of 5 minutes of acute ischemia (5 minutes occlusion of the circumflex coronary artery with 20 minutes reperfusion). Right atrial pacing was performed throughout the experiment at cycle length of 450 ms. The second occlusion served as a control. During the third and fourth occlusion, left or right stellate ganglion stimulation (LSGS or RSGS), respectively, was initiated after 3 minutes of ischemia for 30 seconds. The protocol was repeated after decentralization of both stellate ganglia and bilateral cervical vagotomy. Between 3 and 5 minutes of ischemia, RSGS caused a median of 9 (interquartile range 3-12), ventricular premature beats and in 2 instances ventricular tachycardia and fibrillation. The number of ventricular premature beats was significantly less during LSGS and control conditions (Figure, panel A), during which no ventricular tachycardia or fibrillation occurred. Following decentralization, RSGS was no longer significantly more arrhythmogenic than LSGS or control conditions (Figure, panel A). Additionally, we found that LSGS-induced changes in repolarization are evident in non-ischemic tissue, but not in ischemic tissue, during coronary occlusion (Figure, panel B, note the overlapping T-waves in the ischemic region). LSGS no longer has an effect on myocardium that has been ischemic for 3 minutes by occlusion of the circumflex coronary artery. RSGS was arrhythmogenic in this setting, while LSGS was not. This supports the clinical findings that bilateral sympathectomy is superior to left sympathectomy alone.

Stellate ganglia stimulation counteracts vagal stimulation by significantly increasing heart rate and blood pressure.

Vasovagal syncope (VVS) is the leading cause of syncope. The most frequent mechanism is that of a cardioinhibitory response, vasodepressor response, or mixture of both. Neural stimulation that negates or overcomes the effects of vagal tone may be used as a treatment strategy for VVS. Six male canines were studied. Stimulation (10-Hz, 2ms pulse duration, 2min duration) of the cervical vagus (CV), thoracic vagus (TV), and stellate ganglia (SG) was performed using needle electrodes at 3V, 5V, and 10V output. SG stimulation at an output of 10V overlaying TV stimulation at the same output was performed. Heart rate (HR), blood pressure (BP), and cardiac output (CO) were measured before, during, and after stimulation. Right cervical vagal stimulation was associated with significant hemodynamic changes. HR, SBP, and DBP were reduced (107±16 vs. 78±15bpm [P<0.0001], 116±24 vs. 107±28mmHg [P=0.002] and 71±18 vs. 58±20mmHg [P<0.0001]), respectively, while left cervical vagal stimulation had minimal changes. CV stimulation was associated with greater hemodynamic changes than TV stimulation. Left and right SG stimulation significantly increased systolic blood pressure (SBP), diastolic blood pressure (DBP), and HR at 5V and 10V, which could be observed within 30s after stimulation. An output-dependent increase in hemodynamic parameters was seen with both left and right SG stimulation. No difference between left and right SG stimulation was seen. SG stimulation overlay significantly increased HR, BP, and CO from baseline vagal stimulation bilaterally. Stellate ganglia stimulation leads to increased HR and BP despite significant vagal stimulation. This may be exploited therapeutically in the management of vasovagal syncope.

Acute Modulation of Left Ventricular Control by Selective Intracardiac Sympathetic Denervation.

The sympathetic nervous system plays an integral role in cardiac physiology. Nerve fibers innervating the left ventricle are amenable to transvenous catheter stimulation along the coronary sinus (CS). The aim of the present study was to modulate left ventricular control by selective intracardiac sympathetic denervation. First, the impact of epicardial CS ablation on cardiac electrophysiology was studied in a Langendorff model of decentralized murine hearts (n=10 each, ablation and control groups). Second, the impact of transvenous, anatomically driven axotomy by catheter-based radiofrequency ablation via the CS was evaluated in healthy sheep (n=8) before and during stellate ganglion stimulation. CS ablation prolonged epicardial ventricular refractory period without (41.8 ± 8.4ms vs 53.0 ± 13.5ms; P=0.049) and with β1-2-adrenergic receptor blockade (47.8 ± 7.8ms vs 73.1 ± 13.2ms; P<0.001) in mice. Supported by neuromorphological studies illustrating a circumferential CS neural network, intracardiac axotomy by catheter ablation via the CS in healthy sheep diminished the blood pressure increase during stellate ganglion stimulation (Δ systolic bloodpressure 21.9 ± 10.9mmHg vs 10.5 ± 12.0mmHg; P=0.023; Δ diastolic blood pressure 9.0 ± 5.5mmHg vs 3.0± 3.5mmHg; P=0.039). Transvenous, anatomically driven axotomy targeting nerve fibers along the CS enables acute modulation of left ventricular control by selective intracardiac sympathetic denervation.

Stellate ganglion instrumentation for pharmacological blockade, nerve recording, and stimulation in patients with ventricular arrhythmias: Preliminary experience

Stellate ganglion blockade (SGB) can control ventricular arrhythmias (VAs), but outcomes are unclear. Percutaneous stellate ganglion (SG) recording and stimulation in humans has not been reported. The purpose of this study was to assess the outcomes of SGB and the feasibility of SG stimulation and recording in humans with VA. Two patient cohorts were included-group 1: patients undergoing SGB for drug-refractory VA. SGB was performed by injection of liposomal bupivacaine. Incidence of VA at 24 and 72 hours and clinical outcomes were collected; group 2: patients undergoing SG stimulation and recording during VA ablation; a 2-F octapolar catheter was placed at the SG at the C7 level. Recording (30 kHz sampling, 0.5-2 kHz filter) and stimulation (up to 80 mA output, 50 Hz, 2 ms pulse width for 20-30 seconds) was performed. Group 1 included 25 patients (mean age 59.2 ± 12.8 years; 76% men) who underwent SGB for VAs. Nineteen patients (76.0%) were free of VA up to 72 hours postprocedure. However, 15 (60.0%) had VA recurrence for a mean of 5.47 ± 4.52 days. Group 2 included 11 patients (mean age 63 ± 12.7 years; 82.7% men). SG stimulation caused consistent increases in systolic blood pressure. We recorded unequivocal signals with temporal association with arrhythmias in 4 of 11 patients. SGB provides short-term VA control, but has no benefit in the absence of definitive VA therapies. SG recording and stimulation is feasible and may have value to elicit VA and understand neural mechanisms of VA in the electrophysiology laboratory.

Abstract 11494: Electrophysiological Effects of Sympathoexcitation are Mitigated by Blockade of Neuropeptide Y Y2 Receptors on Cardiac Parasympathetic Nerve Terminals

Introduction: Sympathetic activation releases both norepinephrine and co-transmitter neuropeptide Y (NPY). NPY can predispose to ventricular arrhythmias via receptors on cardiomyocytes. Ex vivo studies suggest that NPY may concomitantly reduce vagal tone via activation of NPY Y2 receptors (Y2R) on parasympathetic nerves, reducing acetylcholine release and further augmenting pro-arrhythmic sympathetic effects. We evaluated if parasympathetic Y2R blockade can prevent NPY-induced vagal inhibition, restore autonomic balance and stabilize cardiac electrophysiology. Methods: Yorkshire pigs (n = 12) underwent bilateral stellate ganglia stimulation (BSGS; 10 Hz, 4 ms) for 45 secs, before and after administration of selective Y2R antagonist BIIE0246 (BIIE; 32 nmol/kg bolus + 2 nmol/kg/min infusion). Hemodynamic and electrophysiological recordings were obtained with a left ventricular pressure (LVP) catheter, surface electrogram and a 56-electrode sock placed over the ventricles to measure activation recovery intervals (ARI), a surrogate of local action potential duration, from unipolar electrograms. Heart rate variability parameters, including low to high frequency ratio (LF/HF), were analyzed pre- and post-BIIE. Results: BSGS significantly increased heart rate (HR) and LVP, and shortened ventricular ARIs. BIIE significantly reduced both the rate of change and the maximal changes in HR and ARIs during BSGS. As anticipated, BSGS significantly increased LF/HF ratio, but this effect was abolished after BIIE. BIIE did not affect BSGS related increases in LVP. Conclusions: Cardiac effects of sympathetic activation are mediated, at least in part, by suppression of vagal tone through binding of NPY to parasympathetic Y2Rs. Blockade of this receptor partially counters pro-arrhythmic electrophysiological effects of BSGS and suggests a possible novel adjuvant role for Y2R blockade as a therapy for reducing consequences of sympatho-excitation.

Selective intracardiac sympathetic denervation acutely modulates left ventricular control

Abstract Funding Acknowledgements Type of funding sources: Public grant(s) – National budget only. Main funding source(s): German Centre for Cardiovascular Research (DZHK) Background The sympathetic nervous system plays an integral role in cardiac physiology. Neuromodulation is emerging as a treatment option for ventricular arrhythmias, but selective intracardiac approaches are rare. Sympathetic nerve fibers innervating the left ventricle have been demonstrated to be amenable to transvenous catheter stimulation along the coronary sinus (CS). Purpose The aim of the present study was to modulate left ventricular control by selective sympathetic denervation using epicardial or standard catheter ablation for intracardiac axotomy at the level of the CS. Methods First, the impact of epicardial CS ablation on cardiac electrophysiology was studied in a Langendorff model of murine hearts (n=10 each, ablation and control). Second, the impact of transvenous, anatomically-driven axotomy by catheter-based radiofrequency ablation along the CS was evaluated in a healthy ovine in vivo model (n=8) before and during left stellate ganglion stimulation (LSGS). Results CS ablation for intracardiac sympathetic axotomy prolonged epicardial ventricular refractory period (VRP) without (41.8±8.4 ms vs. 53.0±13.5 ms; P=0.0487) and with beta1-2-adrenergic receptor blockade (47.8±2.8 ms vs. 73.1±5.0 ms; P=0.0009) and enhanced the increasing effect of beta1-2-adrenergic receptor blockade on epicardial VRP (∆VRP 6.3±7.0 ms vs. 20.0±7.5 ms; P=0.0045) in mice (Figure, A). Mean epicardial wave propagation velocity in the left ventricle was faster in ablated hearts than in controls (1.13±0.05 m/s vs. 1.00±0.02 m/s; P=0.0463), but did not differ in the right ventricle (1.15±0.05 m/s vs. 1.20±0.08 m/s; P=0.7938). Transvenous catheter ablation of the CS reduced systolic (SBP, 57.7±5.0 mmHg vs. 46.9±3.6 mmHg; P=0.0428) and diastolic blood pressure (DBP, 35.5±3.0 mmHg vs. 26.7±1.8 mmHg; P=0.0106) and diminished the blood pressure increase during LSGS in sheep (∆SBP 21.9±3.8 mmHg vs. 10.5±4.2 mmHg; P=0.0234; ∆DBP 9.0±1.9 mmHg vs. 3.0±1.2 mmHg; P=0.0391) (Figure, B, C). Cycle length remained unchanged by LSGS, both before (baseline 653.2±20.6 ms vs. LSGS 627.8±27.5 ms; P=0.2309) and after CS ablation (baseline 734.8±24.2 ms vs. LSGS 746.2±37.3 ms; P=0.7145). Conclusions Anatomically-driven axotomy targeting nerve fibers along the CS enables selective intracardiac sympathetic denervation resulting in acute modulation of left ventricular control.

CE-521-01 STELLATE GANGLION INSTRUMENTATION FOR RECORDING AND STIMULATION IN PATIENTS WITH VENTRICULAR ARRHYTHMIAS. PRELIMINARY EXPERIENCE

Stellate Ganglion (SG) blockade is used for controlling ventricular arrhythmias (VA). In animal models, SG instrumentation with electrode catheters can allow stimulation and recording cardiac sympathetic activity. Studies on direct modulation and recording of the sympathetic nervous system in human are lacking. To assess the feasibility of SG stimulation (SGS) and recording in humans undergoing VA ablation Patients (n=11) undergoing ablation procedures for VAs underwent bilateral SG recording and stimulation. Under ultrasound guidance, a 2F octapolar catheter was advanced in the SG at the C7 level. Signals were recorded at 30 kHz and filtered at 0.5-2kHz bandpass. Nerve activities were defined as a 3-fold increase in the amplitude over baseline. Stimulation was performed up to 80 mA output (50 Hz, 2 ms pulse width) for 20-30 s. Eleven patients (age 63 ± 12.7 years; 82.7% men) with ischemic ventricular tachycardia (VT) (4, 36%), nonischemic VT (5, 45%), and PVCs (2, 18.2%) were included. Stimulation catheter placement was successful without complications in all patients. SGS caused significant increase in the systolic blood pressure (Fig A-B). More after right than left SGS. SGS induced PVCs in 2 patients and VF in 1. We were able to record SG firings preceding VF in a patient with primary VF in the context of ischemic cardiomyopathy (Fig C-E), and left SG firing preceding the arrhythmia after SD stimulation (Fig F-G) in a patient with PVCs induced VF. SG recording and stimulation are feasible in humans. SGS leads to blood pressure increases, more pronounced after right SGS. SG firing can precede VA onset in humans. Technical refinements are needed to improve reliability of SG recordings.

Proarrhythmic Effects of Sympathetic Activation Are Mitigated by Vagal Nerve Stimulation in Infarcted Hearts.

The goal of this study was to evaluate whether intermittent VNS reduces electrical heterogeneities and arrhythmia inducibility during sympathoexcitation. Sympathoexcitation increases the risk of ventricular tachyarrhythmias (VT). Vagal nerve stimulation (VNS) has been antiarrhythmic in the setting of ischemia-driven arrhythmias, but it is unclear if it can overcome the electrophysiological effects of sympathoexcitation in the setting of chronic myocardial infarction (MI). In Yorkshire pigs after chronic MI, a sternotomy was performed, a 56-electrode sock was placed over the ventricles (n=17), and a basket catheter was positioned in the left ventricle (n=6). Continuous unipolar electrograms from sock and basket arrays were obtained to analyze activation recovery interval (ARI), a surrogate of action potential duration. Bipolar voltage mapping was performed to define scar, border zone, or viable myocardium. Hemodynamic and electrical parameters and VT inducibility were evaluated during sympathoexcitation with bilateral stellate ganglia stimulation (BSS) and during combined BSS with intermittent VNS. During BSS, global epicardial ARIs shortened from 384 ± 59 milliseconds to 297 ± 63 milliseconds and endocardial ARIs from 359 ± 36 milliseconds to 318 ± 40 milliseconds. Dispersion in ARIs increased in all regions, with the greatest increase observed in scar and border zone regions. VNS mitigated the effects of BSS on border zone ARIs (from-18.3% ± 6.3% to-2.1% ± 14.7%) and ARI dispersion (from 104ms2 [1 to 1,108ms2] to -108ms2 [IQR: -588 to 30ms2]). VNS reduced VT inducibility during sympathoexcitation (from 75%-40%; P< 0.05). After chronic MI, VNS overcomes the detrimental effects of sympathoexcitation by reducing electrophysiological heterogeneities exacerbated by sympathetic stimulation, decreasing VT inducibility.

Effect of Micro Acupotomy and Stellate Ganglion Stimulation on Patients with Cervical Vertigo

This article aims to evaluate the treatment effect of micro acupotomy and stellate ganglion stimulation on cervical vertigo. 90 patients with cervical vertigo were randomly divided into two groups, observation group and control group, with 45 cases in each group. The observation group was given micro acupotomy and stellate ganglion stimulation and the control group was given regular acupuncture treatment. The two groups were treated for 2 w. The therapeutic effect and evaluation of symptoms and functions of cervical vertigo score of the two groups of patients after treatment were observed. The mean blood flow levels of vertebrobasilar artery, right vertebral artery and left vertebral artery before and after treatment were observed. The results show that there were significant differences in mean changes of vertigo symptoms and functional scores between the two groups of patients (p<0.01) and the improvement of the observation group was larger than that of the control group (p<0.05); there was significant difference in the speeds of the blood flow of the vertebral-basal artery between the two groups before and after treatment (p<0.05) and the improvement of the observation group was larger than that of the control group (p<0.05). By comparison, the clinical effects of the two groups were statistically different (p<0.05), no side effects occurred in the two groups of patients. Micro acupotomy combined with stellate ganglion stimulation is effective in treating cervical vertigo.

Mechanism of ventricular premature beats elicited by left stellate ganglion stimulation during acute ischaemia of the anterior left ventricle.

AimsEnhanced sympathetic activity during acute ischaemia is arrhythmogenic, but the underlying mechanism is unknown. During ischaemia, a diastolic current flows from the ischaemic to the non-ischaemic myocardium. This ‘injury’ current can cause ventricular premature beats (VPBs) originating in the non-ischaemic myocardium, especially during a deeply negative T wave in the ischaemic zone. We reasoned that shortening of repolarization in myocardium adjacent to ischaemic myocardium increases the ‘injury’ current and causes earlier deeply negative T waves in the ischaemic zone, and re-excitation of the normal myocardium. We tested this hypothesis by activation and repolarization mapping during stimulation of the left stellate ganglion (LSG) during left anterior descending coronary artery (LAD) occlusion.Methods and resultsIn nine pigs, five subsequent episodes of acute ischaemia, separated by 20 min of reperfusion, were produced by occlusion of the LAD and 121 epicardial local unipolar electrograms were recorded. During the third occlusion, left stellate ganglion stimulation (LSGS) was initiated after 3 min for a 30-s period, causing a shortening of repolarization in the normal myocardium by about 100 ms. This resulted in more negative T waves in the ischaemic zone and more VPBs than during the second, control, occlusion. Following the decentralization of the LSG (including removal of the right stellate ganglion and bilateral cervical vagotomy), fewer VPBs occurred during ischaemia without LSGS. During LSGS, the number of VPBs was similar to that recorded before decentralization.ConclusionLSGS, by virtue of shortening of repolarization in the non-ischaemic myocardium by about 100 ms, causes deeply negative T waves in the ischaemic tissue and VPBs originating from the normal tissue adjacent to the ischaemic border.

Cardiac sympathetic activation circumvents high-dose beta blocker therapy in part through release of neuropeptide Y

The sympathetic nervous system plays an important role in the occurrence of ventricular tachycardia (VT). Many patients, however, experience VT despite maximal doses of beta blocker therapy, possibly due to the effects of sympathetic cotransmitters such as neuropeptide Y (NPY). The purpose of this study was to determine, in a porcine model, whether propranolol at doses higher than clinically recommended could block ventricular electrophysiological effects of sympathoexcitation via stellate ganglia stimulation, and if any residual effects are mediated by NPY. Greater release of cardiac NPY was observed at higher sympathetic stimulation frequencies (10 and 20 vs. 4 Hz). Despite treatment with even higher doses of propranolol (1.0 mg/kg), electrophysiological effects of sympathetic stimulation remained, with residual shortening of activation recovery interval (ARI), a surrogate of action potential duration (APD). Adjuvant treatment with the NPY Y1 receptor antagonist BIBO 3304, however, reduced these electrophysiological effects while augmenting inotropy. These data demonstrate that high-dose beta blocker therapy is insufficient to block electrophysiological effects of sympathoexcitation, and a portion of these electrical effects in vivo are mediated by NPY. Y1 receptor blockade may represent a promising adjuvant therapy to beta-adrenergic receptor blockade.

Stellate ganglion stimulation causes spatiotemporal changes in ventricular repolarization in pig

Dispersion in ventricular repolarization is relevant for arrhythmogenesis. The purpose of this study was to determine the spatiotemporal effects of sympathetic stimulation on ventricular repolarization. In 5 anesthetized female open-chest pigs, ventricular repolarization was measured from the anterior, lateral, and posterior walls of the left ventricle (LV) and right ventricle using up to 40 transmural plunge needles (4 electrodes each) before and after left stellate ganglion stimulation (LSGS) and right stellate ganglion stimulation. In addition, LSGS was performed in 3 pigs (2 male, 1 female) before and after verapamil (5-10 mg/h) administration. LSGS yielded a biphasic response in repolarization in the lateral and posterior walls of the LV, with prolongation at ∼5 seconds (10 ± 1.5 ms) and shortening at 20-30 seconds of stimulation (-28.9 ± 4.4 ms) during a monotonic pressure increase. While the initial prolongation was abolished by verapamil, late shortening was augmented. Sequential transections of the vagal nerve and stellate ganglia augmented repolarization dispersion responses to LSGS in 2of 5 hearts. An equal pressure increase by aortic occlusion resulted in a homogeneous shortening of repolarization in the LV, and the effects were smaller than those during LSGS. Right stellate stimulation shortened repolarization mainly in the anterior LV wall, but the effects were smaller than those of LSGS. LSGS first prolongs (through the L-type calcium current) and then shortens repolarization. The effect of LSGS was prominent in the posterior and lateral, not the anterior, LV walls.

Abstract P2004: Neural Inflammation in Stellate Ganglia Mediates Lung Injury-Induced Arrhythmogenesis

Background: People who suffer lung injury, incurred through a variety of means, are at greatly increased risk of developing cardiac arrhythmias. Treatment options remain limited. We propose that stellate ganglia neuro-inflammation contributes to lung injury-induced arrhythmogenesis. Methods: We created lung injury in adult Sprague-Dawley rats by a single tracheal instillation of Bleomycin (Bleo, 2.5 mg/kg), and used Saline instillation as a control. We recorded ECGs in conscience, freely moving Bleo and Saline rats treated with and without oral minocycline (20 mg/kg/day for 4 weeks, an anti-inflammatory drug to inhibit microglia/macrophage activation) using implantable radio-telemeters. During terminal experimentation we investigated the effect of minocycline on isolated electrical stellate stimulation-induced cardiac arrhythmias in Bleo rats. Results: Bleo rats exhibited lung lesions at necropsy and lung fibrosis histologically. Bleo rats, on average, had more premature ventricular contractions (PVCs) than Saline rats, an effect largely prevented by chronic treatment with minocycline. (PVC data 1-wk post Bleo: Saline 22±12, Bleo 481±394*#, Bleo+Mino 24±9. PVC data 2-wks post Bleo: Saline 6±2, Bleo 255±165*, Bleo+Mino 21±8. Data are AVG±SEM number of PVCs over 24-hr, n=5-6 for all groups. *P&lt;0.05 between Bleo vs. Saline, #P&lt;0.05 Bleo vs. Bleo+Mino). Isolated electrical stellate ganglia stimulation caused a frequency-dependent increase in heart rate without arrhythmias in normal rats but in Bleo rats triggered a significant number of PVCs, indicating stellate ganglia excitability post lung injury. This effect was greatly reduced in Bleo rats receiving minocycline. Since our isolated stellate preparation is decentralized, these data clearly suggest a local protective effect of minocycline on stellate ganglia in Bleo rats. Immunofluorescence data suggested that compared to sham-operated rats, the number of Iba-1-positive (a macrophage marker) cells in stellate ganglia of bleomycin-treated rats was significantly increased at 1 week post lung injury and lasted for at least 4 weeks. Conclusion: Our data showed that stellate ganglia neuroinflammation contributes to arrhythmogenesis in our Bleo lung injury rat model.

Effect of electroacupuncture on porcine cardiac excitability induced by left stellate ganglion stimulation

Augmentation of cardiac sympathetic tone has been shown to induce ventricular arrhythmias. Acupuncture has been clinically used to treat hypertension, angina pectoris, and atrial arrhythmias. However, the effects of acupuncture on ventricular electrophysiology and autonomic tone remain unknown. We hypothesized that acupuncture attenuates cardiac excitability and corrects the imbalance of autonomic tone during sympathetic hyperactivity. Fourteen Yorkshire pigs were randomized to electroacupuncture (EA, 2 Hz, 0.3-0.5 mA, 0.5 ms duration) or control (without EA) groups. Animals were sedated with terazol. General anesthesia consisted of isoflurane and fentanyl during surgical preparation and was transitioned to α-chloralose during experimental protocols. Through a median sternotomy, the heart was exposed and fitted with an elastic epicardial 56-electrode sock. Cardiac excitability was measured via activation recovery interval (ARI) and dispersion of repolarization (DOR) while autonomic balance was evaluated by heart rate variability (HRV) power spectrum analysis at baseline and during left stellate ganglion stimulation (LSS) with and without EA delivered at P 5-6 acupoints. 30-min of EA did not alter the baseline ARI and DOR, but significantly suppressed cardiac excitability during LSS through attenuation of ARI shortening (EA 2.1 ± 0.3% vs. control 5.2 ± 0.7%, P < 0.05) and DOR (EA 74.3 ± 26.9% vs., control 110.1 ± 22.9%, P < 0.05). EA significantly attenuated the increase in LF/HF (EA 0.6 ± 0.1 vs. control 1.1 ± 0.2, P < 0.05). In conclusion, EA reduces the cardiac excitability induced by LSS through correction of cardiac sympathovagal balance. This study provides mechanistic insights underlying cardiac neuromodulation of EA during sympathoexcitation.

Effects of extrinsic cardiac nerve stimulation on atrial fibrillation inducibility: The regulatory role of the spinal cord.

To investigate the effect of the mutual regulation of the extrinsic cardiac nerves on atrial electrophysiology and atrial fibrillation (AF) vulnerability. Fourteen dogs were randomly divided into two groups: spinal cord stimulation (SCS) group (n = 7) and spinal cord block (SCB) group (n = 7). SCS was performed with 90% of the threshold voltage stimulating the T1 -T2 spinal level, while SCB was performed by injecting 2% lidocaine into the epidural space at the T2-3 level. The effective refractory period (ERP), ERP dispersion, and AF inducibility were measured during atrial pacing combined with different extrinsic cardiac nerve stimulation. ERPs were decreased in the atrium and pulmonary veins and ERP dispersion was increased from baseline during left cervical vagus nerve stimulation (VNS) or left stellate ganglion stimulation (SGS) in the two groups. When combined with SCS, VNS resulted in diminished ERPs at all recording sites, longer ERP dispersion and more episodes of AF than were observed during VNS, whereas ERPs were greater and correspondingly fewer episodes of AF occurred during SCS combined with SGS than SGS. In the SCB group, ERPs were shortened, ERP dispersion was lengthened, and episodes of AF were increased during SGS after SCB. SCS enhanced the activity of the left vagus nerve but attenuated the left stellate ganglion and superior left ganglionated plexus. SCS modulates extrinsic and intrinsic cardiac nerve activity among the vagus nerve, stellate ganglion, and ganglionated plexus. SCS facilitates the effect of VNS and attenuates the effect of SGS on atrial electrophysiology.

Effect of Thoracic Epidural Anesthesia on Ventricular Excitability in a Porcine Model.

Imbalances in the autonomic nervous system, namely, excessive sympathoexcitation, contribute to ventricular tachyarrhythmias. While thoracic epidural anesthesia clinically suppresses ventricular tachyarrhythmias, its effects on global and regional ventricular electrophysiology and electrical wave stability have not been fully characterized. The authors hypothesized that thoracic epidural anesthesia attenuates myocardial excitability and the proarrhythmic effects of sympathetic hyperactivity. Yorkshire pigs (n = 15) had an epidural catheter inserted (T1 to T4) and a 56-electrode sock placed on the heart. Myocardial excitability was measured by activation recovery interval, dispersion of repolarization, and action potential duration restitution at baseline and during programed ventricular extrastimulation or left stellate ganglion stimulation, before and 30 min after thoracic epidural anesthesia (0.25% bupivacaine). After thoracic epidural anesthesia infusion, there was no change in baseline activation recovery interval or dispersion of repolarization. During programmed ventricular extrastimulation, thoracic epidural anesthesia decreased the maximum slope of ventricular electrical restitution (0.70 ± 0.24 vs. 0.89 ± 0.24; P = 0.021) reflecting improved electrical wave stability. Thoracic epidural anesthesia also reduced myocardial excitability during left stellate ganglion stimulation-induced sympathoexcitation through attenuated shortening of activation recovery interval (-7 ± 4% vs. -4 ± 3%; P = 0.001), suppression of the increase in dispersion of repolarization (313 ± 293% vs. 185 ± 234%; P = 0.029), and reduction in sympathovagal imbalance as measured by heart rate variability. Our study describes the electrophysiologic mechanisms underlying antiarrhythmic effects of thoracic epidural anesthesia during sympathetic hyperactivity. Thoracic epidural anesthesia attenuates ventricular myocardial excitability and induces electrical wave stability through its effects on activation recovery interval, dispersion of repolarization, and the action potential duration restitution slope.

Effect of thoracic epidural anesthesia on heart rate variability in a porcine model.

Heart rate variability (HRV) is increasingly recognized as a means of evaluating autonomic tone. Thoracic epidural anesthesia (TEA) has been previously demonstrated to suppress the electrical storms in patients. However, the effect of TEA on HRV during sympathoexcitation remains unknown. In this study, we aimed to determine the effects of TEA on HRV response to left stellate ganglion stimulation (LSS) in a porcine model. In 12 anesthetized pigs after insertion of an epidural catheter to T1 level, a median sternotomy was performed to expose the heart and the left stellate ganglion. A 56‐electrode sock was used for obtaining epicardial activation recovery interval (ARI). Animal received LSS at 4 Hz for 30 sec. After 30 min of bupivacaine epidural injection, LSS was performed in the same way as the baseline condition. LSS significantly increased low‐frequency normalized units (LF: 44.9 ± 6.7 vs. 13.6 ± 3.1 msec2 baseline, P < 0.05) and decreased high‐frequency normalized units (HF: 11.5 ± 4.6 vs. 41.9 ± 5.1 msec2 baseline, P < 0.05). As a result, LF/HF significantly increased from 0.3 ± 0.2 to 3.9 ± 1.4 during LSS. TEA significantly attenuated the LF/HF from 3.9 ± 1.4 to 1.6 ± 0.8 with increased HF components from 11.5 ± 4.6 to 26.5 ± 3.2 msec2. LF component significantly correlates with global ARI (r = −0.81) and dispersion of repolarization (r = 0.85). HRV can precisely reflect the cardiac autonomic tone and TEA modulates the HRV by enhancing the HF components probably through a parasympathetic nerve system.

Overexpression of Sarcoendoplasmic Reticulum Calcium ATPase 2a Promotes Cardiac Sympathetic Neurotransmission via Abnormal Endoplasmic Reticulum and Mitochondria Ca2+ Regulation.

Reduced cardiomyocyte excitation-contraction coupling and downregulation of the SERCA2a (sarcoendoplasmic reticulum calcium ATPase 2a) is associated with heart failure. This has led to viral transgene upregulation of SERCA2a in cardiomyocytes as a treatment. We hypothesized that SERCA2a gene therapy expressed under a similar promiscuous cytomegalovirus promoter could also affect the cardiac sympathetic neural axis and promote sympathoexcitation. Stellate neurons were isolated from 90 to 120 g male, Sprague-Dawley, Wistar Kyoto, and spontaneously hypertensive rats. Neurons were infected with Ad-mCherry or Ad-mCherry-hATP2Aa (SERCA2a). Intracellular Ca2+ changes were measured using fura-2AM in response to KCl, caffeine, thapsigargin, and carbonylcyanide-p-trifluoromethoxyphenylhydrazine to mobilize intracellular Ca2+ stores. The effect of SERCA2a on neurotransmitter release was measured using [3H]-norepinephrine overflow from 340 to 360 g Sprague-Dawley rat atria in response to right stellate ganglia stimulation. Upregulation of SERCA2a resulted in greater neurotransmitter release in response to stellate stimulation compared with control (empty: 98.7±20.5 cpm, n=7; SERCA: 186.5±28.41 cpm, n=8; P<0.05). In isolated Sprague-Dawley rat stellate neurons, SERCA2a overexpression facilitated greater depolarization-induced Ca2+ transients (empty: 0.64±0.03 au, n=57; SERCA: 0.75±0.03 au, n=68; P<0.05), along with increased endoplasmic reticulum and mitochondria Ca2+ load. Similar results were observed in Wistar Kyoto and age-matched spontaneously hypertensive rats, despite no further increase in endoplasmic reticulum load being observed in the spontaneously hypertensive rat (spontaneously hypertensive rats: empty, 0.16±0.04 au, n=18; SERCA: 0.17±0.02 au, n=25). In conclusion, SERCA2a upregulation in cardiac sympathetic neurons resulted in increased neurotransmission and increased Ca2+ loading into intracellular stores. Whether the increased Ca2+ transient and neurotransmission after SERCA2A overexpression contributes to enhanced sympathoexcitation in heart failure patients remains to be determined.

Sympathetic modulation of electrical activation in normal and infarcted myocardium: implications for arrhythmogenesis.

The influence of cardiac sympathetic innervation on electrical activation in normal and chronically infarcted ventricular myocardium is not understood. Yorkshire pigs with normal hearts (NL, n = 12) or anterior myocardial infarction (MI, n = 9) underwent high-resolution mapping of the anteroapical left ventricle at baseline and during left and right stellate ganglion stimulation (LSGS and RSGS, respectively). Conduction velocity (CV), activation times (ATs), and directionality of propagation were measured. Myocardial fiber orientation was determined using diffusion tensor imaging and histology. Longitudinal CV (CVL) was increased by RSGS (0.98 ± 0.11 vs. 1.2 ± 0.14m/s, P < 0.001) but not transverse CV (CVT). This increase was abrogated by β-adrenergic receptor and gap junction (GJ) blockade. Neither CVL nor CVT was increased by LSGS. In the peri-infarct region, both RSGS and LSGS shortened ARIs in sinus rhythm (423 ± 37 vs. 322 ± 30 ms, P < 0.001, and 423 ± 36 vs. 398 ± 36 ms, P = 0.035, respectively) and altered activation patterns in all animals. CV, as estimated by mean ATs, increased in a directionally dependent manner by RSGS (14.6 ± 1.2 vs. 17.3 ± 1.6 ms, P = 0.015), associated with GJ lateralization. RSGS and LSGS inhomogeneously modulated AT and induced relative or absolute functional activation delay in parts of the mapped regions in 75 and 67%, respectively, in MI animals, and in 0 and 15%, respectively, in control animals (P < 0.001 for both). In conclusion, sympathoexcitation increases CV in normal myocardium and modulates activation propagation in peri-infarcted ventricular myocardium. These data demonstrate functional control of arrhythmogenic peri-infarct substrates by sympathetic nerves and in part explain the temporal nature of arrhythmogenesis.NEW & NOTEWORTHY This study demonstrates regional control of conduction velocity in normal hearts by sympathetic nerves. In infarcted hearts, however, not only is modulation of propagation heterogeneous, some regions showed paradoxical conduction slowing. Sympathoexcitation altered propagation in all infarcted hearts studied, and we describe the temporal arrhythmogenic potential of these findings.Listen to this article's corresponding podcast at http://ajpheart.podbean.com/e/sympathetic-nerves-and-cardiac-propagation/.

Effects of Postoperative Methycobal Administration on Digital Replantation Based on Stellate Ganglion Stimulation

To study the impact of stellate ganglion block (SGB) on digital replantation and analyze its mechanism. Digital arterial diameter was enlarged after SGB, and the difference in the survival rate of severed finger after replantation was not statistically significant between the two groups (P>0.05). Through the treatment with Methycobal, the recovery of 2-point discrimination (2-pd) of the experimental groups (A, B) was significantly better than that of the negative control group, between which the difference was statistically significant (P<0.01 between Groups A and C, P<0.05 between Groups B and C), indicating that the methyl vitamin B 12 can significantly promote the regeneration of peripheral nerves. Methycobal is of great significance to the postoperative treatment of digital replantation, which is worthy of being widely applied in clinic practice.