Right Stellate Ganglion Research Articles

Abstract 9479: Defined Subsets of Sympathetic Neurons Innervate the Heart and Differentially Respond to Cardiac Pathology

Introduction: Sympathetic regulatory aspect of cardiac functions is governed by neural circuit originating from postganglionic sympathetic neurons (PGNs) that primarily reside in stellate ganglia. PGNs is comprised of a diversified neuronal population that innervate heart and other tissue beds. Hypothesis: We hypothesize that cardiac innervating stellate ganglionic neurons (SGNs) exhibit diversity and distinction from those innervating other organs. In the settings of cardiac pathology, distribution of cardiac neuronal subtypes is altered, yielding a dominant neuronal subtype. Methods: We utilized method of retrograde axonal transport from heart and paw using adeno-associated virus (AAV-GFP/tdTomato, 1+e12 gc/ml, 10μl) followed by single cell RNA sequencing (scRNAseq) to identify and resolve transcriptomic profiles of SGNs in normal (n=8) and heart-failure mice (n=4). Using NPY-hrGFP mice, we characterized membrane excitability for NPY high and NPY low neurons (n=11). We delineated impact of NPY on cardiac sympathoexcitation by injecting AAV5-Flex-taCasp3 in NPY-Cre mice (n=8) and afterwards electrically stimulating right stellate ganglia (RSG). Results: In our scRNAseq study, we identified 3 adrenergic neuronal subtypes (NA1a, NA1b, and NA3) innervate heart. These subtypes differentiated as NPY high (NA1a) and NPY low (NA1b and NA3) subpopulations. NPY high (4.250±0.90) showed higher number of action potentials compared to NPY low (1.818±0.18). Cardiac sympathoexcitation was diminished in NPY-ablated mice compared to controls in response to escalating intensities (1, 5, 10, 15, & 20 Hz). Maximal heart-rate change was detected at 10 Hz (p = 0.0240) for NPY-ablated mice (91.061±12.62 bpm) vs. controls (27.017±11.88). Across mice, ~70% of cardiac neurons are NPY+. In dilated cardiomyopathy mice, NA1b is a predominant subtype, consists of increased expression of Kcnq2 (M-current) and significant enriched pathways neurodegenerative disorders and neurotrophic signaling. Conclusion: These findings provide novel insights into the unique properties of neurons responsible for cardiac sympathetic regulation, with implications for novel strategies to target specific neuronal subtypes for sympathetic blockade in cardiac disease.

Effects and Mechanisms of Cutting Upper Thoracic Sympathetic Trunk on Ventricular Rate in Ambulatory Canines with Persistent Atrial Fibrillation.

Objective The purpose is to observe the effects and neural mechanism of cutting upper thoracic sympathetic trunk (TST) on the ventricular rate (VR) during persistent atrial fibrillation (AF). Methods Twelve beagle dogs were halving to the control group and experimental group, 6 dogs for each group. Both groups were performed with left atrial rapid pacing (600 beats/min) to induce sustained AF. The experimental group underwent cutting upper TST after a sustained AF model was established, while the control group received thoracotomy without cutting TST. Bilateral stellate ganglion (SG) and left atrial myocardium were harvested for tyrosine-hydroxylase (TH) immunohistochemical staining. Results After cutting upper TST for 30 minutes, the average VR was 121.5 ± 8.7 bpm (95% CI, 114.8 to 128.0) in the experimental group, which was significantly slower than that of the control group (144.5 ± 4.2 bpm (95% CI, 141.5 to 148.0)) (P < 0.001). After cutting upper TST for 1 month, the average VR of the experimental group (106.5 ± 4.9 bpm (95% CI, 102.0 to 110.0)) was also significantly slower versus that of the control group (139.2 ± 5.6 bpm (95% CI, 135.0 to 143.8)) (P < 0.001). Compared with the control group, both left stellate ganglion (LSG) and right stellate ganglion (RSG) of the experimental group caused neural remodeling characterized by decreased ganglionic cell density and reduced TH staining. TH-positive component was significantly decreased in the left atrium of the experimental group compared with the control group. Conclusions Cutting upper TST could reduce fast VR during persistent AF. Cutting upper TST induced bilateral SG neural remodeling and reduced sympathetic nerve density in the left atrium, which could contribute to the underlying mechanism of VR control during AF.

Recording Intrinsic Nerve Activity at the Sinoatrial Node in Normal Dogs With High-Density Mapping.

It is known that autonomic nerve activity controls the sinus rate. However, the coupling between local nerve activity and electrical activation at the sinoatrial node (SAN) remains unclear. We hypothesized that we would be able to record nerve activity at the SAN to investigate if right stellate ganglion (RSG) activation can increase the local intrinsic nerve activity, accelerate sinus rate, and change the earliest activation sites. High-density mapping of the epicardial surface of the right atrium including the SAN was performed in 6 dogs during stimulation of the RSG and after RSG stellectomy. A radio transmitter was implanted into 3 additional dogs to record RSG and local nerve activity at the SAN. Heart rate accelerated from 108±4 bpm at baseline to 125±7 bpm after RSG stimulation (P=0.001), and to 132±7 bpm after apamin injection (P<0.001). Both electrical RSG stimulation and apamin injection induced local nerve activity at the SAN with the average amplitudes of 3.60±0.72 and 3.86±0.56 μV, respectively. RSG stellectomy eliminated the local nerve activity and decreased the heart rate. In ambulatory dogs, local nerve activity at the SAN had a significantly higher average Pearson correlation to heart rate (0.72±0.02, P=0.001) than RSG nerve activity to HR (0.45±0.04, P=0.001). Local intrinsic nerve activity can be recorded at the SAN. Short bursts of these local nerve activities are present before each atrial activation during heart rate acceleration induced by stimulation of the RSG.

The effects of stelleta ganglion resection on heart failure in response to pressure overload

Objective: To observe the impact and difference of resection of left stellate ganglion (LSG) or right stellate ganglion (RSG) on rats with heart failure. Methods: Thirty male SD rats were divided into 3 groups (n=10 each) by random number table method: control group, LSG group, RSG group. All three groups underwent TAC surgery to establish a pressure-overloaded heart failure model. Then, LSG and RSG were bluntly separated and removed in rats assigned to the LSG group or RSG group by surgery, while rats in the control group underwent sham operation. The changes in blood pressure and heart rate before operation, 30 minutes and 10 weeks after operation were recorded; echocardiography was performed before operation and 10 weeks after operation to detect the thickness of the ventricular septum, left ventricle posterior wall diameter, left ventricular end diastolic diameter, left ventricular end diastolic volume, and calculate the left ventricular fractional shortening and left ventricular ejection fraction. HE staining and Masson staining were performed to observe the degree of myocardial hypertrophy and myocardial fibrosis, and to judge the ventricular remodeling. Results: The heart rates of the three groups of rats were (352.4±4.3), (320.3±4.0) and (297.9±5.9) beats/min, and the blood pressure was (142.8±2.3), (123.4±2.7) and (129.6±2.9) mmHg(1 mmHg=0.133 kPa) at thirty minutes after surgery; the heart rates of the three groups of rats were (352.9±4.0), (321.6±3.4) and (301±4.1) beats/min, and the blood pressure was (145.6±1.9), (124.8±1.7) and (130.4±4.4) mmHg at 10 weeks after surgery. The heart rate and blood pressure in the LSG group and RSG group at 30 min and 10 weeks after surgery were significantly lower than those in the control group; at 10 weeks after surgery, the heart rate in the RSG group was significantly lower than that in the LSG group (P both<0.001). After 10 weeks, rats in the control group developed severe left ventricular dilatation. Degree of left ventricular hypertrophy was significantly reduced in the LSG group and RSG group than in the control group, the thickness of the ventricular septum was (3.2±0.3), (2.5±0.1) and (2.5±0.1) mm; the left ventricular end-diastolic diameters were (7.5±0.3), (5.5±0.3) and (5.7±0.2) mm; the left ventricular end-diastolic volume was (9.5±0.3), (4.5±0.2) and (4.8±0.2) ml; the left ventricular fractional shortening was (21.6±1.3)%, (49.1±3.9)% and (47.4±1.5)%; and the left ventricular ejection fraction was (50.9±2.5)%, (81.9±2.1)% and (80.0±2.3)%, respectively in the control group, LSG group and RSG group. Compared with the control group, the left ventricular posterior wall diameter, left ventricular end-diastolic diameter and left ventricular end-diastolic volume were significantly lower and the left ventricular fractional shortening and left ventricular ejection fraction were significantly higher in the LSG group and RSG group (all P<0.001). 10 weeks after operation, the values of type Ⅰ collagen in the control group, LSG group, and RSG group were (0.354±0.013), (0.211±0.012) and (0.243±0.013), respectively. Ratio of type Ⅰ/Ⅲ collagen was (1.109±0.065), (0.737±0.055) and (0.839±0.075), respectively. Compared with the control group, the ratio of type Ⅰcollagen and ratio of type Ⅰ/Ⅲ collagen were significantly lower in the LSG group and RSG group (P<0.001). Conclusion: Both left and right stellate ganglion resection can similarly reduce ventricular remodeling caused by pressure overload and delay the progression of heart failure in tis TAC rat model.

Effect of stellate ganglia stimulation on global and regional left ventricular function as assessed by speckle tracking echocardiography

Left ventricular (LV) twist mechanics and regional strain during cardiac sympathetic efferent activation are poorly understood. The purpose of this study was to compare the effects of left stellate ganglia (LSG) and right stellate ganglia (RSG) stimulation on cardiac twist/untiwst mechanics and regional strain. In nine pigs, echocardiographic imaging and LV pressure-volume measurements were performed before and during unilateral and bilateral stellate ganglion stimulation. LSG and RSG stimulation significantly augmented LV end-systolic pressure by 24% and 22% (P < 0.01), maximal rate of LV pressure change by 167% and 165% (P < 0.01), and time constant of LV relaxation by 20% and 12% (P < 0.01), respectively. RSG stimulation resulted in a greater chronotropic response than LSG stimulation (RSG: 68% vs. LSG: 12%, P < 0.01). Both LSG and RSG stimulation significantly increased global epicardial and endocardial LV rotation and diastolic untwisting rate and reduced the time to peak rotation (P < 0.05). However, LSG stimulation predominantly increased radial and circumferential strain in the LV inferoseptal, inferior, posterior, and lateral regions, whereas RSG stimulation primarily increased radial and circumferential strain in the anteroseptal, anterior, and lateral LV regions. Stimulation of both stellate ganglia led to a uniform increase in all LV segments. Our data suggest that LSG and RSG stimulation lead to a global increase in LV twist, driven by distinct regional strain heterogeneity that may result from myocardial innervation from the LSG and RSG. These findings provide a better understanding of the global and regional functional consequences of regional myocardial innervation from the LSG and RSG.

STELLATE GANGLION ELECTRICAL STIMULATION FOR ESTABLISHING A CANINE MODEL OF ACUTE ATRIAL FIBRILLATION MEDIATED BY SYMPATHETIC NERVE

ObjectivesTo build the methodology of acute animal model of atrial fibrillation (AF) induced by increased sympathetic nerve activity.MethodsSixteen adult mongrel dogs weighing 18 to 25 kg were randomly divided into...

Sympathetic innervation of the anterior left ventricular wall by the right and left stellate ganglia

The sympathetic nervous system is thought to play a role in the genesis of ventricular tachyarrhythmias (VT). Left and added right cardiac sympathectomy have been shown to reduce the burden of arrhythmias in the setting of a VT storm. However, the contribution of the right stellate ganglion (RSG) and the left stellate ganglion (LSG) to the innervation of the anterior left ventricular (LV) wall is not well understood. To evaluate the innervation of the anterior LV wall by the LSG and the RSG. The heart and stellate ganglia were exposed via sternotomy in pigs with normal hearts (n = 8). A 20-electrode catheter was placed on the anterior LV wall to record activation recovery interval (ARI), a surrogate measure of action potential duration. A microdialysis catheter was inserted in a similar location to sample interstitial norepinephrine (NE) content. ARI and NE measurements were recorded at baseline and during LSG and RSG stimulation. LSG stimulation shortened ARI by 17.1% ± 10.5% (mean ± standard error), while RSG stimulation shortened ARI by 42.1% ± 15.7%, P = .04 (LSG vs RSG). LSG stimulation increased interstitial NE levels by 200% ± 65%, while RSG stimulation increased the NE content by 260% ± 40% (P = .012). LSG stimulation increased dispersion in ARI from 376.0 ± 83.7 ms(2) to 1242.5 ± 566 ms(2) (P = .03) and caused ventricular fibrillation in 2 pigs. During RSG stimulation, dispersion increased from 419 ± 65.8 to 474.8 ± 81 ms(2) (P = .4). Both the LSG and the RSG provide significant innervation to the anterior LV wall as demonstrated by both ARI shortening and NE concentrations. LSG stimulation significantly increases ARI dispersion. This study provides mechanistic insight into the beneficial effects of left sympathectomy and the additional role of right sympathectomy in reducing arrhythmias in patients with anterior myocardial scars and VT storm.

Low-Level Right Vagal Stimulation: Anticholinergic and Antiadrenergic Effects

We sought to extend the use of low-level vagal stimulation by applying it only to the right vagus nerve (LL-RVS) to suppress atrial fibrillation (AF). In 10 pentobarbital anesthetized dogs, LL-RVS (20 Hz, 0.1 ms pulse width) was delivered to the right vagal trunk via wire electrodes at voltages 50% below that which slowed the sinus rate (SR) or atrio-ventricular conduction. Electrode catheters were sutured at multiple atrial and pulmonary vein (PV) sites to record electrograms. LL-RVS continued for 3 hours. At the end of each hour, 40 ms of high-frequency stimulation (HFS; 100 Hz, 0.01 ms pulse width) was delivered 2 ms after atrial pacing (during the refractory period) to determine the AF threshold (AF-TH) at each site. Other electrodes were attached to the superior left ganglionated plexi (SLGP) and right stellate ganglion (RSG) so that HFS (20 Hz, 0.1 ms pulse width) to these sites induced SR slowing and acceleration, respectively. Microelectrodes inserted into the anterior right ganglionated plexi (ARGP) recorded neural activity. (1) Three hours of LL-RVS induced a progressive increase in AF-TH at all sites (all P < 0.05). (2) The SR slowing and acceleration response induced by SLGP and RSG stimulation, respectively, was blunted by LL-RVS. (3) The frequency and amplitude of the neural activity recorded from the ARGP were markedly inhibited by LL-RVS. LL-RVS suppressed AF inducibility and the chronotropic responses to parasympathetic and sympathetic stimulation. Inhibition of neural activity in the GP may be a mechanism underlying these results.

Interstitial norepinephrine levels and local electrophysiological properties of the myocardium during sympathetic nerve activation

Cardiac sympathetic innervation originates mainly in the left and right stellate ganglia. The efferent and afferent fibers of the left stellate ganglion (LSG) predominantly innervate the left ventricle (LV), whereas the fibers of the right stellate ganglion (RSG) innervate the right ventricle. The major neurotransmitter, norepinephrine, shortens ventricular action potential duration (APD) and increases contractility. Activation recovery interval (ARI) can serve as a surrogate for APD in both animal models and patients. However, the linkage between myocardial interstitial norepinephrine levels and ARI during stimulation of left and right stellate ganglion remains unclear. In six anesthetized pigs, interstitial norepinephrine concentrations and ARIs were measured in the perfusion areas of the left anterior descending coronary artery. LV pressure and volume were recorded by a 5Fr Millar conductance catheter. LSG stimulation significantly shortened ARI (28%) and increased systemic blood pressure (SBP, 43%), LV dP/dtmax (200%), and interstitial norepinephrine (110%) with a mild change in heart rate (13%). RSG stimulation also significantly shortened ARI (100%) and increased SBP (63%), heart rate (80%), dP/dtmax (300%), and interstitial norepinephrine (120%). We conclude that both LSG and RSG play an important role in regulating LV function and local sympathetic nerve activity.

Differential β-adrenoceptor expression induced by nerve growth factor infusion into the canine right and left stellate ganglia

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

Modulation of QT interval by cardiac sympathetic nerve sprouting and the mechanisms of ventricular arrhythmia in a canine model of sudden cardiac death.

We previously reported that there is a high incidence of sudden cardiac death (SCD) in dogs with myocardial infarction (MI), complete AV block (CAVB), and nerve growth factor (NGF) infusion to the left stellate ganglion (LSG). Whether or not QT interval prolongation underlines the mechanism of SCD was unclear. We analyzed QT intervals in three groups of dogs. All dogs had CAVB and MI. The LSG group (n = 9) and right stellate ganglion (RSG) group (n = 6) received NGF infusion via the osmotic pumps over a 5-week period to LSG and RSG, respectively. The control group (n = 6) received no NGF. The dogs either died suddenly or were sacrificed within 2 to 3 months after MI. Heart rhythm and QT and RR intervals were monitored using implantable cardioverter defibrillator ECG recordings. There was a time-dependent increase of QTc intervals in the LSG group and a time-dependent decrease of QTc intervals in the RSG group. At the end of NGF infusion, QTc intervals in the LSG group (408 +/- 41 msec) were significantly longer than those in the control (350 +/- 41 msec; P < 0.05) and RSG groups (294 +/- 23 msec; P < 0.01). In the LSG group, 4 of 9 dogs died of SCD. There was no SCD in either the RSG or control group. Immunocytochemical staining showed NGF infusion to LSG and RSG resulted in left and right ventricular sympathetic nerve sprouting and hyperinnervation, respectively. NGF infusion to the LSG in dogs with MI and CAVB resulted in increased QT interval and incidence of ventricular tachycardia, ventricular fibrillation, and SCD, whereas NGF infusion to the RSG shortened QT interval and reduced the incidence of ventricular tachycardia. These findings indicate that QT interval prolongation is causally related to the occurrence of ventricular arrhythmia in dogs with nerve sprouting, MI, and CAVB.