Chronic Expression of Interleukin-10 Transgene Modulates Cardiac Sympathetic Ganglion Resulting in Reduced Ventricular Arrhythmia.

The cardiac autonomic nervous system (CANS) is intimately connected to the regulation of electrophysiology and arrhythmogenesis in cardiac systems. This work aimed at investigating whether interleukin-10 (IL-10) could effectively modulate CANS and suppress ischemia-induced ventricular arrhythmia (VA) through chronically acting on the cardiac sympathetic ganglion (CSG). Using an adeno-associated virus (AAV), we achieved local chronic overproduction of IL-10 in the CSG, left stellate ganglion (LSG). As a result, in the IL-10 group, we observed a decreased number of tyrosine hydroxylase-positive (TH+) cells in the LSG. IL-10 markedly downregulated the nerve growth factor, synaptophysin, as well as growth-associated protein 43 expression. In vivo, results from ambulatory electrocardiography showed that IL-10 overexpression significantly inhibited the cardiac sympathetic nervous system activity and improved heart rate variability. Meanwhile, we observed decreased LSG function as well as prolonged ventricular effective refractory period and suppressed VA after myocardial infarction (MI) in the IL-10 group. In addition, IL-10 overexpression attenuated inflammation and decreased norepinephrine levels in the myocardium after acute MI. In conclusion, our data suggest that chronic IL-10 overexpression modulates cardiac sympathetic nerve remodeling and suppresses VA induced by MI. Neuromodulation through AAV-mediated IL-10 overexpression may have the characteristics of and advantages as a potential neuroimmunotherapy for preventing MI-induced VAs.

Neuroimmune modulation mediated by IL-6: A potential target for the treatment of ischemia-induced ventricular arrhythmias.

BACKGROUND: Neural remodeling in the left stellate ganglion (LSG), as mediated by neuroimmune reactions, promotes cardiac sympathetic nerve activity (SNA) and thus increases the incidence of ventricular arrhythmias (VAs). Interleukin-6 (IL-6) is an important factor of the neuroimmune interaction. OBJECTIVE: The present study explored the effects of IL-6 on LSG hyperactivity and the incidence of VAs. METHODS: Eighteen beagles were randomly allocated to a control group (saline with myocardial infarction [MI], n = 6), adeno-associated virus (AAV) group (AAV with MI, n = 6), and IL-6 group (overexpression of IL-6 via AAV vector with MI, n = 6). Ambulatory electrocardiography was performed before and 30 days after AAV microinjection into the LSG. LSG function and ventricular electrophysiology were assessed at 31 days after surgery, and a canine MI model was established. Samples of the LSG were collected for immunofluorescence staining and molecular biological evaluation. Blood samples and 24-hour Holter data were obtained from 24 patients with acute MI on the day after they underwent percutaneous coronary intervention to assess the correlation between IL-6 levels and SNA. RESULTS: IL-6 overexpression increased cardiac SNA and worsened postinfarction VAs. Furthermore, sustained IL-6 overexpression enhanced LSG function, promoted expression of nerve growth factor, c-fos, and fos B in the LSG, and activated the signal transducer and activator of transcription 3/regulator of G protein signalling 4 signaling pathway. Clinical sample analysis revealed a correlation between serum IL-6 levels and heart rate variability frequency domain index as well as T-wave alternans. CONCLUSION: IL-6 levels are correlated with cardiac SNA. Chronic overexpression of IL-6 mediates LSG neural remodeling through the signal transducer and activator of transcription 3/regulator of G protein signalling 4 signaling pathway, elevating the risk of VA after MI.

The potential role of CpG oligodeoxynucleotides on diabetic cardiac autonomic neuropathy mediated by P2Y12 receptor in rat stellate ganglia.

Cardiac autonomic neuropathy has a high prevalence in type 2 diabetes, which increases the risk of cardiovascular system disorders. CpG oligodeoxynucleotide (CpG-ODN), a Toll-like receptor 9 (TLR9) ligand, has been shown to have cardioprotection and cellular protection. Our previous work showed that P2Y12 in stellate ganglia (SG) is involved in the process of diabetic cardiac autonomic neuropathy (DCAN). Here, we aim to investigate whether CpG-ODN 1826 plays a protective role in DCAN and whether this beneficial protection involves regulation of the P2Y12-mediated cardiac sympathetic injury. Our results revealed that CpG-ODN 1826 activated TLR9 receptor, improved the abnormal blood pressure (BP), heart rate (HR), heart rate variability (HRV) and sympathetic nerve discharge (SND) activity in diabetic rats and reduced the up-regulated NF-κB, P2Y12 receptor, TNF-α and IL-1ß in SG. Meanwhile, CpG-ODN 1826 significantly decreased the elevated ATP, nuclear receptor coactivator 4 (NCOA4), iron, ROS and MDA levels and increased GPX4 and GSH levels. In addition, CpG-ODN 1826 contributes to maintain normalization of mitochondrial structure in SG. Overall, CpG-ODN 1826 alleviates the sympathetic excitation and abnormal neuron-glial signal communication via activating TLR9 receptors to achieve a balance of autonomic activity and relieve the DCAN in rats. The mechanism may involve the regulation of P2Y12 receptor in SG by reducing ATP release and NF-κB expression, which counteract neuroinflammation and ferroptosis mediated by activated P2Y12 in SG.

Tiered sympathetic control of cardiac function revealed by viral tracing and single cell transcriptome profiling.

The cell bodies of postganglionic sympathetic neurons innervating the heart primarily reside in the stellate ganglion (SG), alongside neurons innervating other organs and tissues. Whether cardiac-innervating stellate ganglionic neurons (SGNs) exhibit diversity and distinction from those innervating other tissues is not known. To identify and resolve the transcriptomic profiles of SGNs innervating the heart, we leveraged retrograde tracing techniques using adeno-associated virus (AAV) expressing fluorescent proteins (GFP or Td-tomato) with single cell RNA sequencing. We investigated electrophysiologic, morphologic, and physiologic roles for subsets of cardiac-specific neurons and found that three of five adrenergic SGN subtypes innervate the heart. These three subtypes stratify into two subpopulations; high (NA1a) and low (NA1b and NA1c) neuropeptide-Y (NPY) -expressing cells, exhibit distinct morphological, neurochemical, and electrophysiologic characteristics. In physiologic studies in transgenic mouse models modulating NPY signaling, we identified differential control of cardiac responses by these two subpopulations to high and low stress states. 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.

Stellate ganglion block alleviates postoperative cognitive dysfunction via inhibiting TLR4/NF-κB signaling pathway.

Postoperative cognitive dysfunction (POCD) is common in aged patients after major surgery and is associated with increased risk of long-term morbidity and mortality. However, the underlying mechanism remains largely unknown and the clinical management of POCD is still controversial. Stellate ganglion block (SGB) is a clinical treatment for nerve injuries and circulatory issues. Recent evidence has identified the benefits of SGB in promoting learning and memory. We thus hypothesize that SGB could be effective in improving cognitive function after surgery. In present study, we established POCD model in aged rats via partial liver resection surgery. We found that the development of POCD was associated with the activation of toll-like receptor 4/nuclear factor kapa-B (TLR4/NF-κB) signaling pathway in the microglia in dorsal hippocampus, which induced the production of pro-inflammatory mediators (TNF-α, IL-1ß, IL-6) and promoted neuroinflammation. More importantly, we showed evidence that preoperative treatment with SGB could inhibit microglial activation, suppress TLR4/NF-κB-mediated neuroinflammation and effectively attenuate cognitive decline after the surgery. Our study suggested that SGB may serve as a novel treatment to prevent POCD in elderly patients. As SGB is safe procedure widely used in clinic, our findings can be easily translated into clinical practice and benefit more patients.

Stellate ganglion block relieves acute lung injury induced by severe acute pancreatitis via the miR-155-5p/SOCS5/JAK2/STAT3 axis.

Acute lung injury (ALI), a prevalent complication of severe acute pancreatitis (SAP), is also a leading contributor to respiratory failure and even death of SAP patients. Here, we intended to investigate the function and mechanism of stellate ganglion block (SGB) in ameliorating SAP-induced ALI (SAP-ALI). We engineered an SAP-ALI model in rats and treated them with SGB. HE staining and the dry and wet method were implemented to evaluate pathological alterations in the tissues and pulmonary edema. The rats serum changes of the profiles of TNF-α, IL-6, IL-1ß, and IL-10 were examined. The profiles of miR-155-5p and SOCS5/JAK2/STAT3 were detected. Functional assays were performed for confirming the role of miR-155-5p in modulating the SOCS5/JAK2/STAT3 pathway in pulmonary epithelial cells. Our findings revealed that SGB vigorously alleviated SAP rat lung tissue damage and lung edema and lessened the generation of pro-inflammatory cytokines TNF-α, IL-6, and IL-1ß. SGB enhanced SOCS5 expression, hampered miR-155-5p, and suppressed JAK2/STAT3 pathway activation. As evidenced by mechanism studies, miR-155-5p targeted the 3'UTR of SOCS5 and repressed its expression, hence resulting in JAK2/STAT3 pathway activation. During animal trials, we discovered that SGB ameliorated SAP-ALI, boosted SOCS5 expression, and mitigated the levels of pro-inflammatory factors and miR-155-5p in the plasma. In vitro, miR-155-5p overexpression substantially facilitated pulmonary epithelial cell apoptosis, inflammation, and JAK2/STAT3 pathway activation and restrained SOCS5 expression. All in all, our work hinted that SGB could modulate the miR-155-5p/SOCS5/JAK2/STAT3 axis to alleviate SAP-ALI.

Stellate Ganglion Block Improves Postoperative Cognitive Dysfunction in aged rats by SIRT1-mediated White Matter Lesion Repair.

Postoperative cognitive dysfunction (POCD) is a common complication of the central nervous system after surgery, especially in elderly patients. Many factors can influence POCD, one of which is white matter lesion. Nowadays, stellate ganglion block (SGB) is considered as an effective intervention for postoperative cognitive dysfunction and SIRT1 may play a role in that, but the exact mechanism remains unclear. Therefore, the underlying mechanisms that SGB improves postoperative cognitive dysfunction through SIRT1 in aged rats and its association with white matter lesion are yet to be elucidated. The role of SIRT1 in the process that stellate ganglion block improves the cognitive impairment, and its association with white matter lesion was investigated using splenectomy-induced POCD model. To investigate this result further, we performed transection of the cervical sympathetic trunk on the basis of POCD model, and the role of SIRT1 was then verified again by intraperitoneal injection of EX527 (5 mg/kg) five min before surgery. Data show that SGB treatment has neuroprotective effects in POCD rats. SGB treatment can ameliorate cognitive impairment, neuroinflammation and neuronal apoptosis in white matter. Moreover, SGB treatment enhanced the expression of SIRT1 in the hippocampus and white matter, decreased NF-κB activity in the hippocampus and white matter. It also increased the levels of inflammatory factor in serum and white matter, primarily at the level of anti-inflammatory factor. These findings indicated that SIRT1-mediate white matter repair could be a new therapeutic target for neurodegenerative illnesses.

Macrophage depletion in stellate ganglia alleviates cardiac sympathetic overactivation and ventricular arrhythmogenesis by attenuating neuroinflammation in heart failure.

Cardiac sympathetic overactivation is involved in arrhythmogenesis in patients with chronic heart failure (CHF). Inflammatory infiltration in the stellate ganglion (SG) is a critical factor for cardiac sympathoexcitation in patients with ventricular arrhythmias. This study aims to investigate if macrophage depletion in SGs decreases cardiac sympathetic overactivation and ventricular arrhythmogenesis in CHF. Surgical ligation of the coronary artery was used for induction of CHF. Clodronate liposomes were microinjected into bilateral SGs of CHF rats for macrophage depletion. Using cytokine array, immunofluorescence staining, and Western blot analysis, we found that macrophage expansion and expression of TNFα and IL-1ß in SGs were markedly increased in CHF rats. Flow cytometry data confirmed that the percentage of macrophages in SGs was higher in CHF rats than that in sham rats. Clodronate liposomes significantly reduced CHF-elevated proinflammatory cytokine levels and macrophage expansion in SGs. Clodronate liposomes also reduced CHF-increased N-type Ca2+ currents and excitability of cardiac sympathetic postganglionic neurons and inhibited CHF-enhanced cardiac sympathetic nerve activity. ECG data from 24-h, continuous telemetry recording in conscious rats demonstrated that clodronate liposomes not only restored CHF-induced heterogeneity of ventricular electrical activities, but also decreased the incidence and duration of ventricular tachycardia/fibrillation in CHF. Macrophage depletion with clodronate liposomes attenuated CHF-induced cardiac sympathetic overactivation and ventricular arrhythmias through reduction of macrophage expansion and neuroinflammation in SGs.

Glucokinase in stellate ganglia cooperates with P2X3 receptor to develop cardiac sympathetic neuropathy in type 2 diabetes rats.

Glucokinase (GCK) may be involved in inflammatory pathological changes, while the P2X3 receptor in the stellate ganglia (SG) is related to diabetic cardiac autonomic neuropathy. In this study, we explored the relationship between the upregulated GCK in SG and diabetic cardiac sympathy. The expression and location of GCK and P2X3 in SG of type 2 diabetes mellitus (T2DM) rats were assessed. Changes in cardiac function were determined by measuring blood pressure, sympathetic nerve activity, heart rate, and heart rate variability. P2X3 agonist-activated currents in isolated stellate ganglion neurons and cultured human embryonic kidney 293 (HEK293) cells were recorded using whole-cell patch clamp techniques. The upregulated expression of GCK in SG of T2DM rats was decreased after treatment with GCK short hairpin RNA (shRNA). GCK shRNA treatment also improved the blood pressure, sympathetic nerve activity, heart rate, and heart rate variability in T2DM rats. By contrast, the expression of P2X3 and tumor necrosis factor α (TNF-α) was lessened by GCK shRNA treatment. In addition, adenosine triphosphate (ATP)-activated currents in stellate ganglion neurons and HEK293 cells co-transfected with GCK and P2X3 receptor plasmids were reduced after GCK shRNA treatment. In T2DM rats, knockdown of GCK relieved the diabetic cardiac sympathy mediated by P2X3 receptor-involved upregulation of GCK in SG.

68Ga-DOTATATE Uptake by Cervicothoracic (Stellate) Ganglia.

Ga-DOTATATE PET/CT, a functional imaging modality for assessment of well-differentiated neuroendocrine tumors, targeting the somatostatin receptors, has essentially replaced the conventional gamma camera-based imaging with In-labeled octreotide. Physiologic distribution, normal variations, and common pitfalls with Ga-DOTATATE imaging have been well described in the literature. Here, we describe uptake of Ga-DOTATATE in 2 different patients at cervicothoracic junction within the stellate ganglia.

Interaction between Endothelin-1 and Left Stellate Ganglion Activation: A Potential Mechanism of Malignant Ventricular Arrhythmia during Myocardial Ischemia.

Endothelin-1 (ET-1) is synthesized primarily by endothelial cells. ET-1 administration in vivo enhances the cardiac sympathetic afferent reflex and sympathetic activity. Previous studies have shown that sympathetic hyperactivity promotes malignant ventricular arrhythmia (VA). The aim of this study was to investigate whether ET-1 could activate the left stellate ganglion (LSG) and promote malignant VA. Twelve male beagle dogs who received local microinjections of saline (control, n = 6) and ET-1 into the LSG (n = 6) were included. The ventricular effective refractory period (ERP), LSG function, and LSG activity were measured at different time points. VA was continuously recorded for 1 h after left anterior descending occlusion (LADO), and LSG tissues were then collected for molecular detection. Compared to that of the control group, local ET-1 microinjection significantly decreased the ERP and increased the occurrence of VA. In addition, local microinjection of ET-1 increased the function and activity of the LSG in the normal and ischemic hearts. The expression levels of proinflammatory cytokines and the protein expression of c-fos and nerve growth factor (NGF) in the LSG were also increased. More importantly, endothelin A receptor (ETA-R) expression was found in the LSG, and its signaling was significantly activated in the ET-1 group. LSG activation induced by local ET-1 microinjection aggravates LADO-induced VA. Activated ETA-R signaling and the upregulation of proinflammatory cytokines in the LSG may be responsible for these effects.

ERG Channels Regulate Excitability in Stellate and Bushy Cells of Mice Ventral Cochlear Nucleus.

ERG (ether-a-go-go-related gene) channels are the members of the voltage-dependent potassium channel family, which have three subtypes, as ERG1 (Kv 11.1), ERG2 (Kv 11.2), and ERG3 (Kv11.3). There is no information on ERG channels in the cochlear nucleus (CN) neurons, which is the first relay station of the auditory pathway. As occur in some of congenital long QT Syndromes (LQTS), mutation of the KCNQ11 genes for ERG channel has been reported to be accompanied by hearing loss. For that reason, we aimed to study biophysical properties and physiological importance, and contribution of ERG K+ currents to the formation of action potentials in the stellate and bushy neurons of the ventral cochlear nucleus (VCN). A total of 70 mice at 14-17 days old were used for this study. Electrophysiological characterization of ERG channels was performed using patch-clamp technique in the CN slices. In current clamp, ERG channel blockers, terfenadine (10 µM) and E-4031 (10 µM), were applied in both cell types. The activation, inactivation, and deactivation kinetics of the ERG channels were determined by voltage clamp. In conclusion, the findings obtained in the present study suggest that stellate and bushy neurons express ERG channels and ERG channels appear to contribute to setting action potential (AP) frequency, threshold for AP induction, and, possibly, resting membrane potentials in this cells.

Knockdown the P2X3 receptor in the stellate ganglia of rats relieved the diabetic cardiac autonomic neuropathy.

Diabetic cardiac autonomic neuropathy (DCAN) is a common and serious complication of diabetes mellitus (DM), is manifested by nerve fiber injury in the sympathetic and parasympathetic nerve of the autonomic nervous system, and causes hypertension, cardiac arrhythmias, silent myocardial infarction, and sudden death. Our previous study observed that P2X3 receptor in superior cervical ganglia in rat was associated with sympathetic neuropathy caused by myocardial ischemia. However, whether the P2X3 receptor is involved in the diabetic cardiac autonomic neuropathy and the underlying mechanisms remain unclear. The aim of this research was explored the effect of P2X3 short hairpin RNA (shRNA) on information transmission of sympathetic nerve induced by DCAN. Sprague-Dawley (SD) male rats were randomly divided into four groups: Control, DM, DM treated with P2X3 shRNA and DM treated with scramble shRNA. Blood pressure, heart rate and heart rate variability were measured in each group. The expression of P2X3 in stellate ganglion (SG) was detected by immunohistochemistry, western blotting and QPCR. Results showed that P2X3 shRNA alleviated blood pressure and heart rate, improved heart rate variability, decreased the up-regulated expression levels of P2X3, interleukin-1beta and tumor necrosis factor alpha in stellate ganglion (SG) of diabetic rats. P2X3 shRNA also reduced the incremental concentration of serum epinephrine and the phosphorylation level of extracellular regulated protein kinases1/2 in diabetic rats. These results indicated that P2X3 shRNA could decrease sympathetic activity via inhibiting P2X3 receptor in the SG to alleviate DCAN.

Involvement of P2Y12 receptor of stellate ganglion in diabetic cardiovascular autonomic neuropathy.

Diabetes as a chronic epidemic disease with obvious symptom of hyperglycemia is seriously affecting human health globally due to the diverse diabetic complications. Diabetic cardiovascular autonomic neuropathy (DCAN) is a common complication of both type 1 and type 2 diabetes and incurs high morbidity and mortality. However, the underlying mechanism for DCAN is unclear. It is well known that purinergic signaling is involved in the regulation of cardiovascular function. In this study, we examined whether the P2Y12 receptor could mediate DCAN-induced sympathetic reflexes. Our results revealed that the abnormal changes of blood pressure, heart rate, heart rate variability, and sympathetic nerve discharge were improved in diabetic rats treated with P2Y12 short hairpin RNA (shRNA). Meanwhile, the expression of P2Y12 receptor, interleukin-1ß (IL-1ß), tumor necrosis factor-α (TNF-α), and connexin 43 (Cx43) in stellate ganglia (SG) was decreased in P2Y12 shRNA-treated diabetic rats. In addition, knocking down the P2Y12 receptor also inhibited the activation of p38 MARK in the SG of diabetic rats. Taken together, these findings demonstrated that P2Y12 receptor in the SG may participate in developing diabetic autonomic neuropathy, suggesting that the P2Y12 receptor could be a potential therapeutic target for the treatment of DCAN.

Effects of Baicalin on Diabetic Cardiac Autonomic Neuropathy Mediated by the P2Y12 Receptor in Rat Stellate Ganglia.

BACKGROUND/AIMS: Chronic diabetic hyperglycemia can damage various of organ systems and cause serious complications. Although diabetic cardiac autonomic neuropathy (DCAN) is the primary cause of death in diabetic patients, its pathogenesis remains to be fully elucidated. Baicalin is a flavonoid extracted from Scutellaria baicalensis root and has antibacterial, diuretic, anti-inflammatory, anti- metamorphotic, and antispasmodic effects. Our study explored the effects of baicalin on enhancing sympathoexcitatory response induced by DCAN via the P2Y12 receptor. METHODS: A type 2 diabetes mellitus rat model was induced by a combination of diet and streptozotocin. Serum epinephrine was measured by enzyme-linked immunosorbent assay. Blood pressure and heart rate were measured using the indirect tail-cuff method. Heart rate variability was analyzed using the frequency-domain of electrocardiogram recordings. The expression levels of P2Y12, interleukin-1beta (IL-1ß), tumor necrosis factor alpha (TNF-α), and connexin 43 (Cx43) were determined by quantitative real-time reverse transcription-polymerase chain reaction and western blotting. The interaction between baicalin and P2Y12 determined using by molecular docking. RESULTS: Baicalin alleviated elevated blood pressure and heart rate, improved heart rate variability, and decreased the elevated expression levels of P2Y12, IL-1ß, TNF-α, and Cx43 in the stellate ganglia of diabetic rats. Baicalin also reduced the elevated concentration of serum epinephrine and the phosphorylation of p38 mitogen-activated protein kinase in diabetic rats. CONCLUSION: Baicalin decreases sympathetic activity by inhibiting the P2Y12 receptor in stellate ganglia satellite glial cells to maintain the balance between sympathetic and parasympathetic nerves and relieves DCAN in the rat.

Stellate ganglion block ameliorates vascular calcification by inhibiting endoplasmic reticulum stress.

AIMS: Vascular calcification (VC) underlies substantial cardiovascular morbidity and mortality. No clinically therapies have emerged presently. Stellate ganglion block (SGB) is one of the most often used sympathetic blockade procedure, and regulates vascular dilation. However, the effect of SGB on VC is still unknown. Therefore, we aimed to identify the ameliorative effect of SGB on VC. KEY FINDING: In vivo VC was induced in rats by administering vitamin D3 plus nicotine (VDN), and in vitro calcification of rat aortic vascular smooth muscle cells (VSMC) was induced by ß-glycerophosphate. In VDN rats, alkaline phosphatase (ALP) activity and Calcium contents were higher than that in control rats. The transformation of VSMC from contractile to osteoblast-like phenotype was observed in calcified aorta. SGB ameliorated the increase of ALP activity and Calcium content, and the transformation of VSMC in calcified aorta. The stimulation of endoplasmic reticulum stress (ERS) in calcified aorta was also attenuated by SGB treatment. The inducer of ERS, tunicamycin could block the beneficial effect of SGB on VC, and the ERS inhibitor, 4-PBA could mimic the amelioration of SGB. Furthermore, SGB attenuated the increased plasma levels of norepinephrine in VDN rats. In vitro experiments, norepinephrine exaggerated VSMC calcification, phenotype transformation and ERS. SIGNIFICANCE: These results demonstrate that SGB could inhibit sympathetic nervous activity, and then prevent the activation of ERS followed by ameliorating VC. Sympathetic over-activation might play critical role in the pathogenesis of VC, which provides new strategy and target for therapy and prevention of VC.

Atrial Fibrillation in Acute Obstructive Sleep Apnea: Autonomic Nervous Mechanism and Modulation.

BACKGROUND: The mechanisms of atrial fibrillation (AF) induced by obstructive sleep apnea (OSA) are not completely understood. This study investigated the roles of the intrinsic and extrinsic cardiac autonomic nervous system in OSA-induced AF and provided noninvasive autonomic nervous modulation for the suppression of OSA-induced AF by using low-level transcutaneous electrical stimulation (LL-TS) of the auricular branch of the vagus nerve at the tragus. METHODS AND RESULTS: Eighteen dogs received tracheostomy under general anesthesia and were randomly divided into 3 groups: the OSA group (OSA was simulated via clamping of the endotracheal tube at end expiration for 1.5 minutes every 10 minutes, n=6), the LL-TS + OSA group (simulated OSA plus LL-TS, at 80% of the slowing sinus rate, n=6), and the control group (sham surgery without stimulation, n=6). The effective refractory period was significantly shortened after 1 hour of simulated OSA, and the window of vulnerability and plasma norepinephrine levels were both markedly increased in the OSA group. OSA dramatically increased the neural function and activity of the intrinsic and extrinsic cardiac autonomic nervous system, including the superior left ganglionated plexus, the left stellate ganglion, and the left renal sympathetic nerve. OSA also significantly upregulated the expression levels of c-fos and nerve growth factor in the superior left ganglionated plexus and the left stellate ganglion. However, LL-TS markedly improved these parameters. CONCLUSIONS: These findings suggest that the intrinsic and extrinsic cardiac autonomic nervous system plays crucial roles in the acute stage of OSA-induced AF. Noninvasive LL-TS suppressed shortening of atrial refractoriness and autonomic remodeling, which prevented OSA-induced AF.

Increased inflammation promotes ventricular arrhythmia through aggravating left stellate ganglion remodeling in a canine ischemia model.

BACKGROUND: Increased inflammation was found in the left stellate ganglion (LSG) in patients with malignant ventricular arrhythmia (VA). However, the role of inflammation in LSG remodeling is unknown. This study aimed to investigate whether exogenous interleukin-1ß (IL-1ß) could aggravate VA through regulating LSG remodeling. METHODS: Twenty-four canines who received saline (Control, n=8), IL-1ß injection into the LSG (n=8) or IL-1 receptor antagonist (IL-Ra) pre-injection plus IL-1ß injection (n=8) were included. Ventricular electrophysiology parameters, heart rate variability (HRV), LSG activity were measured at different time points. VA was recorded for 60min after ischemia and then LSG tissues were collected for molecular detection. RESULTS: Compared with the control group, IL-1ß injection decreased the effective refractory period, action potential duration (APD)90 and increased the maximal slope of the restitution curve in normal hearts. Besides, the occurrence of VA was significantly increased in the IL-1ß group. Additionally, IL-1ß injection increased the sympathetic indices of HRV and LSG activity in normal and ischemic hearts. Mechanically, the mRNA expression of pro-inflammatory cytokines and protein expression of c-fos, nerve growth factor and neuropeptide Y in LSG were increased, whereas the expression of neuronal nitric oxide synthase was decreased in the IL-1ß group. More importantly, all these effects induced by IL-1ß were attenuated by IL-1Ra pre-injection. CONCLUSION: Increased inflammation induced by IL-1ß injection aggravates ischemia induced VA through regulating the neuronal remodeling of the LSG. Inflammation induced neuroplasticity may be a novel mechanism and therapeutic target for VA.

Blocking the Nav1.8 channel in the left stellate ganglion suppresses ventricular arrhythmia induced by acute ischemia in a canine model.

Left stellate ganglion (LSG) hyperactivity promotes ischemia induced ventricular arrhythmia (VA). Blocking the Nav1.8 channel decreases neuron activity. Therefore, the present study aimed to investigate whether blocking the Nav1.8 channel with its specific blocker A-803467 in the LSG reduces sympathetic activity and exerts anti-arrhythmic effects. Forty canines were divided into dimethylsulfoxide (DMSO) group and 10 mM, 15 mM, and 20 mM A-803467 groups. A volume of 0.1 ml of A-803467 or DMSO was injected into the LSG. The ventricular electrophysiological parameters, LSG function were measured before and 30 min after the injection. VA was assessed for 60 min after ischemia and then LSG tissues were collected for molecular biological experiments. Compared with DMSO, concentration-dependent prolonged action potential duration and effective refractory period, decreased LSG function were identified after A-803467 treatment. Moreover, the severity of ischemia induced VA was decreased in A-803467 groups. Furthermore, decreased nerve growth factor, decreased c-fos and increased sympathetic neuron apoptosis were found in the LSG after A-803467 injection. In conclusion, blocking the Nav1.8 channel could significantly attenuate ischemia-induced VA, primarily by suppressing LSG activity.

Impacts of Renal Sympathetic Activation on Atrial Fibrillation: The Potential Role of the Autonomic Cross Talk Between Kidney and Heart.

BACKGROUND: Recent studies have demonstrated that there is a high variability of renal sympathetic nerve density distribution from proximal to distal renal artery segments. The aim of our study was to investigate the roles of renal sympathetic nerve stimulation (RSS) on atrial fibrillation and cardiac autonomic nervous activity. METHODS AND RESULTS: Twenty-eight dogs were randomly assigned to the proximal RSS group (P-RSS, N=7), middle RSS group (M-RSS, N=7), distal RSS group (D-RSS, N=7), and the control group (sham RSS, N=7). RSS was performed using electrical stimulation on the bilateral renal arteries for 3 hours. Effective refractory period and the window of vulnerability were measured at atrial and pulmonary veins sites. Superior left ganglionated plexi (SLGP) and left stellate ganglion (LSG) function and neural activity were determined. C-fos and nerve growth factor protein expression in the SLGP and LSG were examined. Only P-RSS (1) caused pronounced blood pressure rises, induced a significant decrease in effective refractory period, and generated a marked increase in cumulative window of vulnerability and effective refractory period dispersion; (2) increased the frequency and amplitude of the neural activity in the SLGP and LSG; (3) increased SLGP and LSG function; and (4) upregulated the level of c-fos and nerve growth factor expression in the SLGP and LSG. CONCLUSIONS: This study demonstrated that renal sympathetic nerve activation induced by 3 hours of P-RSS facilitated atrial fibrillation inducibility by upregulating cardiac autonomic nervous activity, suggesting a potential autonomic cross talk between kidney and heart.