Cardioneuroablation for vasovagal syncope: insights on patients' selection, centre settings, procedural workflow and endpoints-results from an European Heart Rhythm Association survey.

AIMS: Cardioneuroablation (CNA) is a catheter-based intervention for recurrent vasovagal syncope (VVS) that consists in the modulation of the parasympathetic cardiac autonomic nervous system. This survey aims to provide a comprehensive overview of current CNA utilization in Europe. METHODS AND RESULTS: A total of 202 participants from 40 different countries replied to the survey. Half of the respondents have performed a CNA during the last 12 months, reflecting that it is considered a treatment option of a subset of patients. Seventy-one per cent of respondents adopt an approach targeting ganglionated plexuses (GPs) systematically in both the right atrium (RA) and left atrium (LA). The second most common strategy (16%) involves LA GP ablation only after no response following RA ablation. The procedural endpoint is frequently an increase in heart rate. Ganglionated plexus localization predominantly relies on an anatomical approach (90%) and electrogram analysis (59%). Less utilized methods include pre-procedural imaging (20%), high-frequency stimulation (17%), and spectral analysis (10%). Post-CNA, anticoagulation or antiplatelet therapy is prescribed, with only 11% of the respondents discharging patients without such medication. Cardioneuroablation is perceived as effective (80% of respondents) and safe (71% estimated <1% rate of procedure-related complications). Half view CNA emerging as a first-line therapy in the near future. CONCLUSION: This survey offers a snapshot of the current implementation of CNA in Europe. The results show high expectations for the future of CNA, but important heterogeneity exists regarding indications, procedural workflow, and endpoints of CNA. Ongoing efforts are essential to standardize procedural protocols and peri-procedural patient management.

Liver Cancer with Overlapping Myasthenia Gravis, Myocarditis, Seronegative Autoimmune Autonomic Ganglionopathy, and Myositis Symptoms Induced by Atezolizumab.

An 83-year-old man with hepatocellular carcinoma developed muscle weakness, ptosis, and dyspnea 3 weeks after receiving atezolizumab. Soon after, mechanical ventilation was initiated, which was followed by marked blood pressure spikes. The levels of creatine kinase and troponin-I were significantly elevated, and acetylcholine receptor antibodies were positive. The patient was diagnosed with immune checkpoint inhibitor (ICI)-induced myositis, myasthenia gravis (MG), myocarditis, and suspected autoimmune autonomic ganglionopathy (AAG). After immunotherapy, the serum markers and blood pressure normalized, and he was weaned from the ventilator after five months. To our knowledge, this is the first reported case of AAG secondary to ICI-induced myositis, MG, and myocarditis.

[A man in his fifties with near-syncope episodes and persistent dizziness]. / En mann i 50-årene med nærbesvimelser og vedvarende svimmelhet.

BACKGROUND: A previously healthy male patient in his fifties presented with subacute onset of severe, diffuse dysautonomia with orthostatic hypotension as the main symptom. A lengthy interdisciplinary workup revealed a rare condition. CASE PRESENTATION: Over the course of a year, the patient was twice admitted to the local department of internal medicine because of severe hypotension. Testing showed severe orthostatic hypotension with normal cardiac function tests and no apparent underlying cause. On referral to neurological examination, symptoms of a broader autonomic dysfunction were discovered, with symptoms of xerostomia, irregular bowel habits, anhidrosis and erectile dysfunction. The neurological examination was normal, except for bilateral mydriatic pupils. The patient was tested for ganglionic acetylcholine receptor (gAChR) antibodies. A strong positive result confirmed the diagnosis of autoimmune autonomic ganglionopathy. There were no signs of underlying malignancy. The patient received induction treatment with intravenous immunoglobulin and later maintenance treatment with rituximab, resulting in significant clinical improvement. INTERPRETATION: Autoimmune autonomic ganglionopathy is a rare but likely underdiagnosed condition, which may cause limited or widespread autonomic failure. Approximately half of the patients have ganglionic acetylcholine receptor antibodies in serum. It is important to diagnose the condition as it can cause high morbidity and mortality, but responds to immunotherapy.

Imaging neuro-urodynamics of mouse major pelvic ganglion with a micro-endoscopic approach.

Postganglionic neurons of the autonomic nervous system lie outside of the central nervous system and innervate specific target effectors such as organs or glands. The major pelvic ganglion (MPG) is one such ganglion that plays a significant role in controlling bladder function in rodents. However, because of technical and physical constraints in recording electrophysiological signals from these neurons in vivo, the functional neural activity in MPG is mostly unknown. Transgenic animal models expressing genetically encoded calcium indicators now provide opportunities to monitor the activity of populations of neurons in vivo to overcome these challenges related to traditional electrophysiological methods. However, like many peripheral neurons, the MPG is not conducive to conventional fluorescent microscopy techniques, as it is located in the pelvic cavity, thus limiting robust optical access by benchtop microscopes. Here, we present an endoscopic approach based on a custom miniscope system (UCLA V3) that allows for effective in vivo monitoring of neural activity in the MPG for the first time. We show that our imaging approach can monitor activity of hundreds of MPG neurons simultaneously during the filling and emptying of the bladder in a urethane-anesthetized transgenic mouse line expressing GCaMP6s in cholinergic MPG neurons. By using custom analysis scripts, we isolated the activity of hundreds of individual neurons and show that populations of neurons have distinct phasic activation patterns during sequential bladder filling and voiding events. Our imaging approach can be adapted to record activity from autonomic neurons across different organs and systems in both healthy and disease models.NEW & NOTEWORTHY The functional activity and information processing within autonomic ganglia is mostly unknown because of technical and physical constraints in recording electrophysiological signals from these neurons in vivo. Here, we use a micro-endoscopic approach to measure in vivo functional activity patterns from a population of autonomic neurons controlling bladder function for the first time. This approach can be adapted to record activity from autonomic neurons across different organs and systems in both healthy and disease models.

Severe treatment-refractory antibody positive autoimmune autonomic ganglionopathy after mRNA COVID19 vaccination.

BACKGROUND: COVID-19 vaccine-associated peripheral and central neuroimmunological disorders have been well described. We present the case of a 56 year old male who developed α3-ganglionic AChR antibody positive Autoimmune Autonomic Ganglionopathy (AAG) after completion of a two-dose course of mRNA (Comirnaty) vaccination for COVID19. RESULTS: A previously hypertensive 56 year old male presented with the subacute onset of severe constipation, urinary retention, erectile dysfunction, sudomotor failure, sicca symptoms, non-reactive pupils and severe orthostatic hypotension shortly after receiving the second dose of an mRNA vaccine against COVID19. Autonomic testing revealed severe cardiovagal, adrenergic and sudomotor impairment, and tonic 'half-mast' pupils with evidence of sympathetic and parasympathetic denervation. Pathological α3-ganglionic ACHR antibodies were positive in serum as detected by a new flow cytometric immunomodulation assay. Malignancy was excluded. The patient was diagnosed with severe, treatment-refractory acute AAG. CONCLUSIONS: While autonomic dysfunction has been previously reported post-COVID19 vaccination, to our knowledge this is the first reported case of antibody-positive AAG in this setting. The severity of this case is in marked contrast to the existing literature on idiopathic antibody-positive autoimmune pandysautonomia.

Paraneoplastic autoimmune autonomic ganglionopathy as the first symptom of bladder cancer: a case report and review of literature.

BACKGROUND: Autoimmune autonomic ganglionopathy is a rare, immune-mediated disorder associated with anti-ganglionic α3-subunit nicotinic acetylcholine receptor (anti-α3gAChR) antibodies, which bind to acetylcholine receptor in autonomic ganglia (parasympathetic and sympathetic) leading to autonomic failure. This disorder is mostly associated with viral infections, but it can also be associated with systemic malignancies. Here, we report the case of a paraneoplastic autonomic ganglionopathy as the first symptom of bladder cancer. METHOD: Case report. RESULTS: A 47-year-old man, without medical history of interest, stated to the emergency department for progressive blurry vision with eye and mouth dryness, constipation, and dizziness upon standing for the last 2 weeks. Orthostatic hypotension was demonstrated by a drop in 13.3 mmHg mean blood pressure (BP) from supine (100/60 mmHg) to 45° reclining sitting position (80/50 mmHg). Blood tests, chest X-ray, brain MRI, and electroneuronography were unremarkable. Electrochemical skin conductance was reduced. Serological examination was positive for anti-α3gAChR antibodies. A full-body CT scan revealed a bladder tumor, which was treated by transurethral bladder resection. The pathologic study demonstrated a low-grade non-muscle-invasive bladder urothelial carcinoma. After tumor resection, and treatment with intravenous immunoglobulins and corticoids, a gradually improvement was observed. Today, the patient remains asymptomatic. CONCLUSION: Subacute panautonomic failure can be the first symptom for systemic malignancies. This case reports a paraneoplastic autonomic ganglionopathy as the first symptom of bladder cancer. This case highlights the importance of a systemic study to rule out the presence of cancer when autoimmune autonomic ganglionopathy is present.

Evaluation of commercially available antibodies and fluorescent conotoxins for the detection of surface ganglionic acetylcholine receptor on the neuroblastoma cell line, IMR-32 by flow cytometry.

Commercially available antibodies that bind to the human muscle acetylcholine receptor (ACHR) have been validated previously for flow cytometric use (Keefe et al., 2009; Leite et al., 2008; Lozier et al., 2015). Despite a multitude of commercially available antibodies to other nicotinic ACHRs, validation in a wide variety of immunoassay formats is lacking; when studied, a large proportion of these antibodies have been deemed not fit for most research purposes (Garg and Loring, 2017). We have recently described a flow cytometric immunomodulation assay for the diagnosis of Autoimmune Autonomic Ganglionopathy (AAG) (Urriola et al., 2021) that utilises the monoclonal antibody mab35(Urriola et al., 2021) which is specific for ganglionic ACHR (gnACHR) that contain α3 subunits (Vernino et al., 1998). Other fluorescent ligands for α3-gnACHR have not been validated for flow cytometric use. We investigated 7 commercially sourced antibodies and 3 synthetic fluorescent novel conotoxins purported to specifically bind to the extracellular domains of the gnACHR, and compared the results to staining by mab35, using flow cytometry with the neuroblastoma cell line IMR-32. We also evaluated the degree of non-specific binding by depleting the cell membrane of the relevant acetylcholine receptor with a pre-incubation step involving the serum from a patient with Autoimmune Autonomic Ganglionopathy containing pathogenic antibodies to the ganglionic acetylcholine receptor. None of the assessed conotoxins, and only one antibody (mab35) was found to perform adequately in flow cytometric staining of the native ganglionic acetylcholine receptor.

Somatostatin immunoreactivity within the urinary bladder nerve fibers and paracervical ganglion urinary bladder projecting neurons in the female pig.

The study was designed to examine the distribution and chemical coding of somatostatin-immunoreactive (SOM-IR) nerve fibers supplying the urinary bladder wall and to establish the distribution and immunohistochemical characteristics of the subpopulation of paracervical ganglion (PCG) SOM-IR neurons projecting to this organ in female pigs. The PCG-urinary bladder projecting neurons (PCG-UBPN) were visualized with retrograde neuronal tracer Fast Blue (FB). Double-labeling immunohistochemistry performed on cryostat sections from the urinary bladder wall revealed that the greatest density of SOM-IR nerve fibers was found in the muscle layer and around blood vessels, a moderate number of these nerve terminals supplied the submucosa and only single SOM-IR axons were encountered beneath the urothelium. In all the investigated sections the vast majority of SOM-IR nerve fibers were immunopositive to vesicular acetylcholine transporter (VAChT) and many SOM-IR axons contained immunoreactivity to neuropeptide Y (NPY). Approximately 65 % of FB-positive (FB+) PCG-UBPN were immunoreactive to SOM. Moreover, PCG FB+/SOM + nerve cells were simultaneously immunoreactive to choline acetyltransferase (ChAT; 64.6 ± 0.6 %), NPY (59.7 ± 1.2 %), neuronal nitric oxide synthase (nNOS; 46.1 ± 0.7 %), vasoactive intestinal polypeptide (VIP; 29.9 ± 2.2 %), Leu5-enkephalin (L-ENK; 19.5 ± 6.3 %), dopamine ß-hydroxylase (DßH; 14.9 ± 1.9 %) or pituitary adenylate cyclase-activating polypeptide (PACAP; 14.8 ± 2.4 %). The present study reveals the extensive expression of SOM in both the nerve fibres supplying the porcine urinary bladder wall and the PCG neurons projecting to this organ, indicating an important regulatory role of SOM in the control of the urinary bladder function.

A Flow Cytometric Assay to Detect Functional Ganglionic Acetylcholine Receptor Antibodies by Immunomodulation in Autoimmune Autonomic Ganglionopathy.

Autoimmune Autonomic Ganglionopathy (AAG) is an uncommon immune-mediated neurological disease that results in failure of autonomic function and is associated with autoantibodies directed against the ganglionic acetylcholine receptor (gnACHR). The antibodies are routinely detected by immunoprecipitation assays, such as radioimmunoassays (RIA), although these assays do not detect all patients with AAG and may yield false positive results. Autoantibodies against the gnACHR exert pathology by receptor modulation. Flow cytometric analysis is able to determine if this has occurred, in contrast to the assays in current use that rely on immunoprecipitation. Here, we describe the first high-throughput, non-radioactive flow cytometric assay to determine autoantibody mediated gnACHR immunomodulation. Previously identified gnACHR antibody seronegative and seropositive sera samples (RIA confirmed) were blinded and obtained from the Oxford Neuroimmunology group along with samples collected locally from patients with or without AAG. All samples were assessed for the ability to cause gnACHR immunomodulation utilizing the prototypical gnACHR expressing cell line, IMR-32. Decision limits were calculated from healthy controls, and Receiver Operating Characteristic (ROC) curves were constructed after unblinding all samples. One hundred and ninety serum samples were analyzed; all 182 expected negative samples (from healthy controls, autonomic disorders not thought to be AAG, other neurological disorders without autonomic dysfunction and patients with Systemic Lupus Erythematosus) were negative for immunomodulation (<18%), as were the RIA negative AAG and unconfirmed AAG samples. All RIA positive samples displayed significant immunomodulation. There were no false positive or negative samples. There was perfect qualitative concordance as compared to RIA, with an Area Under ROC of 1. Detection of Immunomodulation by flow cytometry for the identification of gnACHR autoantibodies offers excellent concordance with the gnACHR antibody RIA, and overcomes many of the shortcomings of immunoprecipitation assays by directly measuring the pathological effects of these autoantibodies at the cellular level. Further work is needed to determine the correlation between the degree of immunomodulation and disease severity.

Anti-arrhythmic and anti-heart failure effects of low-level electrical stimulation on aortic root ventricular ganglionated plexi.

BACKGROUND: It remains uncertain whether low-level electrical stimulation (LL-ES) of the ventricular ganglionated plexi (GP) improves heart function. This study investigated the anti-arrhythmic and anti-heart failure effects of LL-ES of the aortic root ventricular GP (ARVGP). METHODS: Thirty dogs were divided randomly into control, drug, and LL-ES groups after performing rapid right ventricular pacing to establish a heart failure (HF) model. The inducing rate of arrhythmia; levels of bioactive factors influencing HF, including angiotensin II type I receptor (AT-1R), transforming growth factor-beta (TGF-ß), matrix metalloproteinase (MMP), and phosphorylated extracellular signal-regulated kinase (p-ERK1/2); left ventricular stroke volume (LVSV), and left ventricular ejection fraction (LVEF)were measured after treatment with placebo, drugs, and LL-ES. RESULTS: The inducing rate of atrial arrhythmia decreased from 60% in the control group to 50% in the drug group and 10% in the LL-ES group (p = .033 vs. drug group) after 1 week of treatment. The ventricular effective refractory period was prolonged from 139 ± 8 ms in the drug group to 166 ± 13 ms in the LL-ES group (p = .001). Compared to the drug group, the expressions of AT-1R, TGF-ß, and MMP proteins were down-regulated in the LL-ES group, whereas that of p-ERK1/2 was significantly increased (all p = .001). Moreover, in the LL-ES group, LVSV increased markedly from 13.16 ± 0.22 to 16.86 ± 0.27 mL, relative to that in the drug group (p = .001), and LVEF increased significantly from 38.48% ± 0.53% to 48.94% ± 0.57% during the same time frame (p = .001). CONCLUSION: Short-term LL-ES of ARVGP had both anti-arrhythmic and anti-inflammatory effects and contributed to the treatment of tachycardia-induced HF and its associated arrhythmia.

Nicotinic ganglionic acetylcholine receptor autoantibodies associated with paraneoplastic disease in a neuropsychiatric patient.

Nicotinic ganglionic acetylcholine receptor autoantibodies (alpha-3-AChR Ab) are associated with paraneoplastic syndromes when present in low elevations. These antibodies can be tested for as part of an autoimmune encephalopathy panel in neuropsychiatric patients; a mildly elevated titre of alpha-3-AChR Ab that may start as an incidental finding can lead to the diagnosis of a previously undetected cancer. While alpha-3-AChR Ab are most typically associated with thymomas and small cell lung cancer, the presence of these antibodies can suggest a diverse range of other cancers. This case presents a patient with longstanding neuropsychiatric symptoms and possible functional hypothyroidism for whom a low elevation in alpha-3-AChR Ab led to the finding of papillary thyroid carcinoma.

Paracervical ganglion in the female pig during prenatal development: Morphology and immunohistochemical characteristics.

The present study investigated the development of the paracervical ganglion in 5-, 7- and 10-week-old porcine foetuses using double labelling immunofluorescence method. In 5-week-old foetuses single PGP-positive perikarya were visible only along the mesonephric ducts. They contained DßH or VAChT, and nerve fibres usually were PGP/VAChT-positive. The perikarya were mainly oval. In 7-week-old foetuses, a compact group of PGP-positive neurons (3144±213) was visible on both sides and externally to the uterovaginal canal mesenchyme of paramesonephric ducts. Nerve cell bodies contained only DßH (36.40±1.63%) or VAChT (17.31±1.13%). In the 10-week-old foetuses, the compact group of PGP-positive neurons divided into several large and many small clusters of nerve cells and also became more expanded along the whole uterovaginal canal mesenchyme reaching the initial part of the uterine canal of the paramesonephric duct. The number of neurons located in these neuronal structures increased to 4121±259. Immunohistochemistry revealed that PGP-positive nerve cell bodies contained DßH (40.26±0,73%) and VAChT (30.73±1.34%) and were also immunoreactive for NPY (33.24±1,27%), SOM (23.6±0,44%) or VIP (22.9±1,13%). Other substances studied (GAL, NOS, CGRP, SP) were not determined at this stage of the development. In this study, for the first time, the morphology of PCG formation in the porcine foetus has been described in three stages of development. Dynamic changes in the number of neurons and their sizes were also noted, as well as the changes in immunochistochemical coding of maturing neurons.

Peripheral Nerve Stimulation for Facial Pain Using Conventional Devices: Indications and Results.

Trigeminal branch stimulation is a type of peripheral nerve stimulation (PNS) used to treat a variety of craniofacial pain disorders. Common indications include trigeminal neuralgia, trigeminal neuropathic pain, trigeminal deafferentation pain, trigeminal postherpetic neuralgia, supraorbital neuralgia, and migraine headaches. Supraorbital and infraorbital arrays are the most common electrode configurations, although preauricular, mandibular branch, and subcutaneous peripheral nerve field stimulation arrays have also been described. Trigeminal branch stimulation may be used as a stand-alone neuromodulation therapy or it may be combined with occipital nerve, sphenopalatine ganglion, or Gasserian ganglion stimulation to treat more complex pain patterns. Consistent with other forms of PNS, trigeminal branch stimulation is a minimally invasive, safe, and straightforward method of treating medically refractory neuropathic pain.

Diagnostic Algorithm in Hirschsprung's Disease: Focus on Immunohistochemistry Markers.

BACKGROUND/AIM: Hirschsprung disease (HD) is caused by the congenital absence of ganglion cells in the distal bowel (aganglionosis). Rectal biopsy is considered important for its diagnosis. The aim of this study was to apply immunohistochemical staining using a minimal set of antibodies and develop an algorithm that will assist in the diagnosis of HD. PATIENTS AND METHODS: Rectal or colonic biopsies were performed in patients with HD (n=26) or patients treated for other bowel diseases (n=34). Immunohistochemical staining was performed for MAP1b, peripherin, S-100, calretinin, NSE, bcl-2 and CD56 proteins. RESULTS: Staining for CD56, S-100, peripherin and calretinin facilitated the identification of ganglion cells. The use of CD56 and S-100 antibodies together resulted in the highest rate of ganglion cell staining intensity (94%). CONCLUSION: We propose a practical diagnostic algorithm with the application of CD56 and S-100 antibodies that can be used in clinical practice in children suspected of Hirschsprung's disease.

Unexpected High Prevalence of Lymphocytic Infiltrates in Myenteric Ganglions in Intestinal Inertia.

Intestinal inertia is a severe form of gut dysmotility that may require surgical resection. Loss of myenteric ganglion cells has been proposed as a possible etiology. Preclinical models have also suggested that virus infection-associated ganglionitis may be an alternative pathogenic factor. We determined to the extent intestinal inertia is associated with the lack of myenteric ganglion cells or ganglionitis using resection specimens from 27 intestinal inertia and 28 colon cancer patients. A hot spot approach with 5 HPFs was used for quantifying inflammatory cells. CD3, CD8, and CD20 immunohistochemistry was used to quantify T and B lymphocytes, along with subtyping the T-lymphocyte population by CD8. None of the intestinal inertia nor control cases showed the absence of myenteric ganglion cells. A total of 15 (55.6%) of the intestinal inertia cases showed inflammatory cell infiltration in the myenteric ganglion cells, compared with only 1 of 28 (3.6%) control cases (P<0.0001 by Fisher exact test). The inertia cases with inflammatory infiltrates were all associated predominantly with lymphocytes, including 3 cases (11.1%) with concurrent eosinophil infiltration, and 1 case (3.7%) with concurrent neutrophil infiltration. Furthermore, all 15 inertia cases with myenteric lymphocytic ganglionitis were associated with T lymphocytes (100%), including 1 case with a subset of concurrent B lymphocytes. The average CD3 count was 3.8 cells/HPF. CD8 immunohistochemical stain showed positive staining in 12 of the 15 cases (80%) with CD8-positive cells ranging from 1 to 8/HPF. In contrast, the only control case with lymphocytic ganglionitis showed mixed B and T lymphocytes and eosinophils. The high prevalence of T-lymphocyte infiltration in the myenteric ganglion in intestinal inertia cases suggests a possible pathogenic role.

A comprehensive analysis of the clinical characteristics and laboratory features in 179 patients with autoimmune autonomic ganglionopathy.

The clinical importance of autoantibodies against the ganglionic acetylcholine receptor (gAChR) remains to be fully elucidated. We aimed to identify the clinical characteristics of autoimmune autonomic ganglionopathy (AAG) in patients with gAChR autoantibodies. For this cohort investigation, serum samples were obtained from patients with AAG between 2012 and 2018 in Japan. We measured the levels of autoantibodies against gAChRα3 and gAChRß4 and evaluated clinical features, as well as assessing the laboratory investigation results among the included patients. A total of 179 patients tested positive for antibodies, including 116 gAChRα3-positive, 13 gAChRß4-positive, and 50 double antibody-positive patients. Seropositive AAG patients exhibited widespread autonomic dysfunction. Extra-autonomic manifestations including sensory disturbance, central nervous system involvement, endocrine disorders, autoimmune diseases, and tumours were present in 118 patients (83%). We observed significant differences in the frequencies of several autonomic and extra-autonomic symptoms among the three groups. Our 123I-metaiodobenzylguanidine myocardial scintigraphy analysis of the entire cohort revealed that the heart-to-mediastinum ratio had decreased by 80%. The present study is the first to demonstrate that patients with AAG who are seropositive for anti-gAChRß4 autoantibodies exhibit unique autonomic and extra-autonomic signs. Decreased cardiac uptake occurred in most cases, indicating that 123I- metaiodobenzylguanidine myocardial scintigraphy may be useful for monitoring AAG. Therefore, our findings indicate that gAChRα3 and gAChRß4 autoantibodies cause functional changes in postganglionic fibres in the autonomic nervous system and extra-autonomic manifestations in seropositive patients with AAG.

Study of the Distribution of Epicardial Vagal Ganglion and the Relationship Between Delayed Enhancement Magnetic Resonance Imaging and Radiofrequency Ablation in Patients with Atrial Fibrillation.

This article presents a retrospective study of patients undergoing radiofrequency ablation of atrial fibrillation (AF); analyzes the characteristics of heart rate variability (HRV) in patients; and explores the role of delayed enhancement magnetic resonance imaging and autonomic nervous system function, changes in autonomic nervous system function, and recurrence of AF after radiofrequency ablation to understand the effect of denervation of the autonomic nervous system on the efficacy of radiofrequency ablation of AF. The study found that there were no significant differences in clinical baseline characteristics, mean heart rate, and HRV indicators between patients without relapse and patients with relapse (P > 0.05). The overall HRV index was significantly reduced after surgery as well as before surgery. In the relapse-free group, the high-frequency power that responded to vagal tone was more significant, the low-frequency/high-frequency power ratio increased, and other HRV indicators were significantly reduced; in the relapse group, mean heart rate increased, sympathetic response to the low-frequency power of nerve tension was significantly reduced, and the low-frequency/high-frequency power ratio was decreased. The difference was statistically significant (P < 0.05). Therefore, sympathetic and parasympathetic nerve function were significantly reduced after radiofrequency ablation of the pulmonary veins in patients with AF. Reducing vagus nerve tension may inhibit early recurrence of paroxysmal AF in patients after left atrial ring pulmonary vein ablation.

[Autoimmune autonomic ganglionopathy].

Autoimmune autonomic ganglionopathy (AAG) is an acquired immune-mediated disorder of widespread autonomic failure. Approximately half of the patients with AAG have the autoantibodies against the neuronal nicotinic acetylcholine receptor (AChR) in autonomic ganglia. These ganglionic AChR antibodies have the potential to mediate the synaptic transmission in sympathetic, parasympathetic, and enteric ganglia. Therefore, seropositive AAG patients exhibit various autonomic symptoms. Extra-autonomic manifestations (coexistence with brain involvement, sensory disturbance, endocrine disorders, autoimmune diseases and tumors) are present in many patients with AAG. The nicotinic AChRs comprise a family of abundantly expressed ligand-gated cation channels found throughout the central and peripheral nervous systems. Moreover, limited manifestations of autoimmune dysautonomia including autoimmune gastrointestinal dysmotility are newly recognized clinical entity. Although combined immunomodulatory therapy is beneficial for almost all patients with AAG, several case reports of some AAG patients with small benefit exist. This review focuses on the recent progress in the clinical approaches of AAG and its related disorders involving the role of autoantibodies and clinical practice.

Long-Term Outcome of Additional Superior Vena Cava to Septal Linear Ablation in Catheter Ablation of Atrial Fibrillation.

Background We previously reported the benefit of linear ablation from the superior vena cava to the right atrial septum (SVC-L) within a year after circumferential pulmonary vein isolation (CPVI) in patients with paroxysmal atrial fibrillation (AF). We explored the long-term effects of SVC-L and its potential related mechanisms. Methods and Results Among 2140 consecutive patients with AF ablation, we included 614 patients (73.3% male, aged 57.8±10.7 years, 13.7% with persistent AF) who did not undergo an extra-pulmonary vein left atrial ablation after propensity score matching; of those, 307 had additional SVC-L and 307 had CPVI alone. We evaluated the heart rate variability and computational modeling study to explore mechanisms. Although the procedure time was longer in the SVC-L group than the CPVI group (P<0.001), the complication rates did not differ (P=0.560). During 40.5±24.4 months of follow-up, the rhythm outcome was significantly better in the SVC-L group than the CPVI group (log rank, P<0.001). At 2-year follow-up of heart rate variability, a significantly higher mean heart rate (P=0.018) and a lower ratio of low/high-frequency components (P=0.011) were found with SVC-L than CPVI alone. In realistic in silico biatrial modeling, which reflected the electroanatomies of 10 patients, SVC-L significantly reduced biatrial dominant frequency compared with CPVI alone (P<0.001) and increased AF termination and defragmentation rates (P=0.033). Conclusions SVC-L ablation in addition to CPVI significantly improved the long-term rhythm outcome over 2 years after AF catheter ablation by mechanisms involving autonomic modulation and AF organization.

Agonist Selectivity and Ion Permeation in the α3ß4 Ganglionic Nicotinic Receptor.

Nicotinic acetylcholine receptors are pentameric ion channels that mediate fast chemical neurotransmission. The α3ß4 nicotinic receptor subtype forms the principal relay between the central and peripheral nervous systems in the autonomic ganglia. This receptor is also expressed focally in brain areas that affect reward circuits and addiction. Here, we present structures of the α3ß4 nicotinic receptor in lipidic and detergent environments, using functional reconstitution to define lipids appropriate for structural analysis. The structures of the receptor in complex with nicotine, as well as the α3ß4-selective ligand AT-1001, complemented by molecular dynamics, suggest principles of agonist selectivity. The structures further reveal much of the architecture of the intracellular domain, where mutagenesis experiments and simulations define residues governing ion conductance.