Ganglionated Plexi Research Articles

The ectopy-triggering ganglionated plexuses in atrial fibrillation.

BackgroundEpicardial ganglionated plexuses (GP) have an important role in the pathogenesis of atrial fibrillation (AF). The relationship between anatomical, histological and functional effects of GP is not well known. We previously described atrioventricular (AV) dissociating GP (AVD-GP) locations. In this study, we hypothesised that ectopy triggering GP (ET-GP) are upstream triggers of atrial ectopy/AF and have different anatomical distribution to AVD-GP.ObjectivesWe mapped and characterised ET-GP to understand their neural mechanism in AF and anatomical distribution in the left atrium (LA).Methods26 patients with paroxysmal AF were recruited. All were paced in the LA with an ablation catheter. High frequency stimulation (HFS) was synchronised to each paced stimulus for delivery within the local atrial refractory period. HFS responses were tagged onto CARTO™ 3D LA geometry. All geometries were transformed onto one reference LA shell. A probability distribution atlas of ET-GP was created. This identified high/low ET-GP probability regions.Results2302 sites were tested with HFS, identifying 579 (25%) ET-GP. 464 ET-GP were characterised, where 74 (16%) triggered ≥30s AF/AT. Median 97 (IQR 55) sites were tested, identifying 19 (20%) ET-GP per patient. >30% of ET-GP were in the roof, mid-anterior wall, around all PV ostia except in the right inferior PV (RIPV) in the posterior wall.ConclusionET-GP can be identified by endocardial stimulation and their anatomical distribution, in contrast to AVD-GP, would be more likely to be affected by wide antral circumferential ablation. This may contribute to AF ablation outcomes.

Prolongation of QT interval after pulmonary vein isolation for paroxysmal atrial fibrillation.

Pulmonary vein isolation (PVI) affects the ganglionated plexi (GP) around the atrium leading to a modification of intrinsic cardiac autonomic system (ANS). In animal models, GP ablation has the potential risk of QT prolongation and ventricular arrhythmias. However, the impact of PVI on QT intervals in human remains unclear. We analyzed electrocardiograms of 117 consecutive patients with paroxysmal atrial fibrillation (AF) who underwent their first PVI procedures and maintained sinus rhythm without antiarrhythmic drugs at all evaluation points (4 h, 1 day, 1 month, and 3 months after PVI). Heart rate significantly increased at 4 h, 1 day, and 1 month. Raw QT interval prolonged at 4 h (417.1 ± 41.6 ms, p < .001) but shortened at 1 day (376.4 ± 34.1 ms, p < .001), 1 month (382.2 ± 31.5 ms, p < 0.001), and 3 months (385.1 ± 32.8 ms, p < 0.001) compared with baseline (391.6 ± 31.4 ms). Bazett-corrected QTc intervals were significantly prolonged at 4 h (430.8 ± 27.9 ms, p < .001), 1 day (434.8 ± 22.3 ms, p < .001), 1 month (434.8 ± 22.3 ms, p < .001), and 3 months (420.1 ± 21.8 ms, p < .001) compared with baseline (404.9 ± 25.2 ms). Framingham-corrected QTc intervals significantly prolonged at 4 h (424.1 ± 26.6 ms, p < .001) and 1 day (412.3 ± 29.3 ms, p < .01) compared with baseline (399.2 ± 22.7 ms). Multiple regression analysis revealed that female sex is a significant predictor of raw QT and QTc interval increase at 4 h after PVI. Raw QT and QTc were prolonged after PVI, especially in the acute phase. Female sex is a risk factor for QT increase.

A piglet model of iatrogenic rectosigmoid hypoganglionosis reveals the impact of the enteric nervous system on gut barrier function and microbiota postnatal development

BackgroundHirschsprung-associated enterocolitis physiopathology likely involves disturbed interactions between gut microbes and the host during the early neonatal period. Our objective was to create a neonatal porcine model of iatrogenic aganglionosis to evaluate the impact of the enteric nervous system (ENS) on microbiota and intestinal barrier postnatal development. MethodsUnder general anesthesia, the rectosigmoid serosa of 5-day-old suckling piglets was exposed to 0.5% benzalkonium chloride solution (BAC, n = 7) or saline (SHAM, n = 5) for 1 h. After surgery, animals returned to their home-cage with the sow and littermates and were studied 21 days later. ResultsBAC treatment induced partial aganglionosis with absence of myenteric plexus and reduced surface area of submucosal plexus ganglia (−58%, P < 0.05) in one third of the rectosigmoid circumference. Epithelial permeability of this zone was increased (conductance +63%, FITC-dextran flux +386%, horseradish-peroxidase flux +563%, P < 0.05). Tight junction protein remodeling was observed with decreased ZO-1 (−95%, P < 0.05) and increased claudin-3 and e-cadherin expressions (+197% and 61%, P < 0.05 and P = 0.06, respectively). BAC piglets harbored greater abundance of proinflammatory bacteria (Bilophila, Fusobacterium) compared to SHAM in the rectosigmoid lumen. ConclusionsThis large animal model demonstrates that hypoganglionosis is associated with dramatic defects of gut barrier function and establishment of proinflammatory bacteria.Level of evidence

Role of Ganglionated Plexus Ablation in Atrial Fibrillation on the Basis of Supporting Evidence.

The role of the autonomic nervous system (ANS) in the onset and maintenance of atrial fibrillation (AF) may be related to autonomic imbalance. The ANS may cause specific cellular electrophysiological phenomena, such as, shortening of the atrial effective refractory periods (ERPs) and ectopy based on firing activity in pulmonary vein myocytes. High frequency stimulation of atrial ganglionated plexi (GPs) may cause an increase in ERP dispersion and induce AF. Autonomic modification strategies by targeting GPs with catheter ablation have emerged as new targets. Various strategies have been used to detect location of GPs.However, it is still not clear which is the best method to localize GPs, how many GPs should be targeted, and what are the long-term consequences of these therapies. In this review, we discuss available evidence on the clinical impact of GP ablation to treat AF.

P1096Cardioneuroablation changes the type of vaso-vagal response in patients with asystolic reflex syncope

Abstract Funding Acknowledgements Centre of Postgraduate Medical Education No. 501-1-10-14-19 Background. Cardioneuroablation (CNA) - ablation of ganglionated plexi (GP) to eliminate or reduce parasympathetic overactivity, has been recently proposed as a new therapeutic method in patients with vaso-vagal syncope (VVS) due to cardioinhibitory or mixed mechanism. Purpose. To assess the impact of CNA on the type of VV response during tilt testing (TT). Methods. The study group consisted of the first 20 patients (7 males, mean age 38 ± 9 – year – old) enrolled in the ongoing prospective Roman study (NCT 03903744). All patients had a history of ECG documented syncope due to asystole and confirmed asystolic form of VVS at baseline TT. CNA was performed using electroanatomical system Carto 3 and radiofrequency applications delivered in the right and left atrium at the right anterior GP and right inferior GP sites. The second TT was performed three months later. Resting heart rate (HR) and heart rate variability parameter (SDDN) were also assessed. Results. At baseline TT, nineteen patients had cardioinhibitory syncope (asystole ranging from 3 to 60 s) (sinus node arrest – 17 patients, A-V block – 2 patients) and 1 had mixed form of VVS (asystole lasting 3 s preceded by hypotension). During three-month follow-up no syncopal episodes were noted. At the 3-month TT, 6 (30 %) patients had no syncope whereas the remaining 13 (65 %) had syncope – twelve (60 %) due to vasodepressor mechanism and only one (5 %) due to asystole - as before CNA. One patient did not have TT because of pregnancy. Mean resting HR after CNA was significantly faster and SDNN significantly lower than before the procedure (82 ± 9 vs 69 ± 11 beats/min, p = 0.0004 and 74 ± 22 vs 143 ± 40 ms, p = 0.00003, respectively) and these changes were was similar in those who fainted during second TT and those who did not (82 ± 11 vs 81 ± 4 beats/min, p = NS and (75 ± 2 vs 77 ± 18 ms, p = NS, respectively). Conclusions. CNA profoundly affects the type of VV reaction causing normalization of the response to tilting or changing cardiodepression to vasodepression. These effects are also depicted by changes in HR and heart rate variability. Elimination of TT-induced reflex asystole may prevent clinical recurrences of syncope during short-term follow-up. These findings encourage to conduct further studies involving CNA since this method appears to be effective and obviates the need for pacemaker implantation in young people with reflex asystolic syncope.

235Anatomic guided ablation of the right ganglionated plexus is enough for cardiac autonomic denervation in patients with significant bradyarrhythmias

Abstract Background In patients with significant bradyarrhytmias, cardiac denervation is an alternative therapeutic approach. Previous reports proposed different methods (as high frequency ednocardial stimulation of ganglionated plexus and specific atrial electrogram identification) and targets (right and left atrial ganglionated plexus) for adequate denervation. There is no consensus on the best way to perform these procedures, in spite the right atrial ganglia plexus (GP) ablation seeming to be the most contributive to its success. Purpose To assess the results of a purely anatomic approach for ablation of just the right atrial plexus in patients with severe vagal bradyarrhytmias. Methods We enrolled patients referred for ablation of cardiac parasympathetic ganglia, with or without atrial fibrillation ablation. We performed eletroanatomic mapping of the right and left atria and used an irrigated tip catheter for ablation, aiming at the anterior right GP at the right pulmonary veins antrum along with ablation at the superior vena cava junction and the inferior right GP at the posterior aspect of the right inferior pulmonary vein along with ablation of the right aspect of the interatrial septum, between the posterior wall and coronary sinus ostium (Figure 1). We assessed the PW and Wenckenback cycle lengths (CL) pre and post procedure in patients with sinus arrest or AV block, respectively, and the patients had new 24h holter readings at least 30 days from the index procedure. Results We enrolled 12 patients: 9 males (75%), median age of 49,5 years (IQR 36-61,75). All patients had structurally normal hearts. 7 patients had only ablation of the parasympathetic ganglia and 5 patients had simultaneous pulmonary vein isolation for previously documented atrial fibrillation. 7 patients (58,3%) had sinus bradycardia (2 patients had sinus arrest with pauses of 8 and 13 seconds), 2 patients with cardioinhibitory syncope (with pauses of 23 and 28 seconds) and 3 patients had transient high degree AV block. The ablation procedure led to a median sinus rate acceleration of 15 bpm (IQR 3-29), a median decrease of 320 ms in PW (IQR 23,75-609,5) in patients with sinus arrest and a decrease of 80 ms in wenckenback CL (IQR 60-200) in patients with AV block. With a median follow up of 133,50 days (IQR 36-61,75), no patient had recurrence of symptoms or conduction disturbances. Conclusions In selected patients with severe functional paroxysmal bradyarrhytmias, cardiac denervation using an ablation strategy purely based on anatomic aspects and targeting only the right GP, seems to be an effective therapeutic approach. Abstract Figure 1: Abl of right ganglionated plex

P1097Heart rate acceleration is a poor surrogate of complete parasympathetic denervation of sinus node during cardioneuroablation

Abstract Background Ablation of superior paraseptal ganglionic plexi is invariantly associated with the acceleration of sinus rhythm. This is considered a favourable sign during cardioneuroablation for the treatment of recurrent neurally-mediated cardioinhibitory syncope or symptomatic sinus bradycardia. Purpose In this retrospective study, we investigated whether the magnitude of sinus rhythm acceleration corresponds with directly assessed sinus nodal parasympathetic denervation. Methods The study included 48 patients (age: 39 ± 13 years, 58% males) who underwent cardioneuroablation in general anaesthesia. The procedural endpoint was non-responsiveness (i.e. loss of original cardioinhibitory response) of the sinus node to extracardiac high-frequency stimulation of the vagal nerve. The magnitude of sinus rhythm acceleration was compared between patients who reached or did not reach this endpoint. Results All patients had positive atropine test (baseline heart rate: 65 ± 14 bpm; post-atropine: 109 ± 22 bpm). Complete sinus nodal denervation as assessed by vagal nerve stimulation was achieved in 44/48 (92%) patients. Intraprocedurally, heart rate accelerated from 54 ± 11 to 85 ± 14 bpm (difference: 31 ± 10; median 29; interquartile range: 24–40; total range: 13–61 bpm). This change did not correlate with age and was not related to pre-procedural post-atropine sinus rhythm acceleration. There was no difference in heart rate acceleration between the patient with and without sinus nodal denervation (Figure). Conclusions Sinus rhythm acceleration is not reliable endpoint for cardioneuroablation. Guidance by extracardiac vagal nerve stimulation may help to tailor the procedures to increase the clinical success rate and, at the same time, to avoid patient overtreatment. Abstract Figure.

DISTRIBUTION OF PDGFR+ CELLS AND INTERSTITIAL CELLS OF CAJAL IN THE HUMAN FETAL GUT

Two types of interstitial cells, interstitial cells of Cajal (ICC) and fibroblast-like cells, recently named platelet-derived growth factors receptor positive (PDGFRa+) cells, are present within the muscular layer of gastrointestinal (GI) tract. ICC and PDGFRa+ cells represent different classes of cells with unique ultrastructure, molecular phenotype and function, and they occupy the same anatomical niches in the GI tract. It is considered that PDGFRa+ cells such as ICC, mediate enteric inhibitory neurotransmission. Platelet-derived growth factors (PDGFs) are major mitogens for many cell types of mesenchymal origin, like fibroblasts and smooth muscle cells, and during embryogenesis, PDGF signaling is important in organogenesis. In the available literature, there is no data on the presence and distribution of PDGFRa immunoreactive cells in the human intestine during fetal period. The aim of this study was to identify PDGFRa immunoreactive cells in the gut of human fetuses, as well as to determine their distribution in relation to smooth muscle cells, ICC and enteric nerve structures. The material consisted of 12 Human Fetuses, gestational age from 10 to 12 weeks. The immunohistochemical test was carried out with the PDGFR-a antibody, ICC were identified using the C-kit antibody, while the muscle structures were demonstrated by the Desmin antibody. During the development of the human intestine, at week 11, PDGFRa immunoreactive cells are present within the circular muscle layer, while they are absent in the myenteric plexus region and in the parts below the serosa. Unlike them, ICC are present only around the inception of the myenteric plexus ganglia. In the fetal period of the human development, PDGFRa immunoreactive cells are present in all parts of the intestines, they are localized within the circular muscle layer and do not coincide with the ICC.

Clinical course of sinus node dysfunction after thoracoscopic surgery for atrial fibrillation\u2014analysis of the Atrial Fibrillation Ablation and Autonomic Modulation via Thoracoscopic Surgery (AFACT) study

PurposeSinus node dysfunction (SND) may complicate thoracoscopic surgical atrial fibrillation (AF) ablation. Identifying patients at risk is important, as SND may require temporary or permanent pacing. To determine the incidence of postoperative SND and duration of symptoms in patients who underwent thoracoscopic surgical ablation.MethodsPatients with paroxysmal or persistent AF included in the Atrial Fibrillation Ablation and Autonomic Modulation via Thoracoscopic Surgery (AFACT) study underwent pulmonary vein isolation and additional left atrial ablations on indication. Patients were randomized to ganglion plexus ablation or control. SND was defined as symptomatic or asymptomatic junctional rhythm exceeding sinus rate within 30 days postoperatively. The SND risk was assessed by using a univariable logistic regression model. The rate of pacemaker implantation was determined.ResultsThe AFACT study included 240 patients. SND developed in 17 (7.1%) patients, not affected by randomized treatment, p = 0.18. SND patients more often had persistent AF (88.2%) than patients without SND (57.4%), p = 0.01. After univariable testing, persistent AF (OR 5.57 CI 1.52–35.90, p = 0.02) and additional left atrial ablations (OR 12.10 CI 2.40–220.20, p = 0.02) were associated with postoperative SND. Six (35.3%) patients needed temporary pacing for 1–7 days; permanent pacemakers (PMs) were implanted for SND in five (29.4%) patients.ConclusionAdditional left atrial ablations strongly increase the SND risk. The majority of SND was temporary, and sinus rhythm resolved within days, which indicates that a conservative approach with regard to pacemaker implantation should be considered.

Исследование иннервации двенадцатиперстной кишки крысы с использованием нейральных иммуногистохимических маркеров

The purpose of the work is to study the topography, morphology, and mediator status of the nerve apparatus of the rat duodenum using immunohistochemical methods. The use of markers selective for the peripheral nervous system (PGP 9.5, synaptophysin (Syn), serotonin (5HT) and tyrosine hydroxylase (TH) made it possible to reveal in the tissues of the intestinal wall, in addition to the two main submucosal and myienteral ganglionic nerve plexuses), the third plexus is the mucous epithelium villous. Using comparative immunohistochemical analysis, it was found that most of the nerve structures (neurons, nerve fibers, interneuronal and neuromuscular synapses in the ganglion plexuses) are PGP 9.5-immunopositive and cholinergic. There are no catecholaminergic and serotonergic (5HT +) neurons in the studied ganglion plexuses. It is assumed that postganglionic sympathetic fibers enter the duodenum from the outside. They participate in the innervation of the muscle layers of the intestinal wall and arterial vessels, form pericellular synapses on the bodies and dendrites of parasympathetic neurons. A large number of terminal varicose axons were found in the connective tissue of the villi using PGP 9.5, and single bipolar neuron-like cells were found in the epithelium. Sympathetic elements in the villi were not identified. A reaction to serotonin revealed a large number of serotonin-containing cells that were morphologically similar to enterochromaffinocytes.

P179 Alterations of resting heart rate and heart rate viability after cryoballon ablation in the patients with paroxysmal atrial fibrillation

Abstract Background While it is generally accepted that cardiac autonomic nervous system (CANS) plays an important role in atrial fibrillation (AF) and pulmonary vein isolation (PVI) by radiofrequency catheter ablation modifies the ganglionated plexi (GP), the alterations of CANS after PVI are not clarified. Purpose The objective of this study was to investigate the alteration of CANS after conventional cryoballoon ablation (CBA) by using a non-invasive examination method of measuring resting heart rate (R-HR) and coefficient of variation of R-R interval (CVR-R) which is a representative parameter of heart rate viability. CVR-R reflects R-R interval variation affected by respiration. It is calculated from the R-R interval of consecutive 100 heart beats of sinus rhythm recorded at rest. Declines of CVR-R indicate the parasympathetic dysfunction and the normal range of it varies depend on the age. As age increases from 30s to 70s, the average value of CVR-R decreases from 4.0% to 2.4%. Methods Consecutive patients of paroxysmal AF treated with initial CBA in our institute participated. Subjects were limited to the patients who maintained sinus rhythm through the study and whose prescription had not been changed after procedure. All patients recorded 12-lead electrocardiogram to measure R-HR and CVR-R before and the day after the procedure. We compared R-HR and CVR-R of all patients before and after CBA. And in addition, we compared them in each of two groups whose pre-procedural H-RH were under 50 bpm (Group-U50) and over 70 bpm (Group-O70). All procedures were performed with second generation 28mm cryoballoon (CB)s under the conscious sedation with Dexmedetomidine. CB temperature was down to a minimum of -60°C and target application time was 180 seconds. Results In the procedure of all 105 patients (male gender, 54%; age, 66.9 ± 10.4years; CHADS2score, 1.15 ± 1.04; diabetes mellitus,14%; beta-blocker therapy, 16%), 1 of touch-up for PVI, 6 of supra vena cava isolation and 21 of cavotricuspid isthmus linear ablations with radiofrequency catheter were added. In all patients, R-HR increased from 58.9 ± 9.2bpm to 72.4 ± 9.5bpm (P &amp;lt; 0.01) and CVR-R decreased from 2.36 ± 1.08% to 1.24 ± 0.68% (P &amp;lt; 0.01), respectively. In Group-U50 (n = 14; male gender 64%; age 67.6 ± 12.4 years), R-HR increased from 47.1 ± 2.1bpm to 64.4 ± 7.9bpm (P &amp;lt; 0.01) and CVR-R decreased from 2.58 ± 1.59% to 1.34 ± 0.82% (P &amp;lt; 0.01), respectively. In Group-O70 (n = 17; male gender 43%; age 67.4 ± 12.6 years), R-HR increased from 73.7 ± 2.8bpm to 81.8 ± 7.4bpm (P &amp;lt; 0.01) and CVR-R decreased from 2.33 ± 0.94% to 1.14 ± 0.52% (P &amp;lt; 0.01), respectively. Values of CVR-R before and after CBA showed no significant difference between the two groups. Conclusions After CBA, R-HR increment and CVR-R decrement were significantly observed. CVR-R was halved regardless of pre–procedural R-HR. Damages to GP by CBA would be reflected as denervation of vagus nerves in CANS. R-HR increase might be associated with parasympathetic suppression of CANS.

Interactions between metabolism regulator adiponectin and intrinsic cardiac autonomic nervous system: A potential treatment target for atrial fibrillation

BackgroundPrevious studies indicated that inhibiting the cardiac autonomic nervous system (CANS) suppressed atrial fibrillation (AF). Clinical research revealed serum adiponectin (APN) exerted a beneficial influence on sympathetic and vagal tone in patients with type 2 diabetes. However, the effects of APN on CANS is unknown. This study aims to investigate whether APN could regulate CANS and suppress rapid atrial pacing (RAP)-induced AF. MethodsEighteen beagles were divided into the control group (saline plus sham RAP, N = 6), the RAP group (saline plus RAP, N = 6) and the APN + RAP group (APN plus RAP, N = 6). APN (10 μg, 0.1 μg/μL) or saline was microinjected into 4 major ganglionated plexi (GP) prior to RAP. Atrial electrophysiological parameters, anterior right GP (ARGP) function, neural activity and GP tissues were detected. ResultsCompared with the control treatment, RAP shortened effective refractory period (ERP) values at all sites and increased cumulative window of vulnerability (ΣWOV), ARGP function and neural activity, whereas APN injection reversed these changes. Mechanistically, APN ameliorated RAP-induced inflammatory response and down-regulated the expression of c-fos protein and nerve growth factor. Moreover, the APN receptors 1 and APN receptors 2 were detected both in neurons and in non-neuronal cells. APN pretreatment activated downstream adenosine monophosphate-activated protein kinase (AMPK) signaling, inhibited nuclear factor-kappa B signaling and promoted macrophage phenotype switching from proinflammatory to anti-inflammatory state. ConclusionsThis study demonstrates that administration of APN into GP can suppress RAP-induced AF by regulating the CANS. APN signaling may provide a potential therapeutic target to AF.

GRANULAR CELL TUMOR ASSOCIATED WITH SUBGEMMAL NEUROGENOUS PLAQUE—A CASE REPORT

This study reports the occurrence of a granular cell tumor (GCT) and a subgemmal neurogenous plaque (SNP) in the same anatomic location. A female white 59-year-old patient presented with an asymptomatic fibrous nodule located in the right posterior border of the tongue. A second, slightly erythematous, hyperplastic lesion behind the first one was identified. Both lesions were submitted for excisional biopsy. Histopathologic analysis revealed a GCT and an SNP. GCT is an uncommon, benign, soft tissue neoplasm. It presents as an asymptomatic fibrous submucosal nodule. The SNP is a biphasic structure found in the lateral posterior region of the tongue, characterized as nerve plexus aggregates and ganglion cells. The patient is under follow-up care and after 1 year, no relapses were observed. The authors believe that this is the first case showing the association between GCT and SNP.

Oral repeated-dose toxicity studies of BIA 10–2474 in cynomolgus monkeys

BIA 10–2474 (3-(1-(cyclohexyl(methyl)carbamoyl)-1H-imidazol-4-yl)pyridine 1-oxide) is a novel fatty acid amide hydrolase (FAAH) inhibitor developed by BIAL for the treatment of medical conditions which would benefit from enhanced levels of endogenous anandamide (AEA) such as pain disorders. During a Phase I clinical trial one subject died after receiving BIA 10–2474 and others displayed neurological signs. As part of series of papers presenting all the toxicology data available prior to the clinical trial we report here the nonclinical toxicology studies performed in cynomolgus monkeys.Maximum Tolerated Dose (MTD) studies and a preliminary 14-day study by oral (capsule) administration of BIA 10–2474 established a dose between 90 and 120 mg/kg/day as a suitable high dose for a subsequent regulatory toxicity studies. An up-titration scheme was used to achieve these doses. The dose-limiting effect was the early sacrifice for ethical reasons of monkeys at doses from 125 mg/kg/day upwards.Thereafter, regulatory 4- and 13-week oral gavage toxicity studies followed by a 2- or a 4-week recovery period, respectively, were performed. In both cases a 3-4-week up-titration period was used prior to repeat dosing with the target doses. One female was euthanized during the up-titration period after receiving 9 administrations of 75 mg/kg as a result of bleeding erosion on the feet and hands and ulceration on the tongue. These signs were not seen in any other monkeys during these studies. Doses of 10, 50 or 100 mg/kg/day were administered during the 4-week study and clinical signs related to the pharmacological action of BIA 10–2474 (e.g., tremors and weakness, incoordination and loss of balance, reduction in food intake and reduced body weight) were observed in several monkeys from the intermediate and high dose. Histological alterations consisted of axonal dystrophy in the fasciculus cuneatus (dorsal medulla oblongata) characterized by swollen axons and myelin sheath edema, edema in the pars nervosa of the pituitary gland and vacuolation of Meissner's plexus ganglia in all gastrointestinal segments. All lesions recovered and a dose of 100 mg/kg/day was considered to be the NOAEL.In the 13-week oral study the monkeys received BIA 10–2474 daily by gavage at a dose of 6.25, 37.5 or 75 mg/kg/day. Similar clinical signs and histological alterations as noted in monkeys of the 28-day study were observed in monkeys at 37.5 or 75 mg/kg/day. All findings recovered, and the dose of 75 mg/kg/day was considered the NOAEL.

Vagal responses during cardioneuroablation on different ganglionated plexi: Is there any role of ablation strategy?

BackgroundCardioneuroablation has been used to treat vagally mediated bradyarrhythmias (VMB). The aim of this study is to assess vagal response (VR) characteristics during radiofrequency catheter ablation (RFCA) with different ganglionated plexus (GP) order. MethodsA total of 49 consecutive patients with VMB who underwent cardioneuroablation were enrolled. GPs were identified by electroanatomic-mapping-guided strategy. After all GP targets have been identified, patients were divided into 2 groups according to GP ablation strategy. In the left side first group, ablation order of GPs were left superior GP (LSGP), left inferior GP (LIGP), right superior GP (RSGP), and right inferior GP (RIGP). In the right side first group, ablation order was RSGP, RIGP, LSGP, and LIGP. ResultsIn the left side first group, LSGP was the most common GP site at which a VR was observed (36 of 40 cases, 90%). LIGP causes a VR in 9 of 40 (22.5%) cases. In the right side first group, VR was seen only 2 of 9 (22.2%) cases. Comparison of ablation strategy demonstrated a significant difference in VR during ablation on LSGP between groups. Despite, LSGP was the most common GP site at which a VR was observed both groups (90% in left side first group vs 11.1% in right side first group, p < 0.0001). In remaining GPs, VRs were not dependent on the ablation strategy and were not statistically different between groups. ConclusionThe present study demonstrates that the characteristics of VR during RFCA might change according to ablation order of GPs.

Different effects of additional ganglion plexus ablation on catheter and surgical ablation for atrial fibrillation: a systemic review and meta-analysis.

The effect of ganglion plexus (GP) ablation in addition to pulmonary veins isolation (PVI) for atrial fibrillation (AF) remained controversial between the catheter and surgical-based studies. Eleven studies (five randomized controlled trials and six nonrandomized studies) of 1750 patients were included in a meta-analysis to elucidate the incremental benefit of additional GP ablation in patients undergoing catheter or surgical ablation. Risk ratios were calculated for freedom from AF or AT recurrence after a single procedure. Additional GP ablation was associated with a better rhythm outcome for patients undergone catheter ablation but did not seem to increase freedom from AF/AT for surgical patients. Both paroxysmal and non-paroxysmal AF showed a positive outcome comparing additional GP ablation with PVI alone.

Standardized Quantification of Vagal Denervation by Extracardiac Vagal Stimulation during Second Generation Cryoballoon ablation: a Vein per Vein Analysis.

The purpose of this study was to evaluate the contribution in the acute loss in vagal innervation after ablation with the second generation cryoballoon (CB-A) in each distinct pulmonary vein (PV) by means of external cardiac vagal stimulation (ECVS) by positioning a catheter in the internal jugular vein in a cohort of 60 patients. Sixty patients, 50 starting from the left superior pulmonary vein (LSPV) and 10 from the right superior pulmonary vein with symptomatic paroxysmal atrial fibrillation (PAF), having undergone ECVS before the first and after each PV ablation by means of CB-A ablation, were included. The ECVS performed pre-ablation provoked cardioinhibitory responses in all cases with mean pause duration of 10251.83 ms ± 2826.23 ms. At the end of the procedure, the vagal reactions (VR) were significantly diminished. Specifically, compared against the initial pause, responses were 8957.06 ± 2711.66 ms (p < 0.01) after left superior PV, 10017.36 ± 9127.0 ms (p = 0.88) after left inferior PV, 6020.16 ± 3780.709 ms (p < 0.001) after right inferior PV and 1687.5 ± 2183.7 ms (p < 0.001) after right superior PV. Noteworthy, if starting with ablation in the RSPV, VR was immediately reduced by 90.34%, 990.7 ± 379.78 ms (p < 0.001) as compared to baseline response. Although not directly targeting the ganglion plexuses, AF ablation with the CB-A causes a significant acute loss in parasympathetic innervation. The RSPV showed to be associated with the most significant reduction of acute loss in parasympathetic innervation.

Heart rate variability in atrial fibrillation: The balance between sympathetic and parasympathetic nervous system.

Atrial fibrillation (AF) is the commonest abnormal heart rhythm with significant related morbidity and mortality. Several pathophysiologic mechanisms have been advocated to explain the onset of AF. There has been increasing evidence that abnormalities of the autonomic nervous system (ANS) that includes sympathetic, parasympathetic and intrinsic neural network are involved in the pathogenesis of AF. This review will consider the anatomical and pathophysiological concepts of the cardiac neuronal network and discuss how it can be investigated. Relevant articles for this review were selected primarily from Ovid Medline and Embase databases (see appendix). We searched for key terms "atrial fibrillation," "AF," "autonomic dysfunction," "autonomic nervous system," "heart rate variability" and "HRV" to gather relevant studies. Duplicate papers were excluded. Heart is richly innervated by autonomic nerves. Both sympathetic and parasympathetic systems interact in developing AF along with cardiac ganglionated plexi (GP). Thus autonomic dysfunction is present in AF. There are methods including selective ablation that reduce autonomic innervation and show to reduce the incidence of spontaneous or induced atrial arrhythmias. Heart rate variability (HRV) is a useful tool to assess sympathetic and parasympathetic influences on disease states. HRV can be improved following intervention and is thus a useful application in assessing autonomic dysfunction in patients with AF. ANS plays a crucial role in the development, propagation and complexity of AF. Assessment of the autonomic involvement in the propagation of AF may help in explaining why certain patients with AF do not benefit from cardioversion or ablation.

P3752Ablation of the superior left ganglionic plexus is not necessary for effective denervation of the sinoatrial and atrioventricular nodes

Abstract Background Cardioneuroablation by targeting of atrial ganglionic plexi (GP) has been proposed as a new therapeutic option in selected patients with reflex syncope. Contribution of individual GPs to cardiac autonomic regulations is not fully established. Purpose Because consistent vagal responses have been observed during left superior pulmonary vein isolation in patients undergoing ablation for atrial fibrillation, we investigated whether standalone ablation of the superior left GP modifies the vagal input into the sinoatrial (SAN) and atrioventricular node (AVN). Methods Study hypothesis was investigated in otherwise healthy patients undergoing cardioneuroablation for symptomatic bradyarrhythmias. All had preprocedural atropine test suggesting functional disorder. Anatomically-navigated (CARTO-3) radiofrequency (RF) ablation (25–30 W/30 s/20 ml/min) at empirical GP sites was performed in general anaesthesia. Extracardiac high-frequency vagal nerve stimulation (25–60 V/30–50 Hz/0.05–0.1 ms) via right jugular vein was performed at baseline, after initial superior left GP ablation, and after the ablation of remaining septal and inferior GPs. High-frequency vagal nerve stimulation was always done in both sinus rhythm and atrial pacing. The elimination of all stimulation-induced vagal responses was the endpoint of the procedure. Results A study included 8 patients (34±8 years; 5 males). Six of them had recurrent syncope with cardioinhibitory response at the SAN (n=4), AVN (n=1) or both nodes (n=1); and 2 patients had symptomatic sinus bradycardia. At baseline, high-frequency vagal nerve stimulation induced long episodes of sinus arrest and advanced AV block in all patients. Cluster ablation at the superior left GP (RF time: 192±28 s) did not change the sinus rate (59±14 vs 60±15, NS), PQ interval (174±37 vs 173±37, NS), and did not induce any tangible change in SAN/AVN response to high-frequency vagal nerve stimulation. Subsequently, anterior right GP was targeted from the aspect of right atrium (n=7), from the anterior antrum of right pulmonary veins (n=6), and inferior GPs were targeted from the aspect of left atrium (n=7). This lesion set finally resulted in complete non-responsiveness of SAN and AVN to high-frequency vagal nerve stimulation in all patients. Ablation procedure overall (duration: 172±15 min; RF time: 988±306 s; radiation dose: 70±34 μGy·m2) led to sinus rate acceleration by a median of 29 (IQR: 18–38) bpm, increase of Wenckebach point by 21 (IQR: 9–28) bpm, and shortening of AVN effective refractory period by 40 (IQR: 15–73) ms. Conclusions Cardioneuroablation guided by extracardiac high-frequency vagal nerve stimulation can achieve complete denervation of SAN and AVN by ablation of postero(para)septal and inferior GPs only. Ablation of the superior left GP appears unnecessary and can be eliminated from the lesion set design.

3055Interactions between metabolism regulator adiponectin and intrinsic cardiac autonomic nervous system: a potential treatment target for atrial fibrillation

Abstract Background Previous studies indicated that inhibiting the cardiac autonomic nervous system (CANS) suppressed atrial fibrillation (AF). Clinical research revealed that high levels of serum adiponectin (APN) could exert a beneficial influence on sympathetic and vagal tone in patients with type 2 diabetes. The aim of this study was to elucidate whether APN could regulate CANS and subsequently suppress rapid atrial pacing (RAP)-induced AF. Methods Eighteen anesthetized male beagles were randomly divided into three groups: the control group (saline plus sham RAP, N=6), the RAP group (saline plus 3 h RAP, N=6) and the APN + RAP group (APN plus 3 h RAP, N=6). Multielectrode catheters were attached to all atria and pulmonary veins. After bilateral thoracotomy, APN (10 μg, 0.1 μg/μL) or saline was microinjected into 4 fat pads, each containing one of the major atrial ganglionated plexi (GP), prior to RAP. Electrophysiological parameters including atrial effective refractory period (ERP), cumulative window of vulnerability (ΣWOV), anterior right GP (ARGP) function and neural activity were measured at baseline and 3 h after pacing. The fat pads containing the GP were excised for molecular biological testing and pathological staining at the end of the protocol. Results Compared with the control treatment, RAP markedly shortened ERP values at all tested sites and increased ΣWOV, ARGP function and neural activity, whereas APN injection into the GP reversed these changes. Mechanistically, APN treatment ameliorated the increased inflammatory response induced by RAP. In addition, the APN receptors AdipoR1 and AdipoR2 were detected both in neurons and in non-neuronal cells. Downstream of the AdipoRs, AMPK signaling was significantly activated and NF-κB signaling was significantly inhibited. More importantly, binding between APN and AdipoRs promoted macrophage phenotype switching from proinflammatory to anti-inflammatory. Figures Conclusion This study demonstrates that local administration of APN into atrial GP suppress RAP-induced AF by regulating the activity of the CANS. AMPK activation and macrophage phenotype switching may contribute to the attenuation of GP inflammation after APN injection. Therefore, APN signaling may provide a potential therapeutic target to AF.