Vagal Denervation Research Articles

Targets and End Points in Cardiac Autonomic Denervation Procedures.

Autonomic denervation is an alternative approach for patients with symptomatic bradycardia. No consensus exists on the critical targets and end points of the procedure. The aim of this study was to identify immediate end points and critical atrial regions responsible for vagal denervation. We enrolled 14 patients (50% men; age: 34.0±13.8 years) with cardioinhibitory syncope, advanced atrioventricular block or sinus arrest, and no structural heart disease. Anatomic mapping of ganglionated plexuses was performed, followed by radiofrequency ablation. Heart rate, sinus node recovery time, Wenckebach cycle length, and atrial-His (AH) interval were measured before and after every radiofrequency pulse. Wilcoxon signed-rank test was used for comparison. Significant shortening of the R-R interval (P=0.0009), Wenckebach cycle length (P=0.0009), and AH intervals (P=0.0014) was observed after ablation. The heart rate elevation was 23.8±12.5%, and the Wenckebach cycle length and AH interval shortening was 18.1±11% and 24.6±19%, respectively. Atropine bolus injection (0.04 mg/kg) did not increase heart rate further. Targeting a single spot of the left side (64% of the patients) or right side (36%) of the interatrial septum was observed to be responsible for ≥80% of the final R-R and AH interval shortening during ablation. Targeting specific sites of the interatrial septum is followed by an increase in heart rate and atrioventricular nodal conduction properties and might be critical for vagal attenuation. The R-R interval, Wenckebach cycle length, and AH interval shortening, associated with a negative response to atropine, could be considered immediate end points of the procedure.

Vagal denervation in atrial fibrillation ablation: A comprehensive review

Although pulmonary vein isolation is accepted as an established interventional treatment in paroxysmal atrial fibrillation (AF), alternative modalities are being investigated because of the high recurrence rates of nonparoxysmal forms. One of the alternative ablation approaches is ablation or modification of vagal ganglionated plexi (VGP). The technique has not only been used in vagally mediated AF but also investigated in paroxysmal and nonparoxysmal AF. Clinical studies demonstrate significant discrepancy related with detection of VGP sites or ablation targets and definition of procedurel end-points, so far. In this review, we aimed to discuss the current data on the role of VGP in the pathogenesis of AF and potential therapeutic implications of ablation of these ganglia.

Peripheral apelin-13 administration inhibits gastrointestinal motor functions in rats: The role of cholecystokinin through CCK1 receptor-mediated pathway

Apelin is the endogenous ligand of the G protein-coupled receptor APJ. The APJ receptor is widely expressed in gastrointestinal (GI) tissues including stomach and small intestine. Apelin administration was shown to induce the release of cholecystokinin (CCK) which is a well-known alimentary hormone with its inhibitory actions on GI motor functions through CCK1 receptors on vagal afferent fibers. We investigated whether; (i) peripherally injected apelin-13 alters GI motor functions, (ii) apelin-induced changes are mediated by APJ receptor or CCK1 receptor and (iii) vagal afferents are involved in inhibitory effects of apelin. Solid gastric emptying (GE) and colon transit (CT) were measured, whereas duodenal phase III-like contractions were recorded in rats administered with apelin-13 (300μg/kg, ip). CCK1 receptor antagonist lorglumide (10mg/kg, ip) or APJ receptor antagonist F13A (300μg/kg, ip) was administered 30min prior to the apelin-13 injections. Vagal afferent denervation was achieved by systemic administration of vanilloid receptor agonist capsaicin (125mg/kg, sc). Apelin-13 administration significantly (p<0.01) increased the CCK level in portal venous plasma samples. Compared with vehicle-treated rats, apelin-13 significantly delayed both GE (p<0.001) and CT (p<0.01). Pretreatment of lorglumide or F13A completely abolished the apelin-13-induced inhibitory effects on GE and CT, moreover, apelin-13 was found ineffective in rats underwent afferent denervation. F13A administration alone significantly accelerated the basal CT. Apelin-13 noticeably disturbed the duodenal fasting motor pattern by impairing phase III-like contractions while increasing the amplitudes of phase II contractions which were prevented by pretreatment of lorglumide and capsaicin. Compared with vehicle-treated rats, lorglumide and capsaicin significantly (p<0.05) reduced the apelin-13-induced increases in phase II motility index. Peripherally administered apelin-13 inhibits GI motor functions through CCK-dependent pathway which appears to be mediated by CCK1 receptors on vagal afferents. Peripheral apelin might contribute to the motility changes occurred in postprandial period.

Serum Leptin, Obestatin, and Ghrelin Levels and Gastric Emptying Rates of Liquid and Solid Meals in Non-obese Rats with Roux-en-Y Bypass Surgery or Prosthesis Placement: Implications for the Role of Vagal Afferents.

The present study aimed to investigate the effects of Roux-en-Y gastric bypass (RYGB) and prosthesis placement on gastric emptying rate in conjunction with serum ghrelin-obestatin-leptin responses in non-obese rats with intact or denervated afferent innervation. Under anesthesia, male Sprague-Dawley rats underwent either sham operation, RYGB, prosthesis, and/or Gregory cannula placement. Three weeks later, liquid or solid gastric emptying tests were performed and serum ghrelin, leptin and obestatin levels were measured. Both prosthesis placement and RYGB surgery delayed non-nutrient liquid emptying; while solid nutrient emptying was delayed only by RYGB. Nutrient-dependent (acid, hyperosmolal and peptone) delay in liquid emptying was abolished in rats with prosthesis. By vagal afferent denervation, delayed liquid emptying was abolished, while solid emptying was further delayed in rats with prosthesis. Ghrelin and obestatin levels were depressed in prosthesis-placed rats, but RYGB surgery had no impact on both levels. Leptin level was elevated in solid-food-given rats with prosthesis, but not changed in RYGB group, while it was reduced following liquid meal. All the changes observed in ghrelin, obestatin, or leptin levels in response to meal ingestion were reversed with vagal afferent denervation. Both RYGB and prosthesis placement had delaying effects on gastric emptying rate of non-obese rats. Our results indicate that the short-term changes in gastric motility and hormone responses induced by volume reduction are reversed by afferent denervation, suggesting that sparing the vagal innervation could be essential for reaching optimum motility and hormone changes expected after bariatric surgery.

Hypothalamic kappa opioid receptor mediates both diet-induced and melanin concentrating hormone-induced liver damage through inflammation and endoplasmic reticulum stress.

The opioid system is widely known to modulate the brain reward system and thus affect the behavior of humans and other animals, including feeding. We hypothesized that the hypothalamic opioid system might also control energy metabolism in peripheral tissues. Mice lacking the kappa opioid receptor (κOR) and adenoviral vectors overexpressing or silencing κOR were stereotaxically delivered in the lateral hypothalamic area (LHA) of rats. Vagal denervation was performed to assess its effect on liver metabolism. Endoplasmic reticulum (ER) stress was inhibited by pharmacological (tauroursodeoxycholic acid) and genetic (overexpression of the chaperone glucose‐regulated protein 78 kDa) approaches. The peripheral effects on lipid metabolism were assessed by histological techniques and western blot. We show that in the LHA κOR directly controls hepatic lipid metabolism through the parasympathetic nervous system, independent of changes in food intake and body weight. κOR colocalizes with melanin concentrating hormone receptor 1 (MCH‐R1) in the LHA, and genetic disruption of κOR reduced melanin concentrating hormone–induced liver steatosis. The functional relevance of these findings was given by the fact that silencing of κOR in the LHA attenuated both methionine choline–deficient, diet‐induced and choline‐deficient, high‐fat diet–induced ER stress, inflammation, steatohepatitis, and fibrosis, whereas overexpression of κOR in this area promoted liver steatosis. Overexpression of glucose‐regulated protein 78 kDa in the liver abolished hypothalamic κOR‐induced steatosis by reducing hepatic ER stress. Conclusions: This study reveals a novel hypothalamic–parasympathetic circuit modulating hepatic function through inflammation and ER stress independent of changes in food intake or body weight; these findings might have implications for the clinical use of opioid receptor antagonists. (Hepatology 2016;64:1086‐1104)

Effect of vagotomy on the activity of cardiac autonomic ganglia: Insight from left atrial high density frequency mapping

BackgroundBoth extrinsic and intrinsic cardiac autonomic nervous systems are important for initiation and maintenance of atrial fibrillation (AF). We aimed to evaluate the effect of vagotomy on the activity of cardiac autonomic ganglionated plexi (GP) and the change of dominant frequency (DF) distribution in the left atrium (LA) during AF. MethodsA mid-sternal thoracotomy was performed in 6 dogs. High frequency stimulation was applied to locate the GPs. There were four major LA GPs, which were located near the pulmonary vein ostia, and a superior vena cava-aorta (SVC-Ao) GP that was located near the superior vena cava-right atrial junction. Acetylcholine patch was applied on GPs to induce intrinsic vagal response. Vagal denervation was performed thereafter. An Ensite Array was deployed in the LA to record atrial signals before and after vagotomy during induced AF. ResultsThe LA mean DF values (8.2±0.1 vs. 7.6±0.1Hz, p=0.002) were higher during GP activation before than after vagotomy. The maximal DF distribution was located at the primary GPs and the nearby secondary GPs during LA GPs activation and at the LA septum and right superior pulmonary vein during SVC-Ao GP activation before vagotomy. After vagotomy, the maximal DF distribution shifted to non-GP LA sites during activation of the GPs. ConclusionsThe findings suggest the important role of the extrinsic neural input in the activation and interaction of the intrinsic cardiac autonomic activity during cholinergic AF, whereas the non-GP LA sites were responsible for the AF induced without the physiological extrinsic neural input.

Cardioneuroablation in the treatment of neurally mediated reflex syncope: a review of the current literature.

An imbalance between parasympathetic and sympathetic tone is a main cause of neurally mediated reflex syncope (NMRS). These patients may be very symptomatic and the condition may require cardiac pacemaker implantation. Cardioneuroablation (CNA) is a relatively novel technique based on radiofrequency ablation of vagal ganglia that can be used in treatment of NMRS. The aim of this analysis was to compare potential role of CNA in patients with NMRS. In accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses Statement, literature search was conducted using the keywords "cardioneuroablation," "vagal denervation," "reflex syncope," "vagal ablation," and "ganglionic plexi ablation." Retrieved citations were first screened independently by 2 reviewers for inclusion and exclusion criteria. Freedom from syncope and freedom from prodrome were 100% and between 50% and 100%, respectively, in the studies. Ablation was performed via both atria in 3 studies; only left atrial approach was used in the remaining studies. There was no major complication related to the procedure reported. Focused or extensive vagal ganglia ablation may be a potential alternative to pacemaker implantation in a carefully selected patient population. In contrast to pharmacological therapy and pacemaker implantation, ganglia ablation is designed to get to the root of the problem: disturbances in the intrinsic cardiac autonomic nervous system. This novel technique should be evaluated in large-scale, randomized, controlled trials.

Hereditary transthyretine amyloidosis in Slovenia

The prevalence of transthyretin (TTR) amyloidosis in Europe is supposed to be less than one per 100,000 individuals. Slovenia is a rather small country with approximately two million inhabitants and we know of two families with 4 patients with this disease. The first patient (family A) was diagnosed in 2008 when also one of the asymptomatic family members who agreed to molecular genetic testing was found to be a carrier. Other family members up to now disagreed with clinical, laboratory and molecular genetic testing. Patients from family B were diagnosed in 2014. Their siblings were found not to be carriers. The index case from family A was diagnosed at the age of 54. The TTR gene mutation was characterised as Val122Ala. First symptoms were due to dysautonomia and appeared 4 years earlier in the form of abdominal colic associated with vomiting and orthostatic hypotension. He also had symptoms and signs of length-dependent axonal polyneuropathy and hypertrophic restrictive cardiomyopathy. He died the day after liver transplantation. The disease of the family's B index case started approximately one and a half year before the diagnosis with pain in his feet, orthostatic hypotension, sexual impotence, diarrhoea alternating with constipation, and weight loss. Later on he also noticed weakness in his lower limbs but is still able to walk unaided. The Val30Ala mutation was found. Except to polyneuropathy no other organs are affected. He is treated with tafamidis. His sister is asymptomatic but is having electrophysiological signs of polyneuropathy and cardiac vagal denervation. She recently also started taking tafamidis. With increasing awareness of the transthyretin amyloidosis, especially amongst neurologists and cardiologists in our country, we expect to find some more patients in the near future, particularly among members of the affected families. Two other unrelated patients are currently undergoing testing, one of them with transthyretin amyloid tissue deposits.

Simplified Method for Vagal Effect Evaluation in Cardiac Ablation and Electrophysiological Procedures

ObjectivesThe aim of this study is to show a simplified reversible approach to investigate and confirm vagal denervation at any time during the ablation procedure without autonomic residual effect. BackgroundParasympathetic denervation has been increasingly applied in ablation procedures such as in vagal-related atrial fibrillation and cardioneuroablation. This method proposes an easy way to study the vagal effect and to confirm its elimination following parasympathetic denervation through vagal stimulation (VS) by an electrophysiological catheter placed in the internal jugular vein. MethodsA prospective controlled study including 64 patients without significant cardiopathy (48 male [75.0%], age 46.4 ± 16.4 years) who had a well-defined RF ablation indication for symptomatic arrhythmias, comprising a “denervation group” (DG), with indication for ablation with parasympathetic denervation (vagal-related atrial fibrillation or severe cardioinhibitory syncope) and a “control group” (CG), with ablation indication without parasympathetic denervation (accessory pathway or ventricular arrhythmia). By using a neurostimulator, both groups underwent non simultaneous bilateral VS (8 to 12 s, frequency: 30 Hz, pulse width: 50 μs, amplitude: 0.5 to 1 V/kg up to 70 V) through the internal jugular vein pre- and post-ablation. ResultsSignificant cardioinhibition was achieved pre-ablation in all cases (pause of 11.5 ± 1.9 s in DG vs. 11.4 ± 2.1 s in CG; p = 0.79). Eight patients (12.5%) presented catheter progression difficulty in 1 jugular vein (2 right, 6 left); however, the contralateral VS was adequate for cardioinhibition. After ablation, the cardioinhibition was reproduced only in CG (pause of 11.2 ± 2.2 s) as in DG it was entirely eliminated. There was no significant difference between pre- and post-ablation cardioinhibition in CG (p = 0.84). There was no complication (follow-up 8.8 ± 5 months). ConclusionsThe vagal stimulation was feasible, easy, and reliable, and showed no complications. It may be repeated during the procedure to control the denervation degree without residual effect. It could be a suitable tool for vagal denervation confirmation or autonomic tests during electrophysiological studies. Ablation without parasympathetic denervation did not change the vagal response.

Persistent atrial fibrillation after radiofrequency ablation: considerations in treating rheumatic mitral valve disease patients

Atrial fibrillation (AF) in patients with rheumatic heart disease (RHD) results from hemodynamic consequences of valvular or myocardial heart disease and from direct tissue injury of the atrial myocardium by the underlying inflammatory process [1]. About 60% of patients with rheumatic valve disease develop AF. Several studies have clearly demonstrated a low probability of sinus rhythm recovery in patients with preoperative AF undergoing valve surgery for RHD [2,3]. Atrial fibrillation persistence is associated with worse clinical outcomes that include functional status, exercise capacity, quality of life and overall survival. A retrospective analysis was performed on a total of 793 patients who underwent mitral valve replacement with or without tricuspid valve repair [4]. At a mean follow-up of 8.6 ± 2.4 years of patients with preoperative AF, survival was 88.7%, compared with 96.6% in patients with preoperative sinus rhythm (p = 0.002). Several technical approaches and different energy sources have been employed to restore sinus rhythm in patients undergoing valve surgery. The proper way to verify success after an AF ablation procedure is controversial; continuous rhythm monitoring should be the gold standard of follow-up, but very few studies use it, thus results reported in literature are not easily comparable. It is conceivable that in patients followed with periodic ECG evaluation asymptomatic AF recurrences may occur, thus the true effectiveness might remain unknown. The surgical results of the maze procedure for AF associated with rheumatic mitral valve disease have been known to be less effective than for lone or nonrheumatic AF [5]. Preoperative patients characteristics (age, NYHA functional class at the time of surgery, type of prosthetic valve, proportion of paroxysmal and persistent AF, duration of the arrhythmia), concomitant surgical procedures (including vagal denervation) other than the modalities of success rate evaluation at followup, may explain the large variability (55–80%) of results reported in literature [6–9]. In a recent paper, our group demonstrated in patients undergoing radiofrequency (RF) ablation associated with mitral valve surgery that an increased left atrial area (HR: 1.07 per unit increase; 95% CI: 1.01–1.13) and rheumatic etiology of valve disease (HR: 4.52; 95% CI: 1.65–12.4) were significantly associated with the risk of persistence of AF at hospital discharge [10]. Less than 20% with atrial diameter greater than 55 mm and rheumatic mitral disease recovered sinus rhythm. At 6-year follow-up persistent sinus rhythm (SR) and overall survival in patients with rheumatic mitral valve disease in comparison with degenerative mitral (mitral valve prolapse) who underwent RF ablation and valve surgery were, respectively, 58 and 64%, and 84 and 90%. Persistent atrial fibrillation after radiofrequency ablation: considerations in treating rheumatic mitral valve disease patients

Estradiol alters the chemosensitive cardiac afferent reflex in female rats by augmenting sympathoinhibition and attenuating sympathoexcitation.

The chemosensitive cardiac vagal and sympathetic afferent reflexes are implicated in driving pathophysiological changes in sympathetic nerve activity (SNA) in cardiovascular disease states. This study investigated the impact of sex and ovarian hormones on the chemosensitive cardiac afferent reflex. Experiments were performed in anaesthetized, sinoaortic baroreceptor denervated male, female and ovariectomized female (OVX) Wistar rats with either intact cardiac innervation or bilateral vagotomy. To investigate the chemosensitive cardiac afferent reflexes renal SNA, heart rate (HR) and arterial pressure (AP) were recorded before and following application of capsaicin onto the epicardial surface of the left ventricle. Compared to males, ovary-intact females displayed similar cardiac afferent reflex mediated changes in renal SNA albeit with a reduced maximum sympathetic reflex driven increase in renal SNA. In females, ovariectomy significantly attenuated the cardiac vagal afferent reflex mediated inhibition of renal SNA (renal SNA decreased 2 ± 17% in OVX versus -50 ± 4% in ovary-intact females, P < 0.05) and augmented cardiac sympathetic afferent reflex mediated sympathoexcitation (renal SNA increased 91 ± 11% in OVX vs 62 ± 9% in ovary-intact females, P < 0.05) so that overall increases in reflex driven sympathoexcitation were significantly enhanced. Chronic estradiol replacement, but not progesterone replacement, begun at time of ovariectomy restored cardiac afferent reflex responses to be similar as ovary-intact females. Vagal denervation eliminated all group differences. The current findings show ovariectomy in female rats, mimicking menopause in women, results in greater chemosensitive cardiac afferent reflex driven sympathoexcitation and does so, at least partly, via the loss of estradiols actions on the cardiac vagal afferent reflex pathway.

The midterm results of radiofrequency ablation and vagal denervation in the surgical treatment of long-standing atrial fibrillation associated with rheumatic heart disease.

Though maze III procedure is an effective surgical treatment for atrial fibrillation (AF), the complexity and complications prevent its widespread application. Radiofrequency ablation (RA) has become an accepted therapy, but its chronic effects are still unclear. This retrospective clinical study describes our experience of RA and vagal denervation (VD) in surgical treatment of long-standing AF associated with rheumatic heart disease (RHD) during a 5-year follow-up. Between June 2006 and December 2007, a total of 173 consecutive patients with long-standing AF-associated RHD underwent mitral valve replacement and ablation maze procedure. In total, 92 cases had RA alone and 81 had RA + VD. Patients were followed up with clinical examination and electrocardiography, and the data were analyzed by multivariable analysis with Cox hazard model. The average follow-up time was 5.0 ± 0.6 years. Multivariable analysis with Cox hazard model revealed that the duration of AF, the size of the left atrium, and tricuspid regurgitation are risk factors for AF recurrence. In addition, long-standing AF ≥ 7 years, left atrium diameter ≥ 58 mm, and severe tricuspid regurgitation may increase the risk of AF recurrence by 2.16-, 2.37-, and 2.67-fold, respectively. Although the freedom from AF during 2 to 5 postoperative years in the RA and RA + VD groups were similar, the percentage of antiarrhythmic drug therapy was higher in the RA group during the early postoperative period (4th month, 54.1 vs. 34.7%, p = 0.017; 5th month, 39.2 vs. 21.3%, p = 0.018; 6th month, 23.0 vs. 10.7%, p = 0.044). Furthermore, the percentage of those free from AF was lower during the 1st year (6th month, 82.2 vs 93.8%, p = 0.023; 1st year, 76.1 vs. 89.9%, p = 0.019). RA is effective for the surgical treatment of long-standing AF associated with rheumatic valve disease. Though vagal denervation helped to maintain a stable sinus rhythm at an early stage, there was no additional benefit after the 1st year of follow-up.

Role of OCT in a case of VF arrest

Myocardial reperfusion injury can be ameliorated by prior transient limb ischaemia, which induces remote ischaemic preconditioning (RIPC) and contributes to reduced infarct size. The mechanisms by which RIPC causes cardioprotection are unclear, but likely involve neural and/or humoral mechanisms. The aim of this study was to determine the role of vagal innervation in the cardioprotective effect of RIPC. Anaesthetised sheep were randomly allocated into 4 groups, (1) Sham conditioning (n=6), (2) RIPC (n=6), 3) Proximal vagal denervation + RIPC (n=6) and (4) Distal vagal denervation + RIPC (n=6). RIPC involved 3x5 min occlusions of the iliac artery. Subsequently, the animalsunderwent 1h coronary ischaemia followed by 3h reperfusion. Haemodynamic parameters were measured throughout the protocol. At the end of 3h of reperfusion the heartwas excised and infarct size was measured. There were no clinically relevant significant differences in haemodynamic parameters among the 4 treatment groups. Compared with Sham animals, RIPC significantly reduced infarct size following IR (infarct size/area-at-risk, 82±5% vs. 49±7%, respectively, P<0.05). Distal vagotomy enhanced RIPC protection (31±7% infarct size) compared with proximal denervation (69 ±8% infarct size, P<0.05). These data confirm the potential clinical benefits of limb RIPC against myocardial IR injury. Furthermore, they indicate that bilateral resection of the vagus nerves distal to theheart enhanced thecardioprotectiveeffect ofRIPC against reperfusion injury. This finding adds complexity to previous studies indicating that parasympathetic blockade with ganglion blockers inhibited the cardioprotective effect of RIPC against reperfusion injury.

Evidence for a carotid body homolog in the lizard Tupinambis merianae.

The homolog to the mammalian carotid body has not yet been identified in lizards. Observational studies and evolutionary history provide indirect evidence for the existence of a chemoreceptor population at the first major bifurcation of the common carotid artery in lizards, but a chemoreceptive role for this area has not yet been definitively demonstrated. We explored this possibility by measuring changes in cardiorespiratory variables in response to focal arterial injections of the hypoxia mimic sodium cyanide (NaCN) into the carotid artery of 12 unanesthetized specimens of Tupinambis merianae. These injections elicited increases in heart rate (f(H); 101±35% increase) and respiratory rate (f(R); 620±119% increase), but not mean arterial blood pressure (MAP). These responses were eliminated by vagal denervation. Similar responses were elicited by injections of the neurotransmitters acetylcholine (ACh) and serotonin (5-HT) but not norepinephrine. Heart rate and respiratory rate increases in response to NaCN could be blocked or reduced by antagonists to ACh (atropine) and/or 5-HT (methysergide). Finally, using immunohistochemistry, we demonstrate the presence of putative chemoreceptive cells immunopositive for the cholinergic cell marker vesicular ACh transporter (VAChT) and 5-HT on internal lattice-like structures at the carotid bifurcation. These results provide evidence in lizards for the existence of dispersed chemoreceptor cells at the first carotid bifurcation in the central cardiovascular area that have similar properties to known carotid body homologs, adding to the picture of chemoreceptor evolution in vertebrates.

Circumferential ablation of pulmonary vein ostium combined with vagal denervation for the treatment of atrial fibrillation: a clinical study

Circumferential ablation of pulmonary vein ostium combined with vagal denervation for the treatment of atrial fibrillation: a clinical study

Heart Rate Variability and Procedural Outcome in Catheter Ablation for Atrial Fibrillation

In patients with normal hearts, increased vagal tone is associated with onset of paroxysmal atrial fibrillation (AF). Vagal denervation of the atria renders AF less inducible. Circumferential pulmonary vein isolation (CPVI) is effective for treating paroxysmal and persistent AF, and has been shown to impact heart rate variability (HRV) indices, in turn, reflecting vagal denervation. We examined the impact of CPVI on HRV indices, and evaluated the relationship between vagal modification and AF recurrence. Electrocardiogram recordings were collected from 83 consecutive patients (63 male, 20 female, age 56.9 ± 9.3 years) undergoing CPVI for paroxysmal (n = 56) or persistent (n = 27) AF. Recordings were obtained over 10 minutes preprocedure, and at intervals up to 12 months. Antiarrhythmic medications were suspended prior to CPVI, and were resumed for 3 months following. Success was defined as no recurrence of atrial arrhythmia lasting longer than 30 seconds. In patients with successful procedures (n = 56, 42 paroxysmal, 14 persistent), HRV indices were significantly altered, with respect to preprocedure levels, over a sustained period. However, patients with recurrence (n = 27, 14 paroxysmal, 13 persistent) demonstrated similar HRV to their preprocedure levels over the follow-up period. Our results suggest that patients experiencing recurrence after a single CPVI have HRV attenuated by the procedure only intermittently, whereas patients with one successful CPVI experience a sustained change. A short-term HRV recording is a convenient and potentially important marker for recurrence of atrial arrhythmia in a population undergoing CPVI.

Elimination of non-pulmonary vein ectopy by ethanol infusion in the vein of Marshall

Myocardial fibers and nerves adjacent to the vein of Marshall (VOM), that is, the ligament of Marshall (LOM), have been implicated as a source of ectopic beats initiating paroxysmal atrial fibrillation (AF), 1 Lin W.S. Tai C.T. Hsieh M.H. et al. Catheter ablation of paroxysmal atrial fibrillation initiated by non-pulmonary vein ectopy. Circulation. 2003; 107: 3176-3183 Crossref PubMed Scopus (584) Google Scholar as a connection pathway between the left atrium (LA) and left pulmonary veins (PVs), 2 Hwang C. Chen P.S. Ligament of Marshall: why it is important for atrial fibrillation ablation. Heart Rhythm. 2009; 6: S35-S40 Abstract Full Text Full Text PDF PubMed Scopus (50) Google Scholar , 3 Dave A.S. Báez-Escudero J.L. Sasaridis C. Hong T.E. Rami T. Valderrábano M. Role of the vein of Marshall in atrial fibrillation recurrences after catheter ablation: therapeutic effect of ethanol infusion. J Cardiovasc Electrophysiol. 2012; 23: 583-591 Crossref PubMed Scopus (45) Google Scholar and as a source of arrhythmogenic autonomic innervation. 4 Kamanu S. Tan A.Y. Peter C.T. Hwang C. Chen P.S. Vein of Marshall activity during sustained atrial fibrillation. J Cardiovasc Electrophysiol. 2006; 17: 839-846 Crossref PubMed Scopus (44) Google Scholar , 5 Valderrábano M. Chen H.R. Sidhu J. Rao L. Ling Y. Khoury D.S. Retrograde ethanol infusion in the vein of Marshall: regional left atrial ablation, vagal denervation and feasibility in humans. Circ Arrhythm Electrophysiol. 2009; 2: 50-56 Crossref PubMed Scopus (76) Google Scholar This various complex nature of the LOM can constitute the genesis of AF. On the other hand, the VOM location coincides with the areas usually ablated during PV isolation. It has recently been reported that VOM ethanol infusion creates a low-voltage area in the LA adjacent to the VOM and facilitates left PV isolation for AF ablation. 6 Valderrábano M. Liu X. Sasaridis C. Sidhu J. Little S. Khoury D.S. Ethanol infusion in the vein of Marshall: adjunctive effects during ablation of atrial fibrillation. Heart Rhythm. 2009; 6: 1552-1558 Abstract Full Text Full Text PDF PubMed Scopus (70) Google Scholar This advocates that VOM ethanol infusion has favorable adjunctive effects on PV isolation by radiofrequency (RF) ablation. However, considering the roles that the LOM plays in the pathogenesis of AF, VOM ethanol infusion alone may cure AF in some patients. In this report, we describe the first case that underwent VOM ethanol infusion and had non-PV ectopy initiating AF that is eliminated without RF ablation for PV isolation.

Diagnostic Assessment of Diabetic Gastroparesis

Gastroparesis is characterized by a constellation of upper gastrointestinal (GI) symptoms in association with delayed gastric emptying (GE) in the absence of mechanical outlet obstruction from the stomach. Cardinal symptoms are nausea, vomiting, early satiety or postprandial fullness, bloating, and abdominal or epigastric pain (1). Gastric retention may be asymptomatic in some, possibly due to afferent dysfunction in the setting of vagal denervation (2,3), and delayed GE may be associated with recurrent hypoglycemia in patients without upper GI symptoms (4,5). In these individuals, the term “delayed GE” is preferred to gastroparesis (1), although others have used terms such as “gastric hypoglycemia” (6). Thus, clinical manifestations of impaired GE may include anorexia, weight loss, malnutrition, phytobezoar formation, poorer quality-of-life, or impaired glycemic control due to erratic delivery of nutrients to the small bowel for absorption, and these may occur independent of factors such as age, gender, alcohol consumption, tobacco use, and diabetes type (7–9). Upper GI symptoms in diabetic patients may result from accelerated GE, often in association with vagal neuropathy and impaired proximal gastric accommodation (10). In addition, upper GI symptoms in diabetic patients were not significantly different in those with delayed compared with rapid GE, except possibly for postprandial distress ( P = 0.076 on univariate analysis) (11). Hence, it is essential to measure GE in patients with upper GI symptoms if the right treatment is to be selected, such as choice of a prokinetic agent in those with delayed GE. Similarly, one cannot assume that patients with known vagal neuropathy and upper GI symptoms have gastroparesis, because the measured GE may be normal, fast, or slow in such patients. The magnitude of GE delay may also influence diagnosis; there is overlap in the clinical diagnosis of functional dyspepsia and gastroparesis in patients …

Lipid-rich enteral nutrition regulates mucosal mast cell activation via the vagal anti-inflammatory reflex

Nutritional stimulation of the cholecystokinin-1 receptor (CCK-1R) and nicotinic acetylcholine receptor (nAChR)-mediated vagal reflex was shown to reduce inflammation and preserve intestinal integrity. Mast cells are important early effectors of the innate immune response; therefore modulation of mucosal mast cells is a potential therapeutic target to control the acute inflammatory response in the intestine. The present study investigates intestinal mast cell responsiveness upon nutritional activation of the vagal anti-inflammatory reflex during acute inflammation. Mucosal mast cell degranulation was induced in C57/Bl6 mice by administration of Salmonella enterica LPS. Lipid-rich enteral feeding prior to LPS significantly decreased circulatory levels of mouse mast cell protease at 30 min post-LPS compared with isocaloric low-lipid nutrition or fasting. CCK-1R blockage reversed the inhibitory effects of lipid-rich feeding, whereas stimulation of the peripheral CCK-1R mimicked nutritional mast cell inhibition. The effects of lipid-rich nutrition were negated by nAChR blockers chlorisondamine and α-bungarotoxin and vagal intestinal denervation. Accordingly, release of β-hexosaminidase by MC/9 mast cells following LPS or IgE-ovalbumin complexes was dose dependently inhibited by acetylcholine and nicotine. Application of GSK1345038A, a specific agonist of the nAChR α7, in bone marrow-derived mast cells from nAChR β2-/- and wild types indicated that cholinergic inhibition of mast cells is mediated by the nAChR α7 and is independent of the nAChR β2. Together, the present study reveals mucosal mast cells as a previously unknown target of the nutritional anti-inflammatory vagal reflex.

Vagal innervation patterns following Roux-en-Y gastric bypass in the mouse

This study investigated the anatomical integrity of the vagal innervation to the gastrointestinal tract following Roux-en-Y gastric bypass (RYGB) in the mouse. Specifically, the surgical procedure was performed in high-fat-fed reporter mice (Phox2b-Cre-tdTomato), in which the entire vagal innervation of the gastrointestinal tract was fluorescently labeled. As a result, our anatomical observations revealed both qualitative and quantitative changes of the vagal supply to the gut after RYGB. This included the extensive denervation of the glandular and distal stomach, and sites of surgical interventions (clipping and anastomosis). Furthermore, the stomach wall after RYGB frequently contained dystrophic axons and endings, suggestive of vagal neurodegeneration. In contrast, RYGB did not significantly modify the innervation to the rest of the intestines and glucostatic organs. In summary, the present study describes a previously unrecognized pattern of vagal remodeling and denervation following RYGB. Our findings may serve as a guideline for future investigations on the role of gut-brain communication in bariatric surgery.