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Vagal nerve stimulation (VNS) has a strong pathophysiological rationale as a potentially beneficial treatment for heart failure with reduced ejection fraction. Despite several promising preclinical studies and pilot clinical studies, the two large, controlled trials-NECTAR-HF and INOVATE-HF-failed to demonstrate the expected benefit. It is likely that clinical application of VNS in phase III studies was performed before a sufficient degree of understanding of the complex pathophysiology of autonomic electrical modulation had been achieved, therefore leading to an underestimation of its potential benefit. More knowledge on the complex dose-response issue of VNS (i.e., pulse amplitude, frequency, duration and duty cycle) has been gathered since these trials and a new randomized study is currently underway with an adaptive design and a refined approach in an attempt to deliver the proper dose to a more selected group of patients.Für die Vagusnervstimulation (VNS) als einer sinnvollen Therapie bei Herzinsuffizienz bestehen starke pathophysiologische Argumente. Trotz mehrerer vielversprechender präklinischer und Pilotstudien konnten die beiden großen kontrollierten Studien NECTAR-HF und INOVATE-HF den erwarteten klinischen Nutzen jedoch nicht zeigen. Vermutlich wurde hierbei die klinische Anwendung dieser Therapie durchgeführt, bevor die komplexe Pathophysiologie der autonomen elektrischen Modulation ausreichend verstanden worden war, sodass diese Studien nicht in der Lage waren, das Potenzial der VNS zu demonstrieren. Seit diesen Studien wurde mehr Wissen über die klinische Anwendung der VNS erlangt, insbesondere zur Patientenselektion und zur Art der Stimulation („Dosis“, d. h. Amplitude, Impulsfrequenz [Hz], Dauer der Anwendung und Arbeitszyklus der VNS). Eine neue randomisierte Studie mit einem adaptiven Design wird aktuell durchgeführt, um die Fragen nach der optimalen Dosis der VNS zu beantworten.

Background Low‐level tragus stimulation (LLTS) has been shown to significantly reduce atrial fibrillation (AF) burden in patients with paroxysmal AF. P‐wave alternans (PWA) is believed to be generated by the same substrate responsible for AF. Hence, PWA may serve as a marker in guiding LLTS therapy. We investigated the utility of PWA in guiding LLTS therapy in patients with AF. Methods and Results Twenty‐eight patients with AF were randomized to either active LLTS or sham (earlobe stimulation). LLTS was delivered through a transcutaneous electrical nerve stimulation device (pulse width 200 μs, frequency 20 Hz, amplitude 10–50 mA), for 1 hour daily over a 6‐month period. AF burden over 2‐week periods was assessed by noninvasive continuous ECG monitoring at baseline, 3 months, and 6 months. A 5‐minute control ECG for PWA analysis was recorded during all 3 follow‐up visits. Following the control ECG, an additional 5‐minute ECG was recorded during active LLTS in all patients. At baseline, acute LLTS led to a significant rise in PWA burden. However, active patients receiving chronic LLTS demonstrated a significant reduction in both PWA and AF burden after 6 months ( P Conclusions Chronic, intermittent LLTS resulted in lower PWA and AF burden than did sham control stimulation. Our results support the use of PWA as a potential marker for guiding LLTS treatment of paroxysmal AF.

Aims: Microvolt T-wave alternans (TWA), an oscillation in T-wave morphology of the electrocardiogram (ECG), has been associated with increased susceptibility to ventricular tachy-arrhythmias, while vagus nerve stimulation has shown promising anti-arrhythmic effects in in vivo and ex vivo animal studies. We aimed to examine the effect of non-invasive, acute low-level tragus stimulation (LLTS) on TWA in patients with ischemic cardiomyopathy and heart failure.Methods: 26 patients with ischemic cardiomyopathy (left ventricular ejection fraction Results: Right atrial pacing at 100 bpm led to significantly heightened TWA burden compared to sinus rhythm, with or without LLTS. Acute LLTS at both 5 and 20 Hz, during sinus rhythm led to a significant rise in TWA burden in the precordial leads (p < 0.05).Conclusion: Acute LLTS results in a heart-rate dependent increase in TWA burden.

Funding Acknowledgements Type of funding sources: None. OnBehalf N/A Background. Cardioneuroablation (CNA) is a promising method for treatment of vagally-induced vasovagal syncope or functional atrio-ventricular block. Extra-cardiac vagal stimulation (ECVS) from the internal jugular vein is used during CNA to document asystolic response prior to CNA and lack of effects of vagal stimulation on heart rate after CNA. The recommended technique is placing the pacing catheter under fluoroscopy in the internal right and left jugular vein up to the level of the upper wisdom tooth. However, this technique has several limitations such as increased radiation exposure, unselective cranial nerves stimulation and lack of visualization of vagal nerve. Ultrasound-guided (USG) approach may be an interesting option because it allows visualization of the vagal nerve and enables selective stimulation under visual control. Purpose. To assess the utility of USG-guided ECVS during CNA procedures. Methods. The study group consisted of 6 patients (4 males, mean age 35 ± 12-year-old) underwent CNA. Firstly, electrode for ECVS was introduced under fluoroscopy into the right and left jugular veins up to the level of the upper wisdom tooth and ECVS was performed. Next, the USG-guided examinations were performed in supine position with head extension. The probe was placed in the transverse plane above the medial edge of the sternocleidomastoid muscle. The course of vagal nerve was identified and place for imaging in the close neighborhood of the jugular vein was chosen. ECVS was performed when the electrode was in good contact with the vein wall and was in the vicinity of the vagal nerve. In both approaches vagal response (asystole and atrio-ventricular block) during ECVS was assessed before and after CNA. Results. In all patients ECVS was performed from both right and left jugular vein. Localization of vagal nerve using USG was possible in all patients and took less than one minute (see Figure). The effects of ECVS were identical using standard fluoroscopic and USG-guided approach. Conclusions. USG-guided ECVS during CNA is easy, results are comparable with standard fluoroscopic approach and is probably associated with less fluoroscopy. Since this non-invasive method is the only one which enables vagal nerve visualization, it should become a preferred approach when using ECVS during CNA procedures. Abstract Figure. A electrode position for USG-guided ECVS

Background: Vagal hyperactivity is directly related to several clinical conditions as reflex/functional bradyarrhythmias and vagal atrial fibrillation (AF). Cardioneuroablation provides therapeutic vagal denervation through endocardial radiofrequency ablation for these cases. The main challenges are neuromyocardium interface identification and the denervation control and validation. The finding that the AF-Nest (AFN) ablation eliminates the atropine response and decreases RR variability suggests that they are related to the vagal innervation. Method: Prospective, controlled, longitudinal, nonrandomized study enrolling 62 patients in 2 groups: AFN group (AFN group 32 patients) with functional or reflex bradyarrhythmias or vagal AF treated with AFN ablation and a control group (30 patients) with anomalous bundles, ventricular premature beats, atrial flutter, atrioventricular nodal reentry, and atrial tachycardia, treated with conventional ablation (non-AFN ablation). In AFN group, ablation delivered at AFN detected by fragmentation/fractionation of the endocardial electrograms and by 3-dimensional anatomic location of the ganglionated plexus. Vagal response was evaluated before, during, and postablation by 5 s noncontact vagal stimulation at the jugular foramen, through the internal jugular veins (extracardiac vagal stimulation [ECVS]), analyzing 15 s mean heart rate, longest RR, pauses, and atrioventricular block. All patients had current guidelines arrhythmia ablation indication. Results: Preablation ECVS induced sinus pauses, asystole, and transient atrioventricular block in both groups showing a strong vagal response ( P =0.96). Postablation ECVS in the AFN group showed complete abolishment of the cardiac vagal response in all cases (pre/postablation ECVS= P P =0.35), showing that non-AFN ablation promotes no significant denervation. Conclusions: AFN ablation causes significant vagal denervation. Non-AFN ablation causes no significant vagal denervation. These results suggest that AFNs are intrinsically related to vagal innervation. ECVS was fundamental to stepwise vagal denervation validation during cardioneuroablation. Visual Overview A visual overview is available for this article.

Objective: Possible effects of the vagus inhibition and stimulation on the hypothalamic nuclei, myenteric plexes and the vagus nerve were investigated.Methods: The female rats divided to the inhibition (INH), stimulation (STI) and, sham (SHAM) groups were fed with high fat diet (including 40% of energy from animal fat). After nine weeks, the rats were allowed to recover for 4 weeks in INH group. In STI group, the left vagus nerve stimulated (30 Hz/500 msn/30 sec.) starting 2nd post operative day for 5 minutes during 4 weeks. Healthy female rats used as control (CONT). Then, tissue samples were analyzed by biochemical, histological and stereological methods.Results: The mean number of the neurons in the arcuate nucleus of the INH group was significantly less; but, that is significantly more in the STI group compared to the other groups. The neuronal density of ventromedial nucleus in the STI group was higher; while the density in the INH group was lower than the other groups. In the dorsomedial nucleus, neuron density of the INH group was lower than the other groups. In terms of the myenteric plexus volumes, that of the INH group was lowest. The myelinated axon number in the INH group was significantly highest. The myelin sheath thickness and axon area of the INH group was significantly lower than the other groups.Discussion: The results of the study show that the vagal inhibition is more effective than the vagal stimulation on the weight loss in the obesity.

Sinus node (SN) function is an important prognostic factor of atrial fibrillation (AF). However, AF ablation guideline has not recommended SN function test before ablation. SN function testing before AF ablation in patients with tachycardia‐bradycardia syndrome should be beneficial to determine further therapy strategies and prognosis.

John McWilliam was appointed Regius Professor of the Institutes of Medicine (later Physiology) at the University of Aberdeen in 1886, at the age of only 29. The following year he established that electric shocks induced ventricular fibrillation (VF) and, having witnessed this phenomenon in many animals, including mammals, concluded it must also be a cause of sudden death in humans. His research then focused on ways of restarting the heart after cardiac arrest. While he recognised that most cardiac arrests were hopeless, he considered there were probably some situations, such as excessive vagal stimulation, which could be reversible. Believing that one single dramatic shock would induce VF and knowing that a small shock would only lead to a single cardiac contraction, he proposed 'We want a much more effective and speedy mode of exciting rhythmic contraction ... a periodic series of single induction shocks sent through the heart at approximately the normal rate of cardiac action'.

AIMS: The purpose of this study was to systematically quantify the level of acute parasympathetic denervation in a stepwise fashion by means of extracardiac vagal stimulation (ECVS) by positioning a quadripolar catheter in the internal jugular vein, in a cohort of patients undergoing second-generation cryoballoon ablation for paroxysmal atrial fibrillation. METHODS: Fifty patients with symptomatic paroxysmal atrial fibrillation, having undergone extracardiac vagal stimulation before and after ablation by means of second-generation cryoballoon second-generation cryoballoon ablation, were included. RESULTS: The extracardiac vagal stimulation performed preablation provoked cardioinhibitory responses in all patients with mean pause duration of 10130.6 ± 3280.0 ms. At the end of the procedure, the VRs were significantly diminished with mean pause of 1687.5 ms ± 2183.7 ms (P = 0.00 compared with the pause before the procedure). CONCLUSION: The ECVS proved to be a reproducible, feasible and reliable method to quantify the degree of parasympathetic denervation during CB-A. In all patients, significant cardiac parasympathetic denervation could be observed at the end of the procedure. Responses to ECVS were more specific to quantify the vagal denervation than the increase in the heart rate. However larger studies are needed to confirm this observation.

Background/objective Changes in brain metabolism has been investigated thoroughly during unilateral cervical chronic vagal stimulation in epileptic or depressive patients. Bilateral stimulation of the abdominal vagus (aVNS) has received less attention despite the reduction in body weight and an altered feeding behavior in obese animals that could be clinically relevant in obese individuals. Our study aims to examine the changes in brain glucose metabolism (CMRglu) induced by aVNS in obese adult miniature pigs. Dopamine (DAT) and serotonin transporters (SERT) were also quantified to further understand the molecular origins of the alterations in brain metabolism. Subjects/methods Pairs of stimulating electrodes were implanted during laparoscopy on both abdominal vagal trunks in 20 obese adult’s miniature pigs. Half of the animals were permanently stimulated while the remaining were sham stimulated. Two months after the onset of stimulation, dynamic 18FDG PET and 123I-ioflupane SPECT were performed. Food intake, resting energy expenditure and fat deposition were also assessed longitudinally. Results Food intake was halved and resting energy expenditure was increased by 60% in aVNS group compared to sham. The gain in body weight was also 38% less in aVNS group compared to sham. Brain metabolic connectivity increased between numerous structures including striatum, mid-brain, amygdala and hippocampus. On the contrary, increased CMRglu were restricted to the thalamus, the periaqueducal grey and the amygdala. DAT binding potential was decreased by about one third in the striatum while SERT was about doubled in the midbrain. Conclusions Our findings demonstrated that aVNS reduced weight gain as a consequence of diminished daily food intake and increased resting energy expenditure. These changes were associated with enhanced connectivity between several brain areas. A lower striatal DAT together with a doubled mid-brain SERT were likely causative for these changes. Electronic supplementary material The online version of this article (10.1186/s12967-019-1831-5) contains supplementary material, which is available to authorized users.

Atrial fibrillation (AF) is a disorder in which heart rhythm becomes irregular and has an influence on the respiratory rhythm as well as on cardiopulmonary coupling. We applied detrended fluctuation analysis (DFA) method to find correlation properties of heart and respiratory rhythm in order to clarify behavioral pattern of cardiopulmonary coupling in AF. Scaling exponents: α 1 (short-range correlations) and α 2 (long-range correlations) were calculated on RR intervals and respiratory signal (Resp). Their relationship with heart/respiratory frequency was examined by regression analysis. In comparison to the control group, there was a significant reduction of α 1 and α 2 of the heart rhythm in AF group, while a2(Resp) was significantly increased in AF group. In regression analysis, there were significant intrasystemic relationships. In AF, our results imply a compensatory mechanism in regulation of the respiratory rhythm which was not noticed in regulation of the heart rhythm. We can conclude there is a cardiopulmonary coupling in direction heart-respiratory system in AF, but not in the opposite direction because of impaired vagal stimulation of sinoatrial node (SA).

It is suggested that an orienting response to loud sound causes apnea, which, in already asphyxic infants, triggers a maximal secondary chemoreceptor response, with massive vagal stimulation of the heart, which causes heart arrest.

The cardiac autonomic nervous system plays an important role in the genesis and maintenance of atrial fibrillation. Although, pulmonary vein isolation is the cornerstone in today’s approach to atrial fibrillation ablation, a considerable proportion of patients will recur with atrial arrhythmias following this procedure, especially in the non-paroxysmal forms. The pulmonary vein isolation indirectly targets and ablate the ganglionated plexi. This might ultimately enhance the efficacy of the procedure, but an optimal ablation strategy and a reliable method to confirm and quantify the efficacy of vagal denervation following the procedure might be necessary, thus leading to significantly better results.

Controlled breathing maneuver is being widely applied for cardiovascular autonomic control evaluation and cardiac vagal activation through reduction of breathing rate (BR). However, this maneuver presented contradictory results depending on the protocol and the chosen BR. These variations may be related to the individual intrinsic profile baseline sympathetic tonus, as described before by others. In this study, we evaluated the effect of controlled breathing maneuver on cardiovascular autonomic control in 26 healthy subjects allocated into two protocols: (1) controlled breathing in three different rates (10, 15, and 20 breaths/min) and (2) controlled breathing in rates normalized by the individual spontaneous breathing rate (SBR) at 100, 80, 70, and 50%. Our results showed autonomic responses favorable to vagal modulation with the lower BR maneuvers. Nevertheless, while this activation was variable using the standard protocol, all participants of the normalized protocol demonstrated an increase of vagal modulation at 80% BR (HFnu 80 = 67.5% vs. 48.2%, p < 0.0001). These results suggest that controlled breathing protocols to induce vagal activation should consider the SBR, being limited to values moderately lower than the baseline.

Postural Tachycardia Syndrome (POTS) is a clinical syndrome characterized by an excessive increase in heart rate (>= 30 bpm) on standing in the absence of orthostatic hypotension, and frequent orthostatic symptoms for more than 6 months. While most researchers focus on the hyperadrenergic features of POTS, these patients also have significant cardio-vagal (parasympathetic) impairment. We tested the hypothesis that transdermal electrical stimulation of the auricular branch of the vagus nerve will enhance cardio-vagal modulation, reduce heart rate, upright symptoms, and improve orthostatic tolerance. We studied 14 patients with POTS (31.5+/-11.7 years, BMI 22.6+/-3.9 kg/m 2 ). Sham or sub-perception threshold transdermal electrical vagal stimulation was applied in random order to the auricular branch in the right ear in supine and during graded tilt maneuver. Patients with low vagal modulation (low high frequency HF < 200 ms 2 ) responded to vagal stimulation (Kruskal Wallis p=0.01, n=7, Fig left) with significant increase in HF power (eg @50Hz: +51+/-10 ms 2 , p=0.0032). Vagal stimulation during upright tilt tended to reduce orthostatic tachycardia and overall orthostatic symptom score. It improved significantly tilt time (+5.3+/-2.6 min, p=0.0156, Fig right). Patients with higher baseline vagal modulation (HF >= 200 ms 2 ) did not respond to vagal stimulation (interaction p=0.41). This proof of concept study indicates that auricular transdermal vagal stimulation improves supine cardio-vagal function in POTS patients with low vagal modulation. Further research will determine if this approach can be used therapeutically, alone or in combination with other therapies.

Heart failure is a common syndrome associated with substantial morbidity and mortality. The management of symptoms and the strategies for improving prognosis have largely been based on pharmacological treatments. The pathophysiology of heart failure is complex because of the multiple causes responsible for this syndrome. This Series paper presents some examples of advances in heart failure management, in which the treatment specifically targets the underlying pathophysiological mechanisms responsible for the symptoms. These treatments include treatment of electromechanical dyssynchrony and dysrhythmia by cardiac resynchronisation and implantable cardioverter-defibrillators; neurohumoral modification by baroreflex and vagal stimulation; prevention of adverse cardiac remodelling by interatrial shunts; and finally targeting the myocardium directly by cell therapy in an attempt to regenerate new myocardial cells.

Background Ranolazine is generally used to treat anginal symptoms for patients with symptomatic chronic stable angina pectoris. By improving ischemiareperfusion, ranolazine is also observed to have protective effects on myocardial ischemic injury in animal models. It is noteworthy to find interventions that can decrease adverse effects of this drug and thereby increase its clinical application. Methods In this report, we used a rat model of chronic ischemic heart failure (CHF) to examine if vagal stimulation can strengthen the effects of ranolazine on worsened cardiac function in CHF. Plasma norepinephrine (NE) and brain natriuretic peptide [BNP, termed B-type natriuretic peptide-45 (BNP-45) in rats] are regulated by sympathetic nerve activity. Because NE and BNP are considered as neurohormones indicating heart failure progression, we also determined the levels of plasma NE and BNP-45 besides cardiac function. Moreover, we examined the role of sympathetic pro-inflammatory cytokines in engagement of vagal activation. Results Our data show that ranolazine intraperitoneally improved the impaired left ventricular function, and attenuated the exaggerated NE/BNP-45 and cytokines (such as IL-1β, IL-6 and TNF-α) after development of CHF. Particularly, our results show that vagal activation largely amplified the effects of ranolazine on cardiac function in CHF. Conclusion Our data indicate that: 1) ranolazine alleviates sympathetic nerve activity thereby leading to improvement of the worsened cardiac function in CHF; and 2) vagal stimulation augments the effect of ranolazine. Accordingly, results of this study have implications for the role played by a combination of vagal stimulation and ranolazine in improving cardiac function in CHF.

See Article by Panitchob et al > As to the fundamental mechanisms of fibrillation we have plenty of theories, but none is universally accepted… we may note in passing that they all center around two ideas … (a) that the impulses arise from centers or pacemakers, or (b) that the condition is caused by re-entry of impulses and the formation of circles of excitation. Each of these views, again, has two groups of exponents … (a) those who believe that a single focus, or excitation ring, occurs, and (b) those who favor the idea that multiple foci, or numerous circus rings, are developed. > > —Carl J. Wiggers, 19401 Ventricular fibrillation (VF) was likely recognized as early as 3500 BCE when the Ebers Papyrus2 described key features of fibrillation as follows: > “If the heart trembles, has little power and sinks, the disease is advancing and death is near.” The modern scientific effort to understand fibrillation did not begin until 1543, when Vesalius3 described worm-like movements in animal hearts during dissection just before they died. Erichsen4 in 1842 documented tumultuous, tremulous, and irregular behavior of ventricles consequent to coronary ligation. Hoffa and Ludwig5 first recorded VF using a kymograph (mechanical wave recorder) in 1850 (Figure, left). Interestingly, Hoffa, who was Ludwig’s pupil at the time, meant to stimulate neurons but accidentally stimulated the myocardium. They showed that irregular contractions of the ventricles could be induced by faradization (electric stimulation) and resulted in cardiac arrest that could not be checked by vagal stimulation. These studies of autonomic control of the heart suggested a neurogenic VF mechanism. Figure. The first recordings of ventricular fibrillation were acquired by Hoffa and Ludwig using a …

Objectives The 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. Background Parasympathetic 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. Methods A 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. Results Significant 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). Conclusions The 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.

Intraoperative vagal stimulation can lead to onset of atrial fibrillation (AF). The role of vagus mediated AF is not very much acknowledged. We report a case of AF during handling of great vessels in the neck region. After ruling out other causes of AF, we concluded that this sudden occurrence of AF could be a case of vagus nerve stimulation. In our case report, we also discuss the role of cholinergic activity in the development of AF and its treatment.

Both vagal (VS) and sympathetic (SS) stimulations can increase atrial fibrillation (AF) inducibility, with VS being known as more arrhythmogenic in normal hearts. Heart failure (HF) results in autonomic dysfunction (characterized by sympathetic activation and vagal withdrawal) and is associated with an increased AF incidence. This study investigated whether failing hearts, compared with normal control hearts, respond differently to autonomic stimulation-induced AF arrhythmogenesis and the effect of dantrolene on SS-enhanced AF in HF.A rat myocardial infarction (MI) HF model was used. In experiment 1, AF inducibility was compared in 9 MI-HF rats versus 10 sham-control animals at baseline, during VS, and during SS with isoproterenol infusion. In experiment 2, dantrolene treatment (n = 8) was compared with placebo-control (n = 9) on SS-induced AF inducibility in HF. Compared with the sham-control, baseline AF inducibility was higher in the MI-HF group. AF inducibility was augmented in both groups by autonomic stimulation. However, under VS the increased magnitude was less in the MI-HF group (49% ± 11% vs 80% ± 10%; P = .029), but under SS was significantly more (53% ± 8% vs 6% ± 7%; P.001), compared with sham-control. Dantrolene significantly attenuated SS-enhanced AF in HF (69% ± 6% vs 29% ± 9%; P = .006).Failing hearts are less sensitive to VS, but more vulnerable to SS-induced AF compared with normal-control hearts. Dantrolene can significantly attenuate SS-enhanced AF in HF, indicating that cardiac ryanodine receptor dysfunction may play a critical role in SS-enhanced AF in HF, and stabilizing leaky ryanodine receptor with the use of dantrolene may be a new treatment option in this condition.

Supplementary data related to this article can be found at http://dx.doi.org/10.1016/j.brs.2017.04.126; International audience; Background :Abdominal bilateral vagal stimulation reduces food intake in animals. However, the classical square wave, mA range current generator is poorly effective to evoke action potentials on A∂ and C neurons that represent the majority of vagal neurons at the abdominal level.Objective/Hypothesis :(i) To ascertain the capability of very high-frequency stimulation schemes (pulsons) to trigger action potentials in abdominal vagal neurons in anaesthetized pigs. (ii) To compare these stimulation schemes with classical ones using PET imaging of brain metabolism and food intake behaviour in conscious pigs.Methods :The current thresholds for pulsons (S2 & S3) and millisecond pulses (S1) required to trigger action potentials were calculated in 5 anaesthetized pigs using single fibre recording. Similar stimulation protocols were compared chronically to sham stimulation in 24 pigs. After two weeks of chronic stimulation, food intake and brain metabolism were investigated. The electrical characteristics and histology of the vagus nerve were also studied.Results :S3 stimulation required a lower amount of charges to trigger an action potential. Chronically applied S2 & S3 activated the dorsal vagal complex and increased the metabolism of its afferent cortical structures. They also reduced energy intake together with a reduced ingestion of high fat and high sugar diets. All these effects were not observed for the S1 group. The vagal histology for the S1, S2 and S3 groups was not different from that of the sham.Conclusions :These findings demonstrate that pulsons applied bilaterally on the abdominal vagus reduced food intake as a consequence of the activation of the brainstem and higher-order brain areas.

This article provides an overview of trials relevant to the pathophysiology, prevention, and treatment of heart failure, presented at the European Society of Cardiology meeting held in Barcelona in autumn 2014. Trials reported here include PARADIGM-HF (LCZ696 versus enalapril in heart failure), CONFIRM-HF (treatment of iron deficiency in heart failure), and SIGNIFY (ivabradine in patients with stable coronary artery disease). In addition, we discuss recent developments in the treatment of atrial fibrillation and the lack of benefit with the use of beta-blockers in these patients. Finally, the article describes recent advances in the use of vagal stimulation in patients with heart failure. © 2014 The Authors. ESC Heart Failure published by John Wiley & Sons Ltd on behalf of the European Society of Cardiology.

In a previous research, we described that vagal stimulation increases the infarct size by sympathetic co-activation. The aim of this study was to determine if hemodynamic changes secondary to the vagal stimulation are able to activate sympathetic compensatory neural reflexes, responsible for increasing the infarct size. A second goal was to determine if intermittent vagal stimulation avoids sympathetic activation and reduces infarct size by muscarinic activation of the Akt/glycogen synthase kinase 3 β (GSK-3β) pathway. Rabbits were subjected to 30 min of regional myocardial ischemia and 3 h of reperfusion without vagal stimulation, or the following protocols of right vagus nerve stimulation for 10 min before ischemia: (a) continuous vagal stimulation and (b) intermittent vagal stimulation (cycles of 10 s ON/50 s OFF). Continuous vagal stimulation increased the infarct size (70.7 ± 4.3 %), even after right vagal section (68.6 ± 4.1 %) compared with control group (52.0 ± 3.7 %, p < 0.05). Bilateral vagotomy, pacing, and esmolol abolished the deleterious effect, reaching an infarct size of 43.3 ± 5.1, 43.5 ± 2.1, and 46.0 ± 4.6 % (p < 0.05), respectively. Intermittent stimulation reduced the infarct size to 29.8 ± 3.0 % (p < 0.05 vs I/R). This effect was blocked with atropine (50.2 ± 3.6 %, p < 0.05). Continuous vagal stimulation induced bradycardia and increased the loading conditions and wall stretching of the atria. These changes provoked the co-activation reflex of the sympathetic nervous system, observed by the rise in plasmatic catecholamine levels, which increased the infarct size. Sympathetic co-activation was abolished by continuous vagal stimulation with constant heart rate or parasympathetic deafferentation. Intermittent vagal stimulation attenuated the sympathetic tone and reduced the infarct size by the muscarinic activation of the Akt pathway and GSK-3β inhibition. Continuous stimulation only phosphorylated Akt and GSK-3β when esmolol was administered. Fil: Buchholz, Bruno. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Bioquímica y Medicina Molecular. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Instituto de Bioquímica y Medicina Molecular; Argentina Fil: Donato, Pablo Martín. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Bioquímica y Medicina Molecular. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Instituto de Bioquímica y Medicina Molecular; Argentina Fil: Perez, María Virginia. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Bioquímica y Medicina Molecular. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Instituto de Bioquímica y Medicina Molecular; Argentina Fil: Rey Deutsch, Ana Clara. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Bioquímica y Medicina Molecular. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Instituto de Bioquímica y Medicina Molecular; Argentina Fil: Höcht, Christian. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Departamento de Farmacología; Argentina Fil: del Mauro, Julieta Sofía. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Departamento de Farmacología; Argentina Fil: Rodríguez, Manuel. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Bioquímica y Medicina Molecular. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Instituto de Bioquímica y Medicina Molecular; Argentina Fil: Gelpi, Ricardo Jorge. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Bioquímica y Medicina Molecular. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Instituto de Bioquímica y Medicina Molecular; Argentina

A new analysis of the relationship between cardiac output (Q˙) and oxygen consumption V˙O2 is presented (Q˙-V˙O2 diagram). Data from different sources in the literature have been used for validation in three conditions: exercise and rest in normoxia, and exercise in hypoxia. The effects of changes in arterial oxygen concentration CaO2 on Q˙ are discussed, as well as the effects of predominant sympathetic or vagal stimulation. Differences appear depending on whether CaO2 is varied by means of changes in blood haemoglobin concentration or changes in arterial oxygen saturation. The present Q˙-V˙O2 diagram allows comprehensive description of oxygen transport in exercising humans; it expands applicability of the historical Q˙-V˙O2 relationship to include CaO2 variations; it opens new pathways for understanding underlying mechanisms; it allows computation of Q˙ from CaO2 and V˙O2 measurements, when Q˙ cannot be measured.

Heart failure (HF) is accompanied by an autonomic imbalance that is almost always characterized by both increased sympathetic activity and withdrawal of vagal activity. Experimentally, vagal stimulation has been shown to exert profound antiarrhythmic activity and to improve cardiac function and survival in HF models. A open-label pilot clinical study in 32 patients with chronic HF has shown safety and tolerability of chronic vagal stimulation associated with subjective (improved quality of life and 6-min walk test) and objective improvements (reduced left ventricular systolic volumes and improved left ventricular ejection fraction). Three larger clinical studies, including a phase III trial are currently ongoing and will evaluate the clinical role of this new approach.

Background Radiofrequency ablation ( RFA ) for atrioventricular nodal reentrant tachycardia appears to reduce atrial tachycardia, which might relate to parasympathetic denervation at cardiac ganglionated plexuses. Methods and Results Compared to 7 control canines without RFA , in 14 canines, RFA at the bottom of Koch's triangle attenuated vagal stimulation–induced effective refractory periods prolongation in atrioventricular nodal and discontinuous atrioventricular conduction curves but had no effect on the sinoatrial node. RFA attenuated vagal stimulation–induced atrial effective refractory periods shortening and vulnerability window of atrial fibrillation widening in the inferior right atrium and proximal coronary sinus but not in the high right atrium and distal coronary sinus. Moreover, RFA anatomically impaired the epicardial ganglionated plexuses at the inferior vena cava‒inferior left atrial junction. This method was also investigated in 42 patients who had undergone ablation of atrioventricular nodal reentrant tachycardia, or 12 with an accessory pathway ( AP ) at the posterior septum ( AP ‐ PS ), and 34 patients who had an AP at the free wall as control. In patients with atrioventricular nodal reentrant tachycardia and AP ‐ PS , RFA at the bottom of Koch's triangle prolonged atrial effective refractory periods and reduced vulnerability windows of atrial fibrillation widening at the inferior right atrium, distal coronary sinus and proximal coronary sinus but not the high right atrium. In patients with AP ‐free wall, RFA had no significant atrial effects. Conclusions RFA at the bottom of Koch's triangle attenuated local autonomic innervation in the atrioventricular node and atria, decreased vagal stimulation–induced discontinuous atrioventricular nodal conduction, and reduced atrial fibrillation inducibility due to impaired ganglionated plexuses. In patients with atrioventricular nodal reentrant tachycardia or AP ‐ PS , RFA prolonged atrial effective refractory periods, and narrowed vulnerability windows of atrial fibrillation.

An autonomic imbalance consisting in increased sympathetic activity and decreased vagal activity is associated with the occurrence and the progression of heart failure.

Reactive oxygen species (ROS) production is an important mechanism in myocardial ischemia and nicotinamide adenine dinucleotide phosphate (NADPH) oxidase is one of major sources of ROS in the heart. Previous studies showed that vagus nerve stimulation (VNS) is beneficial in treating ischemic heart diseases. However, the effect of VNS on ROS production remains elusive. In this study, we investigated the role of VNS onischemia-induced ROS production. Our results demonstrated that VNS alleviated the myocardial injury, attenuated the cardiac dysfunction, reserved the antioxidant enzyme activity and inhibited the formation of ROS as evidenced by the decreased NADPH oxidase (Nox) activity and superoxide fluorescence intensity as well as the expression of p67phox, Rac1 and nitrotyrosine. Furthermore, VNS resulted in the phosphorylation and activation of adenosine monophosphate activated protein kinase (AMPK), which in turn led to an inactivation of Nox by protein kinase C (PKC); however, the phenomena were repressed by the administration of a muscarinic antagonist atropine. Taken together, these data indicate that VNS decreases ROS via AMPK-PKC-Nox pathway; this may have potential importance for the treatment of ischemic heart diseases.

We examined the transfer function of autonomic heart rate (HR) control in anesthetized sedentary and exercise-trained (16 wk, treadmill for 1 h, 5 times/wk at 15 m/min and 15-degree grade) rats for comparison to HR variability assessed in the conscious resting state. The transfer function from sympathetic stimulation to HR response was similar between groups (gain, 4.2 ± 1.5 vs. 4.5 ± 1.5 beats·min−1·Hz−1; natural frequency, 0.07 ± 0.01 vs. 0.08 ± 0.01 Hz; damping coefficient, 1.96 ± 0.55 vs. 1.69 ± 0.15; and lag time, 0.7 ± 0.1 vs. 0.6 ± 0.1 s; sedentary vs. exercise trained, respectively, means ± SD). The transfer gain from vagal stimulation to HR response was 6.1 ± 3.0 in the sedentary and 9.7 ± 5.1 beats·min−1·Hz−1 in the exercise-trained group ( P = 0.06). The corner frequency (0.11 ± 0.05 vs. 0.17 ± 0.09 Hz) and lag time (0.1 ± 0.1 vs. 0.2 ± 0.1 s) did not differ between groups. When the sympathetic transfer gain was averaged for very-low-frequency and low-frequency bands, no significant group effect was observed. In contrast, when the vagal transfer gain was averaged for very-low-frequency, low-frequency, and high-frequency bands, exercise training produced a significant group effect ( P < 0.05 by two-way, repeated-measures ANOVA). These findings suggest that, in the frequency domain, exercise training augments the dynamic HR response to vagal stimulation but not sympathetic stimulation, regardless of the frequency bands.

The atrial potential duration (APD) restitution has been suggested to play an important role in ventricular fibrillation; however, its role in atrial fibrillation (AF) has not been determined. This study sought to investigate the APD restitution properties in two different AF models: vagally mediated AF and 6-h rapid atrial pacing-induced AF.Twenty anaesthetized open-chest dogs were assigned to Group I, vagally mediated AF (n= 8) or Group II, 6-h rapid atrial pacing-induced AF (n= 12). In both groups, the monophasic APD was subsequently recorded at multiple pulmonary vein and atrial sites. The APD restitution curve was constructed using a dynamic pacing protocol and determined by plotting each APD(90) against the preceding diastolic interval at incremental atrial pacing rates at eight sites. In Group I, vagal stimulation significantly shortened the APD(90), flattened the APD restitution curve (slopes1), and suppressed the APD alternans at each site, while increasing the AF inducibility and duration (P0.05 for all). In Group II, 6-h rapid pacing-induced APD shortening steepened the restitution curves (slopes1), facilitated the APD alternans, and also increased the incidence and duration of AF (P0.05 for all). The spatial dispersion of APD restitution was significantly increased in both groups.This study showed distinct atrial APD restitution properties in vagally mediated AF and 6-h rapid pacing-induced AF, indicating specific restitution kinetics in different mechanisms of AF.

We estimated the transfer function of autonomic heart rate (HR) control by using random binary sympathetic or vagal nerve stimulation in anaesthetized rats. The transfer function from sympathetic stimulation to HR response approximated a second-order, low-pass filter with a lag time (gain, 4.29 ± 1.55 beats min−1 Hz−1; natural frequency, 0.07 ± 0.03 Hz; damping coefficient, 1.96 ± 0.64; and lag time, 0.73 ± 0.12 s). The transfer function from vagal stimulation to HR response approximated a first-order, low-pass filter with a lag time (gain, 8.84 ± 4.51 beats min−1 Hz−1; corner frequency, 0.12 ± 0.06 Hz; and lag time, 0.12 ± 0.08 s). These results suggest that the dynamic characteristics of HR control by the autonomic nervous system in rats are similar to those of larger mammals.

Background Atrioventricular (AV) node vagal stimulation (AVNVS) has recently emerged as a novel approach to controlling AV dromotropic function. Animal studies have demonstrated that selective epicardial AVNVS is effective in controlling ventricular rate (VR) acutely and in the long term. Endocardial AVNVS has been shown to significantly reduce VR acutely during atrial fibrillation (AF) in humans. However, no data are available on its long-term reproducibility. Objectives The purpose of this study was to demonstrate that the posteroseptal right atrium is a suitable site for permanent pacing and allows AVNVS in humans both acutely and during follow-up. Methods In 12 candidates for implantable cardioverter-defibrillator with a history of AF, the atrial lead was implanted in the posteroseptal right atrium, where advanced AV block was achieved during temporary high-frequency stimulation (HFS). On implantation and 3-month follow-up examination, HFS was delivered through the permanent lead to demonstrate the possibility to gradually slow the VR until complete AV block. Results On implantation, VR during AF was gradually slowed until complete AV block, which was elicited at 4.3 V (0.2 ms, 50 Hz). After 3 months, this effect remained reproducible. No significant change in pacing thresholds was observed after 3 months. We observed one dislodgment and one microdislodgement of atrial leads. Conclusions Our study demonstrates, for the first time in humans, that selective placement of the atrial lead yields electrical characteristics suitable for permanent pacing and enables VR to be significantly reduced under HFS. These results, which were reproducible during follow-up, provide data for the development of device-based control of VR during AF.

Recent studies have shown that rapid atrial pacing causes atrial electrical remodeling. However, the influence of the vagus nerve on atrial electrical remodeling is not clear.This study involved 24 dogs divided into three groups. In the control group, the inducibility of atrial fibrillation (AF) during vagal stimulation (VS(1)) was investigated. In the pacing group, the atrial effective refractory period (AERP) was determined before and after pacing in the left superior pulmonary vein (LSPV). In the vagal stimulation (VS) plus pacing group, the LSPV was subjected to rapid electrical pacing after vagal stimulation (VS(2)), and the AERP was measured both before VS(2) and after pacing. The I(KACh) density was measured in LSPV and atrial myocardial cells in the three groups using the patch-clamp technique.The duration of induced AF was greater in the pacing group than in the control or VS-plus-pacing group. In the pacing group, the AERP was markedly shortened and the AERP dispersion (dAERP) was significantly increased (P.05). However, there was no significant change in AERP in the VS-plus-pacing group, though the dAERP increased significantly (P.05). The I(KACh) density was increased in LSPV and atrial myocardial cells after pacing. However, there was no significant change in I(KACh) density after VS(2) plus pacing.Although shortening of the AERP may play a fundamental role, it is not in itself responsible for cholinergically induced AF. Rapid pacing in the LSPV increased the I(KACh). However, VS before rapid pacing partly protected the atria against electrical remodeling.

This article provides information and a commentary on trials relevant to the pathophysiology, prevention and treatment of heart failure presented at the American College of Cardiology meeting in 2009. Unpublished reports should be considered as preliminary, since analyses may change in the final publication. (123)I-mIBG myocardial scintigraphy was a good predictor of mortality in patients with heart failure in ADMIRE-HF. In PRIMA, use of individualized target NT-proBNP levels failed to improve outcomes compared with usual care in patients hospitalized with symptomatic heart failure. In the STICH trial, additional ventricular reconstruction surgery failed to improve outcomes in patients with ischaemic heart failure undergoing CABG. Cardiac resynchronization therapy may modify disease progression in patients with mild heart failure, according to data from REVERSE. Implantation of a defibrillator early after MI in high-risk patients in the IRIS study failed to improve outcomes compared with usual care. Cardiac contractility modulation showed some beneficial effects on symptoms and exercise capacity in the unblinded FIX-HF-5 study. Data from pre-RELAX-AHF show that relaxin may have potential as a treatment for acute heart failure. HF-ACTION showed that patients who complied with an exercise training regime achieved a better outcome, although this may be confounded by the ability of patients with a good prognosis to exercise for longer.

There is a gap in the history of cardiac pacing; this article is designed to fill this gap by bringing together some little-known facts about the history of pacing. There are two indications for cardiac pacing: 1) sinoatrial (S-A) node arrest and 2) atrioventricular (A-V) block. The S-A node, the heart’s natural pacemaker, can be diseased and thus dysfunction. It can be arrested by vagal stimulation. The A-V node can fail to transmit impulses from the atria to the ventricles; it can also fail due to disease or vagal stimulation. Chloroform anesthesia stimulates the vagus nerves and was the first reason for needing cardiac pacing. Surgical repair of the heart (patching a ventricular septal defect or operating on the great vessels of the heart) can cause A-V block and is treat

BACKGROUND AND OBJECTIVES Bicaval heart transplantation (HTx) may promote parasympathetic reinnervation. However, the prevalence and timing of reinnervation have not been fully investigated. Heart rate variability (HRV) and direct vagal stimulation were used to evaluate the presence of parasympathetic reinnervation after bicaval HTx. SUBJECTS AND METHODS A total of 21 patients (time after HTx 0.52-4.41 years, mean 1.8±1.2 years) who received a bicaval HTx was enrolled. Reinnervation was evaluated using HRV values from 24-hour Holter recordings. A cross-sectional analysis of the HRV at 0.5-1, 1-2, and >2 years after HTx was performed. We also applied high-frequency electrical stimulation (16.7 Hz, 1 msec pulse width, ≤10 V) to the cardiac branches of the vagus nerve at the level of the superior vena cava in eight patients at 6 and 12 months after HTx. RESULTS The degree of parasympathetic reinnervation corresponded to the time after HTx. The HRV analysis revealed that the root mean square of the successive differences between consecutive RR-intervals (RMSSD) and high-frequency power were significantly higher during the late period (>2 years) compared with the early period (0.5-1 year) after HTx. None of the eight patients who underwent direct vagal stimulation responded during the stimulation at 6 and 12 months, whereas incremental trends in HRV parameters were observed, which indicated that parasympathetic reinnervation began within 1 year after HTx. CONCLUSION Parasympathetic reinnervation seemed to begin in the early period (

We have postulated that chronic CO2 retention (e.g., U.S. Naval submariners underway, under-ventilated workspaces, hypoventilation disorders) causes chronic vagal stimulation of gastric mucosal blo...

We describe a patient with a history of neurocardiogenic syncopes who had a positive headup tilt test that resulted in an lasting asystole lasting 34 seconds. However, the previously carried out Schellong test with a 30-min phase of standing showed a normal result. The patient showed typical orthostatic symptoms while tilted at the angle of 75 degrees. Shortly before asystole occurred, heart rate variability showed high frequency bands, indicating vagal stimulation. The pathophysiology of neurocardiogenic syncope (NCS) in context with heart rate variability is discussed. This patient was successfully treated with propranolol. This case shows the utility of a provocative head-up tilt test in establishing the diagnosis of NCS. If the Schellong test is normal, still further examination by tilt-table test is indispensable.