Analysis of intrinsic cardiac neuron activity in relation to neurogenic atrial fibrillation and vagal stimulation

La fibrillation auriculaire est le trouble du rythme le plus fréquent chez l'homme. Elle conduit souvent à de graves complications telles que l'insuffisance cardiaque et les accidents vasculaires cérébraux. Un mécanisme neurogène de la fibrillation auriculaire mis en évidence. L'induction de tachyarythmie par stimulation du nerf médiastinal a été proposée comme modèle pour étudier la fibrillation auriculaire neurogène. Dans cette thèse, nous avons étudié l'activité des neurones cardiaques intrinsèques et leurs interactions à l'intérieur des plexus ganglionnaires de l'oreillette droite dans un modèle canin de la fibrillation auriculaire neurogène. Ces activités ont été enregistrées par un réseau multicanal de microélectrodes empalé dans le plexus ganglionnaire de l'oreillette droite. L'enregistrement de l'activité neuronale a été effectué continument sur une période de près de 4 heures comprenant différentes interventions vasculaires (occlusion de l'aorte, de la veine cave inférieure, puis de l'artère coronaire descendante antérieure gauche), des stimuli mécaniques (toucher de l'oreillette ou du ventricule) et électriques (stimulation du nerf vague ou des ganglions stellaires) ainsi que des épisodes induits de fibrillation auriculaire. L'identification et la classification neuronale ont été effectuées en utilisant l'analyse en composantes principales et le partitionnement de données (cluster analysis) dans le logiciel Spike2. Une nouvelle méthode basée sur l'analyse en composante principale est proposée pour annuler l'activité auriculaire superposée sur le signal neuronal et ainsi augmenter la précision de l'identification de la réponse neuronale et de la classification. En se basant sur la réponse neuronale, nous avons défini des sous-types de neurones (afférent, efférent et les neurones des circuits locaux). Leur activité liée à différents facteurs de stress nous ont permis de fournir une description plus détaillée du système nerveux cardiaque intrinsèque. La majorité des neurones enregistrés ont réagi à des épisodes de fibrillation auriculaire en devenant plus actifs. Cette hyperactivité des neurones cardiaques intrinsèques suggère que le contrôle de cette activité pourrait aider à prévenir la fibrillation auriculaire neurogène. Puisque la stimulation à basse intensité du nerf vague affaiblit l'activité neuronale cardiaque intrinsèque (en particulier pour les neurones afférents et convergents des circuits locaux), nous avons examiné si cette intervention pouvait être appliquée comme thérapie pour la fibrillation auriculaire. Nos résultats montrent que la stimulation du nerf vague droit a été en mesure d'atténuer la fibrillation auriculaire dans 12 des 16 cas malgré un effet pro-arythmique défavorable dans 1 des 16 cas. L'action protective a diminué au fil du temps et est devenue inefficace après ~ 40 minutes après 3 minutes de stimulation du nerf vague.

Differences in atrial fibrillation properties under vagal nerve stimulation versus atrial tachycardia remodeling

Fond : Le substrat de fibrillation auriculaire (FA) vagale et celui secondaire à remodelage par tachycardie auriculaire (RTA) partagent beaucoup des caractéristiques : période réfractaire efficace (PRE) réduite, hétérogénéité accrue de PRE et quelques mécanismes moléculaires communs. Cette étude a comparé les 2 substrats à une abréviation comparable de PRE. Méthodes : Chez chacun de 6 chiens de groupe de stimulation vagal (SV), les paramètres de stimulation cervicale bilatérale de nerves vagaux ont été ajustés pour produire la même PRE moyenne (calculé à 8 sites des oreillettes gauche et droite) avec 6 chiens de groupe de RTA assorti à sexe et poids. Des paramètres électrophysiologiques, la durée moyenne de la fibrillation auriculaire (DAF) et les fréquences dominantes (FD) locales ont étés calculés. Résultats : En dépit des PREs assorties (SV: 80±12msec contre RTA: 79±12msec) la DAF était plus longue (*), l’hétérogénéité de conduction était plus élevée (*), la FD était plus rapide (*) et la variabilité de FD plus grande (*) chez les chiens SV. Les zones de maximum FD qui reflètent les zones d’origine de FA étaient à côté de ganglions autonomes chez les chiens SV. Conclusions : Pour un PRE atriale comparable, la FA secondaire à SV est plus rapide et plus persistante que la FA avec un substrat de RTA. Ces résultats sont consistants avec des modèles de travail suggérant que l'hyperpolarisation SV-induite contribue de façon important à la stabilisation et à l'accélération des rotors qui maintiennent la FA. La similitude de la distribution de FD du groupe vagal avec la distribution des lésions d’ablation après cartographie des électrogrammes atriales fragmentés suggère des nouvelles techniques d’ablation. La distribution des FD entre le SV et le RTA fournit de nouvelles idées au sujet de possible rémodelage neuroreceptorial et indique des différences importantes entre ces substrats de FA superficiellement semblables.

Modélisation d'arythmies auriculaires modulées par le système nerveux autonome

La fibrillation auriculaire (FA) est la forme d’arythmie la plus fréquente et représente environ un tiers des hospitalisations attribuables aux troubles du rythme cardiaque. Les mécanismes d’initiation et de maintenance de la FA sont complexes et multiples. Parmi ceux-ci, une contribution du système nerveux autonome a été identifiée mais son rôle exact demeure mal compris. Ce travail cible l’étude de la modulation induite par l’acétylcholine (ACh) sur l’initiation et le maintien de la FA, en utilisant un modèle de tissu bidimensionnel. La propagation de l’influx électrique sur ce tissu est décrite par une équation réaction-diffusion non-linéaire résolue sur un maillage rectangulaire avec une méthode de différences finies, et la cinétique d'ACh suit une évolution temporelle prédéfinie qui correspond à l’activation du système parasympathique. Plus de 4400 simulations ont été réalisées sur la base de 4 épisodes d’arythmies, 5 tailles différentes de région modulée par l’ACh, 10 concentrations d’ACh et 22 constantes de temps de libération et de dégradation d’ACh. La complexité de la dynamique des réentrées est décrite en fonction de la constante de temps qui représente le taux de variation d’ACh. Les résultats obtenus suggèrent que la stimulation vagale peut mener soit à une dynamique plus complexe des réentrées soit à l’arrêt de la FA en fonction des quatre paramètres étudiés. Ils démontrent qu’une décharge vagale rapide, représentée par des constantes de temps faibles combinées à une quantité suffisamment grande d’ACh, a une forte probabilité de briser la réentrée primaire provoquant une activité fibrillatoire. Cette activité est caractérisée par la création de plusieurs ondelettes à partir d’un rotor primaire sous l’effet de l’hétérogénéité du gradient de repolarisation causé par l’activité autonomique.

Prolonged effects of modified sham feeding on energy substrate mobilization

Background: Vagal stimulation in response to nutrients is reported to elicit an array of digestive and endocrine responses, including an alteration in postprandial lipid metabolism. Objective: The objective of this study was to assess whether neural stimulation could alter hormone and substrate metabolism during the late postprandial phase, with implications for body fat mobilization. Design: Vagal stimulation was achieved by using the modified sham feeding (MSF) technique, in which nutrients are chewed and tasted but not swallowed. Ten healthy subjects were studied on 3 separate occasions, 4 wk apart. Five hours after a high-fat breakfast (56 g fat), the subjects were given 1 of 3 test meals allocated in random order: water, a lunch containing a modest amount of fat (38 g), or MSF (38 g fat). Blood was collected for 3 h poststimulus for hormone and metabolite analyses. Results: Plasma insulin and pancreatic polypeptide concentrations peaked at 250% and 209% of baseline concentrations within 15 min of MSF. The plasma glucose concentration increased significantly (P = 0.038) in parallel with the changes observed in the plasma insulin concentration. The nonesterified fatty acid concentration was significantly suppressed (P = 0.006); maximum suppression occurred at a mean time of 114 min after MSF. This fall in nonesterified fatty acid was accompanied by a fall in the plasma glucagon concentration from 122 to 85 pmol/L (P = 0.018) at a mean time of 113 min after MSF. Conclusions: Effects on substrate metabolism after MSF in the postprandial state differ from those usually reported in the postabsorptive state. The effects of MSF were prolonged beyond the period of the cephalic response and these may be relevant for longer-term metabolic regulation.

Parada cardíaca inesperada durante colecistectomia: relato de caso

JUSTIFICATIVA E OBJETIVOS: A parada cardíaca per-operatória é um evento grave, e sua incidência em nosso serviço é de 31:10.000 anestesias. O objetivo deste relato é apresentar um caso de parada cardíaca durante anestesia geral em uma paciente submetida a colecistectomia. RELATO do CASO: Paciente feminina, 16 anos, 62 kg, estado físico ASA I, submetida à colecistectomia por via aberta. Midazolam (15 mg) por via oral foi a medicação pré-anestésica. Foi realizadas indução anestésica com sufentanil (50 µg), propofol (150 mg) e atracúrio (30 mg). A anestesia foi mantida com isoflurano e N2O. Após trinta minutos de cirurgia ocorreu bradicardia sinusal revertida com atropina (0,5 mg). Vinte minutos depois, ocorreu outra bradicardia com bloqueio átrio-ventricular de 3º grau evoluindo rapidamente para parada cardíaca (PCR) em assistolia, apesar da administração de atropina (1 mg). As manobras de reanimação foram iniciadas imediatamente, juntamente com a administração de adrenalina (1 mg), com retorno dos batimentos cardíacos espontâneos após aproximadamente cinco minutos da PCR. A cirurgia foi concluída e a paciente manteve-se estável hemodinami- camente. A paciente foi extubada duas horas após o término da cirurgia apresentando-se sonolenta, não contactante, com bom padrão ventilatório e hemodinâmico. Após doze horas de observação na unidade de terapia intensiva (UTI) a paciente apresentava-se agitada e desconexa. Vinte e quatro horas após a PCR a paciente recebeu alta da UTI consciente, orientada, sem queixas e sem déficit neurológico. Recebeu alta hospitalar no 4º dia do pós-operatório. CONCLUSÕES: Diversos fatores podem contribuir para a ocorrência de disritmias e parada cardíaca no per-operatório, destacando-se a estimulação vagal secundária às manobras cirúrgicas. O diagnóstico precoce e o rápido início das manobras de reanimação são de fundamental importância para a boa evolução neurológica desses pacientes

Left cardiac sympathetic denervation for treatment of symptomatic systolic heart failure patients: a pilot study

To evaluate the feasibility, safety, and potential beneficial effects of left cardiac sympathetic denervation (LCSD) in systolic heart failure (HF) patients. In this prospective, randomized pilot study, inclusion criteria were New York Heart Association (NYHA) functional class II or III, left ventricular ejection fraction (LVEF) 40, sinus rhythm, and resting heart rate 65 b.p.m., despite optimal medical therapy (MT). Fifteen patients were randomly assigned either to MT alone or MT plus LCSD. The primary endpoint was safety, measured by mortality in the first month of follow-up and morbidity according to pre-specified criteria. Secondary endpoints were exercise capacity, quality of life, LVEF, muscle sympathetic nerve activity (MSNA), brain natriuretic peptide (BNP) levels and 24 h Holter mean heart rate before and after 6 months. We studied clinical effects in long-term follow-up. Ten patients underwent LCSD. There were no adverse events attributable to surgery. In the LCSD group, LVEF improved from 25 6.6 to 33 5.2 (P 0.03); 6 min walking distance improved from 167 35 to 198 47 m (P 0.02). Minnesota Living with Heart Failure Questionnaire (MLWHFQ) score physical dimension changed from 21 5 to 15 7 (P 0.06). The remaining analysed variables were unchanged. During 848 549 days of follow-up, in the MT group, three patients either died or underwent cardiac transplantation (CT), while in the LCSD group six were alive without CT. LCSD was feasible and seemed to be safe in systolic HF patients. Its beneficial effects warrant the development of a larger randomized trial. Trail registration: NCT01224899.

Third degree atrioventricular block and accelerated idioventricular rhythm associated with a heart base chemodectoma in a syncopal Rottweiler.

A 7-year-old male intact Rottweiler was presented with a 1-week history of lethargy, anorexia, vomiting and multiple syncopal events. The results of the clinical examination and electrocardiography were consistent with a third degree atrioventricular block and an intermittent accelerated idioventricular rhythm. Haematology, serum biochemistry, serology for Borrelia burgdorferi, blood culture, total T4, thoracic radiography and echocardiography did not reveal the cause of the arrhythmia. Response to medical treatment with isoproterenol was poor. Pacemaker placement was declined by the owners and the dog was euthanized at their request. Histopathological examination of the heart revealed a chemodectoma at the base of the heart. There was no neoplastic infiltration of the conduction tissue. Potential mechanisms explaining the association of the arrhythmias and the tumour, such as vagal stimulation and neuroendocrine factors are discussed.

Paracetamol [acetaminophen]-induced gastrotoxicity: Revealed by induced hyperacidity in combination with acute or chronic inflammation

Paracetamol is regarded as a relatively safe drug in the gastro-duodenal region of humans but recent epidemiological investigations have suggested that at high doses there may be an increased risk of ulcers and bleeding. To investigate the possibility that inflammatory conditions and gastric acidity may play a role in potentiating development of gastric mucosal injury from paracetamol in rats (as noted previously with various non-steroidal anti-inflammatory drugs) we studied the gastric irritant effects of paracetamol and some phenolic and non-phenolic analgesics and antipyretics in rats with adjuvant or collagen II induced arthritis or zymosan-induced paw inflammation and given 1.0 ml hydrochloric acid (HCl) 0.1 M and/or an i. p. injection of the cholinomimetic, acetyl-β-methyl choline chloride 5.0 mg/kg. Gastric lesions were determined 2 h after oral administration of 100 or 250 mg/kg paracetamol or at therapeutically effective doses of the phenolic or non-phenolic analgesics/antipyretics. The results showed that gastric mucosal injury occurred with all these agents when given to animals that received all treatments so indicating there is an adverse synergy of these three factors, namely: (i) intrinsic disease; (ii) hyperacidity; and (iii) vagal stimulation for rapidly promoting gastric damage, both in the fundic as well as the antral mucosa, for producing gastric damage by paracetamol, as well as the other agents. Removing one of these three predisposing factors effectively blunts/abolishes expression of this paracetamol-induced gastrotoxity in rats. These three factors, without paracetamol, did not cause significant acute gastropathy.

Acute Exposure to Terrestrial Trunked Radio (TETRA) has effects on the electroencephalogram and electrocardiogram, consistent with vagal nerve stimulation

BACKGROUND: Terrestrial Trunked Radio (TETRA) is a telecommunications system widely used by police and emergency services around the world. The Stewart Report on mobile telephony and health raised questions about possible health effects associated with TETRA signals. This study investigates possible effects of TETRA signals on the electroencephalogram and electrocardiogram in human volunteers. METHODS: Blinded randomized provocation study with a standardized TETRA signal or sham exposure. In the first of two experiments, police officers had a TETRA set placed first against the left temple and then the upper-left quadrant of the chest and the electroencephalogram was recorded during rest and active cognitive processing. In the second experiment, volunteers were subject to chest exposure of TETRA whilst their electroencephalogram and heart rate variability derived from the electrocardiogram were recorded. RESULTS: In the first experiment, we found that exposure to TETRA had consistent neurophysiological effects on the electroencephalogram, but only during chest exposure, in a pattern suggestive of vagal nerve stimulation. In the second experiment, we observed changes in heart rate variability during exposure to TETRA but the electroencephalogram effects were not replicated. CONCLUSIONS: Observed effects of exposure to TETRA signals on the electroencephalogram (first experiment) and electrocardiogram are consistent with vagal nerve stimulation in the chest by TETRA. However given the small effect on heart rate variability and the lack of consistency on the electroencephalogram, it seems unlikely that this will have a significant impact on health. Long-term monitoring of the health of the police force in relation to TETRA use is on-going.

Voltage-gated potassium currents within the dorsal vagal nucleus: inhibition by BDS toxin

Voltage-gated potassium (Kv) channels are essential components of neuronal excitability. The Kv3.4 channel protein is widely distributed throughout the central nervous system (CNS), where it can form heteromeric or homomeric Kv3 channels. Electrophysiological studies reported here highlight a functional role for this channel protein within neurons of the dorsal vagal nucleus (DVN). Current clamp experiments revealed that blood depressing substance (BDS) and intracellular dialysis of an anti-Kv3.4 antibody prolonged the action potential duration. In addition, a BDS sensitive, voltage-dependent, slowly inactivating outward current was observed in voltage clamp recordings from DVN neurons. Electrical stimulation of the solitary tract evoked EPSPs and IPSPs in DVN neurons and BDS increased the average amplitude and decreased the paired pulse ratio, consistent with a presynaptic site of action. This presynaptic modulation was action potential dependent as revealed by ongoing synaptic activity. Given the role of the Kv3 proteins in shaping neuronal excitability, these data highlight a role for homomeric Kv3.4 channels in spike timing and neurotransmitter release in low frequency firing neurons of the DVN.

Auditory stimulation and cardiac autonomic regulation

Previous studies have already demonstrated that auditory stimulation with music influences the cardiovascular system. In this study, we described the relationship between musical auditory stimulation and heart rate variability. Searches were performed with the Medline, SciELO, Lilacs and Cochrane databases using the following keywords: auditory stimulation, autonomic nervous system, music and heart rate variability. The selected studies indicated that there is a strong correlation between noise intensity and vagal-sympathetic balance. Additionally, it was reported that music therapy improved heart rate variability in anthracycline-treated breast cancer patients. It was hypothesized that dopamine release in the striatal system induced by pleasurable songs is involved in cardiac autonomic regulation. Musical auditory stimulation influences heart rate variability through a neural mechanism that is not well understood. Further studies are necessary to develop new therapies to treat cardiovascular disorders.

Response of cardiac autonomic modulation after a single exposure to musical auditory stimulation

The acute effects after exposure to different styles of music on cardiac autonomic modulation assessed through heart rate variability (HRV) analysis have not yet been well elucidated. We aimed to investigate the recovery response of cardiac autonomic modulation in women after exposure to musical auditory stimulation of different styles. The study was conducted on 30 healthy women aged between 18 years and 30 years. We did not include subjects having previous experience with musical instruments and those who had an affinity for music styles. The volunteers remained at rest for 10 min and were exposed to classical baroque (64-84 dB) and heavy metal (75-84 dB) music for 10 min, and their HRV was evaluated for 30 min after music cessation. We analyzed the following HRV indices: Standard deviation of normal-to-normal (SDNN) intervals, root mean square of successive differences (RMSSD), percentage of normal-to-normal 50 (pNN50), low frequency (LF), high frequency (HF), and LF/HF ratio. SDNN, LF in absolute units (ms (2) ) and normalized (nu), and LF/HF ratio increased while HF index (nu) decreased after exposure to classical baroque music. Regarding the heavy metal music style, it was observed that there were increases in SDNN, RMSSD, pNN50, and LF (ms (2) ) after the musical stimulation. In conclusion, the recovery response of cardiac autonomic modulation after exposure to auditory stimulation with music featured an increased global activity of both systems for the two musical styles, with a cardiac sympathetic modulation for classical baroque music and a cardiac vagal tone for the heavy metal style.

Time course of the hemodynamic responses to aortic depressor nerve stimulation in conscious spontaneously hypertensive rats

The time to reach the maximum response of arterial pressure, heart rate and vascular resistance (hindquarter and mesenteric) was measured in conscious male spontaneously hypertensive (SHR) and normotensive control rats (NCR; Wistar; 18-22 weeks) subjected to electrical stimulation of the aortic depressor nerve (ADN) under thiopental anesthesia. The parameters of stimulation were 1 mA intensity and 2 ms pulse length applied for 5 s, using frequencies of 10, 30, and 90 Hz. The time to reach the hemodynamic responses at different frequencies of ADN stimulation was similar for SHR (N = 15) and NCR (N = 14); hypotension = NCR (4194 +/- 336 to 3695 +/- 463 ms) vs SHR ( 3475 +/- 354 to 4494 +/- 300 ms); bradycardia = NCR (1618 +/- 152 to 1358 +/- 185 ms) vs SHR (1911 +/- 323 to 1852 +/- 431 ms), and the fall in hindquarter vascular resistance = NCR (6054 +/- 486 to 6550 +/- 847 ms) vs SHR (4849 +/- 918 to 4926 +/- 646 ms); mesenteric = NCR (5574 +/- 790 to 5752 +/- 539 ms) vs SHR (5638 +/- 648 to 6777 +/- 624 ms). In addition, ADN stimulation produced baroreflex responses characterized by a faster cardiac effect followed by a vascular effect, which together contributed to the decrease in arterial pressure. Therefore, the results indicate that there is no alteration in the conduction of the electrical impulse after the site of baroreceptor mechanical transduction in the baroreflex pathway (central and/or efferent) in conscious SHR compared to NCR.

Acute adenosine increases cardiac vagal and reduces sympathetic efferent nerve activities in rats

Adenosine is the first drug of choice in the treatment of supraventricular arrhythmias. While the effects of adenosine on sympathetic nerve activity (SNA) have been investigated, no information is available on the effects on cardiac vagal nerve activity (VNA). We assessed in rats the responses of cardiac VNA, SNA and cardiovascular variables to intravenous bolus administration of adenosine. In 34 urethane-anaesthetized rats, cardiac VNA or cervical preganglionic sympathetic fibres were recorded together with ECG, arterial pressure and ventilation, before and after administration of three doses of adenosine (100, 500 and 1000 mu g kg-1). The effects of adenosine were also assessed in isolated perfused hearts (n= 5). Adenosine induced marked bradycardia and hypotension, associated with a significant dose-dependent increase in VNA (+204 +/- 56%, P < 0.01; +275 +/- 120%, P < 0.01; and +372 +/- 78%, P < 0.01, for the three doses, respectively; n= 7). Muscarinic blockade by atropine (5 mg kg-1, i.v.) significantly blunted the adenosine-induced bradycardia (-56.0 +/- 4.5%, P < 0.05; -86.2 +/- 10.5%, P < 0.01; and -34.3 +/- 9.7%, P < 0.01, respectively). Likewise, adenosine-induced bradycardia was markedly less in isolated heart preparations. Previous barodenervation did not modify the effects of adenosine on VNA. On the SNA side, adenosine administration was associated with a dose-dependent biphasic response, including overactivation in the first few seconds followed by a later profound SNA reduction. Earliest sympathetic activation was abolished by barodenervation, while subsequent sympathetic withdrawal was affected neither by baro- nor by chemodenervation. This is the first demonstration that acute adenosine is able to activate cardiac VNA, possibly through a central action. This increase in vagal outflow could make an important contribution to the antiarrhythmic action of this substance.