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      Control of ventricular excitability by neurons of the dorsal motor nucleus of the vagus nerve

      research-article
      , BS * , , , MBBS * , , , PhD, FRCA § , , PhD , , MD, PhD , , PhD , , PhD * , , MBBS, PhD, FRCP , , MBBS, PhD * , , PhD * , *
      Heart Rhythm
      Elsevier
      7-NI, 7-Nitroindazole, AlstR, allatostatin receptor, AVNERP, atrioventricular node effective recovery period, DVMN, dorsal vagal motor nucleus, eGFP, enhanced green fluorescent protein, LVV, lentiviral vector, NO, nitric oxide, nNOS, neuronal nitric oxide synthase, QTc, corrected QT interval, SNRT, sinus node recovery time, vERP, ventricular effective refractory period, VT, ventricular tachycardia, WT, wild type, Arrhythmia, Atrioventricular, Brain, Cardiac electrophysiology, Nitric oxide, parasympathetic, Parkinson’s disease, Vagus nerve, Ventricle
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          Abstract

          Background

          The central nervous origins of functional parasympathetic innervation of cardiac ventricles remain controversial.

          Objective

          This study aimed to identify a population of vagal preganglionic neurons that contribute to the control of ventricular excitability. An animal model of synuclein pathology relevant to Parkinson’s disease was used to determine whether age-related loss of the activity of the identified group of neurons is associated with changes in ventricular electrophysiology.

          Methods

          In vivo cardiac electrophysiology was performed in anesthetized rats in conditions of selective inhibition of the dorsal vagal motor nucleus (DVMN) neurons by pharmacogenetic approach and in mice with global genetic deletion of all family members of the synuclein protein.

          Results

          In rats anesthetized with urethane (in conditions of systemic beta-adrenoceptor blockade), muscarinic and neuronal nitric oxide synthase blockade confirmed the existence of a tonic parasympathetic control of cardiac excitability mediated by the actions of acetylcholine and nitric oxide. Acute DVMN silencing led to shortening of the ventricular effective refractory period (vERP), a lowering of the threshold for triggered ventricular tachycardia, and prolongation of the corrected QT (QTc) interval. Lower resting activity of the DVMN neurons in aging synuclein-deficient mice was found to be associated with vERP shortening and QTc interval prolongation.

          Conclusion

          Activity of the DVMN vagal preganglionic neurons is responsible for tonic parasympathetic control of ventricular excitability, likely to be mediated by nitric oxide. These findings provide the first insight into the central nervous substrate that underlies functional parasympathetic innervation of the ventricles and highlight its vulnerability in neurodegenerative diseases.

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          Most cited references24

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          Baroreflex sensitivity and heart-rate variability in prediction of total cardiac mortality after myocardial infarction. ATRAMI (Autonomic Tone and Reflexes After Myocardial Infarction) Investigators.

          Experimental evidence suggests that autonomic markers such as heart-rate variability and baroreflex sensitivity (BRS) may contribute to postinfarction risk stratification. There are clinical data to support this concept for heart-rate variability. The main objective of the ATRAMI study was to provide prospective data on the additional and independent prognostic value for cardiac mortality of heart-rate variability and BRS in patients after myocardial infarction in whom left-ventricular ejection fraction (LVEF) and ventricular arrhythmias were known. This multicentre international prospective study enrolled 1284 patients with a recent ( 105 ms, BRS >6.1 ms per mm Hg). The association of low SDNN or BRS with LVEF below 35% carried a relative risk of 6.7 (3.1-14.6) or 8.7 (4.3-17.6), respectively, compared with patients with LVEF above 35% and less compromised SDNN (> or = 70 ms) and BRS (> or = 3 ms per mm Hg). ATRAMI provides clinical evidence that after myocardial infarction the analysis of vagal reflexes has significant prognostic value independently of LVEF and of ventricular arrhythmias and that it significantly adds to the prognostic value of heart-rate variability.
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            Vagal stimulation and prevention of sudden death in conscious dogs with a healed myocardial infarction.

            The interest for the antifibrillatory effect of vagal stimulation has been largely limited by the fact that this concept seemed restricted to acute experiments in anesthetized animals. To explore the potentially protective role of vagal stimulation in conscious animals we developed a chronically implantable device to be placed around the cervical right vagus. An anterior myocardial infarction was produced in 161 dogs; 1 month later an exercise stress test was performed on the 105 survivors. Toward the end of the test the circumflex coronary artery was occluded for 2 minutes. Fifty-nine (56%) dogs developed ventricular fibrillation and, before this test was repeated, were assigned either to a control group (n = 24) or to be instrumented with the vagal device (n = 35). Five dogs were excluded because of electrode malfunction. Compared with the heart rate level attained after 30 seconds of occlusion during exercise in the control test, vagal stimulation led to a decrease of approximately 75 beats/min (from 255 +/- 33 to 170 +/- 36 beats/min, p less than 0.001). In the control group 22 (92%) of 24 dogs developed ventricular fibrillation during the second exercise and ischemia test. By contrast, during vagal stimulation ventricular fibrillation occurred in only 3 (10%) of the 30 dogs tested and recurred in 26 (87%) during an additional exercise and ischemia test in the control condition (p less than 0.001 versus the vagal stimulation test; internal control analysis). Combined analysis of the tests performed in the control condition showed that ventricular fibrillation was reproducible in 48 (89%) of the 54 dogs tested. The protective effect of vagal stimulation was also significant in the group comparison analysis and even after exclusion of those four dogs in which ventricular fibrillation was not reproducible (92% versus 11.5%, control versus vagal stimulation, p less than 0.001). When heart rate was kept constant by atrial pacing, the vagally mediated protection was still significant (p = 0.015) as five (55%) of nine dogs survived the test. This study shows that vagal stimulation, performed shortly after the onset of an acute ischemic episode in conscious animals with a healed myocardial infarction, can effectively prevent ventricular fibrillation. This striking result seems to depend on multiple mechanisms having a synergistic action. The decrease in heart rate is an important but not always essential protective mechanism. The electrophysiological effects secondary to the vagally mediated antagonism of the sympathetic activity on the heart are likely to play a major role.
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              Staging of the intracerebral inclusion body pathology associated with idiopathic Parkinson's disease (preclinical and clinical stages).

              The synucleinopathy known as idiopathic Parkinson's disease (IPD) is a multi-system disorder in the course of which only a few predisposed nerve cell types in specific regions of the human brain become progressively involved. The underlying neuropathological process (formation of proteinaceous intraneuronal inclusion bodies) intracerebrally begins in clearly defined induction sites and advances in a topographically predictable sequence. Components of the autonomic, limbic, and motor systems sustain especially heavy damage. During the presymptomatic stages 1 and 2, the IPD-related inclusion body pathology remains confined to the medulla oblongata and olfactory bulb. In stages 3 and 4, the substantia nigra and other nuclear grays of the midbrain and basal forebrain are the focus of initially subtle and, then, severe changes. The illness reaches its symptomatic phase. In end-stages 5 and 6, the pathological process encroaches upon the telencephalic cortex. IPD manifests itself in all of its dimensions, which under the influence of the supervening cortical pathology are subject to increasing complexity.
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                Author and article information

                Contributors
                Journal
                Heart Rhythm
                Heart Rhythm
                Heart Rhythm
                Elsevier
                1547-5271
                1556-3871
                1 November 2015
                November 2015
                : 12
                : 11
                : 2285-2293
                Affiliations
                [* ]Centre for Cardiovascular and Metabolic Neuroscience, Department of Neuroscience, Physiology and Pharmacology, University College London, London, United Kingdom
                []Centre for Advanced Biomedical Imaging, University College London, London, United Kingdom
                []William Harvey Heart Centre, Barts & The London School of Medicine and Dentistry, London, United Kingdom
                [§ ]Department of Medicine, University College London, London, United Kingdom,
                []School of Biosciences, University of Cardiff, Cardiff, United Kingdom
                Author notes
                [* ] Address reprint requests and correspondence: Alexander V. Gourine, Neuroscience, Physiology & Pharmacology, University College London, Gower Street, London WC1E 6BT, United Kingdom; e-mail address: a.gourine@ucl.ac.uk or Andrew Tinker, William Harvey Heart Centre, Barts & The London School of Medicine and Dentistry, London EC1M 6BQ, United Kingdom a.tinker@ 123456qmul.ac.uk
                Article
                S1547-5271(15)00695-5
                10.1016/j.hrthm.2015.06.005
                4631809
                26051529
                28564bdb-bbf8-43d0-a250-cc6b120e1b9f
                © 2015 Elsevier Inc. on behalf of Heart Rhythm Society. All rights reserved.
                History
                Categories
                Article

                Cardiovascular Medicine
                7-ni, 7-nitroindazole,alstr, allatostatin receptor,avnerp, atrioventricular node effective recovery period,dvmn, dorsal vagal motor nucleus,egfp, enhanced green fluorescent protein,lvv, lentiviral vector,no, nitric oxide,nnos, neuronal nitric oxide synthase,qtc, corrected qt interval,snrt, sinus node recovery time,verp, ventricular effective refractory period,vt, ventricular tachycardia,wt, wild type,arrhythmia,atrioventricular,brain,cardiac electrophysiology,nitric oxide,parasympathetic,parkinson’s disease,vagus nerve,ventricle

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