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      Optogenetic Stimulation of Vagal Efferent Activity Preserves Left Ventricular Function in Experimental Heart Failure

      research-article
      , PhD a , , PhD a , b , , PhD c , , PhD b , , PhD a , ∗∗ , , PhD a ,
      JACC: Basic to Translational Science
      Elsevier
      autonomic nervous system, heart failure, myocardial infarction, neuromodulation, vagus nerve stimulation, ABP, arterial blood pressure, DVMN, dorsal motor nucleus of the vagus nerve, eGFP, enhanced green fluorescent protein, GRK2, G-protein−coupled receptor kinase 2, LAD, left anterior descending coronary artery, LV, left ventricle, LV dP/dtMAX, maximum rate of rise of left ventricular pressure, LVEDP, left ventricular end-diastolic pressure, LVESP, left ventricular end-systolic pressure, LVP, left ventricular pressure, LVV, lentiviral vector, MI, myocardial infarction, VNS, vagus nerve stimulation

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          Highlights

          • This study was designed to determine the effect of selective optogenetic simulation of vagal efferent activity on left ventricular function in an animal (rat) model of MI-induced heart failure.

          • Optogenetic stimulation of dorsal brainstem vagal pre-ganglionic neurons transduced to express light-sensitive channels preserved LV function and exercise capacity in animals with MI.

          • The data suggest that activation of vagal efferents is critically important to deliver the therapeutic benefit of VNS in chronic heart failure.

          Summary

          Large clinical trials designed to test the efficacy of vagus nerve stimulation (VNS) in patients with heart failure did not demonstrate benefits with respect to the primary endpoints. The nonselective nature of VNS may account for the failure to translate promising results of preclinical and earlier clinical studies. This study showed that optogenetic stimulation of vagal pre-ganglionic neurons transduced to express light-sensitive channels preserved left ventricular function and exercise capacity in a rat model of myocardial infarction−induced heart failure. These data suggested that stimulation of vagal efferent activity is critically important to deliver the therapeutic benefit of VNS in heart failure.

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          Most cited references37

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          Recommendations for quantitation of the left ventricle by two-dimensional echocardiography. American Society of Echocardiography Committee on Standards, Subcommittee on Quantitation of Two-Dimensional Echocardiograms.

          We have presented recommendations for the optimum acquisition of quantitative two-dimensional data in the current echocardiographic environment. It is likely that advances in imaging may enhance or supplement these approaches. For example, three-dimensional reconstruction methods may greatly augment the accuracy of volume determination if they become more efficient. The development of three-dimensional methods will depend in turn on vastly improved transthoracic resolution similar to that now obtainable by transesophageal echocardiography. Better resolution will also make the use of more direct methods of measuring myocardial mass practical. For example, if the epicardium were well resolved in the long-axis apical views, the myocardial shell volume could be measured directly by the biplane method of discs rather than extrapolating myocardial thickness from a single short-axis view. At present, it is our opinion that current technology justifies the clinical use of the quantitative two-dimensional methods described in this article. When technically feasible, and if resources permit, we recommend the routine reporting of left ventricular ejection fraction, diastolic volume, mass, and wall motion score.
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            Prospective Study of Heart Rate Variability and Mortality in Chronic Heart Failure: Results of the United Kingdom Heart Failure Evaluation and Assessment of Risk Trial (UK-Heart)

            Patients with chronic heart failure (CHF) have a continuing high mortality. Autonomic dysfunction may play an important role in the pathophysiology of cardiac death in CHF. UK-HEART examined the value of heart rate variability (HRV) measures as independent predictors of death in CHF. In a prospective study powered for mortality, we recruited 433 outpatients 62+/-9.6 years old with CHF (NYHA functional class I to III; mean ejection fraction, 0.41+/-0.17). Time-domain HRV indices and conventional prognostic indicators were related to death by multivariate analysis. During 482+/-161 days of follow-up, cardiothoracic ratio, SDNN, left ventricular end-systolic diameter, and serum sodium were significant predictors of all-cause mortality. The risk ratio for a 41.2-ms decrease in SDNN was 1.62 (95% CI, 1.16 to 2.44). The annual mortality rate for the study population in SDNN subgroups was 5.5% for >100 ms, 12.7% for 50 to 100 ms, and 51.4% for <50 ms. SDNN, creatinine, and serum sodium were related to progressive heart failure death. Cardiothoracic ratio, left ventricular end-diastolic diameter, the presence of nonsustained ventricular tachycardia, and serum potassium were related to sudden cardiac death. A reduction in SDNN was the most powerful predictor of the risk of death due to progressive heart failure. CHF is associated with autonomic dysfunction, which can be quantified by measuring HRV. A reduction in SDNN identifies patients at high risk of death and is a better predictor of death due to progressive heart failure than other conventional clinical measurements. High-risk subgroups identified by this measurement are candidates for additional therapy after prescription of an ACE inhibitor.
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              Vagal nerve stimulation markedly improves long-term survival after chronic heart failure in rats.

              Diminished cardiac vagal activity and higher heart rate predict a high mortality rate of chronic heart failure (CHF) after myocardial infarction. We investigated the effects of chronic electrical stimulation of the vagus nerve on cardiac remodeling and long-term survival in an animal model of CHF after large myocardial infarction. Two weeks after the ligation of the left coronary artery, surviving rats were randomized to vagal- and sham-stimulated groups. Using an implantable miniature radio-controlled electrical stimulator, we stimulated the right vagal nerve of CHF rats for 6 weeks. The intensity of electrical stimulation was adjusted for each rat, so that the heart rate was lowered by 20 to 30 beats per minute. The treated rats had significantly lower left ventricular end-diastolic pressure (17.1+/-5.9 versus 23.5+/-4.2 mm Hg, P<0.05) and higher maximum dp/dt of left ventricular pressure (4152+/-237 versus 2987+/-192 mm Hg/s, P<0.05) than the untreated rats. Improvement of cardiac pumping function was accompanied by a decrease in normalized biventricular weight (2.75+/-0.25 versus 3.14+/-0.22 g/kg, P<0.01). Although the 140-day survival of the untreated group was only half, vagal stimulation markedly improved the survival rate (86% versus 50%, P=0.008). Vagal stimulation therapy achieved a 73% reduction in a relative risk ratio of death. Vagal nerve stimulation markedly improved the long-term survival of CHF rats through the prevention of pumping failure and cardiac remodeling.
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                Author and article information

                Contributors
                Journal
                JACC Basic Transl Sci
                JACC Basic Transl Sci
                JACC: Basic to Translational Science
                Elsevier
                2452-302X
                15 July 2020
                August 2020
                15 July 2020
                : 5
                : 8
                : 799-810
                Affiliations
                [a ]Centre for Cardiovascular and Metabolic Neuroscience, Department of Neuroscience, Physiology and Pharmacology, University College London, London, United Kingdom
                [b ]Translational Medicine and Therapeutics, William Harvey Research Institute, Queen Mary University of London, London, United Kingdom
                [c ]Clinical Physiology, Division of Medicine, University College London, London, United Kingdom
                Author notes
                [] Address for correspondence: Dr. Alexander V. Gourine, Neuroscience, Physiology and Pharmacology, University College London, Gower Street, London WC1E 6BT, United Kingdom. a.gourine@ 123456ucl.ac.uk
                [∗∗ ]Dr. Svetlana Mastitskaya, Neuroscience, Physiology and Pharmacology, University College London, Gower Street, London WC1E 6BT, United Kingdom. s.mastitskaya@ 123456ucl.ac.uk
                Article
                S2452-302X(20)30257-6
                10.1016/j.jacbts.2020.06.002
                7452237
                32875170
                a06d72df-4560-478e-81b0-8fee1a40b4b1
                © 2020 The Authors

                This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).

                History
                : 9 December 2019
                : 5 June 2020
                : 6 June 2020
                Categories
                PRECLINICAL RESEARCH

                autonomic nervous system,heart failure,myocardial infarction,neuromodulation,vagus nerve stimulation,abp, arterial blood pressure,dvmn, dorsal motor nucleus of the vagus nerve,egfp, enhanced green fluorescent protein,grk2, g-protein−coupled receptor kinase 2,lad, left anterior descending coronary artery,lv, left ventricle,lv dp/dtmax, maximum rate of rise of left ventricular pressure,lvedp, left ventricular end-diastolic pressure,lvesp, left ventricular end-systolic pressure,lvp, left ventricular pressure,lvv, lentiviral vector,mi, myocardial infarction,vns, vagus nerve stimulation

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