Skip to main content
NCBI home page
Experimental Physiology logoLink to Experimental Physiology
. 2023 Sep 26;109(12):2001–2005. doi: 10.1113/EP090866

Selective efferent vagal stimulation in heart failure

Lindsea C Booth 1,✉, Baagavi Saseetharan 1, Clive N May 1, Song T Yao 2
PMCID: PMC11607613  PMID: 37755233

Abstract

Patients diagnosed with heart failure have high rates of mortality and morbidity. Based on promising preclinical studies, vagal nerve stimulation has been trialled in these patients using whole nerve electrical stimulation, but the results have been mixed. This is, at least in part, due to an inability to selectively recruit the activity of specific fibres within the vagus with whole nerve electrical stimulation, as well as not knowing which the ‘therapeutic’ fibres are. This symposium review focuses on a population of cardiac‐projecting efferent vagal fibres with cell bodies located within the dorsal motor nucleus of the vagus nerve and a new method of selectively targeting these projections as a potential treatment in heart failure.

Keywords: heart failure, optogenetic nerve stimulation, vagal nerve stimulation

  • What is the topic of this review?

    Selective efferent vagal stimulation in heart failure.

  • What advances does it highlight?

    Selectively targeting a population of cardiac‐projecting efferent vagal fibres with cell bodies within the dorsal motor nucleus of the vagus using optogenetics slows the progression of heart failure in rats.

1. INTRODUCTION

Heart failure patients have an impaired quality of life, experiencing dyspnoea, fatigue, oedema, sleeping difficulties, depression and chest pain, with a high risk of hospital admission and a 5‐year mortality rate of 75% (Levy et al., 2002). Although the number of patients hospitalised with heart failure has declined in the last few decades (Chen et al., 2011), mortality and morbidity remain high and new treatment options are required.

Based on promising experimental animal studies, vagus nerve stimulation (VNS) has been trialled in patients with heart failure using whole nerve electrical stimulation. The results have been mixed, with high rates of side effects reported. These are undoubtably in part due to the non‐specific nature of whole nerve electrical stimulation and a lack of clear understanding of which vagal fibres need to be recruited to confer benefit in heart failure. This symposium review will focus on a population of vagal fibres which originate in the dorsal motor nucleus of the vagus (DMV), their functional role in the control of cardiac contractility and a novel optogenetic method for selectively targeting these fibres as a potential treatment of heart failure.

2. VAGAL STIMULATION IN HEART FAILURE

There is a well‐documented loss of cardiac parasympathetic (vagal) activity in heart failure (Eckberg et al., 1971; Watson et al., 2007) and indicators of decreased vagal tone are strong predictors of arrhythmias and adverse outcomes in heart failure patients (Farrell et al., 1991). In animal models of heart failure, VNS has been shown to improve survival (Li et al., 2004), decrease the number of arrhythmias (Zheng et al., 2005), increase the left ventricular (LV) ejection fraction (Zhang et al., 2009) and improve end‐systolic LV function (Hamann et al., 2013).

In view of these findings, electrical stimulation of the vagus nerve has been trialled in heart failure patients (Dusi & De Ferrari, 2021; van Bilsen et al., 2017). Although in early studies LV end systolic volume decreased (Schwartz et al., 2008), the results obtained in randomised controlled trials were less convincing, showing moderate improvements in the 6 min walk test and quality of life scores (Gold et al., 2016). Importantly, across the trials, there have been high rates of reported side effects (e.g., cough, neck pain) and a large range of maximally tolerated stimulation currents have been used, raising questions about whether therapeutic levels of stimulation were reached in all studies (Dusi & De Ferrari, 2021; van Bilsen et al., 2017).

The inability to selectively recruit the activity of ‘therapeutic’ cardiac fibres within the vagus nerve remains a major limitation of whole nerve electrical stimulation. Indeed, the high intensity electrical stimulation required to recruit unmyelinated/lightly myelinated efferent fibres (to increase/restore cardiac parasympathetic activity) simultaneously captures afferent fibres (e.g., pulmonary afferents that inhibit respiration and Aδ fibres that cause cough), leading to significant side effects (Dusi & De Ferrari, 2021). Without precise targeting of specific vagal fibres, it is unsurprising that whole nerve electrical stimulation has had such mixed results in the clinical trials.

3.

The vagus nerve innervates virtually all thoracic and abdominal visceral organs and is a mixed nerve containing efferent (20%) and afferent (80%) fibres (for an extensive review see Ottaviani & Macefield, 2022). On a basic level, afferent vagal fibres carry sensory information from the internal organs to the central nervous system and efferent vagal fibres carry motor signals from the brainstem to visceral organs. However, it should be acknowledged that these fibres exist within a highly complex system of cardiac innervation, and the neuromodulation of different targets within this system has been recently reviewed by Herring et al. (2019). Despite a growing understanding of the vagus nerve and its components, it remains unclear exactly which vagal fibres need to be stimulated to confer the most benefit in heart failure, with a number of potential candidates. For example, in rats, stimulation of vagal afferent fibres has been shown to reset the arterial baroreflex neural arc and inhibit splanchnic sympathetic activity (Saku et al., 2014). On the other side, efferent vagal fibres regulate heart rate, contractility and excitability (Hsieh et al., 1998). When stimulated, the released acetylcholine activates muscarinic receptors in the heart, decreasing heart rate and atrial and ventricular contractility. Hence stimulation of efferent fibres may reduce the cardiac workload and oxygen consumption. Vagal efferent stimulation has also been shown to reduce free radical generation (Tsutsumi et al., 2008) and attenuate noradrenaline release by cardiac sympathetic nerves (Levy & Blattberg, 1976). In addition, electrical stimulation of the vagus nerve has a powerful anti‐inflammatory effect (Komegae et al., 2018), which is likely to be beneficial in heart failure.

Although recruitment of afferent fibres may have beneficial effects in heart failure, the significant side effects of whole nerve stimulation are primarily driven by afferent fibre activation. Therefore, efferent vagal fibres have been the primary target of selective vagal stimulation (discussed below). Vagal efferent fibres originate from the dorsal motor nucleus of the vagus (DMV) and the nucleus ambiguus in the medulla oblongata (Dampney, 1981). Neurons in the nucleus ambiguus provide the majority of the efferent motor innervation to the cardiac ganglia and modulate heart rate (Hsieh et al., 1998). The DMV neurons provide efferent motor output to ganglia innervating the thoracic and abdominal viscera, with a small proportion innervating the cardiac ganglia (Hsieh et al., 1998). This lesser‐studied, but important, population of DMV neurons projecting to the heart will be discussed in more depth below.

4. SELECTIVELY TARGETING THE EFFERENT FIBRES OF THE VAGUS NERVE

There has been a recent flurry of activity around increasing selectivity of vagal nerve stimulation, with the advent of broader neuroscience‐based bioelectric neuromodulation and a greater understanding of the organisation of the vagus nerve in large animals and humans (e.g., Jayaprakash et al., 2023; Settell et al., 2020; Thompson et al., 2023). A comprehensive assessment of these techniques is beyond the scope of this symposium review; however, they include spatially selective VNS (Aristovich et al., 2021), directionally selective VNS (Villalobos et al., 2023), anatomically selective VNS (Butt et al., 2020) and targeted VNS using optogenetics, which is the focus of this review.

5.

In 2015, Machhada et al. (2015) demonstrated that silencing neurons in the DMV, including those projecting to the heart, led to shortening of the ventricular effective refractory period and, importantly, lowered the threshold for triggered ventricular tachycardia in anaesthetised rats. These effects on ventricular excitability were shown to be mediated by nitric oxide (Machhada et al., 2015), in line with the evidence obtained using an isolated innervated rabbit heart model (Brack et al., 2011, 2009, 2021, 2009). Therefore, targeted activation of these vagal efferents in chronic heart failure has the potential to reduce susceptibility to ventricular arrhythmias. The same group then went on to show, in anaesthetised rats, that the cardiac projecting DMV neurons exert a tonic inhibitory drive of left ventricular contractility (Machhada et al., 2016).

The effects of stimulating this population of neurons in heart failure were determined in a more recent study, where the DMV fibres were selectively stimulated using optogenetic approach in a rodent model of myocardial infarction‐induced heart failure (Machhada et al., 2020). DMV neurons express the transcription factor Phox2 and were targeted to express a light‐sensitive chimeric channelrhodopsin derivative, ChIEF, fused with a fluorescent protein, tdTomato. Optogenetic stimulation of DMV neurones in the first 4 weeks after the myocardial infarction was sufficient to slow the progression of heart failure and increase exercise capacity (Machhada et al., 2020). Interestingly, in addition to improvements seen in rats with heart failure, quantitatively similar functional improvements were also seen in the control (sham‐myocardial infarction) group. This control group is rarely, if ever, included in VNS experiments of this type. The results obtained in the experiments using optogenetic stimulation of the vagal efferent fibres suggest that the mechanisms driving the beneficial effects of VNS in heart failure are gain‐of‐function.

The mechanisms underlying these beneficial changes in rats with heart failure have not been fully elucidated; however, in heart failure, increased activity of the sympathetic nervous system leads to a detrimental downregulation and desensitisation of myocardial β1‐adrenoreceptors (β‐AR) and upregulation of a key negative regulator of β‐AR‐mediated signalling, G‐protein coupled receptor kinase 2 (GRK2) (Woo & Xiao, 2012). In a separate study, Machhada et al. have demonstrated that selective optogenetic activation of the DMV in healthy rats decreases the expression of GRK2, which increases responsiveness of the ventricular myocardium to β1‐adrenergic stimulation (Machhada et al., 2017). Therefore, this is one pathway through which optogenetic stimulation of efferent fibres could slow the progression of heart failure (Machhada et al., 2020). The benefits of inhibiting overactive GRKs in heart failure has been recently reviewed (Pfleger et al., 2019).

The beneficial effects of efferent vagal fibre stimulation in heart failure may not all be due to specific activation of cardiac projections. The caudal region of the DMV has been shown to be the origin of cardiac efferent fibres in rats (Machhada et al., 2016); however, there is overlap with neurons projecting to other regions, including the abdominal viscera. This observation raises the question of whether there are additional cardioprotective mechanisms recruited by activation of efferent vagus nerve projections to other organs. For example, it was shown that the vagally mediated release of the gut hormone GLP‐1 is cardioprotective (Basalay et al., 2016). In addition, there is a well‐recognised, though poorly understood, role for inflammation in the progression of heart failure (Hanna & Frangogiannis, 2020) and it is established that vagal nerve stimulation has anti‐inflammatory actions (Caravaca et al., 2022). For example, there is evidence that in a pacing‐induced canine model of heart failure, vagal stimulation reduced the inflammatory marker plasma C‐reactive protein (Zhang et al., 2009). Therefore, reduced inflammation and increased release of circulating factors, such as GLP‐1, may help slow the progression of heart failure (Machhada et al., 2020). Future studies should focus on determining the exact mechanisms by which optogenetic stimulation of the DMV slows the progression of heart failure in rats following myocardial infarction.

6. TARGETING EFFERENT VAGAL FIBRES USING OPTOGENETICS IN A LARGE MAMMAL

Several reports have demonstrated the use of optogenetic tools to stimulate peripheral nerves in small animal models (Maimon et al., 2017; Pincus et al., 2020; Rajendran et al., 2019). However, if optogenetic techniques are to be translated to clinical use and the mechanisms of action dissected, the efficacy of stimulating specific fibres needs to be demonstrated in clinically relevant large animal models. We recently published a technique of targeting the DMV in sheep and showed effective optical stimulation of the cervical vagus nerve (Figure 1) (Booth et al., 2021). This site is easily accessible and is used for implantation of electrodes for electrical stimulation of the vagus. Twelve weeks after the injection of the vectors, sheep expressed optogenetic channels in a subset of efferent vagal fibres at the level of the cervical and cardiac vagus. Mass action potentials were recorded in fascicles of the cervical vagus nerve with light intensities of between 5 and 99 mW/mm2, with a conduction velocity of approximately 6 m/s (Booth et al., 2021). The conduction velocity indicates that the axons of DMV neuron are lightly myelinated (B fibres) in large animals, which is in line with studies in cats (Jones et al., 1998), and in contrast with data from rats, where the DMV neurons have C fibre axons (Nishimura & Oomura, 1987).

FIGURE 1.

FIGURE 1

Open in a new tab

Mass action potential recorded from the transected end of an opsin‐positive cervical vagus nerve, activated with an LED (99 mW/mm2, 2 ms, 1 Hz). Distance between LED and recording electrodes ∼70 mm). (Booth et al., 2021).

As outlined above, the mechanism by which efferent vagal stimulation is effective in heart failure remains incompletely understood. The large animal model is a powerful tool to dissect the effects and functional significance of efferent vagal innervation of specific organs and to map out critical pathways that are beneficial in heart failure.

AUTHOR CONTRIBUTIONS

All authors approved the final version of the manuscript and agree to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. All persons designated as authors qualify for authorship, and all those who qualify for authorship are listed.

CONFLICT OF INTEREST

The authors have no competing interests to declare.

Booth, L. C. , Saseetharan, B. , May, C. N. , & Yao, S. T. (2024). Selective efferent vagal stimulation in heart failure. Experimental Physiology, 109, 2001–2005. 10.1113/EP090866

Handling Editor: Toby Mundel

This review was presented at the ISAN 2022 symposium ‘Fast and slow lanes of the Vagus’, which took place at Cairns, Australia, 5 September 2022.

REFERENCES

  1. Aristovich, K. , Donega, M. , Fjordbakk, C. , Tarotin, I. , Chapman, C. A. R. , Viscasillas, J. , Stathopoulou, T. R. , Crawford, A. , Chew, D. , Perkins, J. , & Holder, D. (2021). Model‐based geometrical optimisation and in vivo validation of a spatially selective multielectrode cuff array for vagus nerve neuromodulation. Journal of Neuroscience Methods, 352, 109079. [DOI] [PubMed] [Google Scholar]
  2. Basalay, M. V. , Mastitskaya, S. , Mrochek, A. , Ackland, G. L. , Del Arroyo, A. G. , Sanchez, J. , Sjoquist, P. O. , Pernow, J. , Gourine, A. V. , & Gourine, A. (2016). Glucagon‐like peptide‐1 (GLP‐1) mediates cardioprotection by remote ischaemic conditioning. Cardiovascular Research, 112(3), 669–676. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Booth, L. C. , Yao, S. T. , Korsak, A. , Farmer, D. G. S. , Hood, S. G. , McCormick, D. , Boesley, Q. , Connelly, A. A. , McDougall, S. J. , Korim, W. S. , Guild, S. J. , Mastitskaya, S. , Le, P. , Teschemacher, A. G. , Kasparov, S. , Ackland, G. L. , Malpas, S. C. , McAllen, R. M. , Allen, A. M. , … Gourine, A. V. (2021). Selective optogenetic stimulation of efferent fibers in the vagus nerve of a large mammal. Brain Stimulation, 14(1), 88–96. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Brack, K. E. , Coote, J. H. , & Ng, G. A. (2011). Vagus nerve stimulation protects against ventricular fibrillation independent of muscarinic receptor activation. Cardiovascular Research, 91(3), 437–446. [DOI] [PubMed] [Google Scholar]
  5. Brack, K. E. , Patel, V. H. , Mantravardi, R. , Coote, J. H. , & Ng, G. A. (2009). Direct evidence of nitric oxide release from neuronal nitric oxide synthase activation in the left ventricle as a result of cervical vagus nerve stimulation. The Journal of Physiology, 587(12), 3045–3054. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Butt, M. F. , Albusoda, A. , Farmer, A. D. , & Aziz, Q. (2020). The anatomical basis for transcutaneous auricular vagus nerve stimulation. Journal of Anatomy, 236(4), 588–611. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Caravaca, A. S. , Gallina, A. L. , Tarnawski, L. , Shavva, V. S. , Colas, R. A. , Dalli, J. , Malin, S. G. , Hult, H. , Arnardottir, H. , & Olofsson, P. S. (2022). Vagus nerve stimulation promotes resolution of inflammation by a mechanism that involves Alox15 and requires the α7nAChR subunit. Proceedings of the National Academy of Sciences, USA, 119(22), e2023285119. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Chen, J. , Normand, S. L. , Wang, Y. , & Krumholz, H. M. (2011). National and regional trends in heart failure hospitalization and mortality rates for Medicare beneficiaries, 1998–2008. JAMA, 306(15), 1669–1678. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Dampney, R. A. (1981). Functional organization of central cardiovascular pathways. Clinical and Experimental Pharmacology & Physiology, 8(3), 241–259. [DOI] [PubMed] [Google Scholar]
  10. Dusi, V. , & De Ferrari, G. M. (2021). Vagal stimulation in heart failure. Herz, 46(6), 541–549. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Eckberg, D. L. , Drabinsky, M. , & Braunwald, E. (1971). Defective cardiac parasympathetic control in patients with heart disease. New England Journal of Medicine, 285(16), 877–883. [DOI] [PubMed] [Google Scholar]
  12. Farrell, T. G. , Paul, V. , Cripps, T. R. , Malik, M. , Bennett, E. D. , Ward, D. , & Camm, A. J. (1991). Baroreflex sensitivity and electrophysiological correlates in patients after acute myocardial infarction. Circulation, 83(3), 945–952. [DOI] [PubMed] [Google Scholar]
  13. Gold, M. R. , Van Veldhuisen, D. J. , Hauptman, P. J. , Borggrefe, M. , Kubo, S. H. , Lieberman, R. A. , Milasinovic, G. , Berman, B. J. , Djordjevic, S. , Neelagaru, S. , Schwartz, P. J. , Starling, R. C. , & Mann, D. L. (2016). Vagus nerve stimulation for the treatment of heart failure: The INOVATE‐HF trial. Journal of the American College of Cardiology, 68(2), 149–158. [DOI] [PubMed] [Google Scholar]
  14. Hamann, J. J. , Ruble, S. B. , Stolen, C. , Wang, M. , Gupta, R. C. , Rastogi, S. , & Sabbah, H. N. (2013). Vagus nerve stimulation improves left ventricular function in a canine model of chronic heart failure. European Journal of Heart Failure, 15(12), 1319–1326. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Hanna, A. , & Frangogiannis, N. G. (2020). Inflammatory cytokines and chemokines as therapeutic targets in heart failure. Cardiovascular Drugs and Therapy, 34(6), 849–863. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Herring, N. , Kalla, M. , & Paterson, D. J. (2019). The autonomic nervous system and cardiac arrhythmias: Current concepts and emerging therapies. Nature Reviews Cardiology, 16(12), 707–726. [DOI] [PubMed] [Google Scholar]
  17. Hsieh, J. H. , Chen, R. F. , Wu, J. J. , Yen, C. T. , & Chai, C. Y. (1998). Vagal innervation of the gastrointestinal tract arises from dorsal motor nucleus while that of the heart largely from nucleus ambiguus in the cat. Journal of the Autonomic Nervous System, 70(1‐2), 38–50. [DOI] [PubMed] [Google Scholar]
  18. Jayaprakash, N. , Song, W. , Toth, V. , Vardhan, A. , Levy, T. , Tomaio, J. , Qanud, K. , Mughrabi, I. , Chang, Y. C. , Rob, M. , Daytz, A. , Abbas, A. , Nassrallah, Z. , Volpe, B. T. , Tracey, K. J. , Al‐Abed, Y. , Datta‐Chaudhuri, T. , Miller, L. , Barbe, M. F. , … Zanos, S. (2023). Organ‐ and function‐specific anatomical organization of vagal fibers supports fascicular vagus nerve stimulation. Brain Stimulation, 16(2), 484–506. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Jones, J. F. , Wang, Y. , & Jordan, D. (1998). Activity of C fibre cardiac vagal efferents in anaesthetized cats and rats. The Journal of Physiology, 507(Pt 3), 869–880. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Komegae, E. N. , Farmer, D. G. S. , Brooks, V. L. , McKinley, M. J. , McAllen, R. M. , & Martelli, D. (2018). Vagal afferent activation suppresses systemic inflammation via the splanchnic anti‐inflammatory pathway. Brain, Behavior, and Immunity, 73, 441–449. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Levy, D. , Kenchaiah, S. , Larson, M. G. , Benjamin, E. J. , Kupka, M. J. , Ho, K. K. , Murabito, J. M. , & Vasan, R. S. (2002). Long‐term trends in the incidence of and survival with heart failure. New England Journal of Medicine, 347(18), 1397–1402. [DOI] [PubMed] [Google Scholar]
  22. Levy, M. N. , & Blattberg, B. (1976). Effect of vagal stimulation on the overflow of norepinephrine into the coronary sinus during cardiac sympathetic nerve stimulation in the dog. Circulation Research, 38(2), 81–84. [DOI] [PubMed] [Google Scholar]
  23. Li, M. , Zheng, C. , Sato, T. , Kawada, T. , Sugimachi, M. , & Sunagawa, K. (2004). Vagal nerve stimulation markedly improves long‐term survival after chronic heart failure in rats. Circulation, 109(1), 120–124. [DOI] [PubMed] [Google Scholar]
  24. Machhada, A. , Ang, R. , Ackland, G. L. , Ninkina, N. , Buchman, V. L. , Lythgoe, M. F. , Trapp, S. , Tinker, A. , Marina, N. , & Gourine, A. V. (2015). Control of ventricular excitability by neurons of the dorsal motor nucleus of the vagus nerve. Heart Rhythm, 12(11), 2285–2293. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Machhada, A. , Hosford, P. S. , Dyson, A. , Ackland, G. L. , Mastitskaya, S. , & Gourine, A. V. (2020). Optogenetic stimulation of vagal efferent activity preserves left ventricular function in experimental heart failure. JACC Basic Translational Science, 5(8), 799–810. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Machhada, A. , Marina, N. , Korsak, A. , Stuckey, D. J. , Lythgoe, M. F. , & Gourine, A. V. (2016). Origins of the vagal drive controlling left ventricular contractility. The Journal of Physiology, 594(14), 4017–4030. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Machhada, A. , Trapp, S. , Marina, N. , Stephens, R. C. M. , Whittle, J. , Lythgoe, M. F. , Kasparov, S. , Ackland, G. L. , & Gourine, A. V. (2017). Vagal determinants of exercise capacity. Nature Communications, 8(1), 15097. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Maimon, B. E. , Zorzos, A. N. , Bendell, R. , Harding, A. , Fahmi, M. , Srinivasan, S. , Calvaresi, P. , & Herr, H. M. (2017). Transdermal optogenetic peripheral nerve stimulation. Journal of Neural Engineering, 14(3), 034002. [DOI] [PubMed] [Google Scholar]
  29. Nishimura, H. , & Oomura, Y. (1987). Effects of hypothalamic stimulation on activity of dorsomedial medulla neurons that respond to subdiaphragmatic vagal stimulation. Journal of Neurophysiology, 58(4), 655–675. [DOI] [PubMed] [Google Scholar]
  30. Ottaviani, M. M. , & Macefield, V. G. (2022). Structure and functions of the vagus nerve in mammals. Comprehensive Physiology, 12, 3989–4037. [DOI] [PubMed] [Google Scholar]
  31. Pfleger, J. , Gresham, K. , & Koch, W. J. (2019). G protein‐coupled receptor kinases as therapeutic targets in the heart. Nature Reviews Cardiology, 16(10), 612–622. [DOI] [PubMed] [Google Scholar]
  32. Pincus, A. B. , Adhikary, S. , Lebold, K. M. , Fryer, A. D. , & Jacoby, D. B. (2020). Optogenetic control of airway cholinergic neurons in vivo. American Journal of Respiratory Cell and Molecular Biology, 62(4), 423–429. [DOI] [PMC free article] [PubMed] [Google Scholar]
  33. Rajendran, P. S. , Challis, R. C. , Fowlkes, C. C. , Hanna, P. , Tompkins, J. D. , Jordan, M. C. , Hiyari, S. , Gabris‐Weber, B. A. , Greenbaum, A. , Chan, K. Y. , Deverman, B. E. , Munzberg, H. , Ardell, J. L. , Salama, G. , Gradinaru, V. , & Shivkumar, K. (2019). Identification of peripheral neural circuits that regulate heart rate using optogenetic and viral vector strategies. Nature Communications, 10(1), 1944. [DOI] [PMC free article] [PubMed] [Google Scholar]
  34. Saku, K. , Kishi, T. , Sakamoto, K. , Hosokawa, K. , Sakamoto, T. , Murayama, Y. , Kakino, T. , Ikeda, M. , Ide, T. , & Sunagawa, K. (2014). Afferent vagal nerve stimulation resets baroreflex neural arc and inhibits sympathetic nerve activity. Physiological Reports, 2(9), e12136. [DOI] [PMC free article] [PubMed] [Google Scholar]
  35. Schwartz, P. J. , De Ferrari, G. M. , Sanzo, A. , Landolina, M. , Rordorf, R. , Raineri, C. , Campana, C. , Revera, M. , Ajmone‐Marsan, N. , Tavazzi, L. , & Odero, A. (2008). Long term vagal stimulation in patients with advanced heart failure: First experience in man. European Journal of Heart Failure, 10(9), 884–891. [DOI] [PubMed] [Google Scholar]
  36. Settell, M. L. , Pelot, N. A. , Knudsen, B. E. , Dingle, A. M. , McConico, A. L. , Nicolai, E. N. , Trevathan, J. K. , Ezzell, J. A. , Ross, E. K. , Gustafson, K. J. , Shoffstall, A. J. , Williams, J. C. , Zeng, W. , Poore, S. O. , Populin, L. C. , Suminski, A. J. , Grill, W. M. , & Ludwig, K. A. (2020). Functional vagotopy in the cervical vagus nerve of the domestic pig: Implications for the study of vagus nerve stimulation. Journal of Neural Engineering, 17(2), 026022. [DOI] [PMC free article] [PubMed] [Google Scholar]
  37. Thompson, N. , Ravagli, E. , Mastitskaya, S. , Iacoviello, F. , Stathopoulou, T. R. , Perkins, J. , Shearing, P. R. , Aristovich, K. , & Holder, D. (2023). Organotopic organization of the porcine mid‐cervical vagus nerve. Frontiers in Neuroscience, 17, 963503. [DOI] [PMC free article] [PubMed] [Google Scholar]
  38. Tsutsumi, T. , Ide, T. , Yamato, M. , Kudou, W. , Andou, M. , Hirooka, Y. , Utsumi, H. , Tsutsui, H. , & Sunagawa, K. (2008). Modulation of the myocardial redox state by vagal nerve stimulation after experimental myocardial infarction. Cardiovascular Research, 77(4), 713–721. [DOI] [PubMed] [Google Scholar]
  39. van Bilsen, M. , Patel, H. C. , Bauersachs, J. , Bohm, M. , Borggrefe, M. , Brutsaert, D. , Coats, A. J. S. , de Boer, R. A. , de Keulenaer, G. W. , Filippatos, G. S. , Floras, J. , Grassi, G. , Jankowska, E. A. , Kornet, L. , Lunde, I. G. , Maack, C. , Mahfoud, F. , Pollesello, P. , Ponikowski, P. , … Lyon, A. R. (2017). The autonomic nervous system as a therapeutic target in heart failure: A scientific position statement from the Translational Research Committee of the Heart Failure Association of the European Society of Cardiology. European Journal of Heart Failure, 19(11), 1361–1378. [DOI] [PubMed] [Google Scholar]
  40. Villalobos, J. , Payne, S. C. , Ward, G. M. , Andrikopoulos, S. , Hyakumura, T. , MacIsaac, R. J. , & Fallon, J. B. (2023). Stimulation parameters for directional vagus nerve stimulation. Bioelectronic Medicine, 9(1), 16. [DOI] [PMC free article] [PubMed] [Google Scholar]
  41. Watson, A. M. , Hood, S. G. , Ramchandra, R. , McAllen, R. M. , & May, C. N. (2007). Increased cardiac sympathetic nerve activity in heart failure is not due to desensitization of the arterial baroreflex. American Journal of Physiology. Heart and Circulatory Physiology, 293(1), H798–H804. [DOI] [PMC free article] [PubMed] [Google Scholar]
  42. Woo, A. Y. , & Xiao, R. P. (2012). beta‐Adrenergic receptor subtype signaling in heart: From bench to bedside. Acta Pharmacologica Sinica, 33(3), 335–341. [DOI] [PMC free article] [PubMed] [Google Scholar]
  43. Zhang, Y. , Popovic, Z. B. , Bibevski, S. , Fakhry, I. , Sica, D. A. , Van Wagoner, D. R. , & Mazgalev, T. N. (2009). Chronic vagus nerve stimulation improves autonomic control and attenuates systemic inflammation and heart failure progression in a canine high‐rate pacing model. Circulation: Heart Failure, 2(6), 692–699. [DOI] [PubMed] [Google Scholar]
  44. Zheng, C. , Li, M. , Inagaki, M. , Kawada, T. , Sunagawa, K. , & Sugimachi, M. (2005). Vagal stimulation markedly suppresses arrhythmias in conscious rats with chronic heart failure after myocardial infarction. Conference of the IEEE Engineering in Medicine and Biology Society, 7, 7072–7075. [DOI] [PubMed] [Google Scholar]

Articles from Experimental Physiology are provided here courtesy of Wiley

RESOURCES