Calming the Nervous Heart: Autonomic Therapies in Heart Failure

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Abstract

Heart failure (HF) is associated with significant morbidity and mortality. The disease is characterised by autonomic imbalance with increased sympathetic activity and withdrawal of parasympathetic activity. Despite the use of medical therapies that target, in part, the neurohormonal axis, rates of HF progression, morbidity and mortality remain high. Emerging therapies centred on neuromodulation of autonomic control of the heart provide an alternative device-based approach to restoring sympathovagal balance. Preclinical studies have proven favourable, while clinical trials have had mixed results. This article highlights the importance of understanding structural/functional organisation of the cardiac nervous system as mechanistic-based neuromodulation therapies evolve.

Disclosure
The authors have no conflicts of interest to declare.
Correspondence
Jeffrey L Ardell, UCLA Cardiac Arrhythmia Center and Neurocardiology Research Program of Excellence, 100 UCLA Medical Plaza, Suite 660, Los Angeles, CA 90095. E: jardell@mednet.ucla.edu
Received date
04 July 2018
Accepted date
18 July 2018
Citation
Cardiac Failure Review 2018;4(2):92–8.
DOI
https://doi.org/10.15420/cfr.2018.20.2
Acknowledgement
Work was supported by the NIH: Grants U01EB025138 (JLA and KS), HL71830 (JLA), HL084261 (KS) & OT2OD023848 (KS & JLA).

Heart failure (HF) is associated with significant morbidity and mortality, and the burden of disease is rising.1 Despite improved survival – partly a result of advances in medical therapy, coronary interventions and ICD – the mortality rate remains high and relatively stagnant.2 Moreover, advanced HF is associated with impaired quality of life (QOL), which is reflected in the significant number of hospitalisations and increased healthcare costs.

The aetiologies of HF are varied but autonomic dysfunction is a hallmark. Imbalance in the complex and dynamic interactions between the sympathetic and parasympathetic efferent limbs of the autonomic nervous system (ANS) is not only reactive to HF as a means of maintaining homeostasis, but also a contributor to HF progression. The interplay between multiple levels of the hierarchy for cardiac control (Figure 1) ultimately results in excessive sympathetic responses with corresponding withdrawal of parasympathetic tone. Furthermore, depressed arterial baroreflex regulation, a major contributor to reflex control of cardiac and peripheral vascular function, is associated with poor survival.3–5 For additional details regarding the pathophysiology of the ANS in HF, we refer the reader to recent articles on the subject.6–8

Medical approaches to treating autonomic dysfunction in HF focus on reducing the overactive sympathetic nervous system through the blockade of the beta-adrenergic or renin–angiotensin–aldosterone systems. However, despite improvements in pharmacologic approaches, treatment of HF remains challenging.9,10 Neuromodulation therapy to restore sympathovagal balance in HF has garnered increasing interest in recent years. Emerging therapies in this area include vagus nerve stimulation (VNS), spinal cord stimulation (SCS), baroreflex activation therapy (BAT), renal denervation (RDN) and stellate ganglionectomy (Figure 2). Here, we summarise the current data in animal models and clinical studies on these autonomic therapies in HF as well as challenges to the implementation of these treatment modalities.

Approach to Cardiac Neuromodulation

When considering the application of bioelectric therapies for cardiac disease, three main concepts of neurocardiology merit discussion.11 Firstly, neural control of cardiac function is exerted through the interactions between central and peripheral components of the cardiac ANS (Figure 1).8 Secondly, the aforementioned interactions may be weakened or strengthened depending on the level of the cardiac neuraxis and the characteristics of the underlying cardiac pathology.12–14 Such neural remodelling is critically dependent on abnormal afferent input.7,8,15,16 Lastly, as the neuromodulation acts on axons of passage, associated neural networks (above and below site of intervention) and the heart itself, the outcome of neuromodulation depends on the stimulation parameters, the location within the neuraxis in which therapy is applied and the cardioneural pathologic substrate against which the therapy is applied. It is highly likely that the optimum neuromodulation approach may be different depending on the status of the patient and that even within a given patient, therapy will need to be adjusted with time, as is already done for pharmacologic approaches.

Vagus Nerve Stimulation

VNS devices were initially developed and approved for use in the treatment of epilepsy and refractory depression.17–22 Interest in VNS has expanded to treatments for visceral disorders and for cardiac pathologies.8,22,23 The central premise of VNS is to increase parasympathetic tone and to restore reflexes that mitigate adrenergic inputs to the heart (Table 1). Additionally, VNS is cardioprotective because it limits cardiomyocyte apoptosis and inflammation.24–26 It also protects the heart by altering substrate use within the heart muscle itself.27,28 At the molecular level, VNS may improve survival through the reduction in connexin 43 loss and promotion of electrical stability.29

When delivered to the cervical vagosympathetic trunk, VNS activates both ascending (afferent) and descending (parasympathetic efferent) projections (Figure 2). The cardiac nervous system works in a push push-back; fashion. Functional cardiac responses to afferent activation are engaged at lower stimulus intensities leading to withdrawal of centrally derived parasympathetic tone with the potential to modify sympathetic activity (Figure 3). As stimulus intensity is increased, parasympathetic efferents are engaged with expected decreases in regional cardiac function (Figure 3); excessive parasympathetic stimulation can lead to rebound effects during the off-phase of intermittent VNS.30–32 When ascending and descending projections within the cervical vagus are activated in a ‘balanced’ fashion, multiple levels of the cardiac neuraxis are engaged with little or no change in basal cardiac function – we refer to this as the neural fulcrum.30,33,34 The major effects of VNS delivered at this operating point are placing restraints on aberrant reflex processing within the peripheral neural networks of the intrinsic cardiac nervous system, rendering myocytes stress-resistant and exerting anti-adrenergic effects on the heart itself.8

Animal studies have demonstrated the efficacy of chronically implantable VNS device therapy in sudden cardiac death and HF. In an acute ischaemia model in dogs with healed MI, chronic right cervical VNS protected against VF.35 Chronic VNS at the right cervical vagus nerve stymied the progression of HF in a canine high-rate pacing model and dramatically improved LVF and survival in a rat model of HF.26,36 Chronic VNS, both left and right, was likewise effective in maintaining cardiac function in guinea pig models of chronic MI and pressure overload.27,28

The Autonomic Neural Therapy to Enhance Myocardial Function in Heart Failure (ANTHEM-HF) study evaluated the use of a VNS system (Demipulse® Model 103 pulse generator and Perennia FLEX® Model 304 lead; Liva Nova, Houston, TX, USA) in patients with HF.37 Its stimulation protocol used titration to the neural fulcrum (as defined above and depicted in Figure 3). Sixty patients with New York Heart Association (NYHA) functional class II–III symptoms, left ventricular ejection fraction (LVEF) ≤40 % and LV end-diastolic diameter (LVEDD) ≥50 mm to <80 mm underwent randomisation for implantation at either the left (n=31) or right (n=29) cervical vagus nerve. Regarding the primary safety endpoint of incidence of procedure- and device-related adverse events, one patient died 3 days after an embolic stroke that occurred during implantation. An additional 20 serious adverse events occurred, but none of these were attributed to the VNS system or its implantation. There were statistically significant improvements in the primary efficacy endpoints of LVEF and LV end-systolic volume (LVESV) as well as the secondary efficacy endpoints of LV end-systolic diameter (LVESD), heart rate variability and 6-minute walk test (6MWT). Although there was a trend for improved efficacy outcomes with right as opposed to left VNS, CIs were wide, and there were no statistically significant differences in most efficacy parameters or safety profiles. Subsequent 12-month follow-up on 49 of the initial 60 patients showed that improvements persisted during longer follow-up and that the device implantation remained safe.38 While this study focused on HF with reduced ejection fraction (HFrEF), the ANTHEM-HF with preserved ejection fraction (HFpEF) study seeks to evaluate the safety and efficacy of right cervical VNS in patients with HFpEF and HF mid-range ejection fraction using a similar stimulation protocol and with at least 12-month follow-up.39 Results should be available in late autumn 2018.

Figure 1: Structural and Functional Organisation of the Cardiac Autonomic Nervous System

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In contrast to the results from ANTHEM-HF, two other recent studies using VNS produced more neutral effects, at least with respect to objective outcomes such as echocardiographic parameters. The NEural Cardiac TherApy foR HF (NECTAR-HF) study was a randomised, sham-controlled trial that evaluated the utility of VNS using the Precision Spectra™ system (Boston Scientific; St Paul, MN, USA).40 In this study, 96 patients with NYHA functional class II–III symptoms, LVEF ≤35 % and LVEDD ≥55 mm were randomised to VNS or control (device implanted but VNS off) in a 2:1 ratio for a 6-month period. Stimulation intensity was titrated, as tolerated, with a target of 20 Hz, a duty cycle of 16.7 %, a pulse width of 300 µs and a proposed maximal current intensity of 4 mA. However, primarily because of off-target effects, stimulus intensity was ~1.4 mA, which is in the region below the neural fulcrum and sub-threshold for optimal stimulation (Figure 3).40 In an analysis of 87 of the 96 patients implanted with available data, there was no statistically significant change in the primary endpoint of LVESD. Regarding adverse events, one patient died in the postoperative period from a pulmonary embolism, and there were three patient deaths between randomisation and 6 months as a result of worsening HF or HF complications. Of the 96 patients in the initial 6-month study, 91 patients were evaluated for a total of 18 months. All devices were activated after the initial 6-month period. Those in the group that crossed over from the control group to VNS activation had decreases in LVESV without significant changes in LVESD and LVEF.41

The INcrease Of VAgal TonE in Heart Failure (INOVATE-HF) trial evaluated the CardioFit system (BioControl Medical, Yehud, Israel) in advanced HF.42 This system used a combination of R-wave triggered VNS pulse delivery with a putative afferent blockade component. In this study, 707 chronic HF patients with NYHA functional class III symptoms and LVEF ≤40 % were randomised to VNS or continued medical therapy in a 3:2 ratio and were followed for a mean of 16 months. Four weeks after implantation, patients in the VNS group underwent stimulation intensity adjustment with a target of 3.5–5.5 mA. Figure 3 illustrates the position of this stimulation protocol in relation to the overall VNS response surface. While the secondary endpoint outcomes of NYHA functional class, QOL and 6MWT improved in the VNS group, the primary efficacy endpoint – a composite of death or HF hospitalisation and/or IV diuretic use – occurred more often in the VNS group than in the control group. The trial achieved the co-primary safety endpoint with a rate of freedom from procedure- and system-related events of 90.6 %. The study was negative in that VNS did not reduce the rate of death or HF events in chronic HF patients.

Figure 2: Intervention Sites within the Cardiac Autonomic Nervous System for the Treatment of Heart Failure

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Table 1: Targets of Autonomic Therapies in Heart Failure within the Cardiac Neuraxis

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Spinal Cord Stimulation

SCS is a Food and Drug Administration-approved therapy for chronic pain syndrome and refractory angina. High thoracic SCS has been used for the treatment of angina caused by coronary artery disease since the 1980s.43–47 Rather than being solely restricted to the spinal cord, SCS is now thought to act at multiple points within the cardiac neuraxis (Table 1).8,48 SCS suppresses the release of cardiac-related afferent neurotransmitters within the dorsal horn of the spinal cord, modulates sympathetic preganglionic neural activity, reduces sympatho-excitation within the intrathoracic extracardiac ganglia and blunts the intrinsic cardiac nervous system reflex response to cardiac stressors (Figure 2).49 SCS has additional cardioprotective effects including reducing arrhythmia burden and apoptosis, while improving contractile function.50–53 In a rabbit model of transient acute ischaemia, SCS reduces infarct size through inhibition of cardiac adrenergic neurons.54 In canine models of healed MI and pacing-induced HF, SCS improved contractile function and reduced the risk of ventricular arrhythmias, plasma brain natriuretic peptide (BNP) and norepinephrine levels.53,55 SCS has also been shown to improve contractile function and myocardial oxygen consumption in a porcine model of MI-induced HF.56

Two clinical studies have evaluated the efficacy of SCS in HF. Thoracic Spinal Cord Stimulation for Heart Failure as a Restorative Treatment (SCS HEART) was a non-randomised, open-label pilot study of 22 patients with NYHA functional class III symptoms and LVEF 20–35 % with ICD on stable, optimal medical therapy with LVEDD of 55–80 mm.57 Seventeen patients underwent implantation of the Eon Mini™ Neurostimulation System (St Jude Medical; Plano, Texas, USA) at levels T1–3 with SCS parameters of 24 h/day, frequency of 50 Hz and pulse width of 200 µs. The primary efficacy endpoint was a composite of six parameters, of which there was significant improvement in NYHA class, QOL, peak maximum oxygen consumption, LVEF and LVESV but not in N-terminal prohormone- (NT pro-) BNP. In terms of safety, there were no deaths or device-device interactions at 6 months. The Determining the Feasibility of Spinal Cord Neuromodulation for the Treatment of Chronic Systolic Heart Failure (DEFEAT-HF) study was a prospective, multi-centre randomised, parallel, single-blind, controlled trial that included 81 patients with NYHA functional class III symptoms, LVEF ≤35 %, QRS duration <120 ms and LVEDD ≥55 mm.58 An eight-electrode lead Medtronic Model 3777/3877 (Medtronic; Minneapolis, MN, USA) was implanted in the epidural space with stimulation applied to levels T2–T4 at 50 Hz for 12 h/day. The primary objective of the study was to evaluate the LVESV index (LVESVi). At 6-month follow-up, there was no significant difference in LVESVi. As SCS exhibits a memory function of approximately 45 minutes for maintained efficacy in the off-phase, future studies should restrict time of the off-phase to less than 1 hour to maximise the potential for effective control of the cardiac nervous system.59

Baroreflex Activation Therapy

As the baroreceptor reflex is involved in blood pressure regulation, BAT was developed as a potential treatment for resistant hypertension.60–63 Its utility has also been demonstrated in angina.64,65 Baroreceptors are stretch receptors located in the carotid sinus and aortic arch whose soma are contained within the petrosal and nodose ganglia, respectively. Baroreceptors transmit information regarding arterial pressure centrally (Figure 2). As part of a negative feedback reflex control mechanism, sympathetic and parasympathetic outflows are thereby modulated (Table 1). In HF, baroreceptor sensitivity is reduced with increased sympathetic activity, which may be mediated, in part, by elevated angiontensin II levels.16 Through electrical stimulation of the baroreceptor afferent fibres, central sympathetic outflow is reduced while parasympathetic tone is augmented.8,66 In that regard, in the Device-based Therapy in Hypertension Trial (DEBuT-HT), 45 patients with refractory hypertension undergoing implantation of a carotid stimulator Rheos® System (CVRx; Minneapolis, MN, USA) had significant blood pressure drop at 2-year follow-up.67

Figure 3: Clinical Application of the Vagus Nerve Stimulation Neural Fulcrum

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Preclinical studies in HF have produced proof-of-concept for BAT efficacy. In a canine model of MI-induced HF, BAT was shown to increase LVEF, reduce LVESV, LV end-diastolic pressure and circulating plasma norepinephrine, as well as normalising expression of cardiac beta1-receptors, beta-adrenergic receptor kinase and nitric oxide synthase.68 On histologic examination, there was reduced fibrosis and hypertrophy. BAT has also been shown to improve survival in a pacing-induced HF canine model.69

The first-in-man pilot study was a single-centre, open-label study involving 11 patients with NYHA functional class III symptoms, LVEF <40 % on optimal medical therapy and ineligible for cardiac resynchronisation therapy (CRT) who underwent BAT for 6 months.70 This study demonstrated safety with only one hospital- and procedure-related complication of anaemia requiring transfusion with no further sequelae. Patients had reductions in muscle sympathetic nerve activity and improvement in baroreflex sensitivity, LVEF, NYHA class, QOL and 6MWT. In addition, there was a decreased rate of HF hospitalisations compared with the 12-month period prior to BAT system implantation. The Barostim neo system (CVRx), which has approval in Europe, has been evaluated in the Barostim Hope for Heart Failure (HOPE4HF) trial. This randomised controlled trial included 146 patients with NYHA functional class II symptoms and LVEF ≤35 %.71 Patients who underwent BAT improved in NYHA functional class, QOL, 6MWT, and had a reduction in NT pro-BNP. There was a trend towards reduction in HF hospitalisations. However, there were no changes in echocardiographic parameters, including LVEF. Given the evidence that CRT reduces the sympathovagal imbalance in HF, a subsequent analysis demonstrated that the most pronounced effect of BAT was in patients not treated with CRT.72,73 This study will be followed by the Baroreflex Activation Therapy® for Heart Failure BeAT-HF) trial, which seeks to randomise 480 patients with NYHA functional class III symptoms and LVEF ≤35 %. Primary outcomes will be cardiovascular and HF mortality and the safety endpoint will be major adverse neurological and cardiovascular events at 6 months.

Renal Denervation

RDN was initially evaluated in the context of refractory hypertension.74,75 Its efficacy is predicated on interrupting axons (afferent and efferent) projecting along renal arteries (Table 1). The electrode catheter is positioned just proximal to the origin of the second-order renal artery branch with four to eight lesions administered circumferentially along the length of each of the two arteries (Figure 2).

Surgical RDN has been shown to have salutary effects in HF in rat and canine models.76–79 Following initially promising results in the Symplicity hypertension (Symplicity HTN-2) trial of catheter-based RDN in hypertension,74 RDN was evaluated in HF. The Renal Artery Denervation in Chronic Heart Failure-pilot (REACH-pilot) study demonstrated the safety of RDN in seven patients with HFrEF on optimal medical therapy and significantly improved 6MWT.80 The REACH study is an on-going prospective, double-blinded randomised study on the safety and effectiveness of RDN in 100 HFrEF patients. The Symplicity HF trial was a feasibility study that evaluated 39 patients with NYHA functional class II-III symptoms and LVEF <40 % on optimal medical therapy with mildly impaired renal function. In the study, one patient did experience renal artery occlusion that may have been related to the RDN procedure.81 The study showed significant reductions in NT pro-BNP without significant changes in LVEF, 6MWT, or estimated glomerular filtration rate. A major complication identified within the Symplicity trials was that substantial variability in efficacy was related to inadequate focus on the extent and verification of axon ablation from the renal artery. Future studies should be designed to assess efficacy at onset and during the course of therapy. A more recent pilot study randomised 60 HF patients with LVEF ≤40 % and NYHA functional class II–IV symptoms to RDN plus optimal medical therapy versus optimal medical therapy alone.82 No adverse effects were identified, and significant improvements were noted in the primary efficacy endpoint of LVEF at 6 months and in secondary endpoints of NYHA functional class, NT pro-BNP, heart rate and Short Form 36 health survey questionnaire in the RDN group.

Stellate Ganglionectomy

Cardiac sympathetic denervation (CSD) via stellate ganglionectomy in cardiovascular disease was initially proposed as a treatment for angina in 1899 and has since demonstrated efficacy in reducing angina and ventricular arrhythmias.83–86 The procedure involves the removal of the lower half of the stellate ganglia through the T2–T4 thoracic ganglia as a means of disrupting afferent and sympathetic postganglionic efferent fibres to the heart. Left CSD (LCSD) has been most commonly performed, although recent data suggest improved effectiveness in ventricular arrhythmia with bilateral approaches.84 A prospective, randomised pilot study has evaluated LCSD for HF.87 In this study, Conceição‐Souza et al. randomised 15 patients with LVEF ≤40 % in sinus rhythm with resting heart rate >65 BPM and on optimal medical therapy to continued medical therapy with left stellate ganglionectomy versus medical therapy alone. The study showed no complications attributed to the surgery and mild improvement in LVEF, 6MWT and Minnesota Living with Heart Failure Questionnaire. A large randomised study evaluating LCSD in systolic HF is currently enrolling.88

Challenges to Autonomic Therapies in Heart Failure

Several challenges to neuromodulation in HF help explain why success in preclinical studies has not translated into clinical benefit in human studies. In particular, just as target dosing of oral medications is critical in conventional therapy for HF, so too are the bioelectric stimulation parameters and protocols. Many trials employed distinct stimulation parameters with respect to frequency, current pulse width and duty cycle, often with minimal mechanistic justification. Cardiac disease is a dynamic process; neuromodulation is too. As a patient’s sympathovagal balance shifts during the course of the disease process, changes in stimulation parameters may be warranted. It is much more than ‘set and forget’. Future studies should also consider relevant biomarkers in assessing engagement of the neural elements and the effects on end-organ function. With such biomarkers, the potential for effective closed-loop systems can become a reality.

Autonomic imbalance plays a crucial role in the pathophysiology of HF. While pharmacologic therapies affect the ANS, limited effectiveness with these approaches has led to interest in applying neuromodulation to HF treatment. VNS has been the most extensively studied modality and the clinical trials have had mixed results, although with the caveat that stimulation parameters may not have been appropriate. Clinical studies in SCS and RDN have had similarly variable results so far. BAT has shown some promise in a pilot study, and we look forward to the results from an on-going clinical trial regarding its efficacy. Neurovisceral science holds great promise in emerging therapies for myriad disease states. To move forwards, it is crucial to understand the structure and function of the ANS and the organs that it targets. It is with anticipation that we await critical aspects of this puzzle. Its various components are being revealed by programmes such as the National Institutes of Health (NIH) – Stimulating Peripheral Activity to Relieve Conditions (SPARC) portfolio, a programme committed to furthering knowledge of nerve-organ interactions and advancing development of neuromodulatory approaches for disease treatment.

References
  1. Benjamin EJ, Virani SS, Callaway CW, et al. Heart Disease and Stroke Statistics–2018 Update: A Report From the American Heart Association. Circulation 2018;137:e67–e492.
    Crossref | PubMed
  2. Roger VL, Weston SA, Redfield MM, et al. Trends in heart failure incidence and survival in a community-based population. JAMA 2004;292:344–50.
    Crossref | PubMed
  3. Mortara A, La Rovere MT, Pinna GD, et al. Arterial Baroreflex Modulation of Heart Rate in Chronic Heart Failure. Circulation 1997;96:3450.
    Crossref | PubMed
  4. La Rovere MT, Bigger JT, Jr., Marcus FI, et al. Baroreflex sensitivity and heart-rate variability in prediction of total cardiac mortality after myocardial infarction. Lancet 1998;351:478–84.
    Crossref | PubMed
  5. Nolan J, Batin PD, Andrews R, et al. Prospective Study of Heart Rate Variability and Mortality in Chronic Heart Failure. Circulation 1998;98:1510.
    Crossref | PubMed
  6. Florea VG, Cohn JN. The autonomic nervous system and heart failure. Circ Res 2014;114:1815–26.
    Crossref | PubMed
  7. Shivkumar K, Ajijola OA, Anand I, et al. Clinical neurocardiology defining the value of neuroscience‐based cardiovascular therapeutics. J Physiol 2016;594:3911–54.
    Crossref | PubMed
  8. Ardell J, Andresen M, Armour J, et al. Translational neurocardiology: preclinical models and cardioneural integrative aspects. J Physiol 2016;594:3877–909.
    Crossref | PubMed
  9. McMurray JJ, Packer M, Desai AS, et al. Angiotensin–neprilysin inhibition versus enalapril in heart failure. N Engl J Med 2014;371:993–1004.
    Crossref | PubMed
  10. Swedberg K, Komajda M, Böhm M, et al. Ivabradine and outcomes in chronic heart failure (SHIFT): a randomised placebo-controlled study. Lancet 2010;376:875–85.
    Crossref | PubMed
  11. Ardell JL, Shivkumar K. Foundational concepts for cardiac neuromodulation. Bioelectron Med 2018;1:9–11.
    Crossref
  12. Rajendran PS, Nakamura K, Ajijola OA, et al. Myocardial infarction induces structural and functional remodelling of the intrinsic cardiac nervous system. J Physiol 2016;594:321–41.
    Crossref | PubMed
  13. Ajijola OA, Hoover DB, Simerly TM, et al. Inflammation, oxidative stress, and glial cell activation characterize stellate ganglia from humans with electrical storm. JCI insight 2017;2:94715.
    Crossref | PubMed
  14. Liu K, Li D, Hao G, et al. Phosphodiesterase 2A as a therapeutic target to restore cardiac neurotransmission during sympathetic hyperactivity. JCI Insight 2018;3:98694.
    Crossref | PubMed
  15. Wang H-J, Wang W, Cornish KG, et al. Cardiac sympathetic afferent denervation attenuates cardiac remodeling and improves cardiovascular dysfunction in rats with heart failure. Hypertension 2014;64:745–55.
    Crossref | PubMed
  16. Zucker IH, Patel KP, Schultz HD. Neurohumoral stimulation. Heart fail clin 2012;8:87–99.
    Crossref | PubMed
  17. Heck C, Helmers SL, DeGiorgio CM. Vagus nerve stimulation therapy, epilepsy, and device parameters Scientific basis and recommendations for use. Neurology 2002;59(6suppl4):S31–S7.
    Crossref | PubMed
  18. Rush AJ, Marangell LB, Sackeim HA, et al. Vagus nerve stimulation for treatment-resistant depression: a randomized, controlled acute phase trial. Biol psychiatry 2005;58:347–54.
    Crossref | PubMed
  19. Terry R, Tarver WB, Zabara J. An implantable neurocybernetic prosthesis system. Epilepsia 1990;31(Suppl 2):S33–7.
    Crossref | PubMed
  20. Milby AH, Halpern CH, Baltuch GH. Vagus nerve stimulation for epilepsy and depression. Neurotherapeutics 2008;5:75–85.
    Crossref | PubMed
  21. Handforth A, DeGiorgio C, Schachter S, et al. Vagus nerve stimulation therapy for partial-onset seizures A randomized active-control trial. Neurology 1998;51:48–55.
    Crossref | PubMed
  22. Bonaz B, Picq C, Sinniger V, et al. Vagus nerve stimulation: from epilepsy to the cholinergic anti‐inflammatory pathway. Neurogastroenterol Motil 2013;25:208–21.
    Crossref | PubMed
  23. De Ferrari GM. Vagal stimulation in heart failure. J Cardiovasc Transl Res 2014;7:310–20.
    Crossref | PubMed
  24. Olshansky B, Sabbah HN, Hauptman PJ, Colucci WS. Parasympathetic nervous system and heart failure. Circulation 2008;118:863–71.
    Crossref | PubMed
  25. Tracey KJ. Physiology and immunology of the cholinergic antiinflammatory pathway. J Clin Invest 2007;117:289–96.
    Crossref | PubMed
  26. Zhang Y, Popovic´ ZB, Bibevski S, et al. Chronic vagus nerve stimulation improves autonomic control and attenuates systemic inflammation and heart failure progression in a canine high-rate pacing model. Circ Heart Fail 2009;2:692–9.
    Crossref | PubMed
  27. Beaumont E, Southerland EM, Hardwick JC, et al. Vagus nerve stimulation mitigates intrinsic cardiac neuronal and adverse myocyte remodeling postmyocardial infarction. Am J Physiol Heart Circ Physiol 2015;309:H1198–206.
    Crossref | PubMed
  28. Beaumont E, Wright GL, Southerland EM, et al. Vagus nerve stimulation mitigates intrinsic cardiac neuronal remodeling and cardiac hypertrophy induced by chronic pressure overload in guinea pig. Am J Physiol Heart Circ Physiol 2016;310:H1349–59.
    Crossref | PubMed
  29. Ando M, Katare RG, Kakinuma Y, et al. Efferent vagal nerve stimulation protects heart against ischemia-induced arrhythmias by preserving connexin43 protein. Circulation 2005;112:164–70.
    Crossref | PubMed
  30. Ardell JL, Nier H, Hammer M, et al. Defining the neural fulcrum for chronic vagus nerve stimulation: implications for integrated cardiac control. J physiol 2017;595:6887–903.
    Crossref | PubMed
  31. Hill M, Wallick D, Martin PJ, Levy MN. Effects of repetitive vagal stimulation on heart rate and on cardiac vasoactive intestinal polypeptide efflux. Am J Physiol 1995;268:H1939–H46.
    Crossref | PubMed
  32. Hill MR, Wallick DW, Martin PJ, Levy MN. Frequency dependence of vasoactive intestinal polypeptide release and vagally induced tachycardia in the canine heart. J Auton Nerv Syst 1993;43:117–22.
    Crossref | PubMed
  33. Ardell JL, Rajendran PS, Nier HA, et al. Central-peripheral neural network interactions evoked by vagus nerve stimulation: functional consequences on control of cardiac function. Am J Physiol Heart Circ Physiol 2015;309:H1740–H52.
    Crossref | PubMed
  34. Yamakawa K, Rajendran PS, Takamiya T, et al. Vagal nerve stimulation activates vagal afferent fibers that reduce cardiac efferent parasympathetic effects. Am J Physiol Heart Circ Physiol 2015;309:H1579–H90.
    Crossref | PubMed
  35. Vanoli E, De Ferrari GM, Stramba-Badiale M, et al. Vagal stimulation and prevention of sudden death in conscious dogs with a healed myocardial infarction. Circ Res 1991;68:1471–81.
    Crossref | PubMed
  36. Li M, Zheng C, Sato T, et al. Vagal nerve stimulation markedly improves long-term survival after chronic heart failure in rats. Circulation 2004;109:120–4.
    Crossref | PubMed
  37. Premchand RK, Sharma K, Mittal S, et al. Autonomic regulation therapy via left or right cervical vagus nerve stimulation in patients with chronic heart failure: results of the ANTHEM-HF trial. J Card Fail 2014;20:808–16.
    Crossref | PubMed
  38. Premchand RK, Sharma K, Mittal S, et al. Extended Follow-Up of Patients With Heart Failure Receiving Autonomic Regulation Therapy in the ANTHEM-HF Study. J Card Fail 2016;22:639–42.
    Crossref | PubMed
  39. DiCarlo LA, Libbus I, Kumar HU, et al. Autonomic regulation therapy to enhance myocardial function in heart failure patients: the ANTHEM-HFpEF study. ESC Heart Fail 2018;5:95–100.
    Crossref | PubMed
  40. Zannad F, De Ferrari GM, Tuinenburg AE, et al. Chronic vagal stimulation for the treatment of low ejection fraction heart failure: results of the NEural Cardiac TherApy foR Heart Failure (NECTAR-HF) randomized controlled trial. Eur Heart J 2015;36:425–33.
    Crossref | PubMed
  41. De Ferrari GM, Stolen C, Tuinenburg AE, et al. Long-term vagal stimulation for heart failure: Eighteen month results from the NEural Cardiac TherApy foR Heart Failure (NECTAR-HF) trial. Int J Cardiol 2017;244:229–34.
    Crossref | PubMed
  42. Gold MR, Van Veldhuisen DJ, Hauptman PJ, et al. Vagus Nerve Stimulation for the Treatment of Heart Failure: The INOVATE-HF Trial. J Am Coll Cardiol 2016;68:149–58.
    Crossref | PubMed
  43. Jessurun GA, DeJongste MJ, Hautvast RW, et al. Clinical follow‐up after cessation of chronic electrical neuromodulation in patients with severe coronary artery disease: a prospective randomized controlled study on putative involvement of sympathetic activity. Pacing Clin Electrophysiol 1999;22:1432–9.
    Crossref | PubMed
  44. Fanciullo GJ, Robb JF, Rose RJ, Sanders JH. Spinal cord stimulation for intractable angina pectoris. Anesth Analg1999;89:305–6.
    Crossref | PubMed
  45. Brodison A, Chauhan A. Spinal-cord stimulation in management of angina. Lancet 1999;354:1748–9.
    Crossref | PubMed
  46. Murphy DF, Giles KE. Dorsal column stimulation for pain relief from intractable angina pectoris. Pain 1987;28:365–8.
    Crossref | PubMed
  47. Wu M, Linderoth B, Foreman RD. Putative mechanisms behind effects of spinal cord stimulation on vascular diseases: a review of experimental studies. Auton Neurosci 2008;138:9–23.
    Crossref | PubMed
  48. Foreman RD, Linderoth B. Neural mechanisms of spinal cord stimulation. Int Rev Neurobiol 2012;107:87–119.
    Crossref | PubMed
  49. Ardell JL. Mechanisms of spinal cord neuromodulation for heart disease. Nat Rev Cardiol 2016;13:127–8.
    Crossref | PubMed
  50. Ardell JL, Cardinal R, Beaumont E, et al. Chronic spinal cord stimulation modifies intrinsic cardiac synaptic efficacy in the suppression of atrial fibrillation. Auton Neurosci 2014;186:38–44.
    Crossref | PubMed
  51. Gibbons DD, Southerland EM, Hoover DB, et al. Neuromodulation targets intrinsic cardiac neurons to attenuate neuronally mediated atrial arrhythmias. Am J Physiol Regul Integr Comp Physiol 2012;302:R357–R64.
    Crossref | PubMed
  52. Southerland EM, Gibbons DD, Smith SB, et al. Activated cranial cervical cord neurons affect left ventricular infarct size and the potential for sudden cardiac death. Auton Neurosci 2012;169:34–42.
    Crossref | PubMed
  53. Lopshire JC, Zhou X, Dusa C, et al. Spinal cord stimulation improves ventricular function and reduces ventricular arrhythmias in a canine postinfarction heart failure model. Circulation 2009;120:286–94.
    Crossref | PubMed
  54. Southerland EM, Milhorn DM, Foreman RD, et al. Preemptive, but not reactive, spinal cord stimulation mitigates transient ischemia-induced myocardial infarction via cardiac adrenergic neurons. Am J Physiol Heart Circ Physiol 2007;292:H311–H7.
    Crossref | PubMed
  55. Issa ZF, Zhou X, Ujhelyi MR, et al. Thoracic spinal cord stimulation reduces the risk of ischemic ventricular arrhythmias in a postinfarction heart failure canine model. Circulation 2005;111:3217–20.
    Crossref | PubMed
  56. Liu Y, Yue W-S, Liao S-Y, et al. Thoracic Spinal Cord Stimulation Improves Cardiac Contractile Function and Myocardial Oxygen Consumption in a Porcine Model of Ischemic Heart Failure. J Cardiovasc Electrophysiol 2012;23:534–40.
    Crossref | PubMed
  57. Tse HF, Turner S, Sanders P, et al. Thoracic Spinal Cord Stimulation for Heart Failure as a Restorative Treatment (SCS HEART study): first-in-man experience. Heart rhythm 2015;12:588–95.
    Crossref | PubMed
  58. Zipes DP, Neuzil P, Theres H, et al. Determining the Feasibility of Spinal Cord Neuromodulation for the Treatment of Chronic Systolic Heart Failure: The DEFEAT-HF Study. JACC Heart Fail 2016;4:129–36.
    Crossref | PubMed
  59. Armour J, Linderoth B, Arora R, et al. Long-term modulation of the intrinsic cardiac nervous system by spinal cord neurons in normal and ischaemic hearts. Auton Neurosci 2002;95:71–9.
    Crossref | PubMed
  60. Krum H, Sobotka P, Mahfoud F, Böhm M, Esler M, Schlaich M. Device-based antihypertensive therapy: therapeutic modulation of the autonomic nervous system. Circulation 2011;123:209–15.
    Crossref | PubMed
  61. Heusser K, Tank J, Engeli S, et al. Carotid baroreceptor stimulation, sympathetic activity, baroreflex function, and blood pressure in hypertensive patients. Hypertension 2010;55:619–26.
    Crossref | PubMed
  62. Neistadt A, Schwartz SI. Effects of electrical stimulation of the carotid sinus nerve in reversal of experimentally induced hypertension. Surgery 1967;61:923–31.
    PubMed
  63. Schwartz SI, Griffith LS, Neistadt A, Hagfors N. Chronic carotid sinus nerve stimulation in the treatment of essential hypertension. Am J Surg 1967;114:5–15.
    Crossref | PubMed
  64. Braunwald E, Epstein SE, Glick G, et al. Relief of angina pectoris by electrical stimulation of the carotid-sinus nerves. N Engl J Med 1967;277:1278–83.
    Crossref | PubMed
  65. Epstein SE, Beiser GD, Goldstein RE, et al. Treatment of angina pectoris by electrical stimulation of the carotid-sinus nerves: Results in 17 patients with severe angina. N Engl J Med 1969;280:971–8.
    Crossref | PubMed
  66. Grassi G, Seravalle G, Quarti-Trevano F, et al. Sympathetic and baroreflex cardiovascular control in hypertension-related left ventricular dysfunction. Hypertension 2009;53:205–9.
    Crossref | PubMed
  67. Scheffers IJ, Kroon AA, Schmidli J, et al. Novel baroreflex activation therapy in resistant hypertension: results of a European multi-center feasibility study. J Am Coll Cardiol 2010;56:1254–8.
    Crossref | PubMed
  68. Sabbah HN, Gupta RC, Imai M, et al. Chronic Electrical Stimulation of the Carotid Sinus Baroreflex Improves Left Ventricular Function and Promotes Reversal of Ventricular Remodeling in Dogs With Advanced Heart Failure. Circ Heart Fail 2011;4:65–70.
    Crossref | PubMed
  69. Zucker IH, Hackley JF, Cornish KG, et al. Chronic baroreceptor activation enhances survival in dogs with pacing-induced heart failure. Hypertension 2007;50:904–10.
    Crossref | PubMed
  70. Gronda E, Seravalle G, Brambilla G, et al. Chronic baroreflex activation effects on sympathetic nerve traffic, baroreflex function, and cardiac haemodynamics in heart failure: a proof-of-concept study. Eur J Heart Fail 2014;16:977–83.
    Crossref | PubMed
  71. Abraham WT, Zile MR, Weaver FA, et al. Baroreflex activation therapy for the treatment of heart failure with a reduced ejection fraction. JACC Heart Fail 2015;3:487–96.
    Crossref | PubMed
  72. Zile MR, Abraham WT, Weaver FA, et al. Baroreflex activation therapy for the treatment of heart failure with a reduced ejection fraction: safety and efficacy in patients with and without cardiac resynchronization therapy. Eur J Heart Fail 2015;17:1066–74.
    Crossref | PubMed
  73. DeMazumder D, Kass DA, O’Rourke B, Tomaselli GF. Cardiac Resynchronization Therapy Restores Sympathovagal Balance in the Failing Heart by Differential Remodeling of Cholinergic Signaling. Circ Res 2015;116:1691–9.
    Crossref | PubMed
  74. Esler MD, Krum H, Sobotka PA, et al. Renal sympathetic denervation in patients with treatment-resistant hypertension (The Symplicity HTN-2 Trial): a randomised controlled trial. Lancet 2010;376:1903–9.
    Crossref | PubMed
  75. Krum H, Schlaich M, Whitbourn R, et al. Catheter-based renal sympathetic denervation for resistant hypertension: a multicentre safety and proof-of-principle cohort study. Lancet 2009;373:1275–81.
    Crossref | PubMed
  76. Dibona GF, Sawin LL. Role of renal nerves in sodium retention of cirrhosis and congestive heart failure. Am J Physiol 1991;260:R298–R305.
    Crossref | PubMed
  77. Villarreal D, Freeman RH, Johnson RA, Simmons JC. Effects of renal denervation on postprandial sodium excretion in experimental heart failure. Am J Physiol 1994;266:R1599–R604.
    Crossref | PubMed
  78. Nozawa T, Igawa A, Fujii N, et al. Effects of long-term renal sympathetic denervation on heart failure after myocardial infarction in rats. Heart Vessels 2002;16:51–6.
    Crossref | PubMed
  79. Souza D, Mill J, Cabral A. Chronic experimental myocardial infarction produces antinatriuresis by a renal nerve-dependent mechanism. Braz J Med Biol Res 2004;37:285–93.
    Crossref | PubMed
  80. Davies JE, Manisty CH, Petraco R, et al. First-in-man safety evaluation of renal denervation for chronic systolic heart failure: primary outcome from REACH-Pilot study. Int J Cardiol 2013;162:189–92.
    Crossref | PubMed
  81. Hopper I, Gronda E, Hoppe UC, et al. Sympathetic response and outcomes following renal denervation in patients with chronic heart failure: 12-month outcomes from the SYMPLICITY HF Feasibility Study. J Card Fail 2017;23:702–7.
    Crossref | PubMed
  82. Chen W, Ling Z, Xu Y, et al. Preliminary effects of renal denervation with saline irrigated catheter on cardiac systolic function in patients with heart failure: a prospective, randomized, controlled, pilot study. Catheter Cardiovasc Interv 2017;89:E153–E61.
    Crossref | PubMed
  83. Jonnesco T. Angine de poitrine gukrie par la resection du sympathique cervico‐thoracique. Bull Acad Med. 1920;84:1920.
  84. Vaseghi M, Barwad P, Corrales FJM, et al. Cardiac sympathetic denervation for refractory ventricular arrhythmias. J Am Coll Cardiol 2017;69:3070–80.
    Crossref | PubMed
  85. Schwartz PJ, Snebold NG, Brown AM. Effects of unilateral cardiac sympathetic denervation on the ventricular fibrillation threshold. Am J Cardiol 1976;37:1034–40.
    Crossref | PubMed
  86. Francois-Franck C. Signification physiologique de la résection du sympathique dans la maladie de Basedow, l’épilepsie, l’idiotie et le glaucome. Bull Acad Med Paris. 1899;41:565–94.
  87. Conceição‐Souza GE, Pêgo‐Fernandes PM, Cruz FdD, et al. Left cardiac sympathetic denervation for treatment of symptomatic systolic heart failure patients: a pilot study. Eur J Heart Fail 2012;14:1366–73.
    Crossref | PubMed
  88. Chin A, Ntsekhe M, Viljoen C, et al. Rationale and design of a prospective study to assess the effect of left cardiac sympathetic denervation in chronic heart failure. Int J Cardiol 2017;248:227–31.
    Crossref | PubMed