Abstract

The autonomic nervous system has a significant role in the pathophysiology and progression of heart failure. The absence of any recent breakthrough advances in the medical therapy of heart failure has led to the evolution of innovative non-pharmacological interventions that can favourably modulate the cardiac autonomic tone. Several new therapeutic modalities that may act at different levels of the autonomic nervous system are being investigated for their role in the treatment of heart failure. The current review examines the role of renal denervation, vagal nerve stimulators, carotid baroreceptors, and spinal cord stimulators in the treatment of heart failure.

Introduction

Heart failure (HF) remains a huge problem to the patient and the treating physician alike, with excessive morbidity and mortality.1 Despite the progress made with medical and device-based therapies, the number of annual admissions for HF continues to increase, posing a substantial burden on healthcare resources. The exponential increase in the total cost of HF is non-sustainable; an estimated total cost of USD $32 billion in 2013 is projected to increase by 120% to 70 billion by 2030.1 Attempts to retard the progression of HF have remained challenging, with implantable left ventricular assist devices and cardiac transplantation being fallback strategies. Both of these therapeutic modalities impose a great inconvenience to lifestyle coupled with significant financial challenges. Newer alternative strategies that may modulate the autonomic nervous system (ANS) to alleviate symptoms, while improving outcomes and reducing hospitalizations for HF are gaining traction as potential interventions. This review examines state-of-the-art non-pharmacological strategies to manipulate the renal nerves, vagus nerve, the carotid baroreceptors, and the spinal cord to control the progression of HF.

Autonomic nervous system, the neurohormonal axis, and heart failure

The interactions between the heart and the ANS have been known for several decades. The ANS has two primary components, the sympathetic and parasympathetic (Figure 1). The sympathetic nervous system (SNS) is the cardio-stimulatory pathway, which increases heart rate and force of contraction, while the parasympathetic nervous system (PNS) is the cardio-inhibitory pathway, and acts through reducing the heart rate, blood pressure, and contractility. Among other factors, it is the constant push and pull between these two limbs of the ANS, which regulates the heart rate, blood pressure, cardiac structure and function, and electrical stability of the myocardium.

Figure 1

Organization of the autonomic nervous system demonstrating the salient interactions involving brain, heart, and kidney.

Figure 1

Organization of the autonomic nervous system demonstrating the salient interactions involving brain, heart, and kidney.

Declining cardiac function is associated with a spectrum of compensatory mechanisms to preserve cardiovascular homoeostasis. Two of the major participants in the neurohormonal system that are intricately intertwined in order to achieve stability are (i) the ANS and (ii) the renin–angiotensin–aldosterone system (RAAS).2,3 A reduction in cardiac output activates afferent stimuli from the baroreceptors to the central nervous system cardio-regulatory centres, which in turn leads to an activation of the sympathetic nervous pathway.4 Reduced renal perfusion, secondary to reduced forward flow activates the RAAS system via renin release. Importantly, renin facilitates the conversion of angiotensinogen to angiotensin I. Angiotensin-converting enzyme subsequently converts angiotensin I to angiotensin II. Although angiotensin II has a central effect on increasing sympathetic activity, it is also involved in sodium and water retention and has a systemic vasoconstrictive effect.5,6 It is noteworthy that these compensatory mechanisms are initially important to maintain cardiac output, but over the long term are detrimental through their adverse impact on the structural adaptive response of the heart.7,8

Heightened sympathetic tone modulates heart rate, enhances AV conductance, as well as myocardial contractility, but when sustained over time it is associated with reduced cardiac sympathetic neuronal density and responsiveness.8 Sympathetic activation in turn increases the vasoconstrictor tone, accompanied by activation of the RAAS and the endothelin 1 and vasopressin system, which may be responsible for peripheral organ dysfunction and damage in the setting of congestive HF.3,7,9

Perturbations of the sympathovagal balance with a preponderance of increased sympathetic activity besides being pro-arrhythmic can also be associated with nitric oxide dysregulation, increased inflammation with excess cytokine release and adverse remodelling of the heart.10–12 Several studies have also shown that diminished vagal activity and a heightened sympathetic activity reflected as an increased heart rate are predictors of high mortality in HF.13 More recently the SHIFT study has clearly demonstrated that high heart rate is a risk factor in patients with HF and that selective lowering of the heart rate improves outcomes.14 Of note, the beneficial impact of modulating the ANS is evident from the proven role of beta-blockers in blocking sympathetic activation and improving outcomes, along with stellate ganglionectomy, which is a useful modality for refractory ventricular arrhythmias.15 Inherent limitations of existing pharmacological strategies to more specifically modulate the limbs of the autonomic-cardiac circuit (e.g. selectively stimulate the vagus/parasympathetic tone), combined with commonly described side effects (bradycardia, fatigue, etc.) and intolerance to drugs has encouraged the evolution of innovative non-pharmacological interventions. Most of these interventions are currently under investigation, and include: spinal cord stimulation, vagal nerve stimulators, baroreceptor stimulation, and renal denervation. The jury is still out regarding which of any of these will improve clinical outcomes in patients with HF.

Worsening HF is in turn often associated with ionic and structural remodelling of the atrial and ventricular myocardium, increasing the susceptibility to arrhythmias. This is accompanied by altered vagal and sympathetic discharges, both of which may serve as triggers for atrial and ventricular arrhythmias.10,16 Notably, autonomic innervation and modulation is different between the atrium and the ventricle. This is illustrated by the fact that the parasympathetic (vagal) limb is protective in the ventricle,11 while it contributes to the arrhythmogenicity of the atrial substrate.17 On the other hand, an up-regulation of the sympathetic nerves and beta-receptors in HF may afflict both the atria and ventricles, promoting arrhythmias.18

Measuring autonomic activity

Objectively quantifying autonomic activity is important, but fraught with limitations. Especially, while attempting to modulate the ANS, objective parameters to define the change in autonomic tone or a quantifiable surrogate for clinical outcomes is important. Available methods for measuring SNS activity may provide direct or indirect, and general or regional measures of sympathetic activity (see Table 1). One of the earliest neurochemical methods involved measuring ‘norepinephrine (NE) spillover’. Severe HF is characterized by regional and central SNS activation. Regional NE spillover can be calculated by radiotracer techniques that involve measuring isotope dilution, with plasma concentrations of NE from regional venous and arterial blood.18 Norepinephrine spillover although used to measure autonomic activity has many limitations and is impractical for routine clinical use. Importantly, there is considerable variation and heterogeneity in the way circulating and locally released catecholamines are handled by different tissues.19 Norepinephrine increase may not be reflective of increased production or secretion from the nerve terminal, but may just be secondary to a reduced clearance. Microneurography is another modality that enables the quantification of nerve firing within the skin and skeletal muscle vasculature and can be evaluated at the level of multiple or single fibres.20,21 Of note, its routine use in clinical practice has been precluded by its low reliability and the enormous amount of time used in its quantification.22

Table 1

Cardiac autonomic tests

Tests  Measurement units Description Additional information 
Heart rate variability     
 
  • Frequency domain

    Total power

    Low-frequency (LF) power (0.04-0.15 Hz)

    High-frequency (HF) power (0.15-0.40 Hz)

    LF/HF

 
ms2
ms2
ms2 
Total variance in heart rate pattern
Sympathetic activity or both
Parasympathetic activity
Balance of sympathetic and parasympathetic activity 
Useful for measuring sympathovagal balance and in risk stratification 
 
  • Time domain

    SDNN

    RMSSD

    PNN50

 
ms
ms
Standard deviation of average R–R interval
Root of mean squares of difference between adjacent intervals
Numbers of pairs of adjacent R–R intervals differing by >50 ms/total number of R–R intervals 
Useful for risk stratification 
Baroreflex Sensitivity Cardiovagal baroreflex sensitivity ms/mmHg Index of baroreflex control of autonomic outflow. Close relationship with cardiac vagal tone
Estimated by changes in heart rate in response to changes in systolic arterial pressure 
Limited availability, but useful in risk stratification and post-myocardial infarction prognostication 
Microneurography Muscle sympathetic nerve activity Burst per 100 beats or bursts/minute Measure of nerve activity using microelectrode in common peroneal nerve
Measures efferent multi-fibre traffic in sympathetic nerves 
Limited use. Low reliability and logistically challenging 
Norepinephrine Levels Norepinephrine spillover Mol/min M2 Plasma NE levels are a sensitive guide to sympathetic nervous function
Isotope dilution method 
Limited availability and utility. Considerable variability in release and uptake of catecholamines in different tissues 
Scintigraphic Imaging 123I-mIBG imaging HMR (Heart to mediastinum ratio) of cardiac MIBG activity
Washout rate 
Myocardial sympathetic innervation imaging Limited availability and standardization. Maybe useful in risk stratification 
Tests  Measurement units Description Additional information 
Heart rate variability     
 
  • Frequency domain

    Total power

    Low-frequency (LF) power (0.04-0.15 Hz)

    High-frequency (HF) power (0.15-0.40 Hz)

    LF/HF

 
ms2
ms2
ms2 
Total variance in heart rate pattern
Sympathetic activity or both
Parasympathetic activity
Balance of sympathetic and parasympathetic activity 
Useful for measuring sympathovagal balance and in risk stratification 
 
  • Time domain

    SDNN

    RMSSD

    PNN50

 
ms
ms
Standard deviation of average R–R interval
Root of mean squares of difference between adjacent intervals
Numbers of pairs of adjacent R–R intervals differing by >50 ms/total number of R–R intervals 
Useful for risk stratification 
Baroreflex Sensitivity Cardiovagal baroreflex sensitivity ms/mmHg Index of baroreflex control of autonomic outflow. Close relationship with cardiac vagal tone
Estimated by changes in heart rate in response to changes in systolic arterial pressure 
Limited availability, but useful in risk stratification and post-myocardial infarction prognostication 
Microneurography Muscle sympathetic nerve activity Burst per 100 beats or bursts/minute Measure of nerve activity using microelectrode in common peroneal nerve
Measures efferent multi-fibre traffic in sympathetic nerves 
Limited use. Low reliability and logistically challenging 
Norepinephrine Levels Norepinephrine spillover Mol/min M2 Plasma NE levels are a sensitive guide to sympathetic nervous function
Isotope dilution method 
Limited availability and utility. Considerable variability in release and uptake of catecholamines in different tissues 
Scintigraphic Imaging 123I-mIBG imaging HMR (Heart to mediastinum ratio) of cardiac MIBG activity
Washout rate 
Myocardial sympathetic innervation imaging Limited availability and standardization. Maybe useful in risk stratification 

Most practical are several dynamic electrocardiographic variables that have been used as surrogates for ANS activity. It is well recognized that the beat-to-beat variability in heart rate and blood pressure is under direct influence of the autonomic tone.23,24 It is possible to distinguish the contribution of each of the limbs of the ANS, based on the physiology, that is, the vagal (parasympathetic) tone and sympathetic tone impact the heart rate in different frequency bands.25 The SNS modulates the low frequency (LF) variance in the heart rate as opposed to the PNS, which regulates the high frequency (HF) component of heart rate variability (HRV).25,26 It is noteworthy that the LF component of HRV may not exclusively reflect sympathetic, but also parasympathetic modulation of the heart rate.26 Notably, a variety of other factors inclusive of respiration, RAAS, and thermoregulations can affect these and other frequency bands of HRV.23–25 In particular, the computation of the LF/HF ratio may help to quantify the sympathovagal balance.26 Other measures that have been used to help quantify ANS activity include heart rate turbulence, entropy, and baroreflex control of heart rate, known as baroreflex sensitivity (BRS).27,28 It has also been proposed that diminished heart rate deceleration measured from Holter recordings reflects impaired autonomic regulation and can risk stratify patients post-myocardial infarction.29

Of note, in the setting of a high sympathetic tone, baroreceptor modulation of the heart is markedly reduced. Heart rate variability and BRS are viable strategies to measure acute ‘central’ and ‘reflex’ effects, providing an indirect assessment of autonomic function, while also having been proved to be valuable in monitoring the long-term clinical course and outcomes of patients.30,31 Recent data from the GISSI-HF trial28 showed that time domain measures (standard deviation of NN interval), frequency domain measures (VLF and LF), and non-linear measures of HRV and heart rate turbulence from Holter recordings in patients with HF were predictive of a long-term outcome.28 Other techniques to quantify autonomic activity are evolving exponentially and include imaging strategies such as MIBG and PET scanning,32–34 implantable sensors,34 and biomarkers.35

Device-based autonomic measurement

Recent work has shown that a spectrum of diagnostic measures available from within implantable devices may help predict the clinical course of the patient.34,36,37 Devices provide information regarding (i) rhythm disturbances (e.g. atrial fibrillation burden, ventricular ectopy, etc.), (ii) system information pertinent to the appropriate functioning (i.e. per cent pacing, lead thresholds, etc.), and (iii) HF diagnostics. The HF diagnostics include measures of physical activity, fluid accumulation (impedance measures), and autonomic activity. The baseline heart rate and measures of HRV (SDANN, HRV footprint) are automatically computed by the devices and can be trended.37 Some preliminary work has shown that changes in autonomic activity tracks favourable remodelling of the heart in patients receiving cardiac resynchronization therapy. There are several reports suggesting that baseline autonomic measures, inclusive of the mean heart rate, are predictive of an improved long-term outcome, inclusive of mortality.36–39 Therefore, implantable devices to modulate the ANS may have the potential to autoregulate the stimulation/pacing rates based on these measured parameters.

Renal denervation

A recent spate of studies has convincingly shown that renal denervation is a successful treatment strategy for treating refractory hypertension.39,40 However, it appears that the benefits of renal denervation are not restricted to blood pressure control alone, but in fact it has other positive effects via sympathetic tone modulation.41 This is exemplified by the underlying pathophysiology, where the heart and the kidney are intricately networked to maintain circulatory homoeostasis (Figure 2). It is important to recognize that the kidney not only receives, but also disseminates sympathetic activity. Of note the efferent nerve fibres follow the renal arteries (within the adventitia), thereby innervating the kidney, its renal cortex, and terminating within the glomerular arteriole.42 Activation of the renal afferents that stimulate the hypothalamus is secondary to renal hypoxia, ischaemia, and concurrent intrinsic renal disease.43

Figure 2

Role of brain and kidney in activation of the renin–angiotensin–aldosterone system in hypertension, and heart failure.

Figure 2

Role of brain and kidney in activation of the renin–angiotensin–aldosterone system in hypertension, and heart failure.

Heart failure is associated with activation of the renal sympathetic efferent nerves, which causes renin release, sodium and water retention, and further reduced renal blood flow. Renal sympathetic activation in turn also results in higher levels of angiotensin II, which then affects the CNS and results in heightened global sympathetic tone. Additionally, the increased sympathetic tone contributes to an increased peripheral vascular resistance and remodelling, as well as left ventricular remodelling. Increased sympathetic activity is associated with sodium retention, hypervolaemia, and further RAAS activation, thereby promoting the vicious cycle. In HF, SNS activation occurs after HF is manifested. In essential hypertension, the cause–effect relationship is reversed, with SNS activation presumably being important in the initiation and maintenance of hypertension. Whether blunting the SNS in HF, which may be an initial adaptive response, will translate into a long-term benefit needs further enquiry.

Typically, the pre-procedural evaluation of the patients involves screening of the renal artery anatomy to assess suitability of the intervention along with renal function tests.44 The imaging modalities that are used may include vascular ultrasound or magnetic resonance imaging, depending on the treating centre. The renal denervation procedure involves the delivery of low- energy radiofrequency applications within the renal artery. Currently, first generation devices use radiofrequency energy delivered via electrode catheters within the renal arteries. The catheters are positioned just proximal to the origin of the second-order renal artery branch. Typically, four to eight lesions are delivered circumferentially in different planes along the length of each of the two arteries. The energy source, the type of catheter being used, and the renal artery anatomy drive the numbers of lesions delivered. For safety reasons, these ablation lesions should be separated by at least 5 mm. Importantly, operators need to be experienced in renal angiography and, consequently, in acutely handling renal dissections or perforations. Of note, there are multitudes of direct radiofrequency ablation catheters (unipolar, bipolar, and multipolar), newer balloon-based technology, and alternative energy sources (e.g. cryo, laser, etc.) evolving. The multipolar and balloon-based catheters will significantly reduce the procedural time and the need for sedation and analgesia during the procedure.

The clinical impact of denervating the sympathetic afferent and efferent nerves to the renal arteries leads to a significant reduction in SNS activity. This facilitates the restoration of impaired natriuresis, improves LV filling pressures, and thereby improves LV function.44 Of note, within hypertensives, the blood pressure response to renal denervation varies significantly, with 8–37% of patients39,45,46 showing only minimal or no changes in blood pressure. There is still much to be understood, as to whether the contributing factors to this non-responsiveness are patient selection, incomplete denervation, or lack of the SNS contributing to the pathophysiology of hypertension in this subgroup of patients.47

The REACH-Pilot study,48 directed at examining the safety of renal denervation, showed that, in a maximally treated HF population, there was no significant drop in blood pressure. In the seven patients with chronic HF who were studied, there were no hypotensive or syncopal episodes and renal function remained stable over a 6-month period. Although limited in size, the pilot study showed that there was a trend towards an improvement in symptoms and exercise capacity.48 This suggested that it might be safe to undertake randomized, blinded sham-controlled clinical trials in this patient population. Importantly, it must be recognized that all the patients selected for this study were normotensive to begin with.48 Early work randomizing 51 patients with NYHA class III and IV to renal denervation with optimal medical therapy vs. optimal medical therapy alone showed, over a follow-up period of 12 months, a trend towards reduced hospitalizations for HF and improvement in LV ejection fraction in the renal denervation arm.49 These preliminary results are encouraging, and will need to be substantiated by longer follow-up and larger randomized studies. The REACH study (NCT01538992),50 which is a prospective, double-blinded, randomized study on the safety and effectiveness of renal denervation in 100 patients with chronic systolic HF, is assessing its impact on functional improvement. Symplicity HF (NCT01392196)51 is studying 40 patients with NYHA class II or III HF, and with LVEF <40% on optimal medical therapy with mildly impaired renal function. These studies are recruiting patients with a baseline systolic blood pressure of at least greater than 100 mmHg.

Recent evidence to suggest that renal denervation may reduce left ventricular hypertrophy52 has created an interest in exploring its role in diastolic HF. The reduction in myocardial hypertrophy has been observed to be independent of the drop in blood pressure, suggesting that this may be a direct effect of modulating the ANS.53 Renal denervation may potentially provide other, non-blood pressure-lowering effects. Indeed, pilot studies indicate beneficial effects on glucose metabolism,54 atrial fibrillation,55,56 ventricular storm,57 heart rate reduction,58 etc. All these disease states represent important comorbidities, characterized by an increased sympathetic tone, having an impact on morbidity and mortality in HF patients.

Importantly, extrapolating the benefit of renal denervation in HF from hypertension studies should be done with caution. There are many unanswered questions, one of which is the long-term impact of renal artery damage in this frail patient group. Many of these patients already have declining renal function, and any additional damage may have a deleterious impact. Also, there may be substantial variability in the renal innervation patterns in HF patients and also individual differences in the contribution of the sympathetic tone to HF progression, which may influence the success of this procedure in this patient population. It is important to remember that sympatholytic strategies may not always be most appropriate in HF patients. The MOXCON study testing a sympatholytic agent, such as moxonidine, was prematurely stopped due to increased mortality. This was observed despite a significant reduction in norepinephrine levels.59 Although the study has its weaknesses and the mechanism of action between moxindine and RDN is not comparable, it should encourage us to pause and carefully examine the pathophysiology and implications of this intervention.

In summary, the role of sympathetic activity in the pathophysiology of HF is well accepted. There is a bidirectional signalling between the brain and the kidney, via the ANS mediated through the renal afferent and efferent nerves. Substantial clinical and experimental data implicate the benefit of renal denervation in reducing hypertension and left ventricular mass, and consequent improvement in diastolic function. Similarly, the role of RDN in treating systolic function and HF is under investigation, with preliminary evidence suggesting its benefit.

Vagal nerve stimulation

Experimental work done nearly 3 decades ago has shown that there is a strong association between depressed vagal reflexes (measured via BRS) and susceptibility to ventricular arrhythmias in the early post-infarction period.60,61 It was later via the ATRAMI (Autonomic Tone and Reflexes After Myocardial Infarction) study that the presence of this link was reinforced.62 This study showed that markers of autonomic activity (BRS and HRV) contributed to the risk stratification of patients after a myocardial infarction. In particular, a depressed BRS in patients with reduced heart function identified patients at high risk for cardiac and arrhythmic mortality.62 Vagal nerve stimulation (VNS), although a well-recognized clinical therapy for epilepsy63 and medically refractory depression,64 is currently under investigation as a therapy for HF and a spectrum of other conditions such as Alzheimer's disease, anxiety, and obesity.60,65–67 Much of its benefit has been shown to be mediated via anti-adrenergic effects that may occur at the central and peripheral level in addition to an observed anti-apoptotic and anti-inflammatory effect.68 Its role in congestive HF is fuelled by the evidence that reduced vagal activity in decompensated HF is associated with increased mortality.61 Experimental work has further elucidated that VNS is accompanied by an improvement in haemodynamics and mortality.69 Recent work has also shown that vagal stimulation, in a rat model of myocardial infarction-induced HF, not only significantly reduced arrhythmias, but also increased long-term survival.67 A mechanistic explanation is that vagal stimulation prevents a loss of connexin 43 induced by ischaemia, thereby improving electrical instability.70 Further work has shown the beneficial effects of VNS on structural remodelling, an improvement in ejection fraction accompanied by a significant reduction in inflammatory markers (i.e. TNF-alpha and interleukin-6).71

The vagus nerve that innervates essentially all the organs in the neck, thorax, and abdomen originates in the medulla. The cervical vagus nerve contains both unmyelinated and myelinated nerve fibres. Afferents from the gastrointestinal tract, heart, and lungs outnumber the parasympathetic efferents to the visceral organs. The left vagus nerve gives rise to cardiac efferents that regulate cardiac contractility and the AV node, while efferents in the right vagus nerve are associated with the sinoatrial node and in regulating the heart rate.72,73 Notably, the mammalian vagal nerve fibres are divided into type A, B, and C fibres. The type of fibres recruited influences the clinical impact of VNS. Even though several thousand devices have been implanted, the exact mechanism for its clinical effect remains unclear. Of note, endovascular VNS may also be possible through stimulation of the coronary sinus ostium and/or superior vena cava, resulting in a slow heart rate and prolonged AV conduction.74

The vagal nerve stimulation system is an implantable neurostimulator system that delivers electrical impulses via an asymmetric bipolar multi-contact cuff electrode around the vagus nerve in the neck. The stimulation electrode is tunnelled to the infraclavicular region and attached to the pulse generator. (Figure 3). The system used in the CardioFit (BioControl Medical Ltd, Yehudi, Israel) study comprised an asymmetric bipolar multi-contact cuff electrode specifically designed to preferentially activate the vagal efferent fibres in the right cervical vagus nerve. The stimulation lead is designed to recruit efferent vagal B-fibres, with minimal recruitment of A-fibres, which when activated could have unwanted central side effects.75 The system also involves placement of a right ventricular sensing electrode to prevent excessive bradycardia from VNS. The implantation procedure often involves a multidisciplinary approach using the expertise of a surgeon and a cardiac electrophysiologist. The stimulation parameters, inclusive of the electrode design and stimulation intensities needed to stimulate the appropriate nerve fibres, are variable. It must be remembered that VNS in its present state results in activation of both the afferent and efferent nerve fibres, and the clinical benefit is a consequence of the balance achieved via stimulation and inhibition of the appropriate vagal nerve fibres. Gradual up-titration of the amplitude of stimulation is achieved, with targets of usually 5.5 mA and a heart rate reduction of 5–10 beats, without any side effects.76 Some common side effects include neck pain, coughing, swallowing difficulty, and voice alteration along with nausea and indigestion.66

Figure 3

X-ray of a patient with a vagal nerve stimulator with a previously implanted implantable cardioverter defibrillator. The arrows show a lead attached to the vagus nerve on the right side and an additional right ventricular sensing lead connected to the vagal nerve stimulator device.

Figure 3

X-ray of a patient with a vagal nerve stimulator with a previously implanted implantable cardioverter defibrillator. The arrows show a lead attached to the vagus nerve on the right side and an additional right ventricular sensing lead connected to the vagal nerve stimulator device.

A recently performed open-label multi-centre pilot study in 32 patients with NYHA class II–IV and LVEF <35% demonstrated the positive impact of VNS on structural and functional endpoints.76 A substantial proportion of patients improved their NYHA class and 6-minute walk test, with an accompanying improvement in ejection fraction.76 The positive results in the pilot study have prompted a larger clinical trial, which is currently underway. The INcrease Of VAgal TonE in congestive heart failure (CHF) (INOVATE-HF) trial is a randomized, multi-centre (USA and European sites), open-label Phase III trial.77 This study aims to enrol 650 patients (NYHA class III, LVEF ≤40%, LV end-diastolic dimension 50–80 mm) in a 3:2 randomization scheme to active VNS therapy vs. standard of care (no implant). The primary efficacy endpoint of this trial is the composite endpoint inclusive of all-cause mortality or hospitalization for HF. Another multi-site study examining VNS in 250 patients is the randomized, double blind, Phase II trial, Neural Cardiac Therapy for Heart Failure Study (NECTAR-HF, NCT01385176), which is examining the clinical efficacy of direct right vagus nerve stimulation in HF patients.78

The full reach of the therapeutic potential of this novel modality is still evolving. Any benefit of VNS may be a consequence of a multitude of mechanisms which include slower heart rate, blunting of the sympathetic axis, inhibition or down-regulation of the RAAS, and enhancing the signalling pathways, which facilitate restoration of the BRS, suppression of the pro-inflammatory cytokines, and suppression of the gap junction remodelling.12,67,79 Some of the challenges that exist are still centred on selecting the right patient and, more importantly, the appropriate pacing protocol. It could be speculated that those patients demonstrating a higher baseline sympathetic activity could be the ones showing an enhanced response, while those with a high scar burden may have a limited ability to remodel through neuromodulation. The issue of dose–response remains an unanswered question, as most studies have not addressed this. Although intravascular stimulation to recruit the vagal efferent fibres with appropriately positioned atrial pacing leads may be possible,80 there remain many technical challenges on this front pertinent to targeting, pain perception, and stimulation protocols.

In summary, there appear to be convincing preliminary data that VNS may be feasible, safe, and useful in patients with HF. The pilot studies have shown significant improvement in subjective and objective endpoints of HF, with results remaining to be confirmed in larger multi-centre randomized studies.

Carotid baroreceptor stimulation

The carotid baroreflex circuit plays a critical role in blood pressure regulation via modulation of the sympathetic tone.81–83 The carotid baroreceptors are mechanoreceptors located in the carotid sinus, which are stretch sensitive to distension of the carotid wall. Simplistically, the afferent signals from the baroreceptors go to the nucleus tractus solitarius located in the dorsal medulla of the brainstem.84 The conversion and processing of these signals occur in the ventrolateral medulla, from where the signals controlling the sympathetic tone are disseminated to the rest of the body. Importantly, activation of the carotid baroreceptor reduces sympathetic outflow and enhances the vagal tone.85,86 Although ∼50 years ago carotid sinus stimulation was studied as a treatment strategy for angina and hypertension, its use was abandoned due to technological limitations and an expanding array of pharmacological interventions. The resurgence of interest has been fuelled by more promising experimental work and technological advancements. The recent phase II non-randomized Device-based Therapy of Hypertension Trial (DEBuT-HT) in 45 patients with drug-resistant hypertension showed a significant drop in the mean BP (33/22 mmHg) after a 2-year follow-up.87 This was further evaluated in the Rheos system pivotal trial, which re-examined the impact of baroreceptor stimulation in 265 patients with severe hypertension on three anti-hypertensive medications. The results were mixed, with a moderate yet non-significant reduction in blood pressure. Multiple procedural adverse events (i.e. transient or permanent nerve injury, surgical or respiratory complications) were noted, implying the need for further technological refinement.88

The emerging interest in the role of carotid baroreceptor stimulation (CBS) in HF is supported by its long-term benefit in hypertensive patients89 and the evidence of a depressed baroreflex control of heart rate in patients with HF.13,90 This depressed function is a direct consequence of abnormalities in the arterial baroreflex coupled with changes in the processing of central neuronal signals. Improving baroreflex function may reverse the neurohormonal excitation that accompanies CHF.13,90 Preclinical work has shown that baroreceptor stimulation was associated with lower plasma norepinephrine levels and enhanced survival in dogs with pacing-induced HF.91 In conjunction with this global reduction in sympathetic outflow, there may also be a reduction in the plasma angiotensin II levels.85,90 As stated earlier, angiotensin II receptor blockade is considered the mainstream therapy for HF patients, thereby making a case for baroreceptor stimulation. Angiotensin II blockade contributes to inhibition of its direct mitogenic effects along with a reduction in its vascular resistance and extracellular volume, thereby retarding the adverse remodelling that accompanies progressive HF.92 It could also be speculated that the combined reduction in plasma norepinephrine and angiotensin II could lead to an enhanced endothelial function93 and, consequently, improved perfusion of vascular beds crucial to the remodelling process. It is unclear how much of the benefit is due to direct cardiac effects and may be more attributable to peripheral vascular and neurohormonal inhibition.

The benefit of baroreceptor activation can be obtained by either unilateral or bilateral carotid sinus stimulation. The most investigated Rheos system (CVRx., Inc., Minneapolis, MN, USA) has three components: an implantable pulse generator, carotid sinus leads, and the programmer (Figure 4A). Briefly, the pulse generator, which is similar to a pacemaker, is implanted in the infraclavicular region and is connected to two electrode leads that are connected to the perivascular tissue of the two carotid sinuses. The procedure requires a skilled and experienced team of vascular surgeons, hypertension specialists, and anaesthesiologists. The second generation (Barostim-neo), with recent approval in Europe, consists of a pulse generator and only one carotid sinus electrode. The system comprises an electrode that is reduced in size and delivers less power, and thus with the potential for a simpler implant and lesser adverse effects.

Figure 4.

(A) Schematic diagram showing a carotid baroreceptor stimulation system. (B) Schematic depiction of a spinal cord stimulator.

Figure 4.

(A) Schematic diagram showing a carotid baroreceptor stimulation system. (B) Schematic depiction of a spinal cord stimulator.

There are a few ongoing studies examining the role of augmenting the baroreflex via baroreceptor activation in patients with diastolic and systolic HF. The CVRx® Rheos® Diastolic Heart Failure Trial is a prospective, randomized, double-blind trial to examine the safety/efficacy of this therapy in 60 patients. Another larger ongoing diastolic heart failure trial is the Rheos HOPE4HF Trial94, which is an open-label randomized study examining the impact of bilateral baroreflex stimulation in 540 patients with diastolic HF (LVEF >40%).95 The Barostim HOPE4HF is another prospective randomized study evaluating the safety and efficacy of the Neo system in 60 subjects with a left ventricular ejection fraction <35%.96 Alternative strategies to examine the stimulation of carotid sinus nerves via endovascular stimulation with a catheter in the internal jugular vein are also being investigated (ACES II study, Acute Carotid Sinus Endovascular Stimulation Study).97 Some newer systems are also evaluating the placement of endovascular stents with external sources of energy to stimulate the carotid baroreceptors.

In summary, CBS through its modulation of the sympathovagal tone and its consequent effective reduction in blood pressure may have potential benefit in patients with HF. The data so far are preliminary and significant advances towards understanding the working mechanism, selecting the appropriate patients, and improving the technology still need to occur. Much work yet needs to be done on appropriate dose (stimulation) delivery, as well as understanding the benefits of unilateral vs. bilateral CBS, while limiting any potential adverse effects.

Spinal cord stimulation

Spinal cord stimulation (SCS) is an FDA-approved therapeutic modality for chronic pain syndromes and refractory angina. This therapy involves the placement of a stimulation electrode in the epidural space tunnelled to a pulse generator in the para-spinal lumbar region. (Figure 4B) The distal poles of the electrode are placed in the region of the fourth and fifth thoracic vertebrae. Spinal cord stimulation is applied at 90% of the motor threshold at a frequency of 50 Hz with a pulse width of 200 ms width for 2 h, three times a day. Several studies have shown that SCS may have a cardio-protective effect, largely mediated through a vagus-dependent mechanism, which reduces heart rate and blood pressure. Zipes and colleagues have shown that SCS at thoracic vertebra T1 may increase the sinus cycle length and prolong intracardiac conduction, both of which appear to be vagally mediated.98

Preclinical work using a canine post-infarction HF model has also demonstrated that SCS administered during coronary artery balloon occlusion may reduce infarct size and suppress ventricular arrhythmias.99,100 The most robust evidence that SCS may have a role in the treatment of HF is the preclinical work undertaken by the same investigators in a chronic HF canine model. An elegant randomized study in canines involved the induction of HF, and then implantation of an implantable cardioverter defibrillator followed by left anterior descending coronary artery embolization to induce a myocardial infarction. Surviving animals entered the neuromodulation stage (stage 2). In this stage, the animals were equally randomized to receive SCS, medical therapy, or a combination of SCS and medical therapy over a 10-week period. Spinal cord stimulation was performed at T4, at 90% the motor threshold, three times a day for 2 h each. A significantly greater decline in brain natriuretic peptide (BNP) and norepinephrine levels, along with a marked reduction in the number of spontaneous ventricular arrhythmias was observed in the SCS and the medical therapy group. Notably, there was an improvement in the LVEF, which was seen to be maximum in the groups receiving SCS. Similar findings were noted in an almost identical experiment in pigs. Continuous SCS was again associated with a reduction in NE and BNP and an improvement in the cardiac function in this species. Additional work has shown that this VT suppressing and LV remodelling effect may be site-specific to a particular spinal segment and stimulation threshold. Significant and similar effects may be obtained with stimulation at 90% of the motor threshold at the T1 or T4 level.99,100

On the basis of this preclinical work, there are a number of studies assessing the efficacy and safety of this modality in systolic HF patients. The SCS HEART (Spinal cord stimulation for Heart Failure, NCT01362725)101 study is a non-randomized, open- label safety study of 20 patients with NYHA class III or IV and LVEF between 20 and 35% on maximal medical therapy, with a dilated left ventricle. The DEFEAT-HF study (Determining the Feasibility of spinal cord neuromodulation for the treatment of chronic HF, NCT01112579)102 is an ongoing, randomized, single-blind study of 250 patients with HF. Another small, open-label, single-arm, safety and efficacy study (Trial of autonomic neuromodulation for treatment of chronic HF, TAME-HF, NCT01820130)103 is examining 20 HF NYHA class III patients, with LVEF <35% and a narrow QRS, for its safety and impact on similar structural and functional endpoints.

Evolving strategies

Recent work has shown that endovascular cardiac plexus stimulation may increase LV contractility without increasing heart rate.104 The cardiac plexus lies within the adventitia of the great vessels between the ascending aorta and pulmonary artery. This plexus receives innervation from post-ganglionic sympathetic and pre-ganglionic parasympathetic cardiac autonomic nerves. Stimulation of these areas via an epivascular or endovascular route with a catheter in the right pulmonary artery has been shown to increase LV contractility and cardiac output with no accompanying heart rate increase. This is very preliminary work, but raises the possibility of selectively recruiting the cardiac plexus to alter the cardiac autonomic tone to improve cardiac function. Similar endeavours to stimulate the vagus nerve via minimally invasive transcutaneous or endovascular approaches are being developed. Along with newer non-pharmacological interventions to modulate the ANS, there are continued advances in sensor strategies to measure autonomic activity. In the foreseeable future, implantable devices will be able to individualize the extent of autonomic modulation via automatic optimization and autoregulation algorithms.

Conclusion

The ANS is intricately intertwined with cardiac function and plays an important role in the progression of HF. Limited advances on the pharmacotherapy front have led to the development of innovative non-pharmacological interventions that can favourably alter the cardiac autonomic tone. Renal denervation, which disrupts the renal nerves from the renal artery, may alter the neurohormonal balance to facilitate favourable remodelling of the ventricles. VNS and CBS have been shown in separate pilot studies to improve functional status and ventricular function. Experimental work with SCS has also been shown to be beneficial in HF. Multiple clinical trials are currently evaluating the safety and efficacy of these therapeutic strategies in the treatment of HF. While being enthusiastic about these potential modalities, we need to be cognizant of the fact that these are invasive, investigational, and still beset with many unknowns. The era of non-pharmacological modulation of the ANS has dawned upon us. It, however, remains to be seen whether it lives up to our expectations.

Conflict of interest: J.P.S. reports receiving research grants from St Jude Medical, Medtronic Inc., Boston Scientific Corp. and Biotronik, consulting from Boston Scientific Corp., Medtronic Inc, Sorin Group, St Jude Medical, Biosense Webster and receiving lecture fees from Boston Scientific Corp., Medtronic, St Jude Medical and Sorin Group. JK & AJC: none relevant to this article.

Acknowledgements

The authors would like to acknowledge the contribution of Dr Eszter M. Vegh towards the preparation of the figures and editing of this manuscript.

References

1
Go
AS
Mozaffarian
D
Roger
VL
Benjamin
EJ
Berry
JD
Borden
WB
Bravata
DM
Dai
S
Ford
ES
Fox
CS
Franco
S
Fullerton
HJ
Gillespie
C
Hailpern
SM
Heit
JA
Howard
VJ
Huffman
MD
Kissela
BM
Kittner
SJ
Lackland
DT
Lichtman
JH
Lisabeth
LD
Magid
D
Marcus
GM
Marelli
A
Matchar
DB
McGuire
DK
Mohler
ER
Moy
CS
Mussolino
ME
Nichol
G
Paynter
NP
Schreiner
PJ
Sorlie
PD
Stein
J
Turan
TN
Virani
SS
Wong
ND
Woo
D
Turner
MB
Heart disease and stroke statistics—2013 update: a report from the American Heart Association
Circulation
 , 
2013
, vol. 
127
 (pg. 
e6
-
e245
)
2
Bristow
MR
The adrenergic nervous system in heart failure
N Engl J Med
 , 
1984
, vol. 
311
 (pg. 
850
-
851
)
3
Parati
G
Esler
M
The human sympathetic nervous system: its relevance in hypertension and heart failure
Eur Heart J
 , 
2012
, vol. 
33
 (pg. 
1058
-
1066
)
4
Floras
JS
Arterial baroreceptor and cardiopulmonary reflex control of sympathetic outflow in human heart failure
Ann N Y Acad Sci
 , 
2001
, vol. 
940
 (pg. 
500
-
513
)
5
Goldsmith
SR
Interactions between the sympathetic nervous system and the RAAS in heart failure
Curr Heart Fail Rep
 , 
2004
, vol. 
1
 (pg. 
45
-
50
)
6
Cohn
JN
Levine
TB
Angiotensin-converting enzyme inhibition in congestive heart failure: the concept
Am J Cardiol
 , 
1982
, vol. 
49
 (pg. 
1480
-
1483
)
7
Triposkiadis
F
Karayannis
G
Giamouzis
G
Skoularigis
J
Louridas
G
Butler
J
The sympathetic nervous system in heart failure physiology, pathophysiology, and clinical implications
J Am Coll Cardiol
 , 
2009
, vol. 
54
 (pg. 
1747
-
1762
)
8
Floras
JS
Sympathetic nervous system activation in human heart failure: clinical implications of an updated model
J Am Coll Cardiol
 , 
2009
, vol. 
54
 (pg. 
375
-
385
)
9
Mann
DL
Bristow
MR
Mechanisms and models in heart failure: the biomechanical model and beyond
Circulation
 , 
2005
, vol. 
111
 (pg. 
2837
-
2849
)
10
Ogawa
M
Zhou
S
Tan
AY
Song
J
Gholmieh
G
Fishbein
MC
Luo
H
Siegel
RJ
Karagueuzian
HS
Chen
LS
Lin
SF
Chen
PS
Left stellate ganglion and vagal nerve activity and cardiac arrhythmias in ambulatory dogs with pacing-induced congestive heart failure
J Am Coll Cardiol
 , 
2007
, vol. 
50
 (pg. 
335
-
343
)
11
Brack
KE
Winter
J
Ng
GA
Mechanisms underlying the autonomic modulation of ventricular fibrillation initiation-tentative prophylactic properties of vagus nerve stimulation on malignant arrhythmias in heart failure
Heart Fail Rev
 , 
2012
, vol. 
18
 (pg. 
389
-
408
)
12
Li
W
Olshansky
B
Inflammatory cytokines and nitric oxide in heart failure and potential modulation by vagus nerve stimulation
Heart Fail Rev
 , 
2011
, vol. 
16
 (pg. 
137
-
145
)
13
Eckberg
DL
Drabinsky
M
Braunwald
E
Defective cardiac parasympathetic control in patients with heart disease
N Engl J Med
 , 
1971
, vol. 
285
 (pg. 
877
-
883
)
14
Swedberg
K
Komajda
M
Bohm
M
Borer
JS
Ford
I
Dubost-Brama
A
Lerebours
G
Tavazzi
L
Ivabradine and outcomes in chronic heart failure (SHIFT): a randomised placebo-controlled study
Lancet
 , 
2010
, vol. 
376
 (pg. 
875
-
885
)
15
Hwang
HS
Hasdemir
C
Laver
D
Mehra
D
Turhan
K
Faggioni
M
Yin
H
Knollmann
BC
Inhibition of cardiac Ca2+ release channels (RyR2) determines efficacy of class I antiarrhythmic drugs in catecholaminergic polymorphic ventricular tachycardia
Circ Arrhythm Electrophysiol
 , 
2011
, vol. 
4
 (pg. 
128
-
135
)
16
Chou
CC
Nguyen
BL
Tan
AY
Chang
PC
Lee
HL
Lin
FC
Yeh
SJ
Fishbein
MC
Lin
SF
Wu
D
Wen
MS
Chen
PS
Intracellular calcium dynamics and acetylcholine-induced triggered activity in the pulmonary veins of dogs with pacing-induced heart failure
Heart Rhythm
 , 
2008
, vol. 
5
 (pg. 
1170
-
1177
)
17
Ng
J
Villuendas
R
Cokic
I
Schliamser
JE
Gordon
D
Koduri
H
Benefield
B
Simon
J
Murthy
SN
Lomasney
JW
Wasserstrom
JA
Goldberger
JJ
Aistrup
GL
Arora
R
Autonomic remodeling in the left atrium and pulmonary veins in heart failure: creation of a dynamic substrate for atrial fibrillation
Circ Arrhythm Electrophysiol
 , 
2011
, vol. 
4
 (pg. 
388
-
396
)
18
Liang
C
Rounds
NK
Dong
E
Stevens
SY
Shite
J
Qin
F
Alterations by norepinephrine of cardiac sympathetic nerve terminal function and myocardial beta-adrenergic receptor sensitivity in the ferret: normalization by antioxidant vitamins
Circulation
 , 
2000
, vol. 
102
 (pg. 
96
-
103
)
19
Eisenhofer
G
Rundquist
B
Aneman
A
Friberg
P
Dakak
N
Kopin
IJ
Jacobs
MC
Lenders
JW
Regional release and removal of catecholamines and extraneuronal metabolism to metanephrines
J Clin Endocrinol Metab
 , 
1995
, vol. 
80
 (pg. 
3009
-
3017
)
20
Lambert
E
Straznicky
N
Schlaich
M
Esler
M
Dawood
T
Hotchkin
E
Lambert
G
Differing pattern of sympathoexcitation in normal-weight and obesity-related hypertension
Hypertension
 , 
2007
, vol. 
50
 (pg. 
862
-
868
)
21
Hogarth
AJ
Graham
LN
Mary
DA
Greenwood
JP
Gender differences in sympathetic neural activation following uncomplicated acute myocardial infarction
Eur Heart J
 , 
2009
, vol. 
30
 (pg. 
1764
-
1770
)
22
Floras
JS
Mak
S
Muscle sympathetic nerve activity in women and men following acute myocardial infarction: a meaningful difference?
Eur Heart J
 , 
2009
, vol. 
30
 (pg. 
1692
-
1694
)
23
Malliani
A
Pagani
M
Lombardi
F
Furlan
R
Guzzetti
S
Cerutti
S
Spectral analysis to assess increased sympathetic tone in arterial hypertension
Hypertension
 , 
1991
, vol. 
17
 
4 Suppl
(pg. 
III36
-
III42
)
24
Furlan
R
Guzzetti
S
Crivellaro
W
Dassi
S
Tinelli
M
Baselli
G
Cerutti
S
Lombardi
F
Pagani
M
Malliani
A
Continuous 24-hour assessment of the neural regulation of systemic arterial pressure and RR variabilities in ambulant subjects
Circulation
 , 
1990
, vol. 
81
 (pg. 
537
-
547
)
25
Adamopoulos
S
Piepoli
M
McCance
A
Bernardi
L
Rocadaelli
A
Ormerod
O
Forfar
C
Sleight
P
Coats
AJ
Comparison of different methods for assessing sympathovagal balance in chronic congestive heart failure secondary to coronary artery disease
Am J Cardiol
 , 
1992
, vol. 
70
 (pg. 
1576
-
1582
)
26
Malliani
A
Pagani
M
Furlan
R
Guzzetti
S
Lucini
D
Montano
N
Cerutti
S
Mela
GS
Individual recognition by heart rate variability of two different autonomic profiles related to posture
Circulation
 , 
1997
, vol. 
96
 (pg. 
4143
-
4145
)
27
Piotrowicz
E
Baranowski
R
Piotrowska
M
Zielinski
T
Piotrowicz
R
Variable effects of physical training of heart rate variability, heart rate recovery, and heart rate turbulence in chronic heart failure
Pacing Clin Electrophysiol
 , 
2009
, vol. 
32
 
Suppl 1
(pg. 
S113
-
S115
)
28
La Rovere
MT
Pinna
GD
Maestri
R
Barlera
S
Bernardinangeli
M
Veniani
M
Nicolosi
GL
Marchioli
R
Tavazzi
L
Autonomic markers and cardiovascular and arrhythmic events in heart failure patients: still a place in prognostication? Data from the GISSI-HF trial
Eur J Heart Fail
 , 
2012
, vol. 
14
 (pg. 
1410
-
1419
)
29
Bauer
A
Kantelhardt
JW
Barthel
P
Schneider
R
Makikallio
T
Ulm
K
Hnatkova
K
Schomig
A
Huikuri
H
Bunde
A
Malik
M
Schmidt
G
Deceleration capacity of heart rate as a predictor of mortality after myocardial infarction: cohort study
Lancet
 , 
2006
, vol. 
367
 (pg. 
1674
-
1681
)
30
La Rovere
MT
Pinna
GD
Hohnloser
SH
Marcus
FI
Mortara
A
Nohara
R
Bigger
JT
Jr
Camm
AJ
Schwartz
PJ
Baroreflex sensitivity and heart rate variability in the identification of patients at risk for life-threatening arrhythmias: implications for clinical trials
Circulation
 , 
2001
, vol. 
103
 (pg. 
2072
-
2077
)
31
Sleight
P
La Rovere
MT
Mortara
A
Pinna
G
Maestri
R
Leuzzi
S
Bianchini
B
Tavazzi
L
Bernardi
L
Physiology and pathophysiology of heart rate and blood pressure variability in humans: is power spectral analysis largely an index of baroreflex gain?
Clin Sci (Lond)
 , 
1995
, vol. 
88
 (pg. 
103
-
109
)
32
Perrone-Filardi
P
Paolillo
S
Dellegrottaglie
S
Gargiulo
P
Savarese
G
Marciano
C
Casaretti
L
Cecere
M
Musella
F
Pirozzi
E
Parente
A
Cuocolo
A
Assessment of cardiac sympathetic activity by MIBG imaging in patients with heart failure: a clinical appraisal
Heart
 , 
2011
, vol. 
97
 (pg. 
1828
-
1833
)
33
Bengel
FM
Schwaiger
M
Assessment of cardiac sympathetic neuronal function using PET imaging
J Nucl Cardiol
 , 
2004
, vol. 
11
 (pg. 
603
-
616
)
34
Merchant
FM
Dec
GW
Singh
JP
Implantable sensors for heart failure
Circ Arrhythm Electrophysiol
 , 
2010
, vol. 
3
 (pg. 
657
-
667
)
35
Lin
YH
Lin
C
Lo
MT
Lin
HJ
Wu
YW
Hsu
RB
Chao
CL
Hsu
HC
Wang
PC
Wu
VC
Wang
SS
Lee
CM
Chien
KL
Ho
YL
Chen
MF
Peng
CK
The relationship between aminoterminal propeptide of type III procollagen and heart rate variability parameters in heart failure patients: a potential serum marker to evaluate cardiac autonomic control and sudden cardiac death
Clin Chem Lab Med
 , 
2010
, vol. 
48
 (pg. 
1821
-
1827
)
36
Whellan
DJ
Ousdigian
KT
Al-Khatib
SM
Pu
W
Sarkar
S
Porter
CB
Pavri
BB
O'Connor
CM
Combined heart failure device diagnostics identify patients at higher risk of subsequent heart failure hospitalizations: results from PARTNERS HF (Program to Access and Review Trending Information and Evaluate Correlation to Symptoms in Patients With Heart Failure) study
J Am Coll Cardiol
 , 
2010
, vol. 
55
 (pg. 
1803
-
1810
)
37
Singh
JP
Rosenthal
LS
Hranitzky
PM
Berg
KC
Mullin
CM
Thackeray
L
Kaplan
A
Device diagnostics and long-term clinical outcome in patients receiving cardiac resynchronization therapy
Europace
 , 
2009
, vol. 
11
 (pg. 
1647
-
1653
)
38
Fantoni
C
Raffa
S
Regoli
F
Giraldi
F
La Rovere
MT
Prentice
J
Pastori
F
Fratini
S
Salerno-Uriarte
JA
Klein
HU
Auricchio
A
Cardiac resynchronization therapy improves heart rate profile and heart rate variability of patients with moderate to severe heart failure
J Am Coll Cardiol
 , 
2005
, vol. 
46
 (pg. 
1875
-
1882
)
39
Esler
MD
Krum
H
Sobotka
PA
Schlaich
MP
Schmieder
RE
Bohm
M
Renal sympathetic denervation in patients with treatment-resistant hypertension (The Symplicity HTN-2 Trial): a randomised controlled trial
Lancet
 , 
2010
, vol. 
376
 (pg. 
1903
-
1909
)
40
Krum
H
Schlaich
M
Whitbourn
R
Sobotka
PA
Sadowski
J
Bartus
K
Kapelak
B
Walton
A
Sievert
H
Thambar
S
Abraham
WT
Esler
M
Catheter-based renal sympathetic denervation for resistant hypertension: a multicentre safety and proof-of-principle cohort study
Lancet
 , 
2009
, vol. 
373
 (pg. 
1275
-
1281
)
41
Hering
D
Lambert
EA
Marusic
P
Walton
AS
Krum
H
Lambert
GW
Esler
MD
Schlaich
MP
Substantial reduction in single sympathetic nerve firing after renal denervation in patients with resistant hypertension
Hypertension
 , 
2013
, vol. 
61
 (pg. 
457
-
464
)
42
Ljungqvist
A
Wagermark
J
The adrenergic innervation of intrarenal glomerular and extra-glomerular circulatory routes
Nephron
 , 
1970
, vol. 
7
 (pg. 
218
-
229
)
43
Sobotka
PA
Mahfoud
F
Schlaich
MP
Hoppe
UC
Bohm
M
Krum
H
Sympatho-renal axis in chronic disease
Clin Res Cardiol
 , 
2011
, vol. 
100
 (pg. 
1049
-
1057
)
44
Mahfoud
F
Luscher
TF
Andersson
B
Baumgartner
I
Cifkova
R
Dimario
C
Doevendans
P
Fagard
R
Fajadet
J
Komajda
M
Lefevre
T
Lotan
C
Sievert
H
Volpe
M
Widimsky
P
Wijns
W
Williams
B
Windecker
S
Witkowski
A
Zeller
T
Bohm
M
Expert consensus document from the European Society of Cardiology on catheter-based renal denervation
Eur Heart J
 , 
2013
, vol. 
34
 (pg. 
2149
-
2157
)
45
Investigators. SH.
Catheter-based renal sympathetic denervation for resistant hypertension: durability of blood pressure reduction out to 24 months
Hypertension
 , 
2011
, vol. 
57
 (pg. 
911
-
917
)
46
Schlaich
MP
Sobotka
PA
Krum
H
Lambert
E
Esler
MD
Renal sympathetic-nerve ablation for uncontrolled hypertension
N Engl J Med
 , 
2009
, vol. 
361
 (pg. 
932
-
934
)
47
Mahfoud
F
Ukena
C
Schmieder
RE
Cremers
B
Rump
LC
Vonend
O
Weil
J
Schmidt
M
Hoppe
UC
Zeller
T
Bauer
A
Ott
C
Blessing
E
Sobotka
PA
Krum
H
Schlaich
M
Esler
M
Bohm
M
Ambulatory blood pressure changes after renal sympathetic denervation in patients with resistant hypertension
Circulation
 , 
2013
, vol. 
128
 (pg. 
132
-
140
)
48
Davies
JE
Manisty
CH
Petraco
R
Barron
AJ
Unsworth
B
Mayet
J
Hamady
M
Hughes
AD
Sever
PS
Sobotka
PA
Francis
DP
First-in-man safety evaluation of renal denervation for chronic systolic heart failure: primary outcome from REACH-Pilot study
Int J Cardiol
 , 
2013
, vol. 
162
 (pg. 
189
-
192
)
49
Ozaki
Y
European Society of Cardiology (ESC) Congress Report from Munich 2012
Circ J
 , 
2012
, vol. 
76
 (pg. 
2530
-
2535
)
50
Hospital BP
Phase 3 study of renal denervation that improves symptoms of heart failure and enhances life quality in advanced heart failure
 
51
Vascular M
Renal denervation in patients with chronic heart failure and renal impairment
 
52
Brandt
MC
Mahfoud
F
Reda
S
Schirmer
SH
Erdmann
E
Bohm
M
Hoppe
UC
Renal sympathetic denervation reduces left ventricular hypertrophy and improves cardiac function in patients with resistant hypertension
J Am Coll Cardiol
 , 
2012
, vol. 
59
 (pg. 
901
-
909
)
53
Zile
MR
Little
WC
Effects of autonomic modulation: more than just blood pressure
J Am Coll Cardiol
 , 
2012
, vol. 
59
 (pg. 
910
-
912
)
54
Mahfoud
F
Schlaich
M
Kindermann
I
Ukena
C
Cremers
B
Brandt
MC
Hoppe
UC
Vonend
O
Rump
LC
Sobotka
PA
Krum
H
Esler
M
Bohm
M
Effect of renal sympathetic denervation on glucose metabolism in patients with resistant hypertension: a pilot study
Circulation
 , 
2011
, vol. 
123
 (pg. 
1940
-
1946
)
55
Linz
D
Mahfoud
F
Schotten
U
Ukena
C
Neuberger
HR
Wirth
K
Bohm
M
Renal sympathetic denervation suppresses postapneic blood pressure rises and atrial fibrillation in a model for sleep apnea
Hypertension
 , 
2012
, vol. 
60
 (pg. 
172
-
178
)
56
Pokushalov
E
Romanov
A
Corbucci
G
Artyomenko
S
Baranova
V
Turov
A
Shirokova
N
Karaskov
A
Mittal
S
Steinberg
JS
A randomized comparison of pulmonary vein isolation with versus without concomitant renal artery denervation in patients with refractory symptomatic atrial fibrillation and resistant hypertension
J Am Coll Cardiol
 , 
2012
, vol. 
60
 (pg. 
1163
-
1170
)
57
Ukena
C
Bauer
A
Mahfoud
F
Schreieck
J
Neuberger
HR
Eick
C
Sobotka
PA
Gawaz
M
Bohm
M
Renal sympathetic denervation for treatment of electrical storm: first-in-man experience
Clin Res Cardiol
 , 
2012
, vol. 
101
 (pg. 
63
-
67
)
58
Ukena
C
Mahfoud
F
Spies
A
Kindermann
I
Linz
D
Cremers
B
Laufs
U
Neuberger
HR
Bohm
M
Effects of renal sympathetic denervation on heart rate and atrioventricular conduction in patients with resistant hypertension
Int J Cardiol
 , 
2012
, vol. 
167
 (pg. 
2846
-
2851
)
59
Cohn
JN
Pfeffer
MA
Rouleau
J
Sharpe
N
Swedberg
K
Straub
M
Wiltse
C
Wright
TJ
Adverse mortality effect of central sympathetic inhibition with sustained-release moxonidine in patients with heart failure (MOXCON)
Eur J Heart Fail
 , 
2003
, vol. 
5
 (pg. 
659
-
667
)
60
Vanoli
E
De Ferrari
GM
Stramba-Badiale
M
Hull
SS
Jr
Foreman
RD
Schwartz
PJ
Vagal stimulation and prevention of sudden death in conscious dogs with a healed myocardial infarction
Circ Res
 , 
1991
, vol. 
68
 (pg. 
1471
-
1481
)
61
Billman
GE
Schwartz
PJ
Stone
HL
Baroreceptor reflex control of heart rate: a predictor of sudden cardiac death
Circulation
 , 
1982
, vol. 
66
 (pg. 
874
-
880
)
62
La Rovere
MT
Bigger
JT
Jr
Marcus
FI
Mortara
A
Schwartz
PJ
Baroreflex sensitivity and heart-rate variability in prediction of total cardiac mortality after myocardial infarction. ATRAMI (Autonomic Tone and Reflexes After Myocardial Infarction) Investigators
Lancet
 , 
1998
, vol. 
351
 (pg. 
478
-
484
)
63
Heck
C
Helmers
SL
DeGiorgio
CM
Vagus nerve stimulation therapy, epilepsy, and device parameters: scientific basis and recommendations for use
Neurology
 , 
2002
, vol. 
59
 
6 Suppl. 4
(pg. 
S31
-
S37
)
64
Rush
AJ
Marangell
LB
Sackeim
HA
George
MS
Brannan
SK
Davis
SM
Howland
R
Kling
MA
Rittberg
BR
Burke
WJ
Rapaport
MH
Zajecka
J
Nierenberg
AA
Husain
MM
Ginsberg
D
Cooke
RG
Vagus nerve stimulation for treatment-resistant depression: a randomized, controlled acute phase trial
Biol Psychiatry
 , 
2005
, vol. 
58
 (pg. 
347
-
354
)
65
Schwartz
PJ
De Ferrari
GM
Sanzo
A
Landolina
M
Rordorf
R
Raineri
C
Campana
C
Revera
M
Ajmone-Marsan
N
Tavazzi
L
Odero
A
Long term vagal stimulation in patients with advanced heart failure: first experience in man
Eur J Heart Fail
 , 
2008
, vol. 
10
 (pg. 
884
-
891
)
66
Milby
AH
Halpern
CH
Baltuch
GH
Vagus nerve stimulation for epilepsy and depression
Neurotherapeutics
 , 
2008
, vol. 
5
 (pg. 
75
-
85
)
67
Li
M
Zheng
C
Sato
T
Kawada
T
Sugimachi
M
Sunagawa
K
Vagal nerve stimulation markedly improves long-term survival after chronic heart failure in rats
Circulation
 , 
2004
, vol. 
109
 (pg. 
120
-
124
)
68
De Ferrari
GM
Schwartz
PJ
Vagus nerve stimulation: from pre-clinical to clinical application: challenges and future directions
Heart Fail Rev
 , 
2011
, vol. 
16
 (pg. 
195
-
203
)
69
Olshansky
B
Sabbah
HN
Hauptman
PJ
Colucci
WS
Parasympathetic nervous system and heart failure: pathophysiology and potential implications for therapy
Circulation
 , 
2008
, vol. 
118
 (pg. 
863
-
871
)
70
Ando
M
Katare
RG
Kakinuma
Y
Zhang
D
Yamasaki
F
Muramoto
K
Sato
T
Efferent vagal nerve stimulation protects heart against ischemia-induced arrhythmias by preserving connexin43 protein
Circulation
 , 
2005
, vol. 
112
 (pg. 
164
-
170
)
71
Zhang
Y
Popovic
ZB
Bibevski
S
Fakhry
I
Sica
DA
Van Wagoner
DR
Mazgalev
TN
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
, vol. 
2
 (pg. 
692
-
699
)
72
Van Stee
EW
Autonomic innervation of the heart
Environ Health Perspect
 , 
1978
, vol. 
26
 (pg. 
151
-
158
)
73
Armour
JA
Cardiac neuronal hierarchy in health and disease
Am J Physiol Regul Integr Comp Physiol
 , 
2004
, vol. 
287
 (pg. 
R262
-
R271
)
74
Schauerte
P
Mischke
K
Plisiene
J
Waldmann
M
Zarse
M
Stellbrink
C
Schimpf
T
Knackstedt
C
Sinha
A
Hanrath
P
Catheter stimulation of cardiac parasympathetic nerves in humans: a novel approach to the cardiac autonomic nervous system
Circulation
 , 
2001
, vol. 
104
 (pg. 
2430
-
2435
)
75
Anholt
TA
Ayal
S
Goldberg
JA
Recruitment and blocking properties of the CardioFit stimulation lead
J Neural Eng
 , 
2011
, vol. 
8
 pg. 
034004
 
76
De Ferrari
GM
Crijns
HJ
Borggrefe
M
Milasinovic
G
Smid
J
Zabel
M
Gavazzi
A
Sanzo
A
Dennert
R
Kuschyk
J
Raspopovic
S
Klein
H
Swedberg
K
Schwartz
PJ
Chronic vagus nerve stimulation: a new and promising therapeutic approach for chronic heart failure
Eur Heart J
 , 
2011
, vol. 
32
 (pg. 
847
-
855
)
77
Hauptman
PJ
Schwartz
PJ
Gold
MR
Borggrefe
M
Van Veldhuisen
DJ
Starling
RC
Mann
DL
Rationale and study design of the increase of vagal tone in heart failure study: INOVATE-HF
Am Heart J
 , 
2012
, vol. 
163
 (pg. 
954
-
962
e1
78
Corporation BS
Neural cardiac therapy for heart failure study
 
79
Sabbah
HN
Ilsar
I
Zaretsky
A
Rastogi
S
Wang
M
Gupta
RC
Vagus nerve stimulation in experimental heart failure
Heart Fail Rev
 , 
2011
, vol. 
16
 (pg. 
171
-
178
)
80
Bianchi
S
Rossi
P
Della Scala
A
Kornet
L
Pulvirenti
R
Monari
G
Di Renzi
P
Schauerte
P
Azzolini
P
Atrioventricular (AV) node vagal stimulation by transvenous permanent lead implantation to modulate AV node function: safety and feasibility in humans
Heart Rhythm
 , 
2009
, vol. 
6
 (pg. 
1282
-
1286
)
81
McCubbin
JW
Green
JH
Page
IH
Baroceptor function in chronic renal hypertension
Circ Res
 , 
1956
, vol. 
4
 (pg. 
205
-
210
)
82
Chapleau
MW
Hajduczok
G
Abboud
FM
Mechanisms of resetting of arterial baroreceptors: an overview
Am J Med Sci
 , 
1988
, vol. 
295
 (pg. 
327
-
334
)
83
Thrasher
TN
Unloading arterial baroreceptors causes neurogenic hypertension
Am J Physiol Regul Integr Comp Physiol
 , 
2002
, vol. 
282
 (pg. 
R1044
-
R1053
)
84
Biaggioni
I
Whetsell
WO
Jobe
J
Nadeau
JH
Baroreflex failure in a patient with central nervous system lesions involving the nucleus tractus solitarii
Hypertension
 , 
1994
, vol. 
23
 (pg. 
491
-
495
)
85
Robertson
D
Hollister
AS
Biaggioni
I
Netterville
JL
Mosqueda-Garcia
R
Robertson
RM
The diagnosis and treatment of baroreflex failure
N Engl J Med
 , 
1993
, vol. 
329
 (pg. 
1449
-
1455
)
86
Heusser
K
Tank
J
Engeli
S
Diedrich
A
Menne
J
Eckert
S
Peters
T
Sweep
FC
Haller
H
Pichlmaier
AM
Luft
FC
Jordan
J
Carotid baroreceptor stimulation, sympathetic activity, baroreflex function, and blood pressure in hypertensive patients
Hypertension
 , 
2010
, vol. 
55
 (pg. 
619
-
626
)
87
Scheffers
IJ
Kroon
AA
Schmidli
J
Jordan
J
Tordoir
JJ
Mohaupt
MG
Luft
FC
Haller
H
Menne
J
Engeli
S
Ceral
J
Eckert
S
Erglis
A
Narkiewicz
K
Philipp
T
de Leeuw
PW
Novel baroreflex activation therapy in resistant hypertension: results of a European multi-center feasibility study
J Am Coll Cardiol
 , 
2010
, vol. 
56
 (pg. 
1254
-
1258
)
88
Bisognano
JD
Bakris
G
Nadim
MK
Sanchez
L
Kroon
AA
Schafer
J
de Leeuw
PW
Sica
DA
Baroreflex activation therapy lowers blood pressure in patients with resistant hypertension: results from the double-blind, randomized, placebo-controlled rheos pivotal trial
J Am Coll Cardiol
 , 
2011
, vol. 
58
 (pg. 
765
-
773
)
89
Bakris
GL
Nadim
MK
Haller
H
Lovett
EG
Schafer
JE
Bisognano
JD
Baroreflex activation therapy provides durable benefit in patients with resistant hypertension: results of long-term follow-up in the Rheos Pivotal Trial
J Am Soc Hypertens
 , 
2012
, vol. 
6
 (pg. 
152
-
158
)
90
Creager
MA
Baroreceptor reflex function in congestive heart failure
Am J Cardiol
 , 
1992
, vol. 
69
 (pg. 
10G
-
15G
discussion 15G-16G
91
Zucker
IH
Hackley
JF
Cornish
KG
Hiser
BA
Anderson
NR
Kieval
R
Irwin
ED
Serdar
DJ
Peuler
JD
Rossing
MA
Chronic baroreceptor activation enhances survival in dogs with pacing-induced heart failure
Hypertension
 , 
2007
, vol. 
50
 (pg. 
904
-
910
)
92
Higashi
T
Kobayashi
N
Hara
K
Shirataki
H
Matsuoka
H
Effects of angiotensin II type 1 receptor antagonist on nitric oxide synthase expression and myocardial remodeling in Goldblatt hypertensive rats
J Cardiovasc Pharmacol
 , 
2000
, vol. 
35
 (pg. 
564
-
571
)
93
Nishida
Y
Ding
J
Zhou
MS
Chen
QH
Murakami
H
Wu
XZ
Kosaka
H
Role of nitric oxide in vascular hyper-responsiveness to norepinephrine in hypertensive Dahl rats
J Hypertens
 , 
1998
, vol. 
16
 (pg. 
1611
-
1618
)
94
CVRx I
 
Health Outcomes Prospective Evaluation for Heart Failure With EF ≥ 40% In CVRx I. Rheos HOPE4HF Study. Available at http://clinicaltrials.gov/show/NCT00718939(25 October 2013)
95
Georgakopoulos
D
Little
WC
Abraham
WT
Weaver
FA
Zile
MR
Chronic baroreflex activation: a potential therapeutic approach to heart failure with preserved ejection fraction
J Card Fail
 , 
2011
, vol. 
17
 (pg. 
167
-
178
)
96
CVRx I
Barostim HOPE4HF Study
 
97
Management MCRD
Acute Carotid Sinus Endovascular Stimulation II Study
 
98
Olgin
JE
Takahashi
T
Wilson
E
Vereckei
A
Steinberg
H
Zipes
DP
Effects of thoracic spinal cord stimulation on cardiac autonomic regulation of the sinus and atrioventricular nodes
J Cardiovasc Electrophysiol
 , 
2002
, vol. 
13
 (pg. 
475
-
481
)
99
Lopshire
JC
Zhou
X
Dusa
C
Ueyama
T
Rosenberger
J
Courtney
N
Ujhelyi
M
Mullen
T
Das
M
Zipes
DP
Spinal cord stimulation improves ventricular function and reduces ventricular arrhythmias in a canine postinfarction heart failure model
Circulation
 , 
2009
, vol. 
120
 (pg. 
286
-
294
)
100
Issa
ZF
Zhou
X
Ujhelyi
MR
Rosenberger
J
Bhakta
D
Groh
WJ
Miller
JM
Zipes
DP
Thoracic spinal cord stimulation reduces the risk of ischemic ventricular arrhythmias in a postinfarction heart failure canine model
Circulation
 , 
2005
, vol. 
111
 (pg. 
3217
-
3220
)
101
Medical SJ
Spinal cord stimulation for heart failure as a restorative treatment
 
102
Management MCRD
Determining the feasibility of spinal cord neuromodulation for the treatment of chronic heart failure
 
103
Medical SJ
Trial of Autonomic neuroModulation for trEatment of Chronic Heart Failure
 
104
Kobayashi
M
Sakurai
S
Takaseya
T
Shiose
A
Kim
HI
Fujiki
M
Karimov
JH
Dessoffy
R
Massiello
A
Borowski
AG
Van Wagoner
DR
Jung
E
Fukamachi
K
Effects of percutaneous stimulation of both sympathetic and parasympathetic cardiac autonomic nerves on cardiac function in dogs
Innovations (Phila)
 , 
2012
, vol. 
7
 (pg. 
282
-
289
)

Comments

0 Comments