Targeting the autonomic nervous system: Measuring autonomic function and novel devices for heart failure management

IJCA-17057; No of Pages 11 International Journal of Cardiology xxx (2013) xxx–xxx

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International Journal of Cardiology journal homepage: www.elsevier.com/locate/ijcard

Review

Targeting the autonomic nervous system: Measuring autonomic function and novel devices for heart failure management☆ Hitesh C. Patel a,b,⁎, Stuart D. Rosen b, Alistair Lindsay a, Carl Hayward a,b, Alexander R. Lyon a,b, Carlo di Mario a a b

NIHR Cardiovascular Biomedical Research Unit, Royal Brompton Hospital, London, United Kingdom National Heart and Lung Institute, Imperial College, London, United Kingdom

a r t i c l e

i n f o

Article history: Received 22 March 2013 Received in revised form 3 September 2013 Accepted 19 October 2013 Available online xxxx Keywords: Heart failure Autonomic nervous system Sympathetic nervous system Renal denervation Devices

a b s t r a c t Neurohumoral activation, in which enhanced activity of the autonomic nervous system (ANS) is a key component, plays a pivotal role in heart failure. The neurohumoral system affects several organs and currently our knowledge of the molecular and systemic pathways involved in the neurohumoral activation is incomplete. All the methods of assessing the degree of activation of the autonomic system have limitations and they are not interchangeable. The methods considered include noradrenaline spillover, microneurography, radiotracer imaging and analysis of heart rate and blood pressure (heart rate variability, baroreceptor sensitivity, heart rate turbulence). Despite the difficulties, medications that affect the ANS have been shown to improve mortality in heart failure and the mechanism is related to attenuation of the sympathetic nervous system (SNS) and stimulation of the parasympathetic nervous system. However, limitations of compliance with medication, side effects and inadequate SNS attenuation are issues of concern with the pharmacological approach. The newer device based therapies for sympathetic modulation are showing encouraging results. As they directly influence the autonomic nervous system, more mechanistic information can be gleaned if appropriate investigations are performed at the time of the outcome trials. However, clinicians should be reminded that the ANS is an evolutionary survival mechanism and therefore there is a need to proceed with caution when trying to completely attenuate its effects. So our enthusiasm for the application of these devices in heart failure should be controlled, especially as none of the devices have trial data powered to assess effects on mortality or cardiovascular events. © 2013 Elsevier Ireland Ltd. All rights reserved.

1. Introduction Heart failure (HF) is a condition that has plagued mankind for centuries and has been described in texts dating back to the era of ancient Greece [1]. Over the centuries life expectancy has increased and concomitantly so has the prevalence of heart failure. Our ability to treat this condition has evolved such that the standardised mortality from heart failure has decreased by 40% between 1987 and 2008 [2]. Nonetheless, the long-term prognosis of heart failure remains dismally poor, with some contemporary studies reporting a 3 year survival of 25% [3]. Initially heart failure was seen as a ‘haemodynamic’ problem that might be best treated with inotropic agents [1]. However it was not until a key paradigm shift–the discovery of an abnormally activated

☆ These authors take responsibility for all aspects of the reliability and freedom from bias of the data presented and their discussed interpretation. ⁎ Corresponding author at: Cardiology Research Fellow, NIHR Cardiovascular Biomedical Research Unit, Royal Brompton and Harefield NHS Foundation Trust, Sydney Street, London SW3 6NP, United Kingdom. Tel.: +44 207 352 8121x2920. E-mail address: [email protected] (H.C. Patel).

and damaging neurohumoral response–that therapies targeted at attenuating this response significantly improved prognosis [1]. The neuronal aspect of this response is represented by sympathetic nervous system (SNS) activation and parasympathetic (PNS) withdrawal. The humoral pathway consists of the renin–angiotensin–aldosterone system, endothelin, vasopressin and cytokines. In health, these pathways maintain blood pressure and central organ perfusion, which is vital in day to day life as it for example, allows us to move from supine to standing without fainting but also it is life saving when experiencing a stressor, e.g. acute blood loss. In this review, we shall briefly summarise our knowledge of sympathetic responses in heart failure and explore the therapeutic modalities that have developed as a consequence. There are now several novel devices which seek directly to modulate the SNS in heart failure. Whilst, definitive trials evaluating the traditional heart failure endpoints of mortality, hospitalisation and quality of life are being designed, smaller, but nonetheless important, feasibility and mechanistic studies are underway. Measuring the effect of these devices on the SNS in heart failure will be a key component of these studies. Our review therefore includes the current techniques used to assess sympathetic activity and their clinical applications, to provide background and context to current

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Please cite this article as: Patel HC, et al, Targeting the autonomic nervous system: Measuring autonomic function and novel devices for heart failure management, Int J Cardiol (2013), http://dx.doi.org/10.1016/j.ijcard.2013.10.058

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and future data using these autonomic nervous system (ANS) modulating devices. 2. Sympathetic nervous system in heart failure The SNS is the component of the neurohumoral pathway that is activated most immediately to maintain cardiac output and in that sense is a most appropriate response to the impaired physiology of the failing heart [4,5]. However, persistent and excessive activation leads to disease acceleration. Floras has neatly created an updated model that describes the multiple and interacting pathways responsible for SNS overactivity in HF (Fig. 1) [5]. Increased sympathetic outflow (efferents) from the central nervous system (CNS) in HF predominately affects three key organs: the heart, the kidney and the peripheral vasculature. Of these, the heart is subject to the greatest drive by the SNS. At the cardiac receptor level, in response to SNS overactivity, the β1-adrenoreceptors are downregulated and developed altered function. Initially this is predominately a protective mechanism to prevent a harmful surge in intracellular cAMP however when sustained it leads to loss of inotropy [6]. The β2 adrenoreceptors are uncoupled from the β1 receptors in HF but the β2 receptor numbers are not decreased [6]. Both of these β adrenoreceptors regulate heart rate, myocardial contractility and relaxation. α1Adrenoreceptors are expressed at lower levels in the heart. They are more commonly located in the major arteries. When stimulated they lead to activation of calcium channels, inhibition of potassium channels and adaptive myocardial hypertrophy. There is a modest upregulation of this receptor in heart failure but the significance of this is not entirely elucidated [6]. Clinically, excessive adrenergic drive to the heart is associated with progressive pump failure secondary to adverse remodelling and hypertrophy, arrhythmias and ischaemia. At the renal level, sympathetic stimulation causes renin release, salt and water retention and reduces renal perfusion [7]. Not surprisingly, these effects have an adverse prognostic implication in heart failure. The central SNS outflow is partly controlled by reflex responses and partly as a result of modulation of peripheral afferent signals that come together in the CNS. Key afferent pathways include [5]:

1. Arterial baroreceptor reflex: in HF, baroreflex mediated heart rate control in response to blood pressure is impaired. However, baroreflex control (inhibitory) of sympathetic nerve activity is still intact, albeit at a higher set point. 2. Cardiopulmonary reflexes: generally inhibit SNS activation. The receptors found in the lung and atria are activated by volume overload and certain breathing patterns. This key reflex is attenuated in HF. 3. Peripheral chemoreceptors: elicit an augmented SNS activation in response to peripheral hypoxia and central hypercapnia. 4. Renal afferents: when stimulated, can induce sympathetic efferent activation to not only the kidney (renorenal reflex) but also to other key organs including the heart. 5. Muscle reflexes: show exaggerated activation of the SNS in response to exercise. SNS activation in HF reflects the balance of these afferent and efferent signals. 3. Measuring the sympathetic nervous system in heart failure The quantification of SNS activity in the whole body or in a particular organ is difficult. In the current heart failure literature, there are four main methods of assessing SNS activity, each unique and contributing different information, much akin to four blind individuals describing an elephant in the room (Fig. 2). 3.1. Noradrenaline spillover Noradrenaline (NA) is the key neurotransmitter of the sympathetic nervous system (SNS) and central nervous system (CNS). Unlike adrenaline, it does not play a prominent role as a circulating hormone. Earlier studies in HF demonstrated a reduced concentration of cardiac NA by performing analysis on cardiac tissue from human hearts [8] at surgery and canine [9] HF models, suggesting SNS denervation to the heart. This in turn led to the belief that β-blockers would be harmful and also that inotropes that are ligands to the β-adrenoreceptors may be beneficial.

Fig. 1. Mechanisms of sympathetic activation in human heart failure. + = excitatory inputs; − = inhibitory inputs; Ach = acetylcholine; CNS = central nervous system; E = adrenaline (epinephrine); NE = noradrenaline (norepinephrine). Renal afferent nerves travelling back to the CNS have not been depicted. Figure reproduced with permission from Elsevier from Floras J, 2009 [5].

Please cite this article as: Patel HC, et al, Targeting the autonomic nervous system: Measuring autonomic function and novel devices for heart failure management, Int J Cardiol (2013), http://dx.doi.org/10.1016/j.ijcard.2013.10.058

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Fig. 2. Different techniques to quantify the different aspects of the sympathetic nervous system. HRV = heart rate variability; BRS = baroreceptor sensitivity; mIBG = metaiodobenzylguanidine; PET = positron emission tomography (diagram adapted from Patel H et al., Springer, UK, data on file).

We now know that both of these assertions are diametrically opposed to current best practice. Several groups have shown that peripheral blood and urine concentrations of NA are higher in HF patients; the higher the level, the worse the prognosis [10,11]. However, both these methods are crude assessments of SNS activity as only 20% of NA released at the nerve terminals enters the circulation and only 2% of the total is excreted in urine [14]. One of the confounding reasons that there is an elevated plasma NA level in heart failure patients, in addition to increased production and release, is that there is also reduced plasma clearance secondary to low cardiac output. This is important, firstly because heart failure is usually a low cardiac output state and hence plasma levels of NA will overestimate the amount of SNS activation, and secondly, a treatment which lowers plasma NA may not have reduced SNS activity, but could merely reflect improvement in renal blood flow and hence NA clearance. Studies have shown that a single venous blood measurement of NA does not have good reproducibility [12]. At the cellular level, experiments involving continuous infusions of NA to both ex-vivo cardiomyocytes and animal models have demonstrated the harmful effects of excess release of this neurotransmitter. Chronic catecholamine administration causes cardiomyocyte apoptosis, cardiac contracture bands and interstitial fibrosis, all of which contribute to heart failure progression [13]. Apoptosis involves many intracellular pathways that include protein kinase A, calcium overload and calmodulin-dependent protein kinase II. The SNS innervates multiple organs (e.g., brain, heart, kidneys, blood vessels, adrenals, skin). Both in health and in disease, SNS activation is not uniform and sometimes is opposing across these beds. Thus plasma or urine measurements reflect a summation of these responses rather than a precise marker of SNS activity in an area of interest [14]. With the development of organ-specific techniques using radiolabelled NA it was possible to overcome some of the limitations described above. To undertake this technique, blood must be sampled across the organ in question (e.g. to determine cardiac spillover samples are required from the coronary sinus and the aorta), whilst radiolabelled NA is infused at a steady state [14]. This method requires considerable expertise, a catheterisation suite capable of invasive sampling safely, radiation exposure [albeit negligible at 1 millisievert (mSv)] and sophisticated laboratory equipment to quantify radio-tracer NA (liquid scintillation counting) and endogenous NA (high-performance liquid chromatography). NA spillover measurements from the heart are up to 50 times increased in HF [15]. This technique can be used to assess SNS outflow from numerous beds including the brain and kidneys.

3.2. Microneurography The sympathetic nerves travel to the brain (afferent) or from the brain (efferent) to a target organ. Afferent fibres travel in autonomic nerves whereas efferent fibres travel either in autonomic or somatic nerves. The efferent sympathetic nerves exit the central nervous system from the cervical and thoraco-lumbar ganglia (T1 to L2). The atria, ventricles and the coronary arteries all receive sympathetic innervation via the cardiac nerves or the thoracic ganglia at T1-4. In the periphery the SNS controls vascular tone. Microneurography is a technique that allows direct quantification of peripheral efferent sympathetic nerve activity in humans. Using the method described by Hagbarth and Vallbo, efferent discharges to the postganglionic unmyelinated sympathetic C fibres can be recorded [16]. Briefly, a tungsten microelectrode is inserted using anatomical landmarks into a peripheral nerve (usually the peroneal or tibial) and sited in the sympathetic fibres. The nerve discharges are amplified, filtered and after quality control to ensure the microelectrode is correctly located, the readings are stored. The majority of the publications report burst frequency/min or burst per 100 heart beats. Microneurography can be used to quantify sympathetic nerve activity to muscle (MSNA) or skin (SSNA), depending on whether the muscle or skin fascicle is impaled. The two are not interchangeable and have distinct burst patterns and durations. MSNA acts on skeletal muscle vasculature and is regulated by arterial and cardiopulmonary baroreflexes, whilst SSNA affects vasomotor tone of blood vessels to the skin. MSNA has been shown to have reproducibility within an individual over time and also across different muscle beds. However, there is a very large inter-individual variability that has made it difficult for investigators to device normal reference values for MSNA [16]. Leimbach et al. were the first to report muscle sympathetic nerve activity (MSNA) in heart failure. They reported a significantly elevated MSNA in patients with moderate/severe heart failure (54 bursts/min) as compared to age-matched controls (25 bursts/min) [17]. In a longitudinal study, MSNA of greater than 49 bursts/min was an independent predictor of heart failure mortality [18]. Therapies that treat heart failure such as β-blockers [19] and biventricular pacing [20] have been shown to reduce MSNA. Microneurography not only permits regional sympathetic activation assessment but also gives a window into central nervous system SNS outflow. By showing reduced MSNA after renal artery denervation, researchers were able to show that although the procedure targets only the renal sympathetic nerves its effects extend to the CNS and other organ beds including skeletal muscle [21]. A further advantage is that

Please cite this article as: Patel HC, et al, Targeting the autonomic nervous system: Measuring autonomic function and novel devices for heart failure management, Int J Cardiol (2013), http://dx.doi.org/10.1016/j.ijcard.2013.10.058

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in animal studies, it has been used to directly show elevated SNS discharges to internal organs of interest including the kidney and heart in heart failure. The technique was initially developed recording multifibre units. It is now possible to measure single fibre sympathetic nerve firing. Though technically demanding to achieve this advance provides additional information regarding the mechanism of SNS activity in HF [16]. A key limitation of microneurography is that it only records efferent sympathetic signals to the muscle, which is perhaps not the key area of interest in human heart failure. Sympathetic overactivity to the heart is potentially more damaging than increased activity to any other organ. In mild heart failure, a heightened SNS can be demonstrated using NA spillover earlier than it can with MSNA, which only becomes abnormal as the disease progresses [22]. Microneurography is very time consuming, invasive (though has a low complication rate) and requires experienced operators. This means that only a few centres worldwide have the capabilities to undertake this investigation and its use in heart failure is restricted predominately for research.

3.3. Analysis of heart rate and blood pressure (autonomic studies) Blood pressure (product of vascular resistance and cardiac output) and heart rate are controlled by balance of both the parasympathetic and sympathetic nervous system activity. Therefore, it is possible to use the simple and widely available measurements of blood pressure and heart rate to gain an insight into the autonomic nervous system. The 4 main methods of doing so are described below and summarised in Table 1. An important limitation of all the methods is that they cannot be used reliably in patients with atrial fibrillation or those who are pacing dependent, which does restrict their application in heart failure populations. 3.3.1. Heart rate The intrinsic heart rate of healthy humans who have had their ANS completely blocked is approximately 100 beats/min [23]. However, most individuals' heart rates undergo a circadian pattern predominately due to regulation of the sino-atrial node by the ANS [24]. Slowing of the

Table 1 Table summarising the key measures of ANS activity using heart rate and blood pressure and their associated pathways and suggested normal values. HR — heart rate; SNS — sympathetic nervous system; PNS — parasympathetic nervous system; HF — heart failure; HRV — heart rate variability; ms — milliseconds; ms2 — milliseconds squared; HFc — high frequency component; LFc — low frequency component; BRS — baroreceptor sensitivity; BEI — baroreceptor effectiveness index; HRT — heart rate turbulence. Test

Description

Heart rate [25] Resting HR Static assessment of heart rate at clinic

Ewing type [27,28] Standing Drop in blood pressure between 1 min and 3 min post standing

Deep breathing Handgrip

Venous pooling of blood leads to reduced cardiac output and decreased baroreceptor discharge. This leads to SNS activation. Heart rate slows due to activation of the PNS via the vagus nerve

Rise in diastolic blood pressure during sustained hand grip for 5 min

Heart rate, blood pressure and vascular resistance increased due to simulation of the SNS and PNS withdrawal

Ratio of LFc to HFc

Normal reference values

Reflects amongst other factors the totality of the SNS and PNS influence on HR In HF aim b 75 beats/ min

Ratio of HR at 30th and 15th beat post standing Drop in heart rate during timed deep breathing

Heart rate variability [29] Time domain (24 h) SDNN Standard deviation of NN intervals Total number of all NN intervals divided by the height of the hisHRV triangular togram of all NN intervals measured on a discrete scale index SDANN Standard deviation of the averages of NN intervals in all 5-minute segments of the entire recording RMSDD The square root of the mean of the sum of the squares of differences between adjacent NN intervals Frequency domain (5 min) Total Variance of all NN intervals power HFc Power in the high frequency spectrum (0.15–0.4 Hz) LFc Power in the low frequency spectrum (0.04–0.15 Hz) LFc/HFc

Pathways

Fall b 10 mm Hg Ratio N 1.03 Fall N 10 beats/ min RiseN16mmHg

Overall HRV and total power Overall HRV and total power

141 ± 39 ms 37 ± 15

Long-term HRV

127 ± 35

Short-term HRV and like HFc

27 ± 12 ms

Overall HRV

3466 ± 1018 ms2 975 ± 203 ms2 1170 ± 416 ms2 1.5–2

Predominately reflects PNS and influences by respiration Unclear but likely a mixture of SNS and PNS with baroreceptor influence Sympathovagal balance

Baroreceptor function [33,35] BRS Slope of regression line in a graph plotting change in blood pressure Baroreceptors are activated by stretch due to arterial pressure. Their firing against change in RR interval induces PNS activation that lowers heart rate. Their function is also modulated by the SNS BEI The proportion of blood pressure ramps that induce change in RR BRS reflects the power of the reflex, BEI quantifies how often the reflex affects intervals the sinus node HRT Analyses the change in RR interval following an ectopic beat. Two Very dependent on the baro-reflex and the PNS. HRT is abolished by atropine. measures are recorded: turbulence onset (TO) and turbulence slope (TS)

N12 ms/mm Hg

N21% TO b 0%, TS N 2.5 ms/R–R interval

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heart rate is mainly under PNS control, which is most apparent at nighttime. In times of ‘stress’, e.g. during waking or on exercise, the heart rate rises and this is related to a sympathetic surge and vagal withdrawal. High resting heart rate has been shown to be an independent risk factor in the development of heart failure. The Rotterdam group showed that for every 10 beats per minute increase in heart rate, the multivariate hazard ratio for new heart failure in otherwise healthy males was significantly higher, at 1.16 [25]. The SHIFT (Systolic Heart Failure Treatment with If Inhibitor) trial showed in patients with heart failure and a heart rate greater than 75 beats per minute that treatment with ivabradine, a pure negatively chronotropic drug blocking the If channel in the sinus node, reduces heart failure hospitalisations and mortality [26]. Though there has been much scientific debate about this trial it does remind the clinician of the importance of monitoring heart rate and if the rate is excessively elevated, there is value in its reduction in the management of heart failure. Heart rate measurement is the simplest and cheapest assessment of ANS activity. However, its limitations include the many confounding factors which contribute to actual heart rate at a given time point, including circadian variation, exercise and temperature. Non cardiac pathologic conditions such as anaemia and dysthyroidism also affect measurements. Heart rate cannot be used to distinguish between SNS activation or PNS withdrawal. 3.3.2. Ewing tests These are assessments of blood pressure and heart rate response to challenges such as standing, deep breathing, hand grip and Valsalva. There is a large literature of the use of these tests in patients with diabetes [27]. These observations identified patients with coexistent autonomic neuropathy and were associated with all cause and cardiovascular mortality. Based on just this information, we demonstrated that it is possible to distinguish autonomic tone in heart failure with reduced ejection fraction from those with preserved ejection fraction [28]. However, whilst they are easily performed at the bedside with widely available equipment they are crude, non-specific and have potential high measurement variability limiting reproducibility. 3.3.3. Heart rate variability (HRV) This refers to quantification of the variations in RR (or NN) interval in consecutive heart beats. There are multiple methods of analysis of HRV, each yielding slightly different information. Analysis can be performed on short recording (5 min) or longer ones (24 h tape). There are two methods of deriving the HRV, using either time domain (statistical or geometric) or frequency domain (parametric and nonparametric) analysis. Time domain analysis is considered the superior technique for long recordings whereas frequency domain analysis is better for shorter recordings. With advances in technology all of the calculations can be automated and integrated into ECG monitoring equipment or can be calculated offline. Further details on technique, interpretation, normal values and advantages/disadvantages of each of these methods have been published by the Task Force of the European Society of Cardiology and the North American Society of Pacing Electrophysiology (Table 1) [29]. A key weakness of HRV is that the results are variable, especially the short recordings unless they are undertaken in controlled conditions. Analogous to Ewing's test, the output parameters of HRV reflect autonomic modulations to the heart (in particular the sino-atrial node as opposed to the ventricle) rather than true levels of autonomic SNS or PNS activity. It is not possible completely to attribute HRV variables to either the SNS or PNS. This is because the ANS is not the only influence on the beat-to-beat changes seen in RR intervals. Central oscillators (in particular respiratory and vasomotor), humoral factors and the sinus node are also key players. The high frequency component (HFc) of HRV is predominately under vagal control. It is still a matter of debate as to what

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the autonomic significance of the low frequency component (LFc) is, but it is likely to reflect both SNS and PNS activity [29]. Compared to the other methods of quantifying the ANS, this method is the easier to apply as only heart rate readings are required. The abundance of data from 24 h Holter ECGs and implanted devices means that HRV analyses are frequently undertaken and hence the studies reporting results have a larger population size than those using other ANS assessment techniques. High levels of SNS activity in HF dampen autonomic modulation and this is reflected in a reduced HRV. In 202 patients with a mean ejection fraction of 24%, a LFc b11 ms2 during controlled breathing was an independent predictor of sudden death [30]. The UK-Heart study followed 433 HF patients for approximately 14 months and found the standard deviation of NN intervals (SDNN) to be the most powerful predictor of death (Table 1) [31]. A SDNN of between 50 and 100 ms was related to an annual mortality of 12.7% compared to a mortality of 5.5% in patients with a SDNN N 100 ms [31]. The HRV sub-study of CIBIS (Cardiac Insufficiency BIsoprolol Study) showed that β-blockers improve HRV and in particular those markers that reflect the PNS [32]. Unfortunately, many of these trials are from the 1990s and their findings in patients with ischaemic cardiomyopathy may not be directly transferable in the contemporary era of revascularisation. 3.3.4. Baroreceptor sensitivity (BRS) BRS assesses the integrity of the carotid and aortic baroreceptors in both detecting and responding to changes in blood pressure. The multiple methods of performing this have been described and reviewed elsewhere [33]. Importantly, there are now non-invasive and automated techniques, which involve analysis of spontaneous beat-to-beat changes in blood pressure and RR interval. There are, however, doubts as to whether the non-invasive assessments are comparable to the invasive measures which include phenylepinephrine infusion [33]. A depressed BRS confers a poorer prognosis. Even though the BRS is higher in patients on β-blockers it can still be of prognostic value in patients independent of heart failure medications [34]. An emerging technique offering further insight into the PNS is heart rate turbulence (HRT). This technique has been described in detail by the International Society of Holter and Noninvasive Electrocardiology (ISHNE) [35]. The technique requires the subject to be in sinus rhythm and depends on analysing all ventricular ectopic beats (minimum 5 required) captured on a 24 h Holter. Two RR intervals prior to the ectopic and 15 immediately after need to be identified. These are used to calculate the turbulence onset (TO), and the turbulence slope (TS). The TO represents early sinus rate acceleration secondary to vagal withdrawal, whereas TS reflects late deceleration of the sinus node due to SNS and PNS activation. The baroreflex is strongly implicated in HRT. In the MUSIC (Muerte Subita e Insuficiencia Cardiaca [Sudden Death in Heart Failure]) study of 651 patients with heart failure, abnormal HRT was an independent predictor of severity as assessed by NHYA class and reduced ejection fraction. Further analysis showed that reduced TS predicted sudden death [36]. β-Blockers and angiotensin-converting-enzyme inhibitors (ACEi) have been shown to improve HRT [35]. However, in parallel to all of the previous techniques, there have been no prospective randomised controls evaluating whether changing management according to the results of an ANS assessment improves outcomes. 3.4. Imaging of sympathetic nerve innervation and activation When a cardiac sympathetic nerve discharges, NA is released from the presynaptic nerve terminal. This neurotransmitter diffuses across the synaptic cleft, binds to and activates the post synaptic βadrenoreceptors on the cardiomyocyte. In a negative feedback control it also binds to the presynaptic α2 adrenoreceptor, which inhibits further NA release. NA is cleared from the cleft, predominately through the uptake-1 mechanism on the presynaptic terminal (NA is either

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stored in vesicles or metabolised by monoamine oxidases) but also from the uptake-2 mechanism on the cardiomyocyte (NA is mainly metabolised by catecholamine-O-methyl transferase). Using radiotracers (labelled NA analogues) with either single photon emission tomography (SPECT) or positron emission tomography (PET) it is possible to image the pre and post synaptic receptors involved in SNS activation. This allows assessment of global and regional myocardial sympathetic innervation [37]. Currently, 123I-meta-iodobenzylguanidine (mIBG) is the most widely used tracer for cardiac SNS imaging. It has a strong affinity for the uptake-1 receptor in the pre-synaptic neurone. Once taken up it is stored in vesicles and is relatively resistant to degradation making it an ideal imaging agent. Three semi-quantitative parameters are routinely assessed during mIBG imaging: heart-to-mediastinum ratio (HMR), washout and defect scores [38]. mIBG tracer images reflect catecholamine storage in cardiac sympathetic nerve fibres. The HMR compares the mean count per pixel, within the cardiac area of interest, to that of the mediastinum (a suitable control), thereby allowing an estimate of neuronal activity. In contrast, myocardial washout compares cardiac pixel counts early (15 min) with late (4 h) after tracer administration and is a marker of neuronal integrity. The regionality of SNS activation within the myocardium is indicated through defect scores. In heart failure, there is reduced myocardial uptake of mIBG. A metaanalysis involving 1755 patients reported that patients with HF with reduced uptake (shown by decreased late HMR or increased myocardial washout ratio) had a worse prognosis [39]. The ADMIRE-HF (AdreView Myocardial Imaging for Risk Evaluation in Heart Failure) study showed in 961 patients with an ejection fraction of b 35%, that a HMR of b 1.6 was associated with a higher rate of heart failure progression, mortality and arrhythmic events [40]. In contrast an increased washout is associated with mortality and heart failure events. These two findings suggest that there is a reduction in SNS innervation to the heart in heart failure on the background of an increase in overall sympathetic tone. Treatment for heart failure with carvedilol and spironolactone has been shown to improve cardiac sympathetic neuronal action, when assessed by mIBG [38]. PET does not have wide-spread clinical use. This is predominately due to cost and limited availability of PET scanners and radiotracers. The isotopes used tend to have a short half life and hence it is necessary to have a cyclotron near to the scanner to produce the radiotracer as needed. The most widely used PET tracer for sympathetic nerve imaging is hydroxyephedrine labelled with carbon-11 (11C-HED), which has a half-life of 20 min. It has a strong affinity for uptake 1 and is resistant to degradation by monoamine oxidases or catecholamine-O-methyl transferase [37]. Nonetheless, when available it has several advantages over mIBG scanning. PET has better spatial and temporal resolution, which enables more accurate quantification and better regionalisation of SNS activity. During imaging, it is possible to co-administer different radiotracers, potentially providing deeper insight into mechanisms at the receptor level [37]. Both procedures involve radiation exposure (mIBG scan ≈5 mSv; cardiac PET scan ≈7 mSv).

4. Interventions that modulate sympathetic tone 4.1. Pharmacological β-Adrenoreceptors, which are activated by NA, are abundant in the myocardium. Agents which block this receptor were investigated in the 1980s to treat patients with heart failure patients. Multiple randomised trials have since shown reduced mortality and hospitalisations in HF patients treated with β-blockers [41]. The beneficial effects of this drug were not just attributed to its sympatholytic effects but also to its ability to inhibit other components of the

neurohumoral system such as the renin–angiotensin system and restoring the PNS function. In the same decade angiotensin-converting-enzyme-inhibitors, which on top of humoral effects also have a sympatholytic effect, were introduced. An improvement in mortality with this class of medication was associated with a reduction in SNS activity. Grassi et al. showed decreased central SNS output to muscle using MSNA in 24 heart failure patients post benazepril [42]. In V-HeFT II (Veterans Affairs VasodilatorHeart Failure Trial), two vasodilators: hydralazine–isosorbide dinitrate and enalapril, were compared [43]. The enalapril arm had better outcomes and this was associated with a decline in NA levels. It is unclear whether ACEi attenuate the SNS directly or whether the SNS improvement is as a surrogate marker for HF severity (as these drugs act on receptors not directly involved with the ANS). Angiotensin II receptors have been found in areas of the brain that regulate SNS activity and its activation not only increases central sympathetic outflow but also progresses heart failure [44]. There is an extensive body of literature describing the autonomic connections between the brain and the heart. It has been shown that stimulation of the lateral hypothalamus causes SNS activation, whereas that of the anterior hypothalamus predominately augments the PNS [45]. Stimulating the feline lateral hypothalamus created not only ECG evidence of myocardial ischaemia but on post mortem studies, myofibrillar degeneration was identified [46]. When a similar procedure was repeated in adrenalectomised cats, no added protection was noted [47]. This suggests that the brain exerts its influence on cardiac disease through direct neural connections. This is further supported by evidence in animal models that drugs causing ganglionic blockade or causing myocardial catecholamine depletion provided myocardial protection from the harmful effects of central SNS overactivity [45]. This provided the rationale for the first trials of central acting sympatholytics. Studies of clonidine (a pre-synaptic α2 adrenoreceptor and imidazoline receptor agonist) in heart failure, though small (n b 50) and dated, did show that this drug not only lowered sympathetic drive in heart failure patients [48] but also improved symptoms [49,50]. However, enthusiasm was curbed with the disappointing results of the Moxonidine Congestive Heart Failure Trial (MOXCON) trial, in which 1934 patients with HF and an EF b 35% were randomised either to slow release moxonidine (a selective imidazoline I1 receptor agonist and a weak α2 adrenoreceptor agonist) or placebo [51]. The study was stopped early due to a significant excess of mortality in the moxonidine arm (5.5%) compared to the placebo arm (3.4%), despite there being an 18.8% reduction in peripheral NA. This negative result may be explained by the fact that the dose of drug administered was almost double the standard dose for hypertension. Also a rapid uptitration protocol had been favoured, unlike the much slower and effective approach that is used for β-blocker titration. It is important to stress that despite being similar, clonidine and moxonidine have different central receptor targets and affinities; furthermore clonidine also has peripheral effects. The potential impact of clonidine in HF has not yet been explored by a randomised controlled trial powered to examine hard-end points. In addition to their opposing roles, the SNS and PNS exert a dynamic effect upon each other [52]. Enhancing the PNS would lead to a reduction in SNS activity. In a stratified randomised control trial of 23 patients, pyridostigmine, a cholinesterase inhibitor, reduced ventricular ectopy by 65% and improved HRV, as determined by time domain parameters [53]. When exercise testing was performed before and 24 h after pyridostigmine administration, the drug was shown to improve heart rate recovery, heart rate reserve and oxygen pulse [54]. Scopolamine (an anti-cholinergic drug), in a placebo controlled randomised cross-over trial of 16 heart failure patients, increased cardiac vagal tone and augmented BRS [55]. Trials of drugs that primarily enhance PNS activity are few and involve small numbers of patients with limited follow up. Side-effects of this class of drug, which include dry mouth and blurred vision, affect their long-term tolerability.

Please cite this article as: Patel HC, et al, Targeting the autonomic nervous system: Measuring autonomic function and novel devices for heart failure management, Int J Cardiol (2013), http://dx.doi.org/10.1016/j.ijcard.2013.10.058

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4.2. Non-medical methods

4.3. Devices

In healthy individuals exercise training is known to increase resting vagal tone and decrease sympathetic drive. Coats et al. showed that a similar beneficial change could be induced in heart failure patients [56]. They assessed the role of exercise in 17 men with HF (mean EF of 20%) in a controlled crossover trial. Exercise not only improved peak oxygen uptake in patients but this was associated with a reduction in markers of SNS activation (whole body NA spillover, HRV). Despite its importance in the development of heart disease, chronic stress is often marginalised as a clinical priority. From a meta-analysis involving 83,014 individuals, work stress conferred an average 50% increased risk of coronary heart disease [57]. A prospective randomised trial from Brazil evaluated the role of meditation on quality of life in patients with heart failure. Interestingly, after 12 weeks, there was an improvement in the Minnesota Living with Heart Failure questionnaire as well as a reduction in plasma NA levels [58].

It is unclear whether treatments which affect the SNS and improve outcomes in HF do so through a direct or indirect action on the SNS. In the latter hypothesis, attenuation of sympathetic activity might still be a useful surrogate. There are now devices that directly modulate the ANS at four sites: (1) renal sympathetic nerves (afferent and efferent), (2) carotid baroreceptors (afferent), (3) vagus nerve (afferent and efferent) and (4) spinal cord (afferent and efferent) (Fig. 3). The results of trials evaluating these modalities in heart failure will bring light on the benefits of modulating this SNS/PNS balance. 4.3.1. Renal sympathetic denervation The kidneys are strongly implicated in the overactivity of the SNS in HF. Petersson et al., found, in 61 patients with heart failure and a mean EF of 26%, that higher renal NA spillover conferred a hazard ratio of 3.1 with respect to all cause mortality or to heart transplantation [59]. This suggests that it may be beneficial to directly reduce sympathetic activity

Fig. 3. Diagram depicting the four sites of action of the ANS modulating devices in heart failure (adapted from Patel H et al., Springer, UK, figure on file). BRS = baroreceptor stimulator; VNS = vagal nerve stimulator; SCS = spinal cord stimulator.

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to and from the kidney. In a rat model of ischaemic heart failure, those rats which had renal sympathetic denervation (RSD) prior to induced myocardial infarction demonstrated better ventricular function than controls [60]. Current RSD devices target the afferent and efferent sympathetic nerves located in the renal artery wall and peri-vascular soft tissue. Several mechanisms have been postulated through which attenuation of the activity of these nerves could confer benefit in heart failure. These include: reduced renin release, improved sodium and water excretion, higher renal blood flow and reduction of sympathetic activation from the central nervous system to all organs [7]. RSD has been used in humans with resistant hypertension, a condition characterised by high SNS activity albeit at a lower level than in HF, for over 5 years. The SYMPLICITY-2 trial, showed an average drop of 32/ 12 mm Hg in blood pressure at 6 months in the 52 patients randomised to RSD [61]. This has been associated with a reduction in MSNA, renal NA spillover and an increase in baroreceptor sensitivity [21]. The procedure is now being trialled in heart failure and currently two centres have published results. Davies et al. undertook a pilot study of 7 patients with a baseline left ventricular ejection fraction (LVEF) of 43 ± 15% and blood pressure of 112/65 [62]. All patients were monitored as an in-patient for 5 days following the procedure. In this acute period, there were no significant haemodynamic or symptomatic fluctuations. Six months after the procedure, no safety concerns were identified. There was a small drop in mean systolic blood pressure by 7.1 mm Hg and a small improvement in serum creatinine by 5.7 μmol/l, however, none of these changes were statistically significant. Subjectively, all of the patients reported symptomatic improvement and this was strengthened by a statistically significant improvement in the 6 minute walk test distance by 27.1 m. Taborsky et al. studied 51 patients with an average LVEF of 25 ± 12% with more than 85% of the patients with NYHA class III/IV [63]. They were randomised 1:1 to RSD or optimal medical therapy (OMT). After 12 months, those patients who underwent renal denervation had a significantly higher LVEF compared to those who had OMT (31 ± 14% vs 28 ± 12%, p b 0.01). NT-proBNP was also significantly lower in the RSD

group at 12 months (1852 ± 1247 pmol/l vs 5836 ± 1470 pmol/l, p b 0.01). They also showed that the cumulative heart failure admission rate was approximately halved in the active group at 1 year follow-up. Both of these studies have shown that it is safe to consider RSD in patients with heart failure and normotension. Both studies have also demonstrated trends in improving surrogate markers for heart failure outcomes. However, larger randomised blinded controlled trials are needed and some are underway (see Table 2). 4.3.2. Baroreceptor modulation The carotid baroreceptor is primarily responsible for blood pressure regulation. It is activated by distension rather than the level of blood pressure per se. When activated it synapses via the nucleus of the solitary tract to the medulla, which is one of the principle sites of central sympathetic outflow. The carotid baroreceptor firing also enhances the parasympathetic nervous system through its innervation of the nucleus ambiguous and vagal motor nucleus. However, when chronically activated, for example, by hypertension or heart failure, it resets itself at a higher activation threshold and consequently its output reduces. In these conditions reduced baroreceptor sensitivity allows sympathetic hyperactivity to persist unchecked [64]. In heart failure, the baroreflex is abnormal and has been studied extensively [65]. This is a result of both intrinsic abnormalities in the baroreceptor and alterations in how the afferent signals are processed [66]. In clinical practice, the ATRAMI (Autonomic Tone and Reflexes after Myocardial Infarction) trial showed, in 1284 post myocardial infarction patients, that a reduced BRS was an independent predictor of cardiac mortality with a relative risk of 2.8 [67]. Proven treatments in heart failure such as biventricular pacing have been shown to increase BRS [68]. It is possible to reset the carotid baroreceptor by electrically stimulation. This procedure involves attaching a small electrode (either unilaterally or bilaterally) to the carotid sinus (extravascular) that is connected to a pulse generator buried in the pectoral region. Analogous to a pacemaker, it can be turned on or off and also have its output titrated via transcutaneous non-invasive programming. Using canine models of heart failure, baroreceptor activation therapy (BAT), has

Table 2 Table summarising the key trials and their endpoints using the various ANS modulating devices in heart failure (data from clinicaltrials.gov) S — safety, M — mortality, CVE — cardiovascular events, LV — dimension, function, mass, volumes, EX — six minute walk test, cardiopulmonary exercise testing, QoL — quality of life, NH — neurohormones. 1 = (co)primary endpoint, 2 = (co)secondary endpoint. Trial ID

Trial no.

Ejection fraction

Randomised

Blinding

Patients

Endpoints S

Renal denervation REACH Pilot Olomouc I Pilot Symplicity HF DIASTOLE REACH Bursa YIEAH RDT-PEF Swan HF

NCT01584700 NCT01870310 NCT01392196 NCT01583881 NCT01639378 NCT01538992 NCT01840059 NCT01402726

M

Completion CVE

Mean 43% Mean 25% b40% N50% b40% b35% N50% b40%, N45%

No Yes No Yes Yes Yes Yes Yes

Open Open Open Open Double Open Open Open

7 51 40 60 100 20 60 200

1 2 1 2 2 1 2 1

1

1

Baroreceptor stimulation Rheos DHF NCT00718939 HOPE4HF NCT01720160 XR Barostim NCT01484288 Barostim HF NCT01471860

N45% b35% Any Any

Yes Yes No Yes

Double Open Open Open

6 60 15 150

1 1

2

2

Vagal nerve stimulator CF-MS-01 NCT00461019 NECTAR-HF NCT01385176 INOVATE HF NCT01303718

b35% b35% b40%

No Yes Yes

Open Double Open

32 250 650

1 1 1

Spinal cord stimulator Methodist SCS NCT01124136 SCS HEART NCT01362725 Defeat HF NCT01112579 TAME-HF NCT01820130

b30% b35% b35% b35%

Yes No Yes No

Double Open Single Open

40 20 250 20

1 1

LV

EX

QoL

NH

2 2

2 2

2 1 2

2 1

2 2 1

1 2 1

2 2 1

1 2

2

2 2

2 2 1

Completed 2014 2014 2014

2 1 2

2 2 2

2 2 2

2

Reported [78] 2015 2015

1 1 1 1

1

1 1

1

2014 2015 2015 2016

2 2 1 2

2

1

2

1 1

2 1

2 2

Reported [62] Reported [63] 2013 2014 2014 To be started 2015 2017

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been shown to reduce sympathetic overactivity (reduction in plasma NA, angiotensin II); cause better structural remodelling (with reduced LV diameter and myocardial fibrosis); improve molecular remodelling (with respect to β-adrenoreceptors and nitric oxide synthase profile) and critically, improve the hard endpoint of mortality (survival of 68.1 ± 7.4 vs 37.3 ± 0.2 days) [69]. In the DEBuT-HT (Device Based Therapy in Hypertension Trial), which was the initial feasibility study of BAT (Rheo System) in resistant hypertension, 42 patients underwent the procedure [70]. At 3 months there was a substantial (21/12 mm Hg) drop in blood pressure, which persisted at 2 years. However, there were 8 (19%) serious adverse events, which included: infection, stroke and hypoglossal nerve damage. The only published randomised, double-blinded trial assessing BAT in hypertension (Rheos Pivotal) failed to achieve its pre-specified five co-primary endpoints (2 related to blood pressure reduction and 3 to safety outcomes) [71]. Nonetheless, at 12 months, 81% of subjects had at sustained drop of at least 10 mm Hg in blood pressure. The risks are comparable to carotid endarterectomy surgery. A single centre open label study of 8 patients with a mean LVEF of 30 ± 8% and NYHA class III, reported a significant decline in MSNA at 1 and 3 months that was coupled with an improvement in 6-minute walk distance of 76.2 ± 14.7 m (p = 0.004) at 3 months post BAT insertion [72]. Furthermore there was no significant decline in blood pressure. Pilot data of 6 patients from another centre, all with LVEF b 35%, showed that BAT therapy significantly reduced NT-proBNP from 2797 to 1352 ng/l (p b 0.05) after an average follow up of 7.1 months [73]. They also showed an increase in 6-minute walk distance by 24 ± 14% (p b 0.05). From the hypertension studies and in particular those patients who had asymptomatic heart failure or were pre-heart failure (Stage A or B, American College of Cardiology classification), BAT has led to beneficial cardiac remodelling on top of blood pressure reduction. From an echocardiographic substudy of 18 individuals, at 12 months, BAT had regression of LV mass index by 25 ± 18.2 g/m2 (p b 0.001), left atrial diameter was reduced by 2.4± 3.5 mm (b 0.01) and mitral A wave Doppler velocity was decreased by 10 ± 13 cm/s (p b 0.005) [74]. This degree of remodelling is much greater than seen from medications such as ACEi. Theoretically, these changes are likely to be associated with improvements in left ventricular filling pressures, reduction in atrial fibrillation susceptibility and improved myocardial relaxation and energetics. These structural changes are associated with reduced SNS activation, enhanced PNS activity, improved organ perfusion and reduced central venous pressure [65]. Cumulatively, these spectra of benefits make BAT an attractive treatment for not only heart failure with reduced systolic function but also heart failure with preserved ejection fraction (HFpEF), a condition which currently does not have any treatment available that has been shown to improve prognosis. There are clearly not enough data to establish the role of BAT in HF. However, what little there is suggests that baroreceptor stimulation does not cause symptomatic hypotension or unacceptable risk. Currently, there are multiple RCTs underway examining the role of BAT in HF (Table 2).

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1997 and for depression since 2005, with an acceptable risk profile. The clear benefit shown in animal models and proven safety in over 50,000 humans for non-cardiac indications has led to investigation of the role of this device in heart failure patients. The implantation procedure requires a surgeon, isolation of the right vagus nerve in the cervical region, intracardiac electrode placement and pulse generator insertion. The initial phase II (non-randomised) trial involved 32 patients of NYHA classes II–IV and all with LVEF b 35% and demonstrated improvement in six minute walk test, Minnesota Living with Heart Failure questionnaire and LVEF. Surprisingly, there was no change in average 24 h heart rate pre and post device therapy. The heart rate independent actions of vagal activity have been suggested to include sympatholytic, anti-apoptotic and anti-arrhythmic effects [78]. Spurred by these findings a randomised-double blind control trial is underway (Table 2). 4.3.4. Spinal cord stimulation The sympathetic nerve trunk runs a course lateral to the spinal vertebral bodies. Stimulating the nerves at the thoracic vertebral level has been exploited clinically for a variety of indications, including: chronic pain, peripheral vascular disease and refractory angina and hence its application already comes with an established clinical experience and safety record. In a canine heart failure model, 15 min of spinal cord stimulation (SCS) not only decreased afterload and lowered systolic blood pressure by 9.8 mm Hg but also reduced the occurrence of ventricular arrhythmias (in response to ischaemia) from 59% to 23% [79]. When acutely administered, SCS has also been shown to deliver a vagus nerve mediated parasympathetic activation [80]. Its value in human hypertension is yet to be proven. To date there have only been studies of small numbers of patients and only minimal reduction in mean arterial pressure of 3.1 mm Hg [81]. Lopshire et al. showed in dogs with ischaemic heart failure that intermittent SCS at T4/5 caused an improvement in ejection fraction from 17 ± 3% to 47 ± 7%, whereas in the medical therapy only group the corresponding change was from 18 ± 3% to 34 ± 4% [82]. The same group further confirmed a beneficial effect of SCS on reduction in ventricular tachyarrhythmias. Another centre randomised 30 pigs with ischaemic heart failure to control or continuous/intermittent SCS at the T1-2 level. They demonstrated a significantly improved ejection fraction, serum NA and BNP in the continuous stimulation arm compared to medical therapy alone at 10weeks [83]. Phase 2 human clinical trials are underway in systolic heart failure. The role of devices that modulate the autonomic nervous system in heart failure is still under investigation. Several benefits of device therapy over pharmacological therapy are apparent: 1. greater SNS blockade/PNS activation can be achieved; 2. compliance is not an issue; and 3. apart from renal denervation the other devices can be turned on/off and their outputs tailored. Key disadvantages of the devices are their invasive nature and procedural complications. As summarised above, we have evidence of safety and efficacy in only a handful of human heart failure patients for these devices. Planned trials in the pipeline have been summarised in Table 2. 5. Summary

4.3.3. Vagal nerve stimulators The parasympathetic nervous system and its role in heart failure have been summarised in detail elsewhere [75]. Firstly, compared to the SNS it is even more difficult to quantify the PNS activity. Nonetheless, using HRV and BRS analysis, PNS withdrawal has been associated with higher mortality in HF [34]. Using single fibre nerve recordings, it has been shown that ipsilateral vagus nerve stimulation results in contralateral vagus nerve firing as well as a reflex inhibition of cardiac sympathetic efferent activity [76]. Multiple animal heart failure models have shown improved survival, LV haemodynamics and ejection fraction with vagus nerve stimulation [77]. The latter has been available for use in epilepsy in the USA since

The neurohumoral system, including the ANS, plays a pivotal role in heart failure. The system affects multiple organs, via numerous mechanisms which interact in a complex manner. Currently our understanding of the substances and pathways involved in the neurohumoral pathway is incomplete. Our methods of assessing the degree of activation of the autonomic system have specific advantages and limitations and are far from being interchangeable. Despite these difficulties and limitations, medications that have an effect on the ANS have been proven to improve mortality in heart failure and the mechanism has been shown to be related to attenuation of the SNS and promotion of the PNS. However, medication adherence, side

Please cite this article as: Patel HC, et al, Targeting the autonomic nervous system: Measuring autonomic function and novel devices for heart failure management, Int J Cardiol (2013), http://dx.doi.org/10.1016/j.ijcard.2013.10.058

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Please cite this article as: Patel HC, et al, Targeting the autonomic nervous system: Measuring autonomic function and novel devices for heart failure management, Int J Cardiol (2013), http://dx.doi.org/10.1016/j.ijcard.2013.10.058