Anatomy of the Autonomic Nervous System

The principle regions of ANS control are located within the medulla oblongata, which in turn is subject to control by the hypothalamus and the cerebral cortex. The medulla receives afferent fibers from the glossopharyngeal nerve and the vagus nerve ( Fig. 42.1 ), which terminates in the nucleus tractus solitarius (NTS). From here, neurons project to the rostral ventrolateral medulla (RVLM) and the nucleus ambiguous in the brainstem. Sympathetic preganglionic neurons of the intermediolateral cell column of the spinal cord arise in the RVLM and may have either inhibitory or excitatory effects on the sympathetic preganglionic neurons. The balance of stimulation in the fibers descending from the medulla and local spinal inputs determines the nature of the effect of the activity of the sympathetic preganglionic neurons. Sympathetic preganglionic neurons travel via the ventral roots of the spinal cord to the sympathetic chain, where most synapse with the cell bodies of the sympathetic postganglionic fibers. Some extend further and may terminate directly in target organs, such as the adrenal medulla. Axons from postganglionic cell bodies are nonmyelinated and travel in mixed peripheral nerves where they terminate in the outer parts of the tunica media. Arteries and larger arterioles have a rich supply of sympathetic vasoconstrictor fibers, with less dense innervation of veins and smaller arterioles. Noradrenaline released by sympathetic postganglionic neurons act on alpha-adrenoreceptors, leading to vasoconstriction ( see also Chapter 6, Chapter 13 ). Cardiac sympathetic fibers travel subepicardially along the main coronary arteries.

Schematic overview of autonomic regulation of the cardiovascular system.

The autonomic outflow to the heart and the peripheral circulation is regulated by cardiovascular reflexes. In humans, the primary mechanism for autonomic modulation is via the baroreflexes. The baroreflex afferents, which are highly specialized stretch-sensitive nerve endings mainly located in the wall of the carotid sinus and in the wall of the aortic arch, change their firing rate with changes in arterial pressure, and project through the glossopharyngeal and vagal nerves to the central nervous systems, where signals are integrated. The baroreflex control of circulatory homeostasis occurs on a negative feedback basis. In general, an increased firing rate of the baroreceptors secondary to a rise in systemic arterial pressure results in increased efferent cardiac vagal activity and decreased sympathetic, which in turn slows down heart rate, decreases cardiac contractility, and decreases peripheral vascular resistance. Opposite hemodynamic changes occur when a decrease in systemic arterial pressure lowers the baroreceptor firing rate, which results in an increase in efferent sympathetic nerve activity, which increases heart rate, increases cardiac contractility, and increases peripheral vascular resistance.

From La Rovere MT, Christensen JH. The autonomic nervous system and cardiovascular disease: role of n-3 PUFAs. Vascul Pharmacol . 2015;71:1–10.

Parasympathetic preganglionic fibers leave the CNS via the cranial and sacral spinal outflows. In comparison with the SNS, they terminate on the postganglionic neurons situated in the end-organs themselves, such as the heart. Below the atrioventricular groove, the parasympathetic fibers penetrate the myocardium and are subendocardial in their distribution. There is a greater density of parasympathetic innervation in the atria compared with the ventricles.

Cardiac Reflexes

Sympathetic outflow to the heart and peripheral tissues is regulated by cardiovascular reflexes. Increasingly these reflexes have served as the primary targets for ANS modulation as a therapy for the treatment of heart failure. Autonomic fibers carry afferent arms of these reflexes, whereas efferent limbs are formed by either somatic or autonomic nerves.

Baroreceptors are high pressure mechanoreceptors located in high pressure areas, such as the wall of the aortic arch and the carotid body (see Fig. 42.1 ). Afferent fibers of these receptors relay information regarding arterial pressure to the brainstem, where they terminate in the NTS. Afferents from the aortic arch travel within the vagus, whereas those from the carotid sinus are carried initially by the carotid sinus nerves, which then merge with the glossopharyngeal. The baroreceptors are dynamic receptors that respond to changes in pressure. At normal levels of blood pressure (MAP 90–100 mm Hg), there is only a modest degree of activity in the afferent nerves, which is in phase with the arterial pulse wave. A steep incline in activity occurs as pressure increases between 60 and 180 mm Hg. This afferent information leads to an increase in vagal activity and a decrease in cardiac sympathetic activity. The vagal activity causes a resultant bradycardia, while the reduction in sympathetic vasoconstriction leads to vasodilatation.

The venous mechanoreceptors that are located in the junction of the atria and the pulmonary arteries send their signals via unmyelinated fibers of the vagus nerve as a part of the Bainbridge reflex. The Bainbridge reflex responds to increases of blood volume in venous circulation by increasing heart rate and ventricular contractility via inhibition of efferent vagal fibers. These cardiovascular reflex arcs are intimately related to each other with the Bainbridge reflex serving to counterbalance the baroreceptor reflex; the Bainbridge reflex is dominant when blood volume is increased, and the baroreceptor reflex is dominant when blood volume is decreased.

In the setting of a failing heart, a range of compensatory functions attempt to preserve cardiac function ( Fig. 42.2 ). The ANS and renin-angiotensin-aldosterone system (RAAS) are the chief curators of cardiovascular homeostasis. Reduced cardiac output increases afferent stimuli from baroreceptors to the CNS cardioregulatory regions, with subsequent activation of the SNS. Though acutely advantageous, the compensatory mechanisms to maintain cardiac output, which are brought about by the SNS activation, in conjunction with vasoconstriction and sodium and water retention brought about by the RAAS system, are detrimental in chronic cardiac dysfunction. It is now established that alterations of the sympathovagal balance with diminished vagal activity and accelerated sympathetic activity is a predictor of increased mortality in heart failure ( see also Chapter 13 ). In addition to being a proarrhythmic state, a shift in the ANS balance toward heightened SNS activity is associated with nitric oxide (NO) dysregulation, excess cytokine release, and adverse cardiac remodeling.

Activation of neurohormonal systems in heart failure.

Decreased cardiac output in patients with heart failure with reduced ejection fraction results in the unloading of high-pressure baroceptors (black dots) in the left ventricle, carotid sinus, and aortic arch. This unloading leads to generation of afferent signals to the central nervous system (CNS) that, in turn, leads to activation of efferent sympathetic nervous system pathways that innervate the heart, kidney, peripheral vasculature, and skeletal muscles. This unloading also leads to afferent signals to the CNS that stimulate cardioregulatory centers in the brain that stimulate the release of arginine vasopressin from the posterior pituitary.

From Hartupee J, Mann DL. Neurohormonal activation in heart failure with reduced ejection fraction. Nat Rev Cardiol . 2017;14[1]:30–38; and adapted from Nohria A. Cusco JA, Creager MA. Neurohumoral, renal, and vascular adjustments in heart failure. In: Colucci WS, ed. Atlas of Heart Failure . 4th ed. New York: Springer; 2004:101–126.

Measurement of Autonomic Nervous System Activity

Measurement of autonomic activity has been demonstrated to correlate with prognosis in HF. The activity of the SNS can be measured in different ways. Examples are measurement of heart rate, plasma or urinary norepinephrine (NE) level, assessment of local tissue NE spillover, muscle sympathetic nerve activity (MSNA), iodine ¹²³ I-metaiodobenzylguanidine ( ¹²³ I-mIBG), or heart rate variability (HRV; Fig. 42.3 ). The simplest assessment of overall ANS function is resting heart rate, which is a marker of SNS activation and PNS withdrawal. The SHIFT trial assessed the efficacy of ivabradine in patients with HF and found that the lowest risk of mortality was in patients with a heart rate of less than 60 beats/min. Guideline documents for the treatment of HF patients recommend treatment the use of β-blockers and ivabradine to reduce heart rate to this target ( see also Chapter 37 ).

Different techniques to quantify the sympathetic nervous system in heart failure patients.

There are four different methods for assessing sympathetic nervous system activity in heart failure patients: norepinephrine spillover, heart rate and blood pressure response, radio-tracer imaging, and microneurography. BRS , Baroreceptor sensitivity; HRV , heart rate variability; mIB G, metaiodobenzylguanidine; PET , positron emission tomography.

Modified from Patel HC, Rosen SD, Lindsay A, Hayward C, Lyon AR, di Mario C. Targeting the autonomic nervous system: measuring autonomic function and novel devices for heart failure management. Int J Cardiol . 2013;170[2]:107–117.

Reduced HRV is a marker of increased mortality in HF patients. The ANS and PNS effect the beat-to-beat variability in different frequency bands. The SNS regulates the low-frequency component of HRV, in contrast to the vagal effects, which modulates the high frequency variance. ANS balance may be assessed by computation of the low frequency/high frequency ratio. Therefore, it may be possible to assess the different contributions of each limb of the ANS. HRV can easily be assessed, requiring just simple measurement of consecutive RR intervals. However, it has a number of limitations. First, the most appropriate technique for HRV measurement remains ill-defined. It can be collected in short (10 minutes) intervals with short-segment electrocardiography or over 24 hours with cardiac monitoring. Secondly, HRV does not correlate specifically with SNS function. It measures both PNS and SNS activity, including both postsynaptic and presynaptic pathways. Finally, the development of atrial fibrillation, increased ectopy, and the use of biventricular pacing as heart failure advances restricts the measurement of HRV.

Quantification of NE spillover was one of the earliest attempts at assessing ANS activity. Radiotracer techniques that involve measuring radioisotopes dilution with plasma concentration of NE can be used to calculate regional NE spillover. However, there is considerable variability in the way that circulating NE is metabolized by different tissues, contributing to limitations in the use of NE spillover. In addition, NE increases may be related to decreased regional clearance rather than increased secretion. Microneurography facilitates measurement of nerve firing within the skin and local vasculature, but its clinical use has been precluded by low reliability.

The radiotracers iodine-labeled metaiodobenzylguanidine ( ¹²³ I-mIBG), which is used for planar and single-photon emission computed topography (SPECT) imaging, and ¹¹ C-hydroxyephedrine, which is used for positron emission topography (PET) imaging, can be used to image local SNS activity. Increased LV function has been seen in HF patients with increased sympathetic innervation as assessed by mIBG scan. The heart-to-mediastinal (H/M) ratio is the most accepted measure used to image cardiac ANS activity. Reduced H/M ratio correlates with increased risk of arrhythmia and mortality. The AdreView Myocardial Imaging for Risk Evaluation in Heart Failure (ADMIRE-HF) study enrolled 961 HF patients. ADMIRE-HF demonstrated that an abnormal mIBG H/M ratio was associated with major adverse cardiovascular events and ventricular arrhythmia. However, other investigators have not been able to demonstrate a clear relationship between mIBG studies and arrhythmia inducibility at during electrophysiology studies.

Pharmacological Targeting of Autonomic Nervous System Dysfunction in Heart Failure

The use of β-blockers to attenuate the effect of NE on Beta-1 and Beta-2 adrenoreceptors is now well established and has been recommended in international HF guidelines for more than 10 years ( see also Chapter 37 ). Targeting the PNS pharmacologically remains more challenging. Acetylcholine (ACh) is released from the presynaptic membrane and binds to parasympathetic muscarinic receptors. ACh is rapidly hydrolyzed by acetylcholinesterase. One proposed method of increasing PNS stimulation is the use of acetylcholinesterase inhibitors (ChEIs). Donepezil is a centrally acting ChEI that crosses the blood-brain barrier and is used in the treatment of Alzheimer’s disease. In a retrospective 2010 study of patients with Alzheimer’s disease, 76 patients who were treated with donepezil were compared with 915 who were not. Those treated with donepezil had a significantly lower rate of cardiovascular mortality compared with the control arm. Donepezil has also been shown to attenuate plasma BNP levels in patients with Alzheimer’s disease, as well as improve LV function and decrease neurohumoral activation in animal models of HF. The most compelling data on the protective effect of donepezil comes from the Swedish National Dementia Registry. In this registry of more than 7000 patients, the use of donepezil was associated with a 34% reduction in the primary endpoint of myocardial infarction or cardiovascular mortality. Pyridostigmine is another ChEI, but it only acts peripherally. It increased HRV and reduced ventricular arrhythmias in a small study of 23 patients with HF. However, in addition to stimulating PNS activity, ChEI may also increase sympathetic cervical, splanchnic, and lumbar ganglionic neurotransmitters. The short-acting ChEI edrophonium increases MSNA after administration. Therefore, in addition to the SNS to restore the ANS imbalance in chronic HF, there is potential therapeutic benefit from pharmacologically targeting the PNS. However, the studies conducted on donepezil and pyridostigmine are small, and further, larger trials are required.

Device-Based Modulation of Autonomic Nervous System Dysfunction in Heart Failure

Interest in research into implantable devices to manipulate the ANS has ignited in recent years ( Table 42.1 ). However, though early studies in animal model have demonstrated promise, this potential has not yet been successfully translated into successful clinical trials in patients with HF. In the following section, we will focus on the preclinical and clinical studies that have employed vagus nerve stimulation (VNS), baroreceptor activation therapy (BAT), spinal cord stimulation (SCS), and renal nerve denervation, with the goal of deconstructing these studies in order to better understand why it has been so difficult to translate the encouraging preclinical studies into successful phase II/III clinical trials. The important therapeutic areas of left cardiac sympathetic denervation have been the subject of several recent reviews and will not be discussed herein.

TABLE 42.1

Trials of Device-Based Modulation of the Autonomic Nervous System in Heart Failure

Trial Name	Device	Trial Design	Patients	Outcomes	Follow-up	Results		References
Vagus Nerve Stimulation
CardioFit	CardioFit, BioControl Medical.	Multicenter, open-label, noncontrolled	32 Patients; EF ≤35%, NYHA II–III; AF and plan for CRT excluded	1. Procedure related adverse events 2. NYHA, QoL, 6MWT, LV volumes	6 months		3 deaths unrelated to procedure 12 patients had device related pain, cough and dysphonia Improved NYHA, QoL, 6MWT, EF
NECTAR-HF	Precision, Boston Scientific	Multicenter, 2:1 randomization, sham-controlled	96 Patients; EF ≤35%, NYHA II–III, LVEDD ≥5.5 cm; AF and planned CRT, or CRT in situ <1 year excluded	1. LVESD 2. LVESV, EF, peak VO 2 , NT-proBNP, QOL, 6MWT	6 months		No Change in LVESD. Improved QoL and NYHA Device related coughing and facial paresthesia
ANTHEM-HF	IPG 103, Cyberonics	Multicenter, open-label, controlled	60 Patients; EF ≤40%, NYHA II–III, LVEDD 5–8 cm, QRS <150 msec	1. Procedure related complications 2. LVESV and EF 3. NYHA, QoL, 6MWT	6 months		1 procedure related death Improved LVESD, EF, NYHA, QoL, 6MWT
INOVATE-HF	CardioFit, BioControl Medical	Multicenter, 3:2 randomized, open-labeled	707 Patients; EF ≤40%, NYHA II–III, LVEDD 5–8; AF excluded	1. All-cause mortality or HFH 2. Freedom from procedure related complications 3. NYHA, 6MWT, LVESV, QoL	16 months		– No benefit in reducing mortality/HFH – No safety issues – Improved NYHA, 6MWT, QoL
Spinal Cord Stimulation
SCS Heart Study	Eon Mini, Abbott	Multicenter, 4 patients who did not fulfill study criteria as controls	22 patients; EF 20%–35%, LVEDD 55–80 mm, ICD, NYHA III; Excluded for AF, prior spinal cord stimulator	1. Death due to VT, MI, or SCD 2. HFH 3. Composite score of QoL, VO 2 , NT-proBNP and others	6 months	Significant improvements in EF, QoL, EF, VO 2, and LVESVi – No deaths
DEFEAT-HF	PrimeAdvanced Neurostimulator, Medtronic	Multicenter, randomized controlled trial. Patients randomized 3:2 to SCS “on” or “off” initially. All “on” at 6 months.	66 patients; EF ≤35%, QRS <120 ms, NYHA III; CRT patients excluded	1. Changes in LVESVi 2. VO 2 max, NT-proBNP	12 months	– No changes in LVESVi. – No significant difference in secondary endpoints
Carotid Baroreceptor Stimulation
Gronda et al.	Barostim neo, CVRx Inc	Single center, open-label, uncontrolled	11 Patients; EF ≤40%, NYHA III; Excluded if no indication for CRT or eGFR <30 mL/min	1. Reduction SNS activity. 2. Safety, BRS, EF, hemodynamics	6 months	Improvements in MSNA and BRS Improved QoL, 6MWT, EF
Barostim neo HF, Barostim HOPE4HF	Barostim neo, CVRx Inc	Multicenter, randomized, open-label, controlled	146 Patients; EF ≤35%, NYHA III; Carotid artery stenosis >50%, eGFR <30 mL/min, and recent CRT excluded	1. Safety (MANCE) 2. NYHA, QoL, 6MWT	6 months	Procedure was safe. MANCE free rate 9.2% Improvements in NYHA, QoL, 6MWT
Renal Nerve Denervation
REACH-pilot	Simplicity, Medtronic	Single center, open-label, uncontrolled	7 Patients; Systolic HF, NYHA III–IV; eGFR <35 mL/min excluded	Safety	6 months	No safety concerns. 6 MWT improved
RDT-PEF	Simplicity, Medtronic	Single center, randomized, open-label	25 Patients; EF >40%, NYHA II–III, BNP >35 ng/L or increased LAV/LVH; Excluded patients with eGFR <45 mL/min or if CMR contraindicated	1. QoL, peak VO 2 , BNP, E/e’, LAV, LVM. 2. Safety	12 months	A signal for improvement in co-primary endpoints at 3 months, which did not persist at 12 months Renal angioplasty required during procedure in 2 patients

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