Device-Based Modulation of the Autonomic Nervous System

Introduction

Rapid advances in the field of detection and modulation of electrical signals within the nervous system have led to the development of a new class of pacing strategies to modulate the nervous system regulating the heart and beyond. Notably, neuromodulation of the peripheral nervous system has attracted considerable attention because the peripheral nerves are more easily targeted, and they control specific organ functions impacted in chronic diseases. The field of bioelectronic devices is burgeoning with possibilities of developing closed loop pacing systems, where devices will be able to record electrical activity, perform real time analyses, and accordingly modulate the neural signaling via pacing strategies.

On the other hand, the autonomic nervous system, which is ubiquitous throughout the body, constitutes a less well understood entity. Dysregulation of the autonomic tone plays a significant role in the pathophysiology and progression of a myriad of disorders, including hypertension, sleep apnea, heart failure, and more. The limited breakthrough advances in the medical therapy on these disease fronts have led to the evolution of innovative nonpharmacologic interventions that can favorably 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, arrhythmias, and other cardiovascular disorders. The current chapter examines the role of stimulating these cardiac and extracardiac neural systems that may have a role in clinical electrophysiology.

Autonomic Control of the Heart

The interactions between the heart and the autonomic nervous system (ANS) have been known for several decades. The ANS comprises the sympathetic and parasympathetic nervous system, and the combined input closely regulates the cardiac output by regulating cardiac contractility, relaxation, conduction, and heart rate. The sympathetic nervous system (SNS) is the cardioacceleratory pathway, which when stimulated, is associated with an increase in heart rate and force of contraction. The parasympathetic nervous system (PNS) is recognized to be the cardioinhibitory pathway and on activation has the exact opposite effects via a reduction in the heart rate (HR), blood pressure (BP), and cardiac contractility. PNS activation significantly affects the peripheral vasculature through vasodilation, reduced arterial stiffness, and increased venous capacitance. Importantly, it is the beat-to-beat balance between these two opposing limbs of the ANS that regulates the HR, BP, cardiac contractility, and electrical stability of the myocardium.

Anatomy

Parasympathetic innervation of cranial, thoracic, and abdominal visceral structures occurs via four cranial nerves (i.e., oculomotor, facial, glossopharyngeal, and vagus). The pelvic visceral organs are innervated by branches of the second to fourth sacral nerves. The ganglia cells are typically clustered within the walls of the viscera, thereby making the parasympathetic postganglionic fibers very short. Cardiac parasympathetic innervation is principally via the tenth cranial nerve, better known as the vagus nerve. Vagal preganglionic neurons arise in the medullary region of the brainstem and travel along the left and right vagus nerve branches, synapsing with neurons in terminal ganglia located within the target organs such as the heart ( Fig. 5-1 ).

Figure 5-1, The Autonomic Nervous System.

The complexity of the cardiac innervation is further enhanced by the presence of intrinsic neurons that form plexuses with the preganglionic nerve terminations and the postganglionic neurons across the cardiac chambers. Notably, the neurons forming this network of connections constitute an intrinsic nerve plexus called the little brain of the heart. These regions also serve as cell stations, which comprise afferent, efferent, and interconnecting neurons that act as a control system coordinating the neural control of the heart. These neuronal stations are in constant communication and feedback to each other through cardio-cardiac reflexes, which control spatially organized regions. The cardiac branch of the PNS responds faster than the SNS (under normal circumstances), and the parasympathetic branch is more sensitive to myocardial damage.

Elegant work from Pauza and colleagues has simplified our understanding of the complex intrinsic cardiac nervous system by describing the epicardial neural plexus, which is a system of seven ganglionated subplexuses, embedded within the epicardial fat pads ( Fig. 5-2 ). These plexuses are located on the surface of the right and left atria, the left and right ventricle, the posterior wall near the ostia of the pulmonary veins, the vena cava, and the coronary sinus, and are essentially epicardial extensions of the mediastinal nerves entering the heart through discrete regions of the hilum. The highest density of epicardial ganglia are in the heart hilum and more so in the dorsal and dorsolateral surfaces of the left atrium ( Fig. 5-3 ). There are approximately a thousand epicardial ganglia in the human heart and the structural organization of these ganglia and nerves within the subplexuses vary between hearts and with age. Parasympathetic fibers below the atrioventricular (AV) groove penetrate the ventricular muscle and are subendocardial in their distribution. Notably, there is a greater concentration of parasympathetic innervation in the atria compared with the ventricles.

Figure 5-2, Schematic Drawing of the Seven Ganglinoated Subplexuses.

Figure 5-3, Macrographs Demonstrating the Anatomic Relationship of Nerves on Pulmonary Veins (PVs) on Epicardial Ganglionated Nerve Subplexuses. A, Macrograph of inferior surface of left PVs. B, Macrograph of anterior surface of right superior PV. The oblong boxed area is enlarged in the bottom right corner. The squared boxed area is enlarged at the top right corner illustrating the appearance of epicardial ganglion located on PV roots. Black arrowheads show epicardial ganglia in the left atrium with increasing magnification on the right side inserts of the image. LD, Left dorsal subplexus; LIPV, left inferior pulmonary vein; LSPV, left superior pulmonary vein; OTrV, orifice of tributaries of pulmonary vein. Dotted line, Limits of the cardiac hilum.

The sympathetic division of the ANS is located from the first thoracic to the third or fourth lumbar segments. The axons of preganglionic neurons leave the ventral aspect of the spinal cord at the level of their cell body and extend to adjacent paravertebral ganglia. These paravertebral ganglia are connected via axons of preganglionic neurons, which project rostrally or caudally to terminate on postganglionic ganglia, which may be located some distance away. In this manner the paravertebral ganglia form the sympathetic chain (or sympathetic trunk) bilaterally. Some preganglionic neurons terminate directly on the viscera, such as the adrenal cortex. Preganglionic sympathetic nerves also synapse with ganglia on the heart; sympathetic influence on the heart is primarily through surface synapses. The axons of some postganglionic neurons reenter the spinal nerves after leaving the chain ganglia. They terminate on targets such as smooth muscle of blood vessels in areas supplied by these spinal nerves. Other postganglionic fibers enter the thoracic cavity after leaving the chain and terminate on visceral organs. Cardiac sympathetic fibers travel subepicardially along the main coronary arteries. Studies in primates suggest that the concentration of SNS fibers decreases from the base of the heart to the apex.

Autonomic TonE and Reflexes

BP and HR are regulated by a close interaction between parasympathetic and sympathetic sensory input and stimuli, mediated through the vasomotor center in the medulla. Cardiovascular reflexes regulate sympathetic outflow to the heart and peripheral tissues. Autonomic fibers carry the afferent limbs of these reflexes, whereas the efferent arms are composed of impulses in either autonomic or somatic nerves. The main reflex responses originate from the baroreceptors of the aortic arch and carotid artery, cardiopulmonary systems (including the Bezold-Jarisch reflex), peripheral chemoreceptors and low-threshold, polymodal receptors. There are primarily four pathways through which the effect of the SNS on the periphery is mediated as follows: (1) norepinephrine (NE) released from neurons—either at the right or left stellate ganglion, which results in an increased HR and AV conduction times, an effect on the sinus and AV nodes; (2) epinephrine (EPI) released from the adrenal cortex affecting peripheral vessels and the myocardium; (3) local effect of EPI and NE, which is a direct effect on peripheral vessels; and (4) circulating NE, which may act in multiple locations.

Understanding the different “reflexes” (i.e., baroreceptor reflex, Bainbridge reflex, chemoreceptor reflex, Bezold-Jarisch reflex) is important, because most of the interventional approaches to manipulate the ANS are based on this physiology. For example, afferent signals arise from mechanoreceptors and chemoreceptors in different parts of the circulatory system. Notably, the stress-sensitive baroreceptors (mechanoreceptors) are present in both the high pressure (arterial) and low pressure (venous) sides of the circulatory system. The arterial baroreceptors that are located in the carotid sinus and aortic arch serve to provide regions for autonomic modulation ( Fig. 5-4 ). Afferent signals from the carotid sinus receptors are carried by the carotid sinus nerve, which joins the glossopharyngeal nerve (ninth cranial nerve). The axons from the aortic arch receptors constitute an afferent branch of the vagus nerve. The carotid sinus and aortic arch baroreceptors relay their signals and provide feedback for the primary regulation of aortic pressure. A drop in BP serves to stimulate the baroreceptor reflex arc to increase the HR. 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 HR 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.

Figure 5-4, Arterial baroreceptors are located on the aortic arch and the carotid sinus.

The chemoreceptor reflex is also involved in BP control. Chemoreceptors are located peripherally near the baroreceptors in the carotid sinus and aortic arch and located centrally in the medulla oblongata. Afferent signals from carotid sinus chemoreceptors travel via the glossopharyngeal nerve, and signals from the aortic arch chemoreceptors travel via the vagus nerve. The peripheral chemoreceptors predominantly sense arterial oxygen and carbon dioxide concentration, whereas the central receptors sense pH and carbon dioxide concentration. When there is a decrease in blood oxygen, an increase in carbon dioxide, or a decreased pH, the firing rate of the chemoreceptors is decreased. As a result, efferent vagus activity decreases and sympathetic activity increases, which increases HR, stroke volume, and vasoconstriction. Mixed receptors, which are sensitive to both mechanical and chemical stimuli, are present in the walls of all cardiac chambers. Their information is transmitted by unmyelinated fibers of the vagus nerve. When activity from these receptors is decreased, sympathetic output is increased, and BP and HR are increased. In the setting of heart failure (HF) with poor forward flow, the cardiovascular reflexes are activated, with afferent signaling informing the brain of decreased blood volume (due to low flow stimulation of arterial baroreceptors), increased blood volume (activated by the venous baroreceptors), and decreased activity with increased volume (from the receptors located in the hearts chambers) activating the cardiovascular reflexes to balance the sympathetic and parasympathetic limbs in order to maintain cardiovascular homeostasis.

Effects of Cardiovascular Adrenergic Receptors

β-Adrenergic Receptors

There are three subtypes of β-adrenergic receptors (β-ARs), each of which are expressed in the human heart. The β1- and β ₂ -ARs have positive inotropic, chronotropic, lusitropic, and dromotropic effects. The β ₁ -ARs predominate over the β ₂ -ARs in a 7 : 3 proportion. β ₃ -ARs are predominantly inactive during rest conditions but produce a negative inotropic effect when activated. Activation of β ₁ - and β ₂ -ARs is the most powerful physiologic mechanism through which cardiac performance may be increased in the human heart. All ARs have seven transmembrane receptors, which signal primarily via heterotrimeric G-proteins. β ₁ -ARs activate G _s proteins and β ₂ -ARs activate both G _s and G _i proteins. G _s protein signaling begins a cascade resulting in the activation of protein kinase A ( Fig. 5-5 ). G _i protein decreases cyclic AMP (cAMP), activates protein kinase, and aids the regulation of receptor signaling and nuclear transcription activation. There are five key effects of protein kinase A activation and induced phosphorylations: (1) Ca ²⁺ entry into the cells increases via L-type Ca ²⁺ channels and the ryanodine receptor. (2) The hyperpolarization-activated cation inward current (I _f ) is generated via hyperpolarization activated cyclic nucleotide-gated channels; this affects the initiation and modulation of rhythmic activity in the cardiac pacemaker cells. (3) Cardiac relaxation is accelerated following increased Ca ²⁺ reuptake into the sarcoplasmic reticulum (SR). This occurs due to phosphorylation of phospholamban, which is a regulator of the SR associated ATP-dependent calcium pump. (4) Phosphorylation of the phospholemman subunit of the Na ⁺ /K ⁺ -ATPase decreases its inhibitory effect on the sodium-pump. (5) Importantly, myofilament sensitivity to Ca ²⁺ decreases, leading to increase relaxation of the myofilaments. This occurs as a result of phosphorylation of troponin I and myosin binding protein C.

Figure 5-5, Beta-Adrenergic Receptor Signaling.

α-Adrenergic Receptors

There are a total of six different α-adrenergic receptors (ARs) (α _1A , α _1B , α _1D , α _2A , α _2B , and α _2C ). α ₁ -ARs heavily populate major arteries such as the aorta, pulmonary arteries, and mesenteric arteries. They are activated via NE and EPI to produce vasoconstriction. The myocardium also expresses α _1A - and α _1B -ARs, though overall there are 20% fewer of these ARs than β-ARs. The α _1A - and α _1B -ARS activate transmembrane G receptors, thereby initiating a cascade of intracellular signaling, which in turn increases intracellular Ca ²⁺ levels, thereby promoting cardiac contractility. Central α _2A inhibits central sympathetic outflow leading to a decrease in BP. In contrast to this, α _2B activation leads to transient vasoconstriction.

Autonomic Dysregulation and Arrhythmias in Heart Failure

As mentioned earlier, declining cardiac function is coupled with a spectrum of compensatory responses to uphold cardiovascular homeostasis. Two of the major contributors in the neurohormonal system that keep the steady state but are intricately entwined include: (1) the autonomic nervous system and (2) the renin-angiotensin-aldosterone system (RAAS). A reduction in the cardiac output activates afferent stimuli from the baroreceptors to the central nervous system cardioregulatory centers, which in turn leads to an activation of the sympathetic nervous pathway. Reduced renal perfusion, secondary to reduced forward flow, activates the RAAS system via renin release. Renin facilitates the conversion of angiotensinogen to angiotensin I. Angiotensin-converting enzyme subsequently converts angiotensin I to angiotensin II. Angiotensin II has a central effect on increasing the sympathetic activity, is also involved in sodium and water retention, and has a systemic vasoconstrictive effect. 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 adaptation of the heart. Although a heightened sympathetic tone modulates the HR and enhances AV conductance in addition to cardiac contractility, when sustained over time, it is associated with reduced sympathetic neuronal density and responsiveness. Sympathetic activation in turn increases the vasoconstrictor tone, accompanied by activation of the RAAS, the endothelin-1 and vasopressin system, which may be responsible for the peripheral organ dysfunction and damage in the setting of congestive heart failure (CHF). Coupled with this, there is abnormal calcium handling and enhanced cellular apoptosis.

A prolonged shift in the sympathovagal balance, besides being proarrhythmic, can also be associated with nitric oxide dysregulation, increased inflammation with excess cytokine release, and adverse remodeling of the heart. Several studies have also shown that diminished vagal activity and a heightened sympathetic activity reflected as an increased HR are predictors of high mortality in HF. Of note, the beneficial impact of modulating the ANS is evident from the proven role of β-blockers in blocking sympathetic activation and improving outcomes. More recently, specific agents that inhibit the cardiac pacemaker I _f current and thereby reduce HR, have been able to positively impact outcome and cardiac remodeling in patients with HF. As a result of inherent limitations of existing pharmacologic and surgical strategies to modulate the autonomic cardiac circuit, more recently, innovative nonpharmacologic interventions have evolved.

Arrhythmias

Worsening HF is in turn associated with ionic and structural remodeling 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. 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, while it contributes to the arrhythmogenicity of the atrial substrate. On the other hand, an upregulation of the sympathetic nerves and β-receptors in HF may afflict both the atrium and ventricles, promoting arrhythmias.

The now well-established association of the ANS with the development of arrhythmias was first suggested by the work of Leriche and colleagues in the early 1930s. Interest in this topic has increased in recent years. As we begin to appreciate the complex interplay between the ANS and the pathogenesis of arrhythmias, we are also beginning to realize how measuring the sympathovagal balance may help us to prognosticate, and further modulating the balance may be useful in treating arrhythmias and lowering the risk. Alterations in the autonomic tone that can be arrhythmogenic could be either systemic via central changes in the tone or locally mediated through regional alterations.

In pathologic states such as myocardial ischemia, the cardiac afferent and efferent stimuli from the myocardial region under threat may be altered to promote a proarrhythmic environment, contributing to the risk for sudden cardiac death. Of note, myocardial infarction causes local denervation in the region of the scar, which when accompanied by nerve sprouting at the edge of the scar, results in hypersensitivity to circulating catecholamines.

At the ionic level, altered expression of L-type Ca ²⁺ channels and K ⁺ channels by the SNS creates a spatial dispersion of action potential duration. Action potential prolongation, in turn, increases susceptibility to early afterdepolarizations (EADs) and/or delayed afterdepolarization (DAD)-triggered activity in hyperinnervated areas, facilitating tachyarrhythmias. Numerous studies have demonstrated how targeting the ANS may provide an adjunctive, or in some cases, alternative treatment to ventricular tachycardia (VT). Left-sided and bilateral sympathectomy have shown benefit in patients with refractory VT, both in ischemic heart disease and channelopathies. In addition to its role in ventricular arrhythmias, the association between ANS activity and atrial arrhythmias is well established. Notably, studies of strategies incorporating ablation of parasympathetic plexuses within the fat pads of the epicardium have had mixed results. Other potential targets for ANS modulation in patients with atrial tachyarrhythmias currently under investigation include renal denervation. Although modifying the sympathovagal balance through pacing strategies is possible, its role in modifying the risk for arrhythmias in humans needs further study.

Quantifying Autonomic Activity

Biomarkers and Microneurography

Quantification of ANS activity is important not only for prognostication, but also to assess response to therapy ( Table 5-1 ). Measuring NE spillover was one of the earliest attempts at measuring autonomic activity. Regional NE spillover can be calculated by radiotracer techniques that involve measuring radioisotopes dilution with plasma concentration of NE from regional venous and arterial blood. However, there are important limitations with this technique that make it impractical for routine clinical use. There is considerable variability in the way that different tissues metabolize local and circulating NE. NE increases may be related to decreased regional clearance rather than increased local secretion. Microneurography enables quantification of nerve firing within the skin and local vasculature, but it has low reliability, which has precluded its clinical use.

TABLE 5-1

Cardiac Autonomic Tests

(Modified from Singh JP, Kandala J, Camm AJ: Non-pharmacological modulation of the autonomic tone to treat heart failure. Eur Heart J 35(2):77-85, 2014.)

Tests		Measurement Units	Description	Additional Information
Heart rate variability—frequency domain	Total power	msec ²	Total variance in heart rate pattern	Useful for measuring sympathovagal balance and in risk stratification.
	Low-frequency power	msec ²	Sympathetic pattern
	High-frequency power	msec ²	Parasympathetic pattern
Heart rate variability—time domain	SDNN	msec ²	Standard deviation of average RR interval	Useful for risk stratification but clinical utility limited; not useful for atrial fibrillation and with frequent PVCs.
	RMSS	msec ²	Root of mean squares of difference between adjacent intervals
	pNN 50	Percentage	Number of pairs of adjacent RR intervals differing by >50 msec/total RR intervals.
Baroreflex sensitivity	Cardiovagal baroreflex sensitivity	msec/mm Hg	Index of baroreflex control of autonomic outflow. Close relationship with cardiac vagal tone. Estimated by changes in systolic arterial pressure.	Limited availability, but useful in risk stratification and postmyocardial prognostication.
Microneurography	Muscle sympathetic nerve activity	Burst per 100 beats or bursts/min	Commonly used to measure nerve activity using microelectrode in nerves such as in common peroneal nerve. Can be used to measure efferent multifiber traffic in sympathetic nerves.	Limited use. Low reliability and logistically challenging.
Norepinephrine levels	Norepinephrine spillover	mol/min M ²	Plasma NE levels are a sensitive guide to global sympathetic nerve activity.	Limited availability and utility, hard to measure. Considerable variability in release and uptake of catecholamines in various tissues.
Scintigraphic imaging	¹²³ I-mIBG imaging	Heart to mediastinum ratio (HMR) of cardiac mIBG activity	Myocardial sympathetic imaging.	Limited availability and standardization. Maybe useful in risk stratification.

¹²³ I-mIBG, A metaiodobenzylguanidine scan with a radioisotope iodine (iodine-123); pNN 50, number of pairs of adjacent RR intervals differing by >50 msec/total RR intervals; PVC, premature ventricular contraction; RMSS, root of mean squares of difference between adjacent intervals; SDNN, standard deviation of average of normal sinus to normal sinus (NN) intervals.

Electrocardiograph-Based Measurements

Most practical for the electrophysiologist 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 HR and BP is under direct influence of the autonomic tone. It is possible to differentiate the contribution of each of the limbs of the autonomic nervous system, based on their clinical effect, because the vagal (parasympathetic) tone and sympathetic tone influence the HR in different frequency bands. The SNS modulates the low frequency variance in the HR as contrasting to the PNS, which regulates the high frequency component of HR variability (HRV) ( Fig. 5-6 ). A range of other parameters inclusive of respiration, RAAS, and thermoregulations can have an effect on these and other frequency bands of HR. Notably, the computation of the low-frequency/high-frequency ratio may aid in quantifying the sympathovagal balance. Other useful autonomic measures include HR turbulence, entropy, and baroreflex control of HR, known as baroreflex sensitivity (BRS).

Figure 5-6, An Example of a Power Spectral Density Curve From Time Domain Heart Rate Data.

Of note, in the setting of a high sympathetic tone, baroreceptor modulation of the heart is distinctly diminished. HRV and BRS are practical methodologies to assess the acute “central” and “reflex” effects, providing an indirect measurement of autonomic function, while also having been proven to be valuable in monitoring the long-term clinical course and outcomes of patients. New data from the GISSI-HF trial demonstrate that frequency domain measures (very low frequency and low frequency), time domain measures (standard deviation of average of normal sinus to normal sinus [NN] intervals), and nonlinear measures of HRV and HR turbulence from Holter recordings in patients with HF were predictive of long-term outcome.

Noninvasive Quantification of Cardiac Autonomic Innervation

Ischemic and infiltrative pathologies may influence the local myocardial substrate and regional innervation patterns. The recent endorsement of radioactive iodine-labeled metaiodobenzylguanidine ( I-mIBG) for imaging in HF by the Food and Drug Administration (FDA) in 2013 has brought renewed interest in radionuclide imaging of sympathetic innervation of the heart. The commonly used radiotracers are ¹²³ I-mIBG for planar and single-photon emission computed tomography imaging and ¹¹ C-hydroxyephedrine for positron emission tomography imaging. The most accepted measure of heart-to-mediastinal ratio (H/M ratio) can be calculated either using planar imaging (area based region of interest) or SPECT imaging (volume-based region of interest). Favorable left ventricular (LV) remodeling in patients with HF has been shown to correlate to improvement in sympathetic innervation by mIBG scan. There is also increasing evidence that a reduced H/M ratio correlates to increased risk of arrhythmias and mortality and may provide additional value over other risk stratification tools. In the largest study to date (ADMIRE-HF), an abnormal mIBG heart to mediastinal ratio was shown to correlate with both major cardiac adverse events (New York Heart Association [NYHA] functional class progression, potentially life-threatening arrhythmic event, or cardiac death) and ventricular arrhythmia events. This was in a population of 961 with symptomatic HF and left ventricular ejection fraction (LVEF) less than or equal to 35%, followed for a median of 17 months using a cut-off value of H/M ratio less than 1.6 as a surrogate for identifying pathologic cardiac denervation ( Fig. 5-7 ). However, others that have sought to investigate the physiology of the relationship have been unable to clearly demonstrate a correlation between the inducibility of ventricular arrhythmia during an electrophysiology (EP) study and the standard indices of ¹²³ I-mIBG imaging.

Figure 5-7, A, H/M ratio in a normal heart (left) and a heart with reduced cardiac autonomic innervation (right). B, Risk of arrhythmic event in the ADMIRE-HF study, stratified for H/M ratio ≥1.6. H/M, Heart-to-Mediastinal.

Device-Based Autonomic Measurements

Recent work has shown that a spectrum of diagnostic measures available from within implantable devices may help predict the clinical course of the patient. Devices provide information regarding (1) rhythm disturbances (e.g., atrial fibrillation [AF] burden, ventricular ectopy, etc.); (2) system information pertinent to the appropriate functioning (i.e., percent pacing, lead thresholds, etc.); and (3) HF diagnostics. The HF diagnostics include measures of physical activity, fluid accumulation (impedance measures) and autonomic activity. The baseline HR and measures of HRV (standard deviation of average NN intervals [SDANN], HRV footprint) are reduced in patients with HF and have been correlated to long-term mortality. They are automatically computed by the devices and can be trended ( Fig. 5-8 ). Some preliminary work has shown that changes in autonomic activity tracks favorable remodeling of the heart in patients receiving cardiac resynchronization therapy. There are several reports suggesting that baseline autonomic measures, inclusive of mean HR, are predictive of improved long-term outcome, inclusive of mortality. In the future, implantable devices that modulate the ANS may have a closed loop system that will permit autoregulation and optimization of the stimulation/pacing rates based on these measured parameters.

Figure 5-8, Device-Based Data With Long-Term Trends for Autonomic Balance, Obtained Via Standard Interrogation of an Implanted Cardiac Resynchronization Defibrillator.

Device-Based Neural Stimulation

There are several extra-cardiac sites that could be stimulated to modify the autonomic tone favorably in patients with underlying cardiac diseases. The information processing through the nervous system and its neurochemical environment is electrically mediated through the generation of action potentials. This in turn is influenced by the rate and pattern of electrical impulses. Extracellular current delivery to the nerve generates transmembrane potentials, thereby exciting the fibers within. The factors determining neural stimulation are the fiber size and proximity to the stimulating electrode. Larger fibers have a lower threshold for activation, and as the distance between the electrode and fiber increases, the threshold increases. Therefore stimulating the autonomic neural system presents two challenges:

The correct level of stimulation must be chosen in order to minimize side effects, while ensuring therapeutic effect at the target-organ level.
The correct type of delivery tool and delivery protocol (e.g., continuous vs. pulsed current, stimulation-frequency, etc.) must be chosen in order to obtain an effect at the desired type of nerve fibers, while avoiding unwanted stimulation of other types of nerve fibers located in the same area.

The true challenge of selective pacing is largely determined by the neural properties at the site of stimulation, namely, the physical characteristics, diameter of the nerve, electrode-fiber distance, and current threshold. Systems designed to selectively activate certain nerve fibers are being tested and developed. There are several strategies to achieve selective fiber activation, one of which is the anodal block technique. The threshold for anodal block is always higher than that for excitation. When using square/rectangular pulses of current between two electrodes, excitation breaking through the anodal block can occur because of passive electrical properties of the connective tissue sheath. However, sufficient hyperpolarization of a membrane can prevent an action potential from passing through. Based on this principle, with different cathodic and anodal configurations using several electrodes and altering the stimulating waveforms, the larger fibers can be selectively and more strongly hyperpolarized than smaller fibers, thereby blocking the larger fibers at lower stimulus strengths than the smaller fibers.

For instance, stimulating the vagus nerve is immersed in much complexity, especially as it communicates with multiple organs. Vagal nerve pacing at parameters to stimulate the cardiac nerves can often times stimulate extracardiac large fibers causing coughing, hoarseness, laryngeal discomfort, jaw pain, and temporal headache. The therapeutic effect of vagal nerve stimulation (VNS) is dependent on selectively stimulating the population of cardiac neurons and fascicles without concomitant stimulation of another neighboring population of neurons and fascicles that may produce the unwanted side effects. The vagus nerve pacing cuff electrodes are designed to prevent current leakage and nerve fatigue and block noncardiac side effects, while enabling easy manipulation and implantation. The chosen frequency and amplitude of stimulation will eventually determine the excitation of the cardiac vagal fibers and in turn the therapeutic outcome. Other regions present similar type of challenges, and those with the greatest level of clinical evidence will all be dealt with in the following sections of this chapter, including stimulation of the spinal cord and carotid sinus baroreceptors.

Vagus Nerve Stimulation

Stimulation of the vagus nerve is an established therapy for the control of depression and refractory epilepsy. Recently, there has been a rapidly increasing interest in the potential role of VNS in the treatment of patients with HF. The current section outlines the anatomy and physiology of the vagus nerve, followed by the preclinical and clinical evidence for this form of device therapy.

Vagus Anatomy and Structure

The vagus nerve is a thick trunk that courses through the neck and contains fibers innervating many different organs. The cervical vagus trunks contain the recurrent branches to the larynx and fibers going to liver, gallbladder, cardiovascular structures, stomach, small intestine, kidneys, pancreas, and the superior part of the large intestine.

The peripheral nerve fibers, based on the anatomic and conductive properties, can be classified into A, B, and C types. The threshold for evoking an action potential within these fibers is lowest for type A, followed by type B and C fibers. Typically, the type A fibers are myelinated and larger (1 to 20 µm in diameter) with high conduction velocities (6 to 120 msec ⁻¹ ), whereas the B fibers are myelinated but smaller (less than 3 µm in diameter) and with lower conduction velocities (2 to 18 msec ⁻¹ ). The C fibers are unmyelinated, are the smallest (less than 1 µm in diameter), and have the lowest conduction velocities (less than 2 msec ⁻¹ ). The type A fibers are further subdivided into two larger trunks (α and β subtypes) that have a lower stimulation threshold (0.3 mA) and two smaller trunks (γ and δ subtypes) with a stimulation threshold at 2.0 mA. The B and C fibers have higher stimulation thresholds at 3.0 mA and 10.0 mA, respectively. The easiest anatomic target for VNS is the cervical part of the nerve, which can be accessed from an incision on the side of the neck during conscious sedation. The cervical vagus nerve comprises fibers with a diameter ranging from 1 to 20 µm, with approximately 16% of these being myelinated. The cardiac vagal fibers are medium sized (6 to 12 µm) and myelinated. B fibers also innervate the heart. Approximately 10% of all fibers in the cervical vagus trunk are cardiac fibers, 80% of which are afferent. The cervical vagal complex carries both parasympathetic and sympathetic motor axons that project neurons to the heart. The parasympathetic stimulation is further divided into a direct pathway of axons that synapse with cardiac cholinergic postganglionic neurons and an indirect pathway of axons that first synapse with local cardiac circuit neurons, which in turn modulate cardiac motor neurons.

Preclinical Evidence

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