Chapter 5 Autonomic Nervous System and Cardiac Arrhythmias

The autonomic nervous system (ANS) comprises the portion of the central nervous system that provides moment-to-moment regulation of the function of the cardiovascular system as well as that of all other organ systems. The ANS continuously monitors afferent neural signals from vascular beds and organ systems and coordinates efferent neural traffic to modify the responses of heart and blood vessels to ever-changing physiological and metabolic requirements. In this context, the sympathetic and parasympathetic components of the ANS are the dominant players (Figures 5-1 and 5-2).¹ However, ANS cardiovascular control also incorporates actions of cardiac and extracardiac neurohumoral agents, intracardiac reflex arcs, and the contributions of certain less well-understood agents such as vasoactive intestinal peptide (VIP), neuropeptide Y, transmitters released by the so-called purinergic nerve endings, serotonin, inflammatory cytokines, vasopressin, and nitric oxide.² Further, with respect to cardiovascular control, the ANS collaborates with the hypothalamic-pituitary-adrenal (HPA) axis. For its part, the HPA-axis, governed from the hypothalamus, participates by prompting the release of glucocorticoids, mainly cortisol and, to a lesser extent, mineralocorticoids. The HPA theater of operation therefore includes inflammatory, immune, metabolic, and pressor effects.³ Both systems (ANS and HPA) are involved in stress responses.^2,3

Figure 5-1 Schematic illustrating the course of sympathetic (dashed line) and parasympathetic (solid line) nerve pathways to key cardiac and vascular structures. The manner in which neural control approaches cardiac structures is far more complex than is suggested in this illustration. Further, the important intracardiac neural signaling structures are not shown.

Figure 5-2 Schematic illustrating a conventional view of the approximate midbrain sites considered important for basic autonomic nervous system control of cardiovascular function.

It is not unexpected that any disturbance of ANS function, given its wide-ranging impact, may lead to clinically important consequences. In terms of cardiac electrophysiology and arrhythmias, common clinical conditions in which ANS effects are evident include acute myocardial ischemia, heart failure, and neurally mediated reflex syncope (particularly the vasovagal faint). Furthermore, it is now widely acknowledged that the nervous system has the capacity to injure the heart acutely (e.g., stress-induced cardiomyopathy); serious acute cerebral disorders such as subarachnoid hemorrhage, intracerebral bleeds, infections, and seizures may induce electrocardiographic changes, myocardial damage, arrhythmias, and even sudden death.^3–7 Perhaps the most publicized direct cardiac effects of presumed autonomic “storms” are the immediate, apparently stress-triggered, increases in the number of cardiovascular events; these include acute myocardial infarctions, sudden cardiac deaths, and presumed stress-induced cardiomyopathy (Table 5-1).^3–5

Table 5-1 Epidemiologic Associations: Stress and Increased Cardiovascular Event Rates

a Stalnikowicz R, Tsafrir A: Acute psychosocial stress and cardiovascular events, Am J Emerg Med 20:488–491, 2002.

b Brown DL: Disparate effects of the 1989 Loma Prieta and 1994 Northridge earthquakes on hospital admissions for acute myocardial infarction: Importance of superimposed triggers, Am Heart J 137:830–836, 1999.

c Watanabe H, Kodama M, Okura Y, et al: Impact of earthquakes on Takotsubo cardiomyopathy. JAMA 294:305–306, 2005.

d Zhang XQ, Chen M, Yang Q, et al: Effect of the Wenchuan earthquake in China on hemodynamically unstable ventricular tachyarrhythmia in hospitalized patients, Am J Cardiol 103(7):994–997, 2009.

e Wilbert-Lampen U, Leistner D, Greven S, et al: Cardiovascular events during World Cup soccer. N Engl J Med 358:475–483, 2008.

f Katz E, Metzker J-T, Marazzi A, Kappenberger L: Increased sudden cardiac deaths in Switzerland during the 2002 FIFA World Cup, Int J Cardiol 107:132–133, 2006.

g Brotman DJ, Golden SH, Wittstein IS: The cardiovascular toll of stress, Lancet 376: 1089–1100, 2007.

h Meisel SR, Kutz I, Dayan KI, et al: Effect of Iraqi missile war on incidence of acute myocardial infarction and sudden death in Israeli civilians, Lancet 338:660–661, 1991.

i Tofler GH, Muller JE: Triggering of acute cardiovascular disease and potential preventive strategies, Circulation 114:1863–1872, 2006.

This chapter provides a brief overview of current concepts regarding the impact of autonomic innervation as they pertain to cardiac arrhythmias, conduction system disturbances, and related disorders.

Anatomic Nervous System and Cardiac Conduction System Physiology

Sinus Node, Atrioventricular Node, and His-Purkinje System

The sinus node (SN) and the atrioventricular (AV) node appear to be represented by separate cells within the nucleus ambiguus. However, it is uncertain whether the nodes are coordinated centrally; in fact, it seems increasingly likely that local circuits, often positioned within the epicardial fat pads of the heart, participate in the coordination of these structures (Figure 5-3).^4,8

Figure 5-3 Diagrammatic representation of the approximate locations of epicardial fat pads; these fat pads are believed to provide sites of intracardiac neural connections and communication. The image depicts the posterior surface of the heart. The principal fat pads are demarcated and labeled. SVC, Superior vena cava; Ao, aorta; PV, pulmonary valve; SA, sinoatrial; RPVs, right pulmonary veins; LPVs, left pulmonary veins; LA, left atrium; IVC, inferior vena cava; AVN, atrioventricular node.

Sinus Node

In humans, at rest, parasympathetic influence appears to predominate in the case of SN chronotropic state. Of course, multiple factors alter this situation; the most obvious of these is physical exercise, but others include the aging process, drug therapy, and emotional state.

ANS influence is the most important of the many extrinsic factors (e.g., drugs, hormones) affecting SN function. In the healthy heart, fluctuation of the ANS influence results in a normal respiratory-induced variation of sinus cycle length (i.e., respiratory sinus arrhythmia). In the case of respiratory sinus arrhythmia, the variations may be substantial (at times suggesting sinus pauses). Absence of sinus arrhythmia has come to be recognized as a sign of cardiac disease with increased mortality risk.

Age-related changes of sinoatrial function are clinically important, given the prevalence of SN dysfunction in older adults. In terms of ANS contribution, parasympathetic influence on SN chronotropism progressively diminishes with increasing age. However, at the same time, an age-related decrease of “intrinsic” heart rate (i.e., the heart rate in the absence of autonomic influences) also occurs. Thus, maintenance of an appropriate heart rate and chronotropic responsiveness in older individuals is increasingly dependent on the integrity of the sympathetic tone of the ANS.

Atrioventricular Node and Cardiac Conduction System

As a rule, AV nodal dromotropic responsiveness in the resting patient is under relatively balanced sympathetic and parasympathetic neural influence. However, this situation is readily altered by physiological events (e.g., exercise, sleep), the impact of disease states, drug effects, or during cardiac electrophysiology procedures when certain atrial regions are stimulated. Any tendency toward parasympathetic predominance markedly enhances the decremental properties of the AV node; in the extreme, this can be associated with transient complete AV nodal block (Figure 5-4). The latter is, in fact, a relatively common finding in sleeping patients and in very fit resting subjects. The relationship between ANS control of SN rate and AV conduction properties appears to foster both the maintenance of 1 : 1 AV conduction and a relatively optimal AV conduction interval.

Figure 5-4 Electrocardiographic recordings obtained from an implanted loop recorder that had been implanted in a 72-year-old man with recurrent syncope of uncertain cause. The recording documents a transient symptomatic period of high-grade atrioventricular block.

The His bundle and bundle branches comprise cells with larger surface areas, more negative resting membrane potentials, and faster (sodium [Na⁺]-dependent) action potentials than those of the AV node. Furthermore, cells that make up the cardiac conduction system have abundant intercellular connections and are physically arranged in such a way as to promote longitudinal conduction. Consequently, decremental conduction is essentially absent, except in the setting of relatively severe conduction system disease. Sympathetic nerve endings are generally better represented in the distal aspects of the specialized conduction system than are parasympathetic nerves. However, it has become evident that parasympathetic influence penetrates farther than had previously been thought.

Ventricular Myocardium

Ventricular sympathetics tend to lie within the subepicardial layer and follow the large coronary vessels as they spread out over the myocardium.^9,10 The parasympathetics, in contrast, tend to penetrate the myocardium after crossing the AV groove and thereafter are subendocardial in location (Figure 5-5). The parasympathetic vagal efferents to the mycardium terminate not on the muscle cells themselves but on intracardiac ganglia. Evidence suggests that these ganglia not only form relay stations but also subserve certain local integrative functions, including the intracardiac reflex activity discussed earlier.

Figure 5-5 Diagram depicting the epicardial and endocardial locations of sympathetic and parasympathetic ventricular nerves, respectively.

(Modified from Zipes DP, Inoue H: Autonomic neural control of cardiac excitable properties. In Kulbertus HE, Franck G, editors: Neurocardiology, Mount Kisco, NY, 1988, Futura Publishing.)

Heightened adrenergic activation in the ventricular myocardium may be arrhythmogenic by causing enhanced pacemaker activity as well as by increasing the frequency and rate of automaticity. In addition, elevated adrenergic tone is known to increase the likelihood of the generation of early after-depolarizations (EADs) and delayed after-depolarizations (DADs).

Parasympathetic effects, in contrast, are thought to operate mainly as an antiadrenergic action in the setting of increased adrenergic tone. Consideration is being given to vagal nerve stimulation as an antiarrhythmic treatment strategy. The outcome of this activity may be diminished production of adrenergically induced EADs and DADs and an apparently anti-inflammatory action (diminished cytokine release and enhanced glucocorticoid release).

Autonomic Nervous System and Specific Bradyarrhythmias and Cardiac Conduction System Disturbances

Sinus Node Dysfunction

SN dysfunction (sick sinus syndrome) encompasses abnormalities of SN impulse generation, disturbances of impulse emergence into the atrium, abnormal impulse transmission within the atria, increased susceptibility to atrial tachycardias (particularly atrial fibrillation), chronotropic incompetence, and inappropriate sinus tachycardia. Clinical manifestations vary from seemingly asymptomatic electrocardiogram (ECG) findings to a wide range of complaints, including syncope, shortness of breath, palpitations, fatigue, and premature mental incapacity.

The causes of SN dysfunction are numerous but may be conveniently categorized as conditions that alter the SN, the sinoatrial structure or function directly (so-called intrinsic SN disease) or those that operate indirectly to impair sinoatrial function (i.e., extrinsic factors such as autonomic disturbances or drug effects). Ageing-associated idiopathic degenerative changes, fibrotic changes, or both are probably the findings most closely associated with “intrinsic” SN dysfunction. In regard to “extrinsic” SN dysfunction, drugs are the most important non-ANS contributors. β-adrenergic blockers, calcium channel blockers, membrane-active antiarrhythmics, and, to a lesser extent, digitalis are the most frequently implicated. Each of these may alter SN function as a result of direct pharmacologic effects (e.g., flecainide, d-sotalol), or indirectly via the ANS (e.g., β-adrenergic blockers) or both (e.g., quinidine, disopyramide, propafenone, amiodarone, digitalis). In terms of clinical outcomes, cardioactive drugs may initiate or aggravate sinus bradyarrhythmias or induce chronotropic incompetence.

Apart from drug-induced autonomic disturbances, the ANS may also contribute to apparent extrinsic disturbances of SN function. Sinus bradycardia, sinus pauses, sinoatrial exit block, and slow ventricular responses in atrial fibrillation may occur in the setting of parasympathetic predominance despite apparently normal underlying intrinsic SN or atrial function. In some cases, bradyarrhythmias are, in fact, extreme forms of sinus arrhythmia. Perhaps the best example of this is the physically fit individual in whom parasympathetic predominance at both the SN and the AV node levels may be present on a chronic basis. In such cases, sinus pauses and various degrees of AV block have been reported during sleep or at rest. Generally, these are asymptomatic and of little clinical consequence. Nonetheless, their occurrence (often detected inadvertently) may cause alarm. Carotid sinus syndrome and related conditions, in which excessive hypervagatonia is transient, are other instances in which intrinsic conduction system function is usually relatively normal and yet manifests clinically important ANS-induced disturbances. Fortunately, even in the setting of an apparently prolonged asystolic event, spontaneous restoration of the cardiac rhythm occurs in, by far, the vast majority of cases.

The syndrome of persistent or inappropriate sinus tachycardia provides another example of a clinical circumstance in which the ANS appears to play a primary role in arrhythmogenesis. The basis for the tachycardia is believed to be abnormal enhanced automaticity within the SN or nearby atrial regions. The cause of inappropriate sinus tachycardia in many cases, excluding those that turn out to be ectopic atrial tachycardias arising in the vicinity of the SN, remains unknown. Diminished parasympathetic control of SN function has been suggested; given the frequent association with recent radiofrequency ablation of cardiac structures (or in former times to surgical ablation of accessory connections), a disturbance of intracardiac vagal reflexes has also been proposed. However, one relatively recent report investigated the prevalence and the functional effects of circulating antiautonomic receptor antibodies in patients with inappropriate sinus tachycardia. Findings suggested a link between inappropriate sinus tachycardia and circulating anti–β-adrenergic receptor antibodies that induce a persistent increment in cyclic adenosine monophosphate (cAMP) production.

The coexistence of periods of bradyarrhythmia and bouts of atrial fibrillation or, less commonly, other paroxysmal primary atrial tachycardias in the same patient is a common manifestation of SN dysfunction (the so-called bradycardia-tachycardia syndrome). In bradycardia-tachycardia syndrome, symptoms may be the result of episodes of rapid heartbeats, the bradycardic component, or both. In this case, ANS influences are rarely entirely to blame. Similarly, true chronotropic incompetence is not usually attributable to ANS effects alone. As a rule, patients with parasympathetic predominance may exhibit low resting heart rates but ultimately manifest normal chronotropic responses to physical exertion. True chronotropic incompetence (i.e., inability of the heart to adjust its rate appropriately in response to metabolic need) implies intrinsic SN dysfunction, an undesirable effect of concomitant drug treatment, or both. In this regard, although conventional exercise testing is not generally useful in identifying most forms of SN dysfunction, such testing may be helpful in differentiating patients with resting sinus bradycardia but essentially normal exercise heart rate responses (e.g., physically trained individuals with presumably higher levels of parasympathetic influence on SN automaticity) from patients with intrinsically inadequate chronotropic responses.

Evaluation of SN responses to pharmacologic interventions and neural reflexes (e.g., carotid sinus massage, Valsalva maneuver, heart rate response to upright tilt, or induced hypotension [e.g., by administration of nitroglycerin]) is an important element in the diagnostic assessment of SN function. For example, pharmacologic interventions may assess SN response to β-adrenergic blockade, β-adrenergic stimulation, or parasympathetic muscarinic blockade (i.e., atropine infusion). The most important of these tests is estimation of intrinsic heart rate (IHR, SN rate in the absence of neural control) by pharmacologic autonomic blockade with combined administration of a β-adrenergic blocker and atropine. A normal IHR in a patient with apparent sinus pauses or marked SN bradycardia suggests extrinsic SN dysfunction.

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