**1. Introduction**

The heart has an intrinsic conduction system that consists of specialized cells. It can spontaneously depolarize to initiate heartbeats from its rhythmic pacing discharge and coordinate heart electrical activity [1, 2]. The sinoatrial (SA) node is the first pacemaker that starts the electrical impulse resulting in the depolarization and contraction of the atrium. This electrical impulse is distributed throughout the heart through the internodal pathway, atrioventricular (AV) node, AV bundle, branches of the bundle of HIS, and through Purkinje fibers. Without the extrinsic (hormonal and neural) influences, the SA node creates about 100 beats per minute; however, to meet the body's oxygen requirement under variable conditions, cardiac output (and thus heartbeat) must vary. This is where the autonomic nervous system (ANS) of the heart plays a role [2].

### **2. Basic science in the ANS of the heart**

The heart receives extensive innervation by both sympathetic and parasympathetic systems of the ANS. The cardiac efferent preganglionic sympathetic neurons originate from the lateral horns of the spinal cord's upper thoracic segment (T1-T4) and leave the spinal cord through the ventral (anterior) roots of the corresponding spinal cord nerves. As they reach the superior cervical, medial cervical, cervicothoracic/stellate, and thoracic ganglia of the paravertebral sympathetic nerve chain (SNC), they synapse onto the postganglionic nerves, namely the cardiac cervical nerves and cardiac thoracic nerves, which travel to the heart along with the epicardial vascular structure [1–4].

The cardiac efferent preganglionic parasympathetic neurons originate in the medulla oblongata's dorsal motor nucleus and nucleus ambiguus. They travel bilaterally within two vagal nerves and synapse onto the postganglionic nerve fibers in the vagal nerve ganglia located in the cardiac plexus, at the base of the heart [3, 4]. Cardiac plexus consists of a complex network of various nerves including the sympathetic, parasympathetic, and cardiac nerves as well as some tiny parasympathetic ganglia to control cardiac activity. The cardiac plexus is divided into two parts: (1) the superficial part located in the aortic arch concavity and (2) the deep part located between the trachea and the aortic arch. Both parts are connected to provide cardiac autonomic innervation [3].

Most of the cardiac afferent fibers travel in sympathetic cardiac nerves. The first-order sympathetic-sensitive afferent fibers have their cell bodies in the first 4–5 thoracic ganglia. They synapse with the second-order fibers in the spinal cord, where they cross the median line and ascend along the anterior spinothalamic tract (ventral spinothalamic fasciculus) to the posteroventral nucleus in the thalamus. Parasympathetic afferent fibers in the heart primarily function as a mediator for some cardiac reflexes, responding to activation of stretch receptors in the atria (Bainbridge reflex) and left ventricle (Jarisch-Bezold reflex) [3].

The ANS influences most heart functions by affecting the SA node, AV node, myocardium, and small and large vessel walls [2]. The ANS regulates heart rate (chronotropic effect), myocardial cells contractility (inotropic effect), signal conductivity (dromotropic effect), excitability (bathmotropic effect), as well as coronary vascular tone and myocardial blood flow. As the sympathetic and parasympathetic systems have opposite effects on heart functions, the final effect on the heart is the net balance between the two systems. However, their influence differs by their distribution in the heart [2, 3].

The sympathetic system carries an excitatory effect on heart functions and is activated in emergency, stressful situations, or any other situations that require increase of cardiac output; therefore, it is also known as "fight or flight response" [2]. It controls heart function mainly in three effects: (1) It speeds up the depolarization of the sinus node increasing heart rate (positive chronotropic), (2) increases conduction velocity in the AV junction, atria, and ventricles (positive dromotropic effect), (3) increases myocardial contractility both in the atria and ventricle (positive inotropic effect) [2, 3]. Most of these effects are mainly mediated by the β1 adrenergic receptors as they predominate in healthy human hearts, whereas β2 receptors are primarily concentrated in the atria and ventricles thus their functions are linked to the inotropic effect. Both β1 and β2 receptors are distributed in all regions of the heart, nevertheless [3]. In addition, sympathetic activation also promotes constriction of the coronary arteries leading to an increase of cardiac output, which is mediated by α1 and α2 receptors, and dilatation mediated by β2 receptors in the coronary arteries [2, 3].

### *Heart Autonomic Nervous System: Basic Science and Clinical Implications DOI: http://dx.doi.org/10.5772/intechopen.101718*

Conversely, the parasympathetic (vagal) system has inhibitory effects on heart functions. It is activated under restful conditions and is therefore known as rest and digest response [2]. It slows down sinus node activity resulting in a decrease of heart rate, slows down electrical conduction through the AV nodes and conduction system, causing delayed conduction and AV block, decreases atria contractility, and promotes dilatation of the coronary arteries, which result in decreased cardiac output. On atrial cells, parasympathetic activation decreases contractility yet shortens the action potential duration causing an increase in conduction speed, thus leading to reentrant tachyarrhythmias. As parasympathetic fibers are predominantly distributed to the atria while poorly distributed to the ventricles, parasympathetic activation does not significantly affect intraventricular conduction and ventricles' contractility. The parasympathetic system influences the heart through the M2 receptor and the coronary arteries through M3 receptors [3].

Both sympathetic and parasympathetic preganglionic neurons release acetylcholine (Ach) and are called cholinergic; however, their postganglionic release different neurotransmitters. Sympathetic postganglionic neurons release norepinephrine (which resembles epinephrine/adrenalin, thus referred to as adrenergic) while most parasympathetic postganglionic neurons release acetylcholine.3

### **3. Influence of ANS on electrical abnormalities in heart**

ANS abnormalities in terms of anatomy and physiology can cause various heart abnormalities. ANS abnormalities are associated with electrical abnormalities which cause heart problems. This can cause a variety of manifestations. In this section, we will discuss more the electrical abnormalities associated with ANS abnormalities in the heart.

### **3.1 Ventricular arrhythmias**

Ventricular arrhythmia remains a common cause of sudden cardiac death in myocardial infarction (MI) patients. Following a myocardial ischemic injury, sympathetic axon fibers within the scar become dysfunctional, degenerate, and die. However, contrary to the central neurons, peripheral neurons commonly regenerate back to their target, a phenomenon called nerve sprouting [4, 5]. This efferent sympathetic regeneration is triggered by nerve growth factor (NGF), which levels are found to be increased after MI, and causes hyperinnervation in the infracted are of the heart thereby promoting ventricular arrhythmia. Studies using 123I-metaiodobenzylguanidine (MIBG) have shown evidence of sympathetic reinnervation in the infracted hearts after MI. A study conducted by Cao et al. [6] demonstrated that the high density of nerve fibers was significantly higher in the peripheral to the area of necrotic tissue of failed hearts. Chen and colleagues also support this phenomenon's discovery that infusion of NGF to the stellate ganglion causes an increase of nerve density and QT interval prolongation, therefore increases and prolongs ventricular arrhythmias [4, 6–8]. Furthermore, there have been findings that demonstrate a notable decrease in parasympathetic tone in patients with comorbidities (such as coronary artery disease, MI, and diabetes) during sleep despite the unopposed sympathetic activity, creating a higher risk of ventricular arrhythmia. Another electrical phenomenon following MI that leads to ventricular arrhythmia is an occurrence of heterogeneous distribution of hyperinnervation of sympathetic nerves, particularly

in the border zone (despite the remaining viable myocardial cells), which can lead to impulses and therefore initiate tachyarrhythmia. On another note, interventions that reduce sympathetic nerve activity have been shown to reduce the risk of arrhythmias in MI patients, both in humans and animals [6]. Some therapies that are suggested to reduce the risk of ventricular arrhythmia include cervical sympathectomy and spinal cord stimulation (inhibiting cardiac sympathetic tone while enhancing parasympathetic tone). Future therapies may focus on preventing nerve sprouting by inhibiting nerve growth or attaining regional cardiac denervation by ganglia ablation [4].

### **3.2 Atrial fibrillation**

The influence of ANS on the pathogenesis of atrial fibrillation (AF) had been discovered since 1978 [3]. In the beginning, AF was thought to be a sympatheticmediated phenomenon; however, studies have shown that sympathetic and parasympathetic systems may contribute to the pathogenesis. Sympathetic-mediated arrhythmia may occur because of β-adrenergic signal pathway activation, which increases Ca2+ transient. On the other hand, parasympathetic activation through Ach stimulation on muscarinic receptors (mainly M2 in the heart) causes a shortened duration of action potential (thus increasing conduction speed) in atria, causing arrhythmias [4, 9]. Studies by Scherf et al. suggested that local application of either aconitine or Ach in the heart may lead to rapid focal firing or AF, which could be terminated by removing the focal source of firing [10, 11]. Whether an AF episode is predominately sympathetic-mediated or parasympathetic-mediated may depend on comorbidities; lone and nocturnal AF (where parasympathetic is profoundly dominant) in patients with normal hearts is usually parasympathetic-mediated whereas AF in patients with organic heart disease or disorders such as phaeochromocytoma or hyperthyroidism is usually sympathetic-mediated. In addition, parasympatheticmediated AF episodes usually occur weekly, predominantly at night, last for a few hours, and are preceded by progressive bradycardia. In contrast, sympatheticmediated AF episodes usually occur during the daytime, during exercise, or under stress. The current primary endpoint target of the ablation procedure is the pulmonary vein isolation (PVI), thereby predisposing to reentrant phenomena and high density of nerves. However, studies have demonstrated that direct stimulation to the ganglionated plexus could result in AF, whereas ablation of the corresponding plexus may reverse the alteration of conduction speed [3, 8]. Multiple clinical studies were conducted to compare whether combining ganglionated plexus (GP) ablation with PVI or PVI alone is more effective in suppressing AF, one of which is done by Katritsis et al. l who found that combination of GP ablation and PVI showed higher success compared to PVI alone [9].

### **3.3 Long QT syndrome**

Long QT syndrome (LQTS) is characterized by prolonged ventricular repolarization (prolonged QT interval), leading to polymorphic ventricular tachycardia and, therefore, risk of sudden death. It is a heterogeneous syndrome resulting from several cardiac ion channels. Arrhythmias in LQTS patients are often emotional or physical stress-related, and sympathetic activation has been suggested as an important triggering factor. However, the response to this trigger may vary depending on LQTS syndrome. For instance, LQTS type 1 has more prominent and prolonged effects from sympathetic activation than LQTS type 2 [4]. A study has been conducted by

Shamsuzzaman [12] to record sympathetic activity using muscle sympathetic nerve activity (MSNA) and skin sympathetic nerve activity (SNA). The result of the study demonstrated that in LQTS patients, the baseline of MSNA is very low and further accompanied by slower heart rates and reduced LF. In contrast, the baseline of skin SNA is normal, indicating that LQTS patients have region-specific decreased cardiac sympathetic drive. In such a setting, surges of sympathetic stimulation caused by emotional or physical stress may lead to cardiovascular events [12].

### **3.4 Brugada syndrome**

Brugada syndrome is an inherited channel disorder characterized by sodium channel abnormality (and thus ECG abnormalities) that predisposes to ventricular arrhythmias and sudden death despite structurally typical hearts [4, 13, 14]. Another exciting characteristic of Brugada syndrome is that ventricular fibrillation and sudden death mainly occur at rest or during sleep, which is the period of parasympathetic dominance. Furthermore, clinical characteristics and typical ECG changes can be variable over time and are influenced by external factors, such as exercise and pharmacological intervention. Exercise can diminish ECG signs of Brugada syndrome, while on the contrary, drugs that interact with the ANS innervation can unmask or intensify the signs. For this occurrence, studies have suggested that the ANS is involved in the natural history of the syndrome. Prior studies have shown a sympathetic-parasympathetic tone imbalance in patients with Brugada syndrome. A study by Wichter et al. demonstrated a reduced I-MIBG reuptake, either because of a reduced number or function of efferent sympathetic neurons and a reduced transporter capacity for NE reuptake, which indicated a presynaptic adrenergic dysfunction [14]. According to the authors of this study, this reduced sympathetic tone may impact protein phosphorylation and spatial calcium heterogeneity, thus leading to arrhythmias, especially in the downregulation of adrenergic activity or in parasympathetic dominance [14].
