Open access peer-reviewed chapter - ONLINE FIRST

Heart Autonomic Nervous System: Basic Science and Clinical Implications

Written By

Elvan Wiyarta and Nayla Karima

Submitted: November 20th, 2021 Reviewed: November 22nd, 2021 Published: February 10th, 2022

DOI: 10.5772/intechopen.101718

IntechOpen
Autonomic Nervous System - Special Interest Topics Edited by Theodoros Aslanidis

From the Edited Volume

Autonomic Nervous System - Special Interest Topics [Working Title]

Dr. Theodoros Aslanidis and M.Sc. Christos Nouris

Chapter metrics overview

53 Chapter Downloads

View Full Metrics

Abstract

The heart has an intrinsic conduction system that consists of specialized cells. The heart receives extensive innervation by both sympathetic and parasympathetic systems of the ANS. The ANS influences most heart functions by affecting the SA node, AV node, myocardium, and small and large vessel walls. The sympathetic system carries an excitatory effect on heart functions. Conversely, the parasympathetic system has inhibitory effects on heart functions. ANS abnormalities in terms of anatomy and physiology can cause various heart abnormalities. ANS abnormalities associated with electrical abnormalities can cause a variety of heart manifestations. Besides electrical abnormalities, ANS also correlates with ischemic heart disease. Following electrical and ischemic instability, ANS also have direct effect on action potential duration restitution. By understanding the mechanism of influence of the anatomy and physiology of the ANS heart and its influence on various heart abnormalities, we can determine the appropriate therapeutic approaches. Therapeutic approaches in neurocardiology fall into two focuses: applying novel treatment and interaction of non-drug and multiple drugs treatments.

Keywords

  • heart
  • sympathetic
  • parasympathetic
  • autonomous
  • neurology

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].

Advertisement

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, 2, 3, 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].

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

Advertisement

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-meta-iodobenzylguanidine (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, 7, 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 sympathetic-mediated 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, parasympathetic-mediated AF episodes usually occur weekly, predominantly at night, last for a few hours, and are preceded by progressive bradycardia. In contrast, sympathetic-mediated 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].

Advertisement

4. Influence of ANS in heart failure and myocardial infarction

Besides electrical abnormalities, ANS also correlates with ischemic heart disease. Following a transmural myocardial infarction (MI), sympathetic fibers within the scar become denervated and die. However, denervation also occurs in the non-infarcted sites distal to the infarction early after occlusion, resulting in a neurotransmission disruption, nerve sprouting, and denervation supersensitivity even in the viable myocardium cells. Not all sites are denervated equally, this disruption leads to a heterogeneous change of effective refractory period (ERP). Together with decreased protection from vagal denervation, this leads to ventricular arrhythmias [4].

As with heart failure, myocardial dysfunction caused by cardiac insult activates neurohormonal mechanisms, including activation of the sympathetic system and the renin-angiotensin-aldosterone system (RAAS) axis. Increased activation of the sympathetic system causes an increase in NE delivery to myocardial cells. High local catecholamine level leads to ventricular hypertrophy and increase susceptibility to arrhythmia, which worsens the heart’s function and, in turn, further increases sympathetic tone [15]. This activation is initially essential to compensate for the weakened myocardial function; however, in the long term, this activation leads to further deterioration of cardiac function, worsening heart failure, and cardiac decompensation. Besides sympathetic activation, there has been evidence of reduced parasympathetic function, which further worsens heart failure. Heart failure can also cause denervation, creating nerve sprouting and electrical remodeling, leading to ventricular arrhythmia and sudden cardiac death [4, 16].

Advertisement

5. Effect of the ANS on action potential duration restitution

Following electrical and ischemic instability, ANS also have a direct effect on action potential duration restitution. The destabilization of activation wavefronts is associated with the alteration in action potential duration (APD) resulting from the alteration of the previous diastolic interval, called restitution. Steepened APD restitution curve slope has been associated with complex, unstable dynamics, while a decrease of the steepness of the curve by drugs may suppress ventricular arrhythmia [17, 18, 19]. A study in porcine models by Taggart et al. has shown that sympathetic stimulation with adrenaline (α – and β-adrenergic agonist) steepens the APD restitution curve [20]. The same effect was confirmed in humans with normal ventricles by a more recent study using isoprenaline (β-adrenergic agonist) and adrenaline, demonstrating that both adrenaline and isoprenaline steepen the APD restitution curve at the minimum range of 40 ms. This evidence suggests a mechanism in which the sympathetic nervous system is contributed to inducing arrhythmia and ventricular fibrillation [16]. Additionally, a study conducted in an isolated rabbit heart model demonstrated that parasympathetic activation exerts a contradictory effect, reducing the steepness of the slope, thereby suppressing ventricular fibrillation [21].

Advertisement

6. Therapeutic approaches involving ANS in the heart

By understanding the mechanism of influence of the anatomy and physiology of the ANS heart and its influence on various heart abnormalities, we can determine the appropriate therapeutic approaches. Therapeutic approaches in neurocardiology fall into two focuses: (1) applying novel treatment and (2) interaction of non-drug and multiple drugs treatments. Patients with cardiomyopathy are suggested to have increased sympathetic innervation and decreased parasympathetic innervation; therefore, interventions aiming to reduce sympathetic tone and thereby increasing parasympathetic tone are beneficial to reduce the susceptibility of ventricular arrhythmia sudden cardiac death. Some options of approaches include the following options [4].

6.1 Selective sympathetic blockade

Multiple studies have shown that in patients with heart failure, pharmacologically inhibition of sympathetic activity may reduce the risk of sudden cardiac death. Current pharmacological therapies include β-blockers (β-receptor antagonist) and angiotensin-converting enzyme inhibitors (ACE-I), which are the mainstay approaches for early hypertension and other cardiovascular disease associated with dysautonomia [22]. Surgical techniques, for instance, sympathectomy, reduce the risk of comorbidities in patients with hypertension and reduce the incidence of ventricular arrhythmia [22].

6.2 Cardiac autonomics modulation therapies

Pharmacological therapies such as β-blockers, ACE-I, angiotensin receptor blockers (ARB), aldosterone antagonists, and statins are proven to decrease the risk of sudden cardiac death in patients with ischemic cardiomyopathy. In addition, these drugs also provide modulations of the ANS by decreasing sympathetic activity and increasing parasympathetic activity. Through baroreflex, Angiotensin II decreases vagal bradycardia. This effect can be reversed with ACEI and ARB by increasing parasympathetic output to the heart. In an experimental study using rat models with ischemic cardiomyopathy, aldosterone antagonist and ACEI showed a decrease of myocardial NE content, demonstrating an antisympathetic effect. Statin therapies show several mechanisms in normalizing sympathetic activity and cardiovascular reflex regulation, such as increased baroreceptor sensitivity for heart rate control, reducing angiotensin II-induced sympathetic responses, decreasing baseline of renal sympathetic activity, and downregulating mRNA and protein expression of Angiotensin II type I receptors as well as NADP oxidase subunits of the heart [4].

6.3 Resynchronization therapy

Biventricular pacing has been suggested to improve hemodynamic status in patients with intraventricular conduction delay and reduced ejection fraction and decreased sympathetic tone in patients with hypertension, thus shifting the autonomic balance of the heart to a less sympathetic more parasympathetic profile [4]. Proper cardiac resynchronization therapy (CRT), in the short term, results in left ventricular systolic function improvement and mitral regurgitation reduction, providing a more optimal ventricular filling. Over a more extended period, CRT promotes left ventricular reverse remodeling, leading to significant functional capacity, survival, and quality of life improvements [23].

6.4 Parasympathetic function mortality and cardiovascular risk

Several measurements that can be used to index parasympathetic function/activity include resting heart rate, heart rate recovery (heart rate decrease following termination of exercise), heart rate variability, and baroreflex sensitivity (the responsiveness of the cardiovascular system to blood pressure changes). Several studies have shown that reduced parasympathetic function is associated with mortality and leads to risk factors for cardiovascular diseases. Those risk factors include biological factors such as hypertension, diabetes, abnormal cholesterol; lifestyle factors such as tobacco use, physical inactivity, and overweight; and non-modifiable factors such as age and family history [4].

6.5 Vagal stimulation

Vagal nerve stimulation (VNS) is a non-pharmacological intervention to normalize autonomic imbalance, directly stimulating the vagus nerve to improve parasympathetic tone and reflex. VNS has been shown to improve left ventricular hemodynamics and increase heart rate variability. VNS also results in better vagal reflex and nitric oxide expression, improvement of the renin-angiotensin system, inflammatory cytokines modulation, reduced heart rate, risk of ventricular arrhythmias, and mortality [24]. A recent multinational, randomized clinical trial called INOVATE-HF (Increase of vagal tone in CHF) demonstrated that VNS significantly resulted in favorable effects on quality of life, NYHA functional class, and 6-min walking distance. However, the ventricular end-systolic volume index was not significantly different [25].

6.6 Renal denervation

Renal efferent signals regulate renin secretion, water and sodium retention, and intrarenal vascular distribution. Efferent signals (as a response to sensory signals from renal) activate sympathetic fibers, inhibit parasympathetic fibers, and cause a release of catecholamines, which in pathology conditions such as myocardial infarction or heart failure, can increase the risk of arrhythmia [26]. Catheter-based renal denervation (RDN) is a neuromodulation treatment that includes catheter-based ablation to the renal artery wall, thus reducing the afferent and efferent sympathetic activity in the kidney and globally [26, 27, 28]. It has been used to treat drug-resistant hypertension. However, the role of RDN has also been studied as adjunctive therapy in patients with ventricular tachycardia and heart failure. By reducing circulating catecholamines, RDN reduces the electrical heterogeneity in the scarred myocardium and border zone regions and thus decreases susceptibility to ventricular arrhythmia and sudden cardiac death [26]. RDN has also been suggested to reduce blood pressure, reduce NT-proBNP, and improve NYHA class symptoms in patients with heart failure. Therefore, RDN is suggested to be favorably impactful for hypertension, MI, and heart failure [28].

Advertisement

7. Conclusion

The heart receives extensive innervation by both sympathetic and parasympathetic systems of the ANS. The sympathetic system carries an excitatory effect on heart functions, while the parasympathetic system has inhibitory effects on heart functions. ANS abnormalities associated with electrical abnormalities can cause a variety of heart manifestations, including ventricular arrhythmias, atrial fibrillation, Long QT Syndrome, and Brugada Syndrome. Besides electrical abnormalities, ANS also correlates with ischemic heart disease. Following electrical and ischemic instability, ANS also have a direct effect on action potential duration restitution. By understanding the mechanism of influence of the anatomy and physiology of the ANS heart and its influence on various heart abnormalities, we can determine the appropriate therapeutic approaches. Therapeutic approaches in neurocardiology fall into two focuses: applying novel treatment and interaction of non-drug and multiple drugs treatments, such as selective sympathetic blockade, cardiac autonomics modulation therapies, resynchronization therapy parasympathetic function mortality and cardiovascular risk, vagal stimulation, and renal denervation.

Advertisement

Acknowledgments

No one to acknowledge.

Advertisement

Conflict of interest

The authors declare no conflict of interest.

Advertisement

Appendices and nomenclature

Acetylcholine

neurotransmitters in ANS

ANS

the autonomic nervous system consists of sympathetic and parasympathetic components

Atrial fibrillation

electrical heart abnormalities which are generally characterized by arrhythmias on electrocardiogram findings

AV block

heart abnormalities based on block of the cardiac conduction system in the AV node

AV node

heart node located at the atrioventricular junction

Bainbridge reflex

compensating reaction occurring in an increase in heart rate after an increase in cardiac preload

Baroreflex

compensating reaction occurring in an increase in heart rate after an increase in cardiac preload

Hyperinnervation

excessive innervation

Jarisch-Bezold reflex

bradycardia, hypotension, and apnea

Myocardial infarction

heart abnormalities in the form of damage to heart cells due to lack of blood supply to the cells concerned

Neurocardiology

the branch of neurology that studies the nervous system of the heart

NYHA functional class

The New York Heart Association’s (NYHA) functional classification system assists in classifying individuals with congestive heart failure based on their symptoms.

Pulmonary Vein Isolation

a treatment used to treat atrial fibrillation, an irregular heart rhythm.

SA node

a cluster of cells in the right atrium. These cells can deliver electrical impulses to the heart muscle cells, causing them to contract regularly and autonomously.

Sympathetic nerve chain

ganglionated chain from the skull base to the coccyx

Vagal nerve stimulation

refers to any procedure that stimulates the vagus nerve, whether physical or electronic.

References

  1. 1. Lemieux J, Edelman E, Strichartz G, Lilly L. Normal cardiac structure and function. In: Lilly L, editor. Pathophysiology of Heart Disease: A Collaborative Project of Medical Students and Faculty. 6th ed. Philadelphia: Wolters Kluwer; 2016. pp. 7-25
  2. 2. Gordan R, Gwathmey JK, Xie LH. Autonomic and endocrine control of cardiovascular function. World Journal of Cardiology. 2015;7(4):204-214
  3. 3. Battipaglia I, Lanza G. The autonomic nervous system of the heart. In: Slart R, Tio R, Elsinga P, Schwaiger M, editors. Autonomic Innervation of the Heart. New York: Springer; 2015. pp. 1-11
  4. 4. Asmundis C, Camp G, Brugada P. Electrophysiology and pathophysiology of the autonomic nervous system of the heart. In: Slart R, Tio R, Elsinga P, Schwaiger M, editors. Autonomic Innervation of the Heart. New York: Springer; 2015. pp. 14-56
  5. 5. Huang WA, Boyle NG, Vaseghi M. Cardiac innervation and the autonomic nervous system in sudden cardiac death. Cardiac Electrophysiology Clinics. 2017;9(4):665-679
  6. 6. Li CY, Li YG. Cardiac sympathetic nerve sprouting and susceptibility to ventricular arrhythmias after myocardial infarction. Cardiology Research and Practice. 2015;2015:698368
  7. 7. Cao JM, Fishbein MC, Han JB, Lai WW, Lai AC, Wu TJ, et al. Relationship between regional cardiac hyperinnervation and ventricular arrhythmia. Circulation. 2000;101(16):1960-1969
  8. 8. Chen PS, Chen LS, Cao JM, Sharifi B, Karagueuzian HS, Fishbein MC. Sympathetic nerve sprouting, electrical remodeling and the mechanisms of sudden cardiac death. Cardiovascular Research. 2001;50(2):409-416
  9. 9. Xi Y, Cheng J. Dysfunction of the autonomic nervous system in atrial fibrillation. Journal of Thoracic Disease. 2015;7(2):193-198
  10. 10. Scherf D, Morgenbesser LJ, Nightingale EJ, Schaeffeler KT. Further studies on mechanism of auricular fibrillation. Proceedings of the Society for Experimental Biology and Medicine. 1950;73(4):650-654
  11. 11. Scherf D. Studies on auricular tachycardia caused by aconitine administration. Proceedings of the Society for Experimental Biology and Medicine. 1947;64(2):233-239
  12. 12. Shamsuzzaman ASM, Ackerman MJ, Kara T, Lanfranchi P, Somers VK. Sympathetic nerve activity in the congenital long-QT syndrome. Circulation. 2003;107(14):1844-1847
  13. 13. Li KHC, Lee S, Yin C, Liu T, Ngarmukos T, Conte G, et al. Brugada syndrome: A comprehensive review of pathophysiological mechanisms and risk stratification strategies. International Journal of Cardiology Heart and Vasculature. 2020;26:100468
  14. 14. Wichter T, Matheja P, Eckardt L, Kies P, Schäfers K, Schulze-Bahr E, et al. Cardiac autonomic dysfunction in Brugada syndrome. Circulation. 2002;105(6):702-706
  15. 15. Goldstein DS. Neurocardiology: Therapeutic implications for cardiovascular disease. Cardiovascular Therapeutics. 2012;30(2):e89-e106
  16. 16. Kishi T. Heart failure as an autonomic nervous system dysfunction. Journal of Cardiology. 2012;59(2):117-122
  17. 17. Taggart P, Sutton P, Chalabi Z, Boyett MR, Simon R, Elliott D, et al. Effect of adrenergic stimulation on action potential duration restitution in humans. Circulation. 2003;107(2):285-289
  18. 18. Chialvo DR, Gilmour RF Jr, Jalife J. Low dimensional chaos in cardiac tissue. Nature. 1990;343(6259):653-657
  19. 19. Garfinkel A, Kim YH, Voroshilovsky O, Qu Z, Kil JR, Lee MH, et al. Preventing ventricular fibrillation by flattening cardiac restitution. Proceedings of the National Academy of Sciences of the United States of America. 2000;97(11):6061-6066
  20. 20. Taggart P, Sutton P, Lab M, Dean J, Harrison F. Interplay between adrenaline and interbeat interval on ventricular repolarisation in intact heart in vivo. Cardiovascular Research. 1990;24(11):884-895
  21. 21. Ng GA, Brack KE, Coote JH. Effects of direct sympathetic and vagus nerve stimulation on the physiology of the whole heart--a novel model of isolated Langendorff perfused rabbit heart with intact dual autonomic innervation. Experimental Physiology. 2001;86(3):319-329
  22. 22. Bardsley EN, Paterson DJ. Neurocardiac regulation: From cardiac mechanisms to novel therapeutic approaches. The Journal of Physiology. 2020;598(14):2957-2976
  23. 23. O'Brien T, Park MS, Youn JC, Chung ES. The past, present and future of cardiac resynchronization therapy. Korean Circulation Journal. 2019;49(5):384-399
  24. 24. Camm AJ, Savelieva I. Vagal nerve stimulation in heart failure. European Heart Journal. 2015;36(7):404-406
  25. 25. Gold MR, Van Veldhuisen DJ, Hauptman PJ, Borggrefe M, Kubo SH, Lieberman RA, et al. Vagus nerve stimulation for the treatment of heart failure: The INOVATE-HF trial. Journal of the American College of Cardiology. 2016;68(2):149-158
  26. 26. Bradfield JS, Vaseghi M, Shivkumar K. Renal denervation for refractory ventricular arrhythmias. Trends in Cardiovascular Medicine. 2014;24(5):206-213
  27. 27. Sharp TE 3rd, Lefer DJ. Renal denervation to treat heart failure. Annual Review of Physiology. 2021;83:39-58
  28. 28. Fudim M, Sobotka PA, Piccini JP, Patel MR. Renal denervation for patients with heart failure: Making a full circle. Circulation. Heart Failure. 2021;14(3):e008301

Written By

Elvan Wiyarta and Nayla Karima

Submitted: November 20th, 2021 Reviewed: November 22nd, 2021 Published: February 10th, 2022