THE PRESENT AND FUTURE JACC FOCUS SEMINAR Autonomic Nervous System Dysfunction JACC Focus Seminar Jeffrey J. Goldberger, MD, a Rishi Arora, MD, b Una Buckley, MD, c Kalyanam Shivkumar, MD, PHD c JACC JOURNAL CME/MOC/ECME This article has been selected as the month’s JACC CME/MOC/ECME activity, available online at http://www.acc.org/jacc-journals-cme by selecting the JACC Journals CME/MOC/ECME tab. Accreditation and Designation Statement The American College of Cardiology Foundation (ACCF) is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians. The ACCF designates this Journal-based CME activity for a maximum of 1 AMA PRA Category 1 Credit(s)Ô. Physicians should claim only the credit commensurate with the extent of their participation in the activity. Successful completion of this CME activity, which includes participa- tion in the evaluation component, enables the participant to earn up to 1 Medical Knowledge MOC point in the American Board of Internal Medicine’s (ABIM) Maintenance of Certification (MOC) program. Par- ticipants will earn MOC points equivalent to the amount of CME credits claimed for the activity. It is the CME activity provider’s responsibility to submit participant completion information to ACCME for the pur- pose of granting ABIM MOC credit. Autonomic Nervous System Dysfunction: JACC Focus Seminar will be accredited by the European Board for Accreditation in Cardiology (EBAC) for 1 hour of External CME credits. Each participant should claim only those hours of credit that have actually been spent in the educational activity. The Accreditation Council for Continuing Medical Education (ACCME) and the European Board for Accredita- tion in Cardiology (EBAC) have recognized each other’s accreditation systems as substantially equivalent. Apply for credit through the post-course evaluation. While offering the credits noted above, this program is not intended to provide extensive training or certification in the field. Method of Participation and Receipt of CME/MOC/ECME Certificate To obtain credit for JACC CME/MOC/ECME, you must: 1. Be an ACC member or JACC subscriber. 2. Carefully read the CME/MOC/ECME-designated article available on- line and in this issue of the Journal. 3. Answer the post-test questions. A passing score of at least 70% must be achieved to obtain credit. 4. Complete a brief evaluation. 5. Claim your CME/MOC/ECME credit and receive your certificate electron- ically by following the instructions given at the conclusion of the activity. CME/MOC/ECME Objective for This Article: Upon completion of this activity, the learner should be able to: 1) describe different levels of autonomic input to the heart and the types of autonomic dysfunction; 2) describe currently available techniques to assess autonomic function; and 3) describe the role of autonomic tone and/or dysfunction in cardiac arrhythmias. CME/MOC/ECME Editor Disclosure: JACC CME/MOC/ECME Editor Ragavendra R. Baliga, MD, FACC, has reported that he has no financial relationships or interests to disclose. Author Disclosures: Dr. Goldeberger is supported by the National Heart, Lung, and Blood Institute (NHLBI) (HL70179). Dr. Arora is supported by the NHLBI (HL093490). Dr. Shivkumar is supported by the NHLBI (HL084261), by NHLBI grant R01HL084261, and by National Institutes of Health grant NIHOT2OD023848. Dr. Arora holds ownership interest in Rhythm Therapeutics, Inc. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose. Medium of Participation: Print (article only); online (article and quiz). CME/MOC/ECME Term of Approval Issue Date: March 19, 2019 Expiration Date: March 18, 2020 ISSN 0735-1097/$36.00 https://doi.org/10.1016/j.jacc.2018.12.064 From the a Cardiovascular Division, Department of Medicine, University of Miami Miller School of Medicine, Miami, Florida; b Feinberg Cardiovascular Research Institute, Division of Cardiology, Department of Medicine, Northwestern University-Feinberg School of Medicine, Chicago, Illinois; and the c Cardiac Arrhythmia Center and Neurocardiology Research Center of Excellence, University of California-Los Angeles Los Angeles, California. Dr. Goldeberger is supported by the National Heart, Lung, and Blood Institute (NHLBI) (HL70179). Dr. Arora is supported by the NHLBI (HL093490). Dr. Shivkumar is supported by the NHLBI (HL084261), by NHLBI grant R01HL084261, and by National Institutes of Health grant NIHOT2OD023848. Dr. Arora holds ownership interest in Rhythm Therapeutics, Inc. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose. Manuscript received April 16, 2018; revised manuscript received December 21, 2018, accepted December 30, 2018. Listen to this manuscript’s audio summary by Editor-in-Chief Dr. Valentin Fuster on JACC.org. JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY VOL. 73, NO. 10, 2019 ª 2019 BY THE AMERICAN COLLEGE OF CARDIOLOGY FOUNDATION PUBLISHED BY ELSEVIER
Transcript
Listen to this manuscript’s
audio summary by
Editor-in-Chief
Dr. Valentin Fuster on
JACC.org.
J O U R N A L O F T H E AM E R I C A N C O L L E G E O F C A R D I O L O G Y V O L . 7 3 , N O . 1 0 , 2 0 1 9
ª 2 0 1 9 B Y T H E AM E R I C A N C O L L E G E O F C A R D I O L O G Y F O UN DA T I O N
P U B L I S H E D B Y E L S E V I E R
THE PRESENT AND FUTURE
JACC FOCUS SEMINAR
Autonomic Nervous System Dysfunction
JACC Focus Seminar
Jeffrey J. Goldberger, MD,a Rishi Arora, MD,b Una Buckley, MD,c Kalyanam Shivkumar, MD, PHDc
JACC JOURNAL CME/MOC/ECME
This article has been selected as the month’s JACC CME/MOC/ECME
activity, available online at http://www.acc.org/jacc-journals-cme by
selecting the JACC Journals CME/MOC/ECME tab.
Accreditation and Designation Statement
The American College of Cardiology Foundation (ACCF) is accredited by
the Accreditation Council for Continuing Medical Education to provide
continuing medical education for physicians.
The ACCF designates this Journal-based CME activity for a maximum
of 1 AMA PRA Category 1 Credit(s)�. Physicians should claim only the
credit commensurate with the extent of their participation in the
activity.
Successful completion of this CME activity, which includes participa-
tion in the evaluation component, enables the participant to earn up to
1 Medical Knowledge MOC point in the American Board of Internal
Medicine’s (ABIM) Maintenance of Certification (MOC) program. Par-
ticipants will earn MOC points equivalent to the amount of CME credits
claimed for the activity. It is the CME activity provider’s responsibility
to submit participant completion information to ACCME for the pur-
pose of granting ABIM MOC credit.
Autonomic Nervous System Dysfunction: JACC Focus Seminar will be
accredited by the European Board for Accreditation in Cardiology
(EBAC) for 1 hour of External CME credits. Each participant should
claim only those hours of credit that have actually been spent in the
educational activity. The Accreditation Council for Continuing
Medical Education (ACCME) and the European Board for Accredita-
tion in Cardiology (EBAC) have recognized each other’s accreditation
systems as substantially equivalent. Apply for credit through the
post-course evaluation. While offering the credits noted above, this
program is not intended to provide extensive training or certification
in the field.
ISSN 0735-1097/$36.00
From the aCardiovascular Division, Department of Medicine, University ofbFeinberg Cardiovascular Research Institute, Division of Cardiology, Departm
School of Medicine, Chicago, Illinois; and the cCardiac Arrhythmia Center a
University of California-Los Angeles Los Angeles, California. Dr. Goldeberger
Institute (NHLBI) (HL70179). Dr. Arora is supported by the NHLBI (HL09
(HL084261), by NHLBI grant R01HL084261, and by National Institutes o
ownership interest in Rhythm Therapeutics, Inc. All other authors have repo
contents of this paper to disclose.
Manuscript received April 16, 2018; revised manuscript received December 2
Method of Participation and Receipt of CME/MOC/ECME Certificate
To obtain credit for JACC CME/MOC/ECME, you must:
1. Be an ACC member or JACC subscriber.
2. Carefully read the CME/MOC/ECME-designated article available on-
line and in this issue of the Journal.
3. Answer the post-test questions. A passing score of at least 70%must be
achieved to obtain credit.
4. Complete a brief evaluation.
5. Claim your CME/MOC/ECME credit and receive your certificate electron-
ically by following the instructions given at the conclusion of the activity.
CME/MOC/ECME Objective for This Article: Uponcompletionof thisactivity,
the learner should be able to: 1) describe different levels of autonomic input
to the heart and the types of autonomic dysfunction; 2) describe currently
available techniques to assess autonomic function; and 3) describe the role
of autonomic tone and/or dysfunction in cardiac arrhythmias.
A utonomic nervous system (ANS) control ofthe heart is a dynamic process in both healthand disease. ANS dysfunction may result
from primary disorders of the autonomic nerves orsecondarily in response to cardiac (or other systemic)disease. Cardiac disease may promote both anatomic(primary) and functional (secondary) changes in car-diac autonomic function. These changes may, inturn, contribute to the progression of disease and/orbe involved in arrhythmogenesis. Beta-adrenergicblockers are the most established autonomic inter-vention associated with improved outcomes. Otherinterventions (e.g., cardiac sympathetic denervation)have shown promise for the management of refrac-tory ventricular arrhythmias (1). Much has beenlearned about the complex interactions along theneuroaxis and their role in cardiac control. What hasbeen most challenging is the development of a simplemethod of assessment of the autonomic effects on theheart and/or autonomic dysfunction. Consequently,there have been a plethora of methods that assesssome aspect of autonomic function. Although manymeasures have been shown to have some prognosticsignificance, none have been adapted or adoptedinto clinical practice. This review highlights some ofthe background and newer concepts in autonomiccontrol of the heart.
NORMAL AUTONOMIC FUNCTION
A brief description of the advances in our under-standing of the physiology of cardiac autonomiccontrol is in order to place autonomic testing and
emerging therapies in context. Autonomic control ofthe heart is achieved by afferent neural impulses thatare transmitted from the heart to the intrinsic neu-rons of the heart, to extracardiac intrathoracic ganglia(e.g., stellate ganglion), to the spinal cord, and to thebrain stem. These afferent neural signals are pro-cessed by various parts of the nervous system toregulate the cardiomotor neural output to the heartvia the sympathetic and parasympathetic nerves. It isimportant to emphasize that the anatomical nervetrunks that reach the heart, which are traditionallydescribed as the sympathetic and parasympathetictrunks, have both afferent and efferent nerve fibers.
ORGANIZATION OF CARDIAC NEURAL CONTROL.
This neuroaxis is organized as multiple levels ofintegrative centers. At the level of the heart, theintrinsic cardiac nervous system (ICNS) is a distrib-uted network system located in the cardiac gangliathat are ganglionated plexi (GPs) that exist in the fatpads around the heart, predominantly in the posteriorand superior aspects of the atria (2). These connectwith the intrathoracic extracardiac ganglia (the sym-pathetic paravertebral ganglia), the extrathoraciccardiac ganglia (the nodose, dorsal root ganglia), andthe central nervous system (3,4). At each level, thesystem has the ability to modulate cardiac activitywith efferent feedback loops (Figure 1).
Afferent neural signals are transmitted to the ICNS,the stellate ganglia, and via the dorsal root ganglia tothe spinal cord and to the nodose ganglia (Figure 2)(5,6). The efferent projections to the heart occurvia short and long feedback loops that occur at
AB BR E V I A T I O N S
AND ACRONYM S
AF = atrial fibrillation
ANS = autonomic nervous
system
BRS = baroreflex sensitivity
GP = ganglionated plexus
HRR = heart rate recovery
HRT = heart rate turbulence
HRV = heart rate variability
ICNS = intrinsic cardiac
nervous system
MI = myocardial infarction
PV = pulmonary vein
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the central nervous system, the spinal cord (inter-mediolateral columns), the intrathoracic ganglia, andthe ICNS. Sensory neurites associated with the ICNSare found in areas of the atrioventricular junction andthe adventitia of major vessels (e.g., coronary ar-teries). It was previously believed that the differentlevels within the ANS were just relay stations, but it isnow well-established that each level processes neuralinformation and coordinates a response by commu-nicating with other levels by these feedback loops(Figure 2).
The ICNS consists of ganglia composed of afferent,efferent, and interconnecting neurons to other car-diac ganglia. These ganglia coordinate the sympa-thetic and parasympathetic inputs received from therest of the cardiac ANS. The ICNS has regional controlover different cardiac functions, such as sinus nodeelectrical activation and propagation, as well asatrioventricular nodal conduction (7,8). Emergingtherapies that target these structures have shown theimportance of emerging research in this area.Sympathet ic af ferents and efferents . The sym-pathetic neurons that regulate cardiac functionare located in the stellate ganglion. It receivespre-ganglionic sympathetic input from the inter-mediolateral column (and other spinal neurons) andcoordinates efferent neural responses either directlyor via the ansa subclavia to the middle cervicalganglia to the heart (9–12). Efferent post-ganglionicfibers travel alongside the coronary vasculature topenetrate the epicardial regions and travel toward theendocardium. Stimulation of the stellate ganglionresults in an increase in dromotropy, chronotropy,lusitropy, and inotropy (13). Cardiac afferent neuronsare mechanosensory, chemosensory, or multimodalin nature (4). They transduce a variety of chemicals,including various neuropeptides, such as substanceP, bradykinin, and calcitonin gene�related peptide.These cardiac afferents are also involved in initiatinglocal inflammatory and vascular reactions that mayplay an important role in cardiac remodeling (14).
The sympathetic nerve fibers are located in theatria and the ventricles. There is a regional responseto the right sympathetic paravertebral ganglia versusthe left sympathetic paravertebral ganglia, withpredominant effects on the anterior and posteriorventricular walls, respectively (15). In addition toincreased sinoatrial node firing and enhancement ofatrioventricular nodal conduction, sympatheticoutput results in ventricular action potential durationshortening (16).Parasympathet i c a f ferents and efferents . Theparasympathetic nervous system also has importantafferent and efferent components (Figures 1 and 2).
The cardiomotor function of this systemhelps slow the heart rate, reduce blood pres-sure, and balances the system to ensure thereis a counterbalance to sympathoexcitation.The parasympathetic effects are coordinatedvia the cervical vagus nerve, which dividesinto the superior and inferior cardiac nervesto finally enter the heart via the cardiacplexus. The parasympathetic nerve fibers aremuch more heterogeneously distributed,with significant innervation of the sinoatrialnode, atrioventricular node (7), and the ven-tricles (17).
The parasympathetic cardiomotor responseis coordinated by neurons in the ICNS that
receive pre-ganglionic parasympathetic input fromthe cervical vagus and provide a homogeneous or co-ordinated response to the atria and ventricles (18,19).Cervical vagus stimulation can produce different re-sponses depending on what aspect of the neuroaxis isengaged. In the intact state, stimulation can resultin both direct and reactive, or reflex initiated re-sponses on the intrinsic cardiac nervous system as aresult of central and peripheral interactions initiatedthroughout the cardiac neuronal hierarchy. Low-levelstimulation delivered to the cervical vagus can resultin tachycardia, probably as a result of engaging cardiacafferent fibers, whereas higher level stimulation re-sults in bradycardia (20). In the resting state, the car-diac ANS is an intricate balance between sympatheticand parasympathetic inputs. Once the cervical vagusis transected from the central nervous system, there isa significant increase in heart rate that suggests thatthe central cholinergic neuronal drive plays a consid-erable role in controlling the basal heart rate (20).Integrat ion of card iac and vascu la r a fferents .Another important afferent control system includesthe baroreceptors, which are stretch receptorsembedded in the adventitia of the aortic wall andcarotid sinus that transduce pressure fluctuations tothe cardiovascular neural reflex pathways responsiblefor heart rate and blood pressure. There is a contin-uous strip of mechanosensory neurites along the in-ner aortic arch (21). They are believed to transducecombined mechanosensory information that mea-sures distortion from pulsatile waves in the aorta inspace and time. The arterial chemoreceptors are inthe carotid arteries, aortic bodies, and medulla, andrespond to hypoxemia and hypercapnia, respectively.The aortic arch mechanoreceptors can be found in thenodose ganglion, whereas some of the carotid sinusafferents are found in the petrosal ganglia. These re-ceptors then transmit information to the nucleus ofthe tractus solitarius, which modulates sympathetic
FIGURE 1 Autonomic Neural Control of the Heart
Autonomic neural control of the heart. Modified with permission from Shivkumar et al. (4). DRG¼ dorsal root ganglion; ICNS¼ intrinsic nervous system; SG¼ stellate ganglion.
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FIGURE 2 Functional Organization of Cardiac Neural Control
The shaded areas (yellow ¼ sympathetic fibers, grey ¼ parasympathetic fibers [vagal trunk]) roughly correspond to the anatomical sympathetic and parasympathetic
nerve fibers that are seen macroscopically. The afferent neural fibers run along with nerves anatomically referred to as sympathetic and parasympathetic trunks.
Modified with permission from Shivkumar et al. (4). Aff ¼ afferent; LCN ¼ local circuit neuron; other abbreviation as Figure 1.
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and parasympathetic output to the cardiovascularsystem.
Finally, the regulation of the cardiac ANS is alsounder central nervous system control. The balance ofactivation and inhibitory neurons is finely tuned andis designed to provide dynamic control of the heartunder a range of physiological conditions rangingfrom rest to severe exertion. This exquisite multilevelneural network is profoundly altered in the presenceof cardiac dysfunction and leads to progression ofheart disease (22).
AUTONOMIC DYSFUNCTION AND ITS ROLE IN
CARDIOVASCULAR DISEASE. Autonomic dysfunc-tion may arise from 2 mechanisms—intrinsic orextrinsic. Intrinsic autonomic dysfunction arises from
diseases that directly affect the autonomic nerves,such as diabetes mellitus and the various syndromesof primary autonomic failure. Extrinsic autonomicdysfunction reflects the changes in autonomic func-tion that are secondarily induced by cardiac or otherdisease. Cardiac diseases, such as myocardial infarc-tion (MI), can also primarily disrupt the autonomicnerves.
PRIMARY AUTONOMIC DYSFUNCTION. Pr imaryautonomic dysfunct ion resu l t ing from diabet i cneuropathy . Diabetes mellitus is associated withthe development of both peripheral and autonomicneuropathy. Because of its widespread prevalence,diabetes is the leading cause of primary autonomicdysfunction. Pathological studies have noted loss of
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and/or damage to myelinated vagus nerve axons (23–25). Although findings in the sympathetic nerves andganglia have been disputed (26), they include giantnerve cells, vacuolization, and neuroaxonal dystrophy(24,26,27). Appenzeller and Richardson (27) noted ab-normalities in 4 of 5 patients with diabetes with neu-ropathy and in 0 of 4 patients without neuropathy.These studies showed significant pathological changesin the autonomic nerves of patients with diabetes whopredominantly had advanced disease and peripheralneuropathy. The pathological basis of early diabeticautonomic neuropathy has not been elucidated.Numerous biochemical mechanisms for hyperglyce-mic injury have been implicated, including the pro-duction of advanced glycosylation end products,hyperglycemic activation of the polyol pathway, aswell as protein kinase C, immunological processes,and neurovascular insufficiency that leads to localischemia. The proposed mechanisms come largelyfrom research on somatic nerves in experimental dia-betic animal models. Although biochemically diverse,the various degenerative mechanisms have a commonpredisposition for distal axon terminals. The patho-genesis of diabetic cardiac autonomic neuropathyin vivo is likely to be heterogeneous and results fromthe interaction of multiple pathways (26,28–30).Because the vagus nerve is the longest autonomicnerve in the body, abnormalities in parasympatheticinnervation of the heart are typically the earliestmanifestation of cardiac autonomic neuropathy (31).
The prevalence of cardiac autonomic neuropathy inpatients with diabetes varies widely depending on thecohort studied and the tests and/or criteria used forassessment, but approximately 15% to 20% ofasymptomatic people with diabetes appear to haveabnormal cardiovascular autonomic function (28,32–34).Only later stages of the disease are associated withsymptoms. Autonomic abnormalities may even bedetected before the onset of diabetes (35–37). Earlyevidence of cardiac autonomic neuropathy can bedetected in children with type 1 diabetes (38). Manymethods are used to diagnose cardiac autonomicneuropathy. Because the heart rate is easily measuredand responds to autonomic stimuli (39), noninvasivestudies to assess cardiac autonomic neuropathy focusprimarily on heart rate or heart rate responses tophysiological manipulations. Cardiac autonomicneuropathy has been diagnosed based on abnormal-ities in heart rate variability (HRV), baroreflex sensi-tivity (BRS), Ewing’s tests (heart rate and/or bloodpressure responses to deep breathing, standing, Val-salva maneuver, and handgrip), and heart rate recov-ery (HRR) (40–44). These parameters are not highlycorrelated with each other (45,46), which presents a
unique challenge in the diagnostic approach to thisentity. Although cardiac autonomic reflex tests(Ewing’s tests) are generally recommended for diag-nosis (47), it is unclear which method, if any, ispreferred. It is also unclear how often any assessmentfor cardiac autonomic neuropathy is performed.
The presence of cardiac autonomic neuropathyconfers an adverse prognosis (48). In a meta-analysisof 15 studies among subjects with diabetes mellitus(49), the pooled relative risk for mortality related tocardiac autonomic neuropathy was 3.45 (95% confi-dence interval: 2.66 to 4.47; p < 0.001). The mecha-nism for the increased mortality has not beenclarified, but various possibilities have been pro-posed, including QT interval prolongation (50–54),renal disease (55–57), and asymptomatic myocardialischemia (28,56,58). Some of these potential mecha-nisms may arise directly from the primary distur-bance of cardiac autonomic function.Other primary disorders of autonomic dysfunction. Otherprimary disorders of autonomic dysfunction and/orfailure include a range of disorders—pure autonomicfailure, idiopathic orthostatic hypotension, Parkin-son’s disease with autonomic failure, and multiplesystem atrophy (59). These disorders are character-ized by orthostatic hypotension in combination withother manifestations. Postural orthostatic tachy-cardia syndrome is a complex syndrome with a majorautonomic component. An autoimmune etiology thattargets ganglionic receptors (nicotinic acetylcholinereceptors) may be the underlying etiology for some ofthese disorders (60). Extensive pathological studieshave not been reported, but in autonomic failure,Lewy bodies (abnormal protein aggregates) havebeen identified in the sympathetic ganglia (61,62).These disorders are discussed in further detail inother studies (63,64).
AUTONOMIC DYSFUNCTION SECONDARY TO MI,
CARDIOMYOPATHY, AND HEART FAILURE, AND ITS ROLE
IN THE GENESIS OF VENTRICULAR ARRHYTHMIAS. Incontrast to disorders that primarily affect the auto-nomic nerves, a variety of cardiac pathologies, suchas MI, heart failure, and cardiomyopathy result insecondary acute and chronic changes within the ANS(65). Direct ischemic damage to cardiac autonomicnerves may result from acute MI (66). In addition, thecardiac ANS responds acutely to preserve homeosta-sis. This may involve increased sympathetic anddecreased parasympathetic activity to maintain car-diac contractility and cardiac output in the setting ofa major insult. Hemodynamic changes that occur as aconsequence of these conditions cause a cascadeof changes in neurohumoral activity in the
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cardiovascular, peripheral vascular, and renalvascular systems. The problem arises when the im-mediate threat has abated, but the imbalance in theANS, driven by altered afferent signaling, persists andis further modulated by cytokines generated as aresponse to the disease state (65). This can lead to avicious cycle, with MI, cardiomyopathy, and heartfailure leading to an outpouring of catecholamines(and inflammatory cytokines), and the catechol-amines, in turn, lead to worsening of cardiomyopa-thy. This cycle of adrenergic activation and cardiacdysfunction has been well established in congestiveheart failure with reduced ejection fraction. Themarked benefit of beta-adrenergic blockers in this en-tity, which improve both ejection fraction and out-comes, is a testament to the critical role of thesecondary changes in the ANS in this disease state andreversibility of congestive heart failure with treatment.
Persistent maladaptations within the ANS as aresult of cardiac dysfunction have been linked toatrial and ventricular arrhythmias (4). These changesresult in a functional reorganization of the ANS andalterations in neural processing at each level of thecardiac neural hierarchy, which leads to a conflictbetween the central (central nervous system) andperipheral (intrathoracic cardiac ganglia) control.Cardiac dysfunction can cause short- and long-termchanges in the neural networks, which results inexaggerated reflex responses. Central sensitizationof neurons can occur secondarily to constantafferent signaling from the site of injury, such as theinfarct zone, which can elicit a cellular processthat changes the excitability of cell membranesand reduces the inhibitory mechanisms within thenervous system (67).
Morphological changes seen in the stellate gan-glion secondarily to ischemic and nonischemic car-diomyopathy include neuronal enlargement (68), aswell as alterations in neurochemical expression pat-terns in the stellate (69). Other changes such as nervesprouting around the border zones or periphery of anischemic territory also occur (70). Regional adrenergicoverexpression with functional denervation may beseen in the border zone after MI in animal models (71)and humans with ischemic cardiomyopathy (72).Clinically, it is well appreciated that excess adren-ergic activity is a negative prognostic indicator post-MI and in congestive cardiac failure. This forms thebasis for the success of beta-blocker therapy in theseconditions.
There is neuronal enlargement within the stellateganglion in both the right and left stellate ganglion,regardless of the territory of the MI (73). This is incontrast to the ICNS, where there are regional
changes as a result of MI (74). The afferent ICneuronal activity is attenuated in the territory of theMI, whereas those IC neurons in remote regions arepreserved. As such, this creates a heterogenousneural response within the myocardium (74). Thissuggests that the ICNS receives and coordinates theinformation that is transmitted to the intrathoracicand extrathoracic ganglia. In relation to otherganglionic changes seen as a result of MI, the dorsalroot ganglia appear not to change morphologically,but they do have a significant change in neurochem-ical properties of the neurons present (increasedneuronal nitric oxide synthase and calcitonin gene-related peptide) (69). Alterations in neurohumoralcontrol, circulating catecholamines, and the renin-angiotensin-aldosterone system also occur as aresult of cardiac injury.
Ventricular arrhythmias that occur in the setting ofischemic and nonischemic cardiomyopathy may beprecipitated as a result of sympathetic overactivity.These occur as a result of an excessive sympatho-neurohumoral response and a reduced para-sympathetic input that results in increased dispersionof electrical activation and repolarization in the ven-tricles from the endocardium to epicardium. In recentyears, neuromodulation, with the goal of increasingparasympathetic tone and suppressing sympathetictone, has become an emerging therapeutic strategyfor the treatment of ventricular arrhythmias.Emerging therapeutic approaches include left cardiacsympathetic denervation, cervical vagal stimulation,and spinal cord stimulation (75). Removal of sympa-thetic efferent input to the heart by surgical resectionor thoracic epidural anesthesia of the stellate gan-glion to T4 can significantly reduce ventricular ar-rhythmias in the setting of a severe life-threateningventricular electrical storm. Although animal studieshave clearly shown that vagal nerve stimulation cansuppress ventricular arrhythmias in heart failure,vagal stimulation has only been used in patients withheart failure in an attempt to improve cardiacremodeling and heart failure (76,75). Similarly, spinalcord stimulation has been shown to be improvesymptoms, functional status, and left ventricularfunction and remodeling in patients with severesymptomatic heart failure (77); however, spinal cordstimulation has not been systematically evaluatedfor its antiarrhythmic benefits in clinical studies.
Despite the potential success of neuromodulationin pre-clinical or clinical studies in preventing ven-tricular arrhythmias, it is important to remember thatcardiac dysfunction results in adverse adaptions ofthe afferent and efferent inputs at various levelsthroughout the cardiac neuroaxis. These adaptions
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may perpetuate cardiac dysfunction and are generallypro-arrhythmic. Further in-depth mechanistic un-derstanding is required to improve the sophisticationof these therapies.ROLE OF AUTONOMIC DYSFUNCTION IN CREATING A
VULNERABLE SUBSTRATE FOR ATRIAL FIBRILLATION.
Atrial fibrillation (AF) is the most common sustainedarrhythmia disturbance and is associated with sig-nificant morbidity and mortality. The morbidity andmortality associated with AF are especially increasedin the setting of congestive heart failure, with up toone-half of all patients with heart failure havingconcomitant AF (78). Several mechanisms contributeto the electrophysiological and structural substratefor AF, including fibrosis, stretch, oxidative stress,and altered calcium handling characteristics (79). TheANS has been hypothesized to have a likely role increation of a vulnerable AF substrate (80), with bothsympathetic and parasympathetic nerves believed tobe involved in the genesis of AF (81,82). Armour et al.(2) demonstrated an intricate pattern of autonomicinnervation in the heart with the atria being inner-vated by at least 5 major atrial fad pads or GPs (80).Direct nerve recordings from the stellate ganglia,vagus nerve, and the cardiac GPs also demonstrateda dynamic interaction between the sympatheticand parasympathetic nervous system in creating AF(83–86). Hou et al. (87,88) suggested the presence ofan intricate, interconnecting neural network in theleft atrium that could contribute to a substrate for AF.
Over the last several years, the pulmonary veins(PVs) and adjoining posterior left atrium have beenshown to play a significant role in the genesis of AF,with this region demonstrating unique structural,molecular, and electrophysiological characteristicsthat appear to contribute to the AF substrate.Anatomical and physiological studies of the auto-nomic innervation of the atria indicate that the pul-monary veins and posterior left atria have a uniqueautonomic profile (86,89–91). Chevalier et al. (92)described several gradients of innervation in andaround the PVs (92). In a canine study, Arora et al.(93) showed that the posterior left atrium was morerichly innervated than the rest of the left atrium, withnerve bundles containing both parasympathetic andsympathetic fibers, with parasympathetic fibers pre-dominating over sympathetic fibers. These caninestudies were in agreement with human studies thatdemonstrated co-localization of sympathetic andparasympathetic nerve fibers in the human leftatrium (80,94). Deneke et al. (95) also demonstratedco-localization of sympathetic and parasympatheticnerves, with patients in persistent AF that demon-strated a shift toward a lower density of cholinergic
nerves and a higher density of adrenergic nerves.There was evidence of sympathetic hyperinnervationin patients with persistent AF (96).
Using direct nerve recordings from the stellateganglia and the vagus nerve in a canine study, Ogawaet al. (86) showed increased sympathetic and vagalnerve discharge before the onset of atrial arrhythmiasin pacing-induced heart failure [these atrial arrhyth-mias were preventable by prophylactic ablation of thestellate ganglion and the T2 to T4 thoracic sympa-thetic ganglia (85)]. In a canine HF model, Ng et al.(78) demonstrated a profound increase in para-sympathetic—and to a lesser extent sympathetic—nerves in the left atrium (78), with nerve growth be-ing most pronounced in the PVs and posterior leftatrium. The increase in vagal innervation noted inthis model was believed to contribute to the AF sub-strate by affecting conduction characteristics of thePVs and posterior left atrium.
Taken together, the previous studies indicated animportant role for the ANS in the genesis of AF notonly in normal hearts, but also in structural heartdisease. These data underscore the potential impor-tance of the ANS as a suitable therapeutic target inAF. A variety of strategies targeting $1 GPs eithersurgically (97,98) or through a transvenous, endo-cardial approach (alone or together with PV isolation)have been used in patients with both paroxysmal andpersistent AF with variable success (99–101). Scana-vacca et al. (102) demonstrated the feasibility of se-lective atrial vagal denervation, as guided by evokedvagal reflexes, to treat patients with paroxysmal AF.Pokushalov et al. (103) reported that regional ablationat the anatomic sites of the left atrial GP could besafely performed and enabled maintenance of sinusrhythm in 71% of patients with paroxysmal AF. Kar-itsis et al (104) and others (105) demonstrated thatwhen GP ablation was combined with PV isolation, ityielded better results than PV isolation alone, withsuccess rates approaching 80% (104). Recent surgicalstudies also attempted to add GP ablation and/orexcision to PV isolation with varying efficacy(97,98,106,107). The efficacy and durability of thisapproach has not been established.
Renal denervation, which is known to lead to areduction of renal norepinephrine spillover (108) anda reduction in firing of single sympathetic vasocon-strictor fibers (a measure of central sympathetic nerveoutflow) (109), has been shown to reduce atrial sym-pathetic nerve sprouting, structural alterations,and AF complexity in goats with persistent AF,independent of changes in blood pressure (110).Early stage clinical data suggests that renal denerva-tion may improve the results of pulmonary vein
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isolation in patients with persistent AF and/or severeresistant hypertension (111). However, the SymplicityHTN-3 trial did not demonstrate efficacy of renaldenervation in reducing blood pressure in patientswith resistant hypertension (112). Its role as apotential therapeutic tool in AF has not beenestablished.
Recent approaches attempted to disrupt auto-nomic signaling by using novel pharmacological andbiological methods. Pokushalov et al. (113,114) re-ported that injection of botulinum toxin in the GPs atthe time of open-heart surgery led to a decrease in theincidence of post-operative AF, as well as a decreaseof AF burden at 1 year of follow-up. The clinicalusefulness of this approach was not established. Inanimal studies, Aistrup et al. (115) showed that para-sympathetic signaling in the atrium could be selec-tively disrupted by using G-protein inhibitorypeptides targeting the C-terminus of the Gai/o sub-units, with the peptides injected either directly (115)or as plasmid expression vectors to obtain constitu-tive administration of Gai2ctp and Gao1ctp (116). Inongoing preclinical studies, the same group of in-vestigators is actively exploring the efficacy andduration of expression of genes targeting the ANS incanine models of chronic AF.
ASSESSMENT OF CARDIAC
AUTONOMIC FUNCTION
Assessment of normal and abnormal autonomicfunction is challenging because of the proliferation oftechniques to assess cardiac autonomic function.Furthermore, most of the techniques currentlyavailable to assess autonomic function—whetherdirect nerve recordings or indirect assessments ofautonomic activity by HRV, heart rate turbulence(HRT), and so on—are difficult to use and reliablyinterpret in day-to-day clinical practice. Nonetheless,a brief review is presented to provide a historicalperspective on how autonomic testing in cardiovas-cular disease has evolved over the years. This reviewlargely focuses on the most widely used heartrate�based tests (HRV, HRT, BRS, HRR, and QT-RRslope), with a secondary emphasis on direct nerverecording techniques. Less widely used imaging-based techniques (sympathetic imaging with meta-iodobenzylguanidine, C-meta-hydroxyephedrine)will not be discussed here. There are many heartrate�based tests, but the core of these involve eval-uation of heart rate or heart rate changes. It is criticalto note that these heart rate evaluations largely relyon how autonomic input affects the sinus node.However, regional autonomic effects on the sinus
node, atrium, atrioventricular node, and ventriclesdiffer in normal subjects and may be even moreaccentuated in the presence of cardiac disease withregional abnormalities in innervation and ganglionicfunction. How closely abnormalities in sinus nodeautonomic function parallel abnormalities in otherareas of the heart may depend on regional differencesin innervation, interruption of feedback loops, andthe underlying disease state. This conundrum ex-tends to the prognostic significance of the heartrate�based measures. For example, although sym-pathoexcitation has been considered to be an impor-tant component in the pathogenesis of life-threatening ventricular arrhythmias, a meta-analysisof predictors of sudden cardiac death andarrhythmic events in patients with nonischemicdilated cardiomyopathy noted that HRV, BRS, or HRT,which are all tests that focus on autonomic effects onthe sinus node, were not significant predictors ofventricular arrhythmic events (117).
Heart rate can be evaluated under resting andsteady state, conditions in which parasympatheticeffects normally predominate. This manifests as res-piratory sinus arrhythmia, the “high-frequency” os-cillations of the heart rate that are noted at therespiratory frequency due to inspiratory suppressionof vagal nerve discharges. Next, the responsiveness ofthe sinus node to small perturbations from the steadystate and resting hemodynamic status can beassessed. Tests such as BRS and HRT evaluate theheart rate response to an acute increase in bloodpressure and premature ventricular beats, respec-tively. Finally, larger perturbations in autonomic ac-tivity can be provoked with exercise. Both theacceleration of heart rate with exercise and the HRRafter cessation of exercise have been studied. Thespectrum of evaluation from steady state to mildperturbations from steady state to the large changesnoted with exercise provides different assessments ofautonomic function, likely related to the differentmultilevel feedback loops that may be engaged ineach condition.HEART RATE VARIABILITY. HRV represents a mea-sure of the oscillation in the intervals betweenconsecutive heart beats. The most common methodsfor measuring the variation in heart rate can bebroadly categorized into either time- or frequency-domain analyses. Various nonlinear analyses havealso been proposed. Time-domain measures of HRV,such as the SD of normal RR intervals, the root meansquare of successive RR interval differences, and thepercentage of normal RR intervals that differ by>50 ms, are calculated based on statistical and/ormathematical operations on RR intervals (118).
FIGURE 3 Diagram of the QT-RR Relationship
RR Interval (ms)
370
390
350
270
290
330
310
400 450 500 550 600 650 700 750
β-blockade
Doubleblockade
BaselineAtropine
QT In
terv
al (m
s)
The QT-RR relationship in the early post-exercise recovery period without autonomic
blockade (baseline [orange]), with beta-blockade (green), with parasympathetic
blockade (atropine [grey]), and double blockade with propranolol and atropine (blue).
Original data from Sundaram et al. (160).
TABLE 1 Common Ca
Conditions
Myocardial infarction
Congestive heart failur
Hypertension
Atrial fibrillation
Long QT syndrome
Neurocardiogenicsyncope
Postural orthostatictachycardiasyndrome
Diabetic cardiacautonomicneuropathy
AF ¼ atrial fibrillation.
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Frequency-domain measures use spectral analysis ofa sequence of RR intervals and provide informationon how power (variance) is distributed as a functionof frequency (39), using either short- (2 to 5 min) orlong-term (24 h) recordings.
Respiratory sinus arrhythmia is a reflection ofthe oscillatory parasympathetic effects on thesinus node related to the respiratory cycle (119,120),which yields the high-frequency component of HRV.
rdiovascular Conditions Linked to the Autonomic Nervous System
Abnormalities in autonomic function tests involvingparasympathetic and sympathetic reflexes
þþþþ
The low-frequency and very–low-frequency compo-nents of HRV have a more complex physiology thatintegrates both sympathetic and parasympatheticactivities. More specifically, the absolute andnormalized low-frequency powers are influenced bysympathetic modulation of the heart rate (121). Up-right tilt-table testing increases sympathetic tone(39); the low frequency and the low-frequency/high-frequency ratio (122) increase with upright tilt, andbeta-blockade blunts these changes. Although thelow-frequency/high-frequency ratio is often consid-ered an index of sympathovagal balance (123,124), theRR interval may actually be a more precise index ofthe net effect of sympathetic and parasympatheticeffects on the sinus node (125) than the time- orfrequency-domain HRV parameters. Fluctuations inthe renin-angiotensin-aldosterone system and varia-tions in thermoregulatory mechanisms have beenspeculated to underlie the very–low-frequencycomponent. In long-term recordings, the physiolog-ical basis for ultralow frequency oscillations has notbeen well defined (126).
Nonlinear analysis techniques have been appliedto further characterize HRV (127,128). A variety ofanalysis techniques and parameters have been usedto measure nonlinear properties of HRV. Analysis of1/f characteristics (i.e., the inverse power–law slope),which describes the slope of the spectral powers inthe ultra-low and very–low-frequency areas has pro-vided prognostic information beyond the traditionalHRV measures (129). None of these techniques havebecome widely used. Importantly, autonomicblockade markedly attenuates all HRV, regardless ofthe measure, providing further evidence of thecomplexity of the various different approaches toassess autonomic effects on the sinus node.
Diminished HRV has been associated with bothsudden cardiac death and nonsudden death in MI andin chronic left ventricular dysfunction, independentof the left ventricular ejection fraction (130–132).Large epidemiological studies have also demon-strated the prognostic significance of diminishedHRV in the general population (133–135). At present,however, measures of HRV by themselves do notprovide adequate refinement of risk of sudden car-diac death due to ventricular tachyarrhythmias.Furthermore, the pathophysiological link betweenreduced HRV and increased mortality is unclear.Although HRV provides a measure of autonomicmodulation, it has not entered the realm of clinicalevaluation even after many decades of study.BAROREFLEX SENSITIVITY. BRS refers to the reflexbradycardia that accompanies a transient increase insystemic blood pressure, and, as such, reflects
CENTRAL ILLUSTRATION Autonomic Nervous System Dysfunction
Goldberger, J.J. et al. J Am Coll Cardiol. 2019;73(10):1189–206.
The complex autonomic changes that may occur secondary to acute myocardial infarction. There is regional denervation in the ischemic zones. Nerve sprouting may
then appear at the border zone. Nerve growth factors and cytokines may also induce remodeling at the stellate ganglion. Afferent and efferent feedback loops to the
brainstem and higher brain centers may modulate the effects of these changes. Stimuli, such as heart failure, will enhance sympathoexcitation and act upon this altered
autonomic substrate. These effects may serve to further enhance heart failure or promote arrhythmias that may be responsible for sudden cardiac death.
DADs ¼ delayed afterdepolarizations; EADs ¼ early afterdepolarizations; NE ¼ norepinephrine; NGF ¼ nerve growth factor; VT/VF ¼ ventricular tachycardia/
ventricular fibrillation.
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intrinsic properties of arterial baroreceptors, but isalso attenuated by afferent cardiac sympatheticstimulation (136). BRS is typically measured after achange in blood pressure has been provoked. This isclassically done by acute administration of phenyl-ephrine (137). From the simultaneous record of RRintervals and blood pressure, BRS is calculated as theslope of the regression line (to assess the dependencyof RR intervals on systolic blood pressure values). As
a result, the greater the slope of the regression line,the stronger the baroreflex.
BRS can also be determined by using neckchamber devices that help activate and/or deactivatecarotid baroreceptors by applying positive pressureor suction to the neck (121). An increase in thepressure around the neck is perceived by the baro-receptors as a decrease in the arterial pressure,whereas neck suction stimulates an increase in
TABLE 2 Noninvasive Tests of Cardiac Autonomic Function
Test Physiological Information Clinical Usefulness
Heart rate Net autonomic effect on the sinus node þþHeart rate variability Autonomic modulation of sinus node —
Heart rate recovery Parasympathetic reactivation aftercessation of exercise
—
Baroreflex sensitivity Sinus node response to baroreceptoractivation
—
Heart rate turbulence Sinus node response to hemodynamicperturbation by a PVC
—
Autonomic reflex testing(Ewing’s maneuvers)
Sinus node response to breathingmaneuvers, Valsalva, tilt, handgrip
Total body spillover to blood/urine þþþ(pheochromocytoma)
Cardiac sympathetic imaging Sympathetic nerve distribution andfunction
—
PVC ¼ premature ventricular complex.
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blood pressure. Neck suction is typically bettertolerated and is therefore more commonly used.Using this method, BRS is typically quantified bythe maximum RR interval lengthening taken fromrepeated applications.
Spontaneous fluctuations in arterial pressure andRR interval may also be assessed to determine BRS.This is most often done by assessing the coherence ofthe power spectra of simultaneously recorded RR andblood pressure modulations. The coherence betweenthe power spectra is usually estimated in the low-frequency band and less often in the high-frequencyband (121).
Animal studies suggest that diminished BRS afterMI denotes an increased risk of ventricular fibrillation(138). Depressed BRS assessed by the phenylephrinemethod was found to be a significant predictor of5-year mortality in survivors of acute MI with pre-served ventricular function (139). However, data inhumans after MI are more conflicting (140,141). In theMarburg Cardiomyopathy Study, BRS did not appearto be helpful for arrhythmia risk stratification forpatients with idiopathic cardiomyopathy (142).
HEART RATE TURBULENCE. In 1999, Schmidt et al.described HRT that was manifested by short-termheart rate changes induced by a premature ventricu-lar beat (143). In healthy subjects, a ventricularpremature beat provokes an early acceleration fol-lowed by a late deceleration of heart rate, whereas insubjects with cardiac dysfunction, such a reaction isdiminished or even completely nonexistent. Basedon data from experimental and clinical studies,HRT is most likely mediated via the baroreceptorreflex; however, other mechanisms such as post-extrasystolic potentiation have been proposed (144–146). A premature ventricular ectopic beat results in
a transient drop in blood pressure that results inbaroreceptor activation and immediate vagal inhibi-tion, and therefore, an increase in heart rate.Augmented myocardial contractility followinga ventricular premature beat and the subsequentincrease in blood pressure lead to an opposite reac-tion with a subsequent decrease in sinus node activ-ity; thus, the biphasic HRT curve of acceleration anddeceleration is created (144).
Several large population studies have shown thatdecreased (or abnormal) HRT identifies patients athigh risk of mortality, including sudden death (147).HRT is represented by 2 numeric descriptors (144):turbulence onset, which reflects the initial accelera-tion of heart rate after a ventricular premature beat;and turbulence slope, which describes subsequentdeceleration of heart rate following a ventricularpremature beat. La Rovere et al. (148) studied therelationship between HRT and BRS in 157 heartfailure patients in whom Holter-derived HRT andphenylephrine-induced BRS were evaluated. Bothturbulence onset and turbulence slope significantlycorrelated with phenylephrine-derived BRS. Thesefindings strongly support the concept that HRT ismediated by the baroreflex response. HRT was eval-uated in 577 survivors of acute MI in the MulticenterPostinfarction Program and in 614 post-MI patientsrandomized to the placebo arm in the EMIAT (Euro-pean Myocardial Infarction Amiodarone Trial).Diminished HRT was a significant predictor of all-cause mortality (143). In contrast, HRT was not asso-ciated with a significant reduction in all-cause mor-tality in the MADIT-II (Multicenter AutomaticDefibrillator Implantation Trial II) (149).HEART RATE RECOVERY. During exercise, there is awell-described increase in sympathetic activity andwithdrawal of parasympathetic activity (150,151).During recovery from exercise, there is an initiallyrapid and then gradual return of heart rate to itsprevious resting level. The dynamic range of changesin sympathetic and parasympathetic activity relatedto exercise are greater than those assessed with HRV,BRS, or HRT. HRR after exercise reflects the sympa-thetic withdrawal and parasympathetic reactivationthat occurs. Although some earlier studies (152) sug-gested that sympathetic withdrawal is the majorautonomic limb contributing to HRR soon after peakexercise cessation (with parasympathetic activationcontributing later in recovery), more recent studiesindicated that parasympathetic reactivation was thekey factor in early HRR (153). Kannankeril et al. (154)studied heart rate and HRR in healthy individualsduring peak exercise and recovery under normalphysiological conditions, as well as during selective
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parasympathetic blockade with atropine. They notedthat even during peak exercise, parasympatheticwithdrawal was not complete. In recovery, para-sympathetic effects on heart rate appeared rapidlywithin the first minute, increased steadily until 4 mininto recovery, and then plateaued.
Another important factor in the analysis of HRR isthe parameter to use: heart rate or the RR interval.These variables are inversely related and cannot beused interchangeably. In an analysis of heart rateand the RR interval after submaximal exercise in33 healthy subjects at baseline conditions and duringselective beta-adrenergic blockade and/or para-sympathetic blockade (155), it was shown that theheart rate changes provided more physiological in-formation and should therefore be the preferredvariable.
Abnormal HRR is also associated with an adverseprognosis. Jouven et al. (156) reported a relative risk of2.2 for sudden cardiac death in those with1-min HRR <25 beats/min versus those with HRR>40 beats/min. Cole et al. (157) demonstrated a 4-foldrisk of death in those with abnormal HRR after peakexercise in a cohort of 2,428 subjects without a historyof heart failure, coronary revascularization, coronaryangiography, or exercise testing. After adjustment forage, sex, medications, perfusion defects on thalliumscintigraphy, standard cardiac risk factors, restingheart rate, change in heart rate with exercise, andworkload achieved, there was still a 2-fold risk ofdeath in those with an abnormal HRR.
QT-RR SLOPE. Ventricular repolarization can beassessed on the electrocardiogram (the QT interval)and is subject to autonomic effects. Because the QTinterval is also strongly influenced by heart rate,determining the independent autonomic effects onthe QT interval is challenging. A variety of approacheshave been proposed. Although rate correction for-mulas are widely used to adjust the QT interval forthe underlying heart rate, these formulas are inade-quate to assess autonomic effects on the QT interval.One approach, assessing the QT-RR slope, has beenshown to provide reliable and reproducible delinea-tion of cardiac repolarization (158,159). The auto-nomic effects on the QT-RR relationship in the first5 min of recovery has been defined (160) with selec-tive autonomic blockade. Figure 3 provides a diagramof the autonomic effects on the QT-RR relationship,showing a strong parasympathetic effect becauseatropine steepens the slope dramatically, and asmaller beta-adrenergic effect as propranolol bluntsthe slope. Thus, there are characteristic autonomiceffects on the QT-RR slope.
DIRECT NERVE RECORDINGS. Sympathet i cmicroneurography . Although heart rate�basedtests are simple noninvasive tools, they donot directly measure autonomic activity. Thedevelopment of microneurography, in which nerveactivity can be recorded directly from intraneuralmicroelectrodes inserted percutaneously in aperipheral nerve in awake patients, has provided awealth of information on the control of sympatheticoutflow to muscle and skin. Recordings of musclesympathetic nerve activity and skin sympatheticnerve activity in different disease states haveincreased our understanding of sympatheticfunction, both in physiological and pathologicalsettings. Several studies have suggested that musclesympathetic nerve activity is a reliable markerof sympathetic response in some internal organs(161). Compared with healthy individuals, musclesympathetic nerve activity is altered in the settingof orthostatic hypotension and syncope, inneurological disorders such as Parkinson’s disease,multiple system atrophy, familial dysautonomia,Guillain-Barre syndrome, and in cardiovasculardisease states such as hypertension and heart failure(162). Increased muscle sympathetic nerve activityin patients with heart failure is associated withreduced exercise capacity (163) and also helpspredict mortality in this patient population (164).Importantly, interventions, such as exercise training,appear to significantly decrease sympathetic activity,as assessed by muscle sympathetic nerve activity,as well as by noninvasive parameters such as HRVand HRR (165).
Direct recordings from cardiac autonomic nerves.Recently, direct recordings of autonomic nerve ac-tivity have been made from the stellate ganglia,vagus nerve, and from the cardiac GPs. These studies,in large animal models of AF, suggest that sympa-thetic and parasympathetic nerve dischargesfrequently precede the onset of atrial arrhythmias,both in the setting of heart failure and in a model ofrapid atrial pacing�induced AF (166). Recent datasuggest that it may be possible to record autonomicnerve activity by electrodes implanted in the subcu-taneous space of the left thorax, and that this sub-cutaneous nerve activity correlates with the stellageganglia nerve activity (167). Of great interest is thepossibility of making these types of recordings fromskin sympathetic activity in humans (168). Futurestudies are needed to assess the applicability of thesetechniques in humans, to better understand the roleof the ANS in the genesis of atrial and ventriculararrhythmias.
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SUMMARY
The link between ANS dysfunction and various car-diovascular disease states has been clearly estab-lished (Table 1). The role of exercise and otherconditions associated with sympathoexcitation as amajor precipitant for MI (169,170) and ventricular ar-rhythmias and/or sudden cardiac death (171,172), andthe proven usefulness of beta-adrenergic blockers toimprove survival after MI and in heart failure withreduced ejection fraction highlight the prominentrole autonomics play in clinical heart disease (CentralIllustration).
The appreciation of the importance of autonomicsled to the development of many noninvasive di-agnostics that interrogate the ANS, but have limitedto no clinical applicability at this time (Table 2). Thismay be due to the fact that the tests are focused onautonomic effects on the sinus node, whereas theadverse cardiac effects are generated by autonomiceffects on the ventricle. In addition, simple tests ofautonomic reflexes may not adequately interrogatethe complex interplay of a multilevel system withmultiple levels of feedback and excitatory and
inhibitory control. Because of the prominent role theANS plays in cardiac disease, other diagnostic ap-proaches are needed. Potentially useful approachesinclude direct nerve recordings and cardiac sympa-thetic imaging.
Therapeutically, the key intervention that hasdemonstrated benefit is beta-blocker therapy. Onlylimited data are available for other medical therapies,such as scopolamine, which can improve HRV andBRS (173) but may not affect survival (174). Other in-terventions that have been tested include autonomicnerve stimulation and autonomic nerve disruption,with mixed results. It is possible that further effortsto develop optimal approaches to interrogate thiscomplex system will enable targeted stimulation anddisruption interventions that can be more specificallytargeted to abnormalities that can be amelioratedwith these approaches.
ADDRESS FOR CORRESPONDENCE: Dr. Jeffrey J.Goldberger, University of Miami, Miller School ofMedicine, Cardiovascular Division, 1120 NW 14thStreet, Miami, Florida 33136. E-mail: [email protected]. Twitter: @DrJGoldberger, @UMiamiHealth.
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KEY WORDS arrhythmia, autonomic, heartfailure, myocardial infarction
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