409

the cardiac plexus. The cardiac plexus, which is divided into the superficial (ventral) and deep (dorsal) cardiac plexus, gives rise to sympathetic nerve branches that run along the coronary arteries on the epicardium and penetrate the myocardium with the vascu-lature. Thus, the nerves are located primarily around blood vessels and between myocytes oriented along their long axis. Further, a gradient in sympathetic innervation is thought to exist from base to apex, as well as from epicardium to endocardium.7,8

Data collected over the past four decades indicate that exten-sive neural processing occurs in the cardiac plexus, otherwise known as the intrinsic cardiac nervous system. This plexus contains afferent neurons, interconnecting interneurons, and sympathetic and parasympathetic efferent postganglionic neurons.9 Further-more, it is composed of seven ganglionic subplexi, containing more than 800 epicardial ganglia. Each subplexus or group of subplexi innervates different chambers of the heart. One sub-plexus innervates the right ventricle, three innervate the left ven-tricle, and the rest innervate the atria. The highest density of epicardial ganglia, approximately 50%, exists near the hilum of the heart, especially on the dorsal and dorsolateral surfaces of the left atrium. The number of neurons in these ganglia decreases with age, from approximately 94,000 neurons in neonates and children to 43,000 intrinsic neurons in the plexus of adults.10 A complex feedback regulatory system allows the cardiac nervous system to modulate sympathetic and parasympathetic input to the heart.

Cardiac nerves can be demonstrated by labeling nerve-specific markers such as S100 protein, neurofilament, and synaptophysin using immunohistochemistry techniques,5,6 and myelinated fibers can be identified by myelin markers, such as myelin basic protein. Sympathetic nerves can be identified by immunolabeling tyrosine hydroxylase. Tyrosine hydroxylase and myelin basic protein stain-ing have confirmed the presence of myelinated sympathetic nerves on all surfaces of the epicardium and endocardium.11

Sympathetic Modulation of Myocardial Excitability

The major neurotransmitter mediating sympathetic response in the heart is norepinephrine. Epinephrine release from intracar-diac neural endings is negligible.12 Along the length of terminal axons are a series of localized swellings known as varicosities. Most of the norepinephrine storage vesicles in a terminal axon are concentrated in these varicosities, which act as specialized sites of norepinephrine storage and release.13 The overall effect of norepinephrine release through multiple signaling pathways is shortening of the ventricular action potential duration (APD) and the refractory period.14 Most norepinephrine undergoes reuptake into nerve terminals by the presynaptic norepinephrine trans-porter. A small fraction diffuses into the vascular space, where it can be measured in coronary sinus blood. Norepinephrine spill-over (both interstitial and in the coronary sinus) can be used to infer that sympathetic outflow to the heart can also be assessed in humans.15

CHAPTER OUTLINE

Anatomy of Cardiac Sympathetic Innervation 409

Sympathetic Modulation of Myocardial Excitability 409

Neural Remodeling in the Presence of Myocardial Pathology 410

Proarrhythmic Effects of Sympathetic Stimulation 412

Effect of Neuraxial Modulation in Reducing Risk of Ventricular Arrhythmias 413

Surgical Sympathetic Denervation in Humans 414

Conclusion 415

The autonomic nervous system plays a significant role in the genesis and maintenance of ventricular arrhythmias, and power-fully modulates the underlying substrate in a dynamic manner.1-3 Blockade of the sympathetic nervous system, whether through medications or neuraxial modulation, has been associated with a reduction in the risk of sudden cardiac death and the burden of ventricular arrhythmias. In this chapter, the anatomy of the cardiac sympathetic nervous system and pathological changes associated with neural remodeling in the setting of scar and car-diomyopathy will be reviewed. Subsequently, the role of sympa-thetic activation in promoting arrhythmias, and the effects of neuraxial modulation in reducing the burden of these arrhyth-mias will be discussed. Finally, cardiac denervation in humans, including feasibility, surgical techniques, and complications, will be considered.

Anatomy of Cardiac Sympathetic Innervation

The preganglionic sympathetic neurons that innervate the heart reside in the intermediate zone of the thoracic spinal cord.4 These preganglionic sympathetic nerves pass through the white rami communicantes, enter the sympathetic trunk, and terminate in the cervicothoracic ganglion as well as in the T2-T4 ganglia. Of note, preganglionic neurons may synapse on neurons within the ganglia at the same thoracic level or may travel within the sympa-thetic chain and synapse on neurons of ganglia at other spinal levels. The preganglionic neurotransmitter within the ganglia is acetylcholine. The right and left cervicothoracic ganglia, which are often a product of the fusion of the C8 and T1 ganglia, are called the left stellate (LSG) and right stellate (RSG) ganglia. LSG and RSG, along with the ganglia of T2-T4, give rise to postgan-glionic axons that target organs including the heart, the esopha-gus, the trachea, and the head and neck (Figure 41-1). Postganglionic nerve fibers from these ganglia then join the branches of the vagus nerve to form the left and right cardiac (cardiopulmonary) nerves, destined for the heart.5,6 These nerves subsequently form a network of neurons on the epicardium, called

41 Sympathetic Innervation, Denervation, and Cardiac Arrhythmias

Marmar Vaseghi, Olujimi A. Ajijola, Aman Mahajan, and Kalyanam Shivkumar

410 NEURAL CONTROL OF CARDIAC ELECTRICAL ACTIVITY

innervation; certain viable sites shorten their repolarization, while others show no response. All denervated areas show dener-vation super-sensitivity, defined as an exaggerated response to norepinephrine infusion.21 The cellular mechanisms for this response do not involve differences in the β-adrenergic receptor or the α-subunit of stimulatory G-protein density.22,23

In patients with recurrent ventricular arrhythmias undergoing ventricular tachycardia (VT) ablation procedures, activation recovery interval (ARI) measurements show a reduced response to indirect sympathetic stimulation via nitroprusside in dense scar and in the viable peri-infarct myocardium, suggesting denerva-tion.24 These sites demonstrate an exaggerated response to iso-proterenol infusion, suggesting the presence of denervation super-sensitivity in humans (Figure 41-3). Further, the response to sympathetic stimulation is extremely heterogeneous, with a greater than 2-fold increase in dispersion in ARI with nitroprus-side infusion.24

These studies were important because they demonstrated that transmural MI and heart failure not only can alter the myocardial substrate for arrhythmias, they can also disrupt innervation to histologically viable myocardium, leading to denervation super-sensitivity and a non-uniform electrophysiological response to sympathetic stimulation. This contributes to the genesis of ven-tricular arrhythmias in both acute and chronic MI.

Cardiac Neural Remodeling and Nerve Sprouting

After studies showed acute denervation, evidence of nerve sprout-ing and heterogeneous hyperinnervation was observed in chronic

Figure 41-1.  The sympathetic chain and in particular the left stellate ganglion (LSG) and the ganglia of thoracic spinal 1-4 (T1-T4) are located in a paravertebral position behind the parietal pleura. 

(Reproduced with permission from Abrahams PH, Spratt JD, Boon J: McMinn’s Clinical Atlas of Human Anatomy, 6th ed, St Louis, 2007, Mosby.)

LSG

T2 Ganglion

T3 Ganglion

T4 GanglionAorta

Leftventricle

Figure 41-2.  Multiple  organs  mediate  sympathetic  outflow  to  the  normal  heart including the brain,  the spinal cord,  the sympathetic chain  (left  stellate ganglion [LSG], right stellate ganglion [RSG], and ganglia of T1-T4), the adrenal medulla by secreting  catecholamines,  and  the  renal  nerves.  E,  Epinephrine;  LSG,  left  stellate ganglion;  NE,  norepinephrine;  RSG,  right  stellate  ganglion;  SAN,  sinoatrial  node; T1-T4, thoracic spinal level 1 through 4. 

Brain andhigher centers

LSG

RSG

SAN

NENE

Adrenalmedulla

2/3 E

1/3 NE

Kidney

Thoracic

T1-T4

Spinalcord

Sympathetic stimulation, predominantly mediated by post-synaptic myocardial β-adrenergic receptors, has important effects on chronotropy, dromotropy, lusitropy, and inotropy. Discharge of the sinoatrial (SA) node and atrioventricular (AV) nodal con-duction are augmented, increasing chronotropy. In the atria and ventricles, contractility and relaxation are enhanced. Both β1 and β2 subtypes are present at a ratio of approximately 5 : 1 in the healthy human heart.16-18 Alpha adrenoreceptors are mainly present in the vascular wall, but are also found in ventricular myocardium, where they account for approximately 15% of cardiac adrenergic receptors.18

Cardiac sympathetic activation is complex and is mediated through multiple organs at multiple levels. The brain (higher centers), brain stem, spinal cord, sympathetic ganglia, adrenal medulla, and renal nerves can increase the net sympathetic output to the heart, dynamically modulating cardiac function (Figure 41-2).

Neural Remodeling in the Presence of Myocardial Pathology

Myocardial infarction (MI) and heart failure, in addition to leading to scar formation, cause remodeling of cardiac nerves. Initial denervation, followed by nerve-sprouting and trans-differentiation of sympathetic nerves, leads to heterogeneity in repolarization and can modulate reentry.

Cardiac Neural Remodeling and Denervation

Myocardial infarction causes death of sympathetic fibers within the scar and loss of efferent sympathetic innervation at nonin-farcted apical sites.19 Norepinephrine depletion in the scar is accompanied by increased production in noninfarcted basal areas.20 In response to LSG stimulation, viable myocardial sites apical to an infarct show evidence of heterogeneity in

SYMPATHETIC INNERVATION, DENERVATION, AND CARDIAC ARRHYTHMIAS 411

41 

“swarm-like” pattern in the periphery of necrotic tissues and in perivascular regions have been observed, and these changes were more prominent in patients with a history of ventricular arrhythmias.29-31 These border zones of infarcts have also been shown to be frequent sites of origin of inducible ventricular tachycardia (VT)/ventricular fibrillation (VF).32,33 Furthermore, nerve sprouting can occur in a noninfarct setting such as stem

MI and heart failure models. Peripheral nerve injury resulting in Wallerian degeneration, which leads to nerve growth factor (NGF), triggered regeneration via nerve sprouting.25,26 Along with denervation, MIBG studies have shown localized re-innervation in injured myocardium in both ischemic and nonischemic cardiomyopathy patients.27,28 In human hearts with cardiomyopathy, local increases in sympathetic nerves in a

Figure 41-3.  A recording multi-electrode catheter on fluoroscopy (left upper panels) and electroanatomical map (right upper panel) in this patient with ischemic cardiomy-opathy (ICM) and a large anteroapical scar are used to record unipolar electrograms from scar, border zone, and viable myocardium. On the electroanatomical map, the purple areas represent viable tissue (normal voltage) and gray represents dense scar. All other colors represent border zones (0.5 mV < voltage < 1.5 mV). The delta activa-tion recovery interval (ARI; change in ARI from baseline) within the cardiomyopathic and normal hearts is shown in the lower panel. Note that in response to isoproterenol, the delta ARI  is greatest  in  the CM-normal site  (viable myocardium) and scar  regions of  the cardiomyopathic heart. The border zones within each patient are  the  least responsive to isoproterenol. On the other hand, in response to nitroprusside, the scar and the CM-NL tissue appear to be the least responsive, even paradoxically increasing their ARI in comparison with border-zone regions. Therefore, it appears that the most denervated regions have the greatest response to catecholamines, consistent with denervation super-sensitivity. 

Recordingcatheter

Recordingcatheter

AICD

10 mV

5 mV

0 mV

AICD

RAOCS

CS

RV

LAO

P = .016

20

Del

ta A

RI (

ms)

10

0

10

20

-30

-40

-50

-60

-70

-80

-90

P = .08

P = .01

P = .0002

Normal hearts CM-normal site CM-border zones CM-scars

Isoproterenol

Nitroprusside

1 2 34

56 7 8

9 10 12

11 13

1415

412 NEURAL CONTROL OF CARDIAC ELECTRICAL ACTIVITY

Figure 41-4.  Human  cardiomyopathy  is  associated  with  stellate  ganglion  neuronal  hypertrophy.  Shown  in  the  figure  are  representative  thionine-stained  right  stellate ganglion neurons from normal controls (NL) and from patients with ischemic (ICM) and nonischemic cardiomyopathy (NICM). Neurons from ICM and NICM are larger and show a more granular appearance compared with normal controls. (Magnification 20×; scale bar 50 µm.) 

NL ICM NICM

400

Mea

n ne

uron

al a

rea

(µm

2 )

350

300

250

NL ICM NICM

cell transplantation,34 in radiofrequency ablation,35 and in rapid pacing–induced heart failure in dogs36 and in hypercholesterol-emic rabbits, where it has been shown to cause QTc dispersion, increased heterogeneity of repolarization, and significantly increased episodes of VF, both spontaneous and induced.37 Fur-thermore, NGF infusion into the LSG promotes nerve sprouting in dogs with MI and complete AV block, and is associated with increased incidence of VF.38 Infusion of NGF into the RSG has not been shown to increase the risk of sudden cardiac death (SCD).39 Of note, NGF and GAP-43 levels are increased in the LSG of these dogs 3 days after MI, without a concomitant increase in mRNA levels, indicating possible retrograde trans-portation of these proteins to the LSG, which then triggers nerve sprouting at noninfarcted LV sites.40

Heart failure can cause trans-differentiation of cardiac sym-pathetic nerves. Cholinergic trans-differentiation of nerve sprouts by production of interleukin-6 cytokines through a gp-130 sig-naling pathway has been demonstrated in rodents,41,42 potentially further promoting heterogeneity in repolarization. However, the exact ramifications of this sympathetic rejuvenation and plasticity are yet unknown. Heart failure is also known to cause remodeling of cardiac ion channels, including increased L-type Ca (ICaL) density, decreased potassium current, decreased Ito density, and changes in Cl and Ca transporters and enzymes in the border zones surrounding the infarct.43-46 Thus, sympathetic stimulation could result in complex effects on the APD and restitution, which, along with increased ICaL density, can lead to intracellular Ca2+ overload–induced triggered activity, potentiating the risk of spontaneous ventricular arrhythmias.

Extracardiac Neural Remodeling

In addition to cardiac neural remodeling, electroanatomical remodeling of the LSG in the setting of MI and heart failure has been described. Increased nerve density along with increased mRNA levels of NGF and GAP-43 in the LSG of dogs with MI

and nerve sprouting has been reported.40 Increased stellate gan-glion nerve activity (SGNA) immediately after MI was associated with intramyocardial nerve sprouts, as well as increased neuronal size and synaptic density in the LSG and RSG.47 Although SCD was not observed in this study, Ogawa et al and Zhou et al had previously shown that sympathetic nerve discharges tend to precede ventricular arrhythmias in the same dog model of MI.48,49 Similarly, in human cadavers with evidence of cardiac scar, neu-ronal number in the LSG is increased as compared with cadavers without evidence of scar.50 Compared with cadavers with normal hearts, those with cardiomyopathy demonstrate increased neuro-nal size and synaptophysin density (Figure 41-4).51 These results provide a possible mechanistic link between neural remodeling (nerve sprouting within the myocardium) and remodeling of the stellate ganglion and ventricular arrhythmias, although further studies are required. Interaction between areas of denervation, regional nerve sprouting and trans-differentiation (neural remod-eling), electrical remodeling due to heart failure, and electroana-tomical remodeling of the stellate ganglia all combine to create a substrate that can be conducive for ventricular arrhythmias and sudden cardiac death (Figure 41-5).

Proarrhythmic Effects of Sympathetic Stimulation

Many studies have suggested that sympathetic nerve stimulation, particularly LSG stimulation, is proarrhythmic. Greater increases in the amplitude of early afterdepolarization have been observed with LSG stimulation.52 Priori et al showed that LSG stimulation caused delayed afterdepolarizations in vivo in cat hearts, suggest-ing triggered activity as the mechanism of ventricular arrhyth-mogenesis.53 Further, an increase in dispersion with sympathetic stimulation, both during ischemia and in normal canine and porcine hearts, has been observed.54-57 In the porcine heart, LSG stimulation increased ARI dispersion by 4-fold and caused VF in

SYMPATHETIC INNERVATION, DENERVATION, AND CARDIAC ARRHYTHMIAS 413

41 

cord, the sympathetic chain, and the β-adrenergic receptors of the myocardium, and it can be attempted by renal denervation (Figure 41-6). General anesthesia, sedation, and intubation can suppress or significantly reduce the burden of ventricular arrhyth-mias and implantable cardioverter-defibrillator (ICD) shocks by reducing the sympathetic drive in electrical storm.62-65 At the spinal cord level, Issa et al demonstrated that in a canine model of ischemic cardiomyopathy, spinal cord stimulation at T1-T2 segments reduced the incidence of ventricular arrhythmia from 59% to 23% during ischemia.66 A simultaneous decrease in heart rate and systolic blood pressure, consistent with the antisympa-thetic effects of spinal cord stimulation, was also observed.67-70 Intrathecal clonidine, when delivered via a catheter at T2-T4 spinal segments, also significantly reduces the occurrence of ven-tricular tachycardia and fibrillation during transient myocardial ischemia.71 The benefit of thoracic epidural anesthesia (TEA) was reported in series of patients with cardiomyopathy and refractory VT. In 66% of the patients, TEA reduced the burden of arrhyth-mias by 80%.72

In humans, postganglionic sympathetic blockade, with medi-cations (β-adrenergic receptor blockers) or via percutaneous stel-late blockade (usually injection of bupivacaine 0.25%), has also been reported to reduce ventricular arrhythmias. Among patients early after MI with recurrent VF (electrical storm), those treated with sympathetic blockade had improved outcomes as compared with those treated with the standard Advanced Cardiac Life Support (ACLS) protocol.73 Sympathetic blockade was estab-lished with the use of LSG blockade in 6 patients and with infu-sions of either propranolol or esmolol in 21 patients without antiarrhythmic therapy, as recommended by ACLS. One-week and 1-year mortality were significantly higher in the group undergoing standard ACLS protocol compared with the sympathetic blockade group (82% vs. 22% at 1 week, 95% vs. 33% at 1 year, respectively).73 It is important to note that in humans with percutaneous RSG or LSG blockade, no significant changes in hemodynamics or ejection fraction during rest or with exercise have been reported.74 Finally, renal denervation has been reported to reduce the burden of ventricular arrhythmias in two patients, as well as electrical storm (one with nonobstructive

25% of the animals.57 In open-chest dogs, electrical stimulation of LSG, the left middle cervical or left caudal pole of the cardio-pulmonary nerve, or the ventrolateral nerve caused VT in 13 of 22 normal dog hearts, with isochronal mapping showing the earliest electrical excitation occurring on the posterior aspect of the ventricles.58 Electrical stimulation of the left ansa subclavia in open-chest dogs during left circumflex occlusion increased the incidence of VF from 35% to 73%.59 The incidence of induced ventricular arrhythmias in dogs with myocardial ischemia increased from 54% to 68% and 63% with LSG and bilateral stellate stimulation, respectively. RSG stimulation had no signifi-cant effect on the incidence of arrhythmias in this study.60 Further, by measuring local VF intervals, Opthof et al showed that LSG stimulation can increase dispersion in refractoriness by shorten-ing refractoriness across nonischemic sites while either not changing or increasing refractoriness at ischemic sites during coronary occlusion, thereby increasing dispersion across the ischemic border by 14% to 59%.55 Finally, subthreshold LSG stimulation has been shown to increase nerve sprouting in dogs with MI. These dogs have a greater number of episodes of VT compared with controls, suggesting that additional mechanisms underlie the increase in dispersion seen in infarcted hearts.61

Effect of Neuraxial Modulation in Reducing Risk of Ventricular Arrhythmias

As augmented sympathetic tone increases the risk of arrhythmias, interventions that aim to reduce sympathetic tone diminish the risk of sudden cardiac death and ventricular arrhythmias.

Strategies and Techniques of Cardiac  Sympathetic Denervation and Effects  on Ventricular Arrhythmias

Modulation and blockade of the sympathetic nervous system can be attempted at multiple levels, including the brain, the spinal

Figure 41-5.  The schematic shows the various changes that occur as a result of myocardial infarction that cause neural remodeling and increased sympathetic activation. Myocardial infarction causes scar formation and denervation leading to release of nerve growth factor (NGF) and cytokines by the surrounding myocardium. This causes remodeling  of  the  stellate  ganglion  and  neural  remodeling  of  the  myocardium,  including  nerve  sprout  formation  and  cholinergic  trans-differentiating,  further  causing heterogeneity in repolarization with sympathetic stimulation. Sympathetic activation then causes EADs, DADs, and increased dispersion in this substrate, leading to ven-tricular arrhythmias. DAD, delayed afterdepolarization; EAD, early afterdepolarization; NGF, neural growth factor. 

Myocardialinfarction

Scar &denervation

NGFCytokines

Cytokin

es

NGF

Heterogenoussubstrate

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Dispersion ofrepolarization

EADs

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+

+

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ScarNerve

sprouts

Normal

414 NEURAL CONTROL OF CARDIAC ELECTRICAL ACTIVITY

in the United States and Europe, it is important to keep in mind that left cervicothoracic sympathectomy has been a successful treatment option for patients with recurrent angina refractory to medical therapy, in sympathetically mediated pain syndromes, and in patients with long QT syndrome and catecholamin-ergic polymorphic VT with repeated episodes of ventricular arrhythmia.80-90 Left cardiac sympathetic denervation can reduce cardiac events in long QT syndrome. However, both in the car-diomyopathy population and in patients with long QT syndrome and catecholaminergic polymorphic ventricular tachycardia (CPVT), left and bilateral cervicothoracic sympathectomies are reserved for patients whose arrhythmias are refractory to medical therapy and/or who are receiving frequent ICD shocks. Most of these cardiomyopathy patients have already undergone one or multiple ablation procedures for treatment of VT.

Surgical Technique

Left and bilateral cervicothoracic sympathectomy involves removal of the lower one-third to one-half of the left or bilateral stellate ganglia and the thoracic ganglia of T2-T4. This proce-dure provides adequate cardiac denervation usually with absence of or minimal Horner’s syndrome in long QT syndrome, CPVT, and cardiomyopathy.72,79,82,83,85,90 This procedure is now most commonly performed using video-assisted thoracoscopic surgical (VATS) techniques, thereby reducing perioperative morbidity and duration of hospitalization.85,87,91 For left cervicothoracic sympathectomy, the patient is placed in a left lateral position, under single-lung ventilation. Three 1-cm incisions are made in the subaxillary region for introduction of endoscopic instru-ments. The stellate and thoracic ganglia are located behind the

hypertrophic cardiomyopathy and another with nonischemic cardiomyopathy).75

Effects of Left and Bilateral Surgical  Cervicothoracic Sympathectomy  on Ventricular Arrhythmias

In 1983 Schwartz et al showed that the incidence of ventricular fibrillation was decreased from 66% to zero by performing left stellectomy in post-MI dogs.76 Further, Stramba-Badiale et al showed that ventricular fibrillation threshold (VFT) decreases with vagotomy or right ganglion stellectomy, while VFT increases with left stellectomy.77 Schwartz et al showed that left cervico-thoracic sympathectomy reduced the risk of sudden cardiac death from 21.3% to 2.7% in high-risk MI patients with at least one episode of ventricular tachycardia or fibrillation.78 This effect was equivalent in magnitude to β-receptor blocker medications. In patients with refractory arrhythmias and cardiomyopathy, left and bilateral cervicothoracic sympathectomy reduced the burden of arrhythmia in more than 60% of patients.72,79 On the basis of these study findings, a suggested approach for sympathetic mod-ulation, particularly in the setting of VT storm, is shown in Figure 41-7.

Surgical Sympathetic Denervation in Humans

Although left and bilateral cervicothoracic sympathectomies have been performed in small series of patients with cardiomyopathy

Figure 41-6.  Neuraxial modulation of the cardiac sympathetic nervous system can occur at multiple levels. Sympathetic outflow from the brain and higher centers can be blocked via general anesthesia. Thoracic epidural anesthesia, spinal cord stimulation, and intrathecal clonidine modulate the preganglionic neuronal output from the spinal cord. Cervicothoracic sympathectomy targets the left stellate ganglia (LSG), right stellate ganglia (RSG), and T1-T4 ganglia of the sympathetic chain. Beta-adrenergic recep-tors at the level of the myocardium can be blocked via β-blockers, and renal denervation at the level of the renal arteries can decrease sympathetic output from the kidneys. All these therapies have been shown to reduce the burden of ventricular arrhythmias. 

Generalanesthesia

Brain and highercenters

LSG

RSG

SAN

Adrenalmedulla

Kidney Functional VTand VF

Macroreentry

NE

Focal VF

NE

ThoracicT1-T4Spinalcord

TEA,SCS, andintrathecalclonidine

Cervicothoracicsympathectomy

Beta blockers

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2/3 E1/3 NE

SYMPATHETIC INNERVATION, DENERVATION, AND CARDIAC ARRHYTHMIAS 415

41 parietal pleura, in the paravertebral position. Then, the lower one-third to one-half of the stellate ganglion, along with the chain from T2-T4, is completely removed. Histopathologic con-firmation of neuronal cell bodies is obtained during the proce-dure. The procedure can be typically performed on one side in less than 60 minutes.82

Risks and Complications of  Cervicothoracic Sympathectomy

Left cervicothoracic sympathectomy can be accompanied imme-diately postoperatively by ipsilateral Horner’s syndrome. However, when the VATS approach is used, it occurs rarely and has been temporary because the sympathetic fibers directed toward the ocular regions usually cross the upper portion of the LSG, which is typically spared in this procedure.82,85 Mild lower-ing of the left eyelid appears transiently after surgery, but seldom persists.82

The effect of left cervicothoracic sympathectomy on LV func-tion has been studied using echocardiography. In patients with sympathetically mediated pain syndrome but normal ventricular function, hemodynamic parameters including heart rate and blood pressure remain unchanged, although afterload reduction—a desired effect in cardiomyopathy patients—does occur.89 Fur-thermore, global and regional systolic function also remains unchanged, although isovolumic relaxation time is slightly pro-longed.88,89 This small effect has not compromised ventricular function, and stroke volume has actually increased as a result of afterload reduction.89

Conclusion

The sympathetic nervous system plays a major role in the patho-genesis of ventricular arrhythmias. Therapies that inhibit the effects of this system have been shown to reduce the burden of arrhythmias. Left and/or bilateral sympathetic denervation tech-niques are feasible and safe options for patients with refractory arrhythmias who have not responded to medical therapy and/or ventricular tachycardia ablation. Further, they may be the only option for patients with refractory arrhythmias who are not can-didates for cardiac transplantation. Randomized studies with longer follow-up are required to assess the long-term risks and benefits of these procedures.

Acknowledgments

Some of the research reported in this chapter is supported by the National Heart, Lung, and Blood Institute grant R01HL084261 (Dr. Shivkumar) and American Heart Association AHA #11FTF6559994 (Dr. Vaseghi).Figure 41-7.  A  suggested  approach  for  neuraxial  modulation  of  a  patient  with 

ventricular tachycardia (VT) storm is shown. 

YES

NO

NO

NO

YES

NO

NO

YES

YES

YES

YES

NO

Adjust TEAlevel

Patient with severe ventricular

arrhythmias

Reversible causes suppressed

arrhythmias?Devise optimal medical therapy and consider substrate mapping if indicated.

Stabilize patient and plan elective catheter mapping and ablation.

Devise optimal medical therapy and ICD implantation if not already present.

Proceed with cardiac transplant work up and listing.

Perform left cardiac sympatheticdenervation (LCSD)

Consider bilateral cardiac sympathetic denervation (BCSD)

Pharmacologic therapy

successful?

Thoracic epidural anesthesia (TEA)

successful?

Emergent catheter mapping and ablation. VT

remains inducible?

Intubation and sedationsuccessful?

Cardiac transplant candidate?

Plan cardiac sympatheticdenervation

(CSD).

If arrhythmia is RVOT, A RVC,

PMVT, RV only scar, or no cardiac scar

If arrhythmia is LV origin, or LV-only scar.

References1. Schwartz PJ, Vanoli E, Stramba-Badiale M, et al:

Autonomic mechanisms and sudden death: New insights from analysis of baroreceptor reflexes in conscious dogs with and without a myocardial infarction. Circulation 78:969–979, 1988.

2. Vaseghi M, Shivkumar K: The role of the auto-nomic nervous system in sudden cardiac death. Prog Cardiovasc Dis 50:404–419, 2008.

3. Zipes DP, Barber MJ, Takahashi N, et al: Influence of the autonomic nervous system on the genesis of

cardiac arrhythmias. Pacing Clin Electrophysiol 6:1210–1220, 1983.

4. Jänig W: Functional anatomy of the peripheral sympathetic and parasympathetic system. In Jänig W, editor: The Integrative Action of the Auto-nomic Nervous System: Neurobiology of Homeo-stasis, Cambridge, 2006, Cambridge University Press, pp 13–34.

5. Janes RD, Brandys JC, Hopkins DA, et al: Anatomy of human extrinsic cardiac nerves and ganglia. Am J Cardiol 57:299–309, 1986.

6. Kawashima T: Anatomy of the cardiac nervous system with clinical and comparative morpho-

logical implications. Anat Sci Int 86:30–49, 2011.

7. Angelakos E, King M, Millard R: Regional distri-bution of catecholamines in the heart of various species. Ann N Y Acad Sci 156:219–240, 1969.

8. Hutchins GD, Miller MA, Zips DP: Neurocardiac imaging. In Zipes DP, Jalife J, editors: Cardiac Electrophysiology: From Cell to Bedside, Philadel-phia, 2009, Saunders Elsevier, pp 391–403.

9. Armour JA: Myocardial ischaemia and the cardiac nervous system. Cardiovasc Res 41:41–54, 1999.

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