JACC: CLINICAL ELECTROPHYSIOLOGY

VOL. 1, NO. 1-2, 2015

ª 2015 BY THE AMERICAN COLLEGE OF CARDIOLOGY FOUNDATION

ISSN 2405-500X/$36.00

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http://dx.doi.org/10.1016/j.jacep.2015.01.005

STATE-OF-THE-ART REVIEW

The Role of the Autonomic Ganglia in Atrial Fibrillation Stavros Stavrakis, MD, PHD, Hiroshi Nakagawa, MD, PHD, Sunny S. Po, MD, PHD, Benjamin J. Scherlag, PHD, Ralph Lazzara, MD, Warren M. Jackman, MD

JACC: CLINICAL ELECTROPHYSIOLOGY CME This article has been selected as the month’s JACC: Clinical Electrophysiology

CME Objective for This Article: Describe the role of the autonomic ganglia

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in the initiation and maintenance of atrial fibrillation; discuss the role of

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inadvertent ablation of the autonomic ganglia and their axons in the success of the pulmonary vein isolation procedure; discuss the benefit of

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adding ablation of the autonomic ganglia to the standard pulmonary vein isolation procedure for patients with paroxysmal atrial fibrillation; and

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describe the concept of neuromodulation and how it may be applied in

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atrial fibrillation.

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from the National Institute of General Medical Sciences to Dr. Stavrakis. The authors have reported that they have no relationships relevant to

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From the Heart Rhythm Institute, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma. This study was funded in part by grant 8P20GM103447 from the National Institute of General Medical Sciences to Dr. Stavrakis. The authors have reported that they have no relationships relevant to the contents of this paper to disclose. Manuscript received January 12, 2015; accepted January 29, 2015.

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Autonomic Ganglia and AF

The Role of the Autonomic Ganglia in Atrial Fibrillation ABSTRACT Recent experimental and clinical studies have shown that the epicardial autonomic ganglia play an important role in the initiation and maintenance of atrial fibrillation (AF). In this review, the authors present the current data on the role of the autonomic ganglia in the pathogenesis of AF and discuss potential therapeutic implications. Experimental studies have demonstrated that acute autonomic remodeling may play a crucial role in AF maintenance in the very early stages. The benefit of adding ablation of the autonomic ganglia to the standard pulmonary vein isolation procedure for patients with paroxysmal AF is supported by both experimental and clinical data. The interruption of axons from these hyperactive autonomic ganglia to the pulmonary vein myocardial sleeves may be an important factor in the success of pulmonary vein isolation procedures. The vagus nerve exerts inhibitory control over the autonomic ganglia, and attenuation or loss of this control may allow these ganglia to become hyperactive. Autonomic neuromodulation using low-level vagus nerve stimulation inhibits the activity of the autonomic ganglia and reverses acute electrical atrial remodeling during rapid atrial pacing and may provide an alternative nonablative approach for the treatment of AF, especially in the early stages. This notion is supported by a preliminary human study. Further studies are warranted to confirm these findings. (J Am Coll Cardiol EP 2015;1-2:1–13) © 2015 by the American College of Cardiology Foundation.

R

ecent experimental and clinical studies have

network that consists of multiple GP, nerve axons,

shown that the intrinsic cardiac autonomic

and interconnecting neurons (Figure 1). These GP,

nervous system (CANS), which is formed by

except the ligament of Marshall, are embedded within

interconnected clusters of autonomic ganglia, known

epicardial fat pads and vary in size, from those that

as ganglionated plexi (GP), plays an important role in

contain just a few neurons to those that contain more

the initiation and maintenance of atrial fibrillation

than 400 neurons (4,5). It should be noted that

(AF) (1). Variations in autonomic tone in humans (2)

although the epicardial surface of both atria is

and hyperactivity of the GP in ambulatory dogs (3)

covered by a dense neural plexus, the highest density

often precede episodes of paroxysmal AF. Four of

of neurons is found at the posterior wall of the left

the left atrial GP heavily innervate each of the myo-

atrium (5). Several studies have demonstrated that

cardial sleeves of the 4 pulmonary veins (PVs) (4,5).

the

Recent experimental evidence suggests that it is the

sympathetic elements, in addition to a variety of

GP activity to the PVs that is important in the patho-

neuropeptides and neuromodulators (8,9). Four of

genesis of AF and that the interruption of axons from

the left atrial GP each innervate 1 of the 4 PVs, as well

these hyperactive GP to the PV myocardial sleeves

as the surrounding atrial myocardium (4,5). These 4

may be an important factor in the success of PV isola-

GP are located within areas of fractionated atrial po-

GP

contain

both

sympathetic

and

para-

tion procedures (6,7). In this review, we present the

tentials during AF and can be identified during elec-

current data on the role of the autonomic ganglia in

trophysiological study by applying high-frequency

the pathogenesis of AF and discuss potential thera-

stimulation (20 Hz) at the respective anatomical lo-

peutic implications.

cations (10,11). The high-frequency stimulation activates

ANATOMY OF THE AUTONOMIC GANGLIA

the

GP,

leading

through

interconnecting

neurons to activation of the inferior right GP. The latter depresses atrioventricular (AV) nodal conducthe

tion, increasing the R-R interval by >50% during AF

extrinsic (central) and the intrinsic CANS. The

(Figure 2). Although the AV block is not mediated by

extrinsic CANS includes the ganglia in the brain or

the vagus nerve, this positive response is often

along the spinal cord, where the cell bodies reside, as

referred to as “vagal response.” This response is

well as their axons (e.g., the vagosympathetic trunk)

specific but not completely sensitive.

The

heart

receives

innervation

from

both

en route to the heart. The intrinsic CANS is essentially an extensive, highly interconnected epicardial neural

On the basis of the response to high-frequency stimulation,

the

anterior

right

GP

is

located

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immediately anterior to the right superior PV and

radiofrequency current or a cryoapplication

ABBREVIATIONS

often extends inferiorly, to the region anterior to

around the PV ostia. The premise of PV

AND ACRONYMS

the right inferior PV (Figure 1). This is the only

isolation is to prevent the ectopic activity

GP directly adjacent to a PV. The superior left GP

arising from the PVs from reaching the atria

is located at the roof of the left atrium, 1 to 2 cm

and thereby inducing AF (14,15). However,

medial to the left superior PV (Figure 1). The

this approach failed to answer at least 4

right and left inferior GP are located at the inferior

fundamental questions: 1) How does the PV

aspect of the posterior wall of the left atrium, 2 to

myocardium initiate premature beats? 2)

3 cm below the right and left PVs, respectively

How do bursts of premature beats from the

(Figure 1) (11).

PVs initiate AF rather than an atrial tachy-

afterdepolarization

cardia? 3) Why do the PVs (with a very small

GP = ganglionated plexi

AUTONOMIC GANGLIA AND AF The mechanism of AF initiation has been a matter of debate during the past 50 years. It was not until 1998 that a seminal observation by Haissaguerre and coworkers established the role of the PVs in the pathogenesis of AF. These investigators found that in most patients with paroxysmal AF, AF was initiated by rapid focal firing arising from the myocardial sleeves of the PVs (12,13). This recurring, rapid, nonsustained focal firing was often responsible for maintaining episodes of AF. This breakthrough observation laid the foundation for the present methodology for catheter ablation of AF, which includes wide, circumferential PV isolation by applying

mass of myocardium) rather than other atrial regions become the sites of focal firing in patients with AF? 4) How does PV isola-

AF = atrial fibrillation AV = atrioventricular CANS = cardiac autonomic nervous system

CFAE = complex fractionated atrial electrogram

EAD = early

LLTS = low-level tragus stimulation

LLVNS = low-level vagus

tion affect the substrate for AF mainte-

nerve stimulation

nance? Addressing these questions may help

PV = pulmonary vein

explain the less than optimal long-term results of PV isolation procedures (16,17) and provide the basis for a novel, mechanistic-based approach to treating AF. A series of recent experimental studies provides several lines of evidence linking the intrinsic CANS with focal firing from the PVs. Scherlag et al. (18) demonstrated that stimuli applied to PVs would not induce AF unless there was simultaneous stimulation of the adjacent GP (20 Hz, 0.1-ms pulse width) that did not excite the atrial myocardium. In another series of experiments, Po et al. (19) showed that injection of acetylcholine into the GP induced, within minutes, focal firing originating from the adjacent PV

F I G U R E 1 Anatomical Location of the Major Left Atrial GP

and sustained AF. Patterson et al. (20,21) demonstrated that PV myocytes have cellular electrophysiological properties that differ from the adjacent left atrial myocardium, specifically, a shorter action potential duration, which plays an important role in the initiation of AF (20,21). In isolated canine PV preparations (with a surrounding left atrial myocardial cuff), local autonomic (both parasympathetic and sympathetic) nerve electrical stimulation (21), or simultaneous administration of acetylcholine plus norepinephrine (or isoproterenol) (20), induced early afterdepolarizations (EADs) and short bursts of triggered firing from the PVs (Figure 3). This triggered firing was similar to the pattern recorded from the PVs in patients with paroxysmal AF. Importantly, local autonomic nerve stimulation had a much greater effect on the PV myocardium compared with the adjacent left atrial myocardium in terms of shortening of action potential duration, EAD formation,

A posteroanterior projection of the left atrium is shown. Hatched areas represent the anterior surface, and solid areas represent the posterior left atrial surface. The ganglionated plexi (GP)

3

Autonomic Ganglia and AF

and triggered firing, indicating that the PV myocardium is more sensitive to autonomic stimulation than

innervate the adjacent pulmonary vein and surrounding atrium.

left atrial myocardium (21). These observations may

Interconnecting neurons connect within and between GP.

explain why the first beat of AF often arises from the PVs.

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Autonomic Ganglia and AF

F I G U R E 2 Identification of GP by HFS

High-frequency stimulation (HFS) of the endocardium close to the inferior left ganglionated plexi (GP) elicits a profound “vagal response,” resulting in marked prolongation of the R-R interval during atrial fibrillation (atrioventricular nodal block).

The ionic mechanisms underlying PV firing have

L-type calcium current to recover from inactiva-

been recently elucidated (20,21). Under increased

tion, resulting in an inward depolarizing current,

GP activity, the increase in parasympathetic tone

leading to an EAD (22,23). Late phase 3 atrial

strikingly shortens action potential duration in the

EADs and triggered firing caused by action poten-

PV myocardium, and the increase in sympathetic

tial prolongation have been implicated in the path-

tone increases calcium loading. The high intracellular

ogenesis of AF in patients with congenital long-QT

calcium concentration during repolarization activates

syndrome (23).

the sodium-calcium exchanger to extrude calcium. Each calcium ion is exchanged for 3 sodium ions,

AUTONOMIC GANGLIA

leading to a net inward (depolarizing) current and

AND ATRIAL REMODELING

EAD as well as triggered firing from the PV myocardium (Figure 3) (20). Triggered firing from the PVs

AF

can be suppressed by muscarinic cholinergic receptor

atrial myocardium (atrial electrical remodeling) and

blockade (atropine), beta-adrenoceptor antagonists,

structural remodeling (e.g., fibrosis), providing the

inhibition of calcium release from the sarcoplasmic

substrate for AF maintenance (24). Although the

reticulum (ryanodine), or sodium-calcium exchange

chronic rapid atrial pacing model developed by

blockade (21), corroborating that both sympathetic

Wijffels et al. (25) provided strong evidence to ex-

and parasympathetic activity, intracellular Ca2þ load,

plain how “AF begets AF” in a chronic state, how AF

causes

electrophysiological

changes

in

the

and sodium-calcium exchanger are all critical ele-

maintains itself in the first few hours remained poorly

ments responsible for rapid PV firing. This mech-

understood. We have recently shown that rapid atrial

anism of EAD and triggered firing needs to be

pacing for 6 h induced acute atrial remodeling

contrasted with late phase 3 EADs, which are asso-

(shortening

ciated with a prolonged, rather than an abbreviated,

increased inducibility of AF) mediated through the

action potential duration. Action potential prolon-

GP, evidenced by reversal of these effects by GP

gation, caused by loss of depolarizing potassium

ablation (26). More recently, we reported that the

currents or excessive late sodium currents, allows

autonomic neural activity recorded from the anterior

of

effective

refractory

period

and

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Autonomic Ganglia and AF

F I G U R E 3 The Role of Autonomic Ganglia in AF Initiation at the Cellular Level

(A) Microelectrode recordings from the left atrium and left superior pulmonary vein (LSPV) at baseline and during high-frequency stimulation (HFS) at the left atrial (LA) myocardium, 3 mm from the pulmonary vein (PV) ostium. At baseline, the LSPV has a shorter action potential duration (APD) than adjacent LA myocardium. With HFS, early afterdepolarizations (EADs) and triggered firing are induced in the LSPV, preceding the LA activation. (B) In PV myocytes, cells with an abbreviated action potential, the duration of the calcium transient exceeds APD, leading to activation of the forward mode of the sodium-calcium exchanger, which in turn generates an EAD. With increased ganglionated plexi (GP) activity, parasympathetic activation, which causes action potential shortening, and sympathetic activation, which enhances calcium loading, result in EAD formation and triggered firing.

right GP increased hour by hour during 6 h of rapid

AUTONOMIC GANGLIA

atrial pacing (27). We proposed that acute atrial

AND PV ISOLATION

electrical remodeling induced by rapid atrial pacing– simulated AF and autonomic remodeling form a vi-

Some degree of autonomic denervation is common

cious cycle, so that one perpetuates the other to

after PV isolation (28,29) and has been associated

maintain AF (Central Illustration). These results may

with decreased risk for AF recurrence (30,31). In a

help explain how AF sustains itself in the very early

recent elegant study, Lemola et al. (6) investigated

stage (the first few hours). Importantly, these data

the role of PVs versus the GP in maintenance of

suggest that the autonomic ganglia may provide not

experimental vagal AF. These investigators per-

only the trigger for AF initiation but also the substrate

formed PV isolation in dogs while preserving the GP

for AF maintenance.

and in others ablated the GP while leaving the PVs

5

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Autonomic Ganglia and AF

that complete electrical isolation of the PVs is not C EN T RA L IL LUSTR AT I ON

The Vicious Cycle Among AF, Autonomic Remodeling, Atrial Electrical Remodeling, and Inflammation

necessary for the maintenance of sinus rhythm support these experimental data (32,33). It should be pointed out that conventional wide-area PV isolation transects both axons transiting from the GP to the PV myocardium, and much of the anterior right GP and some of the superior left GP, but has little impact on the inferior left or right GP. These studies suggest that injury to some GP tissue and interruption of their axons to PVs may contribute to the success of PV isolation procedures and may explain the increase in success found by extending PV isolation from the ostia further into the antrum (34,35). Interruption of the autonomic axons may explain the usual finding of elimination of firing within the PVs by PV isolation procedures (36). This phenomenon was systematically examined in a recent study, in which PV firing induced by intravenous infusion of isoproterenol and adenosine triphosphate was markedly suppressed by PV isolation (36). In a minority of patients who exhibited PV firing after PV isolation, this was eliminated by GP ablation outside the PV isolation line (36). If the PVs themselves were the source of firing, PV firing should have continued after PV isolation, because there was no injury to the tissues inside the isolation lines. These data raise the possibility that PV firing may be an epiphenomenon and that elimination of substrate outside the PV isolation lines (GP and axons) may be responsible for the clinical ablation results. Targeting the cell bodies within the GP may offer the advantage of permanent denervation, as axons interrupted by PV isolation may regenerate (37). Finally, in light of the recent promising findings of focal source (possibly rotor) ablation (38–40), it is

Atrial fibrillation (AF) induces atrial electrical remodeling and promotes autonomic remodeling, as well as inflammation. These 3 remodeling processes form a vicious cycle, each perpetuating the other, thereby maintaining AF. Autonomic neuromodulation

possible that areas of heavy GP innervation overlap with focal AF sources. Although the exact mechanism

(low-level vagus nerve stimulation or low-level tragus stimulation) may reverse acute

by which GP innervation may interact with focal AF

autonomic remodeling and inflammation and suppress AF.

sources remains to be determined, experimental studies suggest that rotor formation in some forms of AF requires intense autonomic stimulation (41,42), supporting the notion that elimination of GP activity

intact. They demonstrated that intact PVs are not

(by ablation) may limit rotor formation. In isolated

needed to maintain experimental vagal AF, whereas

sheep hearts, elevated acetylcholine concentrations

ablation of GP prevented AF (6). The same group of

increase rotor frequency in the left atrium, thus pro-

investigators expanded these results in a different

moting AF (41), while combined acetylcholine and

experimental model of AF showing that PVs play a

isoproterenol infusion leads to high-frequency focal

minor role in AF induced by chronic rapid atrial pac-

discharges that perpetuate AF (42). Elevated local

ing, whereas intact GP play an important role in AF

acetylcholine and adrenergic levels are also the hall-

maintenance in the presence of rapid atrial pacing–

mark of GP hyperactivity (20,21) and may represent

induced remodeling (7). The degree to which the

the common link between GP and localized AF

specific neural elements within the GP (efferent

sources.

neurons, afferent neurons, or interconnecting neu-

It has been suggested that PV isolation affects the

rons) are responsible for the beneficial results of GP

substrate for AF maintenance. However, the mecha-

ablation remains unclear. Clinical studies showing

nisms remain elusive. Fractionated atrial potentials,

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Autonomic Ganglia and AF

also referred to as complex fractionated atrial elec-

PV isolation and GP ablation groups (56% and 48%,

trograms (CFAEs), represent one of the most specific

respectively) and in a significantly greater number

substrate features of AF (43). Recent studies have

of patients in the PV isolation plus GP ablation

provided evidence that CFAEs may be related to GP

group (74%; p ¼ 0.004 by log-rank test), supporting

hyperactivity (44). For example, in a canine model,

the important role of the autonomic nervous system

the distribution of CFAEs correlated well with the

in the pathophysiology of AF (Figure 5). In another

anatomical locations of the GP, consistent with the

randomized

original clinical report by Nademanee et al. (43), and

persistent or long-standing persistent AF, GP abla-

the CFAEs could be eliminated by ablating the GP at a

tion as an adjunct to PV isolation resulted in higher

distance (44). In addition, CFAEs were correlated

rates of sinus rhythm maintenance at 3 years (49%)

with increased GP activity in ambulatory dogs and

compared with PV isolation plus left atrial linear

preceded the onset of paroxysmal AF, suggesting that

lesions (34%) (55) (Figure 5). In addition, left atrial

GP may serve as both the source for CFAEs and the

tachycardias were less common with PV isolation

trigger for AF (3). In patients with AF, Katritsis et al.

plus GP ablation than with PV isolation plus linear

(45,46) showed that CFAEs are usually found sur-

lesions. GP ablation alone was also tested in pa-

rounding the GP areas. Recent studies have shown

tients with drug-refractory long-standing persistent

that the prevalence of CFAE was reduced after

AF, albeit with less optimal results (38% sinus

combined autonomic blockade with atropine and a

rhythm maintenance at 2 years) (56). These studies

beta-blocker (47,48). We have also shown that the

lend credence to the autonomic hypothesis for AF,

GP (identified by high-frequency stimulation) are

which states that GP activity is most important in

always located within an area of fractionated atrial

the early stages of AF, while its importance may

potentials, and the area of fractionated atrial po-

diminish with progression of the disease to more

tentials is much larger than the GP, suggesting that

advance stages and the development of atrial

although GP ablation consistently produces CFAE

remodeling and fibrosis.

study

including

264

patients

with

(or fractionated atrial potential) ablation, CFAE

Further insight into the relative importance of PV

ablation is not equivalent to GP ablation (49). In a

isolation in maintaining sinus rhythm comes from

series of 33 patients with either paroxysmal or

studies investigating the PV reconnection rate in

persistent AF, after GP ablation (before PV isola-

patients with or without AF recurrence after AF

tion), AF was no longer inducible in 14 of 33 pa-

ablation. A high prevalence of PV reconnection has

tients. After GP ablation, if AF remained inducible,

been reported in patients with AF recurrence (57–59),

the area of fractionated atrial potentials was mark-

but studies including patients without recurrence are

edly reduced (median 27.9 to 1.8 cm2; p < 0.01)

limited, mainly because there is no compelling clin-

(Figure 4) (49).

ical indication to perform a repeat electrophysiolog-

Recent clinical evidence from small randomized

ical study in patients without AF recurrence. In such

and cohort studies, in which GP ablation was per-

a study, Jiang et al. (60) systematically examined the

formed either in addition to PV isolation (11,50)

prevalence of PV reconnection during a repeat pro-

or as a stand-alone procedure (51–53), supports the

cedure in patients with and without clinical AF

experimental data. In these studies, the overall

recurrence. Reconnection in at least 1 PV at repeat

success in eliminating AF was increased with the

electrophysiological study was found in 29 of 32 pa-

addition of GP ablation by approximately 25%

tients (91%) without clinical AF recurrence and in 40

(11,50), whereas GP ablation alone in patients with

of 43 (93%) with AF recurrence, supporting the

either paroxysmal or persistent AF was successful in

notion that sustained PV isolation may not be

71% to 86% of patients (51–53). To provide a more

required for freedom from clinical recurrence of AF,

definitive answer to the question of whether the

consistent with prior experimental studies (6,7). In

addition of GP ablation to PV isolation improves the

other words, the success of AF ablation procedures

success of AF ablation in patients with paroxysmal

may also depend on the elimination of substrate

AF and whether GP ablation alone is as effective as

outside the PV isolation lines, which probably rep-

PV isolation, Katritsis et al. (54) designed a large

resents the GP.

clinical study, which randomized a total of 242 patients with paroxysmal AF to conventional PV

INTERACTIONS BETWEEN THE

isolation, PV isolation plus GP ablation, and GP

EXTRINSIC AND INTRINSIC CANS

ablation alone. The patients were followed for at least 2 years. Freedom from atrial tachyarrhythmias

The interactions between the extrinsic CANS and the

was achieved in a similar number of patients in the

intrinsic CANS were studied systematically by Hou

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Autonomic Ganglia and AF

F I G U R E 4 FAP Maps of the Left Atrium and PVs Before and After Left Atrial GP Ablation (Without PV Isolation or Other Ablation)

(Top) Left atrium and PV before left atrial GP ablation; (bottom) left atrium and PV after left atrial GP ablation. An automated algorithm was programmed to identify segments between electrogram peaks of 15 to 80 ms in duration and define fractionated atrial potential (FAP) as those demonstrating more than 40 such segments per 2.5 s. After ganglionated plexi (GP) ablation, there was a marked decrease in the area of FAP, represented by the red area. PA ¼ posterior anterior; PV ¼ pulmonary vein; RAO ¼ right anterior oblique.

et al. (61). They found that the GP function as

nerve stimulation (both at the suprathreshold level,

“integration centers,” which modulate autonomic

which slows the sinus rate, and at the subthreshold

innervation. GP ablation attenuated the effects of

level, which does not alter the sinus rate) suppresses

vagus nerve stimulation on sinus rate, AV nodal

GP activity (64–66). These studies collectively sug-

conduction

in-

gest that the extrinsic autonomic input to the heart

terconnections exist among the GP, and there is a

(i.e., from the brain and spinal cord) exerts inhibi-

common final pathway to the sinus node and AV

tory control over the GP and that attenuation or loss

node through the anterior right GP and inferior right

of this control would allow the GP to become hy-

GP, respectively (61). Similar neural pathways con-

peractive. GP hyperactivity due to the loss of tonic

necting the GP with the PVs, AV node, and sinus

vagal inhibition with advancing age may explain the

node exist in humans, as shown recently in an

increased prevalence of AF in elderly patients. This

elegant study by Malcolme-Lawes et al. (62). Further

hypothesis is consistent with previous data indi-

studies have shown that ablation of the “head sta-

cating that baroreflex function and vagal efferent

tion” GP, located between the extrinsic and intrinsic

control of the heart is attenuated with aging (67).

CANSs at the junction of the superior vena cava,

Importantly, there is evidence of marked degenera-

aorta, and right pulmonary artery, resulted in pro-

tion of vagal efferent axons and terminals in cardiac

gressive electrical remodeling with progressive in-

autonomic ganglia, which in turn may provide the

crease in AF burden, suggesting that there is a tonic

substrate for reduced vagal control of the heart rate,

and

AF

inducibility.

Multiple

inhibitory input to the GP that is important in pre-

attenuated baroreflex function, and increased pro-

serving sinus rhythm (63). Moreover, we have

pensity for AF with aging (68). It should be noted

recently provided evidence that modulating the

that the interaction between the extrinsic and

extrinsic neural input to the GP by applying vagus

intrinsic

CANS

is

characterized

by

a

constant

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Autonomic Ganglia and AF

F I G U R E 5 Randomized Clinical Trials Including GP Ablation for Paroxysmal or Persistent AF

(A) In patients with paroxysmal atrial fibrillation (AF), pulmonary vein isolation (PVI) plus ganglionated plexi (GP) ablation improved survival free of AF or atrial tachyarrhythmia (AT) compared with GP ablation alone or PVI alone. (B) In patients with persistent AF, PVI plus GP ablation resulted in better survival free of AF or AT compared with PVI plus left atrial linear lesions (LL).

coordination between the central and peripheral

amplitude

neurons in respond to afferent information, to control

(Figure 6). The antiarrhythmic effects of LLVNS were

regional electrophysiological, vascular, and contrac-

also observed in ambulatory dogs. In this experi-

tile function. This interaction can be both excitatory

mental model, left-sided LLVNS suppressed left stel-

and inhibitory, depending on afferent neuronal

late ganglion neural activity, especially in the

transduction of the cardiovascular milieu (69).

morning and decreased tyrosine-hydroxylase positive

of

direct

neural

recordings

(27,73)

cells in the left stellate ganglion 1 week after cessa-

AUTONOMIC NEUROMODULATION

tion of LLVNS (74). In the same study, LLVNS prevented paroxysmal AF induced by rapid atrial pacing

Autonomic neuromodulation is a novel therapeutic

(74). Although the exact downstream targets of

approach that takes advantage of the plasticity of the

LLVNS remain to be determined, there is preliminary

neural tissue to provide therapeutic advantage

evidence that these may involve the antiadrenergic

without damage to nerves or myocardium. This

neuropeptide vasostatin-1 (75), the nitric oxide

approach has been successfully used in some dis-

signaling pathway (76), and up-regulation of the

eases, such as drug-refractory epilepsy, in which

small

vagus nerve stimulation can be delivered through an

channel 2 in the left stellate ganglion (77).

conductance

calcium

activated

potassium

implantable device (70,71). We (27,64,65,72,73) and

On the basis of the observation that trans-

others (74) have recently shown that low-level vagus

cutaneous electrical stimulation of the tragus, the

nerve stimulation (LLVNS), at voltages substantially

anterior protuberance of the outer ear, where the

less than the threshold for slowing the sinus rate or

auricular branch of the vagus nerve is located, elicits

AV conduction, significantly increased the effective

evoked potentials in the brainstem in humans (78),

refractory period in the atria as well as the PV

we recently examined the effects of low-level tragus

myocardium,

and

stimulation (LLTS) for inhibiting AF in a canine

decreased the duration of acetylcholine-induced AF

model of rapid atrial pacing (79). The antiarrhythmic

episodes (Figure 6). In those experiments, LLVNS

effects of LLTS were similar to those of LLVNS

applied to both vagal trunks dissected in the neck

delivered to the cervical vagus nerve trunk(s).

(64,72,73), to the right vagal trunk alone (65), or to the

However, LLTS after transection of both vagus

vagal preganglionic fibers at the posterior wall of the

nerves failed to show any antiarrhythmic effect,

superior vena cava (27) exerted equally strong anti-

indicating that the efferent vagus nerves are essen-

suppressed

AF

inducibility,

arrhythmic effects. We have also provided evidence

tial for its antiarrhythmic effects (79). LLTS reversed

that LLVNS resulted in marked inhibition of GP ac-

the autonomic remodeling process that was induced

tivity, as indicated by a decrease in the frequency and

by rapid atrial pacing, as indicated by a return of the

9

10

Stavrakis et al.

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Autonomic Ganglia and AF

F I G U R E 6 Acute Autonomic Remodeling Induced by 6 h of Rapid Atrial Pacing in a Canine Model and Reversal by LLVNS

(A) Neural activity recorded by a tungsten electrode in the anterior right ganglionated plexi (GP) increased steadily over 6 h of rapid atrial pacing. (B) Three hours (4H, 5H, and 6H) of low-level vagus nerve stimulation (LLVNS) progressively suppressed GP neural activity to baseline (BS) value (6H) despite persistence of rapid atrial pacing. (C) LLVNS for 3 h significantly reduced acetylcholine-induced atrial fibrillation (AF) duration.

neural activity of the anterior right GP to baseline

human study support the notion that noninvasive

values (79). More recently, we translated these data

autonomic

in humans with paroxysmal AF. In a randomized

novel, nonpharmacologic, nonablative therapy for

study, we examined the antiarrhythmic and anti-

the treatment of paroxysmal AF (Central Illustration).

inflammatory effects of 1 h of LLTS (n ¼ 20)

Further

compared with sham (n ¼ 20) in patients referred for

measuring long-term outcome end points are war-

AF ablation (80). We demonstrated for the first time

ranted to evaluate the clinical importance of these

in

findings.

humans

that

LLTS

compared

with

control

neuromodulation

large-scale,

may

double-blind

emerge

clinical

as

a

trials

decreased rapid atrial pacing AF duration, increased AF cycle length, increased the atrial effective re-

CONCLUSIONS

fractory period, and suppressed inflammatory cytokines (Figure 7). The importance of the latter finding

The intrinsic CANS plays an important role in the

is

that

initiation and maintenance of AF and may provide

inflammation promotes the persistence of AF (81).

both the substrate and trigger for AF. Acute auto-

The results of this proof-of-concept and first-in-

nomic remodeling may play a crucial role in AF

highlighted

by

accumulating

evidence

F I G U R E 7 Antiarrhythmic and Anti-Inflammatory Effects of LLTS in Humans

Atrial fibrillation (AF) was induced by rapid atrial pacing at baseline and again after 1 h of low-level tragus stimulation (LLTS) (n ¼ 20) or sham (control, n ¼ 20). There was a significant decrease in AF duration (A) and serum tumor necrosis factor–alpha (TNFa) (B) after 1 h of LLTS but not after 1 h of sham (control).

Stavrakis et al.

JACC: CLINICAL ELECTROPHYSIOLOGY VOL. 1, NO. 1-2, 2015 MARCH/APRIL 2015:1–13

Autonomic Ganglia and AF

maintenance in the very early stages. The benefit of

nonablative approach for the treatment of AF,

adding GP ablation to the standard PV isolation

especially in the early stages. This notion is sup-

procedure for patients with paroxysmal AF is sup-

ported by a preliminary human study. Further

ported by both experimental and clinical data. In

studies are warranted to confirm these findings in

addition, given the close association between GP

ambulatory patients with AF and to identify the ef-

activity and CFAEs, GP ablation may replace CFAE

fects of this novel approach at the molecular,

ablation as part of the ablation procedure for

cellular, and tissue levels.

persistent AF. The beneficial effects of this approach may also include decreasing the autonomic activ-

REPRINT REQUESTS AND CORRESPONDENCE: Dr.

ity required for rotor formation. Autonomic neu-

Stavros Stavrakis, Heart Rhythm Institute, University

romodulation

of Oklahoma Health Sciences Center, 1200 Everett

inhibits

acute

electrical

atrial

pacing

atrial

and

GP

activity

remodeling

may

provide

and

reverses

during an

rapid

alternative

Drive, TCH 6E103, Oklahoma City, Oklahoma 73104. E-mail: [email protected].

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KEY WORDS atrial fibrillation, autonomic nervous system, neuromodulation

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The role of the autonomic ganglia in atrial fibrillation.

Recent experimental and clinical studies have shown that the epicardial autonomic ganglia play an important role in the initiation and maintenance of ...
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