review acta cardiol sin 2007;23:1 12 - 中華民國心臟學會 · 2013-11-14 · and on the...

Vagal Atrial Fibrillation

Yung-Hsin Yeh,1,2,4 Kristina Lemola1,2 and Stanley Nattel1,2,3

The autonomic nerve system plays an important role in atrial fibrillation (AF). Vagal AF refers AF (generally

paroxysmal) arising in contexts of enhanced parasympathetic tone. Heterogeneity of refractoriness and action

potential abbreviation resulting from spatially variable parasympathetic enhancement of the acetylcholine-

dependent K+-current (IKACh) underlie vagal AF. Adrenergic influences may also contribute to the occurrence of

vagal AF. Cholinergic stimulation may enhance ectopic firing from pulmonary vein cardiomyocytes, which

potentially contribute to the occurrence of vagal AF. On the other hand, underlying heart disease modulates

cholinergic regulation of atrial myocytes. Careful history taking in AF patients is important for vagal AF management.

Vagal denervation may play a role in the efficacy of ablation procedures, but the results are conflicting. Specific

IKACh channel blockers may become the treatment of choice in the future.

Key Words: Vagal atrial fibrillation � Acetylcholine � Muscarinic receptor � Pulmonary vein � Vagal

denervation

INTRODUCTION

The autonomic nervous system is known to play an

important role in the occurrence of atrial fibrillation

(AF).1 Several clinical observations suggest that en-

hanced parasympathetic tone is involved in some cases

of paroxysmal AF, clinically referred to as “vagal AF”.2,3

Coumel was the first physician to use the terms vagal

and adrenergic AF in his studies on autonomic tone and

AF.1 The effects of parasympathetic stimulation on car-

diomyocytes are mainly through changes in ion channel

function in response to the activation of muscarinic ace-

tylcholine receptors (mAChRs) following release of the

neurotransmitter acetylcholine (ACh). In experimental

animal models, both vagal stimulation and acetylcholine

administration can induce AF without electrical

stimulation of the atrium. In this article we will review

the effects of ACh on ion channels in atrial myocytes

and on the electrophysiology of atrial tissue, as well as

the electrophysiological mechanisms of vagal AF.

Finally, we will discuss clinical relevance and potential

treatment of vagal AF.

Cellular ionic-current effects of acetylcholine

in atrium

The cardiac effects of parasympathetic stimulation

are mediated through the vagus nerve. Release of ACh

activates mAChRs. The parasympathetic system exerts

important physiological influences over pacemaker ac-

tivity, atrioventricular conduction, action potential dura-

tion (APD) and contractile force. In mammals, the M2

receptor is the predominant mAChR subtype expressed

in heart.4 The coupling of M2AChR activation to most

changes in cardiac ion channels is via the pertussis

toxin-sensitive G protein (Gi/o). Gi activation inhibits

adenylyl cyclase. Furthermore, M2AChRs can couple to

certain K+ channels, referred as G-protein regulated in-

ward-rectifier K+ channels (GIRK), and can influence

Ca2+ channels, the “funny” current (If) involved in pace-

1 Acta Cardiol Sin 2007;23:1�12

Review Acta Cardiol Sin 2007;23:1�12

Received: November 22, 2006 Accepted: December 14, 20061Department of Medicine and Research Center, Montreal Heart In-stitute, Quebec, Canada; 2Department of Medicine, University ofMontreal, Quebec, Canada; 3Department of Pharmacology McGillUniversity, Quebec, Canada. 4First Cardiovascular Division, ChangGung Memorial Hospital, Chang Gung University, Tao-Yuan, Taiwan.Address correspondence and reprint requests to: Dr. Stanley Nattel,5000 Belanger Street East, Montréal, Québec, H1T 1C8, Canada.Tel: (514)-376-3330 ext. 3990; Fax: (514)-376-1355; E-mail: [email protected]

making, phospholipase A2, phospholipase D and tyrosine

kinase.5-7 Some studies also suggest that the cyclic

guanosine monophosphate ( cGMP) signaling pathway is

involved in muscarinic activation.8-10

Activation of mAChRs in the heart results in (1)

hyperpolarization and slowed spontaneous depolariza-

tion in sinoatrial node (SAN), (2) shortened APD and

reduced contractile force in atrium and (3) decreased

conduction velocity in the atrioventricular node (AVN).

The effects on cardiac electrophysiology are mainly

through regulation of membrane ion channels and pos-

sibly gap junctions. Figure 1 shows an overview of

mAChR regulation of cardiac ion channels.

Regulation of pacemaker current If

ACh decreases If and shifts its activation to more

negative potentials, thus slowing pacemaker activity in

SAN.11,12 If is a directly cAMP-sensitive current.13 The

ACh-induced decrease in If is mainly via mAChRs and

Gi/o protein, resulting in inhibition of adenylyl cyclase

and decreased cAMP production. In addition, there is an

alternative pathway by which mAChR activation can in-

hibit If via cAMP-independent signaling, but this may be

of lesser importance.14

Regulation of IKACh

IKACh is an inwardly-rectified K+ current carried

by GIRK (Kir3) channel subunits activated by acetyl-

choline or other muscarinic agonists. IKACh activation

is believed to be the principle mediator of parasym-

pathetic effects on the heart. Cardiac GIRK channels

are composed of two homologous proteins: GIRK1

and GIRK4 (Kir3.1 and 3.4).15 In mammals, IKACh is

found in the SAN, atria, AVN and Purkinje fibers.16

When acetylcholine is applied to atrial myocytes,

heterotrimeric Gi/o-proteins (composed of an �, �

and � subunit) coupled to mAChRs dissociate into

their constituent G�i/o and G�� dimer subunits. Dis-

sociated G�i/o and G�� subunits are able to modulate

physiological actions by interacting with numerous

effectors, including protein kinases, phospholipases,

phosphodiesterases and ion channels. G�� is the pri-

mary activator of GIRK channels via a membrane

delimited pathway.17 In SAN, IKACh results in mem-

brane hyperpolarization and slowing of pacemaker

activity. In atrial myocytes, IKACh causes atrial repo-

larization and is the main current that ACh activates to

shorten APD, which facilitates reentry and tachy-

arrhythmia.

Regulation of L-type calcium current ICa.L

Muscarinic activation suppresses ICa,L.18,19 This sup-

pressive effect could be via inhibition of adenyly cyclase,

thereby decreasing cAMP concentrations, or via cGMP/

PKG-dependent activation of okadaic acid-sensitive

protein phosphatase.20,21 This decrease in ICa,L may con-

tribute to the APD shortening by cholinergic stimulation.

Effects on other ion currents

In guinea pig cardiomyocytes, ACh alone has no ef-

fect on delayed rectifier K+ currents (IK), but the increase

in IK by isoproterenol can be antagonized by ACh via re-

duction of intracellular cAMP.22 INa may be enhanced by

muscarinic stimulation23 whereas Cl- current activated

by �-adrenergic agonists are suppressed by muscarinic

stimulation.24 The physiological roles of these responses

in human hearts are still unclear.

Effects on gap junction

Muscarinic activation can also affect gap junction

function in the heart. Takens-Kwak et al.9 showed that

muscarinic activation in neonatal rat cardiomyocytes re-

duces the intercellular current. Gap junction conductance

in cultured neonatal rat cardiomyocytes is also decreased

by carbachol in a cGMP-dependent manner.8,10 These re-

sults suggest that muscarinic activation inhibits gap

junction communication, which could decrease conduc-

tion velocity in atrium, which might facilitate reentry

and lead to arrhythmia.

Acta Cardiol Sin 2007;23:1�12 2

Yung-Hsin Yeh et al.

Figure 1. Overview of signaling pathways responsible for M2AChR

regulation of cardiac ion channels. ACh, acetylcholine; M2, muscarinic

acetylcholine receptor subtype 2; GIRK, G-protein regulated inward-

rectifier K+ channels; IKACh, acetylcholine-sensitive K+ current; If, pace-

maker current; ICa,L, L-type Ca2+ current; PKA, protein kinase A; PKG,

protein kinase G.

Tissue effects of cholinergic stimulation

Cholinergic stimulation abbreviates APD and ERP,

mainly through the activation of IKACh. Experimental

studies also show that vagal stimulation increases the

spatial dispersion in atrial refractoriness,25-28 as well as

in APD. Both absolute APD/ERP shortening and in-

creased APD/ERP heterogeneity facilitate reentry and

tachyarrhythmia. Liu et al.27 showed that vagal stimula-

tion increases the variability in atrial refractoriness, as

indicated by the standard deviation of ERP at different

atrial sites and of activation frequency during AF. Al-

though sympathetic stimulation also decreases atrial

ERP, it has no significant effect on these indexes of ERP

heterogeneity.27 Perhaps because of its lack of effect on

spatial ERP dispersion, sympathetic stimulation was

much less effective than vagal stimulation in promoting

AF. In another animal study in which AF was induced by

vagal stimulation,29 flecainide doses that terminated AF

significantly reduced refractoriness heterogeneity during

nerve stimulation, to the same range under control con-

ditions without nerve stimulation. These observations

suggest that increased heterogeneity may be a very im-

portant atrial proarrhythmic vagal mechanism. This idea

is compatible with both experimental and computer

models of AF which indicate that heterogeneity in

refractoriness is an important determinant of AF occur-

rence.30-32

Potential mechanisms for the increased spatial heter-

ogeneity in refractoriness induced by vagal stimulation

includes inhomogeneous nerve innervation33,34 and vary-

ing IKACh densities due to heterogeneous distribution of

mAChRs and/or GIRK channels over the atria.34-37 La-

beling for the high affinity choline transporter, an in-

dicator of cholinergic nerve fibers, is distributed hetero-

geneously over the atria.34 These fibers are abundant in

the sinus and atrioventricular nodes, interatrial septum,

and much of the right atrium (RA), but less abundant in

the left atrium (LA). Lomax et al.35 also showed that in

mouse atria IKACh current density is significantly higher

in SA node myocytes than either RA or LA myocytes

and IKACh is significantly larger in RA than in LA

myocytes. In sheep, Sarmast et al37 showed a greater

abundance of GIRK1/4 mRNA level and IKACh densities

in LA than in RA, which may account for more ACh-

induced rotors observed by optical mapping in LA than

in RA. Huang et al.36 showed that the densities of

mAChRs and IKACh measured by Western blot and patch

clamp respectively are higher in LA, RA appendage and

LA free wall of dogs than in RA free wall, PVs and

superior vena cava. Administration of amiodarone elimi-

nates the difference in IKACh densities between LA and

RA, but IKACh is still higher in LA and RA appendage.

They suggested that decreased dispersion of IKACh densi-

ties may be a potential mechanism for amiodarone

efficacy in AF.

Mapping studies show that spontaneous premature

atrial premature depolarizations precede spontaneous AF

induced by vagal stimulation.38 The mechanism of thess

spontaneous atrial depolarizations that trigger vagal AF

was proposed to be local microreentry.32,38,39 Computer

simulation suggests that vagal AF is maintained by sin-

gle or a small number of reentry sources with fibrillatory

conduction.32,39 Kneller et al.32 showed that cholinergic

stimulation stabilizes the primary spiral wave generator

and vagal-mediated refractoriness heterogeneity results

in wavefront disorganization and breakup. These results

are compatible with experimental mapping studies which

show that vagal stimulation greatly increases the genera-

tion of atrial extrasystoles initiating AF.38,40,41 In a study

in which AF was induced by ACh perfusion in isolated

canine RA preparations,41 activation sequence mapping

revealed multifocal atrial premature depolarizations and

regions of functional block during AF. In another study,

Sharifov et al.38 stimulated vagus nerve in open chest

dogs to induce AF and showed that vagal-mediated focal

ectopic atrial premature depolarizations are widely

distributed over the atria. The occurrence of atrial tac-

hyarrhythmia events increased proportionally with stimu-

lation intensity. In most cases of sustained AF, a single

leading and stable source of reentry circuit was estab-

lished after second to third beat or after interaction

among unstable sources. Both animal and computer si-

mulation models suggest that spiral wave reentry42 under-

lies vagal AF.

IKACh is essential in the generation of vagal AF. In

Kneller’s32 study the authors suggested that IKACh is a de-

terminant of frequency and stability during vagal AF.

Kovoor et al.43 studied an IKACh-deficient (GIRK4 knock-

out) mouse model and found that AF can’t be induced in

knockout mice lacking IKACh, indicating that activation

of IKACh is required for cholinergic AF. AF was induced

in the presence of carbachol by burst pacing in 10/14



wild type mice, and lasted for a mean of 5.7 � 11 min,

but AF could not be induced in the absence of carbachol.

In knockout mice, atrial arrhythmia could not be induced

with or without the use of carbachol.

Interactions between cholinergic and adrenergic

stimulation

Both cholinergic and adrenergic stimulation can

promote the occurrence of AF, although adrenergic sti-

mulation is much less effective than cholinergic stimula-

tion.27,44 Interaction between adrenergic and cholinergic

tone may play an important role in initiating and perpet-

uating AF:44,45 simultaneous adrenergic stimulation has

been shown to facilitate the induction of ACh-mediated

AF.45 Sharifov et al.44 showed that catecholamine can in-

duce AF (about 20% of the time) in open chest dogs, and

atropine completely prevents catecholamine-mediated

AF, indicating an important role of cholinergic tone in

these AF episodes. ACh induced AF in all dogs and

�-adrenergic blockade didn’t prevent ACh-induced AF,

but increased the threshold ACh concentration for AF in-

duction. Catecholamine administration decreased the

threshold of ACh concentration for AF induction and in-

creased AF duration. These results suggest that both

cholinergic and adrenergic stimulation can contribute to

AF induction during the activation of both systems, and

cholinergic stimulation plays a more potent role in AF

than adrenergic stimulation in this model.

In a human study, Bettoni et al.46 showed that the

occurrence of paroxysmal AF greatly depends on fluctua-

tions in autonomic tone. Using heart rate variability

(HRV) analysis method, they showed an increase in

high-frequency components (which suggest increased

cholinergic tone) as well as a progressive increase in

low-frequency components (which suggest increased

adrenergic tone) at least 20 min before AF. The low/high

frequency ratio showed a linear increase until 10 min be-

fore AF onset, followed by a sharp decrease immediately

before AF. They also showed no difference in HRV

between patients with and without underlying heart dis-

ease. These findings suggest that both components of the

autonomic system are involved in the initiation of parox-

ysmal AF, with an initial increase in adrenergic tone

followed by a shift to vagal predominance.

Cholinergic effects on PV myocyte arrhythmo-

genesis

Pulmonary veins (PVs) are known to be important in

initiating and maintaining AF.47 Radiofrequency catheter

ablation in and around PVs is most effective in curing

AF among patients without structural heart disease. In

dogs PVs have been shown to exert rapid firing of

ectopic foci and triggered AF-mediated by triggered ac-

tivity or abnormal automaticity,48 although this has not

been a universl finding.49

Since both vagal AF and PV-related AF often occur

in patients without structural heart disease,1 it is natural

to investigate the role of cholinergic effects on PVs

arrhythmogenesis. Recent studies showed that the auto-

nomic nervous system plays important role in initiating

PV firing and paroxysmal AF.50-55 Schauerte et al.50 per-

formed high-frequency electrical stimulation in the PVs

in dogs, leading to local ERP shortening and occurrence

of AF. The response to high-frequency electrical stimu-

lation was completely abolished by atropine, but only

blunted by �-adrenergic blockers. Scherlag et al.54 showed

in an open chest canine model that when the autonomic

ganglion located at the base of the PVs was stimulated,

producing a response of reduction in heart rate, fewer

atrial premature depolarizations were required to induce

AF than in control conditions without ganglionic stimu-

lation. The authors suggested that autonomic ganglion

stimulation, which led to vagal responses in this experi-

ment, facilitates the conversion of PV firing into AF.

In a human study, Zimmermann et al.55 showed that

in patients with focal ectopic firing from the PVs, epi-

sodes of AF were associated with variations in autonomic

tone, with a significant shift toward vagal predominance

before AF onset. Takahashi et al.53 further showed in

humans that vagal excitation was associated with shorten-

ing of fibrillatory cycle length in the PVs and facilitated

AF. These studies suggest that the PVs are susceptible to

enhanced vagal tone in triggering AF.

Triggered activity has been proposed to be the mech-

anism of PV arrhythmogenesis resulting from enhanced

parasympathetic tone. Patterson et al.51,56 provided data

suggesting that enhanced sodium-calcium exchange ac-

tivity initiated by the calcium transient is responsible for

focal firing from the PVs during field stimulation. With

the application of ACh, abbreviated APs and early

afterdepolarizations (EADs) were induced in superfused

canine PV preparations. With co-application of ACh and

norepinephrine, tachycardia-pause triggered rapid firing

within the PV sleeve. The authors proposed that in the



PVs, the abbreviation of APs by ACh enhanced calcium

transients, promoting EAD formation and tachyarrhy-

thmia.

Other findings suggest that vagal enhancement can

suppress paroxysmal AF originating from the PVs.57,58

Tai et al.57 showed that in patients with focal AF origi-

nating from the PVs, the frequency of ectopic activity as

well as AF bursts from the PVs were significantly re-

duced after intravenous phenylephrine infusion, which

causes vagal enhancement and sympathetic withdrawal.

The authors proposed that reduced automaticity by vagal

tone may decrease focal firing from PVs. More studies

are needed to explain the role of autonomic function in

PV-related AF.

Figure 2 shows an overview of proposed electro-

physiological mechanisms by which enhanced parasym-

pathetic tone favours the induction of AF.

Vagal remodeling and roles of mAChRs and

GIRK channels in AF

Although most vagal AF occurs in patients without

structural heart disease,2 the parasympathetic system and

its effectors also plays a role in AF patients with under-

lying heart disease. Parasympathetic tone is likely to be

remodeled in AF. Blaauw et al.59 showed that in goats af-

ter 24-hour rapid atrial pacing, there was a significant

increase in HRV, suggesting an increase in vagal tone.

During recovery from atrial ERP shortening, higher

vagal tone was associated with shorter atrial ERP and at-

tenuated recovery. Several studies in human and animal

models also showed that both mAChRs and GIRK chan-

nels are remodeled in AF. In a canine model of AF

induced by heart failure and in humans with AF, IKACh is

downregulated,60,61 and protein or mRNA expression

levels of both GIRK1/4 and M2AChRs are reduced.60-62

On the other hand, the activity of acetylcholinesterase,

the enzyme that hydrolyzes ACh at cholinergic neu-

roeffector junctions, is reduced in chronic AF,63 which

may partially compensate for the reduced IKACh density

by increasing ACh cncentrations in the synaptic cleft.

Ehrlich et al showed that a consitutively-active IKACh

(measurable in the absence of ACh) is present in left

atrium, particularly in PVs, and is upregulated by atrial

tachycardia remodeling.64 Dobrev et al.65 showed that in

patients with chronic AF, IKACh is also upregulated. The

increased constitutively active IKACh could be explained

by higher channel open probability in chronic AF than in

sinus rhythm (5.4 � 0.7% versus 0.13 � 0.05%). In ca-

nine it was also shown that atrial tachycardia remodeling

increased constitutively active IKACh, and a highly selec-

tive GIRK channel antagonist, tertiapin-Q, increased

APD and suppressed atrial tachyarrhythmias in atrial

tachycardia-remodeled preparations.66 These results sug-

gest that GIRK channels are activated in AF even in the

absence of cholinergic stimulation and that this con-

tributes to AF-related APD shortening and AF arrhy-

thmogenesis. Since atrial tachyarrhytmia could be termi-

nated by tertiapin-Q, GIRK channels are a potentially

interesting target in AF.

Wallukat et al.67 showed that autoantibodies directed

against M2AChRs (M2AAB) are present in about 40% of

patients with cardiomyopathy of various etiology. Baba

et al.68 also showed that M2AAB is detected in 40% of

patients with dilated cardiomyopathy and in 23% of AF

patients without structural heart disease, versus 8% in

healthy control. Purified M2AAB obtained from both

lone AF and dilated cardiomyopathy patients were in-

jected into chick embryos, resulting in negative chro-

notropic effects and induced supraventricular arrhy-

thmias. This study suggests that M2AAB could play a

proarrhythmic role in AF patients with or without struc-

tural heart disease via activation of mAChRs.

Clinical relevance

Clinically, vagal AF is considered if paroxysmal AF

episodes occur at rest, after meals or during sleep and



Figure 2. Diagram of proposed electrophysiological mechanisms

contributing to vagal AF. AP, action potential; EAD, early after-

depolarization.

stop in the morning or with exercise (Table 1). Vagal AF

usually occurs in young patients with ages between 30

and 50, more frequently in men and without structural

heart disease. The ECG commonly shows flutter al-

ternating with fibrillation. In contrast, adrenergic AF

usually occurs in the presence of structural heart disease.

Holter monitoring may show sinus bradycardia before

the onset of AF and a slow ventricular response during

AF.1,69 However, manifestations of vagal and adrenergic

AF may coexist in the same patient, and the clinical pat-

tern may change over time.

Characterization and quantification of autonomic

changes and evaluation of vagal AF in humans are diffi-

cult to refine. Analysis of heart rate variability (HRV) is

a noninvasive and useful method to evaluate the balance

between sympathetic and parasympathetic tone.3,70 An

increase of low-frequency/high-frequency (LF/HF) ratio

means an enhancement of sympathetic tone whereas a

decreased ratio means an enhancement of parasympa-

thetic tone. However, this approach is over-simplified

and may not always accurately reflect autonomic func-

tion. Some studies have shown that paroxysmal AF

occurring during sleep are preceded by an increase in

high-frequency components, suggesting increased vagal

activity preceding AF.71-73 However, one group showed

data suggesting that sympathetic tone is increased before

AF onset during sleep.74 Another group showed that both

LF and HF components are increased before AF onset,

with no change in LF/HF ratio.75 These findings may be

due to the presence of autonomic fluctuation before the

onset of paroxysmal AF.46 Different patient groups may

have contributed to discrepancies. Concurrent enhance-

ment of sympathetic tone may play a role in some cases

of vagal AF.

Paroxysmal AF tends to co-exist in patients with

paroxysmal supraventricular tachycardia (PSVT).76 Chen

et al.77 showed that among patients with PSVT, higher

baroreflex sensitivity (BRS), which implies higher vagal

reactivity, and greater atrial ERP dispersion during

episodes of PSVT are seen in patients with PSVT associ-

ated with paroxysmal AF. This observation suggests that

higher vagal reflex tone contributes to the genesis of par-

oxysmal AF in patients with PSVT.

However, evidence regarding the pathophysiological

mechanisms underlying vagal AF is not consistent. van

den Berg et al.69 showed that vagal AF is not caused by

increased vagal reactivity. They grouped vagal AF and

non-vagal AF among paroxysmal AF patients by clinical

criteria. They showed that either a battery of autonomic

tests (with use of the Finapress system) or BRS is not

significantly different between vagal AF and non-vagal

AF patients. Furthermore, vagal reactivity among parox-

ysmal AF patients was below the normal range.78 The

authors suggested that either increased susceptibility of

the heart to vagal influences or increased vagal tone

could potentially play important roles in vagal AF. More

studies are needed.

Therapeutic Implications

Pharmacological treatment

Management of AF should be directed according to

the condition and the underlying disease.45 Studies ava-

ilable so far indicate that no clear advantage exists be-

tween rhythm control and rate control in AF.79,80 Only

anecdotal data are available regarding the pharmacologi-

cal rhythm control of vagal AF.1,81,82 van den Berg et al.

reported a case of typical vagal AF, presenting episodes

predominantly at rest, during sleep, and after physical

activity.81 Medication with digoxin, verapamil, sotalol,

and flecainide was ineffective. The patient was treated

successfully with disopyramide, which has anticholi-

nergic properties. HRV analysis showed a decrease in



Table 1. Characteristics of vagal-mediated and adrenergic-mediated AF

Vagal-meduated AF Adrenergic-mediated AF

More common Less common

Predominence in man, age between 30 and 50 years No particular predominence

Patients without heart disease (long AF) Often in patients with identified heart disease

Preferentially noctural, during rest, after eating or drinking During daytime or diurnal, provoked by exercise or emotional stress

Preceded by bradycardia Preceded by tachycardia

Lower ventricular response rate during AF Higher ventricular response rate during AF

Aggravation by �-blocker and/or digoxin Benefit from �-blocker and/or digoxin

high-frequency components after successful treatment.

Digoxin or �-blockers are generally not beneficial and

can even be detrimental to vagal AF, although they are

commonly used in AF with structural heart disease.

Class I antiarrhythmic drugs with vagolytic effects are

theoretically effective in treating vagal AF. Propafenone

is not very effective because of its �-blocking properties.

Coumel2,82 recommended flecainide, quinidine, and di-

sopyramide in treating vagal AF (in decreasing order,

respectively).

PV isolation and/or vagal denervation

PVs are well-known to provide a focal origin of AF

in many patients, and PV ablation is effective in curing

paroxysmal AF.47 Oral et al.58 showed that PV isolation

is less effective in patients with vagal AF than patients

with adrenergic or mixed form. Razavi et al.83 showed

that ablation around the PV-LA junction decreases the

degree of atrial ERP shortening and vulnerability to AF

induced by vagal stimulation. Their results suggested

that the ganglion plexus around PV-LA junction contrib-

uted to cholinergic innervation in the atria and ablating

this region of ganglion plexi can effectively diminish the

atrial response to vagal stimulation. PVs isolation plus

vagal denervation can be effective in treating vagal AF.84

Pappone et al.84 showed that in patients with paroxysmal

AF, after circumferential PV ablation, adjunctive vagal

denervation significantly reduced the recurrence of AF

at a 12-month follow-up (99% versus 85% in patients

without adjunctive vagal denervatioin). Ablating around

the entrance of PVs achieved vagal denervation at areas

corresponding to areas at which slowing of sinus rhythm

or slowing of ventricular response during AF was ob-

tained during radiofrequency ablation. Scherlag et al.85

also reported the effects of PV isolation plus ganglion

plexus ablation in AF patients. The ganglionic plexi

were also identified around the entrance of PVs. Prior to

PVs isolation, ganglion plexus ablation alone abolished

focal firing from PVs in 95% of cases. These findings

are compatible with experimental studies showing that

enhanced parasympathetic tone facilitates focal firing

from PVs and that vagal denervation abolishes this ef-

fect. Recently, Tan et al.86 showed that adrenergic and

cholinergic nerves are at highest densities within 5 mm

of the PV-LA junction and that both are situated close to

each other and can even be intermixed.

Vagal denervation alone has been evaluated for AF

prevention in both animal models and in patients during

cardiac surgery. Chiou et al.87,88 showed that most vagal

fibers travel through a fat pad located between aortic

root and superior vena cava, then project onto two fat

pads over the heart: one at the junction between inferior

vena cava and LA, the other at the junction of right PV

and RA. They showed that radiofrequency catheter ab-

lation of these fat pads eliminates HRV and BRS. Some

studies suggest that it may not be necessary to ablate all

three pads to suppress AF induced by vagal stimula-

tion.28,89 However, the results of partial vagal dener-

vation are conflicting. One study showed that ventral

cardiac denervation reduces the occurrence of AF after

coronary artery bypass grafting,90 but another group

showed that a similar strategy to prevent post-cardiac

surgical AF is ineffective.91 Cummings et al.92 showed

that removal of a fat pad located between the pulmo-

nary artery and aorta during cardiac surgery prevented

sinus bradycardia induced by vagal nerve stimulation,

suggesting the presence of vagal fibers. Paradoxically,

removal of this fat pad increased the incidence of post-

operative AF. Hirose et al.93 showed that partial vagal

denervation facilitates rather than preventing vagally-

mediated AF. The likely explanation is that partial

vagal denervation worsens autonomic imbalance, as

well as parasympathetic inhomogeneities. Nerve regen-

eration may attenuate the long-term effects of vagal

denervation. Oh et al.94 showed l that epicardial radio-

frequency ablation over fat pads in dogs effectively

reduces the inducibility of vagally-mediated AF, but 4

weeks later the effect is lost.

Selective GIRK channel antagonists

Cardiac-selective specific GIRK channel antagonists

could be useful in the treatment of AF. In GIRK4-

knockout mice,43 vagal AF is prevented without favoring

ventricular arrhythmias or affecting AVN function.

Therefore, GIRK blockers are potentially therapeutic

without adverse effects on ventricular arrhythmia or con-

duction. However, the sinus rate might be accelerated by

GIRK antagonists. In a canine study, Hashimoto et al.95

showed that tertiapin-Q, a specific GIRK channel antag-

onist, prolongs atrial ERP and terminates AF induced by

vagal stimulation, without affecting ventricular repo-

larization. Cha et al.66 showed that a GIRK channel

antagonist is effective in an atrial tachyrdia-induced AF

model.



CONCLUSION

The autonomic nerve system, and particularly the

vagal copmponent, plays an important role in AF. Clini-

cal observations show that enhanced parasympathetic

tone contributes to some cases of paroxysmal AF, clini-

cally referred to as vagal AF. The electrophysiological

mechanisms of vagal AF mainly comprises atrial APD/

ERP shortening and increased dispersion of atrial refrac-

toriness via activation of IKACh. Cholinergic stimulation

may also enhances focal firing from PVs. Interactions

between vagal and adrenergic tone may also playa role

in AF. Vagal denervation likely decreases the occurrence

of some AF but the long-term efficacy of vagal de-

nervation is questionable. Careful history-taking is im-

portant for accurate diagnosis and appropriate pharmaco-

logical treatment of vagal AF. Selective GIRK blockers

could potentially become the treatment of choice for

vagal AF in the future.

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Apr 1 2006.



Review Acta Cardiol Sin 2007;23:1−12

迷走神經性心房顫動

葉勇信1,2,4 Kristina Lemola1,2 Stanley Nattel1,2,3

Department of Medicine and Research Center, Montreal Heart Institute, Quebec, Canada1

Department of Medicine, University of Montreal, Quebec, Canada2

Department of Pharmacology McGill University, Quebec, Canada3

基隆市長庚紀念醫院心臟內科4

自主神經系統在於引起心房顫動扮演重要的角色，迷走神經性心房顫動係指副交感神經興

奮所引起的心房顫動。其作用機轉主要是經由活化乙醯膽鹼鉀離子通道 (IKACh)，在心房造

成不均勻地不反應期與動作電位縮短，形成再進入迴路 (reentry) 因而誘發心房顫動。交

感神經興奮會使迷走神經性心房顫動更容易發生。副交感神經興奮會使肺靜脈異常放電更

容易發生，因此肺靜脈異常放電也可能是引起迷走神經性心房顫動的重要原因。心臟本身

疾病會改變迷走神經對於心房細胞的正常作用，可能也是引起心房顫動的原因。臨床的診

斷仍主要有賴於詳細病史詢問，去迷走神經 (vagal denervation) 是否能治療迷走神經性心

房顫動仍有爭議，特異性乙醯膽鹼鉀離子通道阻斷劑未來可能是治療方式的選擇之一。

關鍵詞：迷走神經性心房顫動、乙醯膽鹼、蕈毒鹼接受器、肺靜脈、去迷走神經化。

12

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