Review Acta Cardiol Sin 2007;23:1-12

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 administration can induce AF without electrical

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
Received: November 22, 2006 Accepted: December 14, 2006
1Department of Medicine and Research Center, Montreal Heart In-
stitute, Quebec, Canada; 2Department of Medicine, University of
Montreal, Quebec, Canada; 3Department of Pharmacology McGill
University, Quebec, Canada. 4First Cardiovascular Division, Chang
Gung 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: stanley.
Nattel@icm-mhi.org
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

 Yung-Hsin Yeh et al.
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 I f 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
I KACh is an inwardly-rectified K + current carried
by GIRK (Kir3) channel subunits activated by acetyl-
choline or other muscarinic agonists. I KACh activation
is believed to be the principle mediator of parasym-
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.
Acta Cardiol Sin 2007;23:1-12
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, I KACh 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 a, b
and g subunit) coupled to mAChRs dissociate into
their constituent Gai/o and Gbg dimer subunits. Dis-
sociated Gai/o and Gbg subunits are able to modulate
physiological actions by interacting with numerous
effectors, including protein kinases, phospholipases,
phosphodiesterases and ion channels. Gbg is the pri-
mary activator of GIRK channels via a membrane
delimited pathway. 17 In SAN, I KACh results in mem-
brane hyperpolarization and slowing of pacemaker
activity. In atrial myocytes, I KACh 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 b-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.
2
 Vagal Atrial Fibrillation
Tissue effects of cholinergic stimulation
Cholinergic stimulation abbreviates APD and ERP,
mainly through the activation of I KACh . 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 I KACh is significantly larger in RA than in LA
myocytes. In sheep, Sarmast et al 37 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
3 Acta Cardiol Sin 2007;23:1-12
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
 Yung-Hsin Yeh et al.
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
b-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
Acta Cardiol Sin 2007;23:1-12
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 b-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
4
 Vagal Atrial Fibrillation
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
5 Acta Cardiol Sin 2007;23:1-12
Figure 2. Diagram of proposed electrophysiological mechanisms
contributing to vagal AF. AP, action potential; EAD, early after-
depolarization.
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 M 2 AAB 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
 Yung-Hsin Yeh et al.
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
Table 1. Characteristics of vagal-mediated and adrenergic-mediated AF
Vagal-meduated AF
More common
Predominence in man, age between 30 and 50 years
Patients without heart disease (long AF)
Preferentially noctural, during rest, after eating or drinking
Preceded by bradycardia
Lower ventricular response rate during AF
Aggravation by b-blocker and/or digoxin
Acta Cardiol Sin 2007;23:1-12
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
Adrenergic-mediated AF
Less common
No particular predominence
Often in patients with identified heart disease
During daytime or diurnal, provoked by exercise or emotional stress
Preceded by tachycardia
Higher ventricular response rate during AF
Benefit from b-blocker and/or digoxin
6
 Vagal Atrial Fibrillation
high-frequency components after successful treatment.
Digoxin or b-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 b-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
7 Acta Cardiol Sin 2007;23:1-12
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.
 Yung-Hsin Yeh et al.
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.
REFERENCES
1. Coumel P. Paroxysmal atrial fibrillation: a disorder of autonomic
tone? Eur Heart J. Apr 1994;15 Suppl A:9-16.
2. Coumel P. Autonomic influences in atrial tachyarrhythmias. J
Cardiovasc Electrophysiol. Oct 1996;7(10):999-1007.
3. Lombardi F, Malliani A, Pagani M, et al. Heart rate variability and
its sympatho-vagal modulation. Cardiovasc Res. Aug 1996;
32(2):208-16.
4. Hulme EC, Birdsall NJ, Buckley NJ. Muscarinic receptor sub-
types. Annu Rev Pharmacol Toxicol. 1990;30:633-73.
5. Felder CC. Muscarinic acetylcholine receptors: signal trans-
duction through multiple effectors. Faseb J. May 1995;9(8):
619-25.
6. Caulfield MP, Birdsall NJ. International Union of Pharmacology.
XVII. Classification of muscarinic acetylcholine receptors. Phar-
macol Rev. Jun 1998;50(2):79-290.
7. Dhein S, van Koppen CJ, Brodde OE. Muscarinic receptors in the
mammalian heart. Pharmacol Res. Sep 2001;44(3):161-82.
8. Burt JM, Spray DC. Single-channel events and gating behavior of
the cardiac gap junction channel. Proc Natl Acad Sci U S A. May
1988;85(10):3431-4.
9. Takens-Kwak BR, Jongsma HJ. Cardiac gap junctions: three
distinct single channel conductances and their modulation by
phosphorylating treatments. Pflugers Arch. Nov 1992;422(2):
198-200.
10. Kwak BR, Jongsma HJ. Regulation of cardiac gap junction
channel permeability and conductance by several phosphory-
Acta Cardiol Sin 2007;23:1-12
lating conditions. Mol Cell Biochem. Apr 12-26 1996;157(1-2):
93-9.
11. DiFrancesco D, Tromba C. Inhibition of the hyperpolarization-
activated current (if) induced by acetylcholine in rabbit sino-atrial
node myocytes. J Physiol. Nov 1988;405:477-91.
12. DiFrancesco D, Tromba C. Muscarinic control of the hyper-
polarization-activated current (if) in rabbit sino-atrial node myo-
cytes. J Physiol. Nov 1988;405:493-510.
13. DiFrancesco D, Tortora P. Direct activation of cardiac pacemaker
channels by intracellular cyclic AMP. Nature. May 9 1991;
351(6322):145-7.
14. Yatani A, Okabe K, Codina J, et al. Heart rate regulation by G
proteins acting on the cardiac pacemaker channel. Science. Sep 7
1990;249(4973):1163-66.
15. Kubo Y, Reuveny E, Slesinger PA, et al. Primary structure and
functional expression of a rat G-protein-coupled muscarinic
potassium channel. Nature. Aug 26 1993;364(6440):802-6.
16. Kurachi Y, Tung RT, Ito H, et al. G protein activation of cardiac
muscarinic K+ channels. Prog Neurobiol. Sep 1992;39(3):229-
46.
17. Yamada M, Inanobe A, Kurachi Y. G protein regulation of po-
tassium ion channels. Pharmacol Rev. Dec 1998;50(4):723-60.
18. Fischmeister R, Hartzell HC. Mechanism of action of acetyl-
choline on calcium current in single cells from frog ventricle. J
Physiol. Jul 1986;376:183-202.
19. Iijima T, Irisawa H, Kameyama M. Membrane currents and their
modification by acetylcholine in isolated single atrial cells of the
guinea-pig. J Physiol. Feb 1985;359:485-501.
20. Sakai R, Shen JB, Pappano AJ. Elevated cAMP suppresses
muscarinic inhibition of L-type calcium current in guinea pig
ventricular myocytes. J Cardiovasc Pharmacol. Aug 1999;34(2):
304-15.
21. Gupta RC, Neumann J, Boknik P, et al. M2-specific muscarinic
cholinergic receptor-mediated inhibition of cardiac regulatory
protein phosphorylation. Am J Physiol. Mar 1994;266(3 Pt 2):
H1138-44.
22. Harvey RD, Hume JR. Autonomic regulation of delayed rectifier
K+ current in mammalian heart involves G proteins. Am J
Physiol. Sep 1989;257(3 Pt 2):H818-23.
23. Matsumoto K, Pappano AJ. Sodium-dependent membrane cur-
rent induced by carbachol in single guinea-pig ventricular myo-
cytes. J Physiol. Aug 1989;415:487-502.
24. Harvey RD, Hume JR. Autonomic regulation of a chloride
current in heart. Science. May 26 1989;244(4907):983-5.
25. Ninomiya I. Direct evidence of nonuniform distribution of vagal
effects on dog atria. Circ Res. Sep 1966;19(3):576-83.
26. Alessi R, Nusynowitz M, Abildskov JA, et al. Nonuniform dis-
tribution of vagal effects on the atrial refractory period. Am J
Physiol. Aug 1958;194(2):406-10.
27. Liu L, Nattel S. Differing sympathetic and vagal effects on atrial
fibrillation in dogs: role of refractoriness heterogeneity. Am J
Physiol. Aug 1997;273(2 Pt 2):H805-16.
28. Zipes DP, Mihalick MJ, Robbins GT. Effects of selective vagal
8
 Vagal Atrial Fibrillation
and stellate ganglion stimulation of atrial refractoriness. Car-
diovasc Res. Sep 1974;8(5):647-55.
29. Wang Z, Page P, Nattel S. Mechanism of flecainide’s anti-
arrhythmic action in experimental atrial fibrillation. Circ Res.
Aug 1992;71(2):271-87.
30. Moe GK, Rheinboldt WC, Abildskov JA. A Computer Model Of
Atrial Fibrillation. Am Heart J. Feb 1964;67:200-20.
31. Wang J, Liu L, Feng J, et al. Regional and functional factors
determining induction and maintenance of atrial fibrillation in
dogs. Am J Physiol. Jul 1996;271(1 Pt 2):H148-58.
32. Kneller J, Zou R, Vigmond EJ, et al. Cholinergic atrial fibrillation
in a computer model of a two-dimensional sheet of canine atrial
cells with realistic ionic properties. Circ Res. May 17 2002;
90(9):E73-87.
33. Hoover DB, Ganote CE, Ferguson SM, et al. Localization of
cholinergic innervation in guinea pig heart by immunohisto-
chemistry for high-affinity choline transporters. Cardiovasc Res.
Apr 1 2004;62(1):112-21.
34. Mabe AM, Hoard JL, Duffourc MM, et al. Localization of
cholinergic innervation and neurturin receptors in adult mouse
heart and expression of the neurturin gene. Cell Tissue Res. May
12 2006.
35. Lomax AE, Rose RA, Giles WR. Electrophysiological evidence
for a gradient of G protein-gated K+ current in adult mouse atria.
Br J Pharmacol. Oct 2003;140(3):576-84.
36. Huang CX, Zhao QY, Liang JJ, et al. Differential densities of
muscarinic acetylcholine receptor and I(K,ACh) in canine sup-
raventricular tissues and the effect of amiodarone on cholinergic
atrial fibrillation and I(K,ACh). Cardiology. 2006;106(1):36-43.
37. Sarmast F, Kolli A, Zaitsev A, et al. Cholinergic atrial fibrillation:
I(K,ACh) gradients determine unequal left/right atrial frequ-
encies and rotor dynamics. Cardiovasc Res. Oct 1 2003;59(4):
863-73.
38. Sharifov OF, Zaitsev AV, Rosenshtraukh LV, et al. Spatial dis-
tribution and frequency dependence of arrhythmogenic vagal
effects in canine atria. J Cardiovasc Electrophysiol. Sep 2000;
11(9):1029-42.
39. Vigmond EJ, Tsoi V, Kuo S, et al. The effect of vagally induced
dispersion of action potential duration on atrial arrhythmoge-
nesis. Heart Rhythm. Sep 2004;1(3):334-44.
40. Schuessler RB, Grayson TM, Bromberg BI, et al. Cholinergically
mediated tachyarrhythmias induced by a single extrastimulus in
the isolated canine right atrium. Circ Res. Nov 1992;71(5):
1254-67.
41. Schuessler RB, Rosenshtraukh LV, Boineau JP, et al. Spontaneous
tachyarrhythmias after cholinergic suppression in the isolated
perfused canine right atrium. Circ Res. Oct 1991;69(4):1075-87.
42. Comtois P, Kneller J, Nattel S. Of circles and spirals: bridging the
gap between the leading circle and spiral wave concepts of
cardiac reentry. Europace. Sep 2005;7 Suppl 2:10-20.
43. Kovoor P, Wickman K, Maguire CT, et al. Evaluation of the role
of I(KACh) in atrial fibrillation using a mouse knockout model. J
Am Coll Cardiol. Jun 15 2001;37(8):2136-43.
9 Acta Cardiol Sin 2007;23:1-12
44. Sharifov OF, Fedorov VV, Beloshapko GG, et al. Roles of
adrenergic and cholinergic stimulation in spontaneous atrial
fibrillation in dogs. J Am Coll Cardiol. Feb 4 2004;43(3):483-90.
45. Hashimoto K, Chiba S, Tanaka S, et al. Adrenergic mechanism
participating in induction of atrial fibrillation by ACh. Am J
Physiol. Nov 1968;215(5):1183-91.
46. Bettoni M, Zimmermann M. Autonomic tone variations before
the onset of paroxysmal atrial fibrillation. Circulation. Jun 11
2002;105(23):2753-9.
47. Haissaguerre M, Jais P, Shah DC, et al. Spontaneous initiation of
atrial fibrillation by ectopic beats originating in the pulmonary
veins. N Engl J Med. Sep 3 1998;339(10):659-66.
48. Chen YJ, Chen SA, Chang MS, et al. Arrhythmogenic activity of
cardiac muscle in pulmonary veins of the dog: implication for the
genesis of atrial fibrillation. Cardiovasc Res. Nov 2000;48(2):
265-73.
49. Cha TJ, Ehrlich JR, Zhang L, et al. Atrial tachycardia remodeling
of pulmonary vein cardiomyocytes: comparison with left atrium
and potential relation to arrhythmogenesis. Circulation. Feb 15
2005;111(6):728-35.
50. Schauerte P, Scherlag BJ, Patterson E, et al. Focal atrial fib-
rillation: experimental evidence for a pathophysiologic role of the
autonomic nervous system. J Cardiovasc Electrophysiol. May
2001;12(5):592-9.
51. Patterson E, Po SS, Scherlag BJ, et al. Triggered firing in pul-
monary veins initiated by in vitro autonomic nerve stimulation.
Heart Rhythm. Jun 2005;2(6):624-31.
52. Patterson E, Yu X, Huang S, et al. Suppression of autonomic-
mediated triggered firing in pulmonary vein preparations, 24
hours postcoronary artery ligation in dogs. J Cardiovasc Elec-
trophysiol. Jul 2006;17(7):763-70.
53. Takahashi Y, Jais P, Hocini M, et al. Shortening of fibrillatory
cycle length in the pulmonary vein during vagal excitation. J Am
Coll Cardiol. Feb 21 2006;47(4):774-80.
54. Scherlag BJ, Yamanashi W, Patel U, et al. Autonomically induced
conversion of pulmonary vein focal firing into atrial fibrillation. J
Am Coll Cardiol. Jun 7 2005;45(11):1878-86.
55. Zimmermann M, Kalusche D. Fluctuation in autonomic tone is a
major determinant of sustained atrial arrhythmias in patients with
focal ectopy originating from the pulmonary veins. J Cardiovasc
Electrophysiol. Mar 2001;12(3):285-91.
56. Patterson E, Lazzara R, Szabo B, et al. Sodium-calcium exchange
initiated by the Ca2+ transient: an arrhythmia trigger within
pulmonary veins. J Am Coll Cardiol. Mar 21 2006;47(6):1196-
206.
57. Tai CT, Chiou CW, Wen ZC, et al. Effect of phenylephrine on
focal atrial fibrillation originating in the pulmonary veins and
superior vena cava. J Am Coll Cardiol. Sep 2000;36(3):788-93.
58. Oral H, Chugh A, Scharf C, et al. Pulmonary vein isolation for
vagotonic, adrenergic, and random episodes of paroxysmal atrial
fibrillation. J Cardiovasc Electrophysiol. Apr 2004;15(4):402-6.
59. Blaauw Y, Tieleman RG, Brouwer J, et al. Tachycardia induced
electrical remodeling of the atria and the autonomic nervous
 Yung-Hsin Yeh et al.
system in goats. Pacing Clin Electrophysiol. Nov 1999;22(11):
1656-67.
60. Dobrev D, Graf E, Wettwer E, et al. Molecular basis of
downregulation of G-protein-coupled inward rectifying K(+)
current (I(K,ACh) in chronic human atrial fibrillation: decrease in
GIRK4 mRNA correlates with reduced I(K,ACh) and muscarinic
receptor-mediated shortening of action potentials. Circulation.
Nov 20 2001;104(21):2551-7.
61. Shi H, Wang H, Li D, et al. Differential alterations of receptor
densities of three muscarinic acetylcholine receptor subtypes and
current densities of the corresponding K+ channels in canine atria
with atrial fibrillation induced by experimental congestive heart
failure. Cell Physiol Biochem. 2004;14(1-2):31-40.
62. Brundel BJ, Van Gelder IC, Henning RH, et al. Alterations in
potassium channel gene expression in atria of patients with
persistent and paroxysmal atrial fibrillation: differential regu-
lation of protein and mRNA levels for K+ channels. J Am Coll
Cardiol. Mar 1 2001;37(3):926-32.
63. Gonzalez RA, Campos EO, Karmelic C, et al. Acetylcholine-
sterase changes in hearts with sinus rhythm and atrial fibrillation.
Gen Pharmacol. Jan 1993;24(1):111-4.
64. Ehrlich JR, Cha TJ, Zhang L, et al. Characterization of a hy-
perpolarization-activated time-dependent potassium current in
canine cardiomyocytes from pulmonary vein myocardial sleeves
and left atrium. J Physiol. Jun 1 2004;557(Pt 2):583-97.
65. Dobrev D, Friedrich A, Voigt N, et al. The G protein-gated
potassium current I(K,ACh) is constitutively active in patients
with chronic atrial fibrillation. Circulation. Dec 13 2005;112(24):
3697-706.
66. Cha TJ, Ehrlich JR, Chartier D, et al. Kir3-based inward rectifier
potassium current: potential role in atrial tachycardia remodeling
effects on atrial repolarization and arrhythmias. Circulation. Apr
11 2006;113(14):1730-7.
67. Wallukat G, Nissen E, Morwinski R, et al. Autoantibodies against
the beta- and muscarinic receptors in cardiomyopathy. Herz. May
2000;25(3):261-6.
68. Baba A, Yoshikawa T, Fukuda Y, et al. Autoantibodies against
M2-muscarinic acetylcholine receptors: new upstream targets in
atrial fibrillation in patients with dilated cardiomyopathy. Eur
Heart J. Jul 2004;25(13):1108-15.
69. van den Berg MP, Hassink RJ, Balje-Volkers C, et al. Role of the
autonomic nervous system in vagal atrial fibrillation. Heart. Mar
2003;89(3):333-5.
70. Heart rate variability: standards of measurement, physiological
interpretation and clinical use. Task Force of the European
Society of Cardiology and the North American Society of Pacing
and Electrophysiology. Circulation. Mar 1 1996;93(5):1043-65.
71. Andresen D, Bruggemann T. Heart rate variability preceding
onset of atrial fibrillation. J Cardiovasc Electrophysiol. Aug
1998;9(8 Suppl):S26-9.
72. Fioranelli M, Piccoli M, Mileto GM, et al. Analysis of heart rate
variability five minutes before the onset of paroxysmal atrial
fibrillation. Pacing Clin Electrophysiol. May 1999;22(5):743-9.
Acta Cardiol Sin 2007;23:1-12
73. Herweg B, Dalal P, Nagy B, et al. Power spectral analysis of heart
period variability of preceding sinus rhythm before initiation of
paroxysmal atrial fibrillation. Am J Cardiol. Oct 1 1998;82(7):
869-74.
74. Coccagna G, Capucci A, Bauleo S, et al. Paroxysmal atrial
fibrillation in sleep. Sleep. Jun 1997;20(6):396-8.
75. Tomita T, Takei M, Saikawa Y, et al. Role of autonomic tone in the
initiation and termination of paroxysmal atrial fibrillation in
patients without structural heart disease. J Cardiovasc Elec-
trophysiol. Jun 2003;14(6):559-64.
76. Roark SF, McCarthy EA, Lee KL, et al. Observations on the
occurrence of atrial fibrillation in paroxysmal supraventricular
tachycardia. Am J Cardiol. Mar 1 1986;57(8):571-5.
77. Chen YJ, Chen SA, Tai CT, et al. Role of atrial electrophysiology
and autonomic nervous system in patients with supraventricular
tachycardia and paroxysmal atrial fibrillation. J Am Coll Cardiol.
Sep 1998;32(3):732-8.
78. van den Berg MP, Hassink RJ, Tuinenburg AE, et al. Quality of
life in patients with paroxysmal atrial fibrillation and its pre-
dictors: importance of the autonomic nervous system. Eur Heart
J. Feb 2001;22(3):247-53.
79. Nattel S, Opie LH. Controversies in atrial fibrillation. Lancet. Jan
21 2006;367(9506):262-72.
80. Fuster V, Ryden LE, Asinger RW, et al. ACC/AHA/ESC Gui-
delines for the Management of Patients With Atrial Fibrillation:
Executive Summary A Report of the American College of
Cardiology/American Heart Association Task Force on Practice
Guidelines and the European Society of Cardiology Committee
for Practice Guidelines and Policy Conferences (Committee to
Develop Guidelines for the Management of Patients With Atrial
Fibrillation) Developed in Collaboration With the North Ame-
rican Society of Pacing and Electrophysiology. Circulation. Oct
23 2001;104(17):2118-50.
81. van den Berg MP, Haaksma J, Brouwer J, et al. Analysis of heart
rate variability in a patient with paroxysmal atrial fibrillation. Eur
Heart J. Dec 1995;16(12):2011-2.
82. Coumel P, Thomas O, Leenhardt A. Drug therapy for prevention
of atrial fibrillation. Am J Cardiol. Jan 25 1996;77(3):3A-9A.
83. Razavi M, Zhang S, Yang D, et al. Effects of pulmonary vein
ablation on regional atrial vagal innervation and vulnerability to
atrial fibrillation in dogs. J Cardiovasc Electrophysiol. Aug
2005;16(8):879-84.
84. Pappone C, Santinelli V, Manguso F, et al. Pulmonary vein
denervation enhances long-term benefit after circumferential
ablation for paroxysmal atrial fibrillation. Circulation. Jan 27
2004;109(3):327-34.
85. Scherlag BJ, Nakagawa H, Jackman WM, et al. Electrical sti-
mulation to identify neural elements on the heart: their role in
atrial fibrillation. J Interv Card Electrophysiol. Aug 2005;13
Suppl 1:37-42.
86. Tan AY, Li H, Wachsmann-Hogiu S, et al. Autonomic innervation
and segmental muscular disconnections at the human pulmonary
vein-atrial junction: implications for catheter ablation of atrial-
10
 Vagal Atrial Fibrillation
pulmonary vein junction. J Am Coll Cardiol. Jul 4 2006;48(1):
132-43.
87. Chiou CW, Zipes DP. Selective vagal denervation of the atria
eliminates heart rate variability and baroreflex sensitivity while
preserving ventricular innervation. Circulation. Jul 28 1998;
98(4):360-8.
88. Chiou CW, Eble JN, Zipes DP. Efferent vagal innervation of the
canine atria and sinus and atrioventricular nodes. The third fat
pad. Circulation. Jun 3 1997;95(11):2573-84.
89. Chevalier P, Obadia JF, Timour Q, et al. Thoracoscopic epicardial
radiofrequency ablation for vagal atrial fibrillation in dogs.
Pacing Clin Electrophysiol. Jun 1999;22(6 Pt 1):880-6.
90. Melo J, Voigt P, Sonmez B, et al. Ventral cardiac denervation
reduces the incidence of atrial fibrillation after coronary artery
bypass grafting. J Thorac Cardiovasc Surg. Feb 2004;127(2):
511-6.
91. Alex J, Guvendik L. Evaluation of ventral cardiac denervation as
11
a prophylaxis against atrial fibrillation after coronary artery
bypass grafting. Ann Thorac Surg. Feb 2005;79(2):517-20.
92. Cummings JE, Gill I, Akhrass R, et al. Preservation of the anterior
fat pad paradoxically decreases the incidence of postoperative
atrial fibrillation in humans. J Am Coll Cardiol. Mar 17 2004;
43(6):994-1000.
93. Hirose M, Leatmanoratn Z, Laurita KR, et al. Partial vagal
denervation increases vulnerability to vagally induced atrial
fibrillation. J Cardiovasc Electrophysiol. Dec 2002;13(12):
1272-9.
94. Oh S, Zhang Y, Bibevski S, et al. Vagal denervation and atrial
fibrillation inducibility: epicardial fat pad ablation does not have
long-term effects. Heart Rhythm. Jun 2006;3(6):701-8.
95. Hashimoto N, Yamashita T, Tsuruzoe N. Tertiapin, a selective
IK(ACh) blocker, terminates atrial fibrillation with selective
atrial effective refractory period prolongation. Pharmacol Res.
Apr 1 2006.
Acta Cardiol Sin 2007;23:1-12
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。

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