The Autonomic Nervous
System and Atrial Fibrillation: The Roles of Pulmonary Vein Isolation and
Ganglionated Plexi Ablation
Credits: Benjamin J. Scherlag,
PhD, Hiroshi Nakagawa, M.D, Ph.D, Eugene Patterson, PhD, Warren M. Jackman,
MD, Ralph Lazzara, MD, Sunny S. Po, MD, PhD, Heart Rhythm Institute at the
University of Oklahoma Health Sciences Center, Oklahoma City, OK
Supported in part by a grant from the American Heart Association (0650077Z, SSP) and the National Heart, Lung and Blood Institute (5K23HL069972, SSP); and from the Helen and Wil Webster Arrhythmia Research Fund (BJS)
Address for Correspondence: Benjamin J. Scherlag, PhD, 1200 Everett Drive, Rm 6E103, Oklahoma City, OK 73104.
After the sequential successes of catheter ablation for the treatment of pre-excitation
syndromes (WPW), junctional reentry (AVNRT) atrial flutter (AFL) and
ventricular arrhythmias, clinical electrophysiologists have focused on the
myocardial basis of atrial fibrillation (AF). Thus, the strategy for ablation
of drug and cardioversion refractory AF was to isolate the myocardial
connections from the focal firing pulmonary veins (PVs) in addition to altering
the atrial substrate maintaining AF. However, the overall success rates have
not achieved those of the other types of ablation procedures. In this review we
have summarized the favorable aspects and drawbacks of pulmonary vein isolation
(PVI). As for the role of the Intrinsic Cardiac Autonomic Nervous System (ICANS),
both basic and clinical evidence has shown that ganglionated plexi (GP)
stimulation promotes initiation and maintenance of AF, and that GP ablation
reduces recurrence of AF following catheter or surgical ablation of these
structures. Based on these findings, the GP Hyperactivity Hypothesis has been
proposed to explain, at least in part, the mechanistic basis for the focal form
of AF. For example, PV isolation may not always be necessary for elimination of
AF, as in the early stages of paroxysmal AF. GP ablation alone, in these
cases, may suffice for focal AF termination. In the persistent and long
standing persistent forms the substrate for AF may be more extensive and
therefore require GP ablation plus PV isolation and/or CFAE ablations. Clinical
reports, both catheter based as well as minimally invasive surgical procedures,
which include PVI plus GP ablation have shown relatively long-term success
rates much closer to or equal to those achieved by myocardial ablation
procedures in patients with WPW, AVNRT and AFL.
Electrophysiology, a subspecialty of Cardiology, had its beginnings in the
1960s and 1970s with the development of new intra-cardiac electrical recordings
techniques [1, 2] and procedures for
provocative pacing of the atria and ventricles . These
diagnostic tools provided more precise insights as to the mechanisms of various
cardiac arrhythmias [4-6] than previously
achieved by the use of the electrocardiogram alone. Another milestone occurred
in 1981 with the use of atrio-ventricular (A-V) junctional ablation to control
the rapid ventricular response in a patient with atrial fibrillation . The use of radiofrequency energy 
became the mainstay for catheter ablation as a curative approach for a number
of cardiac arrhythmias which were previously treated, most not effectively, by
Kuck et al  and Jackman et al. 
used radiofrequency energy for catheter ablation of accessory pathways, and the
A-V junction. These procedures were followed in rapid succession by radiofrequency
ablation of the slow A-V nodal pathway to cure A-V junctional reentrant
tachycardia [11, 12] and the ablation of
the inferior vena cava-tricuspid valve isthmus to terminate atrial flutter . The factor common to this non-surgical,
non-pharmacological therapy was the use of radiofrequency lesions to interrupt
a reentrant circuit which served as the substrate for these cardiac
on the 95-99% success rates resulting from their previous successes, clinical
electrophysiologists confronted the most common and most vexing of the cardiac
arrhythmias, atrial fibrillation (AF). The initial attempts followed the
success of the surgical Maze technique . Instead of cut
and sew, Swartz et al  used radiofrequency catheter
ablation to induce bi-atrial linear lesion sets. Others, 
using similar approaches in an attempt to mimic the surgical procedure but with
the use of radio-frequency energy, had low success rates and unexpected
seminal discovery was made just before the turn of the century with the
observation by the Bordeaux group, that patients with drug and cardioversion
resistant paroxysmal AF consistently manifested focal firing arising from the
myocardial sleeves of the pulmonary veins [17, 18].
This breakthrough observation represented a radical departure from the prevailing
view that the mechanism responsible for AF was based on multiple reentrant
wavelets continuously encircling the atria [19, 20]. Initially, the clinical strategy adopted was to locate the
focal firing sites within the PV(s) and ablate them with radiofrequency current
. Although this strategy was effective in treating this
form of AF, 62% success over the short term, several factors caused this
approach to be abandoned: 1) The danger of PV stenosis, 2) The finding that all
the PVs were potential arrhythmogenic sites and 3) In approximately 15% of this
AF subpopulation non-PV focal firing sites could be identified [22,
factors engendered the strategy of PV isolation (PVI) which was undertaken to
not only prevent the escape of the PV triggers  but
also to markedly reduce the affected substrate maintaining AF. In regard to the
latter, somewhat different procedures were devised including left atrial
circumferential ablation [LACA, 25]; wide area
circumferential ablation [WACA, 26]; and pulmonary vein
antrum isolation [PVAI, 27]. All of these, performed as a
single procedure, have resulted in success rates as high as 84% for paroxysmal
and persistent AF  but relatively lower success rates
for long standing persistent AF.
important catheter based technique for ablation of AF was reported by Nademanee
et al  who specifically targeted sites showing low level
complex fractionated atrial electrograms (CFAE) during AF. They reported, of
the 121 patients treated, 110 (91%) patients were free of arrhythmia and
symptoms, 92 (76%) after one procedure and an additional 18 after two
procedures, with a follow-up of 1 year.
recent studies have combined techniques in order to increase success rates
particularly in patients with long standing persistent forms of AF. In a recent
study by Elayi et al  in 144 patient with long standing persistent AF,
after a mean follow-up of 16 months, these investigators reported that a hybrid
technique consisting of pulmonary vein antrum ablation (PVAI) plus ablation of
CFAE provided a better outcome than either circumferential pulmonary vein
ablation (CPVA) or PVAI with the highest success rates seen with the hybrid
approach after 2 procedures (94%).
PVI procedure could require 100+ radiofrequency applications .
Even those procedures which targeted CFAE,  without PVI,
as few as 40 or as many as 140 radiofrequency applications were delivered to
achieve the ablation endpoint. A recent consensus statement reported serious
complications in 6% of more than 8700 cases including cardiac tamponade, PV
stenosis, phrenic nerve injury, esophageal injury/left atrial fistula, thrombo-embolism,
among others . Early on iatrogenic consequences
were reported with PVI procedures in the form of recurrent tachyarrhythmias. The
lesion sets induced to isolate PV firing by encircling lesion sets tend to
establish a large channel which favors the induction of a macro-reentrant
circuit and subsequent atrial tachycardias. In order to prevent such
occurrences additional lesion sets were introduced: a left atrial roof line and
a mitral isthmus line. More recently other procedures have been introduced as
well, such as ablation of area showing CFAE and areas within the coronary sinus
 or within the superior vena cava .
These additional lesion sets further increase the risk of gaps which in and of
themselves provide channels that can allow macro-reentrant atrial tachycardias
or left atrial flutters to develop. These recurrences have, therefore,
necessitated repeat or even multiple procedures to close gaps and terminate the
iatrogenically induced arrhythmias.
the ablation within or at the ostia of the PV was abandoned most centers
adopted the circumferential approach proposed by Pappone et al .
The rationale for the strategy of PVI was basically to isolate the rapid
ectopic firing arising within or at the ostium of the PV without incurring, PV
stenosis. However the results, albeit positive (70-80% success), were somewhat
counter-intuitive. Pappone et al.  found that “isolation
of PV foci may not be the sole mechanism responsible for the AF
cure, as suggested by our finding of no significant relationship
between lesion completeness and clinical outcome… PV isolation might
have interrupted pathways crucial in the genesis of AF located at
the PV-LA junction…Finally, atrial debulking and/or denervation may have
contributed to suppression of AF.” Subsequent studies further
amplified the questions raised by Pappone et al. For example, Stabile et al.,
using the same anatomic approach with circumferential lesion sets, found that
PVI was “not crucial in determining clinical success” .
Cappato et al  found that, after the first procedure,
clinical success was observed in “32% of patients despite the
presence of late conduction recurrence across the disconnecting line
of one or both superior PVs …in particular, 11 (79%) such patients
had conduction recurrences in both superior PVs”. Cappato et al.
state, “Causes accounting for this effect may include occasional ablation of
the culprit arrhythmogenic focus and severe impairment of conductive PV tissue
crucial for arrhythmia generation…” Whether such an explanation can be applied
to other findings suggesting that clinical success of PVI electrical
disconnection can also be achieved, at least for some time, despite
conduction recurrence [34-36] remains moot. Other possibilities that
may account for these findings are presented below.
Cardiac Autonomic Nervous System
role of the intrinsic cardiac autonomic nervous system (ICANS) under
physiological and pathological circumstances has been of interest for the past
40 years . To paraphrase Ardell 
the intrinsic neural network on the heart and within the pericardium, serves as
more than a relay station for the extrinsic projections of the vagosympathetic
system from the brain and spinal cord to the heart. It functions as an
integrative system which acts cooperatively with the extrinsic innervations but
can act independently to modulate numerous cardiac functions, e.g.,
automaticity, contractility, conduction etc. Early basic studies showed the
relationship between the ICANS and cardiac arrhythmias [39, 40].
Anatomy of ICANS
et al  provided a comprehensive anatomic study of the
ICANS in the human heart by delineating the locations of the major ganglionated
plexi and their axonal fields and peripheral ganglia. This study demonstrated
that the ICANS is “distributed more extensively than previously considered.”
Further elaboration of the anatomy of ICANS has been published by Pauza et al.
In essence these studies revealed that there is an extensive neural network
covering, not only the atria but also both ventricles [Figure 1].
The major modulating centers reside in the clusters of neuronal bodies collectively
housed in ganglionated plexi (GP), which, in turn, are located within fat pads.
Of interest, 4 of these GP lie adjacent to the four PVs and have been reported
to contain 200 or more neuronal cell bodies . On the
other hand, as many as 1500 ganglia have been estimated to be found on the
atrial and ventricular epicardium .
Figure 1:A diagrammatic representation of the neural network that extends over the right and left atria as well as on the epicardial surface of the ventricles. This illustration is the drawing taken from the publication by Pauza et al. showing the course of nerves which were seen after acetycholinesterase staining. In this study, ganglia within fat pads are not depicted although as many as 4300 intrinsic neurons were estimated to be found in the adult human heart. (Reproduced by permission from Pauza et al. Anatomic Record 2000;259:353-382.)
Figure 2A illustrates the “right” fat pads associated with
the right pulmonary veins (RSPV, RIPV) in a patient undergoing thorascopically
guided surgery. The anterior right (AR) GP is found within the large fat pad
lying between the right PVs, whereas the inferior right (IR) GP is located
within the smaller fat pad close to the inferior junction of the right and left
atria. It should be noted that the ARGP and IRGP are to the left of Waterston’s
groove (also known as the sulcus terminalis) which marks the boundary between
the left and right atria. Although the right PVs are seen through a right thoracotomy
their entrance into the left atrial chamber confirms the location of these PV
and their associated GP as left atrial structures.
Figure 2A:View of the fat pads (panel A) on the human heart as seen through a right thorascopic port. The fat pads (which contain the anterior and inferior right GP) are shown within the demarcated areas (dashed lines) lying between the right superior and right inferior pulmonary veins (RSPV, RIPV). Panel B. A thorascopic view from a left sided port showing the left superior and left inferior, LSPV, LIPV as well as the ligament of Marshall (LOM). The superior left GP is located at the junction of the LSPV and the pulmonary artery while the left inferior GP is located inferior and posterior to the LIPV.
thorascopic view of the left side [Figure 2B], locates the
superior left (SL) GP and inferior left (IL) GP in fat pads at the
LSPV/pulmonary artery junction and inferior posterior LIPV border,
respectively. These GP can be located during endocardial catheterization
procedures for AF ablation by electrical activation with high frequency
stimulation (20 Hz). This results in marked slowing of the ventricular
response during AF, at least a ≥ 50% increase in the R-R interval [Figure 3]. In this way the major locations of the GP can be
delineated on a CARTO map [Figure 4]. It should be
mentioned that other GP can be found on the heart itself, e.g., within the
ligament of Marshall  as well as on the large vessels
within the pericardium, e.g., the right pulmonary artery 
and at the base of the aorta/pulmonary artery intersection .
Figure 2B:View of the fat pads (panel A) on the human heart as seen through a right thorascopic port. The fat pads (which contain the anterior and inferior right GP) are shown within the demarcated areas (dashed lines) lying between the right superior and right inferior pulmonary veins (RSPV, RIPV). Panel B. A thorascopic view from a left sided port showing the left superior and left inferior, LSPV, LIPV as well as the ligament of Marshall (LOM). The superior left GP is located at the junction of the LSPV and the pulmonary artery while the left inferior GP is located inferior and posterior to the LIPV.
Figure 3:CARTO map showing the localization of the GP adjacent to the 4 PVs by high frequency stimulation (HFS) from an electrode catheter placed endocardially subjacent to each of the epicardial fat pads containing the GP. Note that the encircled red dots indicate the sites at which a marked slowing of the ventricular rate was observed during HFS applied at that site (see Figure 4).
Figure 4:A typical response to HFS at a GP site during ongoing AF which consists of a marked slowing of the ventricular response due to an initial strong parasympathetic effect causing suppression of A-V conduction for about 3 seconds. With termination of GP stimulation the ventricular rate is quickly restored.
ICANS in Relation to AF-Basic studies
early report by Sharifov et al  implicated autonomic
neurohumors, which were injected into the sino-atrial artery, in the initiation
of AF. Subsequent basic studies addressed some of the fundamental questions
arising from the clinical breakthrough findings that patients with paroxysmal
AF have focal firing that arose from the myocardial sleeves which invest the
PVs . As mentioned previously, another key finding was
reported by Nademanee et al  describing the distribution
of CFAE in the atria in patients with AF. The abnormal PV firing was thought to
provide the triggers for AF, whereas the CFAE was apparently an important
constituent of the substrate for this form of AF since ablation at these sites
was associated with a high rate of termination of AF. From these observations
three critical questions arise.
1. How does the focal firing in the PVs become converted into AF and not just
manifest as atrial tachycardia? Scherlag et al 
demonstrated that the number of stimulated impulses applied to the PV would not
induce AF unless there was simultaneous activation of the GP adjacent to that
PV. Of importance, GP activation is achieved with electrical stimulation using
high frequency (20 Hz) and very short stimuli duration (0.1 ms). During sinus
rhythm, these stimulation parameters, which slow the heart rate, are delivered
at a voltage that does not excite the atrium but does activate the neuronal
clusters found in the fat pads on the heart .
2. What is the mechanism whereby the PVs rather than other atrial regions
become the sites of focal firing in those patients with AF resistant to drugs
and cardioversion? Po et al.  caused focal firing in
either the right or left superior PV after injecting the neurotransmitter
acetylcholine (Ach) into the GP anatomically adjacent to those PV.
Furthermore, additional studies by Patterson et al [49, 50] provided additional evidence suggesting that PV myocytes
show distinctive cellular electrophysiological differences from adjacent
atrium, particularly, a shorter action potential duration (APD). Moreover, the
PV tissue exhibited greater sensitivity to both cholinergic and adrenergic
stimulation than adjacent atrial tissue. Thus, local stimulation of nerve
endings in the PV induced release of acetylcholine which further shortened APD
while release of the adrenergic neurotransmitters induced early after
depolarizations (EADs) leading to rapid, triggered firing. The underlying
mechanism for the EADs relates to the temporal disproportionality between the
very short APD and the longer lasting calcium transient in the PV myocytes.
Under autonomic stimulation these differences are further exacerbated so that
the effects on the sodium-calcium exchanger favors excess calcium entry thereby
leading to EAD formation , i.e., triggered PV firing.
Lemola et al  performed PV isolation in dogs while
preserving the GP and then ablated the GP while leaving the PV intact. Using
vagal induced AF in both cases they concluded, " it is the PV associated
ganglia not the PV themselves that are important in vagally mediated AF
3. In regard to substrate alterations, it has been suggested that PV isolation affects
the substrate for AF maintenance. Yet, what exactly constitutes the AF
substrate has not been clearly defined. The most specific substrate feature
that has been identified has been the prevalence of CFAE whose ablation
resulted in at least a 20% increase in AF ablation success 
compared to PVI alone. As such this approach has been incorporated into the
stepwise ablation procedures used in many centers (see below). However, the
mechanistic basis for this electrogram characteristic had not been elaborated.
To test the hypothesis that autonomic factors might be responsible for CFAE,
Lin et al  applied different concentrations of Ach to
local atrial sites during sustained AF. These sites were chosen specifically
because the bipolar electrograms manifested stable Type I potentials, i.e.,
regular, rapid activation separated by diastolic isoelectric intervals [Figure 5A]. Local application of 1 mM Ach to this electrogram
site showed little, if any change in the electrogram morphology [figure 5B]. On the other hand, local application of 10 mM [Figure 5C] and 100 mM [figure 5D]
resulted in a change from Type I to intermittent CFAE and continuous CFAE,
Figure 5A:The effect of locally applied acetylcholine (ACH) on the conversion of a Type I electrogram to one showing various forms of fractionation, i.e., complex fractionated atrial electrogram, (CFAE). Traces include ECG lead II, His bundle recording (HB), bipolar electrograms from the right (R) and left (L) atrial (A) free walls, R and L pulmonary veins (PVs) and right atrial appendage (RAA). Panel A. The trace labeled RAp represents a bipole on an electrode catheter which showed a Type I electrogram during AF (no CFAE). It was chosen to be locally painted with various concentrations of Ach. Panel B. There was no change when Ach, 1mM was applied to this bipole (no CFAE). Panel C. However, when 10mM Ach was applied to this site intermittent CFAE was noted. Panel D. The subsequent local application of 100mM Ach resulted in the appearance of continuous CFAE. See text for further discussion. (Reproduced with permission from Lin et al J Cardiovasc Electrophysiol 2007;18:1197-1205).
Figure 5B:The effect of locally applied acetylcholine (ACH) on the conversion of a Type I electrogram to one showing various forms of fractionation, i.e., complex fractionated atrial electrogram, (CFAE). Traces include ECG lead II, His bundle recording (HB), bipolar electrograms from the right (R) and left (L) atrial (A) free walls, R and L pulmonary veins (PVs) and right atrial appendage (RAA). Panel A. The trace labeled RAp represents a bipole on an electrode catheter which showed a Type I electrogram during AF (no CFAE). It was chosen to be locally painted with various concentrations of Ach. Panel B. There was no change when Ach, 1mM was applied to this bipole (no CFAE). Panel C. However, when 10mM Ach was applied to this site intermittent CFAE was noted. Panel D. The subsequent local application of 100mM Ach resulted in the appearance of continuous CFAE. See text for further discussion. (Reproduced with permission from Lin et al J Cardiovasc Electrophysiol 2007;18:1197-1205).
Figure 5C:The effect of locally applied acetylcholine (ACH) on the conversion of a Type I electrogram to one showing various forms of fractionation, i.e., complex fractionated atrial electrogram, (CFAE). Traces include ECG lead II, His bundle recording (HB), bipolar electrograms from the right (R) and left (L) atrial (A) free walls, R and L pulmonary veins (PVs) and right atrial appendage (RAA). Panel A. The trace labeled RAp represents a bipole on an electrode catheter which showed a Type I electrogram during AF (no CFAE). It was chosen to be locally painted with various concentrations of Ach. Panel B. There was no change when Ach, 1mM was applied to this bipole (no CFAE). Panel C. However, when 10mM Ach was applied to this site intermittent CFAE was noted. Panel D. The subsequent local application of 100mM Ach resulted in the appearance of continuous CFAE. See text for further discussion. (Reproduced with permission from Lin et al J Cardiovasc Electrophysiol 2007;18:1197-1205).
Figure 5D:The effect of locally applied acetylcholine (ACH) on the conversion of a Type I electrogram to one showing various forms of fractionation, i.e., complex fractionated atrial electrogram, (CFAE). Traces include ECG lead II, His bundle recording (HB), bipolar electrograms from the right (R) and left (L) atrial (A) free walls, R and L pulmonary veins (PVs) and right atrial appendage (RAA). Panel A. The trace labeled RAp represents a bipole on an electrode catheter which showed a Type I electrogram during AF (no CFAE). It was chosen to be locally painted with various concentrations of Ach. Panel B. There was no change when Ach, 1mM was applied to this bipole (no CFAE). Panel C. However, when 10mM Ach was applied to this site intermittent CFAE was noted. Panel D. The subsequent local application of 100mM Ach resulted in the appearance of continuous CFAE. See text for further discussion. (Reproduced with permission from Lin et al J Cardiovasc Electrophysiol 2007;18:1197-1205).
Strategies not Involving PVI
report from Platt et al  described the identification of
the GP at the PV-atrial junctions by applying high frequency stimuli to these
nerve clusters, endocardially. In patients with persistent forms of AF, the
response was a marked slowing of the ventricular response (≥ 50%) during
AF. Ablation of these GP terminated the persistent AF in the 23/26 patients who
had a complete study with an overall success rate of 96% during a 6 month
follow-up. Lemery et al  concluded, “Ganglionated
plexuses can be precisely mapped using high-frequency stimulation and are
located predominantly in the path of (PVI) lesions delivered during ablation of
AF.” More recent studies have reported wide ranging results after ablation of
GP alone. Scanavacca et al.  studied 7 patients with
vagotonic AF in whom GP were identified by electrical stimulation (epicardially
or endocardially) followed by GP ablation. Five of the seven patients showed AF
recurrences over a follow up period ranging from 5-15 months. These authors
concluded that ablation of GP may prevent AF recurrences in “selected” patients
with apparent vagal induced paroxysmal AF. Katritsis et al 
compared the results of GP ablation alone in 19 patients with paroxysmal AF and
19 age and gender matched patients who had circumferential pulmonary vein
ablations. It should be pointed out that, in this study, GP ablation was
performed based on anatomic identification of GP sites. No high frequency
electrical stimulation was used to identify the GP or determine that they were
ablated after radiofrequency applications. Nevertheless, arrhythmia recurrence
was found in 14 of 19 (74%) with GP ablation vs, 7 of 19 (37%) with
circumferential ablation during a 1 year follow-up. In contrast, Pokushalov et
al  also used an anatomic approach to identify the
location of the GP and then applied radiofrequency energy to ablate these
sites. After a 1 year follow-up in 58 patients with persistent and long
standing persistent AF (75%) and paroxysmal AF (25%) they reported an
overall success rate of 86% during a short follow-up of 7 months. Danik et al.  reported on a series of 18 patients whose AF duration
averaged 5 years despite various drug regimens. These investigators were able
to induce AF with burst pacing after acute GP ablation in 17 of 18 patients but
after a 1 year follow-up freedom from AF recurrence was 94% in this same group.
the diverse outcomes reported by several investigators, it is important to
establish some criteria for GP localization so that the optimal number of GP
are effectively ablated in order to obtain results equivalent to PVI or better
if PVI and GP ablation are combined (see below). A clinical example of partial
GP ablations can be seen from Scanavacca et al. [55, figure 3]. Both epicardial and endocardial sites showing a
“vagal” response before but not after ablation were relegated to the posterior
wall of the left atrium. It would appear that the anterior aspect of the left atrium,
where the largest of the GP is located [figure 1], was not
ablated although a parasympathetic response was elicited at this site. The high
AF recurrence rate of patients in this study may have been due to partial
ablation of the major GP located at the PV atrial junctions.
of GP Ablation and PVI Procedures
first clinical study showing the relatively long term success of a combination
of GP ablation and PVI was reported by Pappone et al. .
In a non-randomized study of 297 patients with paroxysmal AF, undergoing left
atrial circumferential ablation to isolate the pulmonary veins, these investigators
found that some 34% showed marked slowing of the ventricular response along
with hypotension during the application of radiofrequency energy to 4 specific
areas adjacent to the PVs. Continued energy application consistently terminated
this “vagal reflex.” In a 12 month follow-up, those 102 patients showed a 99% freedom
from AF, whereas the others had a success rate of 85% over the same follow-up
period. These workers were obviously impressed by these results, so much so,
that their closing suggestion was: "Vagal reflexes can be elicited in
several specific sites around all PV ostia and should be specifically targeted
to cure paroxysmal AF.” Subsequent studies from this group have not indicated
that this advice has been followed. However, there have been other studies
using either endocardial catheter ablation or surgical approaches which have
performed both PVI and GP ablation. For example, in the small series reported
by Scanavacca et al.  in which GP ablation alone accounted
for a success rate of 25%, the addition of PV isolation showed a 100% success
during a follow up of 250 days. In the study by Danik et al. ,
even though, with GP ablation, in 18/19 patients AF was acutely inducible, the
same group with both GP ablation and PVI after a 1 year follow-up had only one
recurrence of AF; a success rate of 94%. In a larger series of 83 patients with
paroxysmal and persistent AF, Nakagawa et al  reported
that the freedom from symptomatic AF and AT at 22 months was 86% after a single
procedure targeting both GP and performing an antral type PVI.
Surgical Reports Combining PVI and GP ablations
minimally invasive surgical techniques, the results of combined PVI and GP
ablation have been more consistent and more encouraging. McClelland et al  over a 1 year follow-up, had 14/16 patients showing and
overall success rate of 87.5%. Mehall et al.  using the
same techniques found 14 /15 patient free of AF after a short 6 month
follow-up. Matsutani et al.  reported the results of a
combined Japan-United States experience using a “thorascopic mini-Maze”
procedure for bilateral PVI plus ablation of the epicardial GP. They found 18
patients (90%) were free of AF over a mean follow-up of 17 months. Some
surgical groups have been applying the combined PVI plus GP ablation approach
in order to prevent post operative AF.
et al.  compared two groups of patients with AF
undergoing mitral valve surgery. Group A (44 patients) underwent left and right
mini-Maze procedure, i.e., PVI using a bipolar clamp radiofrequency device;
whereas, Group B (31 patients) had the PVI plus fat pad resection along the
Waterston’s Groove, left pulmonary veins and Marshall’s ligament. GP were
intra-operatively mapped and fat pad specimens sectioned and analyzed for
presence of GP. At 13 months of follow-up, freedom from atrial fibrillation or
atrial tachycardia without anti-arrhythmic drugs was 73% in Group A and 93% in
Group B. Doll et al  studied 12 patients who had valve
or coronary artery bypass graft procedures but also had AF. The average
duration of AF was 4.5 years, although 5 patients had the paroxysmal form.
After a 1 year follow up, 83% were in sinus rhythm and there were no
recurrences of AF in the 5 with the paroxysmal form.
on the presently accumulated data, the approach, either endocardial or
surgical, combining PVI and GP ablation shows a markedly increased success rate
compared to PVI or GP ablation alone. As previous investigators [19,
20] have surmised, self sustaining AF would require both an
inducing trigger and an appropriate substrate for maintenance. For the
macro-reentrant or multiple wavelet form of AF, atrial premature beats (triggers),
a markedly shortened and dispersed refractory period found in the remodeled
atria, would provide the substrate for AF maintenance . Of
interest this form of AF has been shown to be readily terminated by multiple
class drug therapy . On the other hand, in the drug
resistant form of AF, we postulate that the trigger for focal firing at PV [17,18] or non-PV sites [22,
23] is caused by hyperactivity of the major GP adjacent to
PV ostia  or those associated with the myocardial sleeve
into the superior vena cava  or within the ligament of
Marshall . Intermittent bursts of neural activity in
these hyperactive GP release high concentrations of cholinergic and adrenergic
neurotransmitters at susceptible sites, shortening refractory periods and
inducing EADs as described above [48-50]
thereby, providing the basis for triggered firing and subsequent AF. The same
GP hyperactivity can extend through the inter-connected neural network  causing excessive release of neurotransmitters at multiple
nerve endings leading to CFAE , the latter serving, in
large part, as the substrate for maintenance of AF.
the GP hyperactivity hypothesis engenders the question regarding the pathologic
basis underlying the development of this dysautonomia. Preliminary evidence
from basic studies [70, 71] indicate that
the extrinsic autonomic input to the heart, i.e., from the brain and spinal
cord, exerts an inhibitory control over the ICANS suggesting that attenuation
or loss of this control would allow the GP to become independently hyperactive.
Presumptive evidence in support of this hypothesis can be inferred from the
recent reports describing the incidence of AF in patients with heart
transplants. Khan et al.  did a retrospective analysis
of 923 patients who underwent orthotopic heart transplantation. This group was
age, gender and body mass index matched versus a coronary artery bypass graft
group. The differences in the onset of AF over a 3-7 year period were 0.3% for
the former and 21% for the latter cohort. All the transplants, except 3, were
done using the biatrial technique, whereby the major portion of the recipients
atria are left and a remnant of the two atria from the donor are sutured to the
recipient’s atria. Thus the major GP and their extrinsic innervation remain
intact allowing control by the higher centers over the ICANS. The authors’
state, “…we did observe that the only cases of AF were all in patients who had
bicaval anastomosis.” These three patients lost connection and supposedly
control between the extrinsic autonomic innervation (from recipient) and GP of
the donor heart. Since the PV in both types of anastomoses are isolated the
possible source of the triggering for AF might well arise from the superior
vena caval myocardial sleeve due to hyperactivity of the adjacent GP .
stochastic nature of GP firing  is consistent with the
episodic nature of paroxysmal AF. Insofar as AF progression from paroxysmal to
persistent and long standing persistent forms, the same remodeling mechanisms
described for the progression of the multiple wavelet form of AF would come
into play as the paroxysmal AF burden increased. In addition, more and
prolonged episodes of AF have also been shown to result in autonomic remodeling
which manifests as a greater propensity for AF inducibility .
It is likely, that both electrophysiological and autonomic remodeling factors
are involved in the “AF begets AF” phenomenon, thereby allowing the coexistence
of the neurally based drug resistant focal AF and the myocardial based macro-
or multiple reentrant forms of AF . Indeed, this
coexistence, previously predicted [19, 20]
could explain the findings of Danik et al.  who induced
AF after acute GP ablation in 17 of 18 patients but showed long term (1 year
follow-up) freedom from AF recurrence in 94%. Also, others have reported that
drugs that were ineffective prior to GP ablation could be used to maintain
sinus rhythm in patients still inducible after GP ablation and PVI .
another reported, apparently paradoxical, effect of PVI may be explained by the
hyperactive GP hypothesis. Numerous investigators [33-36] have concluded, “Complete electrical isolation of the PVs
is not a requirement for a successful outcome after LACA” .
should be noted, that although the major GP, containing hundreds of neurons,
are situated close to the PVs, there are many other GP with few neurons
throughout the atria . The interruption of axons from
these hyperactive GP to PVs may have also contributed to PV focal firing. A
recent experimental study showed that myocardial conduction block could be
achieved across the atrial appendages but that subsequent application of Ach to
the appendage could cause focal firing arising from the PV via unblocked neural
connections . The converse can also be predicted, if one
accepts the existence of both a neural as well as a myocardial conduction
system throughout the heart [41, Figure 1].
It seems possible that in some cases, neural connections can be interrupted
from atria to PV while myocardial conduction may return.
recognizing these diverse pathologies developing within this dual cardiac
conduction system, i.e., neural as well as myocardial, new insights into the
diagnosis of various cardiac arrhythmias, besides AF, may emerge and provide
potential new therapeutic approaches to their prevention or termination.
this review we have summarized the favorable aspects and drawbacks of pulmonary
vein isolation (PVI). As for the role of the ganglionated plexi (GP), found
adjacent to the PV atrial entrances, both basic and clinical evidence has
shown that GP stimulation promotes initiation and maintenance of AF, and that
GP ablation reduces recurrence of AF following catheter or surgical ablation of
these structures. Based on these findings, the GP Hyperactivity Hypothesis has
been proposed to explain, at least in part, the mechanistic basis for the focal
form of AF. In addition, the co-existence of both a myocardial and neural
conduction system in the atrium can aid in understanding the greater success
for AF ablation by the combined use of PVI and GP ablations.
thank Mrs. Andrea Moseley, Mr. Joseph Klimkoski and Dr. Tushar Sharma for their
technical assistance in the many experimental studies cited herein.
Giraud G, Puech P, Latour H. The physiological electrical activity of Tawara's node and of His bundle in man. Endocavitary electrocardio-graphic registration. Bull Acad Natl Med 1960;144:363-366.
Scherlag BJ, Lau SH, Helfant RH, Berkowitz WD, Stein E, Damato AN. Catheter technique for recording His bundle activity in man. Circulation. 1969;39(1):13-8.
Wellens HJJ. Electrical Stimulation of the Heart in the Study and Treatment of Tachycardias. Stenfert Kroese, Leiden 1971.
Narula OS. Atrioventricular conduction defects in patients with sinus bradycardia. Analysis by His bundle recordings. Circulation 1971;44:1096-110.
Castellanos A Jr, Castillo C, Cunha D, Myerburg RJ. Value of His bundle recordings in the evaluation of the pre-excitation (Wolff-Parkinson-White) syndrome. Proc K Ned Akad Wet C 1972;75:402-21.
Rosen KM, Bauernfeind RA, Swiryn S, Strasberg B, Palileo EV. Dual AV nodal pathways and AV nodal reentrant paroxysmal tachycardia. Am Heart J 1981;101:691-5.
Scheinman MM, Morady F, Hess DS, Gonzalez R. Catheter-induced ablation of the atrioventricular junction to control refractory supraventricular arrhythmias. JAMA 1982;248:851-5.
Huang SK, Bharati S, Graham AR, Lev M, Marcus FI, Odell RC. Closed chest catheter desiccation of the atrioventricular junction using radiofrequency energy - a new method of catheter ablation. J Am Coll Cardiol 1987;9:349-58.
Kuck KH, Kunze KP, Schlüter M, Geiger M, Jackman WM. Ablation of a left-sided free-wall accessory pathway by percutaneous catheter application of radiofrequency current in a patient with the Wolff-Parkinson-White syndrome. Pacing Clin Electrophysiol 1989;12: 1681-90.
Jackman WM, Wang X, Friday KJ, Roman CA, Moulton KP, Beckman KJ, McClelland JH, Twidale N, Hazlitt HA, Prior MI, Margolis PD, Calame JD, Overholt KD, Lazzara R Catheter ablation of accessory atrioventricular pathways (Wolff-Parkinson-White syndrome) by radiofrequency current. N Engl J Med 1991;324:1605-11.
Haissaguerre M, Gaita F, Fischer B, Commenges D, Montserrat P, d'Ivernois C, Lemetayer P, Warin JF. Elimination of atrioventricular nodal reentrant tachycardia using discrete slow potentials to guide application of radiofrequency energy. Circulation 1992;85:2162-75.
Jackman WM, Wang X, Friday KJ, Roman CA, Moulton KP, Beckman KJ, McClelland JH, Twidale N, Hazlitt HA, Prior MI, Margolis PD, Calame JD, Overholt KD, Lazzara R Treatment of supraventricular tachycardia due to atrioventricular nodal reentry, by radiofrequency catheter ablation of slow-pathway conduction. N Engl J Med 1992;327:313-318.
Cosio FG, López-Gil M, Goicolea A, Arribas F, Barroso JL. Radiofrequency ablation of the inferior vena cava-tricuspid valve isthmus in common atrial flutter. Am J Cardiol 1993;71:705-9.
Cox J,Boineau JP, Scheussler RB, Ferguson TB Jr, Cain ME, Lindsay BD, Corr PB, Kater KM, Lappas DG. Successful surgical treatment of atrial fibrillation. Review and clinical update. JAMA 1991;266:1976-1980.
Swartz JF, Pellersels G, Silvers J, Patten L, Cervantez D. A catheter-based curative approach to atrial fibrillation in humans. Circulation 1994;90:I-335. (abstract)
Haïssaguerre M, Jaïs P, Shah DC, Gencel L, Pradeau V, Garrigues S, Chouairi S, Hocini M, Le Métayer P, Roudaut R, Clémenty J. Right and left atrial radiofrequency catheter therapy of paroxysmal atrial fibrillation. J Cardiovasc Electrophysiol 1996;7:1132-44.
Jaïs P, Haïssaguerre M, Shah DC, Chouairi S, Gencel L, Hocini M, Clémenty J. A focal source of atrial fibrillation treated by discrete radiofrequency ablation. Circulation 1997;95:572-6.
Haïssaguerre M, Jaïs P, Shah DC, Takahashi A, Hocini M, Quiniou G, Garrigue S, Le Mouroux A, Le Métayer P, Clémenty J. Spontaneous initiation of atrial fibrillation by ectopic beats originating in the pulmonary veins. N Engl J Med 1998;339:659-6.
Moe GK. On the multiple wavelet hypothesis of atrial fibrillation. Arch Int Pharmacodyn Ther 1962;140:183-188.
Allessie M, Lammers WJEP, Bonke FIM, Hollen J. Experimental evaluation of Moe’s multiple wavelet hypothesis of atrial fibrillation. In Zipes DP, Jalife (eds) Cardiac Electrophysiology and Arrhythmias. Grune and Stratton, New York 1985, pps 265-275.
Jaïs P, Shah DC, Haïssaguerre M, Hocini M, Garrigue S, Clémenty J. Atrial fibrillation: role of arrhythmogenic foci. J Interv Card Electrophysiol 2000;4:29-37.
Tsai CF, Tai CT, Hsieh MH, Lin WS, Yu WC, Ueng KC, Ding YA, Chang MS, Chen SA. Initiation of atrial fibrillation by ectopic beats originating from the superior vena cava: electrophysiological characteristics and results of radiofrequency ablation. Circulation 2000;102:67-74.
Hwang C, Wu TJ, Doshi RN, Peter CT, Chen PS. Vein of Marshall cannulation for the analysis of electrical activity in patients with focal atrial fibrillation. Circulation 2000;101:1503-5.
Haïssaguerre M, Shah DC, Jaïs P, Hocini M, Yamane T, Deisenhofer I, Chauvin M, Garrigue S, Clémenty J. Electrophysiological breakthroughs from the left atrium to the pulmonary veins. Circulation 2000;102:2463-2475.
Pappone C, Oreto G, Rosanio S, Vicedomini G, Tocchi M, Gugliotta F, Salvati A, Dicandia C, Calabrò MP, Mazzone P, Ficarra E, Di Gioia C, Gulletta S, Nardi S, Santinelli V, Benussi S, Alfieri O. Atrial electroanatomic remodeling after circumferential radiofrequency pulmonary vein ablation: efficacy of an anatomic approach in a large cohort of patients with atrial fibrillation. Circulation 2001;104:2539-44.
Cha YM, Munger TM, Asirvatham SJ, Friedman PA, Monahan KH, Packer DL: Impact of left atrial size on the outcome of wide area circumferential ablation vs lasso-guided pulmonary vein isolation. Heart Rhythm 2005;2:S192.
Verma A, Marrouche NF, Natale A. Pulmonary vein antrum isolation: intracardiac echocardiography–guided technique. J Cardiovasc Electrophysiol 2004;15:1335-1340.
Calkins H, Brugada J, Packer DL, Cappato R, Chen SA, Crijns HJ, Damiano RJ Jr, Davies DW, Haines DE, Haissaguerre M, Iesaka Y, Jackman W, Jais P, Kottkamp H, Kuck KH, Lindsay BD, Marchlinski FE, McCarthy PM, Mont JL, Morady F, Nademanee K, Natale A, Pappone C, Prystowsky E, Raviele A, Ruskin JN, Shemin RJ. Heart Rhythm Society; European Heart Rhythm Association; European Cardiac Arrhythmia Society; American College of Cardiology; American Heart Association; Society of Thoracic Surgeons. HRS/EHRA/ECAS expert consensus statement on catheter and surgical ablation of atrial fibrillation: Recommendations for personnel, policy, procedures and follow-up. Europace 2007;9:335-79.
Nademanee K, Schwab MC, Kosar E, et al. A new approach for catheter ablation of atrial fibrillation: Mapping of the electrophysiologic substrate. J Am Coll Cardiol 2004;43:2044-53.
Elayi CS, Verma A, Di Biase L, Ching CK, Patel D, Barrett C, Martin D, Rong B, Fahmy TS, Khaykin Y, Hongo R, Hao S, Plargonio G, Dello Russo A, Casella M, Santarelly P, Potenza D, Fanelli R, Massaro R, Arruda M, Schweikert RA, Natale A. Ablation for longstanding permanent atrial fibrillation: Results from a randomized study comparing three different strategies. Heart Rhythm 2008;5:1658-1664.
O'Neill MD, Jaïs P, Takahashi Y, Jönsson A, Sacher F, Hocini M, Sanders P, Rostock T, Rotter M, Pernat A, Clémenty J, Haïssaguerre M. The stepwise ablation approach for chronic atrial fibrillation-evidence for a cumulative effect. J Interv Card Electrophysiol 2006; 16:153-167.
Arruda M, Natale A. The adjunctive role of non pulmonary venous ablation in the cure of atrial fibrillation. J Cardiovasc Electrophysiol 2006;17:S37-S43.
Stabile G, Turco P, LaRocca V, Nocerio P, Stabile E, DeSimeone A. Is pulmonary vein isolation necessary for curing atrial fibrillation Circulation 2003;108:657-660.
Cappato R, Negroni S, Pecora D, Bentivegna S, Lupo PP, Carolei A, Esposito C, Furlanello Prospective assessment of late conduction recurrence across radiofrequency lesions producing electrical disconnection at the pulmonary vein ostium in patients with atrial fibrillation.F, De Ambroggi L. Circulation 2003;108:1599-604.
Lemola K, Oral H, Chugh A, Hall B, Cheung P, Han J et al. Pulmonary vein isolation as an end point for left atrial circumferential ablation of atrial fibrillation. J Am Coll Cardiol 2005;46:1060-1066.
Pratola C, Baldo E, Notarstefano P, Toselli T, Ferrari R. Radiofrequency ablation of atrial fibrillation. Circulation 2008;117:136-143.
Randall WC. Changing perspectives concerning neural control of the heart. In: Neurocardiology. Eds: Armour JA, Ardell JL. Oxford University Press, New York, NY 1994. Chap 1.
Ardell JL. Structure and Function of the Mammalian Intrinsic Cardiac Neurons. In: Neurocardiology. Eds: Armour JA, Ardell JL. Oxford University Press, New York, NY 1994. Chap 5.
Armour JA, Hageman GR, Randall WC. Arrhythmias induced by local cardiac nerve stimulation. Am J Physiol 1972;223:1068-1075.
Hageman GR, Goldberg JM, Armour JA, Randall WC. Cardiac dysrhythmias induced by autonomic nerve stimulation. Am J Cardiol 1973;32:823-830.
Armour JA, Murphy DA, Yuan BX, MacDonald S, Hopkins DA. Gross and microscopic anatomy of the human intrinsic cardiac nervous system. Anat Rec 1997;247:289-298.
Pauza DH, Skripka V, Pauziene N, Stropus R. Morphology, distribution, and variability of the epicardiac neural ganglionated subplexuses in the human heart. Anat Rec 2000;259:353-82.
Lin J, Scherlag BJ, Lu Z, Zhang Y, Liu S, Patterson E, Jackman WM, Lazzara R, Po SS. Inducibility of atrial and ventricular arrhythmias along the ligament of Marshall: role of autonomic factors. J Cardiovasc Electrophysiol. 2008;9:955-62.
Chiou CW, Eble JN, Zipes DP. Efferent vagal innervation of the canine atria and sinus and atrioventricular nodes. The third fat pad. Circulation. 1997 Jun 3;95(11):2573-84.
Sharifov OF, Fedorov VV, Beloshajeko GG, Glukhov AV, Yushmanova AV, Rosenshtraukh LV. Roles of adrenergic and cholinergic stimulation in spontaneous atrial fibrillation in dogs. J Amer Coll Cardiol 2004;43:483-490.
Scherlag BJ, Yamanashi WS, Patel U, Lazzara R, Jackman WM. Autonomically induced conversion of pulmonary vein focal firing into atrial fibrillation. J Am Coll Cardiol 2005;45:1575-1880.
Lazzara R, Scherlag BJ, Robinson MJ, Samet P. Selective parasympathetic control of the canine sinoatrial and atrioventricular nodes. Circulation Res 1973;32:383-401.
Po SS, Scherlag BJ, Yamanashi, WS, Edwards J, Zhou J, Wu R, Geng N, Lazzara R, Jackman WM. Experimental model for paroxysmal atrial fibrillation arising at the pulmonary vein-atrial junctions. Heart Rhythm 2006;3:201-208.
Patterson E, Po SS, Scherlag BJ, Lazzara R. Triggered firing in pulmonary veins initiated by in vitro autonomic nerve stimulation. Heart Rhythm 2005;2:624-631.
Patterson E, Lazzara R, Szabo B, Liu H, Tang D, Li YH, Scherlag BJ, Po SS. Sodium-calcium exchange initiated by the Ca2+ transient: An arrhythmia trigger within pulmonary veins. J Am Coll Cardiol 2006;47:1196-1206.
Lemola K, Chartier D, Yeh YH, Dubuc M, Cartier R, Armour JA, Ting M, Sakabe M, Shiroshita-Takeshita A, Comtois P, Nattel S. Pulmonary vein region ablation in experimental vagal atrial fibrillation: Role of pulmonary veins versus autonomic ganglia. Circulation 2008;117:470-477.
Lin J, Scherlag BJ, Zhou J, Lu Z, Patterson E, Jackman WM, Lazzara R, Po SS. Autonomic mechanism to explain complex fractionated atrial electrograms (CFAE). J Cardiovasc Electrophysiol 2007;18:1197-1205.
Platt M, Mandapati R, Scherlag BJ, Yamanashi WS, Nakagawa H, Lazzara R, Jackman WM. Limiting the number and extent of radiofrequency applications to terminate atrial fibrillation and subsequently prevent its inducibility. Heart Rhythm 2004;1:S-11 (abstract).
Lemery R, Birnie D, Tang AS, Green M, Gollub M. Feasibility study of endocardial mapping of ganglionated plexuses during catheter ablation of atrial fibrillation Heart Rhythm 2006;3:387-396.
Scanavacca M, Pisani CF, Hachul D, Lara S, Hardy C, Darrieux F, Trombetta I, Negrão CE, Sosa E. Selective atrial vagal denervation guided by evoked vagal reflex to treat patients with paroxysmal atrial fibrillation. Circulation 2006;114:876-85.
Katritsis D, Grazitzoglou E, Sougamis D, Goumas N, Paxinos G, Camm AJ. Anatomic approach for ganglionic plexi ablation in patients with paroxysmal atrial fibrillation. Amer J Cardiol 2008;102:330-334.
Pokushalov E, Turov A, Shugayev P, Artyomenko S, Romanov A, Shirokova A. Catheter ablation of left atrial ganglionated plexi for atrial fibrillation. Asian Cardiovasc Thoracic Ann 2008;16:194-201.
Danik S, Neuzil P, d'Avila, Malchano ZJ, Kralovec S, Ruskin JN, Reddy VY. Evaluation of catheter ablation of periatrial ganglionic plexi in patients with atrial fibrillation. Am J Cardiol 2008;102:578-583.
Pappone C, Santinelli V, Manguso F, Vicedomini G, Gugliotta F, Augello G, Mazzone P, Tortoriello V, Landoni G, Zangrillo A, Lang C, Tomita T, Mesas C, Mastella E, Alfieri O. Pulmonary vein denervation enhances long-term benefit after circumferential ablation for paroxysmal atrial fibrillation. Circulation 2004;109:327-34.
Nakagawa H, Yokoyama K, Scherlag BJ, Katari V, Aoyama H, Foresti S, Jackman WM. Ablation of autonomic ganglia In: A Practical Approach to Catheter Ablation of Atrial fibrillation. Eds: Calkins H, Jais P, Steinberg JS. Wolters Kluwer/Lippincott Williams & Wilkins. Philadelphia 2008, Chap.?14.
McClelland J, Duke D, Reddy R. Preliminary results of a limited thoracotomy: A new approach to treat atrial fibrillation. J Cardiovasc Electrophysiol 2007;18:1289-1295.
Mehall JR, Kohut RN Jr., Schneeberger EW, Taketani T, Merrill WH, Wolf RK. Intraoperative epicardial electrophysiologic mapping and isolation of autonomic ganglionic plexi. Ann Thorac Surg 2007;83:538-541.
Matsutani N, Takase B, Ozeki Y, Machara T, Lee R. Minimally invasive cardiothoracic surgery for atrial fibrillation: A combined Japan-US experience. Circ J 2008;72:434-436.
Onorati F, Curcio A, Santorpino G, Torcella D, Mastrokobinto P, Tuca B, Indolfi C, Renzutti A. Routine ganglionic plexi ablation during Maze procedure improves hospital and early follow-up results of mitral surgery. J Thorac Cardiovasc Surg 2008;36:408-418.
Doll N, Pritzwald-Stegmann P, Czesla M, Kempfert J, Stenzel MA, Borger MA, Mohr FW. Ablation of ganglionic plexi during combined surgery for atrial fibrillation. Ann Thorac Surg 2008;86:1659-63.
Wijffels MC, Kirchhof CJ, Dorland R, Power J, Allessie MA. Electrical remodeling due to atrial fibrillation in chronically instrumented conscious goats: roles of neurohumoral changes, ischemia, atrial stretch, and high rate of electrical activation. Circulation 1997;18;96:3710-20.
Wijffels MC, Dorland R, Allessie MA. Pharmacologic cardioversion of chronic atrial fibrillation in the goat by class IA, IC, and III drugs: a comparison between hydroquinidine, cibenzoline, flecainide, and d-sotalol. J Cardiovasc Electrophysiol 1999;10:178-93.
Niu G, Scherlag BJ, Lu Z, Ghias M, Lazzara R, Jackman WM, Po SS. Inducibility of atrial fibrillation in the myocardial sleeve of the superior vena cava is mediated by the ganglionated plexi on the right pulmonary artery. Circulation 2007;116:II-40. (abstract).
Hou YL, Scherlag BJ, Lin J, Zhou J, Song J, Zhang Y, Patterson E, Lazzara R, Jackman WM, Po SS. Interactive atrial neural network: Determining the connection between ganglionated plexi. Heart Rhythm 2007;4:56-63.
Gagliardi M, Randall WC, Biger D, Wurster RD, Hopkins DA, Armour JA. Activity of in vivo canine cardiac plexus neurons. Am J Physiol 1988;255:H789-H800.
Zhang Y, Scherlag BJ, Lu Z, Niu GD, Yamanashi WS, Hogan C, Fields J, Ghias M, Lazzara R, Jackman WM, Po S. Comparison of atrial fibrillation inducibility by electrical stimulation of either the extrinsic or the intrinsic autonomic nervous systems. J Interv Card Electrophysiol 2008.
Khan M, Kalahasti V, Rajagopal V, Khaykin Y, Wazni O, Almahameed S, Zuzek R, Shah T, Lakkireddy D, Saliba W, Schweikert R, Cummings J, Martin DO, Natale A. Incidence of atrial fibrillation in heart transplant patients: long-term follow-up. Cardiovasc Electrophysiol 2006;17:827-831.
Lu Z, .Scherlag BJ, Lin J, Niu G, Fung KM, Zhao L, Ghias M, Jackman WM, Lazzara R, Jiang H, Po SS. Atrial Fibrillation Begets Atrial Fibrillation: Autonomic Mechanism for Atrial Electrical Remodeling Induced by Short-Term Rapid Atrial Pacing Circulation: Arrhythmia and Electrophysiology 2008;1:184-192.
Scherlag BJ, Hou Y, Lin J, Lu Z, Po SS. Neurally based focal and myocardial based macroreentrant atrial fibrillation: Two acute models of sustained atrial fibrillation in a single preparation. J Cardiovasc Electrophysiol 2007;18:129 (abstract).
Scherlag BJ, Nakagawa H, Jackman WM, Yamanashi WS, Patterson E, Po S, Lazzara R. Electrical stimulation to identify neural elements on the heart: their role in atrial fibrillation. J Interv Card Electrophysiol 2005;13:37-42.
Scherlag BJ, Hou YL, Lin J, Lu Z, Zacharias S. Dasari TW, Niu G, Ghias M, Patterson E, Jackman WM, Lazzara R. An acute model for atrial fibrillation arising from a peripheral atrial site: Evidence for primary and secondary triggers. J Cardiovasc Electrophysiol 2008;5: 518-527.