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Background: Ganglionated plexuses (GP) are implicated in atrial fibrillation (AF). Endocardial high frequency stimulation (HFS) delivered within the local atrial refractory period can trigger ectopy and AF from specific GP sites (ET-GP). The aim of this study was to understand the role of ET-GP ablation in the treatment of AF. Methods and results: Patients with paroxysmal AF indicated for ablation were recruited. HFS mapping was performed globally around the left atrium to identify ET-GP. ET-GP was defined as atrial ectopy or atrial arrhythmia triggered by HFS. All ET-GP were ablated, and PVs were left electrically connected. Outcomes were compared with a control group receiving PVI. Patients were followed-up for 12 months with multiple 48hr Holter ECGs. Primary endpoint was ≥30s AF/atrial tachycardia in ECGs. 67 patients were recruited and randomised to ET-GP ablation (n=39) or PVI (n=28). In the ET-GP ablation group, 103±28 HFS sites were tested per patient, identifying 21±10 (20%) GPs. ET-GP ablation used 23.3kWs±4.1 total radiofrequency (RF) energy per patient, compared to 55.7kWs±22.7 in PVI (p=<0.0001). Duration of procedure was 3.7hrs±1.0 and 3.3hrs±0.7 in ET-GP ablation group and PVI respectively (p=0.07). Follow-up at 12 months showed that 61% and 49% were free from ≥30secs of AF/AT with PVI and ET-GP ablation respectively (log rank p=0.27). Conclusions: It is feasible to perform a detailed global functional mapping with HFS and ET-GP ablation to prevent AF. This provides direct evidence that ET-GPs are part of the AF mechanism. The lower RF requirement implies that ET-GP targets the AF pathway more specifically This article is protected by copyright. All rights reserved.
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Min-young Kim ORCID iD: 0000-0001-6441-1798
Prapa Kanagaratnam ORCID iD: 0000-0003-3593-2185
Ian Mann ORCID iD: 0000-0002-4793-0673
Vishal Luther ORCID iD: 0000-0003-3274-7128
Targeting the ectopy-triggering ganglionated plexuses without
pulmonary vein isolation prevents atrial fibrillation
Short title: Targeting ET-GP without PVI prevents AF
Belinda Sandlera,c* MRCP, Min-Young Kima,c* PhD, Markus B Sikkela,b,c PhD,
Louisa Malcolme-Lawesb,c PhD, Michael Koa-Wingb,c PhD, Zachary I Whinnettb,c
PhD, Clare Coylea,b,c MRCP, Nick WF Lintona,b,c, Phang Boon Lima,b,c PhD, Prapa
Kanagaratnama,b,c PhD and other members of the Imperial College London,
Cardiovascular Study Group/Consortium.
*Joint first-authors for equal contribution to the study.
Affiliations
a) Myocardial Function Section, National Heart and Lung Institute, Imperial
College London, London, UK
b) Department of Cardiology, Imperial College Healthcare NHS Trust, London,
UK
c) Imperial Centre for Cardiac Engineering, Imperial College London, London,
UK
Funding: British Cardiac Trust; British Heart Foundation, Grant/Award Number:
FS/13/73/30352; St Mary’s Coronary Flow Trust
Disclosures: None. There is no conflict of interest and no relationship with industry.
Data Availability Statement
The data that support the findings of this study are available from the corresponding
author upon reasonable request.
Ethics/Consent Statement
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Accepted Article
This study was approved by the Local Research Ethics Committee and the Health
Research Authority. Patient consent was obtained for all participants of this study.
Clinical Trial Registration
This was a pilot study for the clinical trial registered on ClinicalTrials.gov
(NCT02487654).
Address for correspondence: Prof. Prapa Kanagaratnam
Cardiology Department, St Mary's Hospital
Praed Street,W2 1NY
Telephone: +44 (0) 203 312 3783; Fax: +44 (0) 203 312 1657
Email: p.kanagaratnam@imperial.ac.uk
Abstract
Background
Ganglionated plexuses (GP) are implicated in atrial fibrillation (AF). Endocardial
high frequency stimulation (HFS) delivered within the local atrial refractory period
can trigger ectopy and AF from specific GP sites (ET-GP). The aim of this study was
to understand the role of ET-GP ablation in the treatment of AF.
Methods and Results
Patients with paroxysmal AF indicated for ablation were recruited. HFS mapping was
performed globally around the left atrium to identify ET-GP. ET-GP was defined as
atrial ectopy or atrial arrhythmia triggered by HFS. All ET-GP were ablated, and PVs
were left electrically connected. Outcomes were compared with a control group
receiving PVI. Patients were followed-up for 12 months with multiple 48hr Holter
ECGs. Primary endpoint was 30s AF/atrial tachycardia in ECGs.
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67 patients were recruited and randomised to ET-GP ablation (n=39) or PVI (n=28).
In the ET-GP ablation group, 103±28 HFS sites were tested per patient, identifying
21±10 (20%) GPs. ET-GP ablation used 23.3kWs±4.1 total radiofrequency (RF)
energy per patient, compared to 55.7kWs±22.7 in PVI (p=<0.0001). Duration of
procedure was 3.7hrs±1.0 and 3.3hrs±0.7 in ET-GP ablation group and PVI
respectively (p=0.07). Follow-up at 12 months showed that 61% and 49% were free
from ≥30secs of AF/AT with PVI and ET-GP ablation respectively (log rank p=0.27).
Conclusions
It is feasible to perform a detailed global functional mapping with HFS and ET-GP
ablation to prevent AF. This provides direct evidence that ET-GPs are part of the AF
mechanism. The lower RF requirement implies that ET-GP targets the AF pathway
more specifically.
Keywords: atrial fibrillation, ganglionated plexus, pulmonary vein ectopy, autonomic
nervous system, catheter ablation
Introduction
Atrial fibrillation (AF) is the most common type of arrhythmia that causes stroke and
discomfort in patients and poses a significant health burden around the world1.
Pulmonary vein ectopy is the most common trigger for AF2, and complete pulmonary
vein isolation (PVI) has been the standard treatment for drug-refractory AF for almost
two decades. Clinical trials have repeatedly shown that PVI improves symptoms and
lessens the burden of AF3. However, 40-50% of patients after their first procedure
have recurrence of AF4,5 and patients with or without AF frequently have electrically
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re-connected pulmonary veins6,7. This suggests that the success of AF ablation is
more complex than a simple PVI-based theory.
The ganglionated plexuses (GP) which are part of the intrinsic cardiac autonomic
nervous system have often been cited as being an important component of AF
initiation and maintenance theories8. GPs comprise of dense sympathetic and
parasympathetic nerves and are situated in the epicardial fat pad of human hearts9.
GPs are interconnected with one another10 and nerves communicating with GPs
penetrate through all levels of the atria. This allows for stimulation from the
endocardium, which leads to release of acetylcholine and catecholamines that shorten
the atrial refractory period and causes PV ectopy and AF11.
There are different stimulation techniques to localise GPs. The most common method
involves delivering high frequency stimulation (HFS) (10-14V, 20Hz) continuously
for up to 10 seconds (continuous HFS), or until >50% of RR prolongation is observed
from baseline with atrioventricular dissociation12. This causes asystole for up to
several seconds with blood pressure drop. We previously mapped atrioventricular
dissociating GP (AVD-GP) in the human left atrium and found that they occupy
discrete anatomical regions, and do not conform to all the ‘common GP cluster’
regions as described from previous topographical studies13.
Another method of localising GPs is using HFS within the local refractory period14.
This technique paces the atrium at a fixed rate, and 100ms duration of HFS is
delivered at 10-14V, 20Hz (synchronized HFS). This avoids direct myocardial capture
and has been shown to trigger pulmonary vein (PV) and non-PV ectopy that can lead
to AF15. We previously mapped these ectopy-triggering GPs (ET-GP) which were
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anatomically and functionally distinct from AVD-GP16. ET-GP have not been widely
studied in patients even though the effects are comparable to clinical episodes of AF.
In order to test the hypothesis that ET-GP are part of the triggering mechanism for
AF, we performed selective endocardial ablation of ET-GP and monitored AF
recurrences.
Methods
This was a prospective, single-centre study recruiting patients with paroxysmal AF
indicated for AF ablation. All patients gave written informed consent. The study was
approved by the Local Research Ethics Committee. This was a pilot study for the
clinical trial registered on ClinicalTrials.gov (NCT02487654). The study procedures
took place between December 2013 and May 2017.
Patients were randomised to either ET-GP ablation without PVI or to a control arm of
standard PVI. The purpose of the control arm was to assess the ethical justification of
the study, and an independent Data and Safety Monitoring Board (two
electrophysiologists, one general cardiologist) reviewed outcomes after recruiting 20
consecutive patients. This study was not powered for sample size, as it is a proof-of-
concept study to first establish safety and feasibility of ET-GP ablation, and generate
outcome data for future powered studies.
We performed block randomisation using the ‘sealed envelope’ approach. Patients
and their cardiologists providing their usual care were blinded to their randomisation.
The inclusion and exclusion criteria are included in the Supplementary Table 1. All
patients stopped their antiarrhythmics for at least 48 hours prior to their procedures.
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All had general anaesthesia and transoesophageal echocardiogram (TOE) to rule out
left atrial appendage thrombus at the start of their procedures. Transseptal punctures
were guided by TOE and fluoroscopy to access the left atrium. We used the
CARTOTM system (Biosense Webster, inc.) for 3D electroanatomical mapping of the
left atrium. Intracardiac electrograms were recorded at 1000 Hz by the
electrophysiology recording system (Bard EP, Lowell, MA).
ET-GP mapping with synchronised HFS
Patients randomised to ET-GP ablation were required to be in sinus rhythm, in order
to pace their atrium. If in AF at start of the protocol, patients were electrically
cardioverted to restore sinus rhythm. A 20‐pole circumferential catheter (LassoNav;
Biosense Webster Inc, Diamond Bar, CA) was inserted into the nearest pulmonary
vein to where HFS was being tested. This was to maximise the chances of identifying
the earliest triggered PV ectopy with HFS, with the assumption that GPs are more
likely to have neural connections to adjacent structures.
Pacing was performed from the ablation catheter (bipolar 3.5mm irrigated tip contact
force sensing ablation catheter; Smart‐Touch; Biosense Webster, inc.), at a rate higher
than the intrinsic rate. A minimum contact force 3g was required before delivering
HFS. The Grass S88 stimulator (Astro‐Med, West Warwick, RI) was used to deliver
HFS from each pacing stimulus (“synchronised” to pacing, delivering HFS within the
local atrial refractory period), for 100-120ms duration at 40Hz, 10V, up to 15 trains17
(synchronised HFS). There remained a risk of local myocardial capture if there was
enough shortening of the local refractory period. These could be identified by the
mapping catheter having the earliest signal with no delay from the last pacing artefact.
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If this occurred, we repeated HFS and reduced the duration of HFS until no further
local capture was evident. A “positive” response to synchronised HFS included single
atrial ectopy, few beats of atrial ectopy, atrial tachycardia or AF15. These positive
responses were tagged as “ET-GP” sites on the CARTOTM geometry. An example of
this is shown in Figure 1 (left panel). If there was <3 atrial ectopy triggered with HFS,
we re-tested with HFS up to three times to exclude the possibility of this being due to
spontaneous ectopy or mechanical irritation.
Sometimes, patients developed sustained AF that would not self-terminate within few
minutes of waiting. If this occurred, DC cardioversion was undertaken to restore sinus
rhythm, and mapping resumed with synchronised HFS again.
AVD-GP mapping with continuous HFS
We included all learning curveprocedures in the ET-GP ablation group for the Per
Protocol analysis. The main procedural hurdle was obtaining limited ET-GP maps due
to sustained AF despite multiple cardioversions. Initially, these patients were crossed
over to PVI if they had already undergone 3 DC cardioversions for sustained AF or
had incessant AF that could not be cardioverted. However, we previously showed that
a proportion of ET-GP co-locate with AVD-GP16. Therefore, a protocol amendment
was instituted, and patients randomised to ET-GP ablation with sustained AF had
AVD-GP mapping instead of crossing over to PVI. Randomisation was also later
modified to 2:1 in favour of ET-GP to offset these early crossovers.
In order to map AVD-GP, a quadripolar catheter was inserted into the right
ventricular apex or a continuous arterial blood pressure monitoring was visualised
alongside the intracardiac electrograms. This allowed for more accurate assessment of
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any significant RR prolongation through the HFS artefact noise. With minimum 3g
contact force at the tip of the ablation catheter, HFS was delivered at 40Hz, 10V, up
to 10 seconds continuously (continuous HFS). A “positive” response to continuous
HFS was defined as a site causing >50% increase in the average RR interval during
HFS when compared to 10 RR intervals prior to HFS13. These were marked as “AVD-
GP” on the CARTOTM 3D geometry. An example of this is shown in Figure 2 (top
panel).
Ablation of GP
A target of at least 80 evenly distributed sites were tested around the left atrium. After
completing mapping, both ET-GP and AVD-GP were ablated. Clusters of ablation
lesion were delivered at each GP site, which involved 30secs radiofrequency (RF)
ablation at each lesion for minimum three lesions per GP, and with minimal contact
force >3g. Posterior wall GPs were ablated with power limited to 25W. After
completing ablation, all sites were retested for a positive response with either
synchronised HFS (Figure 1; right panel) or continuous HFS (Figure 2; bottom panel)
according to the pre-ablation characterisation.
If sites still triggered ectopy/AT/AF, then further ablation was performed until no
further response to HFS was evident. Pulmonary veins were checked to confirm all
remained connected.
Pulmonary vein isolation
Patients randomised to PVI had circumferential ablation around the antra of the
pulmonary veins with RF energy. A 3.5mm irrigated tip contact force sensing ablation
catheters (Smart‐Touch; Biosense Webster, inc.) with 10-20g contact force and
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17ml/min flow was used to perform circumferential antral ablation. Entry block of the
pulmonary veins confirmed complete PVI using a circular PV mapping catheter.
Clinical follow-up
All patients were followed-up every 3 months post-ablation with 48hr Holter
monitoring and telephone consultations up to 12 months. Patients were encouraged to
have additional investigations if symptoms reported between 3 monthly follow-ups.
Any arrhythmia within the first 3 months of “blanking period” were discounted as an
endpoint. All patients for repeat ablations received PVI without additional GP
ablation.
Definition of endpoint
The primary end-point was defined as any ≥30secs of AF or AT documented on
electrocardiography, Holters, or on any implantable devices such as pacemakers or
loop recorders1 and/or referral for repeat AF/AT ablations on symptomatic grounds.
The secondary endpoint was complications such as significant groin haematoma,
pericardial effusion or cardiac tamponade requiring drainage, stroke, myocardial
infarction, oesophageal injury or fistula and death.
Statistics
Statistical analysis was performed using GraphPad 5 (Prism, San Diego, California).
Continuous variables were expressed as mean±STD. Categorical variables were
expressed as numbers and percentages. Mann-Whitney U test, Fisher’s exact test and
unpaired t-test were used for comparison of means. The primary end-point analysis
was conducted using the intention-to-treat (ITT) and per-protocol (PP) study
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populations. ITT analysis included patients who were crossed over from their
originally randomised group, and PP analysis excluded all crossed over patients. The
primary endpoint for ITT and PP study populations were each plotted onto a Kaplan-
Meier curve to estimate the event-free survival rate in each group. A p value <0.05
indicated statistical significance.
Results
67 patients were recruited to the study and randomised to ET-GP ablation (n=39) or
PVI (n=28). Initially, 8 patients randomised to ET-GP ablation were crossed over to
PVI due to sustained AF despite multiple cardioversions, preventing completion of
the ET-GP protocol (Figure 3). Subsequently, a new protocol was implemented to
prevent further cross-overs due to sustained AF by including AVD-GP mapping and
ablation, as described in the Methods. Patients were 60yrs±11 and 63% were male.
BMI was 28.6 kg/m2±4.6, left atrial diameter size 3.8mm±0.4, left ventricular systolic
function 64.1%±2.7 and CHA2DS2-VASc score 1.3±1.1. There were no significant
differences in the baseline characteristics between the two groups (Table 1). Most ET-
GP were present around the PV antra, except for the posterior antrum of the right
inferior PV. Further ET-GP were clustered across the roof and in the mid-anterior
wall.
Ablation procedures and complications
There were 26 patients who had ET-GP ablation and 5 patients who had combination
of ET-GP and AVD-GP ablations. We tested total 2787 HFS sites, which identified
570 (20%) GPs. 502 were ET-GPs and 68 were AVD-GPs. Patients had average
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103±28 HFS sites tested which identified 21±10 (20%) GPs per patient. Re-testing
with HFS at all ablated GP sites confirmed no further inducible atrial arrhythmia.
On a per-protocol (PP) basis, the duration of procedure in the ET-GP and PVI groups
were 3.7hrs±1.0 and 3.3hrs±0.7 respectively (p=0.07). The fluoroscopy times in the
two groups were 20.8mins±10.4 and 20.9mins±8.2 respectively (p=0.57) (Table 2).
There was no significant difference in sinus rhythm heart rates in those having ET-GP
ablation (median 70, IQR 15) and PVI (median 67, IQR 18) at 24hrs post ablation.
There was one groin haematoma that was conservatively managed in the PVI group.
In the ET-GP ablation group, there was one patient with phrenic nerve palsy which
was transient and fully resolved within 24 hours. Our HFS mapping protocol did not
include mapping within the PVs. However, when a GP was identified with HFS, we
tried to delineate its boundaries and occasionally, this would cross the PV ostial
border. Ablating in this region may have caused the transient phrenic nerve palsy in
this patient.
Follow-up
At 12 months follow-up with the intention-to-treat (ITT) study population, 61% and
49% were free from ≥30secs of AF/AT or repeat ablation with PVI and ET-GP
ablation respectively (log rank p=0.27). Similarly, with the PP study population, 61%
and 48% were free from ≥30secs of AF/AT or repeat ablation with PVI and ET-GP
ablation respectively (log rank p=0.28). The average RF energy used in the ET-GP
group was 23.3kWs±4.1 compared to 55.7kWs±22.7 in the PVI group (p=<0.0001)
(Figure 4A) (For reference, 25W applied for 20minutes is a total of 30kWs.)
Therefore, although there was no significant difference between PVI and ET-GP
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ablation outcomes, PVI required far more ablation than ET-GP ablation. Also,
average RF energy used in successful PVI was greater at 54.2kWs±17.7 compared to
24.6kWs±15.3 in successful ET-GP ablations (p=<0.0001) (Figure 4B). There was no
significant difference in mean heart rate between the two groups at 3, 6, 9, 12 months
post ablation.
Examples of a successful ET-GP ablation is shown in Figure 5 and from a combined
ET-GP and AVD-GP ablation in Figure 6. In the ET-GP ablation group, 15 patients
who did not reach primary endpoint had 19±8 GPs, and 16 patients who reached
primary end-point had 21±9 GPs (p=0.62) (Figure 7). 8 patients in the ET-GP ablation
group and 5 in the PVI group had repeat ablations for AF or AT within 365 days of
their index procedure (Supplementary Table 2).
Discussion
This is the first study to functionally localise and ablate ET-GP in the left atrium of
patients with paroxysmal AF. We showed that it is safe and feasible to ablate ET-GP,
with an almost 50% efficacy at preventing AF. This was despite the learning-curve we
experienced during this study. ET-GP ablation prevented AF using approximately 2.5
times less ablation energy than PVI (p=<0.0001). There was no significant procedure
time difference between the two groups, despite mapping on average 103 sites with
HFS per patient. This was likely attributed by the shorter duration of ablation for ET-
GPs compared to PVI. There were larger proportion of ET-GPs identified per patient
(20%) compared to AVD-GPs which we previously mapped in a demographically
similar cohort of patients (13%)13. Interestingly, there was no direct relationship
between the number of ET-GPs ablated and prevention of AF.
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Anatomical distribution of ET-GP
Most ET-GP were anatomically located around the PV antra, the roof, and down the
midline of the anterior wall15. Malcolme-Lawes et al previously demonstrated that
PVI can abolish the PV ectopy triggering effect of ET-GP in patients with AF18. Other
studies have also detected myocardium with unique fast-Fourier transform
characteristics in this region that has been associated with improved ablation
outcomes19. This may explain why some patients remain free from AF despite
electrical re-connection of PVs. The ET-GP located in the mid anterior wall and mid
roof are not targeted by conventional PVI lines, which may explain recurrence of AF
despite complete PVI in some patients.
Approaches to Autonomic Modulation
Two studies have previously performed ‘selective’ GP ablation in the human left
atrium to map for AVD-GP using continuous HFS20,21. The larger study of eighty
patients limited functional testing to specific regions of the atria thought to contain
GPs and tested 37 HFS sites spread across both atria, which yielded approximately 5
AVD-GP per patient21. This method of ‘selective’ GP ablation performed
significantly worse than ‘anatomical’ GP ablation at preventing AF (42.5% vs 77.5%;
p=0.02). However, two studies from the same group showed that ‘anatomical’ GP
ablation alone performed significantly worse at preventing AF than PVI22. Addition of
PVI to anatomical GP ablation produced more promising results, achieving
significantly higher success at preventing AF than PVI alone23 (74% vs 56%;
p=0.004). This was not a reproducible finding in the thoracoscopic GP ablation in
addition to PVI for advanced AF (AFACT study)24, in fact, GP ablation in addition to
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PVI had significantly higher complication rates than PVI alone, including major
bleeding, sinus node dysfunction and pacemaker implantations. 4 patients died after 1
year in the GP ablation group and none in the PVI group (p=0.055). Continuous HFS
was used to verify anatomical GP locations, though not all expected GP areas
provoked an atrioventricular dissociating response which were ablated regardless.
We previously showed that both ET-GP and AVD-GP have a variable but discrete
anatomical distribution in the left atrium which does not conform to all the anatomical
areas that are known to contain GPs13,15,16. ET-GP identified with synchronised HFS
produces PV and non-PV ectopy that are reminiscent of clinical AF15. However,
synchronised HFS can only be performed in sinus rhythm, which may be challenging
in patients who develop sustained AF during mapping, as this requires multiple DC
cardioversions. It is well known that the precise location of GP vary between hearts
significantly9, as was the finding in this study. It is only by detailed global functional
mapping with the use of appropriate HFS technique that we can identify all the
relevant GP.
Limitations
The outcome data for GP ablation may be affected by the learning curve we
experienced at the start of the study. We had large number of patients crossed-over
from initial randomization to ET-GP ablation to PVI due to sustained AF.
Maintenance of sinus rhythm was essential to complete a thorough global map of ET-
GP. This was sometimes not possible despite multiple electrical cardioversions, and
therefore some ET-GP may have been missed. We checked for reproducibility of
atrial ectopy triggered by ET-GP, but this does not completely reject the possibility of
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mechanical irritation from the catheter, and not a true autonomic stimulation effect.
General anaesthesia was used on all patients, and we do not know what impact this
would have had on the threshold for triggering atrial ectopy and AF with GP
stimulation. As the procedures were performed between 2013-2017, more modern
ablation tools such as Ablation Index was not used during PVI or GP ablation.
Recurrences of AF/AT were mainly documented from the three monthly 48 hour
Holter ECGs. Asymptomatic arrhythmias outside the Holter monitoring period may
have been missed during follow-up.
Conclusion
It is feasible to perform a global functional mapping and ablation of ET-GP to prevent
AF. This provides direct evidence that ET-GP are part of the AF mechanism.
Freedom from AF/AF with PVI and ET-GP ablation was similar, but ET-GP ablation
required approximately 2.5 times less ablation than PVI. This indicates that GP
ablation is a more specific target in the mechanism of AF. This proof-of-concept
study provides a novel endpoint for AF ablation and justifies further investigation of
the role of ET-GP in AF pathophysiology.
Acknowledgements: This study and some of the authors (BS, FSN, ZW NWFL)
were part-funded by British Heart Foundation, UK; British Cardiac Trust, UK funded
MYK; and Coronary Flow Trust, UK part-funded the study. The department is
supported by the National Institute for Health Research (NIHR) Biomedical Research
Centre based at Imperial College Healthcare NHS Trust and Imperial College
London. The views expressed are those of the author(s) and not necessarily those of
the NHS, the NIHR or the Department of Health. Dr Paul Scott, Consultant Cardiac
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Electrophysiologist (Kings College Hospital), Dr Simon Sporton, Consultant Cardiac
Electrophysiologist, (Barts Hospital), Dr Huw Bethell Consultant Cardiologist
(Northwick Park Hospital) reviewed our data as part of the Data Safety Monitoring
Board for our study.
Group/Consortium Members
Ian Mannb,c, Vishal Lutherb,c PhD, Kevin Leong PhDb,c, Fu Siong Nga,b,c PhD, Afzal
Sohaibb,c, PhD, Michael Fudgeb,c, Elaine Limb,c, Michelle Toddb,c, Ian Wrightb,c,
Norman Qureshib,c PhD, Nicholas S Peters MDa,b,c.
Data Availability Statement
The data that support the findings of this study are available from the corresponding
author upon reasonable request.
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Figures
Figure 1 An example of mapping for an ET-GP site using synchronised HFS is shown
on the left-hand side. PA view of the left atrium at the bottom shows that the ablation
catheter (Map) was positioned in the RIPV roof. The pulmonary vein catheter (Lasso) was
inserted into the RSPV. Pacing was performed first, followed by delivery of HFS coupled to
each pacing stimulus (synchronised HFS). After the third HFS train, PV ectopy was initiated
(earliest PV 13-14) which triggered AF. This site was marked as an “ET-GP” site, tagged
green in the CARTOTM geometry. After performing ablation at this site, re-testing with
synchronised HFS could not trigger the same response as before ablation. This confirmed
adequate ablation at this site. We mapped and ablated the rest of the ET-GPs this way.
Purple tags on CARTOTM represented negative responses to HFS. (ET-GP=ectopy
triggering ganglionated plexus, HFS=high frequency stimulation, RSPV=right superior
pulmonary vein, RIPV=right inferior pulmonary vein, PA=posterior-anterior,
PV=pulmonary vein)
Figure 2. Mapping for AVD-GP and testing after ablation. During AF, continuous
HFS was performed to identify AVD-GPs as in the top panel. Here, we paced 5 times to
ensure that there was no ventricular capture. A continuous train of HFS was then delivered
at the distal poles of an ablation catheter (Map). A significant AV dissociation occurred,
causing asystole of 3.6secs. We stopped HFS at this point and there was a rapid RR interval
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recovery and continuation of AF. This site was determined as an AVD-GP site and ablated
at the end of the procedure. The bottom panel shows that re-testing with continuous HFS at
this ablated site did not trigger any AV dissociation again. This confirmed adequate ablation
at this site. We mapped and ablated the rest of AVD-GPs this way. (AVD-
GP=atrioventricular dissociating ganglionated plexus, BP=blood pressure, HFS=high
frequency stimulation)
Figure 3. Study flowchart. We recruited 67 patients, of which 8 initially randomised to
ET-GP were crossed-over to the PVI group due to sustained AF precluding completion of
ET-GP mapping protocol. After changing our protocol to allow completion of GP mapping
in AF, we randomised patients 2:1 for GP ablation until more equal distribution of patients
into each group. The final number of patients receiving PVI and GP ablation were 36 and 31
respectively. 5 patients from the GP ablation group had a combination of ET-GP and AVD-
GP ablation. (AF=atrial fibrillation, AVD-GP=atrioventricular-dissociating ganglionated
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plexus, ET-GP=ectopy-triggering ganglionated plexus, GP=ganglionated plexus,
PVI=pulmonary vein isolation)
Figure 4. Average RF energy used in PVI and GP ablation. A) A comparison of the
average RF energy used between patients having PVI and GPA. The average RF energy
used in PVI and GPA were 55.7kWs±22.3 and 23.3kWs±14.4 respectively (p=<0.0001). B)
A comparison of the average RF energy used between patients having PVI and GPA who
did not reach primary end-point. The average RF energy used in successful PVI and GPA
were 54.2kWs±17.7 and 24.6kWs±15.3 respectively (p=<0.0001). (GPA=ganglionated
plexus ablation, PVI=pulmonary vein isolation, RF=radiofrequency)
Figure 5. Example of a patient who had ET-GP ablation and free from AF/AT at
12 months follow-up. Different projections of the left atrial CARTOTM 3D map are shown.
6 ET-GPs were identified and ablated. This was a 53yrs old male with hypertension, normal
left ventricular systolic function and normal left atrial size. (AP=anterior-posterior, ET-
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GP=ectopy-triggering ganglionated plexus, HFS=high frequency stimulation, INF=inferior,
LAO=left anterior oblique, LIPV=left inferior pulmonary vein, LSPV=left superior
pulmonary vein, PA=posterior-anterior, RAO=right anterior oblique, RF=radiofrequency,
RIPV=right inferior pulmonary vein, RSPV=right superior pulmonary vein, SUP=superior)
Figure 6. Example of a patient who had both ET-GP and AVD-GP ablated and free
from AF/AT at 12 months follow-up. Different projections of the left atrial CARTOTM 3D
map are shown. 11 ET-GPs and 12 AVD-GPs were identified and ablated. This was a 63yrs
old male with hypertension, diabetes mellitus, previous percutaneous coronary intervention
to the right coronary artery, normal left ventricular systolic function and mildly dilated left
atrium. (AP=anterior-posterior, AVD-GP=atrioventricular-dissociating ganglionated plexus,
ET-GP=ectopy-triggering ganglionated plexus, C-HFS=continuous high frequency
stimulation, S-HFS=synchronised high frequency stimulation, HFS=high frequency
stimulation, INF=inferior, LAO=left anterior oblique, LIPV=left inferior pulmonary vein,
LSPV=left superior pulmonary vein, PA=posterior-anterior, RAO=right anterior oblique,
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RF=radiofrequency, RIPV=right inferior pulmonary vein, RSPV=right superior pulmonary
vein, SUP=superior)
Figure 7. A scatter plot of the number of GPs (ET-GP and AVD-GP) identified in
patients undergoing GP ablation. 16 patients who reached the primary end-point had
average 22±9 GPs ablated. 15 patients who did not reach primary end-point had average
19±8 GPs ablated (p=0.62). The longest line within the scatter plots represent mean and the
error bars represent standard deviation. (AVD-GP=atrioventricular dissociating GP, ET-
GP=ectopy-triggering ganglionated plexus, GP=ganglionated plexus)
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Table 1. Demographics of patients
All (n=67) PVI (n=36) GP ablation (n=31)
p Value
Demographics
Age, yrs 60±10.8 61.7±11.0 58.1±10.5 0.16
Male 42 (63) 20 (56) 22 (71) 0.22
BMI, kg/m2 28.6±4.6 29.4±5.2 28±3.8 0.34
LA diameter, mm 3.8±0.4 3.9±0.4 3.7±0.4 0.11
LVEF, % 64.1±2.7 63.8±3.5 64.6±1.2 0.34
CHA2DS2-VASc 1.3±1.1 1.5 1.1 0.21
HTN 27 (40) 15 (42) 12 (39) 1.00
IHD 8 (12) 6 (17) 2 (6) 0.27
Values are in mean±SD or n (%).
(BMI=body mass index, CHA2DS2-VASc=congestive heart failure, hypertension,
age ≥74yrs, diabetes mellitus, prior stroke, transient ischemic attack, or
thromboembolism, vascular disease, age 65-74yrs, sex female, HTN=hypertension,
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IHD=ischaemic heart disease, GP=ganglionated plexus, LA=left atrial, LVEF=left
ventricular ejection fraction, RF=radiofrequency)
Table 2. Procedural details
Procedural details PVI (n=36) GP ablation (n=31) p Value
RF total energy used, kWs 55.7±22.7 23.3±14.1 <0.0001
Fluoroscopy time, min
20.9±8.2 20.8±10.4 0.57
Duration, hrs
3.3±0.7 3.7±1.0 0.07
Values are in mean±SD or n (%).
(GP=ganglionated plexus, PVI=pulmonary vein isolation, RF=radiofrequency)
... In a recently published study, Kim et al. [43] used a slightly different HFS technique and defined two functional classes of GP: an atrioventricular-dissociating GP type and an ectopy-triggering GP type (ET-GP). A probability atlas of ET-GP revealed a 30-40% probability of ET-GP in the areas of the PV ostia (except for the base of the right inferior PV (RIPV) on the posterior wall), roof, mid-anterior wall, the anterior wall near the RSPV, and the posterior wall near the left inferior PV. ...
... Once positioned at a stable site in the LA, the ablation catheter is paced at a rate higher than the intrinsic sinus rate at a high output at the distal poles to check for the absence of ventricular capture. Typically, at least 80-100 points within a 4-6 mm distance from each other in the LA are globally mapped using HFS [19,[41][42][43]. HFS may also be conducted in the RA, adjacent to the SVC and the septum, and also at the IVC near the CS ostium [54]. ...
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Atrial fibrillation (AF) is the most common supraventricular arrhythmia that is linked with higher cardiovascular morbidity and mortality. Recent evidence has demonstrated that catheter-based pulmonary vein isolation (PVI) is not only a viable alternative but may be superior to antiarrhythmic drug therapy for long-term freedom from symptomatic AF episodes, a reduction in the arrhythmia burden, and healthcare resource utilization with a similar risk of adverse events. The intrinsic cardiac autonomic nervous system (ANS) has a significant influence on the structural and electrical milieu, and imbalances in the ANS may contribute to the arrhythmogenesis of AF in some individuals. There is now increasing scientific and clinical interest in various aspects of neuromodulation of intrinsic cardiac ANS, including mapping techniques, ablation methods, and patient selection. In the present review, we aimed to summarize and critically appraise the currently available evidence for the neuromodulation of intrinsic cardiac ANS in AF.
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Background Ablation of autonomic ectopy-triggering ganglionated plexuses (ET-GP) has been used to treat paroxysmal atrial fibrillation (AF). It is not known if ET-GP localisation is reproducible between different stimulators or whether ET-GP can be mapped and ablated in persistent AF. We tested the reproducibility of the left atrial ET-GP location using different high-frequency high-output stimulators in AF. In addition, we tested the feasibility of identifying ET-GP locations in persistent atrial fibrillation. Methods Nine patients undergoing clinically-indicated paroxysmal AF ablation received pacing-synchronised high-frequency stimulation (HFS), delivered in SR during the left atrial refractory period, to compare ET-GP localisation between a custom-built current-controlled stimulator (Tau20) and a voltage-controlled stimulator (Grass S88, SIU5). Two patients with persistent AF underwent cardioversion, left atrial ET-GP mapping with the Tau20 and ablation (Precision™, Tacticath™ [n = 1] or Carto™, SmartTouch™ [n = 1]). Pulmonary vein isolation (PVI) was not performed. Efficacy of ablation at ET-GP sites alone without PVI was assessed at 1 year. Results The mean output to identify ET-GP was 34 mA (n = 5). Reproducibility of response to synchronised HFS was 100% (Tau20 vs Grass S88; [n = 16] [kappa = 1, SE = 0.00, 95% CI 1 to 1)][Tau20 v Tau20; [n = 13] [kappa = 1, SE = 0, 95% CI 1 to 1]). Two patients with persistent AF had 10 and 7 ET-GP sites identified requiring 6 and 3 min of radiofrequency ablation respectively to abolish ET-GP response. Both patients were free from AF for > 365 days without anti-arrhythmics. Conclusions ET-GP sites are identified at the same location by different stimulators. ET-GP ablation alone was able to prevent AF recurrence in persistent AF, and further studies would be warranted.
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Background The ganglionated plexuses (GP) of the intrinsic cardiac autonomic system may play a role in atrial fibrillation (AF). Objectives We hypothesized that ablating the ectopy-triggering GPs (ET-GP) prevents AF. Methods GANGLIA-AF (NCT02487654) was a prospective, randomized, controlled, 3-centre trial. ET-GP were mapped using high frequency stimulation (HFS), delivered within the atrial refractory period and ablated until non-functional. If triggered AF became incessant, atrioventricular dissociating GPs (AVD-GP) were ablated. We compared GP ablation (GPA) without pulmonary vein isolation (PVI) against PVI, in patients with paroxysmal AF. Follow-up was for 12 months including 3-monthly 48hr Holter monitors. The primary endpoint was documented ≥30s atrial arrhythmia after a 3-month blanking period. Results 102 randomized patients were analysed on a per-protocol basis after GPA (n=52) or PVI (n=50). GPA patients had 89±26 HFS sites tested, identifying median 18.5 (IQR 16; 21%) GPs. RF ablation time in GPA was 22.9±9.8mins and 38±14.4mins in PVI (p<0.0001). The freedom from ≥30s atrial arrhythmia at 12-month follow-up with GPA was 50% (26/52) vs 64% (32/50) with PVI (log rank p=0.09). ET-GP ablation without AVD-GP ablation achieved 58% (22/38) freedom from the primary endpoint. There was a significantly higher reduction in AAD usage post-ablation after GPA vs PVI (55.5% vs 36%; p=0.05). Patients were referred for redo ablations in 31% (16/52) after GPA and 24% (12/50) after PVI (p=0.53). Conclusions GPA did not prevent atrial arrhythmias more than PVI. However, less RF ablation was delivered to achieve a higher reduction in AAD usage with GPA than PVI.
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Demonstration that the myocardial sleeves of the pulmonary veins (PVs) are the main triggering and maintaining foci for paroxysmal atrial fibrillation (AF) have stimulated studies investigating electrophysiological properties of PVs and the adjacent left atrial (LA) myocardium. It has been shown that PV myocytes have a shorter action potential duration and are more prone to effects of local autonomic nerve stimulation in terms of shortening of action potential duration, early after depolarization formation and triggered firing compared to left atrial myocytes (1). The intrinsic cardiac autonomic nervous system (ICANS) forms clusters of neurons called ganglionic plexi (GPs), and studies using histologic examination of heart sections have shown that these GPs are localized preferentially at certain epicardial sites adjacent to the left and right atria (2). The precise role of ICANS in AF continues to be an area of intense research (3), and matters are not helped by the uncertainty regarding the best way to identify and target ICANS peri‐procedurally. As there can be significant variability of GP sites in individual patients, endocardial high‐frequency stimulation (HFS) has been used to aid their localization in the electrophysiology laboratory (4). This article is protected by copyright. All rights reserved.
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Background Epicardial ganglionated plexus (GP) have an important role in the pathogenesis of atrial fibrillation (AF). The relationship between anatomical, histological and functional effects of GP is not well known. We previously described atrioventricular (AV) dissociating GP (AVD-GP) locations. In this study, we hypothesised that “ET-GP” are upstream triggers of atrial ectopy/AF and have different anatomical distribution to AVD-GP. Objectives We mapped and characterised ET-GP to understand their neural mechanism in AF and anatomical distribution in the left atrium (LA). Methods 26 patients with paroxysmal AF were recruited. All were paced in the LA with an ablation catheter. HFS (80 ms) was synchronised to each paced stimulus (after 20 ms delay) for delivery within the local atrial refractory period. HFS responses were tagged onto CARTO™ 3D LA geometry. All geometries were transformed onto one reference LA shell. A probability distribution atlas of ET-GP was created. This identified high/low ET-GP probability regions. Results 2302 sites were tested with HFS, identifying 579 (25%) ET-GP. 464 ET-GP were characterised, where 74 (16%) triggered ≥30s AF/AT. Median 97 (IQR 55) sites were tested, identifying 19 (20%) ET-GP per patient. >30% of ET-GP were in the roof, mid-anterior wall, around all PV ostia except in the right inferior PV (RIPV) in the posterior wall. Conclusion ET-GP can be identified by endocardial stimulation and their anatomical distribution, in contrast to AVD-GP, would be more likely to be affected by wide antral circumferential ablation. This may contribute to AF ablation outcomes.
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Background: Advanced generation ablation technologies have been developed to achieve more effective pulmonary vein isolation (PVI) and minimize arrhythmia recurrence after atrial fibrillation (AF) ablation. Methods: We randomly assigned 346 patients with drug-refractory paroxysmal AF to contact force-guided radiofrequency ablation (CF-RF; n=115), 4-minute cryoballoon ablation (Cryo-4; n=115), or 2-minute cryoballoon ablation (Cryo-2; n=116). Follow-up was 12 months. The primary outcome was time to first documented recurrence of symptomatic or asymptomatic atrial tachyarrhythmia (AF, atrial flutter, or atrial tachycardia) between days 91 and 365 after ablation or a repeat ablation procedure at any time. Secondary end points included freedom from symptomatic arrhythmia and AF burden. All patients received an implantable loop recorder. Results: One-year freedom from atrial tachyarrhythmia defined by continuous rhythm monitoring was 53.9%, 52.2%, and 51.7% with CF-RF, Cryo-4, and Cryo-2, respectively (P=0.87). One-year freedom from symptomatic atrial tachyarrhythmia defined by continuous rhythm monitoring was 79.1%, 78.2%, and 73.3% with CF-RF, Cryo-4, and Cryo-2, respectively (P=0.26). Compared with the monitoring period before ablation, AF burden was reduced by a median of 99.3% (interquartile range, 67.8%-100.0%) with CF-RF, 99.9% (interquartile range, 65.3%-100.0%) with Cryo-4, and 98.4% (interquartile range, 56.2%-100.0%) with Cryo-2 (P=0.36). Serious adverse events occurred in 3 patients (2.6%) in the CF-RF group, 6 patients (5.3%) in the Cryo-4 group, and 7 patients (6.0%) in the Cryo-2 group, with no significant difference between groups (P=0.24). The CF-RF group had a significantly longer procedure duration but significantly shorter fluoroscopy exposure (P<0.001 vs cryoballoon groups). Conclusions: In this multicenter, randomized, single-blinded trial, CF-RF and 2 different regimens of cryoballoon ablation resulted in no difference in 1-year efficacy, which was 53% by time to first recurrence but >98% burden reduction as assessed by continuous cardiac rhythm monitoring. Clinical trial registration: URL: https://www.clinicaltrials.gov. Unique identifier: NCT01913522.
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Introduction The ganglionated plexuses (GPs) of the intrinsic cardiac autonomic system are implicated in arrhythmogenesis. GP localization by stimulation of the epicardial fat pads to produce atrioventricular dissociating (AVD) effects is well described. We determined the anatomical distribution of the left atrial GPs that influence AV dissociation. Methods and Results High frequency stimulation was delivered through a Smart‐Touch™ catheter in the left atrium of patients undergoing atrial fibrillation (AF) ablation. 3D locations of points tested throughout the entire chamber were recorded on the CARTO™ system. Impact on the AV conduction was categorized as ventricular asystole, bradycardia or no effect. CARTO™ maps were exported, registered and transformed onto a reference left atrial geometry using a custom software, enabling data from multiple patients to be overlaid. In 28 patients, 2108 locations were tested and 283 sites (13%) demonstrated atrioventricular dissociation effects (AVD‐GP). There were 10 AVD‐GPs (IQR 11.5) per patient. 80% (226) produced asystole and 20% (57) showed bradycardia. The distribution of the two groups were very similar. Highest probability of AVD‐GPs (>20%) were identified in: infero‐septal portion (41%) and right inferior pulmonary vein base (30%) of the posterior wall, right superior pulmonary vein antrum (31%). Conclusion It is feasible to map the entire left atrium for AVD‐GPs prior to AF ablation. Aggregated data from multiple patients, producing a distribution probability atlas of AVD‐GPs, identified three regions with a higher likelihood for finding AVD‐GPs and these matched the histological descriptions. This approach could be used to better characterise the autonomic network. This article is protected by copyright. All rights reserved.
Chapter
Cardiac control is mediated via a series of reflex control networks involving somata in the (i) intrinsic cardiac ganglia (heart), (ii) intrathoracic extracardiac ganglia (stellate, middle cervical), (iii) superior cervical ganglia, (iv) spinal cord, (v) brainstem, and (vi) higher centers. Each of these processing centers contains afferent, efferent, and local circuit neurons, which interact locally and in an interdependent fashion with the other levels to coordinate regional cardiac electrical and mechanical indices on a beat-to-beat basis. This control system is optimized to respond to normal physiological stressors (standing, exercise, and temperature); however, it can be catastrophically disrupted by pathological events such as myocardial ischemia. In fact, it is now recognized that autonomic dysregulation is central to the evolution of heart failure and arrhythmias. Autonomic regulation therapy is an emerging modality in the management of acute and chronic cardiac pathologies. Neuromodulation-based approaches that target select nexus points of this hierarchy for cardiac control offer unique opportunities to positively affect therapeutic outcomes via improved efficacy of cardiovascular reflex control. As such, understanding the anatomical and physiological basis for such control is necessary to implement effectively novel neuromodulation therapies. © 2016 American Physiological Society. Compr Physiol 6:1635-1653, 2016.
Article
Background: Patients with long duration of atrial fibrillation (AF), enlarged atria, or failed catheter ablation have advanced AF and may require more extensive treatment than pulmonary vein isolation. Objectives: The aim of this study was to investigate the efficacy and safety of additional ganglion plexus (GP) ablation in patients undergoing thoracoscopic AF surgery. Methods: Patients with paroxysmal AF underwent pulmonary vein isolation. Patients with persistent AF also received additional lines (Dallas lesion set). Patients were randomized 1:1 to additional epicardial ablation of the 4 major GPs and Marshall's ligament (GP group) or no extra ablation (control) and followed every 3 months for 1 year. After a 3-month blanking period, all antiarrhythmic drugs were discontinued. Results: Two hundred forty patients with a mean AF duration of 5.7 ± 5.1 years (59% persistent) were included. Mean procedure times were 185 ± 54 min and 168 ± 54 min (p = 0.015) in the GP (n = 117) and control groups (n = 123), respectively. GP ablation abated 100% of evoked vagal responses; these responses remained in 87% of control subjects. Major bleeding occurred in 9 patients (all in the GP group; p < 0.001); 8 patients were managed thoracoscopically, and 1 underwent sternotomy. Sinus node dysfunction occurred in 12 patients in the GP group and 4 control subjects (p = 0.038), and 6 pacemakers were implanted (all in the GP group; p = 0.013). After 1 year, 4 patients had died (all in the GP group, not procedure related; p = 0.055), and 9 were lost to follow-up. Freedom from AF recurrence in the GP and control groups was not statistically different whether patients had paroxysmal or persistent AF. At 1 year, 82% of patients were not taking antiarrhythmic drugs. Conclusions: GP ablation during thoracoscopic surgery for advanced AF has no detectable effect on AF recurrence but causes more major adverse events, major bleeding, sinus node dysfunction, and pacemaker implantation. (Atrial Fibrillation Ablation and Autonomic Modulation via Thoracoscopic Surgery [AFACT]; NCT01091389).
Article
Objectives This study systematically reviewed the prevalence of pulmonary vein (PV) reconnection in subjects with and without AF recurrence and assessed the relationship between PV reconnection and freedom from atrial fibrillation (AF). Background Pulmonary vein reconnection is frequently observed in patients experiencing recurrent AF post catheter ablation. However, its prevalence in AF-free patients has not been well studied. Methods An electronic search was performed for studies describing PV electrical conduction in subjects with and without AF recurrence post PV isolation (PVI). Results Eleven of 5,665 articles met selection criteria. A total of 683 subjects were included in the meta-analysis; 379 had AF recurrence, and 304 were AF-free. Among patients with AF recurrence, 324 of 379 patients (85.5%) had at least 1 pulmonary vein reconnected. Among AF-free patients, 178 of 304 patients (58.6%) had at least 1 PV electrically reconnected, and 126 of 304 (41.4%) had durable PVI. The relative risk (RR) of recurrent AF was significantly lower with durable PVI than with PV reconnection (RR: 0.57; 95% confidence interval [CI]: 0.37 to 0.86; p = 0.008). Analysis of 7 studies including exclusively paroxysmal AF patients (n = 470) showed RR of 0.69 (95% CI: 0.45 to 1.05; p = 0.09). Conclusions This meta-analysis shows that durable PVI is associated with a lower risk of AF recurrence after catheter ablation. However, the association was modest, and PV electrical reconnection is common, affecting 58% of AF-free patients. Analysis of studies that included exclusively patients with paroxysmal AF showed a weaker relationship. Additional research is warranted to better understand the mechanism(s) of benefit of catheter ablation for AF and investigate whether PVI should be the primary goal.
Article
Background Current guidelines recommend pulmonary-vein isolation by means of catheter ablation as treatment for drug-refractory paroxysmal atrial fibrillation. Radiofrequency ablation is the most common method, and cryoballoon ablation is the second most frequently used technology. Methods We conducted a multicenter, randomized trial to determine whether cryoballoon ablation was noninferior to radiofrequency ablation in symptomatic patients with drug-refractory paroxysmal atrial fibrillation. The primary efficacy end point in a time-to-event analysis was the first documented clinical failure (recurrence of atrial fibrillation, occurrence of atrial flutter or atrial tachycardia, use of antiarrhythmic drugs, or repeat ablation) following a 90-day period after the index ablation. The noninferiority margin was prespecified as a hazard ratio of 1.43. The primary safety end point was a composite of death, cerebrovascular events, or serious treatment-related adverse events. Results A total of 762 patients underwent randomization (378 assigned to cryoballoon ablation and 384 assigned to radiofrequency ablation). The mean duration of follow-up was 1.5 years. The primary efficacy end point occurred in 138 patients in the cryoballoon group and in 143 in the radiofrequency group (1-year Kaplan–Meier event rate estimates, 34.6% and 35.9%, respectively; hazard ratio, 0.96; 95% confidence interval [CI], 0.76 to 1.22; P<0.001 for noninferiority). The primary safety end point occurred in 40 patients in the cryoballoon group and in 51 patients in the radiofrequency group (1-year Kaplan–Meier event rate estimates, 10.2% and 12.8%, respectively; hazard ratio, 0.78; 95% CI, 0.52 to 1.18; P=0.24). Conclusions In this randomized trial, cryoballoon ablation was noninferior to radiofrequency ablation with respect to efficacy for the treatment of patients with drug-refractory paroxysmal atrial fibrillation, and there was no significant difference between the two methods with regard to overall safety. (Funded by Medtronic; FIRE AND ICE ClinicalTrials.gov number, NCT01490814.)