The Prognostic Role of Subsequent Atrial Tachycardias Occurring

DOI: 10.1161/CIRCEP.113.001019
The Prognostic Role of Subsequent Atrial Tachycardias Occurring during
Ablation of Persistent Atrial Fibrillation: A Prospective Randomized Trial
Running title: Rostock et al.; Role of ATs in AF mechanisms
Thomas Rostock, MD1,2; Tushar V. Salukhe, MRCP, MD, MD2,3; Boris A. Hoffmann, MD2;
Daniel Steven, MD2; Imke Berner, MD2; Kai Müllerleile, MD2; Cathrin Theis, MD1,2;
Downloaded from http://circep.ahajournals.org/ by guest on November 1, 2016
Step
St
epha
ep
hann Wi
ha
Will
Willems,
llem
ll
ems,
em
s, MD
MD2
Karsten Bock, MD1,2; Helge Servatius, MD2; Arian Sultan, MD2; Stephan
1
II. Medical
Medi
d ca
di
call Clinic,
C in
Cl
nic
ic, Department of Electrop
Electrophysiology,
phy
hysiology, Univers
University
rsit
si y Medical Center,
Center
Johannes
es G
es
Gutenberg-University,
utenbe
beerg-U
University, Mainz; 2Univer
University
rsiity Hospitall Ep
E
Eppendorf,
pendorf, University He
Heart
e
Department ooff El
lec
e tr
trop
ophy
op
hysi
siol
iol
ologgy, Hamburg,
Ham
mbuurg, Germany;
G rm
Ge
r an
ny; 3R
Royal
oyall Brompton
B om
Br
mpt
pton
on Hospital,
Hos
ospii
Center, De
Electrophysiology,
Royal Brompton
Brompton andd Harefield
Harreffield
dN
NHS
HS Fou
Foundation
unddationn T
Trust
rus
ustt an
us
aand
nd Na
Nation
National
nal H
Heart
eart L
Lung
ung Ins
un
Institute,
Institu
stiitu
Imperial
Impe
Im
perial
pe
all C
College
olle
ol
l gee L
London,
ondo
on
don,
do
n, U
United
n te
ni
tedd Ki
K
Kingdom
ngdo
ng
dom
do
m
Correspondence:
ndence
nden
nd
ence
ce::
Thomas Rostock, MD
II. Medical Clinic
Department of Electrophysiology
University Medical Center
Johannes Gutenberg-University Mainz
Langenbeckstr. 1
D-55131 Mainz, Germany
Tel: +49 6131 177218
Fax: +49 6131 175534
E-mail: throstock@gmail.com
Journal Subject Codes: [5] Arrhythmias, clinical electrophysiology, drugs; [22]
Ablation/ICD/Surgery
1
DOI: 10.1161/CIRCEP.113.001019
Abstract:
Background - The role of subsequent atrial tachycardias (AT) in the context of persistent atrial
fibrillation (AF) remains undetermined. This study evaluated the prognostic role of subsequent
ATs for arrhythmia recurrences following catheter ablation of persistent AF.
Methods and Results - A total of 110 patients with persistent AF (63±9 y, 22 female, 61 longlasting persistent AF) underwent pulmonary vein isolation followed by electrogram-guided
ablation. After AF terminated to AT, patients were separated by the randomization protocol to
receive either direct cardioversion (group A) or further ablation of subsequent ATs to sinus
Downloaded from http://circep.ahajournals.org/ by guest on November 1, 2016
rhythm (SR) (group B). After a mean follow-up (FU) of 20.1±13.3 months after the first
procedure, significantly more group B patients were in SR as compared
ed to ppatients
atie
at
ient
ie
ntss in ggroup
nt
rooupp A
(30 (57%) vs. 18 (34%), p=0.02). Moreover, recurrences of AF were significantly
igniffic
ican
antl
an
tlyy le
tl
less
ss ffrequent
r qu
re
of group B tha
than
hann in
ha
n group
gro
roupp A patients (10 (19%) vs. 26 (49%), p=0.001).
p=0..001)
1)). After the last procedure
proced
d
(FU 34.0±6.4
AF
6.4 months), significantly
sign
gnif
iffic
ican
antl
an
tlyy more
tl
mo
ore group
groupp B patients
patieent
n s were
w ree free
we
freee of A
F ass ccompared
o paareed to
om
patients of group
p=0.01).
grou
gr
oupp A (49
ou
(449 (92%)
(92%
%) vs. 399 (74%),
(744%), p=
=0.01). The
h pproportion
he
ro
ropo
port
rtion
tion of
of AT
AT recurrences
recu
c rren
cu
encess ddid
id not
differ between
ween tthe
h two
he
woo ggroups
roup
ups afterr th
up
the first andd fina
final
nall pr
na
pprocedure.
oced
edure. The
ed
hee stronge
strongest
gest ppredictor
ge
redictor for an
arrhythmiaa free survival
endpoint
al aafter
fftter a si
single
ingl
gle pr
gl
pprocedure
oced
dure was ra
randomization
ndomi
d izattio
on to tthe
he pprocedural
rocedu
d ra
rall en
eendp
dpp
of termination
tion
ti
on to
to SR
R by
by elimination
ellim
i in
inat
atio
i n off subsequent
subbse
sequ
quen
entt ATs
ATs (p=0.004).
((pp=00.0004
04).
).
Conclusions - Catheter ablation of subsequent ATs increases freedom from AF but not AT,
suggesting a contributing role of subsequent ATs in the mechanisms of persistent AF.
Clinical Trial Registration - URL: http://www.clinicaltrials.gov. Unique identifier:
NCT01896570.
Key word: atrial fibrillation, atrial tachycardia, catheter ablation, arrhythmia
2
DOI: 10.1161/CIRCEP.113.001019
Introduction
With an increasing complexity of catheter ablation techniques for the treatment of persistent
atrial fibrillation (AF), subsequent atrial tachycardias (AT) have evolved as an important
arrhythmia in terms of mechanistic cause, prognostic relevance and treatment strategies1-6. While
arrhythmia recurrences after pulmonary vein (PV) isolation as the sole procedural strategy
predominantly consist of AF, subsequent ATs represent approximately half of all recurrences
following extensive biatrial substrate ablation1-4,7-9. Therefore, a pro-arrhythmogenic
Downloaded from http://circep.ahajournals.org/ by guest on November 1, 2016
consequence of the ablation procedure itself by creating the basis for zones of slow con
conduction
ndu
ducc
or enhanced electrical automaticity has been proposed to cause these ATs100. However,
Howe
Ho
weve
ver,
r, a
bod
oddy off evidence
ody
evi
v de
dennce emerges demonstratin
ng that subsequent
subsequuent ATs
ATs appear as a resul
l of a
cumulatingg body
demonstrating
result
substrate transformation
ransformation
ra
ansformation too th
the
he inca
incapability
cappabiiliity
ca
y tto
o ma
maintain
aintaain ffibrillatory
i ri
ib
rilllatooryy act
activity
tivvity
ty and a hi
hierarchic
hierarchical
ierrarcchic
11-13
1
-13
o off the
on
the arrhythmia
arrhhyth
thmia
i 11
. Ne
Nevertheless,
Neverthe
hele
he
less
le
ss, th
ss
the
he pr
prog
prognostic
ogno
og
nost
no
sti
st
tic rrole
o e off sub
ol
subsequent
bse
seqqu
quentt AT
A
ATss
organization
occurring after
a
termi
termination
inatio
io
on off ppersistent
ersis
i te
t nt AF
A ffor
or the llong-term
ongg te
t rm outco
outcome
c mee hhas
as nott bbeen
eenn de
ddetermined
term
m
thus far.
The aim of this study was to evaluate the impact of sequential ablation of subsequent ATs
occurring after termination of persistent AF on the outcome and potential consequences on the
type of arrhythmia recurrences during follow-up.
Methods
Study population
The patients were selected using the following inclusion criteria: persistent AF lasting for a
minimum duration of 1 month before the procedure, a history of at least 1 attempt at electrical
cardioversion, AF refractory to antiarrhythmic drug therapy and no previous ablation procedure.
Long-standing persistent AF was defined as arrhythmia duration of at least 12 months. The study
3
DOI: 10.1161/CIRCEP.113.001019
was approved by the institutional review board and ethics committee. All patients provided
written informed consent. Patients were enrolled at the University Heart Centre Hamburg
between June 25, 2009 and October 13, 2010.
Study design
The patients were randomized before the procedure into one of the study arms. In all patients, a
stepwise ablation procedure was performed consisting of PV isolation as the first step followed
by electrogram-based ablation of the left atrium (LA), coronary sinus (CS) and the right atrium
Downloaded from http://circep.ahajournals.org/ by guest on November 1, 2016
(RA) as required. The endpoint of electrogram-based ablation was termination
either
mination of AF ei
ith
theer with
conversion to an AT or directly to sinus rhythm (SR). Atrial tachycardia
was
diaa w
as ddefined
effin
efi
ined
d ass an
an
organized atri
with
endocardial
monomorphic Paatrial
iall ac
aactivity
cti
tiivi
vitty wi
w
th a consistent endocardi
d all activation se
di
ssequence
quuen
ence and monomorph
waves. If the
terminated
directly
ablation,
he ppatient
atient termi
minattedd di
ireectly
y iinto
ntto SR
R during
durrin
ing electrogram-based
e ec
el
e trogra
ram-bbased
ra
d ablat
attio
on, tthe
he
procedure was
without
ablation
randomization
started
w comp
ccompleted
co
omp
mpletedd with
ith
thout ab
abla
latti
la
ti ooff AT
tion
ATs. Th
The ra
rand
n om
nd
omizzat
atiion protocol
protoc
ocol
oc
ol was st
tartted
d after
AF termination
with
cardioverted
a
ation
wiithh conversion
conv
nvversiion to AT.
AT In group
groupp A patients,
patie
i ntts, AT
AT was
w s electrically
wa
elec
el
e tr
t icallly car
rdi
diov
ovvertee
without specific
AT
ecific
ifiic mapping
if
pii and
ndd ablation
blati
tio off A
T and
d PV iisolation
lati
ti was
as confirmed
fi ed
d or completed
lettedd if
necessary during SR. No further ablation was performed. In group B patients, all subsequent ATs
were targeted for ablation until SR was achieved.
Ablation procedures
The following catheters were introduced via a femoral vein access: (1) A steerable decapolar
catheter (InquiryTM, IBI, Irvine Biomedical, Inc., Irvine, CA, USA) was positioned within the
CS; (2) a circumferential decapolar diagnostic catheter (Lasso, Biosense-Webster, Diamond Bar,
CA, USA) for mapping of the PVs; (3) a non-steerable quadripolar diagnostic catheter
(InquiryTM, IBI, Irvine Biomedical, Inc., Irvine, CA, USA) was placed in the right atrial
appendage; and (4) a 3.5 mm externally irrigated-tip ablation catheter (Thermocool, Biosense-
4
DOI: 10.1161/CIRCEP.113.001019
Webster, Diamond Bar, CA, USA). Access to LA was achieved by a single transseptal puncture
with the two catheters placed into the left atrium via the same puncture. A single bolus of 50
IU/kg body weight heparin was administered after transseptal puncture. The activated clotting
time was assessed every 30 minutes and maintained within a range of 250-350 seconds. In all
study patients, the stepwise ablation approach with the desired procedural endpoint of AF
termination was used. The ablation protocol performed as standard at our institution has been
described previously in detail2,9. Electrical isolation of the PVs was the first step in all
Downloaded from http://circep.ahajournals.org/ by guest on November 1, 2016
procedures. PV isolation was defined by elimination or dissociation off PV potentials
p tentials recorded
po
rec
eccor
ord on
the Lasso catheter. After complete electrical PV isolation, mapping and
ablation
was
d ab
bla
l tion
tiion w
as rroutinely
ouuti
tinn
continued in
i the
the LA.
LA.
A For
Forr the
the purpose of AF cycle le
leng
length
n th (AFCL) me
ng
m
measurement,
asuurement, the Lasso
as
catheter was
the
After
as pplaced
as
laced in th
he LA
A aappendage.
ppen
endage
en
ge. Af
A
terr an
an initial
ini
nitial
al assessment
asssessm
ment off AF
AF behavior
beha
h vi
ha
v or (local
(lo
ocall
AFCL within
h the
hin
th
he LA,
LA CS
C andd RA
RA and
an
nd AFCL
AFCL
CL gradient
gra
radi
ra
d entt between
di
b tw
be
tweeen ch
chambers),
ham
a be
b rs), el
elec
electrogram-guided
ectrogram-guii
ec
ablation targeting
rg tiingg specific
rge
spe
p ciifi
ficc electrogram
electrog
l
gram pa
ppatterns
tterns andd el
electrogram
lectrogr
g am bbehaviors
e av
eh
vio
ors was pperformed,
erfo
form
fo
rmed,
rm
consisting off contin
continuous
nti
tin o s electrical
lecttrii l acti
activity,
ti iitt hi
high
high-frequency
gh
h ffreq
r enc complex
comple
le fractionated
fr ti atted
d acti
activity,
cti
ti it llo
locally
short AFCL or intermittent local burst activity, temporal activation gradient between the distal
and proximal bipoles of the roving ablation catheter and local spreading of centrifugal activation.
Ablation of the CS was performed when the LA AFCL became longer than the local AFCL in
the CS. Mapping and ablation using the same criteria was continued in the right atrium (RA) if
AF did not terminate during LA and CS ablation.
Mapping of ATs was performed using conventional techniques6,14. In case of
macroreentrant ATs, linear ablation was performed and the endpoint of bidirectional block was
assessed and confirmed by differential pacing maneuvers after restoration of SR. Focal ATs were
mapped by assessing the earliest endocardial activation in relation to P-wave onset or, if P-wave
5
DOI: 10.1161/CIRCEP.113.001019
onset could not be clearly identified, to a fixed intracardiac electrogram. After AT termination,
no attempt at arrhythmia re-induction was performed.
Ablation was performed with a maximum power output of 30 W using an irrigation rate
of 10 – 30 ml/min (0.9% saline infused with the CoolFlow Pump, Biosense Webster) for the
PVs, 35 W and an irrigation rate between 30 – 60 ml/min in the LA, and up to 30 W in the RA.
RF current was applied within the CS with a maximum of 25 W and a manually adjusted
irrigation rate to keep the tip-temperature below 42 °C.
Downloaded from http://circep.ahajournals.org/ by guest on November 1, 2016
Follow-up
All patients were seen regularly every 3 months in our outpatient clinic.
Before
c. Be
efo
fore
re vvisits,
isit
isit
its,
s, tthe
he
patients received
Holter-ECGs.
detailed
patients’
c ve
ceive
vedd att lleast
eastt ttwo
ea
wo separate 24 hour Holt
ter-ECGs. A det
e aileed history of the patie
symptoms suggestive
was
taken.
sugggestive forr potential
poteentiall arrhythmia
arrhhythm
ytt mia recurrences
reccurre
rrences
es w
as tak
aken. In
ak
n ccase
ase off uundocumented
ndoocum
umen
um
n
symptoms suspicious
additional
suspi
pici
pi
ciou
ci
iou
ous
u for arrhythmia
arrhhythm
th ia recurrences,
recurreenc
n es
es, do
ddocumentation
cume
ment
me
n at
nt
atio
ion by
io
b add
dddit
i iona
nall Tele-ECG
na
Tele
l -EC
ECG
EC
G
recordings was pperformed.
symptomatic
erfo
f rmed
ed
d. A ddocumented
ocumented
d sym
y pt
ptomatic or asymptomatic
asym
y pt
ptomat
atic
at
i arrhythmia
ic
arrhhyt
ythhmiaa episode
episodd
ep
lasting > 300 seconds
ds was
as defined
defi
fi d as recurrence.
rec rrence
An initial banking period of 3 months was accepted. During the blanking period,
antiarrhythmic drug treatment was continued at the discretion of the operator. All antiarrhythmic
drugs (excluding betablocker for the treatment of hypertension) were ceased after the blanking
period. Patients with an arrhythmia recurrence after the blanking period were offered and
scheduled for a redo procedure.
Ablation approach of repeat procedures
As the first step, electrical conduction of the PVs were assessed using a circumferential mapping
catheter and re-isolation was performed. If AF persisted, electrogram-guided ablation was
performed with the same techniques as described for the index procedure. Mapping and ablation
6
DOI: 10.1161/CIRCEP.113.001019
of AT were also performed using the techniques described above. The procedural endpoint was
termination of AF and/or AT upon achievement of SR in all patients regardless to the initial
randomization protocol.
Statistical analysis
All continuous variables are reported as mean r SD and/or medians with ranges, while
categorical variables were summarized as proportions. Categorical variables were compared
using the chi-square-test. Comparison between groups were performed with either Student`s tDownloaded from http://circep.ahajournals.org/ by guest on November 1, 2016
test or the chi-square-test. For non-normally distributed variables, the Mann-Wh
Mann-Whitney
W ittneyy U te
tes
test
s was
used. A p-value of less than 0.05 was considered to indicate a statistically
ally significant
sig
igni
nifi
fica
cant
nt difference.
dif
iffe
ferr
fe
On the basis
clinical
assumed
SUREDELOLW\RIIRUĮHUURUDQGD
i of
is
of our
our cl
liniccal experience, we assume
ed a SUREDELOLW\
\RI IRUĮHUURUDQGD
SUREDELOLW\RIIRUȕHUURUȕ-1
0.85).
With
rate
\ RI
\RI
RIIRUȕHUUURUUȕ-11 = 0.8
85).. W
itth an expected
ex
xpect
cted
ct
ed
d rat
te of tthe
hee aarrhythmia-free
rrrhyth
hmiaa-freee ssurvival
u
of 0.6 (Group
A),
calculated
sample
size
patients.
On
o B) aand
oup
ndd 0.33 ((Group
Gr
Group
A)
), we cal
lcula
latedd a sampl
le si
ize off 1100
00 patie
i nt
ie
nts. O
n the
h
assumptionn of an overall
number
110
ll rate of loss to follow-upp of 10%,
%,, we included
inclluded
d a total numbe
berr of
be
o 11
patients in both
Kaplan-Meier
b h groups. Time
Ti to arrhythmia
h h i recurrence was estimated
i
d using
i the
h K
l M
method and compared by the log-rank test. Multivariate analysis by means of a logistic
regression model and stepwise backward selection was performed to identify significant and
independent predictors of arrhythmia recurrence. Independent variables were chosen when a p <
0.10 emerged on univariate analysis. Variables in the initial model for arrhythmia recurrence
included the procedural endpoint (randomization group), age, male sex, history of hypertension,
diabetes mellitus, congestive heart failure, coronary artery disease, amiodarone treatment, LA
diameter, and left ventricular ejection fraction, time of continuous AF and baseline AFCL in
LAA, RAA and CS, respectively. The 95% confidence limits of correlation coefficients were
determined by Fisher’s r-to-z transformation. Statistical analysis was performed with a statistical
7
DOI: 10.1161/CIRCEP.113.001019
software package (SPSS, version 21, IBM, Armonk, NY, USA).
Results
Patient characteristics
A total number of 110 patients with persistent (n = 49, 45%) and long-standing persistent (n =
61, 55%) AF were included. The mean age was 63 ± 9 years and 22 patients were female. The
patients were in continuous persistent AF for 25 ± 30 months (median: 12, range: 1 – 120). FiftyDownloaded from http://circep.ahajournals.org/ by guest on November 1, 2016
five patients were randomized to a procedural endpoint of cardioversion after AF termination
with conversion to AT (group A) and 55 patients were randomly assigned
group
ned
d tto
o gr
grou
oupp B we
ou
were
ree the
targeted endpoint
ndpoint
ndpoin
int
nt was
wass achievement
wa
acchi
h evement of SR by ablation
ablatio
on of all subsequent
subsequen
nt ATs. The baseline
characteristics
patients
groups
One-third
patients
tics of patient
ti
ntss in
nt
n bboth
othh gr
ot
gro
oups
p are
re ddemonstrated
em
monsstrrateed in
n table
tab
blee 11.. O
nee-t
- hi
h rdd ooff pa
pati
tien
ti
ents
en
t were
on amiodarone
flecainide
dronedarone.
rone
ron
ne (n = 338,
8, 35%),
35%
%),
) 8 (7%)
(7%
7%
%) on
o fle
leecaain
i id
idee orr ppropafenone
r pa
ro
p fe
f no
none
nee aand
nd 2 ((2%)
2%)) on ddronedar
2%
roone
neda
d r
da
Overall, 366 (33%)
patients
control
(33%
3%)) pa
3%
pati
tien
ti
ents
en
ts received
rec
ecei
eive
ei
vedd be
ve
bbetablocker
taabl
b oc
ocke
keer fo
for
or ei
eith
either
ther
th
er vventricular
e tr
en
tric
i ul
ic
u ar rrate
atee co
at
cont
ntro
nt
roll or ttreatment
ro
treatm
reaatm of
re
hypertension.
oon..
on
Procedural results
In all patients, the procedure was started in spontaneous AF. The first step of ablation, PV
isolation, resulted in AF termination in 8 (7%) patients (3 in group A and 5 in group B).
Termination of AF occurred with a mean of 3.4 ± 0.7 PVs isolated and with conversion directly
into SR in all of these patients. The remaining 102 patients underwent electrogram-based
ablation of the atrial substrate. In 11 (10%) patients, AF terminated during ablation directly into
SR (7 during LA ablation and 4 during RA ablation). Sites of AF termination were located in the
LA, CS and RA in 72%, 8% and 19%, respectively. Termination of AF was not achieved by PVI
and biatrial defragmentation in 22 (20%) patients and electrical cardioversion was required to
restore SR (figure 1).
8
DOI: 10.1161/CIRCEP.113.001019
In group A patients, SR was achieved in all patients by electrical cardioversion. In
patients of group B, a total number of 83 AT occurred after AF termination (2.3 ± 0.8 ATs per
patient). Seventy-four (89%) ATs were successfully terminated to SR by ablation. In 2 patients,
the mechanism of the first AT occurring after AF termination could not be identified and the
patients were cardioverted. In another 5 patients, the procedure was not continued after
elimination of at least 2 subsequent ATs due to prolonged procedure durations and the final AT
was terminated by cardioversion. Procedural data of patients in both groups are demonstrated in
Downloaded from http://circep.ahajournals.org/ by guest on November 1, 2016
table 2.
Clinical outcome after ablation
One hundred
patients
analysis.
patients
followe si
ed
sixx pa
pati
t en
ti
entss were
were eligible for outcomee an
nalysis. Three
e pat
atie
at
i nts were lost to fol
l
up and 1 patient
months
ablation
atieent died 16 m
at
onnth
hs after
affteer ab
blatioon ddue
ue too malignancy.
maali
l gn
gnan
ncy
y. Alll rremaining
ema
mainin
ng patients
p tiientts
pa
completed a fol
follow-up
months
after
study
inclusion.
llo
low
w-upp off att le
lleast
ast 244 m
onth
hs af
afte
er st
tuddy in
incl
c us
cl
usiio
ion.
Rhythm Outcome
after
first
ablation
O
aft
f err fir
ft
i stt abl
blattio
bl
i n
After a mean
follow-up
20.1
13.3
significantly
an ffollo
oll
llo
p off 220
0 1 ± 13
3 months
th aft
after
fter tthe
he ffirst
irstt ablation
blati
tio procedure,
proced
ed
d re significant
ignifi
ifi ntt
more group B patients were in SR as compared to patients in group A (30 (57%) vs. 18 (34%),
p=0.02). Moreover, recurrences of AF were significantly less frequent of group B than in group
A patients (10 (19%) vs. 26 (49%), p=0.001). The exact numbers of rhythm outcomes after a
single procedure are demonstrated in figure 2 and 3. The Kaplan-Meier arrhythmia free survival
estimation showed a trend towards a better outcome in group B patients as compared to patients
of group A without reaching statistical significance (figure 4a). However, freedom from AF
survival estimation revealed a significantly better outcome for patients of group B than group A
patients (p=0.005, figure 4b).
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DOI: 10.1161/CIRCEP.113.001019
Rhythm outcome after last ablation
The mean follow-up time for patients with multiple procedures was 34.0 ± 6.4 months. The mean
number of procedures was similar in group A and B patients (1.7 ± 0.7 vs. 1.8 ± 0.7, p=0.857;
figure 3). Ultimately, significantly more group B patients were free of AF after the last procedure
as compared to patients of group A (49 (92%) vs. 39 (74%), p=0.01; figure 5). The arrhythmia
free survival estimation after the last procedure again revealed a more favorable outcome in
group B patients, however failing to achieve statistical significance (figure 6a). Nevertheless,
Downloaded from http://circep.ahajournals.org/ by guest on November 1, 2016
freedom from AF was significantly higher in group B as compared to ggroup
(p=0.016,
roupp A ppatients
atients (p
(p=
=0
figure 6b).
Predictorss for
procedural
or p
roce
ro
c du
ce
dura
ral success
ra
Patient characteristics
baseline
AFCL
were
evaluated
araccteristics as presented
ar
pressennted
d iinn table
taable 1 and
an
nd ba
ase
seline
ne A
FCL
Lw
eree eva
valluated
va
e inn uunied
ni-- aand
ndd
multivariate
adjustment
ventricular
ejection
t regression
te
reg
gre
ress
ssi
ss
sion analysis.
anallys
ysiis. Even
Eveen after ad
adju
ju
justme
ntt ffor
or hhigher
ighher le
ig
lleft
f ventric
ft
icul
ic
u ar eje
ul
j ctio
ti n
fraction and
remained
d a llonger
onge
g r ba
bbaseline
seeliine A
AFCL
FCL
FC
L iin
n the
h rig
right
ighht
ig
ht atri
atrium,
ium, rand
randomization
domiza
z tiionn tto
o gr
ggroup
oupp B re
rema
remaine
maine a
ma
strong predictor
arrhythmia
3).
dictor
di
ctt off arrh
rhh tthmia
hmiia free
f ssurvival
r i all ((table
tabl
bl 3)
Adverse events
In the study patients, no major complications occurred including cardiac tamponade, phrenic
nerve injury, stroke or atria-esophageal fistula. In three patients, groin hematoma occurred after
the ablation procedure, one of them requiring blood transfusion.
Discussion
Main findings
This prospective randomized study revealed the following data on the prognostic role of
subsequent ATs occurring after AF termination: First, the elimination of subsequent ATs is
associated with a significant decrease in recurrences of AF but not ATs. Second, subsequent ATs
10
DOI: 10.1161/CIRCEP.113.001019
can be successfully ablated in the majority of patients with an acceptable procedural investment.
Third, the strongest predictor for an arrhythmia free survival after a single stepwise ablation
procedure was the targeted procedural endpoint of termination to SR by ablation of subsequent
ATs. Thus, these data support the hypothesis of the contributing role of subsequent ATs in the
mechanisms of persistent AF.
Atrial tachycardia substrates in atrial fibrillation
Procedural AF termination is most commonly associated with conversion to AT with the
Downloaded from http://circep.ahajournals.org/ by guest on November 1, 2016
majority of them underlying a macro-reentrant mechanism3,4,9,15,16. Conversion
nversion of AF too AT
AT
characteristically occurs after an arrhythmia organization which is represented
resen
nte
t d by
by a ccontinuous
onti
on
tinnu
ti
nu
3 4 13 16 17
increase off th
the
he AF
A
AFCL
C upp tto
CL
o a critical level around 2200
00 ms3,4,13,16,17
. The
Th
he mechanisms and
antiarrhythmic
hmicc processess bby
hm
yw
which
hich
h eelectrogram-guided
lect
ctrrogr
gram
m-gguide
ded ab
aablation
lattion off AF
la
F rresults
essul
u ts inn aarrhythmia
rrh
rhythm
hmiaa
hm
organization
o ye
on
yet
et is
is still
still not
nott completely
completel
elyy clearr aand
el
nd is
is a crit
critical
itic
it
ical
ic
a ma
al
m
matter
ttterr off di
discussion.
iscusssiion. Re
R
Recently,
centl
tly,, two
different new
e comp
ew
computational
putatio
io
onall mapp
mapping
ppin
pp
i g tech
techniques
hniqu
iq es hhave
ave bbeen
een iintroduced
ntrodu
ducedd to mapp andd ab
du
abla
ablate
laate m
more
specifically the
the arrhythmia-perpetuating
arrh
rrhh thmia
thmiia perpet
ett ating
ti atrial
triiall substrate
s bbstrate
sttratt off persistent
siistt t AF.
AF Th
The FI
FIRM
RM (focal
(fo l
impulse and rotor modulation) approach is based on multi-spline contact mapping of ratedependent repolarization to assess shortest successive activation times and rate-dependent
conduction slowing to identify propagation paths which are depicted in a computational colorcoded map18. In contrast, panoramic mapping is based on non-invasively acquired cardiac
surface potentials and unipolar electrograms using a 252-electrode vest placed on the patients’
torso19. Although these two different mapping techniques revealed divergent data in terms of
spatiotemporal stability of AF sources, both studies demonstrated multiple (at least 2) rotors or
focal activity maintaining the atria in AF20,21. Interestingly, a hierarchical order of
simultaneously existing sources seems to define the dynamics and dominance of each element in
11
DOI: 10.1161/CIRCEP.113.001019
the perpetuation of AF20. Considering that an arrhythmia organizing effect has also been
described for left atrial linear ablation12, the following mechanisms may explain the “antifibrillatory” effect of subsequent AT ablation: 1) the focal, rotor or macro-reentrant activity of a
subsequent AT may have had an arrhythmogenic role in the persistent AF processes and its
elimination potentially decreases the number of residual AF sources. 2) Linear lesions for the
treatment of macroreentrant ATs may constrain dominant or preferred wavefront propagation
paths of meandering sources of AF with the potential to restrict their spatiotemporal propagation.
Downloaded from http://circep.ahajournals.org/ by guest on November 1, 2016
3) Contiguous lesions for the treatment of multiple subsequent ATs in addition to linearr llesions
e
es
create electrical boundaries in the atria (e.g. inferior LA-CS, LAA-anterior
eriorr w
wall,
alll, in
all
iinteratrial
tera
te
r tr
tria
iall
ia
septum etc.)
.) with
wiith the
the
h result
ressullt of a substrate compartmentalization
compartm
men
e talization tha
that
h t pr
pre
prevents
events AF sources too
sustain.
Improvingg outcomes
outc
tcom
tc
omes off persistent
om
persiisttentt A
AF
F abla
ablation
la
ati
tion
o
The best endpoint
n p int for
ndpo
f r pe
fo
per
persistent
rsis
i tent AF
AF ablation
ab
blati
tiion critical
criiticall to arrhythmia-free
arrhy
h thmi
hy
h ia-freee ssurvival
urviivall rema
remains
main
ma
i s
in
,88
contested. B
Broadl
Broadly,
r dl tthe
he spectr
spectrum
ctt m off iinstr
instruments
tr ments
ts consist
siistt off PV isolation
i lati
ti al
alone
l 77,8
, el
electrogramelectrogram
l tr
guided ablation2 and linear ablation22. The stepwise ablation approach combines these
techniques, importantly however, with the endpoint of procedural AF termination16. The
predictive value of AF termination appears to depend on the rate AF termination. While studies
with a low or moderate AF termination rate (< 35%) did not show a correlation to long-term
success23,24, AF termination rates > 50% revealed a significant association to a favorable
outcome when the procedural endpoint was achieved9,15,16,25. We believe our study to be the first
to demonstrate a significant reduction in AF recurrence after a single procedure when the
endpoint of ablation of all subsequent ATs to SR is sought from the outset of persistent AF
ablation. With the FIRM ablation approach, AF terminated by a very limited amount of RF
12
DOI: 10.1161/CIRCEP.113.001019
PHDQ§PLQZLWKFRQYHUVLRQWR$7in one-third of the patients21. Certainly, these more
individualized and patient-tailored approaches will enhance our understanding of the
mechanisms of persistent AF. However, the impact of subsequent ATs on AF recurrences
following such a specified computational-guided mapping approach needs clarity. A similar
result as shown in this trial will further substantiate the theory of an important contributory role
of subsequent ATs in AF mechanisms.
Limitations
Downloaded from http://circep.ahajournals.org/ by guest on November 1, 2016
In the presented study, no significant difference between both groups was observed in te
terms
erm of
recurrences of any atrial tachyarrhythmia after both, the first and last ablat
ablation
procedure.
The
tio
i n pr
proc
ocedur
ed
duree. Th
T
h
study may have
haave been
beeen uunderpowered
nde
derpowered to detect a stati
de
statistically
t stiically signifi
ti
significant
ficant
ntt ddifference
ifference in outcom
outcomes
between thee tw
two
wo groups.
Conclusions
n
ns
Subsequentt atrial
atr
t iaal tachycardias
tach
ta
ch
hyc
ycar
a di
d as are
aree the
the predominant
preedo
d miina
nant
ntt aarrhythmia
rrhy
hyth
hmi
m a re
remnant
emnan
a t af
after
fte
t r AF tterminatio
termination.
e minaati
er
to
Further ablation aiming at elimination of all subsequent ATs significantly reduces recurrences of
AF but not AT. Thus, the results of this study corroborate the hypothesis that subsequent ATs
have the potential to contribute to the multifaceted mechanisms of persistent AF.
Funding Sources: Dr. TV Salukhe was supported by the British Heart Foundation
FS/09/018/26963.
Conflict of Interest Disclosures: None
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F,
MD
D, Wright
Wriight
Wr
ight M,
M, Knecht
K echtt S
Kn
S,, Jais
Jais P,
P, Hocini
Hociinii M,
Ho
M, Takahashi
Taka
Ta
kahhash
ka
shii Y,
Y Jönnson
Jönnsson A, Sacher
Sach
her F
Matsuo S, Lim
Lellouche
N,, Na
Nault
Bordachar
P,, Cl
Clementy
L m KT,
K , Arantes
KT
Aran
Ar
ante
an
t s L,
te
L, Derval
Der
e vaal N, L
ello
el
lo
lou
ouchee N
Naul
ullt I, B
o daach
or
char
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C
em
men
e ty
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Long-term
ablation
using
termination
r M.
rre
M L
ongg-te
teerm follow-up
foll
llow-upp off pe
ppersistent
rsis
i tent atrial
atria
i l fi
ffibrillation
ibr
b illa
l tiion abl
bllattion usi
ingg te
term
rm
minaa
as a procedural
endpoint.
Heart
2009;30:1105-1112.
d
dural
endpo
poin
po
in
int.
nt. Eu
Eurr Hear
He
ear
art JJ.. 20
2009
09;3
09
;30:
;3
0:11
0:
1105
11
05-1
05
-11 12.
-111
2.
Table 1: Patients baseline characteristics.
Age
Female (n, %)
Hypertension (n, %)
Diabetes mellitus (n, %)
Congestive heart failure (n, %)
Coronary artery disease (n, %)
Amiodarone treatment (n, %)
Left atrial size (mm)
LVEF (%)
Duration of continuous AF (months)
Group A
63 ± 10
12 (22)
38 (69)
5 (9)
6 (11)
13 (24)
20 (36)
45 ± 7
58 ± 10
12 (1-120)
16
Group B
64 ± 9
20 (36)
35 (64)
5 (9)
6 (11)
14 (25)
18 (33)
46 ± 6
60 ± 9
13 (1-120)
p
0.454
0.095
0.549
1.000
1.000
0.829
0.692
0.675
0.296
0.220
DOI: 10.1161/CIRCEP.113.001019
Table 2: Comparison of procedural data.
Group A
Group B
p
Baseline AFCL (ms)
- LAA
- RAA
- CS
172 ± 27
175 ± 30
170 ± 24
169 ± 28
175 ± 28
168 ± 27
0.715
0.979
0.662
Procedure duration (min)
Fluoroscopy time(min)
RF time (min)
195 ± 68
53 ± 21
93 ± 37
242 ± 65
66 ± 21
109 ± 33
< 0.001
0.001
0.015
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Table 3: Uni- and
an
nd mu
multivariate
multiv
var
a iate regression analysis for
or predictors of arrhythmia-free
arr
rrhythmia-free surviva
rr
survival
aablation
laation
tii
after first abla
Baseline Variable
Varia
Va
iable
ia
p Value
Valu
luee
lu
Odds
Oddss ratio
rattio
95%
95 confidence
conffid
co
i encee interval
inttervaal
Univariate
U
Un
ivvar
aria
i tee ppredictor
ia
redi
re
d ctor
o ooff ar
arrhythmia
rrhhyt
ythm
h ia
hm
i free
fre
ree su
surv
survival
vivval
a
Randomization
atio
at
ionn to group
gro
roup
up B
0.033
0.03
0.
0333
03
0.426
0.42
0.
4266
42
0.19
0.
0.194
1944 - 0.
19
0.93
0.933
9333
93
Multivariate
M
ult
ltiivariiatte predictors
lt
predi
dictors
t
off arrhythmia
arrhhyth
thmia
i free
free survival
survival
i l
LVEF
Baseline HRA AFCL
Randomization to group B
0.029
0.049
0.004
0.933
0.969
0.191
0.878 - 0.993
0.939 - 1.000
0.063 - 0.581
LVEF = left ventricular ejection fraction, RAA = right atrial appendage, AFCL = atrial fibrillation cycle
length.
Figures Legends:
Figure 1: Study flowchart with numbers of patients.
AT = atrial fibrillation, AF = atrial tachycardia, DC = direct cardioversion, PVI = pulmonary
vein isolation, SR = sinus rhythm.
17
DOI: 10.1161/CIRCEP.113.001019
Figure 2: Rhythm outcome after first ablation at a mean follow-up of 20.1 ± 13.3 months.
SR = sinus rhythm, AT = atrial tachycardia, AF = atrial fibrillation, DC = direct cardioversion.
Figure 3: Rhythm outcome after each ablation procedure. The cumulative outcome after all
procedures is demonstrated in the grey bar at the bottom.
SR = sinus rhythm, AT = atrial tachycardia, AF = atrial fibrillation.
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Figure 4A: Kaplan-Meier survival curve after first ablation (patients in
n SR vs. no SR);
); B:
Kaplan-Meier survival curve after first ablation (patients in AF vs. no AF).
AT = atriall ta
tachycardia,
SR
fibrillation.
achyc
ch
hyc
y arrdi
dia, S
R = sinus rhythm, AF = aatrial
tria
tr
i l fibrillation
o .
on
Figure 5: Rhyt
R
Rhythm
thm outcome
outcome after
aft
fter lastt ab
ft
ablati
ablation
b ionn aatt a mean ffollow-up
ollo
ol
low
lo
w-upp off 334.0
4.0 ± 6.
66.4
4 mo
months.
nths
th .
SR = sinus rhythm,
atrial
cardioversion.
rhy
hyth
hy
hm, AT = atrial
attriiall tachycardia,
tach
hyc
y ardi
d a, AF
di
AF = at
rial
i l ffibrillation,
ib
briill
llattiioon, DC
DC = direct
di
carrdi
diov
ovvers
Figure 6A: Kaplan-Meier survival curve after last ablation (patients in SR vs. no SR); B:
Kaplan-Meier survival curve after last ablation (patients in AF vs. no AF);
AT = atrial tachycardia, SR = sinus rhythm, AF = atrial fibrillation.
18
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PVI
(n = 110)
AF (n = 22)
Electrogram-guided
Ablation
SR (n = 8)
SR (n = 11)
(n = 102)
DC
C
Conversion
onversion
AT
tto
oA
T
((n
n = 69)
69)
Group A
Group B
(n = 35)
(n = 34)
DC
AT ablation
SR
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%
Group A (DC for AT)
80
p = 0.02
Group B (AT ablation)
70
p = 0.001
60
57
50
49
40
30
ns
p=n
s
34
24
20
19
17
10
0
SR
AT
AF
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1st procedure
(n = 110)
SR
AT
AF
(n = 48)
(n = 22)
(n = 36)
2nd procedure
(n = 58)
SR
AT
A
AFF
no further ablation
(n = 24)
(n = 14)
14)
(n = 20)
0)
(n = 14)
3rd
3
rd p
procedure
rocedure
((n
n = 20)
20)
SR
AT
AF
no further ablation
(n = 8)
(n = 8)
(n = 4))
(n = 4)
4th procedure
(n = 8)
SR
AT
AF
(n = 3)
(n = 5)
(n = 0)
SR
AT
AF
(n = 83 / 78%)
(n = 5 / 5%)
(n = 18 / 17%)
Group B (AT ablation)
Group B (AT ablation)
Group A (DC)
Group A (DC)
Arrhythmia free survival
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A
p = 0.005
p = 0.075
Follow up (months)
Group B (AT ablation)
Group A (DC)
AF free survival
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B
p = 0.005
p = 0.075
Group B (AT ablation)
Group A (DC)
Follow up (months)
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%
p = ns
100
Group A (DC for AT)
90
80
70
Group B (AT ablation)
85
72
60
p = 0.018
50
40
p = ns
30
20
2
10
26
7.5
7.5
0
SR
AT
AF
p = 0.125
Arrhythmia free survival
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A
Group B (AT ablation)
Group A (DC)
Follow up (months)
AF free survival
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B
p = 0.016
Group B (AT ablation)
Group A (DC)
Follow up (months)
The Prognostic Role of Subsequent Atrial Tachycardias Occurring during Ablation of
Persistent Atrial Fibrillation: A Prospective Randomized Trial
Thomas Rostock, Tushar V. Salukhe, Boris A. Hoffmann, Daniel Steven, Imke Berner, Kai
Müllerleile, Cathrin Theis, Karsten Bock, Helge Servatius, Arian Sultan and Stephan Willems
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Circ Arrhythm Electrophysiol. published online October 25, 2013;
Circulation: Arrhythmia and Electrophysiology is published by the American Heart Association, 7272 Greenville Avenue,
Dallas, TX 75231
Copyright © 2013 American Heart Association, Inc. All rights reserved.
Print ISSN: 1941-3149. Online ISSN: 1941-3084
The online version of this article, along with updated information and services, is located on the
World Wide Web at:
http://circep.ahajournals.org/content/early/2013/10/25/CIRCEP.113.001019
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