Time Course of Inflammation, Myocardial Injury and Prothrombotic

Transcription

DOI: 10.1161/CIRCEP.113.000876
Response Following Radiofrequency Catheter Ablation for Atrial Fibrillation
Running title: Lim et al.; Time Course of Inflammation Post AF Ablation
Han S. Lim, MBBS, PhD; Carlee Schultz, BHlthSci (Hons); Jerry Dang, MBBS; Muayad
Downloaded from http://circep.ahajournals.org/ by guest on November 2, 2016
Alasady, MBChB; Dennis H. Lau, MBBS, PhD; Anthony G. Brooks, PhD;; Christopher
X. Wong,
p
MBBS; Kurt C. Roberts-Thomson, MBBS, PhD; Glenn D. Young, MBBS;
BBS;
BB
S;; M
Matthew
atth
at
thew
th
ew II.. Wo
Worthley,
MBBS,
MBBS
S, PhD;
PhD Prashanthan
Pra
rashanthan Sanders
Sanders, MBBS
MBBS,
S, PhD
PhD*;; Scott R.
R W
Willoughby
Willoughby,
illoughby, PhD*
Centre for
o H
or
Heart
eart
ea
r R
rt
Rhythm
hyth
hy
t mD
th
Di
Disorders
iso
s rdder
e s (C
(CHR
(CHRD),
RD)
D),, So
Sou
South
uth Australian
A st
Au
stra
rali
ra
liian
nH
Health
e ltth an
ea
and
nd Me
M
Medical
d ca
di
call Re
R
Research
ese
s
Institute (SAHMRI),
( HMRI)
(SAH
I)), Univ
University
iver
iv
ersity
er
y ooff Adelaide & Ro
Royal
oya
y l Adelaide
Addel
e aide Hos
Hospital,
o pi
os
p tal,, Ad
A
Adelaide,
del
e aide,, Austr
el
Australia.
r
*contributed
*con
*c
ontr
on
trib
tr
ibuuted equally
ib
equual
a ly
y aass se
senior
eni
nior
or aauthors
utho
ut
hors
ho
rs
Correspondence:
Prashanthan Sanders
Centre for Heart Rhythm Disorders
Department of Cardiology
Royal Adelaide Hospital
Adelaide, SA 5000
Australia
Tel: +61882222723
Fax: +61882222722
E-mail: prash.sanders@adelaide.edu.au
Journal Subject Codes: [74] Other stroke treatment / medical, [188] Thrombosis risk factors,
[22] Ablation/ICD/surgery
1
DOI: 10.1161/CIRCEP.113.000876
Abstract:
Background - Inflammation has been linked to the genesis of stroke in atrial fibrillation (AF)
and is implicated in early recurrent arrhythmia after AF ablation. We aimed to define the time
course of inflammation, myocardial injury and prothrombotic markers following radiofrequency
(RF) ablation for AF and its relation to AF recurrence.
Methods and Results - Ninety consecutive AF patients (53% paroxysmal) undergoing RF
ablation were recruited. High-sensitivity CRP (hs-CRP), Troponin-T, creatine kinase-MB
(CKMB), fibrinogen and D-Dimer concentrations were measured at baseline, 1, 2, 3, 7-days and
1-month post-ablation. AF recurrence was documented at 3-days, 1, 3 and 6-months follow-up.
Troponin-T and CKMB peaked at day 1 post-procedure (both p<0.05).. Hs
Hs-CRP
Hs-CR
CRP
P peaked
peak
pe
aked
ak
ed aatt dday-3
post-procedure (p<0.05). Fibrinogen (p<0.05) and D-Dimer (p<0.05) concentrations
concen
entr
en
trat
tr
atio
at
ions
io
ns were
wer
eree
significantly
elevated
l el
ly
elev
evat
ev
ated
ed at 11-week
-week post-procedure. Ln
n hhs-CRP
s-CRP elevation
elevat
a ionn correlated
correlated with Ln
Troponin-T
T and
annd fibrinogen
fibrinoge
g n elevation.
ell vat
elev
atio
io
on. The
Th ex
eextent
xtennt of Ln
n hhs-CRP,
s CR
sCRP, Ln Troponin-T
Troopon
Tr
onin
on
in-T
in
T and
a d fibrinogen
an
fibr
fi
brin
brin
inoo
elevation predicted
early
AF
recurrence
within
3-days
post-procedure
p ed
pred
dic
icted ea
arl
ryA
F re
ecurrre
renc
n e wi
with
hin 3-day
ys pos
po
ost-pr
p oced
pr
eduree ((p<0.05
ed
p<0
<0.0
. 5 re
rrespectively),
specctivvel
sp
vely but
not at 3 and
6-months.
d 6-m
months.
s
s.
Conclusions
Patients
response
within
n - Pa
ns
P
tiients undergoing
und
ndergo
g ing RF ablation
abl
b atio
bl
i n for AF exhibit
exhhib
bit
i an inflammatory
infl
in
flam
fl
am
mmatory
y respo
pons
po
nse w
ns
3-days. Thee extent
exte
ex
tent
nt of
of inflammatory
iinnfllam
amma
mato
atory
ry
y response
res
espo
ppons
onsee predicts
ppred
prred
diiccttss early
earl
ea
rlly AF recurrence
rec
ecur
urre
renc
ncee but
bbuut not
not late
late recurrence.
rec
ecuu
Prothrombotic markers are elevated 1-week post-ablation and may contribute to increased risk of
early thrombotic events post AF ablation.
Key words: atrial fibrillation, catheter ablation, inflammation, myocardial inflammation,
thrombosis
2
DOI: 10.1161/CIRCEP.113.000876
Introduction
Inflammation is increasingly recognized to play a significant role in the genesis and perpetuation
of atrial fibrillation (AF).1,2 Markers of inflammation such as C-reactive protein (CRP) are found
to be predictive of increased risk for future development of AF.2 Inflammation as a cause of AF
has also been suggested on the grounds of the time course of post-operative AF following
cardiac surgery, when the inflammatory cascade is most activated.1 Furthermore, patients with
AF undergoing catheter ablation are at increased risk of thromboembolic events, particularly in
the first 2-weeks after the procedure, although the exact mechanisms are not known.3
Radiofrequency (RF) ablation for atrial arrhythmias is known to cause
cau
ause
se aan
n iin
increase
ncr
crea
eaase iin
45
a er
arker
erss of
o iinflammation
nflamm
nf
m ation and myocardial inj
mm
njuury.4,5
nj
Moreover,
Moreo
ove
v r,, bbiomarker
iomarker detection oof
various markers
injury.
myocardiall injury
iinj
njury
nj
ury is a key
ey component
com
mpone
nent in
ne
in the
th
he third
thiirdd universal
unniv
verrsaal dde
definition
efinnition
ni n of
of myocardial
m ocaardi
my
d al inf
infarct
infarction
farrct
and ablation
o is known
on
know
kn
own
ow
w to
t be
be a confounder.
confouund
nder.6 A pr
protra
protracted
ctted
d eelevation
leva
le
vati
va
tionn ooff CR
ti
CRP
RP is
i seen
seen af
after
fter AF
ablation, and
n fo
nd
ffollowing
llowiing successful
ll
suuccessffull abl
ablation
blation off llong-lasting
bl
ongg lastiingg persistent
p rsiisteentt AF,
pe
AF,
F a ddecline
ecliine iin
n CR
CRP at 3,8
8
months is observed.
obser
ob
b
edd 77,8
Studies
St
S
t dies
di linking
linki
ki inflammation
infl
fl
ti levels
llee els
ls att baseline
ba li and
ndd after
ft ablation
blati
tio with
iitt
early and late AF recurrences following ablation have yielded varying results.4,7,9-11
To date, the specific time course of inflammation, myocardial injury and prothrombotic
markers following RF ablation for AF has not been well defined. We aimed to investigate the
inflammatory response post-ablation and its relation to AF recurrence and to examine the
relationship between inflammation and prothrombotic risk after ablation.
Methods
Patient Selection
Ninety consecutive patients undergoing elective RF catheter ablation for AF were prospectively
studied. All patients above the age of 18, with a history of AF were included. Exclusion criteria
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DOI: 10.1161/CIRCEP.113.000876
were: prior myocardial infarction (3-months), unstable angina, surgery or ablation procedure
within the preceding 3-months, congenital heart disease, history of connective tissue disease or
chronic inflammatory condition, acute or chronic infection, chronic renal or liver failure. Type of
AF was defined according to the Heart Rhythm Society (HRS) expert consensus statement.12 All
patients provided written informed consent to the study protocol which was approved by the
Clinical Research Ethics Committee of the Royal Adelaide Hospital, Adelaide, Australia.
Patient Preparation
All patients underwent anticoagulation with warfarin to maintain their international nor
normalized
rma
mal
ratio (INR) between 2-3 IRU-weeks prior to the procedure. Warfarin
n wass st
stopped
top
oppe
pedd 77-days
-da
dayys
ys prior
e uree and
edu
and substituted
sub
ubst
stituted with enoxaparin att a dose of 1-PJNJWZLFHDGD\XQWLOst
1-PJ
PJJNJ
JWZLFHDGD\XQWLO
to the procedure
t the procedure.
proceddurre. Transesophageal
Transe
Tr
sesoph
se
phhag
geal echocardiography
echhoca
cardio
iogr
io
g aapphyy w
gr
as perfo
f rmed
fo
d tto
o eexclude
xcllud
udee left
hours priorr to
was
performed
m
mbus.
Traanstho
Tr
h raciic echoca
caard
rdiograp
d
aphy
ap
hy was per
hy
rfo
form
med aatt ba
bbaseline
seli
l ne aand
nd post
t-procee
atrial thrombus.
Transthoracic
echocardiography
performed
post-procedure.
hy hm
hyt
h ic age
g nt
ntss, with
wiithh the
th
he exception
except
ptiion off ami
pt
ioddarone, wer
re ceas
ased
as
ed 55-half-lives
-ha
h lf
lf-l
f liv
ives
es pprior
riorr to
All antiarrhythmic
agents,
amiodarone,
were
ceased
re D
Details
ettail
ils off the
th ablation
abl
blati
ti procedure
proced
d re are iin th
the online
li onll Data
Datt S
pplement
le ntt
the procedure.
online-only
Supplement.
Blood Collection
Blood samples were taken peripherally for total white cell count (WCC), neutrophil count, highsensitivity CRP (hs-CRP), Troponin-T, creatine kinase (CK), creatine kinase-MB (CKMB),
fibrinogen and D-Dimer measurements at the start of the procedure, and at 1, 2 and 3-days, 1week and 1-month post-procedure. Samples were analyzed immediately.
Markers of Inflammation, Myocardial Injury and Thrombosis
Hs-CRP was analyzed with an immunoturbimetric latex CRP assay (Olympus Diagnostics,
Melville, NY). Total WCC and neutrophil count was analyzed using the Sysmex XE2100
(Sysmex, Kobe, Japan). Cardiac troponin-T was analyzed with the Elecsys Troponin-T
4
DOI: 10.1161/CIRCEP.113.000876
immunoassay (Roche Diagnostics, Indianapolis, IN). CK was analyzed using a kinetic UV serum
test (Olympus, Ireland). CKMB was analyzed with the Elecsys CKMB immunoassay (Roche
Diagnostics, Indianapolis, IN). Fibrinogen and D-Dimer were analyzed using the STAR
coagulation analyzer (Diagnostica Stago, Parsippany, NJ). Normal reference ranges were: WCC:
4.0-11.0 (x109/L), neutrophils: 1.8-7.5 (x109/L), hs-CRP: lower limit of detection (LLD) 0.08
mg/L, Troponin-T: 0-0.1 μg/L (LLD ȝJ/&.<150 U/L (LLD 3 U/L), CKMB: <7.0
μg/L (LLD 0.ȝJ/), Fibrinogen: 1.5-4.0 g/L, D-Dimer: <0.5 FEU. The extent of biomarker
elevation was defined as the maximum recorded value (from day 1 to day
y 30)) minus thee bbaseline
a
value (day 0).
o ow
ollow
ow-u
- p
-u
Patient Follow-up
monitoring was
wa performed
perforrmed for
pe
fo 3-days
3-daayss fo
olllow
win
ingg the
th
he procedure.
prroced
edurre.
e. Body
d tem
dy
empeeraatuu
Continuouss monitoring
following
temperature
r aatt ba
red
baseline prior
priior to
to the
th
he procedure
proced
ed
dur
u e andd 66-hourly
-hhourly
ly dduring
uri
ring
n tthe
ng
he first
st 3 ddays
ays po
stt
was measured
posttp tiient fo
foll
llow ups
ll
p were sch
hedduled at 77-days,
-dday
ys, 11,, 3,
3 and
andd 66-months
-m
month
th
hs post-procedure.
p st-p
po
-pro
prooced
d
procedure. Outpa
Outpatient
follow
scheduled
V month
th following
ffollo
oll
llo iing ablation,
ablation
blati
tio a clinical
linii l review,
re iie EC
ECG
G and
d 77-day
ddaa H
Holter
olt
lte monitor
nit
itor
$WDOOYLVLWV-month
monitoring
was undertaken to determine the presence of recurrent arrhythmias. Recurrent arrhythmia was
defined as per the HRS expert consensus as any atrial arrhyWKPLD-seconds. For the purposes
of this study, early recurrences ZDVGHILQHGDVDQ\DWULDODUUK\WKPLD-seconds within the first
3 days post-procedure while continuous monitoring was undertaken.
Warfarin was continued for a minimum of 3-months. In patients with a CHADS2 score
DQWLFRDJXODQWVZHUHFHDVHGDWWKLVSRLQWLQWKHDEVHQFHRIUHFXUUHQWDUUK\WKPLD,QDOORWKHU
patients anticoagulation was continued for 12-months at which point its cessation was discussed
on an individual basis.
5
DOI: 10.1161/CIRCEP.113.000876
Statistical Analysis
Continuous variables were expressed as mean±SD, and categorical data expressed as counts and
percentages. Data was tested for normality and log-transformed as appropriate. Continuous
variables between two groups were compared using Student t tests. Categorical variables were
compared using Fisher’s exact or Pearson’s chi-square tests as appropriate. Correlations between
the extents of elevation of the biomarkers were analyzed using Spearman’s correlation
coefficient. Linear mixed effects models were created to examine the temporal changes in
biochemical markers following AF ablation, in which time was included
effect
ed as a fixed effe
ect aand
n
where a compound symmetry correlation structure allowed for correlation
within
tion wi
ith
thin
i patients
in
pattie
i nt
ntss due
d to
repeated mea
measurements.
post-hoc
m
asu
sure
r meent
re
nts. Iff the time main effect was
waas significant,
si
pos
o t-hhoc testing was used to
t
reveal where
significant
re tthe
he significan
nt ddifferences
ifffereences llied.
ied.
d.
Univariate
multivariate
linear
regression
analyses
were
used
determine
i iaate
ivaria
te and
an mult
lttiv
i aria
i te li
ine
near reg
egrress
eg
ssiion anal
allys
alys
ysess wer
erre us
ed
d to de
dete
te i e the
termin
th
h
predictors for
Alll univ
univariate
f the extentt of elevation
ellevation
i of each
each
h bbiomarker.
iomarker.
k Al
A
i arriate ppredictors
redi
dicttors wi
di
with
th
h pp<0.10
<0..
were then added
multivariate
model.
For
dded
d tto a m
ltii ariate
lt
iatte model
oddell F
o outcomes
o ttcomes
c
tthat
hatt were
ere llog ttransformed,
transformed
fo ed
d coefficient
coefficie
ffiiciie
ff
estimates and confidence intervals were presented in the exponentiated form to describe the
effect of a one unit increase in the predictor on the geometric mean of the outcome. To predict
AF recurrence at 3 days, 1, 3 and 6 months from the extent of each biochemical marker elevation,
univariate logistic regression models were developed. Multivariate logistic regression models
were developed to identify predictors of early AF recurrence and AF recurrence at 6-months. Pvalues <0.05 were considered statistically significant. Statistical analyses were performed using
PASW Statistics 18 (version 18.0.0).
6
DOI: 10.1161/CIRCEP.113.000876
Results
Patient and Procedural Characteristics
Patient demographics and procedural characteristics are shown in table-1. These patients had
paroxysmal (44%), persistent (43%) and long-standing persistent AF (12%). Mean CHADS2
score was 0.9±0.9. The RF ablation times for PVI, CFAE ablation and linear ablation were
65.8±34.8, 32.3±21.6 and 20.6±16.0-minutes respectively. Total procedural time was
210.3±55.7-minutes.
otic Markers
All measured markers increased significantly over time following RF ablat
ablation
attio
i n fo
ffor
orr AF ((p<0.001
p<00
p<
k rs). Hs
ker
Hs-CR
C P peaked
peaked at days 2-3 and wa
was significantlyy elevated
elev
evated at 1-day to 1-w
ev
w
for all markers).
Hs-CRP
1-week
blatiion (Figure-1A).
bl
(Figuree-1
1A)). T
ota
tall WCC
ta
WC
CC and
an
nd neutrophil
neeutro
rophhil
i ccount
oouunt were
were si
ign
nifficanntly el
levaateed days
post-RF ablation
Total
significantly
elevated
r du
rocedu
dure
ree (Figures-1B
(Figures-11B andd 1C
1C).
1-3 post-procedure
op nin-T
opo
T peaked
p ak
pe
aked
e at dday-1
ed
ay-1
1 ppost-procedure,
ost-pr
p oced
dure, andd was sign
g if
gn
ifiican
nttlly el
levated
d uup
p to da
a
Troponin-T
significantly
elevated
day-3
d re (F
(Fig
(Fi
ig re 2A
2A)) CKMB
CKMB peaked
ak
ked
d similarly
similarl
imil
il l att day-1
da
da 1 post-procedure
postt proced
ed
d re (F
(Fig
(Fi
ig re 2B
2B)) CK
post-procedure
(Figure-2A).
(Figure-2B).
levels were significantly elevated days 1-3 post-procedure (Figure-2C).
Prothrombotic markers seemed to peak slightly later at about 3-days and 1-week postprocedure. Fibrinogen levels were significantly elevated at days 2-3 and 1-week post-procedure
(Figure-3A). D-Dimer levels were significantly elevated and peaked at 1-week post-procedure
(Figure-3B).
Correlation Between Inflammatory, Myocardial Injury and Prothrombotic Markers
The extent of Ln hs-CRP elevation correlated with the extent of Ln Troponin-T elevation
(rs=0.35, p<0.02), Ln CKMB elevation (rs=0.51, p<0.01) and fibrinogen elevation (rs=0.59,
p<0.01). There was a significant correlation seen between the extent of WCC elevation and
7
DOI: 10.1161/CIRCEP.113.000876
neutrophil elevation (rs=0.93, p<0.01), but no significant correlation between these two markers
and Ln hs-CRP. The extent of Ln CKMB elevation correlated with the extent of Ln CK elevation
(rs=0.55, p<0.01).
Predictors of Elevation for Inflammatory, Myocardial Injury and Prothrombotic Markers
Univariate and multivariate linear regression analyses were used to determine the predictors of
the extent of elevation in each biomarker. Variables used were age, male gender, BMI (body
mass index), hypertension, diabetes mellitus, congestive heart failure, history of stroke/TIA
(transient ischemic attack), left atrial diameter, statin therapy, type of AF, baseline hs-CR
hs-CRP,
CR
RP
ablation approach, RF ablation time, total procedural time, fluoroscopy
y tim
time
me an
andd dose
ddose.
ose. Un
Univ
Univariate
iv
o the
th
he extent
exte
ex
t nt
te
n of
of elevation of each specific
specifiic bi
bbiomarker,
omarker, wi
w
th p-values
p-values <0.10 were aas
predictors of
with
follows: hs-CRP
s-CR
sRP elevation
elevatio
on (mg/L):
(m
mg/L):: total
totall procedural
proc
ocedur
urral time
tim
me (5
( minute
minuute
ute units)
unnitts) (coefficient=1.03,
(coeff
(c
c ffficcieent=1
1.003 95%
0 p<0.01);
06,
p<
p<0
<0.01
0 );
01
) Troponin-T
Troponin-T
i
ellevation ((Pg/L):
Pg/L)
g/L)
L : RF
RF ablation
abblattion ti
time (55 minute
miinute
t units)
unit
its))
CI 1.01-1.06,
elevation
(coefficient=1.06,
t
t=1.06,
, 95%
%C
CII 1.03-1.08,, pp<0.01),
<0.01)), total procedural
p ocedural tim
pr
time
me (5
( m
minute
inute units)
s))
1 02 95% CI 11.00-1.04,
00 1 04 p=0.02)
0 02) and
d nonparoxysmall AF ((coefficient=1.53,
ffi i
1 53 95
(coefficient=1.02,
95% CI
1.02-2.28, p=0.04); CK elevation (U/L): RF ablation time (5 minute units) (coefficient=1.05,
95% CI 1.00-1.11, p=0.06); and CKMB elevation (Pg/L): RF ablation time (5 minute units)
(coefficient=1.05, 95% CI 1.00-1.10, p=0.06). A significantly higher Troponin-T elevation was
noted in persistent AF patients compared with paroxysmal AF (Ln Troponin-T 0.49 ± 0.55 vs.
0.06 ± 0.76, p=0.038). Multivariate analysis revealed RF ablation time as the only significant
multivariate predictor for Troponin-T elevation (Pg/L) (RF ablation time, 5 minute units,
coefficient=1.04, 95% CI 1.01-1.08, p<0.05). There was no significant difference in baseline Ln
hs-CRP between patients with paroxysmal and persistent AF in this cohort (p=0.4) and baseline
Ln hs-CRP level was not a predictor of the extent of Ln hs-CRP elevation (p=0.2) or Ln
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DOI: 10.1161/CIRCEP.113.000876
Troponin-T elevation (p=0.7) post-ablation.
Follow-up and AF recurrence
Nineteen-patients (21.1%) had early atrial arrhythmia within 3-days. Twentytwo-patients had AF
recurrence between 4-30-days. Nine-patients had AF between 30-90-days. Forty-patients
sustained no AF. Fourteen had multiple AF recurrences during this period.
Patients with early AF recurrence post-procedure had a significantly higher elevation in
hs-CRP, Troponin-T, CKMB, fibrinogen levels and maximum body temperature compared with
patients without early AF recurrence (Figures 4A-F). Patients with AF
1-month
F recurrence at 1-m
mon
o
also had a higher level of fibrinogen elevation (Figure-4E). The extentt of Ln
L hs
hhs-CRP
-CR
CRP
CR
P elevation
ellev
evat
at
(OR 2.8 CII 1.3-6.0,
elevation
1.3
.3-6
.3
-6.0,
0 p<0.01)
p<0.01
p<
0 ) and Ln Troponin-T elev
evaation (OR 3.22 CII 11.1-9.7,
ev
.1-9.7, p<0.05)
significantly
recurrence
ly predicted
ly
predicted AF rec
currenc
nce att 33-days,
nc
-da
days,, bbut
ut not
not at 1,
1, 3 and
an
nd 6-months
6-mo
m nth
nths post-procedure.
poost-pr
proced
eduur The
ed
extent of fibrinogen
elevation
significantly
within
i
ibrinog
ogen
og
en
n elevati
tiion signif
i ficcantly
y ppredicted
red
ediic
ictedd AF rrecurrences
ecur
urrenc
ur
ncces wi
ith
t in 33-days
-ddays (O
(OR
OR 33.6
.66 CI
1.3-9.7, p=0.01)
month
Maximum
= 01) aand
=0.0
ndd 1 m
onth
h ((OR
OR 22.5
.55 CII 11.1-5.5,
.11-5.
5 5, pp<0.05).
<0.0
0 05).
). M
axim
imum body
im
bod
odyy temperature
temp
perat
a ur
at
u e (°
((°C)
C
during the ffirst
post-ablation
significantly
early
recurrence
irstt 3-days
3 dda s post
stt abl
ablation
blati
ti was
as significantl
ignifi
ifi ntl
tl associated
iattedd with
ith
ith earl
l A
AF
F rec
rrence ((OR
11.1 CI 1.2-102.4, p=0.03).
At 6 months with a 3-month blanking period, 35 patients (39.8%) had AF recurrence. Of
these 35 patients, 30 patients also sustained recurrence during the 3-month blanking period.
There was a nonsignificant trend towards higher 6-month AF recurrence in patients with
persistent AF compared with paroxysmal AF (46% vs. 30%, p=0.1). Of interest, only about half
the patients who sustained initial AF recurrence within 3-days and 4-30 days post-ablation
(47.4% and 54.5% respectively) continued to sustain AF recurrence at 6-months , whereas all
the patients who had initial AF recurrence between 30-90 days continued to sustain recurrence at
6-months (p<0.001 between groups; Figure 5).
9
DOI: 10.1161/CIRCEP.113.000876
Multivariate logistic regression models including age, type of AF, RF ablation time,
baseline Ln hs-CRP and extent of Ln hs-CRP elevation revealed extent of Ln hs-CRP elevation
(OR 2.9 CI 1.3-6.6, p=0.01) as the only significant predictor for early AF recurrence within 3
days. There were no significant interactions between the type of AF, RF ablation time and
baseline Ln hs-CRP with the extent of Ln hs-CRP elevation. However, multivariate logistic
regression models using the same variables did not reveal any significant predictors for AF
recurrence at 6-months.
One patient with a history of persistent AF, previous stroke andd left ventricular
hypertrophy was diagnosed with a TIA 4-days post-procedure with complete
mplet
ette neurological
neur
ne
urol
olloggic
ical
al
recovery, 2-patients
2 paatien
2-pa
tiien
e tss had
had
a ggroin
roin complications and 2-patients
2-pa
p tients had mild
pa
mild fluid
f uidd overload requiring
fl
requirin
n
diuretic therapy.
patients
small
erapy. Seven pa
er
patien
ntss developed
dev
evelopped a sma
ev
maall pericardial
perricar
ardi
diaal effusion
di
efffuusionn onn transthoracic
transth
t or
th
oraccic
echocardiography
post-procedure,
which
resolved
grap
phy pperformed
erformed
d 22-days
-day
d ys po
post-pro
rooce
cedu
d re, wh
du
hic
ichh re
res
solv
lved
lv
ed on fo
ffollow-up
lllow
ow-up
echocardiography;
significant
extent
Ln
hs-CRP
g ap
gr
phy
hy; ho
hhowever
weever there
h was no sig
igniifi
f cant difference
dif
i ference iinn tthe
he ex
exte
t nt off L
n hs
hs-CR
C P
elevation inn these
the patients.
patients
ati
tientt
Discussion
Main Findings
This study presents new information on the specific time course of inflammation, myocardial
injury and prothrombotic response following ablation for AF. The major findings were:
1. Patients undergoing RF catheter ablation for AF exhibited an inflammatory response and
myocardial injury within the first 3-days post-ablation.
2. The extent of inflammatory response predicts early recurrence of AF.
10
DOI: 10.1161/CIRCEP.113.000876
3. Prothrombotic markers are elevated at 1-week post-AF ablation and correlates with the
inflammatory response. This may explain the increased risk of early thromboembolic
events post-ablation.
Inflammation and Myocardial Injury
Results of the current study demonstrate a consistent inflammatory response post-RF ablation for
AF within the first 3-days post-ablation. In the current study markers of myocardial injury were
elevated early (1-day) after RF ablation. The pattern of elevation for these markers was
consistently earlier compared to the inflammatory markers (peak 3-days).
y ). Other studiess on mixed
ys
cohorts of patients undergoing RF ablation have found a peak in markers
myocardial
injury
ers off m
yoca
yo
cardia
rddiall in
inj
ju
ju
5 13
within the first
hours
f st few
firs
f w ho
fe
hour
rs ppost-ablation.
ost-ablation.5,13
The findi
findings
dinngs of RF abla
di
ablation
l tion
on time being an
,133
independent
nt predictor
nt
predictor off Troponin-T
Tropo
poninn-T
nT elevation,
ellev
e ation, consistent
conssissten
nt with
with previous
previou
ous studies,
stuudiess,55,13
aand
ndd hhigher
ig
g
T
onin
on
in T el
in-T
levatio
ti n in
i persistent
perrsi
sistent
i
t AF pat
tie
i nts
t suggest
sugggest that
su
th
hatt markers
rs for
rs
for myoca
rdia
da
extent of Tropon
Troponin-T
elevation
patients
myocardial
injury relate
t to the
te
thhe extent
exten
nt off abl
ablation,
blatio
bl
i n, wit
with
th more extensi
extensive
ive ab
ablation
blatiionn performed
perrfo
formed
d in pa
ppatients
t en
ti
entts w
with
persistent forms
f
off AF
AF.
Our study demonstrated a correlation between markers of myocardial injury and hs-CRP
elevation post-ablation. This is in accordance with the cardiac surgical setting, where a
significant correlation was shown between post-operative troponin-I levels and clinical
inflammation associated parameters.14 With the positive correlation between hs-CRP elevation
and markers of myocardial injury, this inflammatory response could partly be explained by local
myocardial injury. However, the elevation in peripheral WCC, neutrophil count, hs-CRP,
prothrombotic markers and body temperature suggest a systemic inflammatory process in
addition to local inflammation post-RF ablation.
11
DOI: 10.1161/CIRCEP.113.000876
Inflammation and Thrombotic Risk
Inflammation and thrombogenesis in AF are increasingly identified as being intimately
linked.12,15-19 CRP levels are positively correlated with clinical risk factors of stroke.18 We have
previously reported increased thrombogenesis and inflammatory mediators within the human
atrium with the onset of AF.19 Furthermore, D-dimer levels have been shown to predict
thromboembolic events even in anticoagulated AF patients.20
Results of the current study document an elevation in the prothrombotic markers
fibrinogen (Figure-3A) and D-dimer (Figure-3B). Fibrinogen elevation
n po
ppositively
sitively
y correlated
correela
late
t with
te
hs-CRP elevation. The peak elevation of these markers occurred at 7-days
days ppost-ablation
ostt-a
os
-abl
blat
bl
ati
tion
ion
compared to
t th
thee in
iinflammatory
flam
fl
amma
am
matory responses (1-3 days)
ma
s) an
and
nd myocardia
myocardial
i l in
injury
nju
jury (1-day). This de
delayed
prothrombotic
the
finding
that
majority
thromboembolic
oticc timeframee coincides
coin
ncidees with
th
h th
he fin
ndiing th
hatt th
thee m
ajjority of th
hromb
boeemb
mboliic
ic
complications
o following
ons
foll
fo
llow
ll
owing AF
ow
F abl
ablation
blationn occur
bl
oc
within
with
wi
thiin the
th
the
h first
firrst 2-weeks
2-w
weeeks
k post-procedure.
postt-proc
oced
oc
edure.3 Th
ed
Thesee
findings suggest
ugge
ug
g st that
thhat inflammation
i fl
in
flaammation
i couldd be
be an important
imp
porta
t nt contributing
contrib
ib
but
utiingg factor
facttor to
fa
to the
th
he increased
incr
in
crreasee
prothrombotic
otic
oti
ti state
sttatt in
in AF
AF early
earl
rll post-ablation.
post
stt abl
ablation
blati
ti
Inflammation and AF Recurrence
Previous studies have shown that baseline pre-procedural hs-CRP levels were independently
predictive of AF recurrence following RF ablation for AF.11 In this study, we did not find a
significant relationship between the baseline inflammatory state and the extent of elevation in the
markers of inflammation and myocardial injury, and AF recurrence at 6 months. However, our
study found that the degree of inflammatory response post-ablation (extent of hs-CRP elevation)
was significantly associated with early AF recurrence within 3-days post procedure. This finding
is consistent with Koyama et al. who found that acute inflammatory changes after ablation may
be responsible for immediate AF recurrence.9
12
DOI: 10.1161/CIRCEP.113.000876
The impact of early AF recurrence on long term outcome remains debatable. In a study
by Richter et al. AF recurrence within 48-hours of ablation was a predictor of poorer clinical
outcome on follow-up.10 However, in another study, the patient cohort that experienced
immediate AF recurrence within 3 days subsequently had a higher AF-free rate at 6 months
compared with those with later recurrences between 4 and 30 days.9 In our study, we found that
about half of the patients with initial early AF recurrence continued to have AF recurrence at 6months, whereas all patients with recurrence in the 30-day to 3-month period continued to have
recurrence at 6-months. Our results suggest that in about half of the early
arlyy AF recurrences,
recurrencees, tthe
effect is transient and may not have a negative impact on long-term outcome,
utcome
me, whereas
wher
wh
herea
eass
betw
twee
tw
eenn 30
3 ddays
ays to 3 months may be du
due to a different
n pat
atho
at
h physiology, such as
a
recurrencess be
between
pathophysiology,
ve reconnection
reconnect
ctionn and
and co
onfer
ers po
ppoorer
ooreer lon
ng-teerm
m ooutcome.
utcom
me.9
pulmonary vein
confers
long-term
Several
v l sstudies
veral
tudi
tu
dies hhave
di
ave fo
ffound
und th
that
at ameli
ameliorating
liiorati
atting th
the
he ppost-ablation
ostt ab
ablaati
tion inflammatory
infflamm
mmatory response
mm
responn by
1,222
steroids andd anti-inflammatories
antii in
i fl
flamm
mato
t ries
i reduces
red
duces tthe
he iincidence
ncidence off early
early
ly arrhythmic
arrrh
rhyt
ythm
yt
hm
mic
i recurrences.
recurrencces
e .221,22
Colchicine administered
ad
dmiiniistt ed
d for
f 33-months
months
th was
as found
fo
fo ndd to
to decrease
d
early
earl
rll AF recurrences
rec rrences aft
after
fte AF
ablation.22 Transient administration of steroids for 3-days after ablation not only reduced
immediate AF recurrence but also AF recurrence at mid-term follow-up.21 However, in an
experimental porcine study, the use of prophylactic steroids in pigs which underwent atrial
ablation was not shown to alter the systemic inflammatory response or the healing of the
lesions.23
Clinical Implications
This study demonstrated a consistent increased inflammatory response exhibited within 3 days
post-RF ablation for AF. The extent of inflammatory response was associated with early AF
recurrence. There is emerging evidence that early AF recurrence has a different underlying
13
DOI: 10.1161/CIRCEP.113.000876
mechanism, but may still influence long-term recurrence. Understanding the time course of
inflammation could help direct the timing and regimen of future potential interventions aimed at
ameliorating the inflammatory response post-AF ablation.21,22
In our study, increased prothrombotic tendency was documented at about one week postAF ablation. This may explain the increased thromboembolic rates within the first 2-weeks post
catheter ablation for AF.3 Strategic antithrombotic measures targeting this specific time frame
may further decrease post-procedural thromboembolic events.
Study Limitations
The lack of further significant predictors for the elevation in the various
inflammatory,
us in
nfl
flam
amma
mato
tory
y,
myocardiall injury
inj
njur
nj
uryy and
ur
an
nd prothrombotic
prrot
o hrombotic markers in our
ur study
study could be
be due
due to limited numberss in the
study. Alternatively,
mechanism
the
documented
inflammatory
ernatively, thiss ccould
ould
ld be du
dduee to
to the
he mec
ecchani
nism
m ooff tth
he do
docume
mentted infl
flam
fl
am
mma
m to
ory
y
response being
e
eing
m
mu
multifactorial.
ult
ltiifacttoriiall. Secondly,
lt
Second
ndly
nd
l , the earliest
ly
ear
arli
liestt blood
li
blloo
oodd sample
saample
l measurement
le
measurem
men
ent mad
made
de fo
ffollowing
lloo
ll
ablation was
a at post-procedural
as
p st-pprooce
po
c du
d rall da
dday-1,
y 1, which
ywhhichh mayy have
have missed
miissed the
the exact
exac
acct peak
p ak
pe
k for
f r my
fo
myoc
myocardial
ocardii
oc
injury.
Conclusion
Patients undergoing catheter ablation for AF exhibit an inflammatory response and myocardial
injury within the first few days post ablation. The extent of inflammatory response predicts early
AF recurrence but not late recurrence. Prothrombotic markers are elevated one week post
catheter ablation, associated with inflammation and may contribute to the increased risk of early
thrombotic events post AF ablation.
Funding Sources: This study was supported by a Grant-in-Aid from the National Heart
Foundation of Australia. Drs. Lim and Alasady are supported by Postgraduate Research
14
DOI: 10.1161/CIRCEP.113.000876
Scholarships from the National Health and Medical Research Council of Australia (NHMRC)
and Earl Bakken Electrophysiology Scholarships from the University of Adelaide. Dr.
Willoughby is supported by a Career Development Fellowship by the NHMRC. Dr Lau is
supported by Postdoctoral Fellowships from the NHMRC. Drs. Brooks and Sanders are
supported by the National Heart Foundation of Australia. Dr Sanders is supported by a
Practitioner Fellowship from the NHMRC.
Conflict of Interest Disclosures: Dr Sanders reports having served on the advisory board of
Medtronic, St Jude Medical, Sanofi-Aventis and Merck, Sharpe and Dohme. Dr Sanders reports
having received lecture fees and research funding from Biosense-Webster,, Medtronic,, Boston
Scientific, Biotronik and St Jude Medical.
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17
DOI: 10.1161/CIRCEP.113.000876
Table 1. Baseline Clinical, Echocardiographic and Procedural Characteristics of AF Cohort
Characteristics
Patient cohort (n=90)
Age (years)
64.2 ± 16.5
Male gender
58 (64%)
2
BMI (kg/m )
<18.5
(1%)
18.5-24.9
(14%)
25.0-29.9
(49%)

(
)
(36%)
Mean BMI (kg/m2)
29.4
29.44 ± 44.7
.77
Comorbidities
4 (4%)
( %)
(4
%
Congestivee heart
heart fai
failure
iluree
47 (52%)
(52%
%)
Hypertension
sion
si
8 (9%)
(9%
(9
%)
Diabetes mel
mellitus
m
lli
l tu
t s
Dyslipidaemia
e a
emia
29 (32%)
(322%)
Current orr ex-smok
ex-smoker
ker
25 (28%)
(28
28%
%)
Coronary artery disease
8 (9%)
Valvular disease
2 (2%)
Obstructive sleep apnoea
22 (24%)
Previous stroke/TIA
10 (11%)
CHADS2 score
0
36 (40%)
1
36 (40%)
2
12 (13%)

6 (7%)
0.9 ± 0.9
Mean CHADS2 score
Type of AF
Paroxysmal AF
40 (44%)
Persistent AF
39 (43%)
18
DOI: 10.1161/CIRCEP.113.000876
Long-standing persistent AF
11 (12%)
Proportion of Lone AF
34 (38%)
Usual Medications
No. of AAD
0.8 ± 0.4
Amiodarone
7 (8%)
Sotalol
23 (26%)
Flecainide
34 (38%)
Statin therapy
31 (34%)
ACE-inhibitor or ARB
60 (67%)
Echocardiographic parameters
LA diameter,, p
parasternal view ((mm))
40.0
40
0 ± 66.0
0
LA size (cm
m2)
23.2 ± 4.0
m2)
RA size (cm
20.6
20
0.6 ± 44.8
.88
LVEF (%))
58.0
5 .00 ± 110.4
58
0.4
Procedural
details
a det
al
etai
et
aills
ai
PVI only
21
2 (23%)
(23
23%)
%))
PVI and linear ablation
26 (29%)
PVI, linear ablation and CFAE ablation
43 (48%)
RF ablation time (min)
101.7 ± 31.8
Total procedural time (min)
210.3 ± 55.7
Data are mean ± SD or n (%) unless otherwise stated.
BMI = body mass index; TIA = transient ischemic attack; CHADS2 = congestive heart failure,
K\SHUWHQVLRQ DJH \HDUV GLDEHWHV PHOOLWXV DQG SULRU VWURNH7,$ PVI = pulmonary vein isolation;
AAD = antiarrhythmic drugs; CFAE = complex fractionated atrial electrograms; ACE = angiotensin
converting enzyme; ARB = angiotensin receptor blocker.
19
DOI: 10.1161/CIRCEP.113.000876
Figure Legends:
Figure 1. Time Course of Inflammatory Markers Following RF Ablation for AF. (A) Hs-CRP.
*p<0.05 (compared to baseline); p<0.001 (change over time). NB: Descriptive plot shown.
Statistical analyses performed using mixed effects models on logged values, in which statistical
significance was achieved (same applies to subsequent figures on Troponin-T, CKMB, CK and
D-dimer). (B) WCC. *p<0.05 (compared to baseline); p<0.001 (change over time). (C)
Neutrophil Count. *p<0.05 (compared to baseline); p<0.001 (change over time).
time)).
Figure 2. Time
Course
Injury
Following
(A)
T me C
ouurs
rse off Markers of Myocardial In
Inj
jury Followin
ng RF Ablation for AF. (A
A
Troponin-T.
time).
CKMB.
T **p<0.05
T.
p<0.05 (compared
(com
ompaareed to
o bbaseline);
asel
ellin
ne)); p<0.001
p<00.0001 (change
(ccha
hang
nge ov
over tim
ime)). (B) CK
C
M . *p<0.05
MB
*pp<
(compared to bbaseline);
p<0.001
over
asel
as
asel
elin
ine)); p<0.
in
<0 00
0011 (change
(cha
hannge
ha
ng ov
ver
e ttime).
ime)
im
e)). (C)
(C) CK.
CK *p<0.05
*p<0
<0.005 (compared
(com
mpa
paredd tto
o bbaseline);
aselin
ln
p<0.001 (change
time).
h ge over tim
hang
im
me)).
Figure 3. Time Course of Prothombotic Markers Following RF Ablation for AF. (A) Fibrinogen.
*p<0.05 (compared to baseline); p<0.001 (change over time). (B) D-dimer. *p<0.05 (compared
to baseline); p<0.001 (change over time).
Figure 4. Extent of Elevation in Biomarkers and Early AF Recurrence. (A) Hs-CRP. p<0.01 AF
recurrence vs. no recurrence. (B) Troponin-T. p<0.05 AF recurrence vs. no recurrence. (C)
CKMB. p=0.01 AF recurrence vs. no recurrence. (D) Fibrinogen and Early AF Recurrence
within 3-days. p<0.01 AF recurrence vs. no recurrence. (E) Fibrinogen and AF Recurrence at 1-
20
DOI: 10.1161/CIRCEP.113.000876
month. p<0.01 AF recurrence vs. no recurrence. (F) Body Temperature and AF Recurrence
within 3-days. p=0.01 AF recurrence vs. no recurrence.
Figure 5. Prevalence of AF Recurrence at 6-months According to Time of Initial AF Recurrence.
p<0.001 between groups. p=0.01 between the initial 3-days recurrence group vs. 30-90-days
recurrence group; p=0.03 between the initial 4-30-days recurrence group vs. 30-90-days
recurrence group; p=0.8 between the initial 3-days recurrence group vs. 4-30-days recurrence
group; p<0.01 respectively between the no recurrence group and initial
al 3-days,
3-days
y , 4-30-days
4-30-daays aand
30-90-days recurrence groups.
21
Time Course of Inflammation, Myocardial Injury and Prothrombotic Response Following
Radiofrequency Catheter Ablation for Atrial Fibrillation
Han S. Lim, Carlee Schultz, Jerry Dang, Muayad Alasady, Dennis H. Lau, Anthony G. Brooks,
Christopher X. Wong, Kurt C. Roberts-Thomson, Glenn D. Young, Matthew I. Worthley,
Prashanthan Sanders and Scott R. Willoughby
Circ Arrhythm Electrophysiol. published online January 20, 2014;
Circulation: Arrhythmia and Electrophysiology is published by the American Heart Association, 7272 Greenville Avenue,
Dallas, TX 75231
Copyright © 2014 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/2014/01/19/CIRCEP.113.000876
Data Supplement (unedited) at:
http://circep.ahajournals.org/content/suppl/2014/01/20/CIRCEP.113.000876.DC1.html
Permissions: Requests for permissions to reproduce figures, tables, or portions of articles originally published in
Circulation: Arrhythmia and Electrophysiology can be obtained via RightsLink, a service of the Copyright Clearance
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http://circep.ahajournals.org//subscriptions/
SUPPLEMENTAL MATERIAL
Ablation Procedure
Electrophysiological study and ablation was performed with sedation utilizing midazolam
and fentanyl. The left atrium (LA) was accessed using a single transeptal puncture. All
patients underwent wide encircling pulmonary vein ablation with an end point of isolation
confirmed by circumferential mapping (PVI; Lasso, Biosense-Webster, Diamond Bar,
California) with either elimination or dissociation of pulmonary venous potentials. Ablation
of the pulmonary veins was performed using a 3.5mm-tip externally irrigated catheter
(Thermocool, Biosense-Webster) delivering 25-30W of power with irrigation rates of 1730ml/min. Additional substrate modification (linear ablation along the LA roof and/or mitral
isthmus and/or ablation of complex fractionated atrial electrograms (CFAE)) was performed
in patients with an episode of AF ≥48hours, evidence of structural heart disease or with the
largest atrial diameter ≥57mm. Linear ablation and CFAE ablation was performed with a
delivered power of 25-35W with irrigation rates of 30-60-ml/min.
After LA access was achieved, repeated bolus unfractionated heparin was utilized to
maintain the activated clotting time between 300-350s. After ablation, sheaths were removed
without reversal of heparin and warfarin commenced the night of the procedure. Patients
were administered enoxaparin 0.5mg/kg twice a day until the INR≥2.
Supplementary Table 1: Inflammatory, myocardial injury and prothrombotic markers following RF ablation for AF
Baseline
Day 1
Day 2
Day 3
Day 7
Day 30
Hs-CRP (mg/L)
2.57 ± 2.16
12.14 ± 12.09*
36.89 ± 34.87*
44.29 ± 37.37*
11.65 ± 16.39*
1.29 ± 0.81
WCC (x109/L)
6.14 ± 1.98
8.91 ± 2.37*
7.37 ± 2.18*
7.42 ± 2.11*
7.01 ± 2.14*
6.71 ± 1.85
Neutrophil (x109/L)
3.95 ± 1.76
6.78 ± 2.10*
5.13 ± 1.85*
5.14 ± 1.82*
4.66 ± 1.70
3.97 ± 1.20
Troponin-T (µg/L)
0.05 ± 0.08
1.61 ± 1.07*
1.01 ± 0.75*
0.54 ± 0.46*
0.11 ± 0.13
0.07 ± 0.19
CK (U/L)
101.25 ± 53.91
216.31 ± 141.03*
182.59 ± 190.57*
207.25 ± 275.46*
105.75 ± 60.55
72.33 ± 30.83
CKMB (µg/L)
3.21 ± 1.20
10.65 ± 5.10*
4.95 ± 2.27*
3.54 ± 1.10
2.66 ± 0.72
2.27 ± 0.29
Fibrinogen (g/L)
3.11 ± 0.61
3.21 ± 0.55
4.12 ± 0.76*
4.71 ± 0.86*
4.71 ± 1.42*
3.10 ± 0.75
D-Dimer (FEU)
0.28 ± 0.13
0.32 ± 0.24
0.32 ± 0.29
0.44 ± 0.30*
0.58 ± 0.46*
0.41 ± 0.24*
Data presented as mean ± SD. All markers demonstrated a significant increase over time (p<0.001). *p<0.05 compared to baseline values. Note:
Statistical analyses performed using mixed effects models on logged data as appropriate, in which statistical significance was achieved.
Supplementary Table 2: Extent of elevation in biomarkers and early AF recurrence
AF recurrence
No AF recurrence
p-value
Ln Hs-CRP elevation (mg/L)
3.75 ± 0.80
2.79 ± 1.07
<0.005
Ln Troponin-T elevation (µg/L)
0.59 ± 0.62
0.07 ± 0.77
<0.05
Ln CKMB elevation (µg/L)
2.35 ± 0.57
1.38 ± 0.95
0.01
Fibrinogen elevation (g/L)
2.23 ± 1.39
1.14 ± 0.70
<0.005
Fibrinogen elevation (g/L)
1.96 ± 1.25
1.13 ± 0.63
0.005
37.6 ± 0.6
37.2 ± 0.3
0.011
(recurrence at 1-month)
Body temperature (°C)
Data presented as mean ± SD.