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DOI: 10.1161/CIRCEP.113.000253
1
Genetic ACE I/D Polymorphism and Recurrence of Atrial
Fibrillation after Catheter Ablation
Running title: Ueberham et al.; ACE polymorphism – outcome after catheter ablation
Laura Ueberham1; Andreas Bollmann, MD, PhD1; Moore Benjamin Shoemaker, MD2;
Arash Arya, MD1; Volker Adams, PhD3; Gerhard Hindricks, MD1; Daniela Husser, MD1
1Dept of Electrophysiology, 3Dept of Cardiology, Heart Center, Leipzig, Germany; 2Dept of Medicine, Vanderbilt University Medical Center, Nashville, TN
Address for correspondence:
Laura Ueberham
Department of Electrophysiology
Heart Center, Leipzig University
Strümpellstr. 39
04289 Leipzig
Germany
Tel: ++49 341 865 1580
Fax: ++49 341 865 1814
E-mail: [email protected]
Journal Subject Codes: [22] Ablation/ICD/surgery, [109] Clinical genetics
min Shoemaker, MDMDD
1; Daaaaninininielelelelaa a a HuHuHuHusssssssserererr,,,, MDMDMM
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or correspondence:
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DOI: 10.1161/CIRCEP.113.000253
2
Abstract
Background - The ACE deletion allele, ACE D, is associated with increased cardiac ACE
activity, cardiac fibrosis and adverse outcomes in cardiovascular disease and has been linked
with failure of anti-AF drug treatment. This study tested the hypothesis that the angiotensin-
converting enzyme gene (ACE) insertion/deletion (I/D) polymorphism associates with atrial
fibrillation (AF) recurrence after catheter ablation.
Methods and Results - In 238 consecutive patients (69 % male, mean age 58 ± 11 years)
undergoing catheter ablation of paroxysmal (59 %) or persistent (41 %) AF, the ACE
insertion/deletion [I/D] polymorphism was genotyped using polymerase chain reaction. After a
blanking period of 3 months, AF recurrence (defined as any atrial arrhythmia lasting at least 30s)
was detected using serial 7-day-Holter ECG recordings after 3, 6 and 12 months. AF recurrence
was observed in 39 % and was associated with persistent AF, longer history of AF, previous
antiarrhythmic drug use, previous use of diuretics, increased left atrial diameter, increased left
ventricular end diastolic diameter, additional linear ablation lesions and ACE DD polymorphism.
In multivariable analysis, left atrial diameter (OR 1.111, 95 % CI 1.040 – 1.187, p=.002) and
ACE DD genotype (OR 2.251, 95 % CI 1.056 – 4.798, p=.036) remained predictors for AF
recurrence.
Conclusions - Left atrial enlargement and the ACE DD polymorphism are predictors for AF
recurrence after catheter ablation. The association between the ACE DD polymorphism and AF
recidivism supports the use of genetic data for predicting response to AF therapies and highlights
the role of fibrosis in AF development.
Key words: atrial fibrillation, genetics, genetic polymorphism, catheter ablation, ACE polymorphism, ACE I/D genotype
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ved in 39 % and was associated with persistent AF, longer history of AF, previou
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enotype (OR 2.251, 95 % CI 1.056 – 4.798, p=.036) remained predictors for AF
.
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enotytytypepp (((OROROR 2222.22225151515 , , 959595 %%% CCCCI 1.111 050505666 – 4.7979798,8,8, ppp=.03030336)6)6) rememmmaiiineneneeddd d prpp ddeddiici ttorssss fffforororor AF
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DOI: 10.1161/CIRCEP.113.000253
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Introduction
Current atrial fibrillation (AF) guidelines1, 2 recommend catheter ablation for patients with
symptomatic, antiarrhythmic drug refractory AF or as first line therapy if no or minimal heart
disease is present. Single-procedure ablation achieves freedom from AF in 57 %3 to 89 %4
depending on patient characteristics, ablation strategies and follow-up. Prediction of rhythm
outcome remains challenging, although a recent meta-analysis identified non-paroxysmal AF,
valvular AF and increased left atrial diameter as independent clinical predictors for recurring
AF.5
In the past 15 years increasing interest in the genetic background of AF resulted in the
identification of common gene variants that associate with AF.6, 7 However, there is only limited
data correlating genotypes with outcomes of AF therapies8-10 and in particular with rhythm
outcome after AF ablation.11-13 Consequently, this study tested the hypothesis that the
angiotensin-converting enzyme gene (ACE) I/D polymorphism associates with AF recurrence
after catheter ablation. Using a candidate gene approach, this polymorphism was selected since
the ACE deletion allele, ACE D, is associated with increased ACE serum levels, higher cardiac
ACE activity and increased cardiac fibrosis.14-16 The ACE D allele was also demonstrated to
associate with electrical remodeling in patients with lone AF and those with heart disease17 and
has been linked with failure of anti-AF drug therapy and AF recurrence in Chinese-Han.8, 18
Methods
Study population
The study included a total of 238 consecutive patients, enrolled in the Leipzig Heart Center AF
ablation registry, who underwent left atrial radiofrequency catheter ablation for symptomatic,
drug-refractory paroxysmal or persistent AF. All patients received a transthoracic and
nd offff AAAAFFFF reresusultltltltededdd iiiinnn n tt
6 7 m
a
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ter ablation Using a candidate gene approach this pol morphism as selected s
onnn ooooffff ccccomomommmommm n nnffff gegg ne variants that associaaaattte with AF.6, 7 Howewww ver, there is only lim
aaaatittt nnngn genotypeses wiiithhh ouuutcccommees oooff AFF ttherraapieeeess8-10000 anddd in pparrticcccuulu ar wwwwiiti hh rrhytttthmmm
fter AFAFAFAF aaaabblblb atioiii n.1111111 -131313 CCConseseseeqqquentltltly,yyy thihihih s ttst dduddy tetetetestedededed thehehehe hhhhypyp tttothesisisisissss ththhthatttt ttthhhe
n-convertiiinggg eeennnzn ymyy e gegg ne (((ACACACCEEE(((( )))E I/II/D DDD popp lylylymorppphihihihism assssssociaiaiatetetetes withhthh AAAF FFF rerererecucucucurrenyyyy
tt blbl tatiio UU isi dididdatte hch ththiis lol hphiis lle tct ded
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DOI: 10.1161/CIRCEP.113.000253
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transesophageal echocardiography before ablation procedure to exclude left atrial thrombus and
standardized measurements of left atrial diameter, left ventricular ejection fraction,
interventricular septal end diastolic dimension and left ventricular end diastolic diameter were
performed. Antiarrhythmic medication (class I and III antiarrhythmic drugs) was stopped before
ablation procedure. The study was approved by the local ethics committee (Medical Faculty,
University of Leipzig) and all patients gave their written informed consent.
Catheter ablation
Left atrial catheter ablation was performed according to a previously described approach.19 In
brief, patients were studied under deep propofol sedation with continuous invasive monitoring of
arterial blood pressure and oxygen saturation. Non-fluoroscopic 3D catheter orientation, CT
image integration, and tagging of the ablation sites were performed using Ensite NavX, Ensite
Velocity (St. Jude Medical, St. Paul, MN, USA) or CARTO 3 (Biosense Webster, Diamond Bar,
CA, USA). Trans-septal access and catheter navigation were performed with a steerable sheath
(Agilis, St. Jude Medical., St. Paul, MN, USA). Patients presenting with AF at the beginning of
the procedure were electrically cardioverted and ablation was performed during sinus rhythm
(i.e. AF termination with ablation was not attempted). In all patients circumferential left atrial
ablation lines were placed around the antrum of the ipsilateral pulmonary veins (irrigated tip
catheter, pre-selected tip temperature of 48°C and maximum power of 30 – 50 W). In patients
with persistent AF, additional linear lesions were added at the left atrial roof, the basal posterior
wall and the left atrial isthmus. Ablation of complex fractionated electrograms was not
performed.
After circumferential line placement, voltage and pace mapping along the ablation line
were used to identify and close gaps. The isolation of all pulmonary veins with bidirectional
described apppproacch.h.h.h.119
ous ininii vava isiisiveve mmononnnititititoooor
od pressure and oxygen saturation. Non-fluoroscopic 3D catheter orientation, CT
gration, and tag ng of the ablation sites were performed using Ensite NavX, Ens
St. Jude Medical, St. Paul, MN, USA) or CARTO 3 (Biosense Webster, Diamond
.
J de Medical St Pa l MN USA) Patients presenting ith AF at the beginnin
oddd pppprererer sssssurururu ee annnnddd d oxygen saturation. Nonnn-fff-flulull oroscopic 3D33 cccatatata heter orientation, CT
grgrgrratatttion, and tagaggingnng of thththhe abbbblllal tiiioon siiteees wweere pepepeperfrfrfrfoormememed ussinng g g EEnE sitetetee NNNavavX, EEEns
St. JuJudededede MMMMeddiciii llal, StStSSt. PaPP ullll, MNMNMNMN, USUSUSUSA)AA)A) or CACACAARTRTRTRTOOO O 333 (B(B(B(Bioioioosense WeWeWeWebsbsbsbsttter, DDDiiiai mond
. Trans-septptptalalal aaaaccess and dd cathetter navigigigatiiion were ppperfofooormedededd wiiti hhh a steerarararablblblb eeee sh
JJ dd MMedidi ll StSt PPa ll MNMN USUSA)A) PPatiti tts tntiin iithth AAFF tat tthhe bb iin ini
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DOI: 10.1161/CIRCEP.113.000253
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block was verified with a multipolar circular mapping catheter and was defined as the procedural
endpoint.
Follow-up
After ablation procedure, patients were followed in the outpatient clinic for 12 months. There
was no reinitiation of antiarrhythmic drug class I or III therapy after ablation. Anticoagulation
therapy was prescribed for at least 3 months and according to the CHA2DS2-VASc-Score
thereafter and proton pump inhibitors were prescribed for 4 weeks. Recurrence of AF was
detected using serial 7-day Holter ECG recordings after a blanking period of 3 months at 3, 6 and
12 months after CA. When patients’ symptoms referred to AF, supplementary
electrocardiograms and Holter recordings were arranged. AF recurrence was defined as a
documented episode of AF or any other atrial tachycardia lasting at least 30sec. In case of
sustained early recurring AF, patients underwent direct-current cardioversion. Further
antiarrhythmic drug therapy was left to the assessment of the treating physician.
Genotyping
DNA extraction was performed using a commercial isolation kit (peqGOLD Blood DNA Mini
Kit, PeqLab, Erlangen, Germany) according to the manufacturer instructions. ACE I/D
polymorphism was detected using polymerase chain reaction. A set of commercially synthesized
primers (TibMolBiol, Berlin, Germany,
were used for PCR.
DNA amplification contained between 35 and 40 cycles. Agarose gel electrophoresis and
ethidium bromide staining were used to identify the PCR products with lengths of 190 bp (D
allele) and 490 bp (I allele) as illustrated in Figure 1.
riod of 3 months atatatat 33,,
mentatatt ryry
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diogogggrararaamsmms aaaandnnn HHHHoloo ter recordings were arraaangngn ed. AF recuruu rencncncnce was defined as a
edddd eeeepip sode of AFAF orrr aany ooother r atrrriaal tacacchycacardiaiaiaia lalalaastststs inggg aat leaeast 3333000sec.... IInInI caase of
early rererrecuucucurring AFAFAFAF, patientststss underwewewew ntnttnt dddiriii ectttt-cucucucurrrrenenenentttt caaardrdrdr ioiii versioonnnn. FFFuF rttthhher
hmic dddrug gg thhherrrapapapa y yy was lell fftf tto thhhhe assessment of ff hththe treatitiiinggg ppphyhyhyhy isii ician.
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DOI: 10.1161/CIRCEP.113.000253
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Statistical analysis
Continuous variables are presented as mean values ± one standard deviation and categorical
variables as frequencies. Comparison of continuous variables was performed using the unpaired
Student’s t-test and of categorical variables using the Pearson chi-square test. To identify
predictors of AF recurrence, a multivariable logistic regression was performed. We adjusted for
all variables found in univariate analysis with a p-value <.15 in the multivariable logistic
regression analysis, along with variables found to be significantly associated with each genotype.
A two-sided p-value <.05 was considered as statistically significant.
Selection of a recessive genetic model (II and ID vs. DD) was based on pathophysiologic
considerations and previous studies showing (a) a significant association of the ACE DD
genotype and AF recurrence in a population of lone AF subjects of Chinese Han origin,18 and (b)
highest cardiac ACE activity in DD genotype while it was similar in II and ID genotypes.15
Expected and observed genotype frequencies were compared using chi-square test to evaluate
Hardy-Weinberg-equilibrium.
The best left atrial diameter cut-off was determined by analysing the receiver operator
characteristics (ROC) curve (ROC in supplemental materials).
Results
Patient characteristics
Patient characteristics of the total study population and stratified by the ACE genotype are
summarized in Table 1. Genotype frequencies were 23 %, 44 % and 33 % for the ACE II, ID and
DD genotype, respectively and did not differ significantly from those expected by Hardy-
Weinberg equilibrium calculations. DD carriers were more often male and users of inhibitors of
baseedd dd onon pp tattathhhohophphhphysysysysiiioio
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an a
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a u
inberg eq ilibri m
onsnsnsns aaaandndndn pppprerreviiiouououous studies showing (a) a sisisisignnificant assooociatttioioioi n of the ACE DD
nnndn AF recurrenence iiinn a popopopulaaatttit onoon of looone AAF sususubjbjbjjecctss ooof Chhiineeesee Haaann nn ororiggin,,18888 a
rdiac ACACACACEEEE actititi iivittytyt iiin DDDDDDD ggggenenenotypppeeee whhwhwhililile ititit wasasasas simimimimiiili ararar iiiin IIIIII and d IIIIDDDD geg notttypes.1511
and obsbb ervedd d gegegeg notytytypepp fffrequqq en iicies were comppparedddd u iisiingngngg chihihi--sqqquare test t totototo eeevvvav lu
iinbberg iililibbrii
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DOI: 10.1161/CIRCEP.113.000253
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the renin-angiotensin-aldosterone system while other clinical, echocardiographic and procedural
variables were comparable among different ACE genotypes.
Predictors for AF recurrence
Complete pulmonary vein isolation as a procedural end point was achieved in 98 % of cases. AF
recurrence was observed in 39 % between 3 and 12 months. Patients with AF recurrence are
compared to patients without AF recurrence in Table 2. In univariate analysis, recurring AF was
associated with persistent AF, longer history of AF, previous antiarrhythmic drug use, previous
use of diuretics, increased left atrial diameter, increased left ventricular end diastolic diameter,
additional linear ablation lesions and the ACE DD genotype. Both, unadjusted and adjusted
multivariable analysis identified left atrial diameter as predictors for AF recurrence (Table 3). AF
recurrence rates according to left atrial diameter and genotype are depicted in Figure 2.
Receiver operator characteristics (ROC) curve analysis showed LAD 45mm as best cut-
off for AF recurrence prediction. A risk score based on LA size (LAD 45mm) and ACE
genotype (ACE DD) was evaluated and allowed identification of groups at low (0 risk factors),
intermediate (1 risk factor), or high (2 risk factors) recurrence risk. Odds of AF recurrence were
increased 2.75-fold per risk factor (OR 2.75, 95 % CI 1.657 – 4.577, p<.001). The AF recurrence
rate was 21.6 % in the low risk group, 39.7% in the intermediate risk group, and 70% in the high
risk group (Figure 3).
Discussion
Main findings
To the best of our knowledge, this study is the first to investigate the influence of the ACE I/D
polymorphism on AF recurrence after catheter ablation in Caucasians. Analysis of 238 subjects
clearly demonstrated an association between ACE DD polymorphism and AF recurrence 3 to 12
ar end diastolic diamamamame
adjusstetett dd dd anandddd daddadjujujuststststeeeded
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ACE DD) as e al ated and allo ed identification of gro ps at lo (0 risk facto
ble e e ananananalalala ysysyssisisiss idddenenenentified left atrial diameterrr ass predictors ffor AAAAFFF recurrence (Table
rrrrattttes accordingng to leeft aaatrrrial ddidid ammmeterr aaandd ggennnototottypypypypee arrreee deppicctededede in FFiFF ggug rere 2.
ceivererrr oopepepeperator hhchharacteriiiistststticicics (RRRROCOCOCOC))) curve ananalalalalysysissisis shhhhowowowo eddd LLLLADDDD 4445mm as bbbbe
recurrence prprprrededede iciii iition. A AA riiiisk score bbbbaseddd on LALALAA sizii e (L(L(LLADADADA 4444555m5 m)m)m) andndndnd ACACACACE
ACACEE DDDD)) lal ttedd dd lalllo dd idid titififi titi ff tt llo (0(0 iiskk ffa tct
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DOI: 10.1161/CIRCEP.113.000253
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months after ablation. In addition, left atrial enlargement contributed to AF recidivism which is
consistent with previous analyses.5, 20
Comparison with previous studies
In a recent meta-analysis5 that included 4.357 patients with paroxysmal AF, 1.083 with persistent
AF and 1.777 with long-standing AF undergoing 1.23 procedures per patient, the AF recurrence
rate was 31 % after a follow up of 22 months which is comparable to our recurrence rate. Among
the pre-procedural variables, AF recurrence was associated with persistent AF (OR 1.78),
valvular AF (OR 5.20) and a left atrial diameter of more than 50 mm (OR 5.10).5 Both persistent
AF and left atrial enlargement were also associated with AF recurrence and the latter remained
as a significant predictor in multivariable analysis of our population. Interestingly, our left atrial
cut-off of 45 mm mirrors closely the findings of a previous study.20 In contrast, patients with
valvular heart disease represented only a minority of our population.
Only limited data point to the possibility of genotype-based AF rhythm control therapies.
Recently, two single nucleotide polymorphisms on chromosome 4q25 (rs2200733, rs10033464),
identified in a genome wide association study to associate with AF,21 also predicted AF
recurrence after catheter ablation.11 The current patient population is slightly larger and the
follow-up period was extended to 12 months. In addition, the ACE genotype distribution is rather
equal, so that one third of the examined population is affected by the ACE DD ‘risk’ genotype.
We could clearly demonstrate that the presence of ACE DD genotype increases the risk of AF
recurrence following radiofrequency catheter ablation. These results are in accordance to
previous findings on anti-AF drug treatment, where patients with D allele are reported to have
poorer response to antiarrhythmic drug therapy.8
((OR 5.10)).5 Both pepepeperrsr
e andddd ttthehehh llll ttatattettet r r reemammmaii
4 t
e
l r
o single n cleotide pol morphisms on chromosome 4q25 (rs2200733 rs10033
cannnntt prprprp edededdiciciccttor rr ininini multivariable analysis ooof fff oour populationoo . InInInInterestingly, our left
45555 mmmmm mirrorss cclossseely thththheee findndnddinnnggs of aaa prreeviooooususss sssstuudyyy.20 Inn ccontntntrast, ppap ttieentsss wwwit
eart ddddisisiiseaaeaease represe ttnted onlnlnlnlyyy a miiiinononon ririritttyty offf our popopopopupupupulllal tititiononono .
ly yy liiii imiited dd dadd tatataa popp inii t to thehh pppos iisibibibilillitytyty of fff gegg notypypype-bbbaseedd dd AFAFAF rhrhrhrhytytythhhm contrtrtrtrolololo tttther
ii lle lle totidid ll hihi hhr 44q2525 (( 22220000737333 1s100003333
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ACE I/D polymorphism and functionality in AF recurrence
It is assumed that higher ACE and consequently higher angiotensin II levels are responsible for
increased structural remodelling. Left atrial structural remodelling can be classified as
macroscopic measured as left atrial dilation, or microscopic due to left atrial fibrosis.22
Consistent with previous findings, the ACE polymorphism did not correlate with left atrial
enlargement, and in-vivo assessment of left atrial fibrosis is technically challenging and therefore
not assessed in our study. However, the ACE polymorphism has been found to correlate with
abnormal cardiac conduction as manifest in prolongation of PR interval and P-wave duration,
both of which are recognized markers of AF risk.17 Also, it has been shown that the DD
genotype leads to increased ACE serum levels and higher cardiac ACE activity.14, 15
Furthermore, atrial fibrosis is thought to be increased via an angiotensin II mediated increase in
TGF- 1 mRNA expression.23 Regions of atrial fibrosis are known to result in conduction
heterogeneity and increased AF susceptibility.24 Thus, multiple lines of evidence suggest the
theory that ACE DD compared with the II/ID genotype leads to higher cardiac ACE, angiotensin
II and TGF- 1 levels, which in turn promotes structural remodelling and abnormal cardiac
electrophysiology due to fibrosis.
Several previous studies have demonstrated that the reversal of electrical remodelling
occurs early after restoration of sinus rhythm25 while structural remodelling including fibrosis
takes much longer and is the responsible substrate for recurring AF.26 The association of the ACE
DD genotype with a higher rate of recurring AF found in this study supports this concept.
Similarly, a very recent study demonstrated that higher TGF- levels are associated with AF
recurrence after catheter ablation.20 While this and our study resemble identical concepts in AF
prediction after catheter ablation with comparable results, genotyping offers possible advantages
al and P-wave durarararatititt o
hownwn ththhthatattt ththththee DDDDDDDD
e 14 15
r
R
e h
ACE DD compared ith the II/ID genot pe leads to higher cardiac ACE angiot
eadsdsds ttttooo inininncrcrcreasesesesed ACE serum levels andddd hhhhigigii her cardiac ACCCCE EEE activity.14, 15
reeee, ata rial fibrossis isss ttthhhougugugghht to o beee iincrreaased via aa anananan aanngiioootenssinn IIIIIII meddidid aata eed incccreeea
RNAAAA eeexppxpxpressioii n.2323232 RRRRegionsnsnsn of atttriririialalalal ffffibibibibro iisiis ararareeee knknknknooowown nnn ttto result inininin cconduddd tttctioii n
ity yy andd d increaaassses dddd AFAFAF susceptptptibbbbilililiiti yyy.2424242 TThuhhh s, mulltltl ipipipi lell llllinnnnes oof fff evidididence suguguguggegegegest th
ACACEE DDDD ded itithh thth IIII/I/IDD tt lle dad tto hhiighhe drdiia ACACEE iiott
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over fluctuating and non-standardized laboratory measurements. Although research into the
fundamentals of structural remodelling have not yet been exhausted, the use of biomarkers
involved in atrial fibrosis turned out as a new promising approach.
Study limitations
This study included a highly-selected patient population with a high percentage of lone (58 %)
and paroxysmal (59 %) AF. Furthermore, a standardized ablation approach was applied.
Consequently, it is not clear whether these findings are comparable with different ablation
approaches, such as ablation of complex fractionated electrograms or energy sources or different
patient populations.
As recommended previously and commonly applied, we used serial 7-day Holter ECG
monitoring to detect AF. However, even with this strategy asymptomatic AF may have been
missed. Since this would affect the entire cohort, a systematic error seems unlikely. Moreover,
the follow-up was limited to 12 months and thus, possible very late recurrences could not be
analyzed.
ACE genotype distribution was different between male and female AF patients. Further
and larger studies are required to replicate this finding and to explore mechanisms and
consequences.
The use of RAAS modulators, such as ACE inhibitors, angiotensin-receptor blockers or
aldosterone antagonist for secondary AF prophylaxis in general and after AF ablation in
particular is controversial.27 Whether or not genotype-based RAAS modulation offers benefits is
unknown and should be explored in the future.
While this study sought to predict rhythm outcome of AF ablation that is applied to a
minority of the AF population, identification of new molecular targets for improved drug therapy
energgy yy sources or r didididiff
r C
g to detect AF. However, even with this strategy asymptomatic AF may have bee
n v
- b
reccccomomomommememeendndndndeddd ppppreviously and commonlyyyy appplied, we uuused seseses rial 7-day Holter EC
g ttto detect AF. HHowwweeverrr, evenn wwwitth thhiis sttraategggy y y y aasasasymymmptttomattic AAAF mmamm yy y hahave bbee
nce thththhisisis wwwouldldldld afffffff ecttt thtt e enenenntitititire cohohohohororort,tt, a sysysttett mamamamatititiiccc errororoorr seems ununununlilililikkkkely. MMMoM reov
-up pp was liii imiiteteted ddd tot 1112 22 montthhshh anddd thhhus, popp ssibibibible veryyy llllatattte recucucuurrences coululululddd d nonnn t b
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and the discovery of biomarkers for risk stratification remains a major goal in the management of
the growing number of AF patients.28
Most importantly, as with all biomarkers, our findings need to be validated in different
AF populations undergoing AF catheter ablation. Nevertheless it is noteworthy that our study
was hypothesis-driven based on a previous biological assumption and so the need for replication
is not as strict.
Conclusions
Left atrial enlargement and the ACE DD polymorphism are predictors for AF recurrence after
catheter ablation. The association between the ACE DD polymorphism and AF recidivism
further supports the use of genetic data for predicting response to AF therapies and highlights the
dominant role of fibrosis in AF development.
Acknowledgments: The authors thank Mrs. Angela Kricke, Mrs. Tina Fischer and Mrs. Virginia Kootz for their help with laboratory and administrative work as well as the entire staff involved in patient care.
Funding Sources: Daniela Husser was supported by the Volkswagen Foundation (# 84 901),Germany. Laura Ueberham was supported by the German Cardiac Society (Otto-Hess Stipend).
Conflict of Interest Disclosures: None.
References:
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r
d itheir help ith laborator and administrati e ork as ell as the entire staff in o
lationnn.. ThTTheee assosososociation between the ACE DDDD polymorphismmmm and AF recidivism
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hism. CiCiCiC rculllatttioioioion. 191919959595 9;992:222 1131 8787878 -1113838388888.
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Table 1. Characteristics of the study population and stratified by ACE I/D genotype.
Total II/ID genotype DD genotype p Value
n=238 n=160 n=78
Age, yrs 58 ± 11 58 ± 12 59 ±10 0.823
Male (%) 69 64 78 0.030
Persistent AF (%) 41 42 40 0.696
Lone AF (%) 58 59 56 0.710
AF history, month 74 ± 76 72 ± 73 79 ± 81 0.498
BB/ CCB* use (%) 86 84 90 0.261
Digitalis use (%) 22 22 22 0.989
AAD† use (%) 42 40 45 0.498
Diuretic use (%) 33 33 33 0.898
ACEi/ARB/Ri‡ use (%) 65 59 76 0.014
LAD§ , mm 43 ± 6 43 ± 6 43 ± 5 0.548
LVEF (%) 60 ± 9 59 ± 8 61 ± 9 0.120
IVSd¶, mm 12 ± 2 12 ± 2 13 ± 3 0.170
LVED#, mm 49 ± 6 49 ± 7 50 ± 5 0.312
Ablation time, sec 3118 ± 1387 3141 ± 1379 3073 ± 1415 0.771
Additional linear lesions (%) 41 40 43 0.677
‡angiotensin-converting-enzyme inhibitor/ angiotensin II blocker/ renin inhibitor†antiarrhythmic drug*beta blocker/ calcium channel blocker¶interventricular septal enddiastolic dimension§LAD = left atrial diameterleft ventricular ejection fraction
#left ventricular end diastolic diameter
797999 ±± 881111
9090
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s
useee ((((%%%)% 22 22 22
(%(%(%(%) 42 40404040 45
se (%)%%% 33 333 33
BBB/R/Rii‡‡ usususeee (%(%(( )) 6565 5959 7676
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Table 2. Comparison of patient characteristics with and without AF recurrence. Please note that one patient was lost to follow-up.
AF recurrence - AF recurrence + p-value
n=145 n=92
Age, yrs 58 ± 11 59 ± 11 0.280
Male (%) 70 69 0.848
Persistent AF (%) 37 50 0.043
Lone AF (%) 60 53 0.393
AF history, months 68 ± 78 84 ± 72 0.134
BB/ CCB use (%) 86 87 0.755
Digitalis use (%) 24 19 0.305
AAD use (%) 36 51 0.023
Diuretic use (%) 28 41 0.029
ACEi/ARB/Ri use (%) 65 64 0.913
LAD, mm 42 ± 6 45 ± 6 <0.001
LVEF (%) 60 ± 9 60 ± 8 0.828
IVSd, mm 12 ± 2 12 ± 2 0.262
LVEDd, mm 48 ± 6 50 ± 7 0.046
Additional linear lesions (%) 33 55 0.001
ACE DD genotype (%) 28 40 0.043
Abbreviations as in Table 1.
0.0.0.0.11313134444
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Table 3. Univariate and multivariable* analysis of predictors for AF recurrence.
Univariate analysis Unadjusted multivariable analysis Adjusted multivariable analysis
Odds ratio 95 % CI p value Odds ratio 95 % CI p value Odds ratio 95 % CI p value
Persistent AF 1.731 1.015 - 2.950 0.043 0.765 0.465
AF history 1.003 0.999 - 1.006 0.134 0.141 0.114
AAD use 1.848 1.086 - 3.145 0.023 0.447 0.288
Diuretic use 1.847 1.063 - 3.209 0.029 0.147 0.111
LAD 1.108 1.044 - 1.177 <0.001 1.111 1.040 - 1.187 0.002 1.117 1.032 – 1.209 0.006
LVED 1.055 1.000 - 1.144 0.046 0.842 0.934
Additional linear lesions 2.451 1.420 - 4.230 0.001 0.060 0.068
ACE DD genotype 1.766 1.015 - 3.071 0.043 2.251 1.056 - 4.798 0.036 2.724 1.161 – 6.395 0.021
Abbreviations as in Table 1. *All variables with a p<0.15 in univariate analysis were included. Adjusted multivariable analysis has been adjusted for gender and ACEi/ARBi/Ri use.
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Figure Legends:
Figure 1. Determination of the ACE I/D polymorphism using 2 % agarose gel electrophoresis. -
A representative gel demonstrates genotype of 7 patients. Fragment sizes are 190 bp for D allele
and 490 bp for I allele (M=marker). Please note the following genotypes below: 1) DD, 2) II, 3)
ID, 4) ID, 5) II, 6) DD.
Figure 2. AF recurrence in relation to ACE genotype and left atrial diameter. – ACE genotype
(left panel, 34.4 % vs. 48.1 %, OR=1.766, 95 % CI 1.015 - 3.071, p=.043) and left atrial diameter
(right panel, 42±5mm vs. 45±6mm, OR=1.108 per mm increase, 95 % CI 1.044 – 1.177, p<.001)
are predictors for AF recurrence.
Figure 3. AF recurrence in relation to the presence of risk factors i.e. left atrial enlargement 45
mm and ACE DD genotype. – Note the increased risk for AF recurrence if none, one or two risk
factors are present (21.6 % vs. 39.7 % vs. 70.0 %, OR 2.754 per risk factor, 95 % CI 1.657 –
4.577, p<.001).
ameter. – ACE ggenennnototoo yyE
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l, 42424242±5±5±5± mmmmmmmm vs.s.s.. 4445±6mm, OR=1.108 per r mmmmm increase, 9599 %%%% CI 1.044 – 1.177, p<
oooorsrs for AF reccurrrencnnce.
AF recurrence ee iiini r llelatioii n tot the pppresence ffof riiisk kkk faff ctorss iii.i e. lllefefefeft t tat iirial enlllarararargegegeg mmmem n
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Gerhard Hindricks and Daniela HusserLaura Ueberham, Andreas Bollmann, Moore Benjamin Shoemaker, Arash Arya, Volker Adams,
I/D Polymorphism and Recurrence of Atrial Fibrillation after Catheter AblationACEGenetic
Print ISSN: 1941-3149. Online ISSN: 1941-3084 Copyright © 2013 American Heart Association, Inc. All rights reserved.
Dallas, TX 75231is published by the American Heart Association, 7272 Greenville Avenue,Circulation: Arrhythmia and Electrophysiology
published online July 22, 2013;Circ Arrhythm Electrophysiol.
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SUPPLEMENTAL MATERIAL
Figure 1. Receiver operator characteristics (ROC) curve for determination of the best left atrial
diameter cut-off (AUC 0.673).
Figure 2. AF recurrence in relation to
48.1 % for ACE II, ID and DD, respectively
SUPPLEMENTAL MATERIAL
Receiver operator characteristics (ROC) curve for determination of the best left atrial
AF recurrence in relation to ACE genotype. AF recurrence occurred in 29.1 %, 37.1 % and
respectively.
Receiver operator characteristics (ROC) curve for determination of the best left atrial
29.1 %, 37.1 % and