genetic ace i/d polymorphism and recurrence of atrial...

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

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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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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

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ter ablation Using a candidate gene approach this pol morphism as selected s

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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

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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

.

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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.

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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

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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

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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

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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

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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

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11

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:

1. Camm AJ, Kirchhof P, Lip GY, Schotten U, Savelieva I, Ernst S, Van Gelder IC, Al-Attar N, Hindricks G, Prendergast B, Heidbuchel H, Alfieri O, Angelini A, Atar D, Colonna P, De Caterina R, De Sutter J, Goette A, Gorenek B, Heldal M, Hohloser SH, Kolh P, Le Heuzey JY, Ponikowski P, Rutten FH. Guidelines for the management of atrial fibrillation: The task force for the management of atrial fibrillation of the european society of cardiology (ESC). Eur Heart J.2010;31:2369-2429.

2. Calkins H, Kuck KH, Cappato R, Brugada J, Camm AJ, Chen SA, Crijns HJ, Damiano RJ, Jr., Davies DW, DiMarco J, Edgerton J, Ellenbogen K, Ezekowitz MD, Haines DE, Haissaguerre M,

ffor AAAAF F F F rerererecucucucurrrrrrrrenenenencececece aaaaffff

lation The association between the ACE DD polymorphism and AF recidivism

ports the use of genetic data for predicting response to AF therapies and highligh

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d itheir help ith laborator and administrati e ork as ell as the entire staff in o

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H,,, ReReReReynyynolololo dsddd MMMMR, Spector P, Sondhi M, XuXXu Y, Martin AAA, WiWiWiW lliams CJ, Sledge I.ofofofof aaaatrial fibrbrbrb illllalalaationnon wwwitititith anananantitititiara rhrhrhytyy hmhmhmicii ddruugsss oooor rrr rarrar diiidiofofofofrerereququuquenee cyyyy aaaablblblb ataa iooon:n:n:n TTTwowww lllil teeeerature reviiewws annd mmmeeeta-anaa aallyysess. Cirrc Arrrrrrhyhyhythttht m ElEE ectrroophyhyhyh siol. 2202 0909;2:::34449

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H. Angiotensin-converting enzyme in the human heart. Effect of the deletion/insh

n a MP Dia Ara a G Carreno JE M no D Ri eros JP Jalil JE La andero S

B, HHHHubububbereerttt C,CC AAAAlhlhlhlhenc-Gelas F, Cambien FFF, CoCC rvol P, Soubuu riiiererere F. An insertion/delehismsmsmsm in the anaanangigiigiotoo enenensisisinnn n I-cococoonvnvnvnverrertititingngng eeenznn ymmee gegegenenenene aaaccccouououountntntinning ggg for r hahahahalflflfl thehehe vavavavariririianaaa cymemememe levels. J ClClin IIInnvesssttt. 1990909090;88866:13343-13446.

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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

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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.

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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).

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oooorsrs for AF reccurrrencnnce.

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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

genetic ace i/d polymorphism and recurrence of atrial...

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