4 q 25 and ZFHX 3 Single Nucleotide Polymorphisms are Associated with Electroanatomical Characteristics of Left Atrium and Clinical Outcomes of Radiofrequency Catheter Ablation in Patients with Atrial Fibrillation

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I. INTRODUCTION
Atrial fibrillation (AF) is the most common form of cardiac arrhythmia in clinical practice and causes significant morbidity and mortality. 1,2 lthough many risk factors for AF such as advanced age, hypertension, structural heart disease, and congestive heart failure have been identified, a subset of younger subjects develops AF in the absence of established risk factors.The mechanisms underlying AF are not fully understood, but growing evidence supports a heritable component underlying AF and genetic variation may play a role in its pathogenesis. 3Familial cases among young patients with lone AF underscore a genetic basis for disease, 4 and research implicates pathogenic mutations and risk-conferring functional polymorphisms in AF development. 5er the last few years, several genetic variants associated with AF have been identified in genome-wide association studies (GWAS) performed in populations of European-descent. 6To date, three genomic regions/candidate genes have shown strong association with AF: 4q25 near paired-like homeodomain transcription factor 2 (PITX2), zinc finger homeobox 3 (ZFHX3) on 16q22, and potassium intermediate/small conductance calcium-activated channel, subfamily N, member 3 (KCNN3) on 1q21. 7,8 q25 gene is adjacent to PITX2, a transcription factor that determines left-right asymmetry of the heart. 9,10 ecently, some non-coding single nucleotide polymorphisms (SNPs) on chromosome 4q25 have been reported to be associated with the occurrence of AF in different populations. 7,11 he sequence variant rs2106261 is an intronic SNP located in ZFHX3 gene on chromosome 16q22, also called AT motif-binding factor 1 (ATBF1) and was highly associated with AF in the Chinese GeneID study. 12KCNN3 on chromosome 1q21 has been reported to be an SNP most significantly associated with lone AF in a study of European ancestry consisting of 1,335 individuals with lone AF and 12,844 unrelated individuals without AF. 13Meanwhile, one of the long-term risk factors for AF is prolonged PR interval on electrocardiography (ECG). 14Increased P-wave duration has been reported to indicate abnormal phenotypic characteristics such as left or right atrial hypertrophy and or enlargement, which reflect delayed intra-or inter-atrial conduction. 15Multiple researches have also shown the value of P-wave prolongation as a predictor for AF after cardiac interventions such as coronary artery bypass surgery. 16,17 enetic variants in 4q25 and 16q22 and PR intervals also have been reported to dispose individuals to AF. 18,19 Recently, AF has been most effectively treated with radiofrequency catheter ablation (RFCA), a procedure that isolates and terminates the source of ectopic activity. 20As the use of RFCA is increasing around the world, 21 analysis of pre-procedural characteristics that stratify the procedural efficacy and safety might be helpful, given the cost and potential complications of this procedure. 22Interestingly, 4q25 SNP recently has been reported to predict the recurrence of AF after RFCA. 23In this study, we hypothesized that phenotypes of AF patients including electroanatomical characteristics of left atrium (LA) and recurrence after RFCA were modulated by the common AF susceptibility alleles, rs2200733 and rs6843082 at 4q25, rs2106261 at ZFHX3, and rs13376333 at KCNN3.

Study population
The study protocol was approved by the Institutional Review Board of the Yonsei University Health System and adhered to the Declaration of Helsinki.
All patients provided written informed consent.Participants included 659 consecutive Korean patients with AF who underwent RFCA and 659 age, sexmatched healthy controls who were included in Ansan-Ansung cohort study of Korean National Institute of Health (KNIH) database.Exclusion criteria were as follows: 1) permanent AF refractory to electrical cardioversion; 2) LA size >55 mm as measured by echocardiogram; 3) AF with rheumatic valvular disease; 4) associated significant structural heart disease; 5) prior AF ablation or maze surgery.Three-dimensional (3D) spiral computed tomography (CT) scans (64 Channel, Light Speed Volume CT, Philips, Brilliance 63, Netherlands) were performed to visually define the pulmonary vein (PV) and LA anatomy.Trans-thoracic echocardiography (Sonos 5500, Philips Medical System, Andover, MA, USA or Vivid 7, GE Vingmed Ultrasound, Horten, Norway) was performed to evaluate the presence of structural heart disease, degree of LA remodeling, or ventricular function.Using trans-esophageal echocardiography, we ensured that no LA thrombus was present.All antiarrhythmic drugs were discontinued for at least five half-lives of the respective drugs.Amiodarone was discontinued at least four weeks prior to the procedure.Anticoagulation therapy was maintained before RFCA.

Electrophysiologic mapping and radiofrequency catheter ablation
Intracardiac electrograms were recorded using the Prucka CardioLab TM electrophysiology system (General Electric Health Care System Inc., Milwaukee, WI, USA), and catheter ablation was performed in all patients using 3-D electroanatomical mapping (St.Jude Medical Inc., Minnetonka, MN, USA) merged with 3-D spiral CT.If the initial recording identified a sinus rhythm, a LA 3-D electroanatomical voltage map was generated during atrial pacing by obtaining contact bipolar electrograms from 350-400 points on the LA endocardium.The bipolar electrograms were filtered from 32-300 Hz.For patients with initial rhythm of AF during the procedure, we generated voltage maps during pacing after internal electrical cardioversion (2 to 10J, biphasic shocks with R wave synchronization, anodal decapolar catheter in high right atrium to cathodal duo-decapolar catheter inside of the coronary sinus, Lifepak12, Physiocontrol Ltd.).We did not obtain an LA voltage map if frequently re-initiating AF required electrical cardioversion more than three times.We generally performed RFCA in sinus rhythm after electrical cardioversion.However, if sinus rhythm could not be maintained due to immediate recurrence of AF, RFCA was performed while in AF.We used an open irrigated-tip catheter (Celsius, Johnson & Johnson Inc.; Diamond Bar, CA, USA; irrigation flow rate 20 to 30 mL/min; 30 W; 47C) to deliver radiofrequency energy for ablation (Stockert generator, Biosense Webster Inc.; Diamond Bar, CA, USA).All patients initially underwent circumferential PV isolation and bi-directional block of the cavo-tricuspid isthmus.For patients with paroxysmal AF, additional linear ablation or complex fractionated atrial electrogram (CFAE) ablation guided by 3D-CFAE-CL map 24 was conducted depending on the operator's decision.In patients with persistent AF, circumferential PV isolation, cavo-tricuspid isthmus block, roof line, posterior inferior line, and anterior line 25 were performed as a standard lesion set.If AF persisted, CFAE ablation was done depending on the operator's decision.If AF persisted despite administration of the aforementioned ablation protocols, procedures were stopped after internal cardioversion.Procedural end-point was defined as when there was no immediate recurrence of AF after cardioversion during isoproterenol infusion (5-20 g/min).If non-PV foci were identified under isoproterenol, they were all ablated.

Post-ablation follow-up
Patients were asked to visit an outpatient clinic at 1, 3, 6, and 12 months after RFCA and then every 6 months thereafter for follow-up.ECG was performed at each visit and anytime the patient reported palpitations.A Holter ECG (24or 48-hour) and/or event recorder was performed on patient at every sixmonth follow-up and whenever the patient complained of symptoms for at least two years according to 2012 ACC/AHA/ESC expert consensus guideline for AF management. 26We defined recurrence of AF as any episode of AF or atrial tachycardia of at least 30 seconds in duration. 27If AF was found on ECG within the three-month of blanking period during follow-up, the patient was diagnosed with early recurrence of AF, and any AF recurrence thereafter was diagnosed as clinical recurrence 27 and antiarrhythmic medications were prescribed.

Off-line analyses of color-coded 3-D maps and CT images
Color-coded voltage maps were generated by recording bipolar electrograms and measuring peak-to-peak voltage during high right atrial pacing with a cycle length of 500 ms as previously described. 28We analyzed color-coded voltage maps of both anterior-posterior (AP) and posterior-anterior (PA) views that had been converted to image files as previously reported. 29PVs were not included in the analysis.Digital measurements of color-coded voltage maps were performed by a single investigator, using a consistent method, who was blinded to the clinical information of the maps.The percentage of color-coded areas in each quadrant of the voltage maps was analyzed using customized software (Image Pro), and referenced to the color scale bars.Low voltage areas, defined as LA voltage  0.2 mV, were coded gray; high voltage areas (> 5.0 mV) were coded purple.The mean LA voltage was calculated by adding together the % area of each color, multiplying by the representative voltage, and then dividing by the total area of LA.The reference distance was measured by the inter-electrode distances of coronary sinus catheters (duodecapolar catheter, St. Jude Medical Inc.Minnetonka, MN, USA.).To calculate local conduction velocity, the conduction distance was measured on the AP and PA views of the isochronal map, and the measured distance on the isochronal map were divided by the time difference as described before. 28The 3D spiral CT images of LA were analyzed on an image processing workstation (Aquarius, Terarecon Inc., USA).Each LA image was divided into portions according to the embryological origin as follows: the venous LA (posterior LA including the antrum and posterior wall), anterior LA (excluding the LA appendage and venous LA), and LA appendage.
The absolute and relative volumes of each portion were calculated and compared.

Electrocardiography
Standard 12 lead ECGs were recorded few hours to a day before catheter ablation procedure.Digitally stored ECGs were magnified at a high resolution computer screen and measured with a computerized caliper (Cardio Calipers, ver 3.3, ICONICO, NY, USA).Lead I, II, III, aVL, aVF, and Lead V1 were measured using Cardio Calipers, while PR intervals were automatically measured with the GE Marquette MAC 5000 (GE Marquette Inc., Milwaukee, WI).P wave durations in Lead I, II, III, aVL, and aVF were measured from the onset of the P wave to the return to the baseline.P wave amplitudes of the equivalent leads were measured from the crest of the P wave to the trough of the wave.The biphasic deflection in Lead V1 was measured as the following.
Duration of the initial positive deflection was measured from the onset of the P wave to the return to its baseline before the onset of the negative deflection.
Duration of negative P wave deflection was calculated by subtracting duration of the positive deflection from the duration of the entire P wave.Amplitude of the terminal negative deflection was measured from the trough of the wave to the baseline (Figure 1).

Genotyping
We used whole blood sample for the DNA extraction and genetic analyses, and it was collected by using EDTA as an anticoagulant.Genotyping of 4q25 rs2200733, PITX2 rs6843082, ZFHX3 rs2106261, and KCNN3 rs13376333 was performed using the validated TaqMan assays (Life Technologies, Carlsbad, CA, USA).Polymerase chain reaction product was amplified using 0.9 µm each of the forward and reverse primers, 0.2 µm each of the fluorescein amidite and VIC minor groove binder sequence-specific probes, 3 ng DNA, 5.0 mM MgCl 2 , and 1xTaqMan Universal PCR Master Mix containing AmpliTaq gold DNA polymerase in a 5.5-µL reaction volume.All SNPs had a call rate of > 99%.All genotyping was performed by laboratory personnel blinded to all clinical data.

Statistical analysis
All values are expressed as the mean ± standard deviation.Multiple variables including clinical features, echocardiography parameters, and degree of electroanatomical remodeling of LA were compared according to different genotypes.The Student's t-test or Mann-WhitneyU test or Kruskal-WallisH test was used as appropriate for comparisons between the continuous data and the chi-square test or Fisher's exact test was used for comparisons between the categorical data.A chi-square test was used to test the deviation of genotype distribution from Hardy-Weinberg equilibrium.A Kaplan-Meier survival analysis with Log Rank test was used to present the recurrence of AF.
A multivariate analysis was performed with the Cox stepwise forward regression model to determine the independent predictors of the recurrence of AF and odds ratios (ORs) with their 95% confidence intervals (CIs).A pvalue less than 0.05 was considered as statistically significant.All statistical analyses were performed using SPSS version 20.0 (SPSS Inc.Chicago, IL, USA).

Clinical characteristics
All AF patients underwent RFCA, and 457 of them had paroxysmal (PAF) and 202 had persistent AF (PeAF).Baseline characteristics of AF patients and control are summarized in Table 1.Representative images of color-coded 3D voltage map of LA.LA voltage, especially venous LA voltage, is higher in a patient with rs2106261 AA genotype (A) than AG+GG (B).

Characteristics and predictors of clinical recurrence of AF after RFCA
The clinical recurrence after RFCA was observed in 26.2%.

IV. DISCUSSION
In the present study, we found that both nuclear polymorphism at chromosome 4q25 PITX2 and 16q22 ZFHX3 detected from peripheral blood were associated with AF.The 4q25 rs2200733 and ZFHX3 rs2106261 genotypes were associated with electroanatomical remodeling of LA.The presence of variant allele of ZFHX3 rs2106261 was also associated with recurrence after RFCA.

AF is a hereditable disease and related to genetic polymorphisms
Although AF has been known to be a degenerative disease with a multifactorial background, such as aging and oxidative stress, growing evidence has shown that genetic variation may also play a role in the pathogenesis of AF. 30 Fox et al. 31 reported that a parental history of AF increased the risk of AF by 1.9 times, while Lubitz et al. 32 also showed a 39 % increase in the incidence of AF in patients with a family history of AF in their 1 st degree relatives.Recently, genome-wide associate studies revealed several nuclear polymorphisms significantly associated with AF, such as KCNN3 on chromosome 1q21, PITX2 on chromosome 4q25, and ZFHX3 on chromosome 16q22. 11,33 ommon SNPs in a non-coding region on chromosome 4q25 have been shown to be associated with AF, and rs2200733 is the most reliable genetic variant associated with AF. 7,34 SNPs found in the 4q25 region are near PITX2, a gene believed to be involved in cardiac development, specifically sinus node development and susceptibility to atrial arrhythmias. 35There is emerging evidence that highly conserved non-coding regions may act as regulatory elements and contribute to phenotypic diversity. 36However, the mechanism by which genetic variation at the chromosome 4q25 locus leads to AF remains to be elucidated.In this study, we evaluated the robust SNPs associated with AF, rs2200733 and rs6843082 at chromosome 4q25, rs2106261 at ZFHX3, and rs13376333 at KCNN3.The AF risk allele of SNP rs2200733 and that of SNP rs2106261 have been reported to be much more frequent among Chinese subjects, in both affected and unaffected individuals 11,12 in concordance with our results.However, rs13376333 in KCNN3 was not associated with AF in our study population, which was not consistent with previous ones. 13The possible explanation is that intrinsic racial differences in myocardial membrane stability, myocardial conduction pathways, or genetic polymorphisms cause different susceptibility to the development of AF. 37 Another possibility is that the difference could be a result of complicated gene-gene and gene-environment interactions, which can dilute or accentuate genetic effects in complex traits such as AF. 38tential mechanism of genetic polymorphisms for the development of

AF
Clinical studies have demonstrated that myocardial sleeves in PVs generate ectopic beats that play a substantial role in initiating and maintaining AF. 39 Electrical isolation of those sleeves is a cornerstone for most AF ablation procedures. 27PITX2c-deficient mice do not develop pulmonary myocardial sleeves. 10Expression of PITX2 is remodeled during cardiac looping, becoming localized to the ventral portion of the developing ventricular chambers, while maintaining a distinct left-sided atrial expression. 40In addition, PITX2 might also trigger AF by altering the conduction properties of the cardiac conduction system.Wang et al. 41 have demonstrated that PITX2 haplo insufficiency predisposes to AF in electrically stimulated adult mice.
Notably, ANK2, a gene for familial long QT syndrome, sinus node dysfunction, and AF, is also located near rs2200733. 42The ZFHX3 gene on chromosome 16q22 encodes a transcription factor that was originally identified as a regulator of alpha-fetoprotein expression. 43ZFHX3 has been associated with Kawasaki disease, as well as malignancies such as prostate cancer.However, in human cardiac and pulmonary tissue, its expression pattern and mechanism are not fully known. 44The KCNN channels are also expressed in vascular endothelial cells, and suppression of KCNN3 expression in a mouse model has been associated with increased blood pressure. 45In a rabbit burst-pacing model designed to simulate pulmonary venous ectopy, pharmacologic blockade of KCNN channels inhibited pacing-induced shortening of pulmonary venous and atrial action potential duration. 46ortening of the atrial action potential duration reduces the refractory period of atrial myocytes and promotes re-entry, an important mechanism for the development and maintenance of AF. 47 Although the association of rs13376333 in KCNN3 with AF was not demonstrated in the present study, a future research will be warranted to further investigate the association between them and elucidate the functional pathways behind.

The genetic polymorphisms and phenotypes of AF
There have been only very few studies that have evaluated the correlation of genetic variants, AF phenotypes, and response to AF therapies.For instance, Firouzi et al. 48demonstrated increased dispersion of atrial refractoriness in patients with structurally normal hearts who carried the AA genotype of the connexin 40-promoter polymorphism.Husser et al. 49 found lower AF rates on the surface electrocardiogram in individuals carrying the KCNE1 GG genotype.In the present study, we found the association of genetic polymorphisms with phenotypes of AF patients.Increased risk of AF from 1.04 to 3.9-fold have been observed in patients with prolonged PR interval, and prolonged PR interval is consistently one of the most significant phenotypes related to AF. 14 PR interval is a measure of atrial and atrioventricular nodal conduction, and it can reflect left or right atrial hypertrophy or enlargement. 50,51  recent genome-wide association study of PR interval found links between PR interval and AF related genes such as CAV1-CAV2, NKX2-5, SOX5, SCN10A, SCN5A, and multiple other genes.52 Our AF cohort shows a significant increase in PR interval and negative P wave terminal force in Lead V1 among patients with rs2200733 risk allele.

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This study showed the common AF susceptibility alleles at 4q25 and ZFHX3 are associated with electroanatomical characteristics of left atrium and clinical outcomes of catheter ablation in Korean patients with AF.These findings imply that gene variants may have a potential role for risk stratification of ablation therapy and post-ablation management.Key words: atrial fibrillation, single nucleotide polymorphisms, catheter ablation 4q25 and ZFHX3 Single Nucleotide Polymorphisms are Associated with Electroanatomical Characteristics of Left Atrium and Clinical Outcomes of Radiofrequency Catheter Ablation in Patients with Atrial Fibrillation Jaemin Shim Department of Medicine The Graduate School, Yonsei University (Directed by Professor Hui-Nam Pak)

Figure 1 .
Figure 1.Measurement of PR interval, P wave duration, and P wave amplitude in Lead V1.Representative images of a patient with rs2200733 CC genotype (A) and TT genotype (B) are shown.

Figure 3 .
Figure 3. (A) Kaplan-Meier curves of AF free survival in patients with and without the rs2200733 variant allele after RFCA of AF. (B) Kaplan-Meier curves of AF free survival in patients with and without the rs2106261 variant allele after RFCA of AF.

Figure 4 .
Figure 4. Kaplan-Meier curves of AF free survival according to the number of variant alleles of rs2200733 and rs2106261 (Group A: no variant; n=15, Group B: 1 variant; n=158, Group C: 2 variants; n=439).

Negative P wave terminal
force in Lead V1 is indicative of LA conduction impairment or hypertrophy.Our results indicate that LA hypertrophy or enlargement modulated by 4q25 genetic variant may increase risk for AF development.In regard to the treatment of AF, catheter ablation is one of the most effective modalities for patients with drug-refractory PAF or PeAF.26Many positive outcomes have emerged from the therapy, but adverse effects resulting from scar tissue formation and inability to restore the function of the treated myocardium as well as procedure related complications remain as concerns.Therefore, a better prediction of recurrence of AF after catheter ablation is necessary.The exact mechanism of the recurrence of AF after catheter ablation remains elusive.However, multiple researches showed an impaired clinical response to RFCA of AF in patients carrying 4q25 rs2200733 variant allele.In a research by Shoemaker53 , a cohort of 378 patients who underwent catheter-based AF ablations showed 24% shorter recurrence-free time for rs2200733 risk allele compared to non-risk allele.In our study, even though the association of rs2200733 with the recurrence of AF after RFCA did not reach the statistical significance, a graded risk of AF recurrence was observed with an increasing number of risk alleles at 4q25 and ZFHX3 gene.The combination of rs2200733 and rs2106261 might serve as a risk factor for increased recurrence of AF after catheter ablation.Our findings suggest that multimarker allele combinations can be used as a clinical tool for selection of patients for AF ablation.Further research will be warranted to determine whether risk stratification and patient management can be improved by the incorporation of genetic findings.V. CONCLUSIONThis study shows the common AF susceptibility alleles, 4q25 and ZFHX3 SNPs, are associated with electroanatomical characteristics of LA and clinical outcomes of catheter ablation in Korean patients with AF.These findings imply that gene variants may have a potential role for risk stratification of ablation therapy and post-ablation management.BD, Mansour M, Marchlinski FE, McCarthy PM, Mont JL, Morady F, Nademanee K, Nakagawa H, Natale A, Nattel S, Packer DL, Pappone C, Prystowsky E, Raviele A, Reddy V, Ruskin JN, Shemin RJ, Tsao HM, Wilber D, Heart Rhythm Society Task Force on C, Surgical Ablation of Atrial F. 2012 hrs/ehra/ecas expert consensus statement on catheter and surgical ablation of atrial fibrillation: Recommendations for patient selection, procedural techniques, patient management and follow-up, definitions, endpoints, and research trial design: A report of the heart rhythm society (hrs) task force on catheter and surgical ablation of atrial fibrillation.Developed in partnership with the european heart rhythm association (ehra), a registered branch of the european society of cardiology (esc) and the european cardiac arrhythmia society (ecas); and in collaboration with the american college of cardiology (acc), american heart association (aha), the asia pacific heart rhythm society (aphrs), and the society of thoracic surgeons (sts).Endorsed by the governing bodies of the american college of cardiology foundation, the american heart association, the european cardiac arrhythmia society, the european heart rhythm association, the society of thoracic surgeons, the asia pacific heart rhythm society, and the heart rhythm society.Heart Rhythm.2012;9:632-696 e621 27.Calkins H, Brugada J, Packer DL, Cappato R, Chen SA, Crijns HJ, Damiano RJ, Jr., Davies DW, Haines DE, Haissaguerre M, Iesaka Y, Jackman W, Jais P, Kottkamp H, Kuck KH, Lindsay BD, Marchlinski FE, McCarthy PM, Mont JL, Morady F, Nademanee K, Natale A, Pappone C, Prystowsky E, Raviele A, Ruskin JN, Shemin RJ.Hrs/ehra/ecas expert consensus statement on catheter and surgical ablation of atrial fibrillation: Recommendations for personnel, policy, procedures and follow-up.A report of the heart rhythm society (hrs) task force on catheter and surgical ablation of atrial fibrillation.Heart ABSTRACT (IN KOREAN)4q25 와 ZFHX3 단일염기 다형성은 심방세동 환자에서 좌심방의 전기해부학적인 특성 및 고주파 전극도자절제술의 예후와 연관성이 있다.지도교수: 박희남 연세대학교 대학원 의학과 심재민 연구배경: 이전의 연구들에서 몇 가지의 단일염기 다형성과 심방세 동과의 연관성이 보고되었다.본 연구에서는 심방세동 환자의 표현 형과 감수성 유전인자들이 연관되어 있는지를 알아보고자 하였다.재료 및 방법: 발작성 또는 지속성 심방세동으로 전극도자절제술을 시행 받는 총 659명의 환자 (57±9 세, 76% 남성) 와 연령, 성별을 맞춘 대조군에서 심방세동과 연관된 단일염기 다형성의 유전자형을 조사하였다 (4q25 의 rs2200733 과 rs6843082, ZFHX3 유전자의 rs2106261, 그리고 KCNN3 유전자의 rs13376333).좌심방의 전기해부 학적인 특성 및 전극도자절제술 후의 재발을 포함한 심방세동 환자 의 표현형과 유전자형을 비교하였다.결과: rs2200733, rs6843082, 그리고 rs2106261 의 유전자형 분포는 환 자군과 대조군에서 유의한 차이가 있었다.(모든 p<0.001).반면, rs13376333 유전자형의 빈도는 두 군간에 차이가 없었다.rs2200732 변이형 유전자를 가진 환자는 표준형 유전자를 가진 환자보다 더 높은 E' (6.9±2.2 대. 7.7±2.4cm/s, p=0.028) 과 더 큰 좌심방 부피 (113.5±29.2대. 128.5±40.7 mL, p=0.020) 를 보였다.rs2200733 위험 유

Table 1 .
Baseline characteristics of AF patients and control

Comparison of AF patients with and without the rs2200733 variant
vs. 0.05±0.04mV, p=0.015).In addition, risk allele carriers had a tendency of higher recurrence of AF, although which was not statistically significant.

Table 3 .
Comparison of AF patients with and without the rs2200733 variant

Table 4 .
Comparison of AF patients with and without the rs2106261 variant

Table 5
4, Log Rank p=0.015).The univariate Cox regression identified PeAF, LA size, and the number of variant in rs2200733 and rs2106261 were associated with the recurrence of AF after RFCA.The multivariate analysis showed that

Table 5 .
Comparison of AF patients with and without clinical recurrence of AF

Table 6 .
Cox regression analysis of AF recurrence after catheter ablation