Association of the angiotensinogen M235T polymorphism with recurrence after catheter ablation of acquired atrial fibrillation

Journal of the Renin-Angiotensin-Aldosterone System, Dec 2015

Purpose: Previous studies showed that genetic variants of the angiotensinogen (AGT) gene conferred higher risk for acquired atrial fibrillation (AF). The present study investigated whether AGT variants correlate with the clinical outcome in patients with acquired AF after catheter ablation (CA).

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Association of the angiotensinogen M235T polymorphism with recurrence after catheter ablation of acquired atrial fibrillation

Downloaded from by guest on September Association of the angiotensinogen M235T polymorphism with recurrence after catheter ablation of acquired atrial fibrillation Qunshan Wang 2 Xiaofeng Hu 1 Shuyuan Li 0 Xiaofeng Wang 0 Jun Wang 2 Rui Zhang 2 Jian Sun 2 Pengpai Zhang 2 Xiangfei Feng 2 Yi-Gang Li 2 0 School of Life Sciences and Institutes of Biomedical Sciences, Fudan University , China 1 Department of Cardiology, Zhejiang Hospital , China 2 Department of Cardiology, Shanghai Jiaotong University School of Medicine , China Purpose: Previous studies showed that genetic variants of the angiotensinogen (AGT) gene conferred higher risk for acquired atrial fibrillation (AF). The present study investigated whether AGT variants correlate with the clinical outcome in patients with acquired AF after catheter ablation (CA). Methods: A total of 150 acquired symptomatic drug-refractory AF patients (mean age 63.7±11.0 years, 24.6% nonparoxysmal AF) with acquired AF underwent a single CA procedure in our department and were included in this retrospective analysis. Eight tagging single nucleotide polymorphisms (tSNPs) in the AGT gene were genotyped. Standard electrocardiographs (ECGs) and 24-hour Holter recordings were performed during a median follow-up period of 57.5 months to detect AF recurrence. Results: Sixty-one patients (40.7%) suffered AF recurrences after a single CA procedure during follow up. Of the eight tSNPs, the frequency of the M allele of M235T was significantly higher in the recurrence group (28%) compared to the non-recurrence group (18%) (p=0.042). The recurrence rates of patients with the TT, MT, and MM genotypes were 34.4%, 50%, and 55.6%, respectively (ptrend=0.049). After adjusting for age, sex, body mass index, hypertension, left atrial volume index (LAVI) and other covariates, M235T increased the risk of AF recurrence in additive and dominant models with odds ratios of 2.023 (95% confidence interval (CI): 1.034-3.926, p=0.033) and 2.601 (95% CI: 1.102-6.056, p=0.025), respectively. However, in multiple correction analyses, the p values of multiple comparisons were not statistically significant (pcorrect>0.05). Conclusions: The M allele of M235T might be associated with an increased risk of AF recurrence after CA. Genotyping may thus be helpful on identifying patients with higher risks of AF recurrence after CA and developing optimal follow-up strategies. These strategies may differ and should be individualized according to patients` genotype. Future studies are warranted to validate the potential effect of AGT M235T on AF recurrence post CA. Atrial fibrillation; catheter ablation; recurrence; angiotensinogen; gene; polymorphism - Atrial fibrillation (AF) is the most common rhythm disturbance in clinical practice. It is associated with high morbidity and mortality, and serves as a significant socioeconomic burden.1–3 Acquired AF, accounting for >70% of all AF cases, is usually associated with acquired structural heart disease, including valvular heart disease, coronary artery disease, congestive heart failure, and hypertension.4–6 Results from previous studies suggest that acquired AF is more likely to occur in individuals with a genetic predisposition.7–10 Percutaneous *Qunshan Wang and Xiaofeng Hu contributed equally to the study. radiofrequency catheter ablation (CA) is widely accepted as an effective treatment for AF and is currently recommended for symptomatic patients that are refractory to antiarrhythmic drug (AAD) therapy.11 However, the recurrence rates of AF post-CA are high during the longterm follow-up.12,13 Although multiple factors which were linked with AF recurrence were identified in previous studies, limited data are available regarding the association between genetic variants and AF recurrence after CA.14–16 The renin-angiotensin system (RAS) is involved in the pathogenesis of many cardiovascular diseases including acquired AF.17–20 A growing body of evidence highlights an important role of the RAS in AF pathophysiology. 8,16,21,22–24 It was shown that M235T, G-6A, and G-217A polymorphisms of the angiotensinogen (AGT) gene were significantly associated with acquired AF in a case–control study.8 The AGT A-20C polymorphism, alone and in combination with the angiotensin-converting enzyme (ACE) insertion/deletion (I/D) polymorphism, was linked with an increased risk of AF.21 Experimental studies also indicated that the RAS might be involved in the development of atrial structural25 and electrical remodeling,22 which serves as fundamental mechanisms for AF development. In addition, clinical trials showed that RAS inhibitors (ACE inhibitors or angiotensin receptor blockers (ARBs)) were beneficial for patients with AF, indicating that attenuating RAS activation could be an effective therapy strategy for AF patients.23,26,27 Current evidence suggests that common genetic risk factors are also associated with limited clinical response to AF therapies. Carriers of risk variants on chromosome 4q25 was linked with poor outcome to a variety of AF therapies.14,28,29 A recent report demonstrated that the ACE D allele was associated with adverse outcomes to both AADs30 and CA16 in AF patients. Previous work from our group and others also showed that genetic variants of the AGT gene conferred higher risk for acquired AF.8,24 Therefore, we hypothesized that polymorphisms in the AGT gene might be associated with AF recurrences after CA. Thus the aim of this study was to analyze whether AGT polymorphisms correlate with AF recurrence in AF patients post-CA. Study population A total of 174 consecutive patients who underwent a single CA procedure for symptomatic AF resistant to one or more AADs in our department were retrospectively recruited from January 2007–July 2008. Exclusion criteria were patients with idiopathic cardiomyopathy, overt renal dysfunction (serum creatinine >1.2 mg/dL), a family history of AF, and those patients who were <60 years old, without clinical or echocardiographic evidence of cardiopulmonary disease (lone AF). Echocardiographic examinations were performed in all patients immediately before the ablation procedure to assess the left atrium diameter (LAD), left atrial volume index (LAVI), left ventricular ejection fraction (LVEF), left ventricular end-systolic dimension (LVESD), and left ventricular end-diastolic dimension (LVEDD). In the present study, persistent and permanent AF were classified as non-paroxysmal AF. Written informed consent was obtained from each patient. The study protocol conforms to the ethical guidelines of the 1975 Declaration of Helsinki and was approved by the Human Ethics Committee of Xinhua Hospital. CA procedure All AADs except amiodarone were stopped at least five half-lives before ablation. Patients were anticoagulated with warfarin to maintain an international normalized ratio (INR) of 2–3 for at least four weeks prior to the ablation procedure. Trans esophageal echocardiography was mandatorily performed within three days before the procedure to exclude left atrial thrombus. Circular lesions set around the left and right pulmonary vein ostia under the guidance of a CARTO mapping system (Biosense Webster, Diamond Bar, California, USA) were considered the initial ablation step in all patients. A large circumferential area around both ipsilateral pulmonary veins was isolated with verification of conduction block. Left atrial linear ablation of the roof and mitral isthmus was generally reserved for patients with persistent or longstanding persistent AF (i.e. patients whose AF continued despite pulmonary vein isolation (PVI)). In these cases, sinus rhythm was restored by an intermediate step of one or multiple atrial tachycardias (ATs), which were then mapped conventionally and ablated. If abnormal heart rhythms were not terminated after these steps, direct current electrical cardioversion was applied to convert the normal sinus rhythm. Mapping and ablation were performed with an open irrigated tip catheter (7F Navistar, Biosense Webster). The radiofrequency current was deployed at 30~35 W with a maximum temperature of 43°C. Heparinized saline (2 units/mL) was infused through the ablation catheter at a pump rate of 2 mL/min during mapping and 17–30 mL/min during radiofrequency delivery. After circumferential line placement, voltage and pace mapping along the ablation line were used to identify and close gaps. Isolation of each pulmonary vein with a bidirectional block was verified using a multipolar circular mapping catheter and was defined as the procedural end point. After the procedure, all patients received AADs (amiodarone or propafenone) for 2–3 months to prevent early recurrence of AF. In patients without atrial arrhythmia 228915454 228915325 228912417 228911615 228910744 228910337 228908132 228906719 AA chg: amino acid change; MAF: minor allele frequency. recurrence, AADs were stopped 2–3 months after the procedure. Patients underwent regular follow-ups (two weeks to one month after the CA procedure, then every 1–3 months thereafter) at our department. During each visit, standard ECGs were performed. Twenty-four-hour Holter monitoring was performed every three months after the procedure during the first year, and every 6–12 months thereafter if the patient remained asymptomatic. Every three months, telephone inquiries were used to evaluate the severity of symptoms. All patients were asked to undergo additional ECGs and 24-hour Holter recordings when their symptoms were suggestive of tachycardia. An AF recurrence was defined as an atrial tachycardia episode lasting longer than 30 s and confirmed by an ECG three months (blanking period) after the ablation.11 Tagging single nucleotide polymorphisms (tSNPs) selection and genotyping Haplotype tSNPs of the AGT gene were selected using the publicly available HapMap CHB databank (public data release 21 a/phase II, January 2007; http://www.hapmap. org/cgi-perl/gbrowse/hapmap_B35/). To identify common haplotype tagging SNPs, eligible SNPs were entered into the Tagger program implemented in Haploview version 3.32. We defined common variants as those with minor allele frequency (MAF) of >5% and set the threshold of 0.8 for the linkage disequilibrium (LD) measure r2. Eight tSNPs of the AGT gene (rs3889728, rs2004776, rs699 (M235T), rs6687360, rs2478545, rs3789670, rs2478523, rs1926723) that captured 27 genotyped alleles with a mean r2 of 0.94 were selected. The characteristics of these genotyped tSNPs are shown in Table 1. DNA samples were prepared from blood as described by Boom et al.31 with minor modifications. All primers were designed using a web tool (Beckman Coulter Inc., Fullerton, California, USA,, synthesized, and detected by Invitrogen, Shanghai, China. Genotyping was conducted by Orchid BioSciences using the GenomeLab SNPstream genotyping platform (Beckman Coulter) and SNPstream software suite.32 This method combines solution-phase multiplex single nucleotide extension (SNE) with a solid-phase sorting of labeled SNE primers by hybridization to a chip that contains 384 4×4 arrays of multiplex oligonucleotide tags and four oligonucleotides for positive and negative controls. Separation of the 4×4 arrays during hybridization was achieved using a patented gasket. Statistical analyses Deviation of the genetic variants from Hardy–Weinberg equilibrium was tested using chi-squared tests. Continuous variables were presented as mean±standard deviation (SD) or median and interquartile range (IQR) (depending on the normality of distribution). Variables were compared between the recurrence group and non-recurrence group using unpaired student’s t-tests for normally-distributed continuous variables or Wilcoxon rank sum tests for skewed variables. Categorical variables are represented by frequencies and percentages, and were compared using chi-squared tests. Differences in continuous variables across the three genotype groups were tested using one-way analyses of variance (ANOVAs). Cochran– Armitage trend tests were used to estimate p for an additive effects trend of SNP. Logistic regression analyses were used to compute odds ratios (ORs) and 95% confidence intervals (CIs). Additive, dominant, and recessive genetic models of the minor allele were assumed in association analyses, and analyses were performed with or without adjustment for confounding risk factors. For M235T, the M allele is the minor allele in our study population. Thus, we developed the definite dominant model MM+MT vs TT, recessive model MM vs MT+TT, and additive model M vs T. Furthermore, the Bonferroni correction was used to define the effective number of independent marker loci. All analyses were performed using SAS Version 9.1 (SAS Institute, Cary, North Carolina, USA). All statistical tests were based on a two-tailed probability and p<0.05 was considered statistically significant. AADs: antiarrhythmic drugs; ACEi: ACE inhibitor; ARB: angiotensin receptor blocker; BB: beta-blocker; BMI: body mass index; CCB: calcium channel blocker; LAD: left atrial diameter; LVEDD: left ventricular end-diastolic dimension; LVEF: left ventricle ejection fraction; LVESD: left ventricular end-systolic dimension. We excluded 24 patients who did not receive regular follow-up after the ablation. Finally, 150 patients (62 women, 37 non-paroxysmal AF, mean age of 63.7±11.0 years) were included in this study. The mean AF duration was 39.4±33.3 months, and the mean LAD was 39.0±6.0 mm, LAVI was 23.2±7.4 mL/m2. Sixty-one patients (40.7%) suffered from recurrences after CA during a median follow-up period of 57.5 months (IQR: 50–61). As shown in Table 2, compared to the non-recurrence group, patients in the AF recurrence group had higher body mass indices (BMIs) (25.0±2.9 kg/ m2 vs 23.8±3.0 kg/m2, p=0.018), more non-paroxysmal AF (36.1% vs 16.9%, p=0.007), higher incidence of congestive heart failure (29.5% vs 12.4%, p=0.009), larger LAD (41.5±5.6 mm vs 37.3±5.8 mm, p<0.001), lower LVEF (65.3±8.9% vs. 69.3±7.4%, p=0.004), larger LVESD (31.8±5.7 mm vs 29.3±5.2 mm, p=0.007) and LVEDD (50.7±5.2 mm vs 48.5±4.6 mm, p=0.008). Age, sex distribution, AF history, incidence of hypertension, diabetes mellitus, and use of drugs (AADs, calcium channel blocker (CCB), beta-blocker (BB), and ACE inhibitors/ARB) did not differ between the AF recurrence and non-recurrence groups. The genotyping success rates of the eight tSNPs ranged from 99.3–100%. Genotype and allele distributions of the eight tSNPs among the groups are shown in Table 3. There were no differences in genotype and allele distribution of the tSNPs between the follow-up group (n=150) and nonfollow-up group (n=24) (data not shown). The genotypes at all loci were consistent with Hardy–Weinberg equilibrium in both the recurrence and non-recurrence groups, minimizing the possibility of selection bias. The overall pairwise LDs constructed by the eight AGT tSNPs are weak (data not shown). Moreover, we observed no haplotype that significantly increased the risk of AF recurrence. There were no significant differences in genotype distribution for M235T between the recurrence and nonrecurrence group (p=0.131); however, the frequency of the minor allele M was significantly higher in the recurrence group compared to the non-recurrence group (28% vs 18%, p=0.042). AF recurrence rates for the AGT gene TT genotype, MT genotype, and MM genotype were 34.4%, 50.0%, and 55.6%, respectively (Figure 1). The Cochran– Armitage trend test (p=0.049) suggested a nominal trend in recurrence rates among carriers of more M alleles in our cohort. We observed no difference in genotype and allele distribution of the other seven tSNPs between two groups. Additionally, we examined the association between the AGT M235T polymorphism and baseline parameters to determine possible clinical mediators of the M235T polymorphism. Except sex distribution, no significant differences were observed between this polymorphism and the baseline parameters (Table 4). Of the eight tSNPs, only M235T was associated with an increased risk of AF recurrence using a non-adjusted dominant model with an OR of 1.974 (95% CI: 1.007–3.869, Genotype and allele )50 % ( s40 e t a r e30 c n e rr20 u c e r10 tSNP: tagging single nucleotide polymorphism. MM p=0.048). After adjusting for age, sex, and BMI, M235T increased the risk of AF recurrence in additive and dominant models with ORs of 1.799 (95% CI: 1.015–3.189, p=0.044) and 2.097 (95% CI: 1.018–4.317, p=0.044), respectively. When additionally adjusted for LAVI, AF type, hypertension, congestive heart failure, CCB use, LVEF, LVESD, and LVEDD, the significance remained in the additive and dominant models with ORs of 2.023 (95% CI: 1.034–3.926, p=0.033) and 2.601 (95% CI: 1.102– 6.056, p=0.025), respectively (Table 5)L. However, the association initially detected was not significant after Bonferroni correction (Table 5). Primary finding In this study, we investigated the association of AGT polymorphisms with AF recurrence of acquired AF after CA. We found that M allele of M235T might be linked with an TT genotype (n=93) MT genotype (n=48) MM genotype (n=9) OR (95% CI) 1.711(0.995–2.945) 1.974(1.007–3.869) 1.799(1.015–3.189) 2.097(1.018–4.317) 2.023(1.034–3.926) 2.601(1.102–6.056) Non-adjusted model Adjusted model 1 Adjusted model 2 AADs: antiarrhythmic drugs; ACEi: ACE inhibitor; ARB: angiotensin receptor blocker; BB: beta-blocker; BMI: body mass index; CCB: calcium channel blocker; LAD: left atrial diameter; LAVI: left atrial volume index; LVEDD: left ventricular end-diastolic dimension; LVEF: left ventricle ejection fraction; LVESD: left ventricular end-systolic dimension. BMI: body mass index; CCB: calcium channel blocker; CI: confidence interval; LAVI: left atrial volume index; LVEDD: left ventricular end-diastolic dimension; LVEF: left ventricle ejection fraction; LVESD: left ventricular end-systolic dimension; OR: odds ratio; pcorrect: p value after Bonferroni correction test. Adjusted model 1: adjusted by age, sex, BMI. Adjusted model 2: additionally adjusted by AF type, hypertension, CCB use, LAVI, congestive heart failure, LVEF, LVESD, LVEDD. increased risk of AF recurrence post-CA during long-term follow-up. To the best of our knowledge, this is the first report showing that the AGT M235T polymorphism might be associated with AF recurrence after CA. Genetic variants and response to AF therapies Over the past years, data have emerged to support a genetic contribution to AF. Association studies have reported that common SNPs in genes encoding cardiac ion channels,7,33 RAS proteins,8 or connexin409 may predispose patients to AF development. More recently, the genome-wide association study (GWAS) approach identified several genomic regions which were associated with AF.34–36 Despite numerous studies on AF genetics, limited data are available to assess the genetic impact on responses to AF therapies. Darbar et al. first assessed the relationship between an AF-associated variant and the response to antiarrhythmic medication.29 They found that the ACE I/D polymorphism modulated the response to AADs, and that the ID/ DD genotype was a strong predictor for drug failure. More recently, Ueberham et al. reported that patients with the ACE DD genotype had a 2.251-fold increased risk of AF recurrence post-CA compared to patients with the II+ID genotype.16 Husser et al. demonstrated that rs2200733 and rs10033464 on chromosome 4q25 were independently associated with an increased risk of recurrence after CA.14 In addition, rs10033464 was reported to be linked with failure to AADs therapy whereas rs2200733 was an independent genetic predictor of AF recurrence after successful restoration of sinus rhythm after direct current cardioversion.27,28 These findings indicate that genetic risk factors of AF were also associated with adverse responses to AF therapies. Tsai et al. demonstrated that the presence of the 235M allele conferred a 2.5-fold risk of AF.8 In our previous work, we observed that compared to the MT+TT genotype, the MM genotype increased the risk of AF by 90%.24 M235T had a MAF of 22% among our cohort, which is similar to that found in Hap Map (dbSNP; http://www. among Chinese Han patients (MAF=19%). We report here that the minor M allele of M235T conferred an increased risk of AF recurrence after CA. This study supplies complementary evidence for the important role of RAS activation in the pathomechanism of AF recurrence post CA, which was also evidenced by the Ueberham et al. study,16 in which a genetic variant of ACE was associated with AF recurrence post-CA. Unlike previous studies, our cohort did not include lone AF, which represents only 5–30% of AF cases.4–6 The main reasons that we exclude patients with lone AF are as follows: 1. We want to investigate genetic predisposition might confer an increased risk of very late AF recurrence after catheter ablation procedure in patient with acquired AF. Our prior study suggested that acquired AF is more likely to occur in individuals with a genetic predisposition.24 2. Genotype might also be responsible for lone AF, however, lone AF is largely a monogenetic disease, usually caused by functional mutations in ion channel genes and somatic mutations in the atrial tissue.37–39 3. Five patients with lone AF underwent CA in our center from study period. The sample size would not be enlarged too much by including these five patients in our cohort. Our study included acquired patients. Acquired AF is estimated to represent approximately 70–95% of all AF cases and is commonly encountered in clinical practice. In addition, our current study has the longest follow-up time to date for investigating the association between genetic factors and clinical outcomes in AF patients post-CA. M235T genotyping and AF recurrence post-CA The M235T polymorphism of the AGT gene, located at 1q 41–42 of exon 2, is associated with plasma and tissue AGT.40,41 M235T is also associated with greater stimulation of AGT secretion in plasma after ethinylestradiol administration.42 A recent study reported that the M235T polymorphism might have an additive effect with hypertension on arterial stiffness by potentially promoting Ang II-mediated mechanisms independent of hypertension.43 However, M235T has been excluded as a functional variant by biochemical analyses.44 It is possible that M235T is linked to other functional loci in the AGT gene. Haplotype analyses have shown that M235T and G-6A were in strong linkage disequilibrium.45 Tsai et al. demonstrated that the association between the M235 allele with AF may be mediated through its tight linkage with the G-6 allele in the promoter region of AGT.8 They found that the frequencies of the M235 allele in exon 2 and the G-6 allele in the promoter region of AGT were significantly higher in AF patients compared to controls. G-6A was reported to influence AGT transcriptional activity and subsequently, plasma AGT concentrations.46 An association was also observed between G-6A and non-familial sick sinus syndrome, perhaps by modulating AGT gene expression.47 M235T is also in linkage disequilibrium with the AGT A-20C polymorphism.48 A-20C, located in the proximal 5’-flanking region, is associated with differences in plasma AGT concentration,49 and is also associated with in vitro changes in transcription levels induced by AGT promoters.50 G-6A and A-20C are located in two distinct regulatory elements of the core promoter in the AGT gene. Subsequently, these two variants might affect gene transcription and/or the stability of the resulting mRNA, and in turn play an important role in RAS activation. Importantly, the impact of the T allele of M235T on the etiopathogenesis of cardiovascular diseases has been studied in previous reports.18–20,40 We propose that the difference in the results might be based on differences in the genetic composition of the patient populations. We did not find any association between the M235T genotype and baseline parameters. The association of M235T with AF recurrence persisted after adjusting for LAVI, hypertension, and congestive heart failure, indicating that the effect might not be mediated by known risk factors for AF recurrence, but rather by genotype. This suggests that carriers of particular genotypes of AGT may result in different pathophysiological effects that affecting AF recurrence. It is plausible that a specific genotype may cause higher AGT gene transcription activity, which in turn might contribute to higher angiotensin II (Ang II) concentrations in plasma and atrium tissue. Ang II triggers the mitogen-activated protein kinase (MAPK) pathway, which acts as an important downstream mediator of Ang II effects on tissue structure and alters gap-junctional coupling, which may induce AF propensity.51 Ang II could also up-regulate transforming growth factor-β1 (TGF-β1), which causes atrial fibrosis, conduction heterogeneity, and increases the propensity to develop AF.52 In contrast, higher tissue Ang II concentrations may electrically contribute to the recurrence of AF. Ang II could enhance Ca2+/calmodulin-dependent protein kinase (CaMKII) phosphorylation of ryanodine receptor type2 (RyR2), which results in spontaneous Ca2+ release, thereby contributing to AF-related ectopic activity.53 These effects collectively might cause atrial structural and electrical remodeling, thus contributing to AF recurrence. Study limitations This study has several limitations that should be acknowledged. First, the follow-up to assess AF post-ablation was not robust and thus we might missed asymptomatic AF recurrences. All patients were followed with ECGs, 24-hour Holter monitoring, and were questioned about symptoms; however, it is recognized that AF recurrences may have occurred without symptoms, particularly if episodes were of short duration. Therefore, it is possible that our study underestimated the rates of AF recurrence. Second, our sample size is too small to draw conclusions regarding the genetic effects on AF recurrence. Because subgroup analyses (paroxysmal and non-paroxysmal) included small numbers of patients, the results were not significant for either subgroup. Thus, we did not highlight the differences between the paroxysmal and non-paroxysmal subgroups. Third, the tSNPs selected for this study might not sufficiently capture all genetic variations. Some common AGT variants that are possibly associated with AF were not analyzed in our study. It is possible that the M235T variant is linked to other loci in the AGT gene (or in other genes that are not yet identified) and exerts its effects on the AF recurrence post-CA. Finally, our initial analyses revealed a significant association between M235T and AF recurrences; however, the association was not retained after Bonferroni correction (the corrected p values were multiplied by the eight SNPs studied). Further investigations with a larger population and more associated variants are necessary in order to confirm present findings. AGT M235T polymorphism might possibly be associated with AF recurrence post-CA. Genotyping is helpful for identifying patients with high risk of AF recurrence after CA and developing individualized follow-up strategy according to genotype results. Since the follow-up strategy is not robust enough and the sample size of this study is relatively small, future well-designed large-scale studies are warranted to validate the potential effect of AGT M235T on AF recurrence after CA. Acknowledgements All authors take responsibility for all aspects of the reliability and freedom from bias of the data presented and their discussed interpretation. Conflict of interest This work was supported in part by the National Science Foundation of China (81270259). 1. Wang TJ , Larson MG , Levy D , et al. Temporal relations of atrial fibrillation and congestive heart failure and their joint influence on mortality: the Framingham Heart Study . Circulation 2003 ; 107 : 2920 - 2925 . 2. Ringborg A , Nieuwlaat R , Lindgren P , et al. Costs of atrial fibrillation in five European countries: results from the Euro Heart Survey on atrial fibrillation . Europace 2008 ; 10 : 403 - 411 . 3. Kim MH , Johnston SS , Chu BC , et al. 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Qunshan Wang, Xiaofeng Hu, Shuyuan Li, Xiaofeng Wang, Jun Wang, Rui Zhang, Jian Sun, Pengpai Zhang, Xiangfei Feng, Yi-Gang Li. Association of the angiotensinogen M235T polymorphism with recurrence after catheter ablation of acquired atrial fibrillation, Journal of the Renin-Angiotensin-Aldosterone System, 2015, 888-897, DOI: 10.1177/1470320315594315