Association of the angiotensinogen M235T polymorphism with recurrence after catheter ablation of acquired atrial fibrillation
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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
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
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.
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.
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
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
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, http://www.autoprimer.com),
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
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
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
tSNP: tagging single nucleotide polymorphism.
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).
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)
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
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.
ncbi.nlm.nih.gov/SNP/) 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
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
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
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.
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
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.
All authors take responsibility for all aspects of the reliability and
freedom from bias of the data presented and their discussed
Conflict of interest
This work was supported in part by the National Science
Foundation of China (81270259).
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