Nonfamilial Atrial Fibrillation Research Articles

Coexistent HCN4 and GATA5 Rare Variants and Atrial Fibrillation in a Large Spanish Family

BackgroundFamilial association of atrial fibrillation (AF) can involve single gene variants related to known arrhythmogenic mechanisms; however, genome-wide association studies often disclose complex genetic variants in familial and nonfamilial AF, making it difficult to relate to known pathogenetic mechanisms. MethodsThe finding of 4 siblings with AF led to studying 47 members of a family. Long-term Holter monitoring (average 298 hours) ruled out silent AF. Whole-exome sequencing was performed, and variants shared by the index cases were filtered and prioritised according to current recommendations. HCN4 currents (IHCN4) were recorded in Chinese hamster ovary cells expressing human p.P1163H or native HCN4 channels with the use of the patch-clamp technique, and topologically associating domain analyses of GATA5 variant were performed. ResultsThe clinical study diagnosed 2 more AF cases. Five family members carried the heterozygous p.P1163H HCN4 variant, 14 carried the intronic 20,61040536,G,A GATA5 rare variant, and 9 carried both variants (HCN4+GATA5). Five of the 6 AF cases (onset age ranging from 33 to 70 years) carried both variants and 1 carried the GATA5 variant alone. Multivariate analysis showed that the presence of HCN4+GATA5 variants significantly increased AF risk (odds ratio 32.7, 95% confidence interval 1.8-591.4) independently from age, hypertension, and overweight. Functional testing showed that IHCN4 generated by heterozygous p.P1163H were normal. Topologically associating domain analysis suggested that GATA5 could affect the expression of many genes, including those encoding microRNA-1. ConclusionThe coincidence of 2 rare gene variants was independently associated with AF, but functional studies do not allow the postulation of the arrhythmogenic mechanisms involved.

Copy number variation of gasdermin D gene is associated with atrial fibrillation-related thromboembolic stroke.

Atrial fibrillation (AF) is one of the major causes of ischaemic stroke. In addition to clinical risk evaluated by the CHA2DS2-VASC score, the impact of genetic factors on the risk of AF-related thromboembolic stroke has been largely unknown. We found several copy number variations (CNVs) in novel genes that were associated with thromboembolic stroke risk in our AF patients by genome-wide approach. Among them, the gasdermin D (GSDMD) gene was related to inflammation. We aimed to test whether GSDMD deletion was associated with AF-related stroke. A total of 400 patients with documented non-familial AF were selected, of which 100 patients were diagnosed with ischaemic stroke. The baseline characteristics of age, sex, valvular heart disease, coronary artery disease, heart failure, and CHA2DS2-VASc scores were not statistically different between cases and controls. We found that individuals who carried GSDMD homozygous deletion genotype had a higher risk for ischaemic stroke (odds ratio 2.195; 95% confidence interval, 1.24-3.90; P = 0.007), even adjusted by CHA2DS2-VASc scores. We also validated the association of GSDMD with AF stroke in a large Caucasian population (UK Biobank). We found a link between the homozygous deletion of the GSDMD gene and an increased risk of stroke in patients with AF. This may implicate the use of therapy targeting GSDMD in the prevention of ischaemic stroke for AF patients.

Clinical profile and outcome of familial versus non-familial atrial fibrillation

BackgroundThere is paucity of information on clinical characteristics and outcome of patients with familial atrial fibrillation (AF). The present study was aimed to compare clinical profile and outcome of familial AF with those of non-familial AF. MethodsBetween February 2017 and February 2018, we enrolled 738 participants (60% men, median age, 51 years in familial AF vs. 61 years in non-familial AF) from Iranian Registry of AF. All patients were followed for 12 months. Clinical characteristics and main outcome measures for AF patients were obtained from patient's medical records. ResultsA positive history of AF in first-degree relative was reported in 15.3% of our AF population. Familial AF group were significantly younger than non-familial group (p = 0.001). Concomitant sinus node dysfunction and cardiomyopathies were more common in familial AF group (p = 0.02, p = 0.004, respectively). Patients with familial AF were also likely to receive cardiac devices and AF catheter ablation (all p < 0.05). However, all-cause mortality and thromboembolic events were similar (all p > 0.05). ConclusionsFamilial AF patients were more likely to have associated rhythm disorders and dilated cardiomyopathies. Cardiac interventions were also more common in familial patients. However, they did not differ significantly in their long-term outcome.

Genetic modulation of atrial fibrillation risk in a Hispanic/Latino cohort.

Atrial fibrillation (AF) is the most prevalent cardiac rhythm disorder worldwide but the underlying genetic and molecular mechanisms and the response to therapies is not fully understood. Despite a greater burden of AF risk factors in Hispanics/Latinos the prevalence of AF remains low. Over the last decade, genome-wide association studies have identified numerous AF susceptibility loci in mostly whites of European descent. The goal of this study was to determine if the top 9 single nucleotide polymorphisms (SNPs) associated with AF in patients of European descent also increase susceptibility to AF in Hispanics/Latinos. AF cases were prospectively enrolled in the University of Illinois at Chicago (UIC) AF Registry and control subjects were identified from the UIC Cohort of Patients, Family and Friends. AF cases and controls were genotyped for 9 AF risk SNPs at chromosome 1q21: rs13376333, rs6666258; chr1q24: rs3903239; chr4q25: rs2200733; rs10033464; chr10q22: rs10824026; chr14q23: rs1152591; chr16q22: rs2106261 and rs7193343. The study sample consisted of 713 Hispanic/Latino subjects including 103 AF cases and 610 controls. Among the 8 AF risk SNPs genotyped, only rs10033464 SNP at chromosome (chr) 4q25 (near PITX2) was significantly associated with development of AF after multiple risk factor adjustment and multiple testing (adj. odds ratio [OR] 2.27, 95% confidence interval [CI] 1.31–3.94; P = 3.3 x 10−3). Furthermore, the association remained significant when the analysis was restricted to Hispanics of Mexican descent (adj. OR 2.32, 95% CI 1.35–3.99; P = 0.002. We confirm for the first time the association between a chromosome 4q25 SNP and increased susceptibility to AF in Hispanics/Latinos. While the underlying molecular mechanisms by which the chr4q25 SNP modulates AF risk remains unclear, this study supports a genetic basis for non-familial AF in patients of Hispanic descent.

Familial clustering of atrial fibrillation and comparative longitudinal outcomes of familial and non-familial atrial fibrillation.

Several studies have suggested that family history of atrial fibrillation (AF) is an important risk factor for AF, with several specific genetic regions now implicated through Genome Wide Association Studies. In addition, familial AF is associated with earlier age of onset and affects patients with fewer comorbid conditions than their non-familial counterparts. While those with familial AF have worse symptoms, all-cause mortality and risk of thromboembolic complications are similar among familial and non-familial AF patients.

Common variants predict recurrence after nonfamilial atrial fibrillation ablation in Chinese Han population

BackgroundGenome-wide association studies (GWAS) have identified several loci associated with atrial fibrillation (AF) and have been reportedly associated with response to catheter ablation for AF in patients of European ancestry; however, associations between susceptibility loci and clinical recurrence of AF after catheter ablation have not been examined in Chinese Han populations. To the personalization of catheter ablation for AF, we examined whether these single nucleotide polymorphisms (SNPs) can predict clinical outcomes after catheter ablation for AF in Chinese Han population. Methods and resultsThe association between 8 SNPs and AF was studied in 1418 AF patients and 1424 controls by the unconditional logistic regression analysis. The survival analyses were used to compare AT/AF recurrence differences among 438 AF patients, which were classified by the genotype of rs2200733. rs2200733 and rs6590357 were significantly associated with AF in Chinese Han population. In addition, rs2200733 was associated with clinical recurrence of AF after catheter ablation. In Kaplan–Meier survival analysis, the recurrence-free rates for AF with TT and with TC+CC were 35.5% and 61.9%, respectively (P=0.0009). In multivariate Cox regression analysis, rs2200733 was strong independent risk factor for recurrence. Conclusionrs2200733 risk allele at the 4q25 predicted impaired clinical response to catheter ablation for AF in Chinese Han population. Our findings suggested rs2200733 polymorphism may be used as a clinical tool for selection of patients for AF catheter ablation.

Outcomes Associated With Familial Versus Nonfamilial Atrial Fibrillation: A Matched Nationwide Cohort Study.

BackgroundWe examined all‐cause mortality and long‐term thromboembolic risk (ischemic stroke, transient ischemic attack, systemic thromboembolism) in patients with and without familial atrial fibrillation (AF).Methods and ResultsUsing Danish nationwide registry data, we identified all patients diagnosed with AF (1995–2012) and divided them into those with familial AF (having a first‐degree family member with a prior AF admission) and those with nonfamilial AF. We paired those with and without familial AF according to age, year of AF diagnosis, and sex in a 1:1 match. Using cumulative incidence and multivariable Cox models, we examined the risk of long‐term outcomes. We identified 8658 AF patients (4329 matched pairs) with and without familial AF. The median age was 50 years (interquartile range 43–54 years), and 21.4% were women. Compared with nonfamilial AF patients, those with familial AF had slightly less comorbid illness but similar overall CHA 2 DS 2‐VASc score (P=0.155). Median follow‐up was 3.4 years (interquartile range 1.5–6.5 years). Patients with familial AF had risk of death and thromboembolism similar to those with nonfamilial AF (adjusted hazard ratio 0.91 [95% CI 0.79–1.04] for death and 0.90 [95% CI 0.71–1.14] for thromboembolism).ConclusionsAlthough family history of AF is associated with increased likelihood for development of AF, once AF developed, long‐term risks of death and thromboembolic complications were similar in familial and nonfamilial AF patients.

Polymorphisms of renin-angiotensin-aldosterone system gene in chinese han patients with nonfamilial atrial fibrillation.

BackgroundAtrial fibrillation(AF) is the most common arrhythmia in the adult population. The activated renin-angiotensin-aldosterone system (RAS) has been reported to play an important role in the pathogenesis of atrial fibrillation. The aim of this study was to investigate the association between nonfamilial AF and polymorphisms in RAS gene.MethodsA total of 931 patients with nonfamilial AF, 663 non-AF heart disease patients and 727 healthy subjects were selected. 10 tagSNPs (tSNPs) (ACE gene rs8066114, AGT gene rs7539020, rs3789678, rs2478544, rs11568023, rs2478523, rs4762, rs699 and CYP11B2 rs3802230, rs3097) were chosen and genotyped in our study. Single-locus analysis and haplotype analysis were used in this study.ResultsIn single-locus analysis, we found rs11568023 and rs3789678 in AGT gene were associated with nonfamilial AF in Chinese Han population. AF risk was associated with rs3789678 between the AF group and control groups. Under dominant model, the significant AF risk was observed in rs3789678 between the AF group and non AF heart control group; And the protective effect was found in rs11568023, compared with the non-AF heart disease control group. In multilocus haplotype analysis, the association between frequencies of the haplotypes and AF risk was showed in AGT gene (rs7539020-rs3789678), compared ‘TT’ haplotype with the common ‘TC’ haplotype, adjusted for age, gender, LVEF, LVEDD, LAD and frequency of hypertension and diabetes. The diplotype with ‘TC’, carrying rs3789678-C-allele, was associated with reduced risk of AF between the AF group and the healthy control group. The diplotype with ‘TT’ haplotype in the same block, carrying rs3789678-T-allele, was associated with increased risk of AF.ConclusionsVia a large-scale case-control study, we found that rs3789678 site was potential susceptible locus of AF whereas rs11568023 was protective factor.

MicroRNA as a novel player in atrial fibrillation.

Atrial fibrillation (AF), with an extremely highly age-dependent prevalence, is a most frequent type of sustained arrhythmia in the clinic both in developing and developed countries (Dobrev and Nattel, 2011). AF patients have a lot of symptoms including palpitations, dizziness, breathlessness, and chest pain. AF will lead to an increased risk of stroke and aggravate congestive heart failure (Shi et al., 2013). Compared with familial AF, the non-familial AF occupies the majority of AF. In China, at least 10 million people are affected by it. Therefore, AF is associated with a remarkable morbidity and mortality, leading to a large socio-economic burden. Unfortunately, the underling mechanisms of AF are still exclusive (Wang et al., 2011; Liu et al., 2012a,b). Several hypotheses have been proposed for AF. Focal activity, single-circuit reentry, and multiple-circuit reentry have been generally considered as three classic models for AF. In addition, different substrates which facilitate the formation of AF have also been revealed including electrical remodeling, structure remodeling, and intracellular Ca2+ handling remodeling. Moreover, various genetic mutations such as chromosomal loci (10q22-q24 and 6q14-16) mutations, ion channel (Ka+ and Na+) mutations, connexin (GJA5 and GJA1) mutations in the familial AF and more recently several common variants on 4q25, 16q22, and 1q21 in the non-familial AF have been identified (Xiao et al., 2011a,b; Liu et al., 2012a,b). Despite this, the definitive elucidation of AF still remains relatively limited and unclear (Zhang et al., 2011). MicroRNAs (miRNAs, miRs) are a novel class of endogenous non-coding RNAs of around 22 nucleotides in length, which are widely accepted to possess a key role in the gene expression regulatory network at the post-transcriptional level (Wang et al., 2011; Fu et al., 2013). So far, at least one thousand miRNAs have been identified and they have been reported to participate in many fundamental biological processes including cell proliferation, growth, differentiation, apoptosis, and tissue remodeling. Dysregulated miRNAs have been shown to be related to the genesis of many cardiovascular diseases, including arrhythmia, hypertrophy, and heart failure. Moreover, miRNAs have also been identified to be necessary for the differentiation of human-derived cardiomyocyte progenitor cells (Xiao et al., 2012). Furthermore, circulating miRNAs can also be served as promising biomarkers for acute myocardial infarction and heart failure etc. (Dimmeler and Zeiher, 2010; Li et al., 2013). Thus, it is not surprising that miRNAs gain a critical position in the physiological and pathological processes of the cardiovascular system (Wang et al., 2011; Xiao et al., 2011a,b; Liu et al., 2012a,b). Several studies have presented interesting connections between miRNAs and AF. Of note, a group of miRNAs has been identified to regulate target genes encoding cardiac ion channels/transporters/Ca2+-handling proteins, which may participate in the genesis of AF (Wang et al., 2011; Dobrev, 2012). Interestingly, many available data have demonstratedthatmiR-1, miR-21, miR-26, miR-29, miR-30, miR-133, miR-208, miR-328, miR-499, and miR-590 might take part in the genesis of AF (Dawson et al., 2013; Shi et al., 2013). Most of these miRNAs promote the electrical or structural remodeling in the atrium. MiR-26 family contributes to AF via repressing the expression of KCNJ2/Kir2.1/IK1 while miRNA-1 via regulating IK1 expression and Ca2+ handling proteins. In addition, miR-499 regulates KCNN3/SK3 while miR-328 targets CACNA1C and CACNB, contributing to adverse electrical remodeling (Lu et al., 2010). Moreover, miR-133 and miR-590 have been found to target transforming growth factor-β 1 (TGF-β 1) and TGF-β receptor type II (TGF-β RII), leading to structure remodeling in AF (Shan et al., 2009). Interestingly, circulating levels of miR-328 and miR-150 have been reported to be down-regulated in AF patients though the functional role is still unclear (Liu et al., 2012a,b; McManus et al., 2014). With more systematic and insightful studies exploring the miRNAs basis for AF, novel therapeutics will be developed and ultimately lead to advanced treatment (Zhao et al., 2013).

Abstract 18309: Familial Atrial Fibrillation - Common Atrial Fibrillation Susceptibility Alleles and Response to Catheter Ablation

Background: Familial atrial fibrillation (AF) is common but AF-causing rare genetic variants are infrequently found supporting the multigenetic nature of this arrhythmia. On the other hand, genome-wide association studies have identified common AF susceptibility alleles, but their possible relation with familial AF is unknown. The aim of this study was to compare familial and sporadic AF with respect to common alleles on chromosomes 1q21 (rs13376333), 4q25 (rs10033464 and rs2200733) and 16q22 (rs7193343) and rhythm outcome after radiofrequency catheter ablation (CA). Methods: A total of 393 patients (mean age 59 +/- 10 years, 68 % males, 38 % persistent AF), who underwent CA were studied. The family history of AF was considered positive if at least one of the first-degree family members had AF based on patient's interviews, chart and ECG reviews. Genotypes were determined using real-time polymerase chain reaction and fluorescence resonance energy transfer. AF recurrence &gt; 30 sec was detected using serial 7-day Holter ECG recordings after a blanking period between 3 and 12 months after radiofrequency CA. Results: Familial AF was found in 14.2 % and was associated with the absence of structural heart disease (OR 1.888, 95 % CI 1.017 - 3.505, p=0.042) and age (OR 0.964, 95 % CI 0.938 - 0.991, p=0.009). In familial AF, minor allele frequency of AF risk alleles on chromosomes 1q21 (40.0 % vs. 32.8 %) and 4q25 (rs10033464: 26.4 % vs. 11.0 % and rs2200733: 39.4 % vs. 27.2 %) tended to be higher compared with non-familial AF. Using a dominant genetic model, rs2200733 on chromosome 4q25 showed the strongest association with familial AF (OR 2.222, 95 % CI 1.015 - 4.865, p=0.042). AF recurrence was observed in 27.6 % of non-familial AF and in 30.9 % of familial AF patients (p=0.621). Conclusion: This study, for the first time, shows a dominant modulating function of a common AF susceptibility allele on chromosome 4q25 also in familial AF. Ablation outcome is comparable in familial and non-familial AF highlighting the role of the pulmonary veins in AF development.

The Genetics of Atrial Fibrillation: From the Bench to the Bedside

Atrial fibrillation (AF) has become a growing global epidemic and a financial burden for society. The past 10 years have seen significant advances in our understanding of the genetic aspects of AF: At least 2 chromosomal loci and 17 causal genes have been identified in familial AF, and an additional 7 common variants and single-nucleotide polymorphisms in 11 different genes have been indicated in nonfamilial AF. However, the current management strategies for AF are suboptimal. The integration of genetic information into clinical practice may aid the early identification of AF patients who are at risk as well as the characterization of molecular pathways that culminate in AF, with the eventual result of better treatment. Never before has such an opportunity arisen to advance our understanding of the biology of AF through the translation of genetics findings from the bench to the bedside.

Relationship between −344T/C polymorphism in the aldosterone synthase gene and atrial fibrillation in patients with essential hypertension

Aldosterone plays an important role in the pathogenesis of non-familial atrial fibrillation (AF). We tested the hypothesis that the -344T/C polymorphism in the aldosterone synthase gene may be associated with non-familial AF in Chinese patients with hypertension. We performed a 1:1 paired case-control study in 310 cases of hypertension with AF and same number matched controls. The -344T/C polymorphism was determined with polymerase chain reaction-restriction fragment length polymorphism. The distribution of the CYP11B2 genotypes (TT, TC and CC) was 41.9%, 50.6%, and 7.4% in AF patients, which was not different from controls (48.4%, 44.5%, and 7.1%, χ(2) = 2.675, p = 0.263). The difference between the C allele (32.3% vs. 29.4%) was also not significant between two groups (χ(2) = 1.661, p = 0.197). Logistic regression analysis showed that LAD and LVEDD (both p < 0.001), rather than the C allele of the CYP11B2 gene (p= 0.107) were significant predictors for AF. The LAD of C allele carriers is significantly larger than that of non-C allele carriers (p = 0.009). Our results indicate that the -344T/C polymorphism in the aldostrone synthase gene is not associated with AF but it might be associated with atrial remodelling in hypertensives.

Common variants for atrial fibrillation: results from genome-wide association studies

Atrial fibrillation (AF) affects more than 5 million people worldwide; however, none of the anti-arrhythmic drugs available now are entirely optimal in terms of efficacy and safety. A better understanding of the molecular mechanism of AF will facilitate the process of finding new strategies to prevent AF. As the non-familial AF is the major form of AF, identifying common variants for AF in these populations by genome-wide association studies will definitely accelerate this process. This review summarizes the recently identified common AF variants on 4q25, 16q22, and 1q21 and discusses their implications for the clinic.

Genetic Polymorphisms Conferring Risk of Non-Valvular Atrial Fibrillation in Korean Population: Chromosome 4q25, PITX2, and 16q22 ZFHX3

Background: GWAS revealed several genomes related with atrial fibrillation (AF), such as genetic variants on chromosome 4q22, PITX2, or chromosome 16q22 (ZFHX3). We evaluated those genetic polymorphisms in Korean patients with non-familial non-valvular AF. Methods and Results: We evaluated and compared the allelic frequencies of genetic polymorphisms of chromosome 4q22, PITX2, or 16q22 (ZFHX3) in 454 patients with non-valvular AF (296 paroxysmal AF [PAF], 158 persistent AF [PeAF]) and 422 sex-matched healthy controls by direct DNA sequencing and SNaPshotTM assay. Results: 1. The 4q25 rs2200733 (OR 0.368 (0.246–0.549), p<0.0001), the PITX2 rs17042171 (OR 0.368 (0.246–0.551), p<0.0001), the PITX2 rs6843082 (OR 0.234 (0.15–0.366), p<0.0001), and the 16q22 rs2106261 (OR 2.439 (1.62–3.672), p<0.0001) genotypes were more prevalent in patients with AF than control group. 2. In the haplotype analyses, the 4q25 rs17042171–rs2200733–rs6843082–rs10033464 A–T–G–G (OR 3.3421 (1.867–5.982), p<0.0001) and 4q25 without C–C–A–G (OR 4.630 (2.924–7.299), p<0.0001) were more predisposed in AF than in control group. 3. The 16q22 rs7193343–rs210626116q22 A–G haplotype was more prevalent in patients with AF (OR 0.477 (0.242–0.939), p=0.0322) than control group. Conclusion: This study demonstrates the Chromosom 4q25, PITX2, and 16q22 ZFHX3 polymorphisms were associated with non-familial non-valvular AF in Korean population. The 4q25 and PITX2 were closely related with Korean non-valvular AF in haplotype analyses.

Familial Aggregation of Atrial Fibrillation

Background— Heritability may play a role in nonfamilial atrial fibrillation (AF). We hypothesized that a monozygotic (MZ) twin whose co-twin was diagnosed with AF would have an increased risk of the disease compared with a dizygotic (DZ) twin in the same situation. Methods and Results— A sample of 1137 same-sex twin pairs (356 MZ and 781 DZ pairs) in which one or both members were diagnosed with AF were identified in The Danish Twin Registry. Concordance rates were twice as high for MZ pairs than for DZ pairs regardless of sex (22.0% versus 11.6%, P &lt;0.0001). In a Cox regression of event-free survival times, we compared the time span between occurrences of disease in MZ and DZ twins. The unaffected twin was included when his or her twin-sibling (the index twin) was diagnosed with AF. After adjustment for age at entry, MZ twins had a significantly shorter event-free survival time (hazard ratio, 2.0; 95% CI, 1.3 to 3.0), thereby indicating a genetic component. Using biometric models, we estimated the heritability of AF to be 62% (55% to 68%), due to additive genetics. There were no significant differences across sexes. Conclusions— All the analyses of twin similarities in the present study indicate that genetic factors play a substantial role in the risk of AF for both sexes. The recurrence risk for co-twins (12% to 22%) is clinically relevant and suggests that co-twins of AF-affected twins belong to a high-risk group for AF.

Renin-angiotensin system gene polymorphisms and atrial fibrillation.

The activated local atrial renin-angiotensin system (RAS) has been reported to play an important role in the pathogenesis of atrial fibrillation (AF). We hypothesized that RAS genes might be among the susceptibility genes of nonfamilial structural AF and conducted a genetic case-control study to demonstrate this. A total of 250 patients with documented nonfamilial structural AF and 250 controls were selected. The controls were matched to cases on a 1-to-1 basis with regard to age, gender, presence of left ventricular dysfunction, and presence of significant valvular heart disease. The ACE gene insertion/deletion polymorphism, the T174M, M235T, G-6A, A-20C, G-152A, and G-217A polymorphisms of the angiotensinogen gene, and the A1166C polymorphism of the angiotensin II type I receptor gene were genotyped. In multilocus haplotype analysis, the angiotensinogen gene haplotype profile was significantly different between cases and controls (chi2=62.5, P=0.0002). In single-locus analysis, M235T, G-6A, and G-217A were significantly associated with AF. Frequencies of the M235, G-6, and G-217 alleles were significantly higher in cases than in controls (P=0.000, 0.005, and 0.002, respectively). The odds ratios for AF were 2.5 (95% CI 1.7 to 3.3) with M235/M235 plus M235/T235 genotype, 3.3 (95% CI 1.3 to 10.0) with G-6/G-6 genotype, and 2.0 (95% CI 1.3 to 2.5) with G-217/G-217 genotype. Furthermore, significant gene-gene interactions were detected by the multifactor-dimensionality reduction method and multilocus linkage disequilibrium tests. This study demonstrates the association of RAS gene polymorphisms with nonfamilial structural AF and may provide the rationale for clinical trials to investigate the use of ACE inhibitor or angiotensin II antagonist in the treatment of structural AF.