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Background: Recurrence after atrial fibrillation (AF) ablation remains common. We evaluated the association between recurrence and levels of biomarkers of cardiac remodeling, and their ability to improve recurrence prediction when added to a clinical prediction model., Methods and Results: Blood samples collected before de novo catheter ablation were analyzed. Levels of bone morphogenetic protein-10, angiopoietin-2, fibroblast growth factor-23, insulin-like growth factor-binding protein-7, myosin-binding protein C3, growth differentiation factor-15, interleukin-6, N-terminal pro-brain natriuretic peptide, and high-sensitivity troponin T were measured. Recurrence was defined as ≥30 seconds of an atrial arrhythmia 3 to 12 months postablation. Multivariable logistic regression was performed using biomarker levels along with clinical covariates: APPLE score (Age >65 years, Persistent AF, imPaired eGFR [<60 ml/min/1.73m 2 ], LA diameter ≥43 mm, EF <50%; which includes age, left atrial diameter, left ventricular ejection fraction, persistent atrial fibrillation, and estimated glomerular filtration rate), preablation rhythm, sex, height, body mass index, presence of an implanted continuous monitor, year of ablation, and additional linear ablation. A total of 1873 participants were included. A multivariable logistic regression showed an association between recurrence and levels of angiopoietin-2 (odds ratio, 1.08 [95% CI, 1.02-1.15], P =0.007) and interleukin-6 (odds ratio, 1.02 [95% CI, 1.003-1.03]; P =0.02). The area under the receiver operating characteristic curve of a model that only contained clinical predictors was 0.711. The addition of any of the 9 studied biomarkers to the predictive model did not result in a statistically significant improvement in the area under the receiver operating characteristic curve., Conclusions: Higher angiopoietin-2 and interleukin-6 levels were associated with recurrence after atrial fibrillation ablation in multivariable modeling. However, the addition of biomarkers to a clinical prediction model did not significantly improve recurrence prediction.

Background: Experimental evidence suggests genetic variation in 4q25/PITX2 modulates pulmonary vein (PV) myocardial sleeve length. Although PV sleeves are the main target of atrial fibrillation (AF) ablation, little is known about the association between different PV sleeve characteristics with ablation outcomes., Objectives: This study sought to evaluate the association between clinical and genetic (4q25) risk factors with PV sleeve length in humans, and to evaluate the association between PV sleeve length and recurrence after AF ablation., Methods: In a prospective, observational study of patients undergoing de novo AF ablation, PV sleeve length was measured using electroanatomic voltage mapping before ablation. The sentinel 4q25 AF susceptibility single nucleotide polymorphism, rs2200733, was genotyped. The primary analysis tested the association between clinical and genetic (4q25) risk factors with PV sleeve length using a multivariable linear regression model. Covariates included age, sex, body mass index, height, and persistent AF. The association between PV sleeve length and atrial arrhythmia recurrence (>30 seconds) was tested using a multivariable Cox proportional hazards model., Results: Between 2014 and 2019, 197 participants were enrolled (median age 63 years [IQR: 55 to 70 years], 133 male [67.5%]). In multivariable modeling, men were found to have PV sleeves 2.94 mm longer than women (95% CI: 0.99-4.90 mm; P < 0.001). Sixty participants (30.5%) had one 4q25 risk allele and 6 (3.1%) had 2 alleles. There was no association between 4q25 genotype and PV sleeve length. Forty-six participants (23.4%) experienced arrhythmia recurrence within 3 to 12 months, but there was no association between recurrence and PV sleeve length., Conclusions: Common genetic variation at 4q25 was not associated with PV sleeve length and PV sleeve length was not associated with ablation outcomes. Men did have longer PV sleeves than women, but more research is needed to define the potential clinical significance of this observation., Competing Interests: Funding Support and Author Disclosures This research work was supported in part by the National Institutes of Health grant K23 HL127704 (Shoemaker). The project was also supported by CTSA award UL1TR000445 from the National Center for Advancing Translational Sciences. Its contents are solely the responsibility of the authors and do not necessarily represent official views of the National Center for Advancing Translational Sciences or the National Institutes of Health. Dr. Shoemaker serves on the advisory board; and has received sponsored research funds from Roche Diagnostics. Dr. Kanagasundram has received speakers fees from Biosense Webster and Janssen. Dr. Crossley has received consulting fees or honoraria from Bayer Healthcare, Boston Scientific, Janssen Pharmaceuticals, Medtronic, and Spectranetics. Dr. Richardson has received research funding from Medtronic Inc, Abbott Inc; and served as a consultant for Philips Inc and Biosense Webster. Dr. Ellis has received research funding from Boston Scientific, Medtronic, Boehringer Ingelheim; and consulting fees from Medtronic, Boston Scientific, Abbott Medical, and Atricure. Dr. Michaud has received consulting fees or honoraria from Boston Scientific, Medtronic, Biotronik, Abbott, and Biosense Webster. Vanderbilt receives fellowship support from Medtronic Inc, Boston Scientific Inc, Abbott Labs, Biotronik, and Johnson & Johnson. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Published by Elsevier Inc.)

Importance: Patients with early-onset atrial fibrillation (AF) are enriched for rare variants in cardiomyopathy and arrhythmia genes. The clinical significance of these rare variants in patients with early-onset AF is unknown., Objective: To assess the association between rare variants in cardiomyopathy and arrhythmia genes detected in patients with early-onset AF and time to death., Design, Setting, and Participants: This prospective cohort study included participants with AF diagnosed before 66 years of age who underwent whole-genome sequencing through the National Heart, Lung and Blood Institute's Trans-Omics for Precision Medicine program. Participants were enrolled from November 23, 1999, to June 2, 2015. Data were analyzed from February 26 to September 19, 2021., Exposures: Rare variants identified in a panel of 145 genes that are included in cardiomyopathy and arrhythmia panels used by commercial clinical genetic testing laboratories., Main Outcomes and Measures: The primary study outcome was time to death and was adjudicated from medical records and the National Death Index. Multivariable Cox proportional hazards regression was used to evaluate the association of disease-associated variants with risk of death after adjustment for age at AF diagnosis, sex, race, body mass index, left ventricular ejection fraction, and an interaction term of age at AF diagnosis and disease-associated variant status., Results: Among 1293 participants (934 [72%] male; median age at enrollment, 56.0 years; IQR, 48.0-61.0 years), disease-associated (pathogenic or likely pathogenic) rare variants were found in 131 (10%). During a median follow-up of 9.9 years (IQR, 6.9-13.2 years), 219 participants (17%) died. In univariable analysis, disease-associated variants were associated with an increased risk of mortality (hazard ratio, [HR], 1.5; 95% CI, 1.0-2.1; P = .05); the association remained significant in multivariable modeling when adjusted for age at AF diagnosis, sex, race, body mass index, left ventricular ejection fraction, and an interaction term between disease-associated variant status and age at AF diagnosis. The interaction demonstrated that disease-associated variants were associated with a significantly higher risk of mortality compared with no disease-associated variant when AF was diagnosed at a younger age (P = .008 for interaction). Higher body mass index (per IQR: HR, 1.4; 95% CI, 1.2-1.6; P < .001) and lower left ventricular ejection fraction (per IQR: HR, 0.8; 95% CI, 0.7-0.8; P < .001) were associated with higher mortality risk. There were 73 cardiomyopathy-related deaths, 40 sudden deaths, and 10 stroke-related deaths. Mortality among patients with the most prevalent genes with disease-associated variants was 26% (10 of 38 patients) for TTN, 33% (6 of 18) for MYH7, 22% (2 of 9) for LMNA, 0% (0 of 10) for MYH6, and 0% (0 of 8) for KCNQ1., Conclusions and Relevance: The findings suggest that rare variants in cardiomyopathy and arrhythmia genes may be associated with increased risk of mortality among patients with early-onset AF, especially those diagnosed at a younger age. Genetic testing may provide important prognostic information for patients with early-onset AF.

There is increasing evidence regarding the prevalence of genetic cardiomyopathies, for which arrhythmias may be the first presentation. Ventricular and atrial arrhythmias presenting in the absence of known myocardial disease are often labelled as idiopathic, or lone. While ventricular arrhythmias are well-recognized as presentation for arrhythmogenic cardiomyopathy in the right ventricle, the scope of arrhythmogenic cardiomyopathy has broadened to include those with dominant left ventricular involvement, usually with a phenotype of dilated cardiomyopathy. In addition, careful evaluation for genetic cardiomyopathy is also warranted for patients presenting with frequent premature ventricular contractions, conduction system disease, and early onset atrial fibrillation, in which most detected genes are in the cardiomyopathy panels. Sudden death can occur early in the course of these genetic cardiomyopathies, for which risk is not adequately tracked by left ventricular ejection fraction. Only a few of the cardiomyopathy genotypes implicated in early sudden death are recognized in current indications for implantable cardioverter defibrillators which otherwise rely upon a left ventricular ejection fraction ≤0.35 in dilated cardiomyopathy. The genetic diagnoses impact other aspects of clinical management such as exercise prescription and pharmacological therapy of arrhythmias, and new therapies are coming into clinical investigation for specific genetic cardiomyopathies. The expansion of available genetic information and implications raises new challenges for genetic counseling, particularly with the family member who has no evidence of a cardiomyopathy phenotype and may face a potentially negative impact of a genetic diagnosis. Discussions of risk for both probands and relatives need to be tailored to their numeric literacy during shared decision-making. For patients presenting with arrhythmias or cardiomyopathy, extension of genetic testing and its implications will enable cascade screening, intervention to change the trajectory for specific genotype-phenotype profiles, and enable further development and evaluation of emerging targeted therapies.

Importance: Early-onset atrial fibrillation (AF) can be the initial manifestation of a more serious underlying inherited cardiomyopathy or arrhythmia syndrome., Objective: To examine the results of genetic testing for early-onset AF., Design, Setting, and Participants: This prospective, observational cohort study enrolled participants from an academic medical center who had AF diagnosed before 66 years of age and underwent whole genome sequencing through the National Heart, Lung, and Blood Institute's Trans-Omics for Precision Medicine program. Participants were enrolled from November 23, 1999, to June 2, 2015. Data analysis was performed from October 24, 2020, to March 11, 2021., Exposures: Rare variants identified in a panel of 145 genes that are included on cardiomyopathy and arrhythmia panels used by commercial clinical genetic testing laboratories., Main Outcomes and Measures: Sequencing data were analyzed using an automated process followed by manual review by a panel of independent, blinded reviewers. The primary outcome was classification of rare variants using American College of Medical Genetics and Genomics criteria: benign, likely benign, variant of undetermined significance, likely pathogenic, or pathogenic. Disease-associated variants were defined as pathogenic/likely pathogenic variants in genes associated with autosomal dominant or X-linked dominant disorders., Results: Among 1293 participants (934 [72.2%] male; median [interquartile range] age at enrollment, 56 [48-61] years; median [interquartile range] age at AF diagnosis, 50 [41-56] years), genetic testing identified 131 participants (10.1%) with a disease-associated variant, 812 (62.8%) with a variant of undetermined significance, 92 (7.1%) as heterozygous carriers for an autosomal recessive disorder, and 258 (20.0%) with no suspicious variant. The likelihood of a disease-associated variant was highest in participants with AF diagnosed before the age of 30 years (20 of 119 [16.8%; 95% CI, 10.0%-23.6%]) and lowest after the age of 60 years (8 of 112 [7.1%; 95% CI, 2.4%-11.9%]). Disease-associated variants were more often associated with inherited cardiomyopathy syndromes compared with inherited arrhythmias. The most common genes were TTN (n = 38), MYH7 (n = 18), MYH6 (n = 10), LMNA (n = 9), and KCNQ1 (n = 8)., Conclusions and Relevance: In this cohort study, genetic testing identified a disease-associated variant in 10% of patients with early-onset AF (the percentage was higher if diagnosed before the age of 30 years and lower if diagnosed after the age of 60 years). Most pathogenic/likely pathogenic variants are in genes associated with cardiomyopathy. These results support the use of genetic testing in early-onset AF.

Background: Although catheter ablation is an effective therapy for atrial fibrillation (AF), the most common cardiac arrhythmia encountered in clinical practice, AF ablation generates inflammation and oxidative stress in the early postoperative period predisposing to recurrence of AF. Isolevuglandins (IsoLGs) are reactive lipid mediators of oxidative stress injury that rapidly react with endogenous biomolecules to compromise their function. 2-Hydroxybenzylamine (2-HOBA), a potent small molecule scavenger of IsoLGs, sequesters the reactive species as inert adducts. This mechanism, coupled with reported safety in humans, supports the investigation of 2-HOBA as a novel therapeutic to reduce AF caused by oxidative stress, such as that which occurs after catheter ablation. Accordingly, we seek to test the hypothesis that treatment with 2-HOBA will decrease early recurrence of AF and other atrial arrhythmias following AF ablation by decreasing IsoLG adducts with native biomolecules., Methods: The proposed trial will randomly assign 162 participants undergoing cryo- or radiofrequency catheter ablation for AF to 2-HOBA (N = 81) or placebo (N = 81). Individuals will begin the study drug 3 days prior to ablation and continue for 28 days. Participants will be given a wearable smartwatch capable of detecting and recording atrial arrhythmias. They will be instructed to record ECGs daily with additional ECGs if they experience symptoms of AF or when alerted by the smartwatch AF detection alarm. The primary clinical endpoint will be an episode of AF, atrial tachycardia, or atrial flutter lasting 30 s or more within 28 days post-AF ablation. Secondary measures will be the change in IsoLG adduct levels from blood samples collected immediately pre-ablation and post-ablation and reduction in AF burden as calculated from the smartwatch., Discussion: The proposed trial will test the hypothesis that 2-HOBA reduces post-ablation atrial arrhythmias through sequestration of reactive IsoLG species. The results of this study may improve the understanding of the role of IsoLGs and oxidative stress in AF pathogenesis and provide evidence to advance 2-HOBA and related compounds as a new therapeutic strategy to treat AF., Trial Registration: ClinicalTrials.gov NCT04433091 . Registered on June 3, 2020., (© 2021. The Author(s).)

Context: A genetic predisposition to lower thyrotropin (TSH) levels is associated with increased atrial fibrillation (AF) risk through undefined mechanisms., Objective: Defining the genetic mediating mechanisms could lead to improved targeted therapies to mitigate AF risk., Methods: We used 2-sample mendelian randomization (MR) to test associations between TSH-associated single-nucleotide variations and 16 candidate mediators. We then performed multivariable mendelian randomization (MVMR) to test for a significant attenuation of the genetic association between TSH and AF, after adjusting for each mediator significantly associated with TSH., Results: Four candidate mediators (free thyroxine, systolic blood pressure, heart rate, and height) were significantly inversely associated with genetically predicted TSH after adjusting for multiple testing. In MVMR analyses, adjusting for height significantly decreased the magnitude of the association between TSH and AF from -0.12 (SE 0.02) occurrences of AF per SD change in height to -0.06 (0.02) (P = .005). Adjusting for the other candidate mediators did not significantly attenuate the association., Conclusion: The genetic association between TSH and increased AF risk is mediated, in part, by taller stature. Thus, some genetic mechanisms underlying TSH variability may contribute to AF risk through mechanisms determining height occurring early in life that differ from those driven by thyroid hormone-level elevations in later life., (© The Author(s) 2021. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Postoperative atrial fibrillation (PoAF) remains a significant risk factor for increased morbidity and mortality after cardiac surgery. The ability to accurately identify patients at risk through clinical risk factors is limited. There is growing evidence that polygenic risk contributes significantly to PoAF and incorporating measures of genetic risk could enhance prediction., Methods: A retrospective cohort study of 1047 patients of White European ancestry who underwent either coronary artery bypass grafting or valve surgery at a tertiary academic center and were free from a history or persistent preoperative atrial fibrillation. The primary outcome was defined as PoAF based on postoperative ECG reports, medical record documentation, and changes in medication. The exposure was a polygenic risk score (PRS) comprising 2746 single-nucleotide polymorphisms previously associated with atrial fibrillation risk. The prediction of PoAF risk was assessed using measures of model discrimination, calibration, and net reclassification improvement., Results: A total of 259 patients (24.7%) developed PoAF. The PRS was significantly associated with a higher risk for PoAF (odds ratio, 1.63 per SD increase in PRS [95% CI, 1.41-1.90]). Addition of PRS to patient- and procedure-related predictors of PoAF significantly increased the C statistic from 0.742 to 0.782 (change in C statistic, 0.040 [95% CI, 0.021-0.060]) while maintaining good calibration. The addition of the PRS to patient- and procedure-related predictors of PoAF improved model fit (likelihood ratio test, P =2.8×10 -15 ) and significantly improved measures of reclassification (net reclassification improvement, 0.158 [95% CI, 0.066-0.274])., Conclusions: The PRS for PoAF was associated with improved discrimination, calibration, and risk reclassification compared with conventional clinical predictors suggesting that a PoAF PRS may enhance risk prediction of PoAF in patients undergoing coronary artery bypass grafting or valve surgery.

Susceptibility to atrial fibrillation (AF) is determined by well-recognized risk factors such as diabetes mellitus or hypertension, emerging risk factors such as sleep apnea or inflammation, and increasingly well-defined genetic variants. As discussed in detail in a companion article in this series, studies in families and in large populations have identified multiple genetic loci, specific genes, and specific variants increasing susceptibility to AF. Since it is becoming increasingly inexpensive to obtain genotype data and indeed whole genome sequence data, the question then becomes to define whether using emerging new genetics knowledge can improve care for patients both before and after development of AF. Examples of improvements in care could include identifying patients at increased risk for AF (and thus deploying increased surveillance or even low-risk preventive therapies should these be available), identifying patient subsets in whom specific therapies are likely to be effective or ineffective or in whom the driving biology could motivate the development of new mechanism-based therapies or identifying an underlying susceptibility to comorbid cardiovascular disease. While current guidelines for the care of patients with AF do not recommend routine genetic testing, this rapidly increasing knowledge base suggests that testing may now or soon have a place in the management of select patients. The opportunity is to generate, validate, and deploy clinical predictors (including family history) of AF risk, to assess the utility of incorporating genomic variants into those predictors, and to identify and validate interventions such as wearable or implantable device-based monitoring ultimately to intervene in patients with AF before they present with catastrophic complications like heart failure or stroke.

Background: Ablation is a widely used therapy for atrial fibrillation (AF); however, arrhythmia recurrence and repeat procedures are common. Studies examining surrogate markers of genetic susceptibility to AF, such as family history and individual AF susceptibility alleles, suggest these may be associated with recurrence outcomes. Accordingly, the aim of this study was to test the association between AF genetic susceptibility and recurrence after ablation using a comprehensive polygenic risk score for AF., Methods: Ten centers from the AF Genetics Consortium identified patients who had undergone de novo AF ablation. AF genetic susceptibility was measured using a previously described polygenic risk score (N=929 single-nucleotide polymorphisms) and tested for an association with clinical characteristics and time-to-recurrence with a 3 month blanking period. Recurrence was defined as >30 seconds of AF, atrial flutter, or atrial tachycardia. Multivariable analysis adjusted for age, sex, height, body mass index, persistent AF, hypertension, coronary disease, left atrial size, left ventricular ejection fraction, and year of ablation., Results: Four thousand two hundred seventy-six patients were eligible for analysis of baseline characteristics and 3259 for recurrence outcomes. The overall arrhythmia recurrence rate between 3 and 12 months was 44% (1443/3259). Patients with higher AF genetic susceptibility were younger ( P <0.001) and had fewer clinical risk factors for AF ( P =0.001). Persistent AF (hazard ratio [HR], 1.39 [95% CI, 1.22-1.58]; P <0.001), left atrial size (per cm: HR, 1.32 [95% CI, 1.19-1.46]; P <0.001), and left ventricular ejection fraction (per 10%: HR, 0.88 [95% CI, 0.80-0.97]; P =0.008) were associated with increased risk of recurrence. In univariate analysis, higher AF genetic susceptibility trended towards a higher risk of recurrence (HR, 1.08 [95% CI, 0.99-1.18]; P =0.07), which became less significant in multivariable analysis (HR, 1.06 [95% CI, 0.98-1.15]; P =0.13)., Conclusions: Higher AF genetic susceptibility was associated with younger age and fewer clinical risk factors but not recurrence. Arrhythmia recurrence after AF ablation may represent a genetically different phenotype compared to AF susceptibility.

Importance: Increased free thyroxine (FT4) and decreased thyrotropin are associated with increased risk of atrial fibrillation (AF) in observational studies, but direct involvement is unclear., Objective: To evaluate the potential direct involvement of thyroid traits on AF., Design, Setting, and Participants: Study-level mendelian randomization (MR) included 11 studies, and summary-level MR included 55 114 AF cases and 482 295 referents, all of European ancestry., Exposures: Genomewide significant variants were used as instruments for standardized FT4 and thyrotropin levels within the reference range, standardized triiodothyronine (FT3):FT4 ratio, hypothyroidism, standardized thyroid peroxidase antibody levels, and hyperthyroidism. Mendelian randomization used genetic risk scores in study-level analysis or individual single-nucleotide polymorphisms in 2-sample MR for the summary-level data., Main Outcomes and Measures: Prevalent and incident AF., Results: The study-level analysis included 7679 individuals with AF and 49 233 referents (mean age [standard error], 62 [3] years; 15 859 men [29.7%]). In study-level random-effects meta-analysis, the pooled hazard ratio of FT4 levels (nanograms per deciliter) for incident AF was 1.55 (95% CI, 1.09-2.20; P = .02; I2 = 76%) and the pooled odds ratio (OR) for prevalent AF was 2.80 (95% CI, 1.41-5.54; P = .003; I2 = 64%) in multivariable-adjusted analyses. The FT4 genetic risk score was associated with an increase in FT4 by 0.082 SD (standard error, 0.007; P < .001) but not with incident AF (risk ratio, 0.84; 95% CI, 0.62-1.14; P = .27) or prevalent AF (OR, 1.32; 95% CI, 0.64-2.73; P = .46). Similarly, in summary-level inverse-variance weighted random-effects MR, gene-based FT4 within the reference range was not associated with AF (OR, 1.01; 95% CI, 0.89-1.14; P = .88). However, gene-based increased FT3:FT4 ratio, increased thyrotropin within the reference range, and hypothyroidism were associated with AF with inverse-variance weighted random-effects OR of 1.33 (95% CI, 1.08-1.63; P = .006), 0.88 (95% CI, 0.84-0.92; P < .001), and 0.94 (95% CI, 0.90-0.99; P = .009), respectively, and robust to tests of horizontal pleiotropy. However, the subset of hypothyroidism single-nucleotide polymorphisms involved in autoimmunity and thyroid peroxidase antibodies levels were not associated with AF. Gene-based hyperthyroidism was associated with AF with MR-Egger OR of 1.31 (95% CI, 1.05-1.63; P = .02) with evidence of horizontal pleiotropy (P = .045)., Conclusions and Relevance: Genetically increased FT3:FT4 ratio and hyperthyroidism, but not FT4 within the reference range, were associated with increased AF, and increased thyrotropin within the reference range and hypothyroidism were associated with decreased AF, supporting a pathway involving the pituitary-thyroid-cardiac axis.

Importance: Thyroid hormone levels are tightly regulated through feedback inhibition by thyrotropin, produced by the pituitary gland. Hyperthyroidism is overwhelmingly due to thyroid disorders and is well recognized to contribute to a wide spectrum of cardiovascular morbidity, particularly the increasingly common arrhythmia atrial fibrillation (AF)., Objective: To determine the association between genetically determined thyrotropin levels and AF., Design, Setting, and Participants: This phenome-wide association study scanned 1318 phenotypes associated with a polygenic predictor of thyrotropin levels identified by a previously published genome-wide association study that included participants of European ancestry. North American individuals of European ancestry with longitudinal electronic health records were analyzed from May 2008 to November 2016. Analysis began March 2018., Main Outcomes and Measures: Clinical diagnoses associated with a polygenic predictor of thyrotropin levels., Exposures: Genetically determined thyrotropin levels., Results: Of 37 154 individuals, 19 330 (52%) were men. The thyrotropin polygenic predictor was positively associated with hypothyroidism (odds ratio [OR], 1.10; 95% CI, 1.07-1.14; P = 5 × 10-11) and inversely associated with diagnoses related to hyperthyroidism (OR, 0.64; 95% CI, 0.54-0.74; P = 2 × 10-8 for toxic multinodular goiter). Among nonthyroid associations, the top association was AF/flutter (OR, 0.93; 95% CI, 0.9-0.95; P = 9 × 10-7). When the analyses were repeated excluding 9801 individuals with any diagnoses of a thyroid-related disease, the AF association persisted (OR, 0.91; 95% CI, 0.88-0.95; P = 2.9 × 10-6). To replicate this association, we conducted an inverse-variance weighted average meta-analysis using AF single-nucleotide variant weights from a genome-wide association study of 17 931 AF cases and 115 142 controls. As in the discovery analyses, each SD increase in predicted thyrotropin was associated with a decreased risk of AF (OR, 0.86; 95% CI, 0.79-0.93; P = 4.7 × 10-4). In a set of AF cases (n = 745) and controls (n = 1680) older than 55 years, directly measured thyrotropin levels that fell within the normal range were inversely associated with AF risk (OR, 0.91; 95% CI, 0.83-0.99; P = .04)., Conclusions and Relevance: This study suggests a role for genetically determined variation in thyroid function within a physiologically accepted normal range as a risk factor for AF. The clinical decision to treat subclinical thyroid disease should incorporate the risk for AF as antithyroid medications to treat hyperthyroidism may reduce AF risk and thyroid hormone replacement for hypothyroidism may increase AF risk.

Importance: Atrial fibrillation (AF) is the most common arrhythmia affecting 1% of the population. Young individuals with AF have a strong genetic association with the disease, but the mechanisms remain incompletely understood., Objective: To perform large-scale whole-genome sequencing to identify genetic variants related to AF., Design, Setting, and Participants: The National Heart, Lung, and Blood Institute's Trans-Omics for Precision Medicine Program includes longitudinal and cohort studies that underwent high-depth whole-genome sequencing between 2014 and 2017 in 18 526 individuals from the United States, Mexico, Puerto Rico, Costa Rica, Barbados, and Samoa. This case-control study included 2781 patients with early-onset AF from 9 studies and identified 4959 controls of European ancestry from the remaining participants. Results were replicated in the UK Biobank (346 546 participants) and the MyCode Study (42 782 participants)., Exposures: Loss-of-function (LOF) variants in genes at AF loci and common genetic variation across the whole genome., Main Outcomes and Measures: Early-onset AF (defined as AF onset in persons <66 years of age). Due to multiple testing, the significance threshold for the rare variant analysis was P = 4.55 × 10-3., Results: Among 2781 participants with early-onset AF (the case group), 72.1% were men, and the mean (SD) age of AF onset was 48.7 (10.2) years. Participants underwent whole-genome sequencing at a mean depth of 37.8 fold and mean genome coverage of 99.1%. At least 1 LOF variant in TTN, the gene encoding the sarcomeric protein titin, was present in 2.1% of case participants compared with 1.1% in control participants (odds ratio [OR], 1.76 [95% CI, 1.04-2.97]). The proportion of individuals with early-onset AF who carried a LOF variant in TTN increased with an earlier age of AF onset (P value for trend, 4.92 × 10-4), and 6.5% of individuals with AF onset prior to age 30 carried a TTN LOF variant (OR, 5.94 [95% CI, 2.64-13.35]; P = 1.65 × 10-5). The association between TTN LOF variants and AF was replicated in an independent study of 1582 patients with early-onset AF (cases) and 41 200 control participants (OR, 2.16 [95% CI, 1.19-3.92]; P = .01)., Conclusions and Relevance: In a case-control study, there was a statistically significant association between an LOF variant in the TTN gene and early-onset AF, with the variant present in a small percentage of participants with early-onset AF (the case group). Further research is necessary to understand whether this is a causal relationship.

Atrial fibrillation (AF) affects more than 33 million individuals worldwide 1 and has a complex heritability 2 . We conducted the largest meta-analysis of genome-wide association studies (GWAS) for AF to date, consisting of more than half a million individuals, including 65,446 with AF. In total, we identified 97 loci significantly associated with AF, including 67 that were novel in a combined-ancestry analysis, and 3 that were novel in a European-specific analysis. We sought to identify AF-associated genes at the GWAS loci by performing RNA-sequencing and expression quantitative trait locus analyses in 101 left atrial samples, the most relevant tissue for AF. We also performed transcriptome-wide analyses that identified 57 AF-associated genes, 42 of which overlap with GWAS loci. The identified loci implicate genes enriched within cardiac developmental, electrophysiological, contractile and structural pathways. These results extend our understanding of the biological pathways underlying AF and may facilitate the development of therapeutics for AF.

Background: Genome-wide association studies (GWAS) have yielded variants at >30 loci that associate with atrial fibrillation (AF), including rare coding mutations in the sarcomere genes MYH6 and MYL4., Objectives: The aim of this study was to search for novel AF associations and in doing so gain insights into the mechanisms whereby variants affect AF risk, using electrocardiogram (ECG) measurements., Methods: The authors performed a GWAS of 14,255 AF cases and 374,939 controls, using whole-genome sequence data from the Icelandic population, and tested novel signals in 2,002 non-Icelandic cases and 12,324 controls. They then tested the AF variants for effect on cardiac electrical function by using measurements in 289,297 ECGs from 62,974 individuals., Results: The authors discovered 2 novel AF variants, the intergenic variant rs72700114, between the genes LINC01142 and METTL11B (risk allele frequency = 8.1%; odds ratio [OR]: 1.26; p = 3.1 × 10 -18 ), and the missense variant p.Gly4098Ser in PLEC (frequency = 1.2%; OR: 1.55; p = 8.0 × 10 -10 ), encoding plectin, a cytoskeletal cross-linking protein that contributes to integrity of cardiac tissue. The authors also confirmed 29 reported variants. p.Gly4098Ser in PLEC significantly affects various ECG measurements in the absence of AF. Other AF variants have diverse effects on the conduction system, ranging from none to extensive., Conclusions: The discovery of a missense variant in PLEC affecting AF combined with recent discoveries of variants in the sarcomere genes MYH6 and MYL4 points to an important role of myocardial structure in the pathogenesis of the disease. The diverse associations between AF variants and ECG measurements suggest fundamentally different categories of mechanisms contributing to the development of AF., (Copyright © 2017 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

It is unclear whether genetic markers interact with risk factors to influence atrial fibrillation (AF) risk. We performed genome-wide interaction analyses between genetic variants and age, sex, hypertension, and body mass index in the AFGen Consortium. Study-specific results were combined using meta-analysis (88,383 individuals of European descent, including 7,292 with AF). Variants with nominal interaction associations in the discovery analysis were tested for association in four independent studies (131,441 individuals, including 5,722 with AF). In the discovery analysis, the AF risk associated with the minor rs6817105 allele (at the PITX2 locus) was greater among subjects ≤ 65 years of age than among those > 65 years (interaction p-value = 4.0 × 10 -5 ). The interaction p-value exceeded genome-wide significance in combined discovery and replication analyses (interaction p-value = 1.7 × 10 -8 ). We observed one genome-wide significant interaction with body mass index and several suggestive interactions with age, sex, and body mass index in the discovery analysis. However, none was replicated in the independent sample. Our findings suggest that the pathogenesis of AF may differ according to age in individuals of European descent, but we did not observe evidence of statistically significant genetic interactions with sex, body mass index, or hypertension on AF risk.

Background: Atrial fibrillation (AF) is a mechanistically heterogeneous disorder, and the ability to identify sub-phenotypes ("endophenotypes") of AF would assist in the delivery of personalized medicine. We used the clinical response to pulmonary vein isolation (PVI) to identify a sub-group of patients with non-PV mediated AF and sought to define the clinical associations., Methods: Subjects enrolled in the Vanderbilt AF Ablation Registry who underwent a repeat AF ablation due to arrhythmia recurrence were analyzed on the basis of PV reconnection. Subjects who had no PV reconnection were defined as "non-PV mediated AF". A comparison group of subjects were identified who had AF that was treated with PVI-only and experienced no arrhythmia recurrence >12 months. They were considered a group enriched for "PV-mediated AF". Univariate and multivariable binary logistic regression analysis was performed to investigate clinical associations between the PV and non-PV mediated AF groups., Results: Two hundred and twenty nine subjects underwent repeat AF ablation and thirty three (14%) had no PV reconnection. They were compared with 91 subjects identified as having PV-mediated AF. Subjects with non-PV mediated AF were older (64 years [IQR 60,71] vs. 60 [52,67], P = 0.01), more likely to have non-paroxysmal AF (82% [N = 27] vs. 35% [N = 32], P<0.001), and had a larger left atrium (LA) (4.2cm [3.6,4.8] vs. 4.0 [3.3,4.4], P = 0.04). In univariate analysis, age (per decade: OR 1.56 [95% CI: 1.04 to 2.33], P = 0.03), LA size (per cm: OR 1.8 [1.06 to 3.21], P = 0.03) and non-paroxysmal AF (OR 8.3 [3.10 to 22.19], P<0.001) were all significantly associated with non-PV mediated AF. However, in multivariable analysis only non-paroxysmal AF was independently associated with non-PV mediated AF (OR 7.47 [95% CI 2.62 to 21.29], P<0.001), when adjusted for age (per decade: OR 1.25 [0.81 to 1.94], P = 0.31), male gender (OR 0.48 [0.18 to 1.28], P = 0.14), and LA size (per 1cm: 1.24 [0.65 to 2.33], P = 0.52)., Conclusions: Non-paroxysmal AF was the only clinical variable found to be independently associated with non-PV mediated AF. We demonstrated that analysis of AF ablation outcomes data can serve as a tool to successfully identify a sub-phenotype of subjects who have non-PV mediated AF., Clinical Trial Registration: ClinicalTrials.gov ID # NCT02404415.

Aim: Rare variants of genes encoding the cardiac sodium channel and associated compounds have been linked with atrial fibrillation (AF). Nevertheless, current expert consensus does not support genetic testing in AF, which is in part based on the fact that "there is no therapeutic impact derived from AF genetic test results". However, there are no studies available supporting this recommendation. Consequently, this study analyzed the impact of rare variants affecting the cardiac sodium channel on rhythm outcome of AF catheter ablation., Methods and Results: In 137 consecutive patients with lone AF enrolled in the Leipzig Heart Center AF ablation registry, screening for mutations in SCN5A, SCN1B - 4B, CAV3, GPD1L, SNTA1 and MOG1 was performed. We identified 3 rare non-synonymous variants in SCN5A, 5 in SCN1B, 1 in SCN4B, 1 in CAV3, 6 in GPD1L, 3 in SNTA1 and 3 in MOG1 (16%). Variant carriers were otherwise comparable with non-variant carriers. Analysis of AF recurrence rates after radiofrequency AF catheter ablation by serial 7-day Holter ECG monitoring between 3 and 12 months revealed no difference between groups, i.e. 45% in variant carriers vs. 49% in non-variant carriers., Conclusions: Rare variants in genes encoding the cardiac sodium channel and associated compounds are frequently found in lone AF but were not found to impact the outcome of AF catheter ablation. This finding supports current recommendations not to screen for rare variants for the ablation outcome in AF. Nevertheless, it may at least be helpful for understanding AF mechanisms and larger studies are needed to further explore the possible association between genotype and response to AF therapies.

Atrial fibrillation affects more than 33 million people worldwide and increases the risk of stroke, heart failure, and death. Fourteen genetic loci have been associated with atrial fibrillation in European and Asian ancestry groups. To further define the genetic basis of atrial fibrillation, we performed large-scale, trans-ancestry meta-analyses of common and rare variant association studies. The genome-wide association studies (GWAS) included 17,931 individuals with atrial fibrillation and 115,142 referents; the exome-wide association studies (ExWAS) and rare variant association studies (RVAS) involved 22,346 cases and 132,086 referents. We identified 12 new genetic loci that exceeded genome-wide significance, implicating genes involved in cardiac electrical and structural remodeling. Our results nearly double the number of known genetic loci for atrial fibrillation, provide insights into the molecular basis of atrial fibrillation, and may facilitate the identification of new potential targets for drug discovery.

Background: Atrial fibrillation (AF) has a substantial genetic basis. Identification of individuals at greatest AF risk could minimize the incidence of cardioembolic stroke., Methods: To determine whether genetic data can stratify risk for development of AF, we examined associations between AF genetic risk scores and incident AF in 5 prospective studies comprising 18 919 individuals of European ancestry. We examined associations between AF genetic risk scores and ischemic stroke in a separate study of 509 ischemic stroke cases (202 cardioembolic [40%]) and 3028 referents. Scores were based on 11 to 719 common variants (≥5%) associated with AF at P values ranging from <1×10 -3 to <1×10 -8 in a prior independent genetic association study., Results: Incident AF occurred in 1032 individuals (5.5%). AF genetic risk scores were associated with new-onset AF after adjustment for clinical risk factors. The pooled hazard ratio for incident AF for the highest versus lowest quartile of genetic risk scores ranged from 1.28 (719 variants; 95% confidence interval, 1.13-1.46; P =1.5×10 -4 ) to 1.67 (25 variants; 95% confidence interval, 1.47-1.90; P =9.3×10 -15 ). Discrimination of combined clinical and genetic risk scores varied across studies and scores (maximum C statistic, 0.629-0.811; maximum ΔC statistic from clinical score alone, 0.009-0.017). AF genetic risk was associated with stroke in age- and sex-adjusted models. For example, individuals in the highest versus lowest quartile of a 127-variant score had a 2.49-fold increased odds of cardioembolic stroke (95% confidence interval, 1.39-4.58; P =2.7×10 -3 ). The effect persisted after the exclusion of individuals (n=70) with known AF (odds ratio, 2.25; 95% confidence interval, 1.20-4.40; P =0.01)., Conclusions: Comprehensive AF genetic risk scores were associated with incident AF beyond associations for clinical AF risk factors but offered small improvements in discrimination. AF genetic risk was also associated with cardioembolic stroke in age- and sex-adjusted analyses. Efforts are warranted to determine whether AF genetic risk may improve identification of subclinical AF or help distinguish between stroke mechanisms., (© 2016 American Heart Association, Inc.)

Background: One potential use for the PR interval is as a biomarker of disease risk. We hypothesized that quantifying the shared genetic architectures of the PR interval and a set of clinical phenotypes would identify genetic mechanisms contributing to PR variability and identify diseases associated with a genetic predictor of PR variability., Methods and Results: We used ECG measurements from the ARIC study (Atherosclerosis Risk in Communities; n=6731 subjects) and 63 genetically modulated diseases from the eMERGE network (Electronic Medical Records and Genomics; n=12 978). We measured pairwise genetic correlations (rG) between PR phenotypes (PR interval, PR segment, P-wave duration) and each of the 63 phenotypes. The PR segment was genetically correlated with atrial fibrillation (rG=-0.88; P =0.0009). An analysis of metabolic phenotypes in ARIC also showed that the P wave was genetically correlated with waist circumference (rG=0.47; P =0.02). A genetically predicted PR interval phenotype based on 645 714 single-nucleotide polymorphisms was associated with atrial fibrillation (odds ratio=0.89 per SD change; 95% confidence interval, 0.83-0.95; P =0.0006). The differing pattern of associations among the PR phenotypes is consistent with analyses that show that the genetic correlation between the P wave and PR segment was not significantly different from 0 (rG=-0.03 [0.16])., Conclusions: The genetic architecture of the PR interval comprises modulators of atrial fibrillation risk and obesity., (© 2017 American Heart Association, Inc.)

In atrial fibrillation (AF), left atrial diameter (LAD) and low voltage area (LVA) are intermediate phenotypes that are associated with AF type and progression. In this study, we tested the hypothesis, that these phenotypes share common, genetically-determined pathways using pathway enrichment analysis of GWAS data. Samples from 660 patients with paroxysmal (n = 370) or persistent AF (n = 290) were genotyped for ~1,000,000 SNPs. SNPs found significantly associated with LAD, LVA or AF type were used for gene-based association tests in a systematic biological Knowledge-based mining system for Genome-wide Genetic studies (KGG). Associated genes were tested for pathway enrichment using two enrichment tools (WebGestalt and GATHER) and the databases provided by Kyoto Encyclopedia of Genes and Genomes. The calcium signaling pathway (hsa04020) was the only pathway that reached statistical significance for LAD and LVA in both enrichment tools and was also significantly associated with AF type. Within this pathway, there were 39 genes (i.e. CACNA1C, RyR2) that were associated with LAD, LVA and AF type. In conclusion, there is a genomic contribution to electroanatomical remodeling (LAD, LVA) and AF type via the calcium signaling pathway. Future and larger studies are necessary to replicate and apply these findings.

Background: Mutations in the coding sequence of SCN5A, which encodes the cardiac Na(+) channel α subunit, have been associated with inherited susceptibility to various arrhythmias. Variable expression of SCN5A is a possible mechanism responsible for this pleiotropic effect; however, it is unknown whether variants in the promoter and regulatory regions of SCN5A also modulate the risk of arrhythmias., Methods and Results: We resequenced the core promoter region of SCN5A and the regulatory regions of SCN5A transcription in 1298 patients with arrhythmia phenotypes (atrial fibrillation, n=444; sinus node dysfunction, n=49; conduction disease, n=133; Brugada syndrome, n=583; and idiopathic ventricular fibrillation, n=89). We identified 26 novel rare variants in the SCN5A promoter in 29 patients affected by various arrhythmias (atrial fibrillation, n=6; sinus node dysfunction, n=1; conduction disease, n=3; Brugada syndrome, n=14; idiopathic ventricular fibrillation, n=5). The frequency of rare variants was higher in patients with arrhythmias than in controls. In the alignment with chromatin immunoprecipitation sequencing data, the majority of variants were located at regions bound by transcription factors. Using a luciferase reporter assay, 6 variants (Brugada syndrome, n=3; idiopathic ventricular fibrillation, n=2; conduction disease, n=1) were functionally characterized, and each displayed decreased promoter activity compared with the wild-type sequences. We also identified rare variants in the regulatory region that were associated with atrial fibrillation, and the variant decreased promoter activity., Conclusions: Variants in the core promoter region and the transcription regulatory region of SCN5A were identified in multiple arrhythmia phenotypes, consistent with the idea that altered SCN5A transcription levels modulate susceptibility to arrhythmias., (© 2016 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley Blackwell.)

Background: Common single nucleotide polymorphisms (SNPs) at chromosomes 4q25 (rs2200733, rs10033464 near PITX2), 1q21 (rs13376333 in KCNN3), and 16q22 (rs7193343 in ZFHX3) have consistently been associated with the risk of atrial fibrillation (AF). Single-center studies have shown that 4q25 risk alleles predict recurrence of AF after catheter ablation of AF. Here, we performed a meta-analysis to test the hypothesis that these 4 AF susceptibility SNPs modulate response to AF ablation., Methods and Results: Patients underwent de novo AF ablation between 2008 and 2012 at Vanderbilt University, the Heart Center Leipzig, and Massachusetts General Hospital. The primary outcome was 12-month recurrence, defined as an episode of AF, atrial flutter, or atrial tachycardia lasting >30 seconds after a 3-month blanking period. Multivariable analysis of the individual cohorts using a Cox proportional hazards model was performed. Summary statistics from the 3 centers were analyzed using fixed effects meta-analysis. A total of 991 patients were included (Vanderbilt University, 245; Heart Center Leipzig, 659; and Massachusetts General Hospital, 87). The overall single procedure 12-month recurrence rate was 42%. The overall risk allele frequency for these SNPs ranged from 12% to 35%. Using a dominant genetic model, the 4q25 SNP, rs2200733, predicted a 1.4-fold increased risk of recurrence (adjusted hazard ratio,1.3 [95% confidence intervals, 1.1-1.6]; P=0.011). The remaining SNPs, rs10033464 (4q25), rs13376333 (1q21), and rs7193343 (16q22) were not significantly associated with recurrence., Conclusions: Among the 3 genetic loci most strongly associated with AF, the chromosome 4q25 SNP rs2200733 is significantly associated with recurrence of atrial arrhythmias after catheter ablation for AF., (© 2015 American Heart Association, Inc.)

There is wide variation in the management of patients with atrial fibrillation (AF) in the emergency department (ED). We aimed to derive and internally validate the first prospective, ED-based clinical decision aid to identify patients with AF at low risk for 30-day adverse events. We performed a prospective cohort study at a university-affiliated tertiary-care ED. Patients were enrolled from June 9, 2010, to February 28, 2013, and followed for 30 days. We enrolled a convenience sample of patients in ED presenting with symptomatic AF. Candidate predictors were based on ED data available in the first 2 hours. The decision aid was derived using model approximation (preconditioning) followed by strong bootstrap internal validation. We used an ordinal outcome hierarchy defined as the incidence of the most severe adverse event within 30 days of the ED evaluation. Of 497 patients enrolled, stroke and AF-related death occurred in 13 (3%) and 4 (<1%) patients, respectively. The decision aid included the following: age, triage vitals (systolic blood pressure, temperature, respiratory rate, oxygen saturation, supplemental oxygen requirement), medical history (heart failure, home sotalol use, previous percutaneous coronary intervention, electrical cardioversion, cardiac ablation, frequency of AF symptoms), and ED data (2 hours heart rate, chest radiograph results, hemoglobin, creatinine, and brain natriuretic peptide). The decision aid's c-statistic in predicting any 30-day adverse event was 0.7 (95% confidence interval 0.65, 0.76). In conclusion, in patients with AF in the ED, Atrial Fibrillation and Flutter Outcome Risk Determination provides the first evidence-based decision aid for identifying patients who are at low risk for 30-day adverse events and candidates for safe discharge., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Background: Postoperative atrial fibrillation (PoAF) is common after coronary artery bypass grafting. We previously showed that atrial fibrillation susceptibility single nucleotide polymorphisms (SNPs) at the chromosome 4q25 locus are associated with PoAF. Here, we tested the hypothesis that a combined clinical and genetic model incorporating atrial fibrillation risk SNPs would be superior to a clinical-only model., Methods and Results: We developed and externally validated clinical and clinical/genetic risk models for PoAF. The discovery and validation cohorts included 556 and 1164 patients, respectively. Clinical variables previously associated with PoAF and 13 SNPs at loci associated with atrial fibrillation in genome-wide association studies were considered. PoAF occurred in 30% and 29% of patients in the discovery and validation cohorts, respectively. In the discovery cohort, a logistic regression model with clinical factors had good discrimination, with an area under the receiver operator characteristic curve of 0.76. The addition of 10 SNPs to the clinical model did not improve discrimination (area under receiver operator characteristic curve, 0.78; P=0.14 for difference between the 2 models). In the validation cohort, the clinical model had good discrimination (area under the receiver operator characteristic curve, 0.69) and addition of genetic variables resulted in a marginal improvement in discrimination (area under receiver operator characteristic curve, 0.72; P<0.0001)., Conclusions: We developed and validated a model for the prediction of PoAF containing common clinical variables. Addition of atrial fibrillation susceptibility SNPs did not improve model performance. Tools to accurately predict PoAF are needed to risk stratify patients undergoing coronary artery bypass grafting and identify candidates for prophylactic therapies., (© 2015 American Heart Association, Inc.)

Background: Studies in individuals or small kindreds have implicated rare variants in 25 different genes in lone and familial atrial fibrillation (AF) using linkage and segregation analysis, functional characterization, and rarity in public databases. Here, we used a cohort of 20 204 patients of European or African ancestry with electronic medical records and exome chip data to compare the frequency of AF among carriers and noncarriers of these rare variants., Methods and Results: The exome chip included 19 of 115 rare variants, in 9 genes, previously associated with lone or familial AF. Using validated algorithms querying a combination of clinical notes, structured billing codes, ECG reports, and procedure codes, we identified 1056 AF cases (>18 years) and 19 148 non-AF controls (>50 years) with available genotype data on the Illumina HumanExome BeadChip v.1.0 in the Vanderbilt electronic medical record-linked DNA repository, BioVU. Known correlations between AF and common variants at 4q25 were replicated. None of the 19 variants previously associated with AF were over-represented among AF cases (P>0.1 for all), and the frequency of variant carriers among non-AF controls was >0.1% for 14 of 19. Repeat analyses using non-AF controls aged >60 (n=14 904), >70 (n=9670), and >80 (n=4729) years did not influence these findings., Conclusions: Rare variants previously implicated in lone or familial forms of AF present on the exome chip are detected at low frequencies in a general population but are not associated with AF. These findings emphasize the need for caution when ascribing variants as pathogenic or causative., (© 2014 American Heart Association, Inc.)

Aims: To test the hypothesis that vulnerability to atrial fibrillation (AF) is associated with rare coding sequence variation in the SCN10A gene, which encodes the voltage-gated sodium channel isoform NaV1.8 found primarily in peripheral nerves and to identify potentially disease-related mechanisms in high-priority rare variants using in-vitro electrophysiology., Methods and Results: We re-sequenced SCN10A in 274 patients with early onset AF from the Vanderbilt AF Registry to identify rare coding variants. Engineered variants were transiently expressed in ND7/23 cells and whole-cell voltage clamp experiments were conducted to elucidate their functional properties. Resequencing SCN10A identified 18 heterozygous rare coding variants (minor allele frequency ≤1%) in 18 (6.6%) AF probands. Four probands were carriers of two rare variants each and 14 were carriers of one coding variant. Based on evidence of co-segregation, initial assessment of functional importance, and presence in ≥1 AF proband, three variants (417delK, A1886V, and the compound variant Y158D-R814H) were selected for functional studies. The 417delK variant displayed near absent current while A1886V and Y158D-R814H exhibited enhanced peak and late (INa-L) sodium currents; both Y158D and R818H individually contributed to this phenotype., Conclusion: Rare SCN10A variants encoding Nav1.8 were identified in 6.6% of patients with early onset AF. In-vitro electrophysiological studies demonstrated profoundly altered function in 3/3 high-priority variants. Collectively, these data strongly support the hypothesis that rare SCN10A variants may contribute to AF susceptibility., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2014. For permissions please email: journals.permissions@oup.com.)

Aims: Positional cloning and candidate gene approaches have shown that atrial fibrillation (AF) is a complex disease with familial aggregation. Here, we employed whole-exome sequencing (WES) in AF kindreds to identify variants associated with familial AF., Methods and Results: WES was performed on 18 individuals in six modestly sized familial AF kindreds. After filtering very rare variants by multiple metrics, we identified 39 very rare and potentially pathogenic variants [minor allele frequency (MAF) ≤0.04%] in genes not previously associated with AF. Despite stringent filtering >1 very rare variants in the 5/6 of the kindreds were identified, whereas no plausible variants contributing to familial AF were found in 1/6 of the kindreds. Two candidate AF variants in the calcium channel subunit genes (CACNB2 and CACNA2D4) were identified in two separate families using expression data and predicted function., Conclusion: By coupling family data with exome sequencing, we identified multiple very rare potentially pathogenic variants in five of six families, suggestive of a complex disease mechanism, whereas none were identified in the remaining AF pedigree. This study highlights some important limitations and challenges associated with performing WES in AF including the importance of having large well-curated multi-generational pedigrees, the issue of potential AF misclassification, and limitations of WES technology when applied to a complex disease., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2014. For permissions please email: journals.permissions@oup.com.)

For many patients with atrial fibrillation, ventricular rate control with atrioventricular (AV) nodal blockers is considered first-line therapy, although response to treatment is highly variable. Using an extreme phenotype of failure of rate control necessitating AV nodal ablation and pacemaker implantation, we conducted a genome-wide association study (GWAS) to identify genomic modulators of rate control therapy. Cases included 95 patients who failed rate control therapy. Controls (n = 190) achieved adequate rate control therapy with ≤2 AV nodal blockers using a conventional clinical definition. Genotyping was performed on the Illumina 610-Quad platform, and results were imputed to the 1000 Genomes reference haplotypes. A total of 554,041 single-nucleotide polymorphisms (SNPs) met criteria for minor allele frequency (>0.01), call rate (>95%), and quality control, and 6,055,224 SNPs were available after imputation. No SNP reached the canonical threshold for significance for GWAS of p <5 × 10(-8). Sixty-three SNPs with p <10(-5) at 6 genomic loci were genotyped in a validation cohort of 130 cases and 157 controls. These included 6q24.3 (near SAMD5/SASH1, p = 9.36 × 10(-8)), 4q12 (IGFBP7, p = 1.75 × 10(-7)), 6q22.33 (C6orf174, p = 4.86 × 10(-7)), 3p21.31 (CDCP1, p = 1.18 × 10(-6)), 12p12.1 (SOX5, p = 1.62 × 10(-6)), and 7p11 (LANCL2, p = 6.51 × 10(-6)). However, none of these were significant in the replication cohort or in a meta-analysis of both cohorts. In conclusion, we identified several potentially important genomic modulators of rate control therapy in atrial fibrillation, particularly SOX5, which was previously associated with heart rate at rest and PR interval. However, these failed to reach genome-wide significance., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Aims: SCN10A encodes the sodium channel Nav1.8 implicated by genome-wide association studies as a modulator of atrioventricular conduction (PR interval). In a cohort of patients with atrial fibrillation (AF), we examined whether there was an association between common variants in SCN10A and both the PR interval during normal sinus rhythm and the heart rate response during AF., Methods and Results: Patients prospectively enrolled in the Vanderbilt AF registry with electrocardiograms in normal sinus rhythm and/or AF within 1 year of enrollment were genotyped for two common SCN10A variants rs6795970 and rs12632942. Both variants were associated with the PR interval duration in a gene-dose effect on unadjusted analysis; after adjustment for the covariates age, gender, body mass index, hypertension, congestive heart failure, and medication usage, the association remained for rs6795970 only (P = 0.012, partial R(2) = 0.0139). On unadjusted analysis, heart rate response during AF was associated with rs6795970 (P = 0.035, partial R(2) = 0.015), but not with rs12632942 (P = 0.89), and neither association was significant after adjustment for covariates., Conclusion: The common variant rs6795970 in SCN10A is associated with the PR interval duration among healthy patients and those with AF. In addition, this single nucleotide polymorphism trended towards an association with heart rate response during AF indicating the importance of this common SCN10A polymorphism as a marker of atrioventricular conduction.

Single nucleotide polymorphisms (SNPs) at chromosome 4q25 (near PITX2) are strongly associated with atrial fibrillation (AF). We assessed whether a 4q25-tagging SNP (rs2200733) is associated with PR interval duration in patients with lone and typical AF and controls. Patients with lone (n = 169) and typical (n = 269) AF enrolled in the Vanderbilt AF registry and controls (n = 1,403) derived from the Vanderbilt DNA Biobank were studied. Carriage of the rs2200733T allele (CT or TT genotype) was more common in patients with lone (39%) than typical (25%) AF or controls (21%, p <0.01 for both comparisons). In both AF cohorts, we observed an association between genotype and PR interval duration (median PR interval for CC, CT, and TT: 162, 178, and 176 ms, respectively, for lone, p = 0.038 and 166, 180, and 196 ms, respectively, for typical, p = 0.001). After adjustment for covariates, the association between T allele and PR prolongation persisted, with mean effect size of 10.9, 12.8, and 4.4 ms for patients with lone and typical AF and controls, respectively (p <0.05 for each comparison). We found that a common 4q25 AF susceptibility allele (rs2200733) is associated with PR interval prolongation in patients with lone and typical AF and controls with no AF. Given that prolonged PR interval is an established risk factor for AF, this observation, in the context of previously described functional effects of PITX2 deficiency, provides further knowledge about the pathophysiological link of 4q25 variants with AF., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Background: Rare variants in candidate atrial fibrillation (AF) genes have been associated with AF in small kindreds. The extent to which such polymorphisms contribute to AF is unknown., Objective: The purpose of this study was to determine the spectrum and prevalence of rare amino acid coding (AAC) variants in candidate AF genes in a large cohort of unrelated lone AF probands., Methods: We resequenced 45 candidate genes in 303 European American (EA) lone AF probands (186 lone AF probands screened for each gene on average [range 89-303], 63 screened for all) identified in the Vanderbilt AF Registry (2002-2012). Variants detected were screened against 4300 EAs from the Exome Sequencing Project (ESP) to identify very rare (minor allele frequency ≤0.04%) AAC variants and these were tested for AF co-segregation in affected family members where possible., Results: Median age at AF onset was 46.0 years [interquartile range 33.0-54.0], and 35.6% had a family history of AF. Overall, 63 very rare AAC variants were identified in 60 of 303 lone AF probands, and 10 of 19 (52.6%) had evidence of co-segregation with AF. Among the 63 lone AF probands who had 45 genes screened, the very rare variant burden was 22%. Compared with the 4300 EA ESP, the proportion of lone AF probands with a very rare AAC variant in CASQ2 and NKX2-5 was increased 3-5-fold (P <.05)., Conclusion: No very rare AAC variants were identified in ~80% of lone AF probands. Potential reasons for the lack of very rare AAC variants include a complex pattern of inheritance, variants in as yet unidentified AF genes or in noncoding regions, and environmental factors., (© 2013 Heart Rhythm Society Published by Heart Rhythm Society All rights reserved.)

Background: Postoperative atrial fibrillation (PoAF) after cardiac surgery is common and associated with increased morbidity and mortality. Increased sympathetic activation after surgery contributes to PoAF, and β-blockers are the first-line recommendation for its prevention. We examined the hypothesis that common functional genetic variants in the β1-adrenoreceptor, the mediator of cardiac sympathetic activation and drug target of β-blockers, are associated with the risk for PoAF and with the protective effect of β-blockers., Methods: In a prospective cohort study, we studied 947 adult European Americans who underwent cardiac surgery at Vanderbilt University between 1999 and 2005. We genotyped 2 variants in the β1-adrenoreceptor, rs1801253 (Arg389Gly) and rs1801252 (Ser49Gly), and used logistic regression to examine the association between genotypes and PoAF occurring within 14 days after surgery, before and after adjustment for demographic and clinical covariates., Results: Postoperative atrial fibrillation occurred in 239 patients (25.2%) and was associated with rs1801253 genotype (adjusted P = .008), with Gly389Gly having an odds ratio of 2.63 (95% CI 1.42-4.89) for PoAF compared to the common Arg389Arg (P = .002). In a predefined subgroup analysis, this association appeared to be stronger among patients without β-blocker prophylaxis (adjusted odds ratio 7.00, 95% CI 1.82-26.96, P = .005) compared to patients with β-blocker prophylaxis, among whom the association between rs1801253 genotype and PoAF was not statistically significant (adjusted P = .11)., Conclusion: The Gly389 variant in the β1-adrenoreceptor is associated with PoAF, and this association appears to be modulated by β-blocker therapy. Future studies of the association of other adrenergic pathway genes with PoAF will be of interest., (© 2014.)

Atrial fibrillation (AF) is the most-common sustained arrhythmia observed in clinical practice, but response to therapy is highly variable between patients. Current drug therapies to suppress AF are incompletely and unpredictably effective and carry substantial risk of proarrhythmia and noncardiac toxicities. The limited success of therapy for AF is partially the result of heterogeneity of the underlying substrate, interindividual differences in disease mechanisms, and our inability to predict response to therapies in individual patients. In this Review, we discuss the evidence that variability in response to drug therapy is also conditioned by the underlying genetic substrate for AF. Increased susceptibility to AF is mediated through diverse genetic mechanisms, including modulation of the atrial action-potential duration, conduction slowing, and impaired cell-to-cell communication, as well as novel mechanisms, such as regulation of signalling proteins important in the pathogenesis of AF. However, the translation of genetic data to the care of the patients with AF has been limited because of poor understanding of the underlying mechanisms associated with common AF-susceptibility loci, a dearth of prospective, adequately powered studies, and the challenges associated with determining efficacy of antiarrhythmic drugs. What is apparent, however, is the need for appropriately designed, genotype-directed clinical trials.

Background: Genome-wide association studies have identified numerous common polymorphisms associated with atrial fibrillation (AF). The 3 loci most strongly associated with AF occur at chromosome 4q25 (near PITX2), 16q22 (in ZFHX3), and 1q21 (in KCNN3)., Objective: To evaluate whether timing of AF recurrence after direct current cardioversion (DCCV) is modulated by common AF susceptibility alleles., Methods: A total of 208 patients (age 65 ± 11 years; 77% men) with persistent AF underwent successful DCCV and were prospectively evaluated at 3, 6, and 12 months for AF recurrence. Four single nucleotide polymorphisms--rs2200733 and rs10033464 at 4q25, rs7193343 in ZFHX3, and rs13376333 in KCNN3--were genotyped., Results: The final study cohort consisted of 184 patients. In 162 (88%) patients, sinus rhythm was restored with DCCV, of which 108 (67%) had AF recurrence at a median of 60 (interquartile range 29-176) days. In multivariable analysis, the presence of any common single nucleotide polymorphism (rs2200733, rs10033464) at the 4q25 locus was an independent predictor of AF recurrence (hazard ratio 2.1; 95% confidence interval 1.21-3.30; P = .008). Furthermore, rs2200733 exhibited a graded allelic dose response for early AF recurrence (homozygous variants: 7 [interquartile range 4-56] days; heterozygous variants: 54 [28-135] days; and wild type: 64 [29-180] days; P = .03)., Conclusions: To our knowledge, this is the first study to evaluate whether genomic markers can predict timing of AF recurrence in patients undergoing elective DCCV. Our findings show that a common polymorphism on chromosome 4q25 (rs2200733) is an independent predictor of AF recurrence after DCCV and point to a potential role of stratification by genotype., (Copyright © 2013 Heart Rhythm Society. Published by Elsevier Inc. All rights reserved.)

Background: Common single nucleotide polymorphisms at chromosome 4q25 (rs2200733, rs10033464) are associated with both lone and typical atrial fibrillation (AF). Risk alleles at 4q25 have recently been shown to predict recurrence of AF after ablation in a population of predominately lone AF, but lone AF represents only 5%-30% of AF cases., Objective: To test the hypothesis that 4q25 AF risk alleles can predict response to AF ablation in the majority of AF cases., Methods: Patients enrolled in the Vanderbilt AF Registry underwent 378 catheter-based AF ablations (median age 60 years; 71% men; 89% typical AF) between 2004 and 2011. The primary end point was time to recurrence of any nonsinus atrial tachyarrhythmia (atrial tachycardia, atrial flutter, or AF)., Results: Two-hundred atrial tachycardia, atrial flutter, or AF recurrences (53%) were observed. In multivariable analysis, the rs2200733 risk allele predicted a 24% shorter recurrence-free time (survival time ratio 0.76; 95% confidence interval [CI] 0.6-0.95; P = .016) compared with wild type. The heterozygous haplotype demonstrated a 21% shorter recurrence-free time (survival time ratio 0.79; 95% CI 0.62-0.99) and the homozygous risk allele carriers a 39% shorter recurrence-free time (survival time ratio 0.61; 95% CI 0.37-1.0; P = .037)., Conclusions: Risk alleles at the 4q25 loci predict impaired clinical response to AF ablation in a population of patients with predominately typical AF. Our findings suggest that the rs2200733 polymorphism may hold promise as an objectively measured patient characteristic that can be used as a clinical tool for selecting patients for AF ablation., (Copyright © 2013 Heart Rhythm Society. Published by Elsevier Inc. All rights reserved.)

Atrial fibrillation (AF) is the most common cardiac arrhythmia and carries a significant risk of stroke and heart failure. The molecular etiologies of AF are poorly understood, leaving patients with limited therapeutic options. AF has been recognized as an inherited disease in almost 30% of patient cases. However, few genetic loci have been identified and the mechanisms linking genetic variants to AF susceptibility remain unclear. By sequencing 193 probands with lone AF, we identified a Q76E variant within the coding sequence of the bone morphogenetic protein (BMP) antagonist gremlin-2 (GREM2) that increases its inhibitory activity. Functional modeling in zebrafish revealed that, through regulation of BMP signaling, GREM2 is required for cardiac laterality and atrial differentiation during embryonic development. GREM2 overactivity results in slower cardiac contraction rates in zebrafish, and induction of previously identified AF candidate genes encoding connexin-40, sarcolipin and atrial natriuretic peptide in differentiated mouse embryonic stem cells. By live heart imaging in zebrafish overexpressing wild-type or variant GREM2, we found abnormal contraction velocity specifically in atrial cardiomyocytes. These results implicate, for the first time, regulators of BMP signaling in human AF, providing mechanistic insights into the pathogenesis of the disease and identifying potential new therapeutic targets.

Obese patients with atrial fibrillation (AF) are frequently treated with AF ablation. We sought to examine whether a body mass index (BMI) threshold exists beyond which the odds of experiencing a complication from AF ablation increases. All patients enrolled in the Vanderbilt AF Registry who underwent catheter-based AF ablation from May 1999 to February 2012 were included. Major complications were recorded. Morbid obesity was defined as a BMI >40 kg/m(2) and examined in multivariable analysis. A total of 35 complications (6.8%) occurred in 512 ablations. Morbidly obese patients experienced a greater rate of complications (6 of 42, 14.3%) than the nonmorbidly obese (29 of 470, 6.2%; p = 0.046). Using a discrete BMI cutoff, the odds of complications increased 3.1-fold in those with morbid obesity (odds ratio [OR] 3.1, 95% confidence interval [CI] 1.1 to 8.4, p = 0.03) and 2.1-fold for female gender (OR 2.1, 95% CI 1.04 to 4.38, p = 0.04). With BMI as a continuous variable, the odds of complications increased by 5% per 1 unit increase in BMI (OR 1.05, 95% CI 1.0 to 1.11, p = 0.05), and the increase for female gender was 2.2-fold (OR 2.2, 95% CI 1.1 to 4.6, p = 0.03). In conclusion, morbid obesity represents a BMI threshold above which the odds of complications with AF ablation increase significantly. The increase in complications appears to be driven primarily by events in women, suggesting that morbidly obese women are a special population when considering AF ablation., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Despite a greater burden of traditional risk factors, atrial fibrillation (AF) is less common among blacks than whites for reasons that are unclear. The aim of this study was to examine race- and gender-specific influences of demographic, lifestyle, anthropometric, and medical factors on AF in a large cohort of blacks and whites. Among white and black participants in the Southern Community Cohort Study (SCCS) aged ≥65 years receiving Medicare coverage from 1999 to 2008 (n = 8,836), diagnoses of AF (International Classification of Diseases, Ninth Revision, Clinical Modification code 427.3) were ascertained. Multivariate logistic regression was used to compute AF odds ratios associated with participant characteristics, including histories of hypertension, diabetes, stroke, and myocardial infarction or coronary artery bypass graft surgery, ascertained at cohort entry. Over an average of 5.7 years of Medicare coverage, AF was diagnosed in 1,062 participants. AF prevalence was significantly lower among blacks (11%) than whites (15%) (p <0.0001). Odds ratios for AF increased with age and were higher among men, the tall and obese, and patients with each of the co-morbid conditions, but the AF deficit among blacks compared to whites persisted after adjustment for these factors (odds ratio 0.64, 95% confidence interval 0.55 to 0.73). The patterns of AF risk were similar for blacks and whites, although associations with hypertension, diabetes, and stroke were somewhat stronger among blacks. In conclusion, these findings confirm the lower prevalence of AF among blacks than whites and suggest that traditional risk factors for AF apply similarly to the 2 groups and thus do not appear to explain the AF paradox in blacks., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Aim: The Kir 6.1 K(atp) channel is believed to play an important role in ventricular repolarization as determined from both functional and genetic studies of the potassium inwardly-rectifying channel, subfamily J, member 8 (KCNJ8)-S422L missense mutation in patients with J-wave syndromes. Although Kir6.1 is also present in atrial tissue, it is unknown whether this channel modulates atrial repolarization and hence whether the S422L mutation portends a greater risk of atrial arrhythmias. This study sought to examine whether there was an increased frequency of the KCNJ8-S422L mutation among patients with atrial fibrillation (AF) and early repolarization (ER) as a possible novel susceptibility gene for AF., Methods and Results: A total of 325 lone AF probands were identified from the Vanderbilt AF Registry, a collection of clinical data and DNA from consented, consecutively enrolled participants. The coding regions of KCNJ8 were sequenced, and the patient's presenting electrocardiogram (ECG) was reviewed by two independent physicians for ER abnormalities. The KCNJ8-S422L mutation was identified in two AF probands while no other candidate gene variants were identified in these cases. Twenty-two (7%) patients were found to have ER on the ECG, including the two probands carrying the S422L variant. In one small AF kindred, the S422L variant co-segregated with AF and ER., Conclusions: The KCNJ8-S422L variant is associated with both increased AF susceptibility and ER indicating a role for Kir 6.1 K(atp) channel in both ventricular and atrial repolarization.

Objectives: The aim of this study was to test the hypothesis that 2 common polymorphisms in the chromosome 4q25 region that have been associated with atrial fibrillation (AF) contribute to the variable penetrance of familial AF., Background: Although mutations in ion channels, gap junction proteins, and signaling molecules have been described for Mendelian forms of AF, penetrance is highly variable. Recent studies have consistently identified 2 common single-nucleotide polymorphisms in the chromosome 4q25 region as independent AF susceptibility alleles., Methods: Eleven families in which AF was present in ≥2 members who also shared a candidate gene mutation were studied. These mutations were identified in all subjects with familial lone AF (n = 33) as well as apparently unaffected family members (age >50 years with no AF; n = 17)., Results: Mutations were identified in SCN5A (n = 6), NPPA (n = 2), KCNQ1 (n = 1), KCNA5 (n = 1), and NKX2.5 (n = 1). In genetic association analyses, unstratified and stratified according to age of onset of AF and unaffected age >50 years, there was a highly statistically significant association between the presence of both common (rs2200733 and rs10033464) and rare variants and AF (unstratified p = 1 × 10(-8), stratified [age of onset <50 years and unaffected age >50 years] p = 7.6 × 10(-5)) (unstratified p < 0.0001, stratified [age of onset <50 years and unaffected age >50 years] p < 0.0001). Genetic association analyses showed that the presence of common 4q25 risk alleles predicted whether carriers of rare mutations developed AF (p = 2.2 × 10(-4))., Conclusions: Common AF-associated 4q25 polymorphisms modify the clinical expression of latent cardiac ion channel and signaling molecule gene mutations associated with familial AF. These findings support the idea that the genetic architecture of AF is complex and includes both rare and common genetic variants., (Copyright © 2012 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Objectives: This study tested the hypothesis that response to antiarrhythmic drugs (AADs) is modulated by 3 common loci associated with atrial fibrillation (AF)., Background: Recent genome-wide association studies have identified 3 loci, on chromosomes 4q25 (near PITX2), 16q22 (in ZFHX3), and 1q21 (in KCNN3), that associate with either typical or lone AF. These findings indicate that variable mechanisms contribute to AF susceptibility, and suggest that response to therapy may be genotype dependent., Methods: We studied 478 and 198 Caucasian patients in the discovery cohort and validation cohort, respectively, who were prospectively enrolled in the Vanderbilt AF registry. Response was defined prospectively as successful rhythm control if the patient remained on the same AAD therapy for a minimum of 6 months with ≥75% reduction in symptomatic AF burden. We also evaluated AF recurrence by 12-lead electrocardiogram (ECG) at 3, 6, and 12 months. Symptomatic patients were also given a 24- to 48-h Holter monitor or 30-day event recorder when AF recurrence was not captured by 12-lead ECG., Results: In the discovery cohort, 399 (83%) patients were successfully rhythm controlled. Multiple clinical variables (including age, hypertension, lone AF) failed to significantly predict response to AADs; however, single nucleotide polymorphism (SNP) rs10033464 at 4q25 was an independent predictor of successful rhythm control in patients with typical AF carrying the ancestral allele (wild type) versus carriers of variant allele (odds ratio [OR]: 4.7, 95% confidence interval [CI]: 1.83 to 12, p = 0.0013. In the validation cohort, 143 (72%) patients met the criteria for successful rhythm control, and rs10033464 was again an independent predictor of successful rhythm control, OR: 1.5, 95% CI: 1.02 to 3.06, p = 0.04. This SNP (rs10033464) was an independent predictor of AF recurrence in the discovery (39% AF recurrence) and validation (38% AF recurrence) cohorts; OR: 3.27, 95% CI: 1.7 to 6, p < 0.001 and OR: 4.3, 95% CI: 1.98 to 9.4, p < 0.001, respectively., Conclusions: These results suggest that a common SNP on chromosome 4q25 associated with AF modulates response to AAD therapy and points to a potential role for stratification of therapeutic approaches by genotype., (Copyright © 2012 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Atrial fibrillation (AF) is more common in those with obstructive sleep apnea (OSA) than in unaffected subjects and recurs more frequently in the presence of severe OSA after electrical cardioversion and AF ablation. However, it is unknown whether the severity of OSA influences the efficacy of antiarrhythmic drug (AAD) therapy in patients with OSA and AF. The aim of this study was to examine the impact of OSA severity on the treatment of patients with symptomatic AF using AADs. Sixty-one patients (mean age 62 ± 15 years, 21 women) treated with AADs for symptomatic AF who underwent overnight polysomnography were studied. Rhythm control was prospectively defined as successful if a patient remained on the same AAD therapy for ≥6 months with ≥75% reduction in symptomatic AF burden. Twenty-four patients (40%) had severe OSA. Thirty patients (49%) were rhythm controlled with AADs. Nonresponders to AADs were more likely to have severe OSA than milder disease (52% vs 23%, p <0.05); those with severe OSA were less likely to respond to AADs than participants with nonsevere OSA (39% vs 70%, p = 0.02). Nonresponders had higher apnea-hypopnea indexes than responders (34 ± 25 vs 22 ± 18 events/hour, p = 0.05), but there were no differences between these groups in minimum oxygen saturation or percentage of time spent in rapid eye movement sleep. In conclusion, patients with severe OSA are less likely to respond to AAD therapy for AF than those with milder forms of OSA., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Atrial fibrillation is a highly prevalent arrhythmia and a major risk factor for stroke, heart failure and death. We conducted a genome-wide association study (GWAS) in individuals of European ancestry, including 6,707 with and 52,426 without atrial fibrillation. Six new atrial fibrillation susceptibility loci were identified and replicated in an additional sample of individuals of European ancestry, including 5,381 subjects with and 10,030 subjects without atrial fibrillation (P < 5 × 10(-8)). Four of the loci identified in Europeans were further replicated in silico in a GWAS of Japanese individuals, including 843 individuals with and 3,350 individuals without atrial fibrillation. The identified loci implicate candidate genes that encode transcription factors related to cardiopulmonary development, cardiac-expressed ion channels and cell signaling molecules.

Objectives: In this study, we evaluated the impact of 2 common β1-adrenergic receptor (β1-AR) polymorphisms (G389R and S49G) in response to ventricular rate control therapy in patients with atrial fibrillation (AF)., Background: Randomized studies have shown that ventricular rate control is an acceptable treatment strategy in patients with AF. However, identification of patients who will adequately respond to rate-control therapy remains a challenge., Methods: We studied 543 subjects (63% men; age 61.8 ± 14 years) prospectively enrolled in the Vanderbilt AF registry and managed with rate-control strategy. A "responder" displayed adequate ventricular rate control based on the AFFIRM (Atrial Fibrillation Follow-Up Investigation of Rhythm Management) criteria: average heart rate (HR) at rest ≤80 beats/min; and maximum HR during a 6-min walk test ≤110 beats/min or average HR during 24-h Holter ≤100 beats/min., Results: A total of 295 (54.3%) patients met the AFFIRM criteria. Baseline clinical characteristics were similar in responders and nonresponders except for mean resting HR (76 ± 20 beats/min vs. 70 ± 15 beats/min; p < 0.01) and smoking (6% vs. 1%; p < 0.01). Multiple clinical variables (age, gender, hypertension) failed to predict response to rate-control therapy. By contrast, carriers of Gly variant at 389 were more likely to respond favorably to rate-control therapy; 60% versus 51% in the Arg389Arg genotype, p = 0.04. This association persisted after correction for multiple clinical factors (odds ratio: 1.42, 95% confidence interval: 1.00 to 2.03, p < 0.05). Among responders, subjects carrying the Gly389 variant required the lowest doses of rate-control medications; atenolol: 92 mg versus 68 mg; carvedilol: 44 mg versus 20 mg; metoprolol: 80 mg versus 72 mg; diltiazem: 212 mg versus 180 mg, and verapamil: 276 mg versus 200 mg, respectively (p < 0.01 for all comparisons)., Conclusions: We have identified a common β1-AR polymorphism, G389R, that is associated with adequate response to rate-control therapy in AF patients. Gly389 is a loss-of-function variant; consequently, for the same adrenergic stimulation, it produces reduced levels of adenyl cyclase, and hence, attenuates the β-adrenergic cascade. Mechanistically, the effect of rate-control drugs will be synergistic with that of the Gly389 variant, which could possibly explain our findings. These findings represent a step forward in the development of a long-term strategy of selecting treatment options in AF based on genotype., (Copyright © 2012 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)