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Cardiovascular disease and heart failure are a major health challenge, with sex differences in pathophysiology and treatment responses critically influencing patient outcomes. G protein-coupled receptor (GPCR) kinase 2 (GRK2) is a pivotal regulator of cellular signaling whose elevation is a hallmark of heart failure progression. Its complex network of protein interactions impact a wide range of physiological and pathophysiological processes including cardiac function. In this study, we examined the effects of cardiac-restricted expression of an amino-terminal peptide of GRK2 (βARKnt) in female mice subjected to acute and chronic pressure overload. Our findings reveal that that βARKnt affects hypertrophy development and cardiac function differently in female mice than in males, leading to a transition to heart failure not observed in control females or βARKnt males. Notably, the βARKnt female mice exhibited baseline hypertrophy with distinct left atrial morphology, increased fibrosis, and immune cell infiltration compared to the controls, which progressed under chronic stress, indicating adverse cardiac remodeling. Furthermore, βARKnt female mice, unlike males, exhibit impaired tissue respiration following acute pressure overload and altered glucose sensitivity and insulin tolerance, highlighting significant remodeling of cardiac and systemic metabolism.

Background: Atrial fibrillation GWAS (genome-wide association studies) identified significant associations for rs1152591 and linked variants in the SYNE2 gene encoding Nesprin-2, which connects the nuclear membrane with the cytoskeleton., Methods: Reporter gene vector transfection and CRISPR-Cas9 editing were used to identify the causal variant regulating the expression of SYNE2α1 . After SYNE2 knockdown or SYNE2α1 overexpression in human stem cell-derived cardiomyocytes, nuclear phenotypes were assessed by imaging and atomic force microscopy. Gene expression was assessed by RNAseq and gene set enrichment analysis. Fura-2 AM staining assessed calcium transients. Optical mapping assessed action potential duration and conduction velocity., Results: The risk allele of rs1152591 had lower promoter and enhancer activity and was significantly associated with lower expression of the short SYNE2α1 isoform in human stem cell-derived cardiomyocytes, without an effect on the expression of the full-length SYNE2 mRNA. SYNE2α1 overexpression had dominant negative effects on the nucleus with its overexpression or SYNE2 knockdown leading to increased nuclear area and decreased nuclear stiffness. Gene expression results from SYNE2α1 overexpression demonstrated both concordant and nonconcordant effects with SYNE2 knockdown. SYNE2α1 overexpression had a gain of function on electrophysiology, leading to significantly faster calcium reuptake and decreased assessed action potential duration, while SYNE2 knockdown showed both shortened assessed action potential duration and decreased conduction velocity., Conclusions: rs1152591 was identified as a causal atrial fibrillation variant, with the risk allele decreasing SYNE2α1 expression. Downstream effects of SYNE2α1 overexpression include changes in nuclear stiffness and electrophysiology, which may contribute to the mechanism for the risk allele's association with AF., Competing Interests: None.

Genome-wide association studies have identified a locus on chromosome 10q22, where many co-inherited single nucleotide polymorphisms (SNPs) are associated with atrial fibrillation (AF). This study seeks to identify the impact of this locus on gene expression at the transcript isoform level in human left atria and to gain insight into potential causal variants. Bulk RNA sequencing was analyzed to identify myozenin 1 ( MYOZ1 ) and synaptopodin 2-like ( SYNPO2L ) transcript isoforms and the association of common SNPs in this region with transcript isoform expression levels. Chromatin marks were used to suggest candidate regulatory SNPs in this region. Protein amino acid changes were examined for predicted functional consequences. Transfection of MYOZ1 and two SYNPO2L isoforms were performed to localize their encoded proteins in cardiomyocytes derived from stem cells. We identified one MYOZ1 transcript isoform and four SYNPO2L transcript isoforms, two of which encode proteins, while the other two encode long noncoding RNAs (lncRNAs). The risk allele of the strongest AF susceptibility SNP on chromosome 10q22 is associated with decreased MYOZ1 expression and increased expression of the two SNYPO2L lncRNA isoforms. There are many SNPs co-inherited with the top AF-associated SNP due to linkage disequilibrium (LD), including rs11000728, which we propose as the MYOZ1 regulatory SNP, confirmed by reporter gene transfection. In addition, this LD block includes three missense SNPs in the SYNPO2L gene, with the minor protective haplotype predicted to be detrimental to protein function. MYOZ1 and both protein isoforms of SYNPO2L were localized to the sarcomere. This is a complex locus with the potential for several SNPs in a haplotype to alter AF susceptibility by opposing effects on MYOZ1 and SYNPO2L lncRNA expression, along with effects on SYNPO2L protein function.

Background: While sleep disorders are implicated in atrial fibrillation (AF), the interplay of physiologic alterations and symptoms remains unclear. Sleep-based phenotypes can account for this complexity and translate to actionable approaches to identify at-risk patients and therapeutic interventions., Objectives: This study hypothesized discrete phenotypes of symptoms and polysomnography (PSG)-based data differ in relation to incident AF., Methods: Data from the STARLIT (sleep Signals, Testing, And Reports LInked to patient Traits) registry on Cleveland Clinic patients (≥18 years of age) who underwent PSG from November 27, 2004, to December 30,2015, were retrospectively examined. Phenotypes were identified using latent class analysis of symptoms and PSG-based measures of sleep-disordered breathing and sleep architecture. Phenotypes were included as the primary predictor in a multivariable-adjusted Cox proportional hazard models for incident AF., Results: In our cohort (N = 43,433, age 51.8 ± 14.5 years, 51.9% male, 74.9% White), 7.3% (n = 3,166) had baseline AF. Over a 7.6- ± 3.4-year follow-up period, 8.9% (n = 3,595) developed incident AF. Five phenotypes were identified. The hypoxia subtype (n = 3,245) had 48% increased incident AF (HR: 1.48; 95% CI: 1.34-1.64), the apneas + arousals subtype (n = 4,592) had 22% increased incident AF (HR: 1.22; 95% CI: 1.10-1.35), and the short sleep + nonrapid eye movement subtype (n = 6,126) had 11% increased incident AF (HR: 1.11; 95% CI: 1.01-1.22) compared with long sleep + rapid eye movement (n = 26,809), the reference group. The hypopneas subtype (n = 2,661) did not differ from reference (HR: 0.89; 95% CI: 0.77-1.03)., Conclusions: Consistent with prior evidence supporting hypoxia as an AF driver and cardiac risk of the sleepy phenotype, this constellation of symptoms and physiologic alterations illustrates vulnerability for AF development, providing potential value in enhancing our understanding of integrated sleep-specific symptoms and physiologic risk of atrial arrhythmogenesis., Competing Interests: Funding Support and Author Disclosures This work was supported by a Transformative Neuroscience Research Resource Development Award funded by the Cleveland Clinic Foundation; a Neurological Institute Center for Outcomes Research and Evaluation Pilot Grant funded by the Cleveland Clinic Foundation; SMARRT (Supporting Multidisciplinary Achievement in Respiratory Research Training) grant T32HL155005 funded by the National Heart, Lung, and Blood Institute of the National Institutes of Health; and Physician Scientist Training Grant 302-PA-23 funded by the American Academy of Sleep Medicine Foundation. The authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2024 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Background: We leverage a large clinical cohort to elucidate sleep-disordered breathing and sleep-related hypoxia in incident atrial fibrillation (AF) development given the yet unclear contributions of sleep-related hypoxia and pulmonary physiology in sleep-disordered breathing and AF., Methods and Results: Patients who underwent sleep studies at Cleveland Clinic January 2, 2000, to December 30, 2015, comprised this retrospective cohort. Cox proportional hazards models were used to examine apnea hypopnea index, percentage time oxygen saturation <90%, minimum and mean oxygen saturation, and maximum end-tidal carbon dioxide on incident AF adjusted for age, sex, race, body mass index, cardiopulmonary disease and risk factors, antiarrhythmic medications, and positive airway pressure. Those with spirometry were additionally adjusted for forced expiratory volume in 1 second, forced vital capacity, and forced expiratory volume in 1 second/forced vital capacity. This cohort (n=42 057) was 50.7±14.1 years, 51.3% men, 74.1% White individuals, had median body mass index 33.2 kg/m 2 , and 1947 (4.6%) developed AF over 5 years. A 10-unit apnea hypopnea index increase was associated with 2% higher AF risk (hazard ratio [HR], 1.02 [95% CI, 1.00-1.03]). A 10-unit increase in percentage time oxygen saturation <90% and 10-unit decreases in mean and minimum oxygen saturation were associated with 6% (HR, 1.06 [95% CI, 1.04-1.08]), 30% (HR, 1.30 [95% CI, 1.18-1.42]), and 9% (HR, 1.09 [95% CI, 1.03-1.15]) higher AF risk, respectively. After adjustment for spirometry (n=9683 with available data), only hypoxia remained significantly associated with incident AF, although all coefficients were stable., Conclusions: Sleep-related hypoxia was associated with incident AF in this clinical cohort, consistent across 3 measures of hypoxia, persistent after adjustment for pulmonary physiologic impairment. Findings identify a strong role for sleep-related hypoxia in AF development without pulmonary physiologic interdependence.

Background: Genomewide association studies have associated >100 genetic loci with atrial fibrillation (AF), but establishing causal genes contributing to AF remains challenging., Objective: The purpose of this study was to determine candidate novel causal genes and mechanistic pathways associated with AF risk loci by incorporating gene expression and coexpression analyses and to provide a resource for functional studies and targeting of AF-associated genes., Methods: Cis-expression quantitative trait loci were identified for candidate genes near AF risk variants in human left atrial tissues. Coexpression partners were identified for each candidate gene. Weighted gene coexpression network analysis (WGCNA) identified modules and modules with overrepresentation of candidate AF genes. Ingenuity pathway analysis (IPA) was applied to the coexpression partners of each candidate gene. IPA and gene set over representation analysis were applied to each WGCNA module., Results: One hundred sixty-six AF-risk single nucleotide polymorphisms were located in 135 loci. Eighty-one novel genes not previously annotated as putative AF risk genes were identified. IPA identified mitochondrial dysfunction, oxidative stress, epithelial adherens junction signaling, and sirtuin signaling as the most frequent significant pathways. WGCNA characterized 64 modules (candidate AF genes overrepresented in 8), represented by cell injury, death, stress, developmental, metabolic/mitochondrial, transcription/translation, and immune activation/inflammation regulatory pathways., Conclusion: Candidate gene coexpression analyses suggest significant roles for cellular stress and remodeling in AF, supporting a dual risk model for AF: Genetic susceptibility to AF may not manifest until later in life, when cellular stressors overwhelm adaptive responses. These analyses also provide a novel resource to guide functional studies on potential causal AF genes., (Copyright © 2023 Heart Rhythm Society. Published by Elsevier Inc. All rights reserved.)

A specific genetic variant associated with atrial fibrillation risk, rs17171731, was identified as a regulatory variant responsible for controlling FAM13B expression. The atrial fibrillation risk allele decreases FAM13B expression, whose knockdown alters the expression of many genes in stem cell-derived cardiomyocytes, including SCN2B , and led to pro-arrhythmogenic changes in the late sodium current and Ca 2+ cycling. Fam13b knockout mice had increased P-wave and QT interval duration and were more susceptible to pacing-induced arrhythmias vs control mice. FAM13B expression, its regulation, and downstream effects are potential targets for investigation of patient-specific therapeutics., Competing Interests: This work was supported by the National Institutes of Health (NIH) grants RO1 HL 111314 and P01HL158502 to Drs Chung, Van Wagoner, Barnard, and Smith; an American Heart Association Strategically Focused Research Network grant 18SFRN34110067 to Drs Chung, Van Wagoner, Barnard, and Smith; the NIH National Center for Research Resources for Case Western Reserve University and Cleveland Clinic Clinical and Translational Science Award UL1-RR024989; the Cleveland Clinic Department of Cardiovascular Medicine philanthropy research funds; and the Tomsich Atrial Fibrillation Research Fund. Dr Ponce-Balbuena was supported by an American Heart Association Career Development Award 20CDA35320040. Dr Hsu was supported by NIH training grant T32 GM 088088. Dr Smith was supported by the Geoffrey Gund Endowed Chair for Cardiovascular Research. The Fusion Lumos LC-MS instrument was purchased from the NIH shared instrument grant 1S10OD023436. The authors have reported that they have no relationships relevant to the contents of this paper to disclose., (© 2023 The Authors.)

Background: The gut microbiota-dependent metabolite phenylacetylgutamine (PAGln) is both associated with atherothrombotic heart disease in humans, and mechanistically linked to cardiovascular disease pathogenesis in animal models via modulation of adrenergic receptor signaling., Methods: Here we examined both clinical and mechanistic relationships between PAGln and heart failure (HF). First, we examined associations among plasma levels of PAGln and HF, left ventricular ejection fraction, and N-terminal pro-B-type natriuretic peptide in 2 independent clinical cohorts of subjects undergoing coronary angiography in tertiary referral centers (an initial discovery US Cohort, n=3256; and a validation European Cohort, n=829). Then, the impact of PAGln on cardiovascular phenotypes relevant to HF in cultured cardiomyoblasts, and in vivo were also examined., Results: Circulating PAGln levels were dose-dependently associated with HF presence and indices of severity (reduced ventricular ejection fraction, elevated N-terminal pro-B-type natriuretic peptide) independent of traditional risk factors and renal function in both cohorts. Beyond these clinical associations, mechanistic studies showed both PAGln and its murine counterpart, phenylacetylglycine, directly fostered HF-relevant phenotypes, including decreased cardiomyocyte sarcomere contraction, and B-type natriuretic peptide gene expression in both cultured cardiomyoblasts and murine atrial tissue., Conclusions: The present study reveals the gut microbial metabolite PAGln is clinically and mechanistically linked to HF presence and severity. Modulating the gut microbiome, in general, and PAGln production, in particular, may represent a potential therapeutic target for modulating HF., Registration: URL: https://clinicaltrials.gov/; Unique identifier: NCT00590200 and URL: https://drks.de/drks&#95;web/; Unique identifier: DRKS00020915.

Chronic inflammation is a continuous low-grade activation of the systemic immune response. Whereas downstream inflammatory markers are associated with atrial fibrillation (AF), upstream inflammatory effectors including eicosanoids are less studied. To examine the association between eicosanoids and incident AF. We used a liquid chromatography-mass spectrometry for the non-targeted measurement of 161 eicosanoids and eicosanoid-related metabolites in the Framingham Heart Study. The association of each eicosanoid and incident AF was assessed using Cox proportional hazards models and adjusted for AF risk factors, including age, sex, height, weight, systolic/diastolic blood pressure, current smoking, antihypertensive medication, diabetes, history of myocardial infarction and heart failure. False discovery rate (FDR) was used to adjust for multiple testing. Eicosanoids with FDR < 0.05 were considered significant. In total, 2676 AF-free individuals (mean age 66 ± 9 years, 56% females) were followed for mean 10.8 ± 3.4 years; 351 participants developed incident AF. Six eicosanoids were associated with incident AF after adjusting for multiple testing (FDR < 0.05). A joint score was built from the top eicosanoids weighted by their effect sizes, which was associated with incident AF (HR = 2.72, CI = 1.71-4.31, P = 2.1 × 10 -5 ). In conclusion, six eicosanoids were associated with incident AF after adjusting for clinical risk factors for AF., (© 2022. The Author(s).)

Effective drugs for atrial fibrillation (AF) are lacking, resulting in significant morbidity and mortality. This study demonstrates that network proximity analysis of differentially expressed genes from atrial tissue to drug targets can help prioritize repurposed drugs for AF. Using enrichment analysis of drug-gene signatures and functional testing in human inducible pluripotent stem cell (iPSC)-derived atrial-like cardiomyocytes, we identify metformin as a top repurposed drug candidate for AF. Using the active compactor, a new design analysis of large-scale longitudinal electronic health record (EHR) data, we determine that metformin use is significantly associated with a reduced risk of AF (odds ratio = 0.48, 95%, confidence interval [CI] 0.36-0.64, p < 0.001) compared with standard treatments for diabetes. This study utilizes network medicine methodologies to identify repurposed drugs for AF treatment and identifies metformin as a candidate drug., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Objective: Creeping fat, the wrapping of mesenteric fat around the bowel wall, is a typical feature of Crohn's disease, and is associated with stricture formation and bowel obstruction. How creeping fat forms is unknown, and we interrogated potential mechanisms using novel intestinal tissue and cell interaction systems., Design: Tissues from normal, UC, non-strictured and strictured Crohn's disease intestinal specimens were obtained. The muscularis propria matrisome was determined via proteomics. Mesenteric fat explants, primary human preadipocytes and adipocytes were used in multiple ex vivo and in vitro cell migration systems on muscularis propria muscle cell derived or native extracellular matrix. Functional experiments included integrin characterisation via flow cytometry and their inhibition with specific blocking antibodies and chemicals., Results: Crohn's disease muscularis propria cells produced an extracellular matrix scaffold which is in direct spatial and functional contact with the immediately overlaid creeping fat. The scaffold contained multiple proteins, but only fibronectin production was singularly upregulated by transforming growth factor-β1. The muscle cell-derived matrix triggered migration of preadipocytes out of mesenteric fat, fibronectin being the dominant factor responsible for their migration. Blockade of α5β1 on the preadipocyte surface inhibited their migration out of mesenteric fat and on 3D decellularised intestinal tissue extracellular matrix., Conclusion: Crohn's disease creeping fat appears to result from the migration of preadipocytes out of mesenteric fat and differentiation into adipocytes in response to an increased production of fibronectin by activated muscularis propria cells. These new mechanistic insights may lead to novel approaches for prevention of creeping fat-associated stricture formation., Competing Interests: Competing interests: FR is consultant to Agomab, Allergan, AbbVie, Boehringer-Ingelheim, Celgene, Cowen, Genentech, Gilead, Gossamer, Guidepoint, Helmsley, Index Pharma, Jannsen, Koutif, Metacrine, Morphic, Pfizer, Pliant, Prometheus Biosciences, Receptos, RedX, Roche, Samsung, Takeda, Techlab, Thetis, UCB and receives funding from the Crohn’s and Colitis Foundation of America, the Helmsley Charitable Trust, Kenneth Rainin Foundation and the National Institute of Health. CF received speaker fees from UCB, Genentech, Sandoz, Janssen and he is consultant for Athos Therapeutics., (© Author(s) (or their employer(s)) 2022. No commercial re-use. See rights and permissions. Published by BMJ.)

Objective: To identify radiomic and clinical features associated with post-ablation recurrence of AF, given that cardiac morphologic changes are associated with persistent atrial fibrillation (AF), and initiating triggers of AF often arise from the pulmonary veins which are targeted in ablation. Methods: Subjects with pre-ablation contrast CT scans prior to first-time catheter ablation for AF between 2014-2016 were retrospectively identified. A training dataset (D 1 ) was constructed from left atrial and pulmonary vein morphometric features extracted from equal numbers of consecutively included subjects with and without AF recurrence determined at 1 year. The top-performing combination of feature selection and classifier methods based on C-statistic was evaluated on a validation dataset (D 2 ), composed of subjects retrospectively identified between 2005-2010. Clinical models ([Formula: see text]) were similarly evaluated and compared to radiomic ([Formula: see text]) and radiomic-clinical models ([Formula: see text]), each independently validated on D 2 . Results: Of 150 subjects in D 1 , 108 received radiofrequency ablation and 42 received cryoballoon. Radiomic features of recurrence included greater right carina angle, reduced anterior-posterior atrial diameter, greater atrial volume normalized to height, and steeper right inferior pulmonary vein angle. Clinical features predicting recurrence included older age, greater BMI, hypertension, and warfarin use; apixaban use was associated with reduced recurrence. AF recurrence was predicted with radio-frequency ablation models on D 2 subjects with C-statistics of 0.68, 0.63, and 0.70 for radiomic, clinical, and combined feature models, though these were not prognostic in patients treated with cryoballoon. Conclusions: Pulmonary vein morphology associated with increased likelihood of AF recurrence within 1 year of catheter ablation was identified on cardiac CT. Significance: Radiomic and clinical features-based predictive models may assist in identifying atrial fibrillation ablation candidates with greatest likelihood of successful outcome.

Atrial fibrillation (AF) is strongly associated with risk of stroke and heart failure. AF promotes atrial remodeling that increases risk of stroke due to left atrial thrombogenesis, and increases energy demand to support high rate electrical activity and muscle contraction. While many transcriptomic studies have assessed AF-related changes in mRNA abundance, fewer studies have assessed proteomic changes. We performed a proteomic analysis on left atrial appendage (LAA) tissues from 12 patients with a history of AF undergoing elective surgery; atrial rhythm was documented at time of surgery. Proteomic analysis was performed using liquid chromatography with mass spectrometry (LC/MS-MS). Data-dependent analysis identified 3090 unique proteins, with 408 differentially expressed between sinus rhythm and AF. Ingenuity Pathway Analysis of differentially expressed proteins identified mitochondrial dysfunction, oxidative phosphorylation, and sirtuin signaling among the most affected pathways. Increased abundance of electron transport chain (ETC) proteins in AF was accompanied by decreased expression of ETC complex assembly factors, tricarboxylic acid cycle proteins, and other key metabolic modulators. Discordant changes were also evident in the contractile unit with both up and downregulation of key components. Similar pathways were affected in a comparison of patients with a history of persistent vs. paroxysmal AF, presenting for surgery in sinus rhythm. Together, these data suggest that while the LAA attempts to meet the energetic demands of AF, an uncoordinated response may reduce ATP availability, contribute to tissue contractile and electrophysiologic heterogeneity, and promote a progression of AF from paroxysmal episodes to development of a substrate amenable to persistent arrhythmia.

Background: Elevated intracardiac pressure attributable to heart failure induces electrical and structural remodeling in the left atrium (LA) that begets atrial myopathy and arrhythmias. The underlying molecular pathways that drive atrial remodeling during cardiac pressure overload are poorly defined. The purpose of this study is to characterize the response of the ETV1 (ETS translocation variant 1) signaling axis in the LA during cardiac pressure overload in humans and mouse models and explore the role of ETV1 in atrial electrical and structural remodeling., Methods: We performed gene expression profiling in 265 left atrial samples from patients who underwent cardiac surgery. Comparative gene expression profiling was performed between 2 murine models of cardiac pressure overload, transverse aortic constriction banding and angiotensin II infusion, and a genetic model of Etv1 cardiomyocyte-selective knockout ( Etv1 f/f Mlc2a Cre /+ )., Results: Using the Cleveland Clinic biobank of human LA specimens, we found that ETV1 expression is decreased in patients with reduced ejection fraction. Consistent with its role as an important mediator of the NRG1 (Neuregulin 1) signaling pathway and activator of rapid conduction gene programming, we identified a direct correlation between ETV1 expression level and NRG1 , ERBB4 , SCN5A , and GJA5 levels in human LA samples. In a similar fashion to patients with heart failure, we showed that left atrial ETV1 expression is downregulated at the RNA and protein levels in murine pressure overload models. Comparative analysis of LA RNA sequencing datasets from transverse aortic constriction and angiotensin II-treated mice showed a high Pearson correlation, reflecting a highly ordered process by which the LA undergoes electrical and structural remodeling. Cardiac pressure overload produced a consistent downregulation of ErbB4 , Etv1 , Scn5a , and Gja5 and upregulation of profibrotic gene programming, which includes Tgfbr1/2, Igf1 , and numerous collagen genes. Etv1 f/f Mlc2a Cre /+ mice displayed atrial conduction disease and arrhythmias. Correspondingly, the LA from Etv1 f/f Mlc2a Cre /+ mice showed downregulation of rapid conduction genes and upregulation of profibrotic gene programming, whereas analysis of a gain-of-function ETV1 RNA sequencing dataset from neonatal rat ventricular myocytes transduced with Etv1 showed reciprocal changes., Conclusions: ETV1 is downregulated in the LA during cardiac pressure overload, contributing to both electrical and structural remodeling.

Standard sleep apnea (SA) screening instruments perform suboptimally in the atrial fibrillation (AF) population. We evaluated and optimized common OSA screening tools in the AF population. Participants of the Sleep Apnea and Atrial Fibrillation Biomarkers and Electrophysiologic Atrial Triggers (SAFEBEAT, NCT02576587) age (±5 years)-, sex-, body mass index (BMI ± 5 kg/m 2 )-matched case control study (n = 150 each group) completed concurrent questionnaires and overnight polysomnography. Models based on STOP, STOP-BANG, Berlin, NoSAS and Epworth Sleepiness Scale and also models with STOP-BANG predictors with resting heart rate or left atrial volume were constructed. "Best subset" analysis was used to select a predictor subset for evaluation. We assessed test performance for two outcome thresholds: apnea-hypopnea index (AHI) ≥ 5 and AHI ≥ 15. Paroxysmal AF participants were: 61.3 ± 12.1 years, BMI = 31.2 ± 6.6 kg/m 2 with median AHI = 11.8(IQR: 3.8, 24.5); 65 (43.3%) with AHI ≥ 15. Only STOP and STOP-BANG did not perform worse in AF relative to controls. For AHI ≥ 15, STOP-BANG (AUC 0.71, 95%CI:0.55-0.85) did not perform as well as NABS - a composite of neck circumference, age, and BMI as continuous variables and snoring (AUC 0.88, 95%CI:0.76-0.96). Optimal model for AHI ≥ 15 was NABS (sensitivity = 45%, specificity = 97%). For AHI ≥ 5, NABS was also the best performing (AUC 0.82, 95%CI:0.68-0.92, sensitivity = 78%, specificity = 67%). We identify a novel, short-item SA screening instrument for use in paroxysmal AF, i.e. NABS, with improved discriminative ability compared to commonly-used instruments. Further validation studies are needed to assess utility in other AF subtypes. Trial registration : clinicaltrials.gov NCT02576587., Competing Interests: AM consulted for Jazz Pharmaceuticals. RM received funds from the American Board of Medicine Sleep Medicine Exam test writing committee and royalties from UpToDate.

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: 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.

Background: Endothelin-1 (ET-1) is a potent vasoconstrictor, mitogen and inflammatory factor that may contribute to development of atrial fibrillation (AF). Plasma ET-1 levels are increased in hyperthyroid patients, but studies evaluating its relation to AF development in hyperthyroid patients are lacking., Objective: The present study seeks to evaluate the relation of plasma ET-1 to AF development as a function of thyroid status., Methods: Blood samples from euthyroid patients (n = 41), hypothyroid (n = 61), hyperthyroid (n = 41), AF with hyperthyroidism (n = 9), and euthyroid AF (n = 10) patients were collected. Plasma ET-1, CRP, and thyroid hormone levels were measured and compared between groups., Results: Plasma ET-1 levels were higher in hyperthyroid and euthyroid AF patients> hyperthyroid-non-AF > hypo and euthyroid non-AF patients. Plasma ET-1 levels positively correlated with free T3 and T4 levels, and negatively with TSH levels. By multivariate analysis, plasma ET-1 was positively associated with AF, hyperthyroidism, and age. Plasma CRP did not vary by study group in either univariate or multivariate analyses., Conclusion: Plasma ET-1 is associated with AF, elevated in hyperthyroid patients and positively correlated with thyroid hormone levels, suggesting that hyperthyroidism may increase ET-1 expression and release. This study may guide development of novel predictors of AF associated with hyperthyroidism, and may help to personalize therapy in hyperthyroid patients., Competing Interests: The authors have declared that no competing interests exist.

Electrocardiographic PR interval measures atrio-ventricular depolarization and conduction, and abnormal PR interval is a risk factor for atrial fibrillation and heart block. Our genome-wide association study of over 92,000 European-descent individuals identifies 44 PR interval loci (34 novel). Examination of these loci reveals known and previously not-yet-reported biological processes involved in cardiac atrial electrical activity. Genes in these loci are over-represented in cardiac disease processes including heart block and atrial fibrillation. Variants in over half of the 44 loci were associated with atrial or blood transcript expression levels, or were in high linkage disequilibrium with missense variants. Six additional loci were identified either by meta-analysis of ~105,000 African and European-descent individuals and/or by pleiotropic analyses combining PR interval with heart rate, QRS interval, and atrial fibrillation. These findings implicate developmental pathways, and identify transcription factors, ion-channel genes, and cell-junction/cell-signaling proteins in atrio-ventricular conduction, identifying potential targets for drug development.

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: Genetic variants at the SCN5A / SCN10A locus are strongly associated with electrocardiographic PR and QRS intervals. While SCN5A is the canonical cardiac sodium channel gene, the role of SCN10A in cardiac conduction is less well characterized., Methods: We sequenced the SCN10A locus in 3699 European-ancestry individuals to identify variants associated with cardiac conduction, and replicated our findings in 21,000 individuals of European ancestry. We examined association with expression in human atrial tissue. We explored the biophysical effect of variation on channel function using cellular electrophysiology., Results: We identified 2 intronic single nucleotide polymorphisms in high linkage disequilibrium ( r   2 =0.86) with each other to be the strongest signals for PR (rs10428132, β=-4.74, P =1.52×10 -14 ) and QRS intervals (rs6599251, QRS β=-0.73; P =1.2×10 -4 ), respectively. Although these variants were not associated with SCN5A or SCN10A expression in human atrial tissue (n=490), they were in high linkage disequilibrium ( r   2 ≥0.72) with a common SCN10A missense variant, rs6795970 (V1073A). In total, we identified 7 missense variants, 4 of which (I962V, P1045T, V1073A, and L1092P) were associated with cardiac conduction. These 4 missense variants cluster in the cytoplasmic linker of the second and third domains of the SCN10A protein and together form 6 common haplotypes. Using cellular electrophysiology, we found that haplotypes associated with shorter PR intervals had a significantly larger percentage of late current compared with wild-type (I962V+V1073A+L1092P, 20.2±3.3%, P =0.03, and I962V+V1073A, 22.4±0.8%, P =0.0004 versus wild-type 11.7±1.6%), and the haplotype associated with the longest PR interval had a significantly smaller late current percentage (P1045T, 6.4±1.2%, P =0.03)., Conclusions: Our findings suggest an association between genetic variation in SCN10A , the late sodium current, and alterations in cardiac conduction., (© 2018 American Heart Association, Inc.)

Background: Genome-wide association studies have identified 23 loci for atrial fibrillation (AF), but the mechanisms responsible for these associations, as well as the causal genes and genetic variants, remain undefined., Methods: To identify the effect of common genetic variants on gene expression that might explain the mechanisms linking genome-wide association loci with AF risk, we performed RNA sequencing of left atrial appendages from a biracial cohort of 265 subjects., Results: Combining gene expression data with genome-wide single nucleotide polymorphism data, we found that approximately two-thirds of the expressed genes were regulated in cis by common genetic variants at a false discovery rate of <0.05, defined as cis-expression quantitative trait loci. Twelve of 23 reported AF genome-wide association loci displayed genome-wide significant cis -expression quantitative trait loci, at PRRX1 (chromosome 1q24), SNRNP27 (1q24), CEP68 (2p14), FKBP7 (2q31), KCNN2 (5q22), FAM13B (5q31), CAV1 (7q31), ASAH1 (8p22), MYOZ1 (10q22), C11ORF45 (11q24), TBX5 (12q24), and SYNE2 (14q23), suggesting that altered expression of these genes plays a role in AF susceptibility. Allelic expression imbalance was used as an independent method to characterize the cis-control of gene expression. One thousand two hundred forty-eight of 5153 queried genes had cis -single nucleotide polymorphisms that significantly regulated allelic expression at a false discovery rate of <0.05., Conclusions: We provide a genome-wide catalog of the genetic control of gene expression in human left atrial appendage. These data can be used to confirm the relevance of genome-wide association loci and to direct future functional studies to identify the genes and genetic variants responsible for complex diseases such as AF., (© 2018 American Heart Association, Inc.)

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: The P wave on an ECG is a measure of atrial electric function, and its characteristics may serve as predictors for atrial arrhythmias. Increased mean P-wave duration and P-wave terminal force traditionally have been used as markers for left atrial enlargement, and both have been associated with increased risk of atrial fibrillation. Here, we explore the genetic basis of P-wave morphology through meta-analysis of genome-wide association study results for P-wave duration and P-wave terminal force from 12 cohort studies., Methods and Results: We included 44 456 individuals, of which 6778 (16%) were of African ancestry. Genotyping, imputation, and genome-wide association study were performed at each study site. Summary-level results were meta-analyzed centrally using inverse-variance weighting. In meta-analyses of P-wave duration, we identified 6 significant ( P <5×10 - 8 ) novel loci and replicated a prior association with S CN10A. We identified 3 loci at SCN5A , TBX5 , and CAV1/CAV2 that were jointly associated with the PR interval, PR segment, and P-wave duration. We identified 6 novel loci in meta-analysis of P-wave terminal force. Four of the identified genetic loci were significantly associated with gene expression in 329 left atrial samples. Finally, we observed that some of the loci associated with the P wave were linked to overall atrial conduction, whereas others identified distinct phases of atrial conduction., Conclusions: We have identified 6 novel genetic loci associated with P-wave duration and 6 novel loci associated with P-wave terminal force. Future studies of these loci may aid in identifying new targets for drugs that may modify atrial conduction or treat atrial arrhythmias., (© 2017 American Heart Association, Inc.)