Association Between Family History and Early-Onset Atrial Flutter Across Racial and Ethnic Groups.

BACKGROUND: Genetic and familial contributions to early-onset atrial fibrillation are described primarily in individuals of European ancestry. However, the role of racial and familial contributions in the pathogenesis of early-onset atrial flutter (EOAFL) is unclear. METHODS AND RESULTS: In this cross-sectional study, participants were enrolled prospectively from 2015 to 2021 in multiple academic centers with a diagnosis of atrial flutter (AFL) confirmed by ECG. EOAFL was defined as a diagnosis of AFL before age 66 years with no concomitant or previous diagnosis of atrial tachyarrhythmias. Family history was adjudicated through baseline questionnaires and direct family interviews about the diagnosis of atrial tachyarrhythmias, stroke, and cardiomyopathy. The primary exposure was a positive family history in first-degree relatives, and the primary outcome was the odds of EOAFL versus late-onset AFL. A total of 909 patients were enrolled. Participants with a positive family history of atrial tachyarrhythmias were younger, less likely to be of Black race, and more likely to have EOAFL. The adjusted odds ratio (OR) for EOAFL in those with a positive family history was 1.8 (95% CI, 1.1-3.0). There was an increased odds of EOAFL in those of Black race (OR, 2.1 [95% CI, 1.4-3.2]), alcohol use (OR, 1.6 [95% CI, 1.0-2.6]), and obstructive sleep apnea (OR, 1.9 [95% CI, 1.0-3.4]). Use of cardioselective ß blockers or calcium channel blockers before the diagnosis of AFL were associated with a lower odds of EOAFL (OR, 0.5 [95% CI, 0.2-0.9]). CONCLUSIONS: These findings suggest a potentially hereditary predisposition to EOAFL across race and ethnicity, warranting further study of the genetic contributions to AFL.

Dissecting the associations of KCNH2 genetic polymorphisms with various types of cardiac arrhythmias.

BACKGROUND: Cardiac arrhythmia, a common cardiovascular disease, is closely related to genetic polymorphisms. However, the associations between polymorphisms in KCNH2 and various arrhythmias remain inadequately explored. METHODS: Guided by the assumption that KCNH2 genetic polymorphisms significantly contribute to the development of arrhythmias, we thoroughly explored the associations between 85 KCNH2 genetic variations and 16 cardiac arrhythmias in a sample obtained from the UK Biobank (UKBB, N = 307,473). The illnesses documented in the electronic medical records of the sample were mapped to a phecode system for a more accurate representation of distinct phenotypes. Survival analysis was used to test the effect of KCNH2 variants on arrhythmia incidence, and a phenotype-wide association study (PheWAS) was performed to investigate the effect of KCNH2 polymorphisms on 102 traits, including physical measurements, biomarkers, and hematological indicators. RESULTS: Novel associations of variants rs2269001 and rs7789585 in KCNH2 with paroxysmal tachycardia (PT) and atrial fibrillation/flutter (AF/AFL), respectively, were identified. Moreover, with an increase in the number of minor alleles of these two variants, the incidence rates of PT and AF/AFL decreased. In addition, the PheWAS results suggested that these two single nucleotide polymorphisms were associated with multiple parameters in physical measurements and neutrophil percentage. CONCLUSION: The multiple novel associations observed in this study illustrate the importance of KCNH2 genetic variations in the pathogenesis of arrhythmia.

The expanding phenotypes of cohesinopathies: one ring to rule them all!

Preservation and development of life depend on the adequate segregation of sister chromatids during mitosis and meiosis. This process is ensured by the cohesin multi-subunit complex. Mutations in this complex have been associated with an increasing number of diseases, termed cohesinopathies. The best characterized cohesinopathy is Cornelia de Lange syndrome (CdLS), in which intellectual and growth retardations are the main phenotypic manifestations. Despite some overlap, the clinical manifestations of cohesinopathies vary considerably. Novel roles of the cohesin complex have emerged during the past decades, suggesting that important cell cycle regulators exert important biological effects through non-cohesion-related functions and broadening the potential pathomechanisms involved in cohesinopathies. This review focuses on non-cohesion-related functions of the cohesin complex, gene dosage effect, epigenetic regulation and TGF-ß in cohesinopathy context, especially in comparison to Chronic Atrial and Intestinal Dysrhythmia (CAID) syndrome, a very distinct cohesinopathy caused by a homozygous Shugoshin-1 (SGO1) mutation (K23E) and characterized by pacemaker failure in both heart (sick sinus syndrome followed by atrial flutter) and gut (chronic intestinal pseudo-obstruction) with no intellectual or growth delay. We discuss the possible impact of SGO1 alterations in human pathologies and the potential impact of the SGO1 K23E mutation in the sinus node and gut development and functions. We suggest that the human phenotypes observed in CdLS, CAID syndrome and other cohesinopathies can inform future studies into the less well-known non-cohesion-related functions of cohesin complex genes. Abbreviations: AD: Alzheimer Disease; AFF4: AF4/FMR2 Family Member 4; ANKRD11: Ankyrin Repeat Domain 11; APC: Anaphase Promoter Complex; ASD: Atrial Septal Defect; ATRX: ATRX Chromatin Remodeler; ATRX: Alpha Thalassemia X-linked intellectual disability syndrome; BIRC5: Baculoviral IAP Repeat Containing 5; BMP: Bone Morphogenetic Protein; BRD4: Bromodomain Containing 4; BUB1: BUB1 Mitotic Checkpoint Serine/Threonine Kinase; CAID: Chronic Atrial and Intestinal Dysrhythmia; CDK1: Cyclin Dependent Kinase 1; CdLS: Cornelia de Lange Syndrome; CHD: Congenital Heart Disease; CHOPS: Cognitive impairment, coarse facies, Heart defects, Obesity, Pulmonary involvement, Short stature, and skeletal dysplasia; CIPO: Chronic Intestinal Pseudo-Obstruction; c-kit: KIT Proto-Oncogene Receptor Tyrosine Kinase; CoATs: Cohesin Acetyltransferases; CTCF: CCCTC-Binding Factor; DDX11: DEAD/H-Box Helicase 11; ERG: Transcriptional Regulator ERG; ESCO2: Establishment of Sister Chromatid Cohesion N-Acetyltransferase 2; GJC1: Gap Junction Protein Gamma 1; H2A: Histone H2A; H3K4: Histone H3 Lysine 4; H3K9: Histone H3 Lysine 9; HCN4: Hyperpolarization Activated Cyclic Nucleotide Gated Potassium and Sodium Channel 4;p HDAC8: Histone deacetylases 8; HP1: Heterochromatin Protein 1; ICC: Interstitial Cells of Cajal; ICC-MP: Myenteric Plexus Interstitial cells of Cajal; ICC-DMP: Deep Muscular Plexus Interstitial cells of Cajal; If: Pacemaker Funny Current; IP3: Inositol trisphosphate; JNK: C-Jun N-Terminal Kinase; LDS: Loeys-Dietz Syndrome; LOAD: Late-Onset Alzheimer Disease; MAPK: Mitogen-Activated Protein Kinase; MAU: MAU Sister Chromatid Cohesion Factor; MFS: Marfan Syndrome; NIPBL: NIPBL, Cohesin Loading Factor; OCT4: Octamer-Binding Protein 4; P38: P38 MAP Kinase; PDA: Patent Ductus Arteriosus; PDS5: PDS5 Cohesin Associated Factor; P-H3: Phospho Histone H3; PLK1: Polo Like Kinase 1; POPDC1: Popeye Domain Containing 1; POPDC2: Popeye Domain Containing 2; PP2A: Protein Phosphatase 2; RAD21: RAD21 Cohesin Complex Component; RBS: Roberts Syndrome; REC8: REC8 Meiotic Recombination Protein; RNAP2: RNA polymerase II; SAN: Sinoatrial node; SCN5A: Sodium Voltage-Gated Channel Alpha Subunit 5; SEC: Super Elongation Complex; SGO1: Shogoshin-1; SMAD: SMAD Family Member; SMC1A: Structural Maintenance of Chromosomes 1A; SMC3: Structural Maintenance of Chromosomes 3; SNV: Single Nucleotide Variant; SOX2: SRY-Box 2; SOX17: SRY-Box 17; SSS: Sick Sinus Syndrome; STAG2: Cohesin Subunit SA-2; TADs: Topology Associated Domains; TBX: T-box transcription factors; TGF-ß: Transforming Growth Factor ß; TGFBR: Transforming Growth Factor ß receptor; TOF: Tetralogy of Fallot; TREK1: TREK-1 K(+) Channel Subunit; VSD: Ventricular Septal Defect; WABS: Warsaw Breakage Syndrome; WAPL: WAPL Cohesin Release Factor.

A genotype-directed comparative effectiveness trial of Bucindolol and metoprolol succinate for prevention of symptomatic atrial fibrillation/atrial flutter in patients with heart failure: Rationale and design of the GENETIC-AF trial.

BACKGROUND: Few therapies are available for the safe and effective treatment of atrial fibrillation (AF) in patients with heart failure. Bucindolol is a non-selective beta-blocker with mild vasodilator activity previously found to have accentuated antiarrhythmic effects and increased efficacy for preventing heart failure events in patients homozygous for the major allele of the ADRB1 Arg389Gly polymorphism (ADRB1 Arg389Arg genotype). The safety and efficacy of bucindolol for the prevention of AF or atrial flutter (AFL) in these patients has not been proven in randomized trials. METHODS/DESIGN: The Genotype-Directed Comparative Effectiveness Trial of Bucindolol and Metoprolol Succinate for Prevention of Symptomatic Atrial Fibrillation/Atrial Flutter in Patients with Heart Failure (GENETIC-AF) trial is a multicenter, randomized, double-blinded "seamless" phase 2B/3 trial of bucindolol hydrochloride versus metoprolol succinate, for the prevention of symptomatic AF/AFL in patients with reduced ejection fraction heart failure (HFrEF). Patients with pre-existing HFrEF and recent history of symptomatic AF are eligible for enrollment and genotype screening, and if they are ADRB1 Arg389Arg, eligible for randomization. A total of approximately 200 patients will comprise the phase 2B component and if pre-trial assumptions are met, 620 patients will be randomized at approximately 135 sites to form the Phase 3 population. The primary endpoint is the time to recurrence of symptomatic AF/AFL or mortality over a 24-week follow-up period, and the trial will continue until 330 primary endpoints have occurred. CONCLUSIONS: GENETIC-AF is the first randomized trial of pharmacogenetic guided rhythm control, and will test the safety and efficacy of bucindolol compared with metoprolol succinate for the prevention of recurrent symptomatic AF/AFL in patients with HFrEF and an ADRB1 Arg389Arg genotype. (ClinicalTrials.govNCT01970501).

Cardiac voltage-gated sodium channel mutations associated with left atrial dysfunction and stroke in children.

Aims: Cardiac atrial arrhythmias are the most common type of heart rhythm disorders. Its genetic elucidation remains challenging with poor understanding of cellular and molecular processes. These arrhythmias usually affect elderly population but in rare cases, young children may also suffer from such electrical diseases. Severe complications, including stroke, are commonly age related. This study aims to identify a genetic link between electro-mechanic atrial dysfunction and stroke in children. Methods and results: In two unrelated boys of 11 and 14 years with both stroke and atrial arrhythmias, the clinical phenotype was determined through a complete physical examination, electrocardiogram (ECG), Holter ECG, and computed tomography. The genetic testing was performed on a large 95 genes panel implicated in myocardial electrical imbalance, using the next generation sequencing method. The panel also includes the genes usually associated with the development of cardiomyopathies. In one child, a left atrial dilation was observed. The 2nd boy suffered from atrial standstill. Both suffered from atrial bradycardia, flutter, and fibrillation. The complete genetic testing revealed the SCN5A c.3823G>A (p.D1275N) mutation in the first family, c.1141-2A>G and c.3157G>A (p.E1053K) mutations in the second family. Conclusion: Our results strengthen the association between Nav1.5 mutations and the occurrence of stroke in young patients. It emphasizes the need to look for atrial myopathy in the decision process for anticoagulation in young patients with atrial arrhythmic events.

Compound Heterozygous SCN5A Mutations in a Toddler - Are they Associated with a More Severe Phenotype?

Compound heterozygosity has been described in inherited arrhythmias, and usually associated with a more severe phenotype. Reports of this occurrence in Brugada syndrome patients are still rare. We report a study of genotype-phenotype correlation after the identification of new variants by genetic testing. We describe the case of an affected child with a combination of two different likely pathogenic SCN5A variants, presenting sinus node dysfunction, flutter and atrial fibrillation, prolonged HV interval, spontaneous type 1 Brugada pattern in the prepubescent age and familiar history of sudden death.

Compound Heterozygous SCN5A Mutations in a Toddler - Are they Associated with a More Severe Phenotype? / Heterozigose Composta no Gene SCN5A em Criança - Há Associação com Gravidade da Doença?

Abstract Compound heterozygosity has been described in inherited arrhythmias, and usually associated with a more severe phenotype. Reports of this occurrence in Brugada syndrome patients are still rare. We report a study of genotype-phenotype correlation after the identification of new variants by genetic testing. We describe the case of an affected child with a combination of two different likely pathogenic SCN5A variants, presenting sinus node dysfunction, flutter and atrial fibrillation, prolonged HV interval, spontaneous type 1 Brugada pattern in the prepubescent age and familiar history of sudden death.

Resumo A heterozigose composta é descrita em arritmias hereditárias, geralmente associada a um fenótipo mais grave. Relatos dessa ocorrência em pacientes com síndrome de Brugada ainda são raros. Neste estudo, descrevemos o caso de uma criança com a combinação de duas novas variantes distintas no gene SCN5A, apresentando disfunção do nó sinusal, flutter e fibrilação atrial, intervalo HV prolongado, padrão tipo 1 espontâneo de Brugada na idade pré-puberal e história familiar de morte súbita.

Influence of Genotype on Structural Atrial Abnormalities and Atrial Fibrillation or Flutter in Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy.

INTRODUCTION: Arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD/C) is associated with desmosomal mutations. Although desmosomal disruption affects both ventricles and atria, little is known about atrial involvement in ARVD/C. OBJECTIVE: To describe the extent and clinical significance of structural atrial involvement and atrial arrhythmias (AA) in ARVD/C stratified by genotype. METHODS: We included 71 patients who met ARVD/C Task Force Criteria and underwent cardiac magnetic resonance (CMR) imaging and molecular genetic analysis. Indexed atrial end-diastolic volume and area-length-ejection-fraction (ALEF) were evaluated on CMR and compared to controls with idiopathic right ventricular outflow tract tachycardia (n = 40). The primary outcome was occurrence of AA (atrial fibrillation or atrial flutter) during follow-up, recorded by 12-lead ECG, Holter monitoring or implantable cardioverter defibrillator (ICD) interrogation. RESULTS: Patients harbored a desmosomal plakophilin-2 (PKP2) (n = 37) or nondesmosomal phospholamban (PLN) (n = 14) mutation. In 20 subjects, no pathogenic mutation was identified. Compared to controls, right atrial (RA) volumes were reduced in PKP2 (P = 0.002) and comparable in PLN (P = 0.441) mutation carriers. In patients with no mutation identified, RA (P = 0.011) and left atrial (P = 0.034) volumes were increased. Bi-atrial ALEF showed no significant difference between the groups. AA were experienced by 27% of patients and occurred equally among PKP2 (30%) and no mutation identified patients (30%), but less among PLN mutation carriers (14%). CONCLUSION: Genotype influences atrial volume and occurrence of AA in ARVD/C. While the incidence of AA is similar in PKP2 mutation carriers and patients with no mutation identified, PKP2 mutation carriers have significantly smaller atria. This suggests a different arrhythmogenic mechanism.

Exome sequencing of a family with lone, autosomal dominant atrial flutter identifies a rare variation in ABCB4 significantly enriched in cases.

BACKGROUND: Lone atrial flutter (AFL) and atrial fibrillation (AF) are common and sometimes consequential cardiac conduction disorders with a strong heritability, as underlined by recent genome-wide association studies that identified genetic modifiers. Follow-up family-based genetic analysis also identified Mendelian transmission of disease alleles. Three affected members were exome-sequenced for the identification of potential causative mutations, which were subsequently validated by direct sequencing in the other 3 affected members. Taqman assay was then used to confirm the role of any mutation in an independent population of sporadic lone AFL/AF cases. RESULTS: The family cluster analysis provided evidence of genetic inheritance of AFL in the family via autosomal dominant transmission. The exome-sequencing of 3 family members identified 7 potential mutations: of these, rs58238559, a rare missense genetic variant in the ATP-binding cassette sub-family B, member 4 (ABCB4) gene was carried by all affected members. Further analysis of 82 subjects with sporadic lone AF, 63 subjects with sporadic lone AFL, and 673 controls revealed that the allele frequency for this variation was significantly higher in cases than in the controls (0.05 vs. 0.01; OR = 3.73; 95% CI = 1.16-11.49; P = 0.013). CONCLUSIONS: rs58238559 in ABCB4 is a rare missense variant with a significant effect on the development of AFL/AF.

LKB1 knockout mouse develops spontaneous atrial fibrillation and provides mechanistic insights into human disease process.

BACKGROUND: Atrial fibrillation (AF) is a complex disease process, and the molecular mechanisms underlying initiation and progression of the disease are unclear. Consequently, AF has been difficult to model. In this study, we have presented a novel transgenic mouse model of AF that mimics human disease and characterized the mechanisms of atrial electroanatomical remodeling in the genesis of AF. METHODS AND RESULTS: Cardiac-specific liver kinase B1 (LKB1) knockout (KO) mice were generated, and 47% aged 4 weeks and 95% aged 12 weeks developed spontaneous AF from sinus rhythm by demonstrating paroxysmal and persistent stages of the disease. Electrocardiographic characteristics of sinus rhythm were similar in KO and wild-type mice. Atrioventricular block and atrial flutter were common in KO mice. Heart rate was slower with persistent AF. In parallel with AF, KO mice developed progressive biatrial enlargement with inflammation, heterogeneous fibrosis, and loss of cardiomyocyte population with apoptosis and necrosis. Atrial tissue was infiltrated with inflammatory cells. C-reactive protein, interleukin 6, and tumor necrosis factor α were significantly elevated in serum. KO atria demonstrated elevated reactive oxygen species and decreased AMP-activated protein kinase activity. Cardiomyocyte and myofibrillar ultrastructure were disrupted. Intercellular matrix and gap junction were interrupted. Connexins 40 and 43 were reduced. Persistent AF caused left ventricular dysfunction and heart failure. Survival and exercise capacity were worse in KO mice. CONCLUSIONS: LKB1 KO mice develop spontaneous AF from sinus rhythm and progress into persistent AF by replicating the human AF disease process. Progressive inflammatory atrial cardiomyopathy is the genesis of AF, through mechanistic electrical and structural remodeling.

Common genetic variants and response to atrial fibrillation ablation.

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.

Early postnatal diagnosis of Costello syndrome.

Costello syndrome is a rare congenital disease with typical craniofacial and musculoskeletal features, cutaneous lesions, cardiac defects and cancer susceptibility. Affected patients show severe feeding difficulties for the first years of life and developmental delay. We present the case of a patient, in whom fetal tachycardia, polyhdramnios and physical characteristics led to an early diagnosis of Costello syndrome. Based on this patient we describe challenges and problems of therapeutic management of infants with Costello syndrome.

p.Y1449C SCN5A mutation associated with overlap disorder comprising conduction disease, Brugada syndrome, and atrial flutter.

Mutations in the SCN5A gene, which encodes the cardiac sodium channel, have been associated with cardiac arrhythmia syndromes and conduction disease. Specific SCN5A mutations had initially been considered to cause specific phenotypes. More recently, some SCN5A mutations have been associated with overlap syndromes, characterized by phenotypic heterogeneity within and between mutation carriers. Here we report and associate the presence of the p.Y1449C SCN5A mutation in a single family with a spectrum of cardiac phenotypes including conduction disease, Brugada syndrome and atrial arrhythmias, for the first time to our knowledge.

Cavotricuspid isthmus ablation and subcutaneous monitoring device implantation in a 2-year-old baby with 2 SCN5A mutations, sinus node dysfunction, atrial flutter recurrences, and drug induced long-QT syndrome: a tricky case of pediatric overlap syndrome?

We describe the case of 2-year-old baby with compound heterozygosity for paternal and maternal alleles mutation of α-subunit of the cardiac sodium channel (SCN5A), sinus node dysfunction, atrial flutter recurrences, and drug induced long-QT syndrome. In this setting, we chose at first to perform linear ablation of cavotricuspid isthmus resulting in a bidirectional isthmus block. As a second step, we decided to implant a miniaturized loop recorder that, with a minimally invasive procedure, permits us to follow the development of the disease in order to define the future strategy. After 8 months follow-up, automatic daily loop-recorder transmissions disclose the complete absence of any arrhythmia along with asymptomatic ventricular pauses due to sinus node dysfunction. Echocardiography shows normal findings, in particular no left ventricular dysfunction.

Complex atrial arrhythmias as first manifestation of catecholaminergic polymorphic ventricular tachycardia: an unusual course in a patient with a new mutation in ryanodine receptor type 2 gene.

Catecholaminergic polymorphic ventricular tachycardia is a rare life-threatening arrhythmogenic disorder. An association with paroxysmal atrial fibrillation and other atrial arrhythmias has been described, but in all published cases the initial manifestation of the disease was ventricular arrhythmia. This is the first report about a patient who presented with complex atrial tachycardia and sinus node dysfunction about 1 year before the typical ventricular arrhythmias were observed, leading to the diagnosis of catecholaminergic polymorphic ventricular tachycardia. In this girl, a mutation of the ryanodine receptor type 2 gene, which has not been described so far, was discovered.

Impact of a 4q25 genetic variant in atrial flutter and on the risk of atrial fibrillation after cavotricuspid isthmus ablation.

BACKGROUND: The prediction of atrial fibrillation (AF) following catheter ablation of atrial flutter (Afl) would be helpful to facilitate targeted arrhythmia monitoring and anti-coagulation strategies. A single nucleotide polymorphism, rs2200733, is strongly associated with AF. We sought to characterize the association between rs2200733 and prevalent Afl and to determine if the variant could predict AF after cavotricuspid isthmus ablation. METHODS AND RESULTS: We performed a genetic association study of 295 patients with Afl and/or AF and 469 controls using multivariable logistic regression. The variant was then assessed as a predictor of incident AF after cavotricuspid isthmus ablation in 87 consecutive typical Afl patients with Cox proportional hazards models. The rs2200733 rare allele was associated with an adjusted 2.06-fold increased odds of isolated Afl (95% CI: 1.13-3.76, P = 0.019) and an adjusted 2.79-fold increased odds of a combined phenotype of AF and Afl (95% CI: 1.81-4.28, P < 0.001). Following catheter ablation for Afl, carrier status of rs2200733 failed to predict an increased risk of AF either among all subjects (adjusted HR: 0.94; 95% CI: 0.58-1.53, P = 0.806) or among those with isolated Afl (adjusted HR: 1.29; 95% CI: 0.51-3.26, P = 0.585). CONCLUSIONS: Our study demonstrates that Afl, whether occurring in isolation or along with AF, is associated with the rs2200733 AF risk allele. Genetic carrier status of rs2200733 failed to predict an increased risk of incident or recurrent AF following catheter ablation for Afl. These findings suggest that the causal mechanism associated with rs2200733 is germane to both AF and Afl.