Early-onset Atrial Fibrillation Research Articles

Genetic variants, pathophysiological pathways, and oral anticoagulation in patients with hypertrophic cardiomyopathy and atrial fibrillation.

Atrial fibrillation (AF) is commonly prevalent in patients with hypertrophic cardiomyopathy (HCM). However, whether the prevalence and incidence of AF are different between genotype-positive vs. genotype-negative patients with HCM remains controversial. Recent evidence has indicated that AF is often the first presentation of genetic HCM patients in the absence of a cardiomyopathy phenotype, implying the importance of genetic testing in this population with early-onset AF. However, the association of the identified sarcomere gene variants with HCM occurrence in the future remains unclear. How the identification of these cardiomyopathy gene variants should influence the use of anticoagulation therapy for a patient with early-onset AF is still undefined. In this review, we sought to assess the genetic variants, pathophysiological pathways, and oral anticoagulation in patients with HCM and AF.

Genetic Basis of Early Onset Atrial Fibrillation in Patients without Risk Factors.

Atrial fibrillation (AF) is the most common arrhythmia and typically occurs in elderly patients with other cardiovascular and extracardiac diseases. However, up to 15% of AF develops without any related risk factors. Recently, the role of genetic factors has been highlighted in this particular form of AF. The aims of this study were to determine the prevalence of pathogenic variants in early-onset AF in patients without known disease-related risk factors and to identify any structural cardiac abnormalities in these patients. We conducted exome sequencing and interpretation in 54 risk factor-free early-onset AF patients and further validated our findings in a similar AF patient cohort from the UK Biobank. Pathogenic/likely pathogenic variants were found in 13/54 (24%) patients. The variants were identified in cardiomyopathy-related and not arrhythmia-related genes. The majority of the identified variants were TTN gene truncating variants (TTNtvs) (9/13 (69%) patients). We also observed two TTNtvs founder variants in the analysed population-c.13696C>T p.(Gln4566Ter) and c.82240C>T p.(Arg27414Ter). Pathogenic/likely pathogenic variants were found in 9/107 (8%) individuals from an independent similar AF patient cohort from the UK Biobank. In correspondence with our Latvian patients, only variants in cardiomyopathy-associated genes were identified. In five (38%) of the thirteen Latvian patients with pathogenic/likely pathogenic variants, dilation of one or both ventricles was identified on a follow-up cardiac magnetic resonance scan. We observed a high prevalence of pathogenic/likely pathogenic variants in cardiomyopathy-associated genes in patients with risk factor-free early-onset AF. Moreover, our follow-up imaging data indicate that these types of patients are at risk of developing ventricular dilation. Furthermore, we identified two TTNtvs founder variants in our Latvian study population.

Association of Cardiac Electrical Disorders With KCND3 Gene Mutation.

Globally, cardiac channelopathies leading to electrical disorders are responsible for a significant number of sudden cardiac deaths without structural heart disease. Many genes encoding different ion channels in the heart were identified and their impairment was found to be associated with life-threatening cardiac abnormalities. KCND3, one of the genes expressed both in the heart and brain, is reported to have an association with Brugada syndrome, early-onset atrial fibrillation, early repolarization syndrome, and sudden unexplained death syndrome. KCND3 genetic screening could be a promising tool for functional studies for an understanding of the pathogenesis and genetic determinants of the above-mentioned electrical disorders.

Abstract 10026: Augmentation of Slow Repolarizing Potassium Channel (I Ks ) Links Truncated Titin Mutations to Atrial Fibrillation

Introduction: Rare titin-truncating variants ( TTN tv) are associated with early-onset atrial fibrillation (AF) but the pathogenic mechanisms and therapeutic implications remain unclear. To determine the function of a highly conserved immunoglobulin-like domain of the A-band of TTN , a region enriched in AF-associated variants, we employed CRISPR-Cas9-mediated deletion of 9 amino acids (Δ9) in human induced pluripotent stem cells and then derived atrial cardiomyocytes (hiPSC-aCMs) for electrophysiological (EP) analysis. Hypothesis: We hypothesized that the TTN -Δ9 mutation results in augmentation of the slow delayed rectifier potassium current (I Ks ) resulting in shortened action potential duration (APD). Methods: TTN -WT hiPSC-aCMs (healthy control) and TTN -Δ9 hiPSC-aCMs (isogenic mutant) were matured with metabolic conditioning, electrical stimulation, co-culture with atrial fibroblasts, and micropatterning. We used transmission electron microscopy (TEM) to assess sarcomeric defects, RNA-sequencing and RT-qPCR to assess molecular ion channel remodeling, and high throughput automated patch clamp and optical voltage mapping to assess the EP properties of TTN -Δ9 hiPSC-aCMs. We also performed targeted pharmacological inhibition of I Ks . Results: We showed that TTN -Δ9 hiPSC-aCMs displayed disrupted organization and myofibril assembly ( Fig. 1A-B ), upregulated voltage-gated potassium channel complexes and increased KCNQ1 expression ( Fig 1C-D ), and shortened APD ( Fig. 1E-F ). I Ks was significantly augmented in TTN -Δ9 hiPSC-aCMs ( Fig. 1G-H ). Infusion of the I Ks -specific blocker HMR-1556, and not I Kr blocker dofetilide, fully restored the shortened APD 90 and partially recovered defects in contractility in TTN -Δ9 hiPSC-aCMs compared to TTN -WT hiPSC-aCMs ( Fig. 1I-J ). Conclusion: Our findings suggest that augmentation of I Ks contributes to the pathogenic mechanism of TTN -mediated AF, pointing to I Ks as a potential therapeutic target.

Abstract 12110: The Multi-Racial Clinical and Familial Characteristics of Early and Late Onset Atrial Flutter

Introduction: Studies in Whites of European descent have shown that atrial fibrillation (AF) have a strong genetic component especially in probands with early-onset (EO) AF. However, the role of family history in the pathogenesis of EO atrial flutter (EOAFL) across race-ethnicity remains unclear. Here, we sought to determine if African American, European American, and Hispanic/Latino probands with EOAFL have a higher rate of arrhythmia recurrence in first-degree family members than ethnically-matched patients with late-onset AFL (LOAFL). Methods: In this cohort study, 917 adults with AFL were identified between 2015 and 2021 across 3 sites in the Chicagoland area. EOAFL was defined as AFL occurring before 60 years of age. Primary analysis of reported family history in first-degree relatives with sensitivity analysis restricted to those in whom a family history was confirmed by medical record review and electrocardiogram was done. Results: Those with EOAFL were more overweight, Black or White, and had more comorbidities ( Table 1 ). Multivariate analysis showed that BMI ≥ 40 kg/m 2 (odds ratio [OR]: 5.4; 95% confidence interval [CI]: 3.2-9.4, p <0.001) and a family history (OR: 3.7; 95% CI: 2.1-6.9, P <0.001) carried the highest adjusted odds of EOAFL followed by alcohol use (OR: 2.1; 95% CI: 1.5-3.0, P <0.001), Black race (OR: 1.6; 95% CI: 1.1-2.3, P =0.021), and heart failure (OR: 1.4; 95% CI: 1-1.9, P =0.03). Adjusting for effect modification on the association of family history and race, among Whites, the odds of EOAFL in patients with family history was 6.1 (95% CI: 2.1-22.3, P =0.002) comparative to those with no family history, and among Blacks, it was 4.9 (95% CI: 1.6-6.1, P =0.021). Conclusion: Obesity and family history were strongly associated with EOAFL. Whites with EOAFL were more likely to have a first-degree relative with AF/AFL when compared to Blacks or Hispanics/Latinos. These findings support genetic predisposition to EOAFL across all 3 races.

EP News: Basic and Translational.

Laws et al (Circ Res 2022;130:1698, PMID 35617362) provided a timely and comprehensive review on the prevalence of genetic cardiomyopathies with arrhythmias as the first presentation. 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 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.

High prevalence of deleterious variants in cardiomyopathy genes in patients with early onset atrial fibrillation

Abstract Background Atrial Fibrillation (AF) is a common cardiac arrhythmia associated with increased morbidity and mortality. AF has a significant heritable component and genome-wide association studies have associated numerous loci in the human genome with AF. The arrhythmia is relatively rare in younger individuals, but studies have shown that individuals with early-onset AF may harbour a considerable burden of pathogenic genetic variants. In recent years, the concept of atrial cardiomyopathy has emerged as a mechanism involved in AF pathogenesis. Genes well-known to be related to ventricular structure, including cardiomyopathies have now also been associated with AF. Purpose Using targeted genetic sequencing, this study aimed to elucidate the role of deleterious genetic variants in cardiomyopathy genes in early-onset AF, and provide new insights into AF pathogenesis. Methods We performed targeted genetic sequencing of 445 Danish individuals with onset of AF before age 40 years and no other cardiovascular co-morbidities, and of 387 controls with no history of AF. Based on guidelines for genetic testing for clinical use, we focused on 30 genes with well-established associations with dilated cardiomyopathy, hypertrophic cardiomyopathy and arrhythmogenic right ventricular cardiomyopathy. We examined the prevalence of loss-of-function variants (defined as variants leading to premature stop-codon, frameshift or splice-site variants), as these are most likely to be disease-causing. We filtered for rare variants using a minor allele frequency <0.1%. The difference in prevalence in the two groups was analyzed using a logistic regression model. Results We found that 38 of the 445 early-onset AF patients carried loss-of-function variants in well-established cardiomyopathy genes. The prevalence of rare, loss-of-function variants was enriched in cases compared with controls (8.5%. vs. 1.0%, P=8.27x10–7). The variants were identified in eight different genes, with most rare variants found in the TTN gene (Table 1). In sensitivity analyses excluding TTN variants, we found that 12 individuals (∼2.7%) with AF harbored deleterious loss-of-function variants (P=0.0396). Conclusions Individuals with early onset of AF have a considerable burden of rare, deleterious variants in established cardiomyopathy genes. These new insights could help inform future recommendations for genetic testing and follow-up to detect early cardiomyopathy manifestations to prevent adverse outcomes in patients with early onset of AF. These findings support the presence of atrial cardiomyopathy. Funding Acknowledgement Type of funding sources: Foundation. Main funding source(s): Hallas-Møller emerging investigator grant, The Novo Nordisk Foundation (NNF: NNF17OC0031204)The John and Birthe Meyer Foundation

Habitual Alcohol Intake and Risk of Atrial Fibrillation in Young Adults in Korea

Guidelines recommend that all risk factors for early-onset atrial fibrillation, including lifestyle factors, be proactively managed, considering the poor prognosis of the disease. Not much is known about the association of cumulative alcohol intake with the risk of atrial fibrillation in young adults aged 20 to 39 years, especially among heavy drinkers. To explore the association of alcohol consumption with the risk of incident atrial fibrillation in young adults. Using the National Health Insurance Service database, a nationwide population-based cohort study of adults aged 20 to 39 years without prior atrial fibrillation who underwent 4 serial annual health examinations between 2009 and 2012 was conducted. The cumulative alcohol consumption burden over 4 years was calculated by assigning 1 point to more than moderate drinking (≥105 g of alcohol per week) each year. Additionally, a semiquantitative cumulative burden was calculated by assigning 0, 1, 2, and 3 points to non, mild (<105 g per week), moderate (105-210 g per week), and heavy (≥210 g per week) drinking, respectively. Data were analyzed from May to June 2021. Amount of alcohol intake in 4 years. The primary outcome was incident atrial fibrillation during the follow-up period. A total of 1 537 836 participants (mean [SD] age 29.5 [4.1] years, 1 100 099 [71.5%] male) were included in the final analysis. According to the 4-year cumulative burden of alcohol consumption stratified by moderate to heavy drinking, 889 382 participants (57.8%) were in the burden 0 group, 203 374 participants (13.2%) in the burden 1 group, 148 087 participants (9.6%) in the burden 2 group, 144 023 participants (9.4%) in the burden 3 group, and 152 970 participants (9.9%) in the burden 4 group. During a median (IQR) follow-up of 6.13 (4.59-6.48) years, atrial fibrillation was newly diagnosed in 3066 participants (0.36 per 1000 person-years). Participants with a cumulative burden of 4 points who continued more than moderate drinking for 4 years showed a 25% higher risk of atrial fibrillation compared with 0-point participants who kept non-to-mild drinking over 4 years (adjusted HR, 1.25; 95% CI, 1.12-1.40). In a semiquantitative analysis, participants who sustained heavy drinking for 4 consecutive years were associated with a 47% higher atrial fibrillation risk than those who remained nondrinkers over 4 years (aHR, 1.47, CI 1.18-1.83). Persistent moderate to heavy drinking and higher cumulative alcohol consumption burden might increase the risk of atrial fibrillation even in young adults aged 20 to 39 years.

Arrhythmias as Presentation of Genetic Cardiomyopathy.

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.

Mortality Among Patients With Early-Onset Atrial Fibrillation and Rare Variants in Cardiomyopathy and Arrhythmia Genes

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. To assess the association between rare variants in cardiomyopathy and arrhythmia genes detected in patients with early-onset AF and time to death. 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. Rare variants identified in a panel of 145 genes that are included in cardiomyopathy and arrhythmia panels used by commercial clinical genetic testing laboratories. 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. 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. 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.

Genetic Testing for Early-Onset Atrial Fibrillation—Is It Time to Personalize Care?

Genetic Testing for Early-Onset Atrial Fibrillation—Is It Time to Personalize Care?

Atrial Fibrillation Ablation Usually Improves Ejection Fraction In Otherwise Unexplained Cardiomyopathy

Introduction The prevalence of cardiomyopathy (CM) attributable to atrial fibrillation (AF) is uncertain among patients undergoing AF ablation without other known cause of CM. Objective: To (1) determine how often patients improved from left ventricular ejection fraction (LVEF) < 50% by at least 10 percentage points with ablation (AF-CM) and (2) compare AF-CM profiles to patients with AF and no history of LVEF < 50% (No AF-CM). Methods Patients with early-onset AF (age of onset < 65 without known structural or toxin-associated heart disease) were identified from a prospective AF ablation registry with LVEF measured before and after ablation. CM was defined as pre-ablation LVEF < 50% and AF-CM as CM that improved by at least 10 percentage points post-ablation to ≥ 50%. Results Of 302 patients (age 55 ± 10 years at first AF ablation), CM was present pre-ablation in 57 (19%) patients, of whom 51 (89%) met the definition of AF-CM, with mean LVEF improving from 38 ± 10% pre-ablation to 60 ± 6% post-ablation (Figure). Of 245 with normal LVEF pre-ablation, 6 developed CM after ablation. AF-CM patients were more likely than No AF-CM to be male, have persistent or permanent AF, and have shorter duration of known AF pre-ablation (4.9 ± 0.6 vs. 6.7 ± 0.7 years, p < 0.01). Pre-ablation heart rate was adequately controlled in both groups but higher in AF-CM (83 ± 26 vs. 70 ± 20 beats per minute, p < 0.01). LV end diastolic dimension was higher in AF-CM (5.2 ± 0.7 vs. 4.8 ± 0.6 cm, p < 0.01) but without severe dilation. Conclusion Patients with early-onset AF referred for ablation and otherwise unexplained CM are likely to improve to EF ≥ 50% after ablation. AF ablation should be considered to treat heart failure in these patients, regardless of symptom burden. The prevalence of cardiomyopathy (CM) attributable to atrial fibrillation (AF) is uncertain among patients undergoing AF ablation without other known cause of CM. Objective: To (1) determine how often patients improved from left ventricular ejection fraction (LVEF) < 50% by at least 10 percentage points with ablation (AF-CM) and (2) compare AF-CM profiles to patients with AF and no history of LVEF < 50% (No AF-CM). Patients with early-onset AF (age of onset < 65 without known structural or toxin-associated heart disease) were identified from a prospective AF ablation registry with LVEF measured before and after ablation. CM was defined as pre-ablation LVEF < 50% and AF-CM as CM that improved by at least 10 percentage points post-ablation to ≥ 50%. Of 302 patients (age 55 ± 10 years at first AF ablation), CM was present pre-ablation in 57 (19%) patients, of whom 51 (89%) met the definition of AF-CM, with mean LVEF improving from 38 ± 10% pre-ablation to 60 ± 6% post-ablation (Figure). Of 245 with normal LVEF pre-ablation, 6 developed CM after ablation. AF-CM patients were more likely than No AF-CM to be male, have persistent or permanent AF, and have shorter duration of known AF pre-ablation (4.9 ± 0.6 vs. 6.7 ± 0.7 years, p < 0.01). Pre-ablation heart rate was adequately controlled in both groups but higher in AF-CM (83 ± 26 vs. 70 ± 20 beats per minute, p < 0.01). LV end diastolic dimension was higher in AF-CM (5.2 ± 0.7 vs. 4.8 ± 0.6 cm, p < 0.01) but without severe dilation. Patients with early-onset AF referred for ablation and otherwise unexplained CM are likely to improve to EF ≥ 50% after ablation. AF ablation should be considered to treat heart failure in these patients, regardless of symptom burden.

Genetically based atrial fibrillation: Current considerations for diagnosis and management.

Atrial fibrillation (AF) is the most common atrial arrhythmia and is subcategorized into numerous clinical phenotypes. Given its heterogeneity, investigations into the genetic mechanisms underlying AF have been pursued in recent decades, with predominant analyses focusing on early onset or lone AF. Linkage analyses, genome-wide association studies (GWAS), and single gene analyses have led to the identification of rare and common genetic variants associated with AF risk. Significant overlap with genetic variants implicated in dilated cardiomyopathy syndromes, including truncating variants of the sarcomere protein titin, have been identified through these analyses, in addition to other genes associated with cardiac structure and function. Despite this, widespread utilization of genetic testing in AF remains hindered by the unclear impact of genetic risk identification on clinical outcomes and the high prevalence of variants of unknown significance (VUS). However, genetic testing is a reasonable option for patients with early onset AF and in those with significant family history of arrhythmia. While many knowledge gaps remain, emerging data support genotyping to inform selection of AF therapeutics. In this review, we highlight the current understanding of the complex genetic basis of AF and explore the overlap of AF with inherited cardiomyopathy syndromes. We propose a set of criteria for clinical genetic testing in AF patients and outline future steps for the integration of genetics into AF care.

Whole-exome sequencing reveals a rare missense variant in DTNA in an Iranian pedigree with early-onset atrial fibrillation

Atrial fibrillation (AF) is a morbid and heritable irregular cardiac rhythm that affects about 2%–3% of the population. Patients with early-onset AF have a strong genetic association with the disease; nonetheless, the exact underlying mechanisms need clarification. We herein present our evaluation of a 2-generation Iranian pedigree with early-onset AF. Whole-exome sequencing was applied to elucidate the genetic predisposition. Direct DNA sequencing was utilized to confirm and screen the variants in the proband and his available family members. The pathogenicity of the identified nucleotide variations was scrutinized via either segregation analysis in the family or in silico predictive software. The comprehensive variant analysis revealed a missense variant (c.G681C, p.E227D, rs1477078144) in the human α-dystrobrevin gene (DTNA), which is rare in genetic databases. Most in silico analyses have predicted this variant as a disease-causing variant, and the variant is co-segregated with the disease phenotype in the family. Previous studies have demonstrated the association between the DTNA gene and left ventricular noncompaction cardiomyopathy. Taken together, we provide the first evidence of an association between a nucleotide variation in the DTNA gene and early-onset AF in an Iranian family. However, the genetic testing of AF in the Iranian population is still limited. This finding not only further confirms the significant role of genetics in the incidence of early-onset AF but also expands the spectrum of the gene variations that lead to AF. Additionally, it may have further implications for the treatment and prevention of AF.

Genome-wide association study-based prediction of atrial fibrillation using artificial intelligence

ObjectiveWe previously reported early-onset atrial fibrillation (AF) associated genetic loci among a Korean population. We explored whether the AF-associated single-nucleotide polymorphisms (SNPs) selected from the Genome-Wide Association Study (GWAS) of...

Abstract 14025: Atrial Fibrillation is Associated With Reduced Telomere Length

Background: Atrial Fibrillation (AF) is common pathophysiologically complex. Age is among the most important AF risk factors. However, some young patients develop early-onset AF, whereas many others do not despite an advanced age. Advanced biological aging as opposed to advanced calendar age may be an explanation. Telomere length is associated with age and may be considered a measurable marker of biological age. AF and telomere length have previously been associated, but results remained inconclusive. Hypothesis: AF is age-related and associates with telomere length in a large case-control cohort. Methods: Between 2005 and 2018, we enrolled 2475 early-onset AF patients into the prospective AFLMU cohort. 3077 AF-free individuals from the community-based KORA study (enrollment 2006-08) served as controls. Clinical characteristics, an electrocardiogram, and a blood sample was obtained in all participants. We determined telomere length by a qPCR-based method using a multiplex TaqMan assay. Telomere length was expressed as delta-CT referenced to the single copy gene 36B4 .Lower CT values indicate shorter telomere length. Telomere length in cases vs. controls was assessed using multi-variably adjusted logistic regression. Results: Mean age was 58 years in AFLMU and 56 years in KORA. Men accounted for 72.3% in AFLMU and for 51.7% in KORA. For quality control, we confirmed a reduction of telomere length with age and demonstrated shorter telomere length in men compared to women. Median telomere length was also significantly shorter in AF patients compared to controls (9.81 [5.98, 13.1] vs. 13,10 [12.60, 13.63], p&lt;0,001). The association remained significant after adjustment for sex, body mass index, hypertension, and diabetes (odds ratio per telomere length unit 0.77 [95% confidence interval 0.74-0.77], p&lt;0.001). Conclusion: In a large case-control cohort, AF significantly associates with telomere length. Information on telomere length may help to inform if a patient develops AF due to premature biological aging. The underlying pathomechanisms for premature aging remain to be elucidated.

Early-Onset Atrial Fibrillation and the Prevalence of Rare Variants in Cardiomyopathy and Arrhythmia Genes

Early-onset atrial fibrillation (AF) can be the initial manifestation of a more serious underlying inherited cardiomyopathy or arrhythmia syndrome. To examine the results of genetic testing for early-onset AF. 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. Rare variants identified in a panel of 145 genes that are included on cardiomyopathy and arrhythmia panels used by commercial clinical genetic testing laboratories. 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. 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). 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.

Early-Onset Atrial Fibrillation and Heritable Heart Disease—To Test or Not to Test?

Early-Onset Atrial Fibrillation and Heritable Heart Disease—To Test or Not to Test?

Epistatic interaction of PDE4DIP and DES mutations in familial atrial fibrillation with slow conduction

The genetic causes of atrial fibrillation (AF) with slow conduction are unknown. Eight kindreds with familial AF and slow conduction, including a family affected by early-onset AF, heart block, and incompletely penetrant nonischemic dilated cardiomyopathy (DCM) underwent whole exome sequencing. A known pathogenic mutation in the desmin (DES) gene resulting in p.S13F substitution (NM_001927.3:c.38C>T) at a PKC phosphorylation site was identified in all four members of the kindred with early-onset AF and heart block, while only two developed DCM. Higher penetrance for AF and heart block prompted a genetic screening for DES modifier(s). A deleterious mutation in the phosphodiesterase-4D-interacting-protein (PDE4DIP) gene resulting in p.A123T substitution (NM_001002811:c.367G>A) was identified that segregated with early-onset AF, heart block, and the DES mutation. Three additional novel deleterious PDE4DIP mutations were identified in four other unrelated kindreds. Characterization of PDE4DIPA123T in vitro suggested impaired compartmentalization of PKA and PDE4D characterized by reduced colocalization with PDE4D, increased cAMP activation leading to higher PKA phosphorylation of the β2-adrenergic-receptor, and decreased PKA phosphorylation of desmin after isoproterenol stimulation. Our findings identify PDE4DIP as a novel gene for slow AF and unravel its epistatic interaction with DES mutations in development of conduction disease and arrhythmia.

B-AB13-03 NOVEL ROLE OF PDE4DIP IN FAMILIAL ATRIAL FIBRILLATION WITH SLOW VENTRICULAR RESPONSE

The genetic causes of atrial fibrillation (AF) with slow conduction are unknown. To investigate the genetic causes of familial atrial fibrillation with slow conduction. Eight kindreds with familial AF and slow conduction, including a family affected by early onset AF, heart block and incompletely penetrant non-ischemic cardiomyopathy (NICM) underwent whole exome sequencing. A known pathogenic mutation in the desmin (DES) gene resulting in S13F substitution at a PKC phosphorylation site was identified in all four members of the kindred with early-onset AF and heart block, while only two developed NICM. Higher penetrance of the mutation for AF and heart block prompted the screening for DES modifier(s). A second deleterious mutation in the phosphodiesterase 4D interacting-protein (PDE4DIP) gene resulting in A123T substitution segregated with early onset AF, heart block and the DES mutation. Three additional novel deleterious PDE4DIP mutations were identified in four other unrelated kindreds. Characterization of PDE4DIPA123T in vitro suggested impaired compartmentalization of PKA and PDE4D characterized by reduced colocalization with PDE4D, increased cAMP activation leading to higher PKA phosphorylation of the β2-adrenergic-receptor, and decreased PKA phosphorylation of Desmin in response to isoproterenol stimulation compared to wildtype PDE4DIP. Our findings identify an epistatic interaction between DES and PDE4DIP variants, increasing the penetrance for conduction disease and arrhythmia.