Multimodal data integration to predict atrial fibrillation.

Genetic Risk Prediction for CKD: A Journey of a Thousand Miles

BackgroundIncreased concentrations of circulating fibroblast growth factor 23 (FGF‐23) have been associated with higher risk of cardiovascular disease. The association between FGF‐23 and the risk of atrial fibrillation (AF), a common arrhythmia, is less defined. Thus, we explored whether FGF‐23 concentration was associated with AF incidence in a large community‐based cohort.Methods and ResultsWe studied 12 349 men and women enrolled in the Atherosclerosis Risk in Communities (ARIC) study, without prevalent AF at baseline in 1990–1992. Serum intact FGF‐23 concentration was measured with the Kainos 2‐site ELISA. Incident AF through 2010 was ascertained from study ECGs and hospital discharge codes. Cox proportional hazards models adjusted for potential confounding factors, including kidney function, were used to estimate the association between FGF‐23 and AF risk. We identified 1572 AF events during a mean follow‐up of 17 years. In multivariable analysis, a difference of 1 SD (16 pg/mL) in baseline FGF‐23 was not associated with the risk of AF (hazard ratio [HR], 1.04; 95% confidence interval [CI], 0.99, 1.09). Results were similar when FGF‐23 was modeled in quartiles (HR, 1.09; 95% CI, 0.94, 1.26, comparing extreme quartiles). Reduced kidney function was associated with increased AF risk across quartiles of FGF‐23 levels.ConclusionIn this large community‐based cohort, baseline FGF‐23 levels were not associated with AF risk independently of kidney function. Our results do not support a major role for FGF‐23 as a risk factor for AF or as a mediator of the association between chronic kidney disease and AF.

Taiwan Atrial Fibrillation Score: A New Clinical Tool for Predicting New Onset Atrial Fibrillation in Asian Populations.

[This corrects the article DOI: 10.1371/journal.pone.0185228.].

BackgroundAlthough current alcohol consumption is a risk factor for incident atrial fibrillation (AF), the more clinically relevant question may be whether alcohol cessation is associated with a reduced risk.Methods and resultsWe studied participants enrolled in the Atherosclerosis Risk in Communities Study (ARIC) between 1987 and 1989 without prevalent AF. Past and current alcohol consumption were ascertained at baseline and at 3 subsequent visits. Incident AF was ascertained via study ECGs, hospital discharge ICD-9 codes, and death certificates. Of 15,222 participants, 2,886 (19.0%) were former drinkers. During a median follow-up of 19.7 years, there were 1,631 cases of incident AF, 370 occurring in former consumers. Former drinkers had a higher rate of AF compared to lifetime abstainers and current drinkers. After adjustment for potential confounders, every decade abstinent from alcohol was associated with an approximate 20% (95% CI 11–28%) lower rate of incident AF; every additional decade of past alcohol consumption was associated with a 13% (95% CI 3–25%) higher rate of AF; and every additional drink per day during former drinking was associated with a 4% (95% CI 0–8%) higher rate of AF.ConclusionsAmong former drinkers, the number of years of drinking and the amount of alcohol consumed may each confer an increased risk of AF. Given that a longer duration of abstinence was associated with a decreased risk of AF, earlier modification of alcohol use may have a greater influence on AF prevention.

Sex differences have the potential to impact diagnostic and therapeutic interventions in a wide variety of medical conditions, and cardiac arrhythmias are no exception.1 Studies evaluating pathophysiology, disease course, and therapeutic options for cardiac arrhythmias have been performed predominantly in male patients. However, catheter and device-based therapies coupled with landmark clinical trials have contributed to an improved understanding of this important aspect. The objective of this review is to present the current state of knowledge on sex differences in cardiac arrhythmias with a focus on clinical management, while highlighting gaps in knowledge that would benefit from future investigation. ### Atrial Fibrillation and Atrial Flutter #### Disease Burden Atrial fibrillation (AF) and atrial flutter (AFL) are the most commonly encountered tachyarrhythmias in clinical practice, with significant implications for public health and healthcare costs. Stroke, hospitalization, and loss of productivity are the major consequences of AF.2 The incidence of AF (per 1000 person-years) is reported to be between 1.6 and 2.7 in women and between 3.8 and 4.7 in men.2 The age-adjusted incidence and prevalence of AF is lower in women compared with that in men, and accordingly, the lifetime risk of AF from the Framingham Heart Study at 40 years of age was higher in men (26.0% for men versus 23.0% for women).3 Another analysis from the Framingham Heart Study demonstrated no significant sex differences in the risk of developing AFL.4 The prevalence of AF continues to rise among both men and women. In a study investigating the global burden of disease from 1980 to 2010, there was not only an increase in overall burden, incidence, and prevalence of AF, but most importantly an increase in AF-associated mortality in both men and women (Figure 1).5 The age-adjusted mortality for women was consistently higher compared with that for men from 1990 to 2010 (Figure …

Combining polygenic and clinical risk scores in atrial fibrillation risk prediction: Implications for population screening.

Elevated blood pressure (BP) is reportedly associated with an increased risk of atrial fibrillation (AF). However, the association between cumulative BP exposure in midlife and incident AF in mid-to-late life remains unclear. Participants enrolled in the ARIC (Atherosclerosis Risk in Communities) study with 4 consecutive BP measurements and no prevalent AF at baseline were included. Cumulative BP was calculated as the area under the curve from visit 1 to visit 4. Incident AF was identified by study visit ECGs, hospital discharge codes, or death certificates. A total of 9892 participants were included (44.6% men and mean age 62.9±5.7 years at visit 4) with 1550 (15.7%) individuals who developed new-onset AF during an average follow-up of 15.4 years. The incidence rates of AF per 1000 person-years across the 4 quartiles of cumulative systolic BP were 7.9, 9.2, 12.5, and 16.9, respectively. After multivariable adjustment, the hazard ratios for incident AF among participants in the highest quartile of cumulative systolic BP, pulse pressure, and mean arterial pressure were 1.48 (95% CI, 1.27-1.72), 1.81 (95% CI, 1.53-2.13), and 1.22 (95% CI, 1.05-1.41), respectively, compared with those in the lowest quartile. The addition of cumulative systolic BP or pulse pressure slightly improved the ability to predict new-onset AF. Higher exposure to cumulative systolic BP, pulse pressure, and mean arterial pressure was significantly associated with increased risk of incident AF.

BackgroundAtrial myopathy is increasingly recognized as a distinct clinical entity, and an important underlying component in atrial fibrillation (AF). While histological examination of atrial biopsies is the gold-standard for diagnosis of atrial myopathy, it is often impractical in a clinical setting.PurposeThis study aimed to examine the prevalence and inter-relationships of indirect atrial myopathy markers, identify associations with incident AF, and explore clinical or genetic risk scores for risk-stratification in individuals with markers of atrial myopathy.MethodsThe study cohort consisted of European ancestry individuals from the UK Biobank with cardiac magnetic resonance imaging and electrocardiographic information, and no prior history of AF, heart failure, or cardiac conduction disorders. Three markers of atrial myopathy were examined: Left atrial (LA) dilation (indexed LA volume >60 ml/m2), mechanical dysfunction (LA emptying fraction <45%), and electrical dysfunction (P-wave duration >120 ms). Hazard ratios (HR) for AF were examined in a multivariate Cox regression adjusted for sex, age, body-mass index, hypertension, coronary artery disease and diabetes. The cohort was stratified by LA myopathy markers, genetic risk of AF (using a previously validated polygenic risk score [PRS]), and clinical risk of AF (using the HARMS2-AF score). Genetic risk was stratified by PRS tertiles, and clinical risk was stratified by HARMS2-AF score ≤2 (low risk), HARMS2-AF score between 3-6 (intermediate risk), and HARMS2-AF score ≥7 (high risk). Five-year incidences of AF were calculated using the Aalen-Johansen estimator, with all-cause mortality as a competing risk.ResultsAmong 26,026 individuals, 2,447 (9.7%) had at least one marker of atrial myopathy, while 244 (0.9%) had two or more markers. The largest overlap was seen between LA dilation and mechanical dysfunction. During a median follow-up of 5 years, 583 (2.2%) were diagnosed with incident AF. Having one LA myopathy marker conferred a HR of 2.53 (95% confidence interval [CI]: 2.06-3.11; P<0.001) for AF. Higher rates were observed in individuals with two or more markers (HR for AF: 6.34; 95% CI: 4.56-8.81; P<0.001). Individuals with one or more LA myopathy marker, and high clinical and genetic risk, had a 11.7% (95% CI: 7.5-16.0%) 5-year risk of incident AF, compared with a 0.7% (95% CI: 0.4-0.9%) risk in those with no LA myopathy markers, and low clinical and genetic risk.ConclusionsIn a cohort without prior history of AF, almost one in ten individuals had at least one marker of atrial myopathy. Although overlap between different markers was modest, a dose-response-like relationship was observed between amount of atrial myopathy markers and rates of AF. Integration of clinical and genetic risk scores showed a several-fold risk gradient, highlighting that PRS and clinical risk scores may be useful aids in risk stratification of individuals with markers of LA myopathy.Co-occurence of atrial myopathy markers Rates of incident atrial fibrillation

BackgroundNew-onset postoperative atrial fibrillation (POAF) complicates 1 in 3 cardiac surgeries and is associated with morbidity, mortality and clinical AF in long-term follow-up. Clinical risk scores have modest performance for predicting POAF. Polygenic risk scores are derived from the summation of up to millions of genetic variants and have shown good predictive ability for incident AF in the community. The ability of polygenic risk scores to predict POAF and subsequent recurrence of clinical AF in cardiac surgery patients is unclear.MethodsWe performed a prospective cohort study of patients from 4 regions (Canada, Hong Kong, Malaysia, United Kingdom) without a pre-operative history of atrial fibrillation (AF) who underwent cardiac surgery and were followed for 1 year. From pre-operative blood samples, we extracted DNA and calculated each participant’s polygenic risk score for AF using a penalized regression method (lassosum) to combine the effects of 5,000,621 genetic variants, weighted by their association with AF status from a previous genome-wide association study by Miyazawa (Nature Genetics, 2023). We estimated the association of this polygenic risk score for AF with the incidence of new-onset POAF using analyses adjusted for genetic ancestry. We assessed the ability of the polygenic risk score to predict POAF when added to common clinical risk scores. As a secondary objective, among patients who developed POAF, we estimated the association of the polygenic risk score with AF recurrence in follow-up beyond 30 post-operative days.ResultsAmong 3031 patients (63.5% isolated coronary artery bypass grafting), 1282 patients (42.3%) developed new-onset POAF. The polygenic risk score for AF was strongly associated with the risk for POAF (odds ratio 1.3 per standard deviation increase in polygenic risk score [95% CI 1.2-1.4]). The 10% of participants with highest polygenic risk had a risk of POAF of 50.5% as compared to 41.4% for the bottom 90% (odds ratio 1.4 [95% CI 1.1-1.8]).When the polygenic risk score was added to the clinical risk scores, it improved the model fit for all scores, significantly improved the C-statistic for the CHA2DS2-VASc, POAF and HATCH Scores and improved measures of risk classification for all scores (Table).Follow-up data on AF status beyond 30 days were available for 902 patients; 71 patients (7.9%) had AF recurrence detected beyond 30 days post-operatively. The polygenic risk score was not significantly associated with a higher risk for AF recurrence (odds ratio, 1.1 per standard deviation increase in polygenic risk score [95% CI, 0.9-1.5]).ConclusionsA higher polygenic risk score for AF is associated with the development of new-onset POAF following cardiac surgery and improves risk classification compared with clinical risk scores alone. However, this study failed to demonstrate an association of the polygenic risk score with AF recurrence in patients who develop POAF.

Introduction: Prior studies demonstrate correlation between atrial fibrillation (AF) polygenic risk score (PRS) and ischemic stroke, especially cardioembolic (CE) stroke, suggesting shared genetic components. In this study, we hypothesized that an AF PRS can discriminate CE from non-CE strokes. Methods: We evaluated AF and stroke risk in 26,145 individuals of European descent from the NINDS Stroke Genetics Network (SiGN) with study-adjudicated TOAST subtypes. AF genetic risk was estimated using two newly derived PRS (LDpred-funct and sBayesR) and two previously validated PRS (pruning and thresholding and LDpred). A clinical risk score (CRS) was derived within separate individuals in UK Biobank utilizing components of the Cohorts for Aging and Genomic Research in Epidemiology (CHARGE-AF) model available in SiGN. We regressed each AF PRS on AF status and separately CE stroke in logistic regression models adjusted for CRS, imputation group, and the first 10 principal components. We calculated discrimination of AF and CE stroke, and compared across models using 2000-iteration bootstrapping and pairwise Z-testing. We also assessed category-free reclassification of CE stroke risk with the addition of PRS to a) CRS, and b) a modified CHA 2 DS 2 -VASc score including all available score components. Results: Each AF PRS was significantly associated with AF and CE stroke after adjustment for the CRS. Addition of any AF PRS significantly improved model discrimination as compared to the CRS alone, and LDpred discriminated both AF and CE better than other PRSs ( Figure ; P &lt;0.005). Adding LDpred PRS to CRS resulted in appropriate reclassification of CE stroke risk compared to the CRS or the modified CHA 2 DS 2 -VASc score alone ( Figure ). Conclusions: Addition of AF polygenic risk to clinical risk factors improves discrimination of CE from non-CE strokes, as well as reclassification of stroke subtype. AF polygenic risk may be a useful biomarker for identifying AF-related strokes.

The prevalence of atrial fibrillation (AF) in patients with heart failure (HF) is high, but longitudinal studies suggest that the incidence of AF is relatively low. The authors investigated this paradox prospectively in an epidemiologically representative population of patients with HF and persistent AF. In all, 891 consecutive patients with HF [mean age, 70+/-10 years; 70% male; left ventricular ejection fraction, 32%+/-9%] were enrolled. The prevalence of persistent AF at baseline was 22%. The incidence of persistent AF at 1 year was 26 per 1000 person-years, ranging from 15 in New York Heart Association class I/II to 44 in class III/IV. AF occurred either at the same time or prior to HF in 76% of patients and following HF in 24%. A risk score was developed to predict the occurrence of persistent AF. The annual risk of persistent AF developing was 0.5% (0%-1.3%) for those in the low-risk group compared with 15% (3.4%-26.6%) in the high-risk group. Despite a high prevalence of persistent AF in patients with HF, the incidence of persistent AF is relatively low. This is predominantly due to AF coinciding with or preceding the development of HF. The annual risk of persistent AF developing can be estimated from clinical variables.

Background Previous studies have suggested only modest benefits of adding genetic information to conventional risk factors for prediction of atrial fibrillation (AF). However, these studies have been based on limited numbers of AF cases and pre-date recent AF genetic discoveries. Purpose To examine the independent relevance of common genetic risk factors over and above established non-genetic risk factors for predicting AF amongst 270,000 participants from UK Biobank, and to determine potential clinical utility. Methods UK Biobank (UKB) is a large prospective study of over 500,000 British individuals aged 40 to 69 years at recruitment. Incident AF was ascertained using hospital episode statistics and death registry data. The CHARGE-AF score, which combines the relevance of age, height, weight, blood pressure, use of antihypertensives, diabetes, heart failure, and myocardial infarction (MI) was used to estimate 5-year risk of AF at baseline. A polygenic risk score (PRS) was constructed based on 142 independent variants previously associated with AF in a genome-wide meta-analysis of 60,620 AF cases from the AFGen Consortium, weighted by their published effect sizes. A total of 270,254 individuals were analysed after exclusions for genetic QC, non-White British ancestry, and prevalent AF. Cox proportional hazard models were used to estimate associations between risk scores (based on standard deviation [SD] units) and incident AF. Standard methods were used to assess predictive value. Results During a median follow-up of 8.1 years, 12,407 incident AF cases were identified. The CHARGE-AF risk score strongly predicted incident AF in UK Biobank, and was associated with a ∼3-fold higher risk of AF per SD (Hazard ratio [HR]=2.88; 95% CI: 2.82–2.94). The PRS was associated with a 54% higher risk of AF per SD (HR=1.54; 95% CI: 1.51–1.57). The independent impact of the PRS, after adjusting for the CHARGE-AF score, was unchanged and remained strongly predictive (HR=1.57, 95% CI: 1.54–1.60), with participants in the upper tertile of the PRS having more than a 2.5-fold higher risk (HR=2.59, 95% CI: 2.47–2.71) when compared with those in the lower tertile. The addition of the PRS improved the C-statistic from 0.758 (CHARGE-AF alone) to 0.783 (Δ=0.025) and correctly reclassified 8.7% of cases and 2.6% of controls at 5 years. Both non-genetic and genetic risk scores were well-calibrated in the UK Biobank participants, and sensitivity of the results to alternative PRS selection approaches and age at risk were also examined. Conclusion In a large prospective cohort, genetic determinants of AF were independent of conventional risk factors and significantly improved prediction over a well-validated clinical risk algorithm. This illustrates the potential added benefit of genetic information to identify higher-risk individuals who may benefit from earlier monitoring and personalised risk management strategies. Funding Acknowledgement Type of funding source: Foundation. Main funding source(s): British Heart Foundation

Background: Traditional risk factors for atrial fibrillation (AF) likely contribute to the pathogenesis of AF through their effects on left atrial (LA) enlargement. However, little is known about risk factors for AF in individuals with normal LA size. Hypothesis: We hypothesized that the risk factors for AF differ between individuals with normal and enlarged LA. Methods: LA diameter was measured by cardiac echocardiography in participants in the Atherosclerosis Risk in Communities (ARIC) study during 2011 - 13. AF was defined by ECGs and/or hospital discharge ICD-9 codes. Gender-specific cut points (3.9 cm for females and 4.1 cm for males were used to dichotomize the sample into normal and enlarged LA. Univariate and multivariate logistic regression models adjusting for age, gender, race, diabetes, hypertension, alcohol use (&gt;1 drink/day), height, weight, coronary artery disease, heart failure, and exercise (&gt;1 day per week) were used to evaluate risk factors for AF among ARIC participants with and without enlarged LA. Results: Of 5540 (mean age 75.6±5.2, women 58.6%) participants enlarged LA was present in 955 (16.2%). AF was prevalent in 3.9% of normal LA and 20% of enlarged LA participants. In multivariate analysis, alcohol use and exercise (&gt;1 per week) were independently associated with AF in participants with normal sized LA (p&lt;0.05)(table). Interaction terms of alcohol use, and exercise with LA size were statistically significant despite adjusting for age, gender, height, weight and race in the multivariate model. The population attributable risk of AF for alcohol use and lack of exercise were 5.5% and 6.4%, respectively. ` Conclusion: Many of the risk factors for AF are similar irrespective of the LA size. However, lack of exercise and alcohol drinking are associated with prevalent AF only in the normal sized LA group. More research is warranted to determine the potential benefits of interventions targeting these two modifiable risk factors in the setting of normal LA size.

Background: Little is known about how incident atrial fibrillation (AF) affects the clinical outcomes in chronic kidney disease (CKD) patients and whether there is a different influence between pre-existing and incident AF. Methods: Incident CKD patients from 2000 to 2013 were retrieved from the National Health Insurance Research Database (NHIRD) of Taiwan and they were classified as non-AF (n = 15,251), prevalent AF (n = 612), and incident AF (n = 588). The outcomes of interest were end-stage renal disease (ESRD) requiring dialysis, all-cause mortality, cardiovascular (CV) mortality, acute myocardial infarction (AMI), stroke or systemic thromboembolism. Results: Compared with CKD patients without AF, those with prevalent or incident AF were associated with higher adjusted rates of ESRD (hazard ratio (HR), 1.40; 95% confidence interval (CI), 1.32–1.48; HR, 2.91; 95% CI, 2.74–3.09, respectively), stroke or systemic thromboembolism (HR, 1.89; 95% CI, 1.77–2.03; HR, 1.67; 95% CI, 1.54–1.81, respectively), AMI (HR, 1.24; 95% CI, 1.09–1.41; HR, 1.99; 95% CI, 1.75–2.27, respectively), all-cause mortality (HR, 1.64; 95% CI, 1.56–1.72; HR, 2.17; 95% CI, 2.06–2.29, respectively), and CV mortality (HR, 2.95; 95% CI, 2.62–3.32; HR, 4.61; 95% CI, 4.09–5.20, respectively). Intriguingly, CKD patients with prevalent AF were associated with lower adjusted rates of ESRD, AMI, all-cause mortality, and CV mortality compared with those with incident AF. Conclusion: Both incident and prevalent AF were independently associated with greater risks of AMI, all-cause mortality, CV mortality, ESRD, and stroke or systemic thromboembolism. Our findings are novel in that, compared with prevalent AF, incident AF possessed an even higher risk of some clinical consequences, including ESRD, all-cause mortality, CV mortality, and AMI.