Aims Biomarkers have the potential to improve risk prediction beyond clinical characteristics. We examined the association of four emerging cardiovascular biomarkers [angiopoietin 2 (Angpt2), bone morphogenetic protein 10 (BMP10), fibroblast growth factor 23 (FGF23), insulin-like growth factor binding protein 7 (IGFBP7)] in comparison with N-terminal pro B-type natriuretic peptide (NT-proBNP) across the disease course of atrial fibrillation (AF).Methods and results We enrolled patients from a prospective cohort of patients at risk of AF or with manifest arrhythmia. The circulating vascular biomarkers were quantified using high-throughput, high-precision precommercial assays (Roche Diagnostics). A combined endpoint comprised: stroke, transient ischaemic attack (TIA), myocardial infarction, incident coronary heart disease, heart failure, and all-cause mortality. Of the total n = 1047 individuals, n = 527 had prevalent AF, and n = 507 were free of AF at baseline. Median follow-up was 42 months. A total of n = 66 individuals died; the combined endpoint occurred in n = 198 individuals. All five biomarkers were significantly associated with the incidence of AF, both in multistate analysis (MSA) and Cox regression, although the association with FGF23 was only significant in the age- and sex-adjusted Cox model. AF recurrence was significantly associated with all biomarkers, most strongly with NT-proBNP. In prevalent AF, NT-proBNP, FGF23, and IGFBP7 were associated with the combined endpoint and all-cause mortality, and Angpt2 was associated with all-cause mortality. NT-proBNP showed the strongest association for all-cause mortality, and IGFBP7 for the combined endpoint in prevalent AF. In incident AF the association with the combined outcome was statistically significant for NT-proBNP in multivariable-adjusted models. All-cause mortality in individuals with incident AF was associated with NT-proBNP, Angpt2, FGF23, and IGFBP7 both in the MSA and Cox model.Conclusion All novel biomarkers Angpt2, BMP10, FGF23, and IGFBP7 showed predictive value for incident and recurrent AF. Individual biomarkers showed distinct strengths in prediction of outcomes across the disease spectrum of AF.

Atrial fibrillation (AF) increases the risk of adverse cardiovascular events, yet the underlying biological mechanisms remain unclear. We evaluate a panel of 12 circulating biomarkers representing diverse pathophysiological pathways in 3817 AF patients to assess their association with adverse cardiovascular outcomes. We identify 5 biomarkers including D-dimer, growth differentiation factor 15 (GDF-15), interleukin-6 (IL-6), N-terminal pro-B-type natriuretic peptide (NT-proBNP), and high-sensitivity troponin T (hsTropT) that independently predict cardiovascular death, stroke, myocardial infarction, and systemic embolism, significantly enhancing predictive accuracy. Additionally, GDF-15, insulin-like growth factor-binding protein-7 (IGFBP-7), NT-proBNP, and hsTropT predict heart failure hospitalization, while GDF-15 and IL-6 are associated with major bleeding events. A biomarker model improves predictive accuracy for stroke and major bleeding compared to established clinical risk scores. Machine learning models incorporating these biomarkers demonstrate consistent improvements in risk stratification across most outcomes. In this work, we show that integrating biomarkers related to myocardial injury, inflammation, oxidative stress, and coagulation into both conventional and machine learning-based models refine prognosis and guide clinical decision-making in AF patients.

Emerging evidence indicates that the circulating biomarker angiopoietin-2 (ANGPT2), bone morphogenetic protein2 10 (BMP10), fibroblast growth factor 23 (FGF23), and insulin-like growth factor-binding protein7 (IGFBP7) reflect distinct pathophysiological vascular and cardiac processes contributing to adverse cardiac remodeling in the context of volume or pressure overload. This study aims to investigate the association between these circulating biomarkers, and the presence of hemodynamically significant pressure or volume overload and adverse clinical outcomes. Methods:In an observational cohort of outpatient cardiology patients (N = 1506) the relationship between the four emerging biomarkers and pressure/volume overload using multivariable-adjusted regression models was examined. Results:Elevated levels of the four biomarkers were positively associated with the presence of significant volume overload compared to none/mild valve disease. (ANGPT2: Odds ratio (OR) 1.26 (95 % confidence interval (CI): 1.17-1.35), p < 0.001; BMP10: OR = 2.57 (95 %-CI: 1.89-3.48), p < 0.001; FGF23: OR = 1.51 (95 %-CI: 1.14-1.20), p = 0.004; IGFBP7: OR = 1.39 (95 %-CI: 1.14-1.69), p = 0.001, NT-proBNP: OR = 1.69 (95 %-CI: 1.47-1.95), p < 0.001).FGF23 and NT-proBNP demonstrated statistically significant associations with pressure overload compared to none/mild burden.Higher concentrations of all biomarkers were predictive of all-cause mortality in patients with volume overload. Conclusions:This study highlights that circulating biomarkers associated with distinct pathophysiological vascular pathways, including inflammation, fibrosis, and calcification, are elevated in patients with hemodynamically significant volume overload. Given their association with mortality, these biomarkers merit further investigation of their underlying pathways, particularly in conjugation with the established biomarker NT-proBNP, to clarify their potential for more targeted clinical applications.

Familial hypercholesterolemia (FH) is a monogenic disease characterized by pathogenic mutations in genes involved in low-density lipoprotein cholesterol (LDL-C) metabolism. Optimal strategies for identifying FH in the general population are still unknown. To assess the prevalence of genetic FH (genFH) in a contemporary population-based sample of adult Hamburg residents and to evaluate its association with hypercholesterolemia phenotype. In 7,373 participants of the population-based a City Health Study (HCHS) the FH genes LDLR, APOB, PCSK9, LDLRAP1, and APOE were analyzed to identify genFH, based on short-read whole-genome sequencing. LDL-C concentrations were adjusted for intake and intensity of lipid-lowering medication and categorized using the following thresholds: ≥130/≥160/≥190 mg/dL. Severe hypercholesterolemia was defined by LDL-C ≥190 mg/dL. Among 7,373 adults, median age was 62.0 (quartiles 54.0-69.0) years, and 49.1% of these were women. Twenty-three individuals had heterozygous genFH (prevalence 0.31%; 95%CI: 0.21% to 0.47% [corresponding to 1:321]), all caused by mutations in the LDLR gene. Median treatment-corrected LDL-C was higher in subjects with genFH (191 mg/dL, quartiles 149-210 mg/dL) compared to 128 mg/dL (quartiles 105-153 mg/dL) in those without genFH. Severe hypercholesterolemia was observed in 476 of 7,275 (6.5%) subjects with available LDL-C values. Of those, only 2.3% (n=11) were positive for genFH. Moreover, 9.1% of carriers of FH-causing variants had LDL-C values below 130 mg/dL, 32.8% below 160 mg/dL and only 50% of subjects with genFH had severe hypercholesterolemia (Table). Applying a phenotypic LDL-C threshold of ≥190 mg/dL, ≥160 mg/dL and ≥130 mg/dL to screen for genFH would results in numbers needed to screen of 43, 99 or 174, respectively. The prevalence of genetically verified FH in this contemporary German population-based cohort was very similar to the worldwide prevalence of FH (0.31% versus 0.32%, respectively). Only half of the adult individuals with genFH had severe hypercholesterolemia, and only (2.3%) of individuals with LDL-C ≥190 mg/dL had genFH. More robust evidence of genotype-phenotype associations of FH mutations is needed to accurately infer at-risk individuals from genetic screening. Two first and two last auhors contributed equally to this work.

The role of biomarkers in diagnosing pulmonary hypertension (PH) and distinguishing between pre- and post-capillary PH remains poorly understood. We aimed to identify biomarkers with a strong association with mean pulmonary arterial pressure, mPAP (PH diagnosis) and pulmonary vascular resistance, PVR (pre-capillary component), but not with pulmonary arterial wedge pressure, PAWP (post-capillary component). Blood samples were collected in patients undergoing right heart catheterization within a prospective cross-sectional study. Biomarkers measured included BMP10, NT-proBNP, ANG2, ESM1/endocan, FGF23, GDF15, IGFBP7, IL6, MyBPC3, proC3, and proC6/endotrophin. Primary outcomes were mPAP, PVR, and PAWP, while secondary outcomes included PH diagnosis (mPAP > 20 mmHg) and elevated PVR (> 2 Wood units). Multivariable linear and logistic regression models were used to assess the relationship between biomarkers and outcomes. Of the 127 patients included (age 66 ± 13 years, 54

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

Background BMP10 (bone morphogenic protein 10) has emerged as a novel biomarker associated with the risk of ischemic stroke and other outcomes in patients with atrial fibrillation (AF). The study aimed to determine if repeated BMP10 measurements improve prognostication of cardiovascular events in patients with AF. Methods and Results BMP10 was measured using a prototype Elecsys immunoassay in plasma samples collected at randomization and after 2 months in patients with AF randomized to apixaban or warfarin in the ARISTOTLE (Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation) trial (n=2878). Adjusted Cox‐regression models were used to evaluate the association between 2‐month BMP10 levels and outcomes. BMP10 levels increased by 7.8% ( P <0.001) over 2 months. The baseline variables most strongly associated with BMP10 levels at 2 months were baseline BMP10 levels, body mass index, sex, age, creatinine, diabetes, warfarin treatment, and AF‐rhythm. During median 1.8 years follow‐up, 34 ischemic strokes/systemic embolism, 155 deaths, and 99 heart failure hospitalizations occurred. Comparing the third with the first sample quartile, higher BMP10 levels at 2 months were associated with higher risk of ischemic stroke (hazard ratio [HR], 1.33 [95% CI, 0.67–2.63], P =0.037), heart failure (HR, 1.91 [95% CI, 1.17–3.12], P =0.012) and all‐cause death (HR, 1.61 [95% CI, 1.17–2.21], P <0.001). Adding BMP10 levels at 2 months on top of established risk factors and baseline BMP10 levels improved the C‐indices for ischemic stroke/systemic embolism (from 0.73 to 0.75), heart failure hospitalization (0.76–0.77), and all‐cause mortality (0.70–0.72), all P <0.05. Conclusions Elevated levels of BMP10 at 2 months strengthened the associations with the risk of ischemic stroke, hospitalization for heart failure, and all‐cause mortality. Repeated measurements of BMP10 may further refine risk stratification in patients with AF.

Abstract Despite marked progress in the management of atrial fibrillation (AF), detecting AF remains difficult and AF-related complications cause unacceptable morbidity and mortality even on optimal current therapy. This document summarizes the key outcomes of the 8th AFNET/EHRA Consensus Conference of the Atrial Fibrillation NETwork (AFNET) and the European Heart Rhythm Association (EHRA). Eighty-three international experts met in Hamburg for 2 days in October 2021. Results of the interdisciplinary, hybrid discussions in breakout groups and the plenary based on recently published and unpublished observations are summarized in this consensus paper to support improved care for patients with AF by guiding prevention, individualized management, and research strategies. The main outcomes are (i) new evidence supports a simple, scalable, and pragmatic population-based AF screening pathway; (ii) rhythm management is evolving from therapy aimed at improving symptoms to an integrated domain in the prevention of AF-related outcomes, especially in patients with recently diagnosed AF; (iii) improved characterization of atrial cardiomyopathy may help to identify patients in need for therapy; (iv) standardized assessment of cognitive function in patients with AF could lead to improvement in patient outcomes; and (v) artificial intelligence (AI) can support all of the above aims, but requires advanced interdisciplinary knowledge and collaboration as well as a better medico-legal framework. Implementation of new evidence-based approaches to AF screening and rhythm management can improve outcomes in patients with AF. Additional benefits are possible with further efforts to identify and target atrial cardiomyopathy and cognitive impairment, which can be facilitated by AI.

BACKGROUND: Atrial fibrillation is a major risk factor for stroke and silent brain infarcts. We studied whether a multimodal approach offers additional insights to the CHA 2 DS 2 -VASc score in predicting stroke or new brain infarcts on magnetic resonance imaging (MRI) over a 2-year follow-up. METHODS: Swiss-AF is a prospective, multicenter cohort study of patients with known atrial fibrillation. We included patients with available brain MRI both at enrollment and 2 years later. The dates of the baseline and follow-up visits ranged from March 2014 to November 2020. The primary outcome was assessed 2 years after baseline and was defined as a composite of clinically identified stroke or any new brain infarct on the 2-year MRI. We compared a multivariable logistic regression model including prespecified clinical, biomarker, and baseline MRI variables to the CHA 2 DS 2 -VASc score. RESULTS: We included 1232 patients, 89.8% of them taking oral anticoagulants. The primary outcome occurred in 78 patients (6.3%). The following baseline variables were included in the final multivariate model and were significantly associated with the primary outcome: white matter lesion volume in milliliters (adjusted odds ratio [aOR], 1.91 [95% CI, 1.45–2.56]), NT-proBNP (N-terminal pro-B-type natriuretic peptide; aOR, 1.75 [95% CI, 1.20–2.63]), GDF-15 (growth differentiation factor-15; aOR, 1.68 [95% CI, 1.11–2.53]), serum creatinine (aOR, 1.50 [95% CI, 1.02–2.22]), IL (interleukin)-6 (aOR, 1.37 [95% CI, 1.00–1.86]), and hFABP (heart-type fatty acid–binding protein; aOR, 0.48 [95% CI, 0.31–0.73]). Overall performance and discrimination of the new model was superior to that of the CHA 2 DS 2 -VASc score (C statistic, 0.82 [95% CI, 0.77–0.87] versus 0.64 [95% CI, 0.58–0.70]). CONCLUSIONS: In patients with atrial fibrillation, a model incorporating white matter lesion volume on baseline MRI and selected blood markers yielded new insights on residual stroke risk despite a high proportion of patients on oral anticoagulants. This may be relevant to develop further preventive measures.

Early detection of atrial fibrillation (AF) enables initiation of anticoagulation and early rhythm control therapy to reduce stroke, cardiovascular death, and heart failure. In a cross-sectional, observational study, we aimed to identify a combination of circulating biomolecules reflecting different biological processes to detect prevalent AF in patients with cardiovascular conditions presenting to hospital. Twelve biomarkers identified by reviewing literature and patents were quantified on a high-precision, high-throughput platform in 1485 consecutive patients with cardiovascular conditions (median age 69 years [Q1, Q3 60, 78]; 60% male). Patients had either known AF (45%) or AF ruled out by 7-day ECG-monitoring. Logistic regression with backward elimination and a neural network approach considering 7 key clinical characteristics and 12 biomarker concentrations were applied to a randomly sampled discovery cohort (n = 933) and validated in the remaining patients (n = 552). In addition to age, sex, and body mass index (BMI), BMP10, ANGPT2, and FGF23 identified patients with prevalent AF (AUC 0.743 [95% CI 0.712, 0.775]). These circulating biomolecules represent distinct pathways associated with atrial cardiomyopathy and AF. Neural networks identified the same variables as the regression-based approach. The validation using regression yielded an AUC of 0.719 (95% CI 0.677, 0.762), corroborated using deep neural networks (AUC 0.784 [95% CI 0.745, 0.822]). Age, sex, BMI and three circulating biomolecules (BMP10, ANGPT2, FGF23) are associated with prevalent AF in unselected patients presenting to hospital. Findings should be externally validated. Results suggest that age and different disease processes approximated by these three biomolecules contribute to AF in patients. Our findings have the potential to improve screening programs for AF after external validation.

Abstract Aims Several biomarkers are associated with clinical outcomes in patients with atrial fibrillation (AF), but a causal relationship has not been established. This study aimed to evaluate angiopoietin-2, a novel candidate biomarker of endothelial inflammation and vascular remodelling, in patients with AF. Methods and results Angiopoietin-2 was measured in plasma obtained from patients with AF treated with aspirin monotherapy (exploration cohort, n = 2987) or with oral anticoagulation (validation cohort, n = 13 079). Regression models were built to assess the associations between angiopoietin-2, clinical characteristics, and outcomes. In both cohorts, plasma angiopoietin-2 was independently associated with AF on the baseline electrocardiogram and persistent/permanent AF, age, history of heart failure, female sex, tobacco use/smoking, body mass index, renal dysfunction, diabetes, and N-terminal pro-B-type natriuretic peptide (NT-proBNP). Angiopoietin-2 was independently associated with subsequent hospitalization for heart failure after adjusting for age, creatinine, and clinical characteristics in the exploration cohort [c-index 0.79, 95% confidence interval (CI) 0.75–0.82; third vs. first quartile, hazard ratio (HR) 1.74, 95% CI 1.26–2.41] and in the validation cohort (c-index 0.76, 95% CI 0.74–0.78; HR 1.58, 95% CI 1.37–1.82). In both cohorts, the association persisted when also adjusting for NT-proBNP (P ≤ 0.001). In full multivariable models also adjusted for NT-proBNP, angiopoietin-2 did not show statistically significant associations with ischaemic stroke, cardiovascular and all-cause death, or major bleeding that were consistent across the two cohorts. Conclusions In patients with AF, plasma levels of angiopoietin-2 were independently associated with subsequent hospitalization for heart failure and provided incremental prognostic value to clinical risk factors and NT-proBNP.

Heart failure (HF) is a rising global cardiovascular epidemic driven by aging and chronic inflammation. As elderly populations continue to increase, precision treatments for age-related cardiac decline are urgently needed. Here we report that cardiac and blood expression of IGFBP7 is robustly increased in patients with chronic HF and in an HF mouse model. In a pressure overload mouse HF model, Igfbp7 deficiency attenuated cardiac dysfunction by reducing cardiac inflammatory injury, tissue fibrosis and cellular senescence. IGFBP7 promoted cardiac senescence by stimulating IGF-1R/IRS/AKT-dependent suppression of FOXO3a, preventing DNA repair and reactive oxygen species (ROS) detoxification, thereby accelerating the progression of HF. In vivo, AAV9-shRNA-mediated cardiac myocyte Igfbp7 knockdown indicated that myocardial IGFBP7 directly regulates pathological cardiac remodeling. Moreover, antibody-mediated IGFBP7 neutralization in vivo reversed IGFBP7-induced suppression of FOXO3a, restored DNA repair and ROS detoxification signals and attenuated pressure-overload-induced HF in mice. Consequently, selectively targeting IGFBP7-regulated senescence pathways may have broad therapeutic potential for HF.

The growing elderly population worldwide represents a major challenge for caregivers, healthcare providers, and society. Older patients have a higher prevalence of cardiovascular (CV) disease, high rates of CV risk factors, and multiple age-related comorbidities. Although prevention and management strategies have been shown to be effective in older people, they continue to be under-used, and under-studied. In addition to hard endpoints, frailty, cognitive impairments, and patients' re-assessment of important outcomes (e.g. quality of life vs. longevity) are important aspects for older patients and emphasize the need to include a substantial proportion of older patients in CV clinical trials. To complement the often skewed age distribution in clinical trials, greater emphasis should be placed on real-world studies to assess longer-term outcomes, especially safety and quality of life outcomes. In the complex environment of the older patient, a multidisciplinary care team approach with the involvement of the individual patient in the decision-making process can help optimize prevention and management strategies. This article aims to demonstrate the growing burden of ageing in real life and illustrates the need to continue primary prevention to address CV risk factors. It summarizes factors to consider when choosing pharmacological and interventional treatments for the elderly and the need to consider quality of life and patient priorities when making decisions.

Background Patients with atrial fibrillation (AF) face an increased risk of death and major adverse cardiovascular events (MACE). We aimed to assess the predictive value of the novel atrial‐specific biomarker BMP10 (bone morphogenetic protein 10) for death and MACE in patients with AF in comparison with NT‐proBNP (N‐terminal prohormone of B‐type natriuretic peptide). Methods and Results BMP10 and NT‐proBNP were measured in patients with AF enrolled in Swiss‐AF (Swiss Atrial Fibrillation Study), a prospective multicenter cohort study. A total of 2219 patients were included (median follow‐up 4.3 years [interquartile range 3.9, 5.1], mean age 73±9 years, 73% male). In multivariable Cox proportional hazard models, the adjusted hazard ratio (aHR) associated with 1 ng/mL increase of BMP10 was 1.60 (95% CI, 1.37–1.87) for all‐cause death, and 1.54 (95% CI, 1.35–1.76) for MACE. For all‐cause death, the concordance index was 0.783 (95% CI, 0.763–0.809) for BMP10, 0.784 (95% CI, 0.765–0.810) for NT‐proBNP, and 0.789 (95% CI, 0.771–0.815) for both biomarkers combined. For MACE, the concordance index was 0.732 (95% CI, 0.715–0.754) for BMP10, 0.747 (95% CI, 0.731–0.768) for NT‐proBNP, and 0.750 (95% CI, 0.734–0.771) for both biomarkers combined. When grouping patients according to NT‐proBNP categories (<300, 300–900, >900 ng/L), higher aHRs were observed in patients with high BMP10 in the categories of low NT‐proBNP (all‐cause death aHR, 2.28 [95% CI, 1.15–4.52], MACE aHR, 1.88 [95% CI, 1.07–3.28]) and high NT‐proBNP (all‐cause death aHR, 1.61 [95% CI, 1.14–2.26], MACE aHR, 1.38 [95% CI, 1.07–1.80]). Conclusions BMP10 strongly predicted all‐cause death and MACE in patients with AF. BMP10 provided additional prognostic information in low‐ and high‐risk patients according to NT‐proBNP stratification. Registration URL: https://www.clinicaltrials.gov ; Unique identifier: NCT02105844.

BACKGROUND:Large-scale screening for atrial fibrillation (AF) requires reliable methods to identify at-risk populations. Using an experimental semi-quantitative biomarker assay, B-type natriuretic peptide (BNP) and fibroblast growth factor 23 (FGF23) were recently identified as the most suitable biomarkers for detecting AF in combination with simple morphometric parameters (age, sex, and body mass index [BMI]). In this study, we validated the AF model using standardised, high-throughput, high-sensitivity biomarker assays.METHODS AND FINDINGS:For this study, 1,625 consecutive patients with either (1) diagnosed AF or (2) sinus rhythm with CHA2DS2-VASc score of 2 or more were recruited from a large teaching hospital in Birmingham, West Midlands, UK, between September 2014 and February 2018. Seven-day ambulatory ECG monitoring excluded silent AF. Patients with tachyarrhythmias apart from AF and incomplete cases were excluded. AF was diagnosed according to current clinical guidelines and confirmed by ECG. We developed a high-throughput, high-sensitivity assay for FGF23, quantified plasma N-terminal pro-B-type natriuretic peptide (NT-proBNP) and FGF23, and compared results to the previously used multibiomarker research assay. Data were fitted to the previously derived model, adjusting for differences in measurement platforms and known confounders (heart failure and chronic kidney disease). In 1,084 patients (46% with AF; median [Q1, Q3] age 70 [60, 78] years, median [Q1, Q3] BMI 28.8 [25.1, 32.8] kg/m2, 59% males), patients with AF had higher concentrations of NT-proBNP (median [Q1, Q3] per 100 pg/ml: with AF 12.00 [4.19, 30.15], without AF 4.25 [1.17, 15.70]; p < 0.001) and FGF23 (median [Q1, Q3] per 100 pg/ml: with AF 1.93 [1.30, 4.16], without AF 1.55 [1.04, 2.62]; p < 0.001). Univariate associations remained after adjusting for heart failure and estimated glomerular filtration rate, known confounders of NT-proBNP and FGF23. The fitted model yielded a C-statistic of 0.688 (95% CI 0.656, 0.719), almost identical to that of the derived model (C-statistic 0.691; 95% CI 0.638, 0.744). The key limitation is that this validation was performed in a cohort that is very similar demographically to the one used in model development, calling for further external validation.CONCLUSIONS:Age, sex, and BMI combined with elevated NT-proBNP and elevated FGF23, quantified on a high-throughput platform, reliably identify patients with AF.TRIAL REGISTRATION:Registry IRAS ID 97753 Health Research Authority (HRA), United Kingdom.

Background: Early detection of atrial fibrillation (AF) and subsequent initiation of anticoagulation and rhythm control therapy markedly reduce stroke, cardiovascular death, and heart failure, but unselected ECG screening for AF is time- and resource-intensive. Combining biomarkers reflecting different biological processes may identify patients at high risk of AF, enabling targeted ECG screening.Methods: We systematically reviewed literature and patent information to define candidate biomarkers for AF detection. The top 12 biomarkers identified through this process were quantified on a high-precision, high-throughput platform in 1485 consecutive patients at risk for AF presenting acutely to hospital (median age 69 years [Q1, Q3 60,78]; 60% male). Patients had either known AF (45%) or AF ruled out by 7-day ECG-monitoring. A model simultaneously considering 7 key clinical characteristics and all biomarkers was developed in a randomly sampled discovery cohort (n=933) and validated in the remaining patients (n=552). Neural networks were also applied.Findings: Using backward elimination, a model using age, sex, body mass index (BMI), BMP10, ANG2, and FGF23 discriminated between patients with and without AF with an AUC of 0·743 [95% confidence interval (CI) 0·712-0·775]. The biomarkers represent distinct pathways relevant for atrial cardiomyopathy and AF, namely hypertrophy and fibrosis (FGF23), endothelial dysfunction (ANG2), and atrial oxidative stress and the genomic predisposition to AF (BMP10). The SHAP procedure for neural networks identified the same variables as the regression. The validation yielded an AUC of 0·719 (95%CI 0·677, 0·762), corroborated using deep neural networks (AUC 0·784 [95%CI 0·745, 0·822]).Interpretation: The combination of three simple characteristics (age, sex, BMI) and three biomarkers (BMP10, ANG2, and FGF23) robustly identifies patients with AF. Such an approach enables targeted screening for AF and provides a platform to develop personalised prevention and treatment in patients with AF.Funding Statement: This work was partially supported by the European Commission (grant agreements no. 633196 [CATCH ME]) to PKi, LF, BC, SH, SK, LM, MFS, US, and no. 116074 [BigData@Heart EU IMI] to PKi, British Heart Foundation (FS/13/43/30324 and (AA/18/2/34218) to PKi and LF), German Centre for Cardiovascular Research supported by the German Ministry of Education and Research (DZHK, via a grant to AFNET to PKi), and Leducq Foundation (14CVD01) to PKi.Declaration of Interests: LF has received institutional research grants and non-financial support from European Union, British Heart Foundation, Medical Research Council (UK), and DFG and Gilead. PKi has received additional support for research from the European Union, British Heart Foundation, Leducq Foundation, Medical Research Council (UK), and German Centre for Heart Research, from several drug and device companies active in atrial fibrillation, honoraria from several such companies. PKi and LF are listed as inventors on two patents held by University of Birmingham (Atrial Fibrillation Therapy WO 2015140571, Markers for Atrial Fibrillation WO 2016012783). PKa is an employee of Roche Diagnostics GmbH. AZ is an employee of Roche Diagnostics Intl. All other authors have reported no relationships relevant to the contents of this paper to disclose.Ethics Approval Statement: This study complied with the Declaration of Helsinki, was approved by the National Research Ethics Service Committee (IRAS ID 97753), and was sponsored by the University of Birmingham.

Introduction: Natriuretic peptides and cardiac troponin are associated with clinical outcomes in patients with atrial fibrillation (AF) but the search for disease-specific biomarkers is ongoing. We evaluated a novel candidate biomarker of endothelial remodeling and vascular growth, Angiopoietin-2 (Ang2), and its associations with clinical characteristics and outcomes in patients with AF not receiving oral anticoagulation. Methods: We used a prototype electroimmunoassay (Roche Diagnostics) to measure levels of Ang2 in plasma samples obtained at baseline from patients with AF randomized to aspirin monotherapy in two clinical trials. Associations of Ang2 with clinical characteristics and outcomes were explored using linear and Cox regression models. Results: A total of 2,987 patients were included (median age 71 years, 58% male and 13% with prior stroke). Median (25th-75th percentile) Ang2 plasma level was 3.12 (2.15-4.88) ng/mL. In adjusted analyses, Ang2 showed significant associations with AF-rhythm on the baseline ECG, age, heart failure, non-paroxysmal AF, female sex, active smoking, higher body mass index, creatinine and diabetes. Adjusting for age and other clinical characteristics, Ang2 was associated with subsequent ischemic stroke (third vs. first quartile, hazard ratio [HR] 1.76, 95% confidence interval [CI] 1.19-2.61), heart failure hospitalization (HR 1.75, 95% CI 1.27-2.41), cardiovascular (HR 2.01, 95% CI 1.36-2.97) and all-cause death (HR 1.24, 95% CI 1.01-1.53), but not major bleeding. The association with heart failure remained after additional adjustment for N-terminal pro-B-type natriuretic peptide (p=0.002). There was no interaction with cardiac rhythm at baseline for any of the outcomes. Conclusions: Plasma levels of circulating Ang2 were associated with clinical characteristics and outcomes in patients with AF not receiving oral anticoagulation. Ang2 was a particularly strong predictor of heart failure hospitalization.

Aims Biomarkers specifically related to atrial tissue may increase the understanding of the pathophysiology of atrial fibrillation (AF) and further improve risk prediction in this setting. Bone morphogenetic protein 10 (BMP10) is a protein expressed in the atrial myocardium. We evaluated the association between BMP10 and the risk of ischaemic stroke and other cardiovascular events in large cohorts of patients with AF, treated with and without oral anticoagulation (OAC). Methods and results BMP10 was measured in plasma samples collected at randomisation in patients with AF without OAC in the ACTIVE A and AVERROES trials (n = 2974), and with OAC in the ARISTOTLE trial (n = 13 079). BMP10 was analysed with a prototype Elecsys immunoassay. Associations with outcomes were evaluated by Cox-regression models adjusted for clinical characteristics, kidney function, and N-terminal pro-B-type natriuretic peptide (NT-proBNP). Median concentrations of BMP10 were 2.47 and 2.44 ng/mL, in the non-OAC and OAC cohort, respectively. Increasing BMP10 was associated with lower body mass index, older age, female sex, kidney dysfunction, and AF rhythm. BMP10 was consistently associated with ischaemic stroke. In the non-OAC cohort, BMP10 increased the concordance index of the multivariable model from 0.713 to 0.733 (P = 0.004) and in the OAC cohort from 0.673 to 0.694 (P < 0.001). Additionally, BMP10 maintained a significant prognostic value after additionally adjusting for NT-proBNP. BMP10 was not independently associated with bleeding or with death. Conclusion The novel atrial biomarker BMP10 was independently associated with ischaemic stroke in patients with AF irrespective of OAC treatment. BMP10 seems to be more specifically related to the risk of ischaemic stroke in AF. One-sentence Summary In this study, BMP10 may be a novel specific biomarker of ischaemic stroke in patients with atrial fibrillation, irrespective of oral anticoagulation.

Background: Biomarkers specifically related to the atrial tissue might increase the understanding of the pathophysiology and improve risk prediction in atrial fibrillation (AF). Bone morphogenetic protein 10 (BMP10) is a novel biomarker expressed in atrial myocardium. We evaluated the association between BMP10 and the risk of stroke, bleeding, and death in patients with AF not treated with oral anticoagulation. Methods: BMP10 was measured in 2,974 plasma samples collected at randomisation in patients with AF randomized to aspirin in two cohorts, the ACTIVE-A (n=951) and AVERROES (n=2023) trials, median follow-up of 3.8 and 1.2 years, respectively. BMP10 was analysed with a prototype Elecsys electrochemiluminescence immunoassay. Associations between BMP10 and outcomes were evaluated by Cox-regression analyses adjusted for clinical characteristics, kidney function, and NT-proBNP. Results: Median age was 71 years, 58.1% were men. The median concentration of BMP10 was 2.46 (25 th -75 th percentiles, 2.09 - 2.94) ng/L. The variables most strongly associated with higher BMP10 levels were: heart rhythm (AF vs sinus), older age, female sex, lower BMI, and kidney dysfunction. BMP10 was the baseline variable most strongly associated with ischemic stroke during follow-up (Figure). After adjustments, the hazard ratio for ischemic stroke (BMP10 3rd vs 1st quartile) was 1.57 [95%CI 1.08-2.28], p=0.025), and the discriminatory value (c-index) was 0.643 (vs 0.634 of CHA 2 DS 2 -VASc score) and improved the full model from 0.737 to 0.746. BMP10 was not associated with bleeding or death. The results were consistent across both cohorts and irrespective of cardiac rhythm at blood sampling. Conclusions: In patients with AF, circulating plasma levels of BMP10 are independently associated with the risk of ischemic stroke but not with bleeding or death. BMP10 has an incremental discriminatory value for the risk of ischemic stroke, and may be a novel specific biomarker in patients with AF.

Abstract Objectives Biotin >20.0 ng/mL (81.8 nmol/L) can reduce Elecsys® Troponin T Gen 5 (TnT Gen 5; Roche Diagnostics) assay recovery, potentially leading to false-negative results in patients with suspected acute myocardial infarction (AMI). We aimed to determine the prevalence of elevated biotin and AMI misclassification risk from biotin interference with the TnT Gen 5 assay. Methods Biotin was measured using an Elecsys assay in two cohorts: (i) 797 0-h and 646 3-h samples from 850 US emergency department patients with suspected acute coronary syndrome (ACS); (ii) 2023 random samples from a US laboratory network, in which biotin distributions were extrapolated for higher values using pharmacokinetic modeling. Biotin >20.0 ng/mL (81.8 nmol/L) prevalence and biotin 99th percentile values were calculated. AMI misclassification risk due to biotin interference with the TnT Gen 5 assay was modeled using different assay cutoffs and test timepoints. Results ACS cohort: 1/797 (0.13%) 0-h and 1/646 (0.15%) 3-h samples had biotin >20.0 ng/mL (81.8 nmol/L); 99th percentile biotin was 2.62 ng/mL (10.7 nmol/L; 0-h) and 2.38 ng/mL (9.74 nmol/L; 3-h). Using conservative assumptions, the likelihood of false-negative AMI prediction due to biotin interference was 0.026% (0-h result; 19 ng/L TnT Gen 5 assay cutoff). US laboratory cohort: 15/2023 (0.74%) samples had biotin >20.0 ng/mL (81.8 nmol/L); 99th percentile biotin was 16.6 ng/mL (68.0 nmol/L). Misclassification risk due to biotin interference (19 ng/L TnT Gen 5 assay cutoff) was 0.025% (0-h), 0.0064% (1-h), 0.00048% (3-h), and <0.00001% (6-h). Conclusions Biotin interference has minimal impact on the TnT Gen 5 assay’s clinical utility, and the likelihood of false-negative AMI prediction is extremely low.