Data-driven discovery and validation of circulating blood-based biomarkers associated with prevalent atrial fibrillation

Abstract

Aims Undetected atrial fibrillation (AF) is a major health concern. Blood biomarkers associated with AF could simplify patient selection for screening and further inform ongoing research towards stratified prevention and treatment of AF. Methods and results Forty common cardiovascular biomarkers were quantified in 638 consecutive patients referred to hospital [mean ± standard deviation age 70 ± 12 years, 398 (62%) male, 294 (46%) with AF] with known AF or ≥2 CHA 2 DS 2 -VASc risk factors. Paroxysmal or silent AF was ruled out by 7-day ECG monitoring. Logistic regression with forward selection and machine learning algorithms were used to determine clinical risk factors, imaging parameters, and biomarkers associated with AF. Atrial fibrillation was significantly associated with age [bootstrapped odds ratio (OR) per year = 1.060, 95% confidence interval (1.04–1.10); P = 0.001], male sex [OR = 2.022 (1.28–3.56); P = 0.008], body mass index [BMI, OR per unit = 1.060 (1.02–1.12); P = 0.003], elevated brain natriuretic peptide [BNP, OR per fold change = 1.293 (1.11–1.63); P = 0.002], elevated fibroblast growth factor-23 [FGF-23, OR = 1.667 (1.36–2.34); P = 0.001], and reduced TNF-related apoptosis-induced ligand-receptor 2 [TRAIL-R2, OR = 0.242 (0.14–0.32); P = 0.001], but not other biomarkers. Biomarkers improved the prediction of AF compared with clinical risk factors alone (net reclassification improvement = 0.178; P < 0.001). Both logistic regression and machine learning predicted AF well during validation [area under the receiver-operator curve = 0.684 (0.62–0.75) and 0.697 (0.63–0.76), respectively]. Conclusion Three simple clinical risk factors (age, sex, and BMI) and two biomarkers (elevated BNP and elevated FGF-23) identify patients with AF. Further research is warranted to elucidate FGF-23 dependent mechanisms of AF.

Why does Russia have such high cardiovascular mortality rates? Comparisons of blood-based biomarkers with Norway implicate non-ischaemic cardiac damage

“…Elevated NT-proBNP is a biomarker of cardiac dysfunction related to several pathological processes in the cardiovascular system: heart failure, 25 atrial fibrillation 26 and stroke. 12 We suggest that elevated NT-proBNP in KYH compared with Tromsø 7 may be explained by higher heart damage due to non-ischaemic pathways to heart disease.…”

Cell-Free Circulating Mitochondrial DNA: A Potential Blood-Based Marker for Atrial Fibrillation

“…Currently, there is a great need to early detect AF stage and recurrence after treatment. Studies searching for AF serum biomarkers are not new, as several biomarkers, including troponin, brain natriuretic peptide, creatinine, C-reactive protein, and fibroblast growth factor 23, have been associated with AF pathology, progression, and treatment effects [2,[9][10][11]. Nevertheless, the use of biomarkers has not been integrated into clinical management of AF due to lack of AF specificity.…”

“…So far, no specific serum biomarkers to assess AF stage and to predict the outcome of AF treatment are available. Nevertheless, several AF serum biomarkers, such as troponin (myocardial injury) [2], brain natriuretic peptide (cardiovascular stress) [2,9], creatinine (renal dysfunction) [10], C-reactive protein (inflammation) [11], and fibroblast growth factor 23 [9], have been associated with AF pathology. Only in 2016, the European Society of Cardiology implemented the use of troponin and natriuretic peptide into their guidelines, to predict stroke and bleeding risk in AF patients [2].…”

Evaluating Serum Heat Shock Protein Levels as Novel Biomarkers for Atrial Fibrillation

“…At present, there are no recommendations on the use of AF-specific biomarkers in the most recent guidelines [ 3 , 6 ], despite the fact that several blood-based biomarkers related to AF pathology have been identified. These biomarkers include brain natriuretic peptides, cancer-antigen-125, fibroblast growth factor-23 [ 7 , 8 ] and -21 [ 9 ], highly sensitive cardiac troponin I [ 10 ], homocysteine [ 11 ], (a)symmetric dimetylarginine [ 12 ], interleukine-6 and matrix metalloproteinase-9/tissue inhibitor of metalloproteinase-1 ratio [ 13 ]. Although potential AF-related biomarkers are available, the role of these biomarkers in staging of AF (paroxysmal or (longstanding) persistent AF) or predicting AF recurrence after AF therapy has only be moderately studied.…”