Association of blood-based biomarkers with radiologic markers and cognitive decline in atrial fibrillation patients



      Atrial fibrillation (AF) has been associated with an increased risk of silent brain infarcts (SBI) and cognitive impairment, even in patients with low embolic risk. We aimed to test the association between 11 blood-biomarkers representing different AF-related pathways, and SBI, white matter hyperintensities (WMH), and cognitive decline in patients with AF and low embolic risk.


      The present study followed a cross-sectional design. 70 patients with a history of AF and CHADS2 score ≤1, and 10 controls with neither AF nor SBI were included. All patients underwent a 3T brain MRI. Cortical and large subcortical ischemic lesions were considered presumed embolic origin lesions. White matter hyperintensities (WMH) were measured according to the Fazekas scale. A subset of patients underwent cognitive evaluation with the MoCA test. Circulating proteins were measured under blind conditions in a laboratory at Roche Diagnostics, Germany.


      45 patients presented SBI in the MRI, and 25 did not. Ang-2, FGF-23, and BMP-10 were increased in patients with SBI. Ang-2 was elevated only in patients with embolic infarcts, whereas FGF-23 and BMP-10 tended to be elevated in patients with both types of infarcts. Ang-2 (OR = 1.56 [0.94-2.59], p = 0.087), and BMP-10 (OR = 4.83 [0.99–23.60], p = 0.052) were the biomarkers that showed the highest association with SBI when entered in a multivariable logistic regression model corrected by age. No biomarker was found associated with WMH or mild cognitive impairment.


      BMP-10, and Ang-2 were increased in patients with SBI. Its usefulness to detect SBI in AF patients should be further explored.



      SBI (Silent brain infarcts), WMH (White matter hyperintensities), AF (atrial fibrillation)
      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'


      Subscribe to Journal of Stroke and Cerebrovascular Diseases
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect


        • Wolf P.A.
        • Abbott R.D.
        • Kannel WB.
        Atrial fibrillation as an independent risk factor for stroke: the framingham study.
        Stroke. 1991; 22: 983-988
        • Stewart S.
        • Hart C.L.
        • Hole D.J.
        • McMurray JJV.
        A population-based study of the long-term risks associated with atrial fibrillation: 20-Year follow-up of the renfrew/paisley study.
        Am J Med. 2002; 113: 359-364
        • Marini C.
        • De Santis F.
        • Sacco S.
        • et al.
        Contribution of atrial fibrillation to incidence and outcome of ischemic stroke: Results from a population-based study.
        Stroke. 2005; 36: 1115-1119
        • Friberg L.
        • Rosenqvist M.
        • Lindgren A.
        Andreas Terént, Bo Norrving KA. High prevalence of atrial fibrillation among patients with ischemic stroke.
        Stroke. 2014; 45: 2599-2605
        • Vermeer S.E.
        • Longstreth W.T.
        • Koudstaal PJ.
        Silent brain infarcts: a systematic review.
        Lancet Neurol. 2007; 6: 611-619
        • Kalantarian S.
        • Ay H.
        • Gollub R.L.
        • et al.
        Association between Atrial fibrillation and silent cerebral infarctions: a systematic review and meta-analysis.
        Ann Intern Med. 2014; 161: 650-658
        • Fanning J.P.
        • Wesley A.J.
        • Wong A.A.
        • Fraser JF.
        Emerging spectra of silent brain infarction.
        Stroke. 2014; 45: 3461-3471
        • Gupta A.
        • Giambrone A.E.
        • Gialdini G.
        • et al.
        Silent brain infarction and risk of future stroke: a systematic review and meta-analysis.
        Stroke. 2016; 47: 719-725
        • Lip G.Y.H.
        • Nieuwlaat R.
        • Pisters R.
        • et al.
        Refining clinical risk stratification for predicting stroke and thromboembolism in atrial fibrillation using a novel risk factor-based approach: The Euro Heart Survey on atrial fibrillation.
        Chest. 2010; 137: 263-272
        • Escudero-Martínez I.
        • Ocete R.F.
        • Mancha F.
        • et al.
        Prevalence and risk factors of silent brain infarcts in patients with AF detected by 3T-MRI.
        J Neurol. 2020; 267: 2675-2682
        • Kalantarian S.
        • Stern TA.
        • Mansour M.
        • Ruskin J.N.
        Cognitive impairment associated with atrial fibrillation: a meta- analysis.
        Ann Intern Med. 2013; 158 (Cognitive): 338-346
        • Rivard L.
        • Friberg L.
        • Conen D.
        • et al.
        Atrial fibrillation and dementia: a report from the AF-SCREEN international collaboration.
        Circulation. 2022; 145: 392-409
        • Diener H.C.
        • Hart R.G.
        • Koudstaal P.J.
        • Lane D.A.
        • Lip GYH.
        Atrial fibrillation and cognitive function: JACC review topic of the week.
        J Am Coll Cardiol. 2019; 73: 612-619
        • Kalantarian S.
        • Ruskin JN.
        Atrial Fibrillation and cognitive decline: phenomenon or epiphenomenon?.
        Cardiol Clin. 2016; 34: 279-285
        • De Leeuw F.E.
        • De Groot J.C.
        • Oudkerk M.
        • et al.
        Atrial fibrillation and the risk of cerebral white matter lesions.
        Neurology. 2000; 54: 1795-1800
        • Kobayashi A.
        • Iguchi M.
        • Shimizu S.
        • Uchiyama S.
        Silent cerebral infarcts and cerebral white matter lesions in patients with nonvalvular atrial fibrillation.
        J Stroke Cerebrovasc Dis. 2012; 21: 310-317
        • Shi Y.
        • Thrippleton M.J.
        • Makin S.D.
        • et al.
        Cerebral blood flow in small vessel disease: a systematic review and meta-analysis.
        J Cereb Blood Flow Metab. 2016; 36: 1653-1667×16662891
        • Noubiap J.J.
        • Sanders P.
        • Nattel S.
        • Lau DH.
        Biomarkers in atrial fibrillation: pathogenesis and clinical implications.
        Card Electrophysiol Clin. 2021; 13: 221-233
      1. Palà E., Bustamante A., Pagola J., et al. Blood-based biomarkers to search for atrial fibrillation in high-risk asymptomatic individuals and cryptogenic stroke patients. 2022;9(July):1-11. doi:10.3389/fcvm.2022.908053

        • Wardlaw J.M.
        • Smith E.E.
        • Biessels G.J.
        • et al.
        Neuroimaging standards for research into small vessel disease and its contribution to ageing and neurodegeneration.
        Lancet Neurol. 2013; 12: 822-838
      2. Smith E.E., Saposnik G., Biessels G.J., et al. Prevention of stroke in patients with silent cerebrovascular disease: a scientific statement for healthcare professionals from the American heart association/American stroke association. Vol 48.; 2017. doi:10.1161/STR.0000000000000116

        • Fazekas F.
        • Chawluk J.B.
        • Alavi A.
        MR signal abnormalities at 1.5 T in Alzheimer's dementia and normal aging.
        Am J Neuroradiol. 1987; 8: 421-426
        • Nasreddine Z.S.
        • Phillips N.A.
        • Bédirian V.
        • et al.
        The montreal cognitive assessment, MoCA: A brief screening tool for mild cognitive impairment.
        J Am Geriatr Soc. 2005; 53: 695-699
        • Delgado C.
        • Araneda A.
        • Behrens MI.
        Validation of the spanish-language version of the montreal cognitive assessment test in adults older than 60 years.
        Neurologia. 2019; 34: 376-385
        • Ojeda N.
        • del Pino R.
        • Ibarretxe-Bilbao N.
        • Schretlen D.J.
        • Peña J.
        Montreal cognitive assessment test: normalization and standardization for Spanish population.
        Rev Neurol. 2016; 63: 488-496
        • Staszewsky L.
        • Meessen J.
        • Novelli D.
        • et al.
        Total NT-proBNP, a novel biomarker related to recurrent atrial fibrillation.
        BMC Cardiovasc Disord. 2021; 21: 1-11
        • Hijazi Z.
        • Lindbäck J.
        • Alexander J.H.
        • et al.
        The ABC (age, biomarkers, clinical history) stroke risk score: a biomarker-based risk score for predicting stroke in atrial fibrillation.
        Eur Heart J. 2016; 37: 1582-1590
        • Krisai P.
        • Eken C.
        • Aeschbacher S.
        • et al.
        Biomarkers, clinical variables, and the CHA2DS2-VASc score to detect silent brain infarcts in atrial fibrillation patients.
        J Stroke. 2021; 23: 449-452
        • Smith E.E.
        • Saposnik G.
        • Biessels G.J.
        • et al.
        Prevention of stroke in patients with silent cerebrovascular disease: a scientific statement for healthcare professionals from the American heart association/American stroke association.
        Stroke. 2017; 48: e44-e71
        • Norby F.L.
        • Tang W.
        • Pankow J.S.
        • et al.
        Proteomics and risk of atrial fibrillation in older adults (from the atherosclerosis risk in communities [ARIC] study).
        Am J Cardiol. 2021; 161: 42-50
        • Ko D.
        • Benson M.D.
        • Ngo D.
        • et al.
        Proteomics Profiling and Risk of New-Onset Atrial Fibrillation: Framingham Heart Study.
        J Am Heart Assoc. 2019; 8
        • Choudhury A.
        • Freestone B.
        • Patel J.
        • Lip GYH.
        Relationship of soluble CD40 ligand to vascular endothelial growth factor, angiopoietins, and tissue factor in atrial fibrillation: a link among platelet activation, angiogenesis, and thrombosis?.
        Chest. 2007; 132: 1913-1919
        • Freestone B.
        • Chong A.Y.
        • Lim H.S.
        • Blann A.
        • Lip GYH.
        Angiogenic factors in a trial fibrillation: a possible role in thrombogenesis?.
        Ann Med. 2005; 37: 365-372
        • Chua W.
        • Law J.P.
        • Cardoso V.R.
        • et al.
        Quantification of fibroblast growth factor 23 and N-terminal pro-B-type natriuretic peptide to identify patients with atrial fibrillation using a high-throughput platform: a validation study.
        PLoS Med. 2021; 18: 1-17
        • Mathew JS.
        Fibroblast growth factor-23 and incident atrial fibrillation: the multi-ethnic study otherosclerosis (MESA) and the cardiovascular health study (CHS).
        Circulation. 2014; 130: 298-307
        • Wright C.B.
        • Shah N.H.
        • Mendez A.J.
        • et al.
        Fibroblast growth factor 23 is associated with subclinical cerebrovascular damage: the northern manhattan study (NOMAS).
        Stroke. 2016; 47: 923-928
        • Neuhaus H.
        • Rosen V.
        • Thies RS.
        Heart specific expression of mouse BMP-10 a novel member of the TGF-β superfamily.
        Mech Dev. 1999; 80: 181-184
        • Reyat J.S.
        • Chua W.
        • Cardoso V.R.
        • et al.
        Reduced left atrial cardiomyocyte PITX2 and elevated circulating BMP10 predict atrial fibrillation after ablation.
        JCI Insight. 2020; 5: 1-16
        • Hijazi Z.
        • Benz A.P.
        • Lindback J.
        • Connolly S.J.
        • Eikelboom J.W.
        • Kastner P.
        • Ziegler A.
        • Oldgren J.
        • Siegbahn A. .
        • Abstract WL.
        13230: bone morphogenetic protein 10 - a novel biomarker of ischemic stroke in patients with atrial fibrillation.
        Circulation. 2021; : 144
        • Yan Y.
        • Gong P.
        • Jin W.
        • et al.
        The cell-specific upregulation of bone morphogenetic protein-10 (BMP-10) in a model of rat cortical brain injury.
        J Mol Histol. 2012; 43: 543-552
        • Meyre P.B.
        • Aeschbacher S.
        • Blum S.
        • et al.
        Biomarkers associated with rhythm status after cardioversion in patients with atrial fibrillation.
        Sci Rep. 2022; 12: 1-11
        • D'Souza A.
        • Butcher K.S.
        • Buck B.H.
        The multiple causes of stroke in atrial fibrillation: thinking broadly.
        Can J Cardiol. 2018; 34: 1503-1511
        • Ding M.
        • Wang R.
        • Kalpouzos G.
        • et al.
        Cerebral small vessel disease associated with atrial fibrillation among older adults: a population-based study.
        Stroke. 2021; (August): 2685-2689
        • McGrath E.R.
        • Himali J.J.
        • Levy D.
        • et al.
        Growth differentiation factor 15 and nt-probnp as blood-based markers of vascular brain injury and dementia.
        J Am Heart Assoc. 2020; 9
        • Dadu R.T.
        • Fornage M.
        • Virani SS.
        • Nambi V.
        • Hoogeveen RC.
        • Boerwinkle E.
        • Alonso A.
        • Gottesman RF.
        • Mosley TH.
        • Christie M.
        • Ballantyne
        Cardiovascular biomarkers and subclinical brain disease in the atherosclerosis.
        Stroke. 2013; 44: 1803-1808
        • Vilar-Bergua A.
        • Riba-Llena I.
        • Penalba A.
        • et al.
        N-terminal pro-brain natriuretic peptide and subclinical brain small vessel disease.
        Neurology. 2016; 87: 2533-2539
        • Grueter B.E.
        • Schulz UG.
        Age-related cerebral white matter disease (Leukoaraiosis): a review.
        Postgrad Med J. 2012; 88: 79-87
        • Meinel T.R.
        • Kaesmacher J.
        • Roten L.
        • Fischer U.
        Covert brain infarction: towards precision medicine in research, diagnosis, and therapy for a silent pandemic.
        Stroke. 2020; 51: 2597-2606