EURO PEAN SOCI ETY OF CARDIOLOGY ® Original scientific paper Single and multiple cardiovascular biomarkers in subjects without a previous cardiovascular event Manan Pareek 1,2,3 , Deepak L Bhatt 1 , Muthiah Vaduganathan 1 , Tor Biering-Sørensen 1,4 , Arman Qamar 1 , Axel CP Diederichsen 5 , Jacob Eifer Møller 5 , Peter Hindersson 6 , Margre ´t Leo ´ sdo ´ ttir 7,8 , Martin Magnusson 7,8 , Peter M Nilsson 8 and Michael H Olsen 3 Abstract Aims: To assess the incremental value of biomarkers, including N-terminal prohormone of brain natriuretic peptide (NT-proBNP), high-sensitivity troponin T (hs-TnT), high-sensitivity C-reactive protein (hs-CRP), interleukin-6 (IL-6), growth differentiation factor 15 (GDF-15), and procollagen type 1 N-terminal propeptide (P1NP), in predicting incident cardiovascular events and mortality among asymptomatic individuals from the general population, beyond traditional risk factors, including fasting glucose and renal function (cystatin C), medication use, and echocardiographic measures. Methods and results: Prospective population-based cohort study of 1324 subjects without a previous cardiovascular event, who underwent baseline echocardiography and biomarker assessment between 2002 and 2006. The clinical endpoint was the composite of myocardial infarction, invasively treated stable/unstable ischemic heart disease, heart failure, stroke, or all-cause mortality. Predictive capabilities were evaluated using Cox proportional-hazards regression, Harrell’s concordance index (C-index), and net reclassification improvement. Median age was 66 (interquartile range: 60–70) years, and 413 (31%) were female. During median 8.6 (interquartile range: 8.1–9.2) follow-up years, 368 (28%) composite events occurred. NT-proBNP, hs-TnT, GDF-15, and IL-6 were significantly associated with outcome, inde- pendently of traditional risk factors, medications, and echocardiography (p < 0.05 for all). Separate addition of NT-proBNP and GDF-15 to traditional risk factors, medications, and echocardiographic measurements provided signifi- cant improvements in discriminative ability (NT-proBNP: C-index 0.714 vs. 0.703, p ¼ 0.03; GDF-15: C-index 0.721 vs. 0.703, p ¼ 0.02). Both biomarkers remained significant predictors of outcome upon inclusion in the same model (p < 0.05 for both). Conclusions: NT-proBNP and GDF-15 each enhance prognostication beyond traditional risk factors, glucose levels, renal function, and echocardiography in individuals without known cardiovascular disease. Keywords Biomarkers, discrimination, echocardiography, prognosis, reclassification Received 23 May 2017; accepted 4 June 2017 1 Brigham and Women’s Hospital Heart & Vascular Center, Harvard Medical School, Boston, USA 2 Cardiovascular and Metabolic Preventive Clinic, Department of Endocrinology, Centre for Individualized Medicine in Arterial Diseases (CIMA), Odense University Hospital, Denmark 3 Cardiology Section, Department of Internal Medicine, Holbæk Hospital, Denmark 4 Department of Cardiology, Herlev and Gentofte Hospital, University of Copenhagen, Denmark 5 Department of Cardiology, Odense University Hospital, Denmark 6 Department of Clinical Biochemistry, Regional Hospital of Northern Jutland, Hjørring, Denmark 7 Department of Cardiology, Ska ˚ne University Hospital, Malmo ¨, Sweden 8 Department of Clinical Sciences, Lund University, Ska ˚ne University Hospital, Malmo ¨, Sweden Corresponding author: Michael H Olsen, Cardiology Section, Department of Internal Medicine, Holbaek Hospital, Smedelundsgade 60, DK-4300 Holbaek, Denmark. Email: michael.olsen@dadlnet.dk European Journal of Preventive Cardiology 0(00) 1–12 ! The European Society of Cardiology 2017 Reprints and permissions: sagepub.co.uk/journalsPermissions.nav DOI: 10.1177/2047487317717065 journals.sagepub.com/home/ejpc