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Although natriuretic peptides like B-type natriuretic peptide (BNP) are valuable biomarkers for diagnosing and managing HF, the utility of combining BNP with other blood-based biomarkers to predict subtypes of new-onset HF remains underexplored.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Objectives<\/jats:title>\n            <jats:p>This study sought to investigate and evaluate the diagnostic significance of adding blood-based biomarkers to BNP for identifying heart failure with preserved ejection fraction (HFpEF) or reduced ejection fraction (HFrEF), with the goal of enhancing diagnostic assays beyond BNP measurements.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Methods<\/jats:title>\n            <jats:p>We identified candidate blood protein biomarkers using untargeted proteomics workflows from a cohort of individuals recruited to the STOP-HF trial who were at risk of HF and subsequently developed either HFpEF or HFrEF over time (\u201cHF progressors\u201d; n\u2009=\u200940). Candidate biomarkers were verified in an independent cohort (n\u2009=\u200952) from a community-based rapid access HF diagnostic clinic. The biological processes associated with these proteins were assessed, and the diagnostic values of biomarker panels were evaluated using a machine learning approach.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Results<\/jats:title>\n            <jats:p>Within HF progressors, we identified 3 proteins associated with HFpEF development: vascular cell adhesion protein 1 (VCAM1), insulin-like growth factor 2 (IGF2), and inter-alpha-trypsin inhibitor heavy chain 3 (ITIH3). Additionally, 4 proteins were linked to HFrEF development: C-reactive protein (CRP), interleukin-6 receptor subunit beta (IL6RB), phosphatidylinositol-glycan-specific phospholipase D (PHLD), and noelin (NOE1). These findings were verified in an independent cohort to distinguish HF subtypes from controls. Moreover, a random forest algorithm demonstrated that combining these candidate biomarkers with BNP measurement significantly improved the prediction of HF subtypes.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Conclusions<\/jats:title>\n            <jats:p>We identified candidate proteins linked to HFpEF and HFrEF in a longitudinal HF progressor cohort and validated them in a community-based cohort. Adding these proteins to BNP led to a significant improvement in HF subtype prediction. Study results have clinical implications for blood-based screening of HF subtypes using panels of biomarkers, particularly in resource-limited settings.<\/jats:p>\n          <\/jats:sec>","DOI":"10.1186\/s12967-025-06563-7","type":"journal-article","created":{"date-parts":[[2025,5,15]],"date-time":"2025-05-15T16:19:45Z","timestamp":1747325985000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Proteomic-based biomarker discovery reveals panels of diagnostic biomarkers for early identification of heart failure subtypes"],"prefix":"10.1186","volume":"23","author":[{"given":"Narainrit","family":"Karuna","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Claire","family":"Tonry","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mark","family":"Ledwidge","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nadezhda","family":"Glezeva","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joe","family":"Gallagher","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ken","family":"McDonald","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8749-0732","authenticated-orcid":false,"given":"Chris J.","family":"Watson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,5,15]]},"reference":[{"key":"6563_CR1","doi-asserted-by":"publisher","first-page":"808","DOI":"10.1016\/j.jchf.2016.05.001","volume":"4","author":"V Xanthakis","year":"2016","unstructured":"Xanthakis V, Enserro DM, Larson MG, Wollert KC, Januzzi JL, Levy D, Aragam J, Benjamin EJ, Cheng S, Wang TJ, et al. 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