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The present study evaluated associations of proteomic biomarkers with CV outcome in patients with CAD and HF with reduced ejection fraction (HFrEF), shortly after a worsening HF episode. We performed a case\u2013control study within the COMMANDER HF international, double-blind, randomized placebo-controlled trial investigating the effects of the factor-Xa inhibitor rivaroxaban. Patients with the following first clinical events: HF hospitalization, SCD and the composite of MI or stroke were matched with corresponding controls for age, sex and study drug. Plasma concentrations of 276 proteins with known associations with CV and cardiometabolic mechanisms were analyzed. Results were corrected for multiple testing using false discovery rate (FDR). In 485 cases and 455 controls, 49 proteins were significantly associated with clinical events of which seven had an adjusted FDR\u2009&lt;\u20090.001 (NT-proBNP, BNP, T-cell immunoglobulin and mucin domain containing 4 (TIMD4), fibroblast growth factor 23 (FGF-23), growth differentiation factor-15 (GDF-15), pulmonary surfactant-associated protein D (PSP-D) and Spondin-1 (SPON1)). No significant interactions were identified between the type of clinical event (MI\/stroke, SCD or HFH) and specific biomarkers (all interaction FDR\u2009&gt;\u20090.20). When adding the biomarkers significantly associated with the above outcome to a clinical model (including NT-proBNP), the C-index increase was 0.057 (0.033\u20130.082), p\u2009&lt;\u20090.0001 and the net reclassification index was 54.9 (42.5 to 67.3), p\u2009&lt;\u20090.0001. In patients with HFrEF and CAD following HF hospitalization, we found that NT-proBNP, BNP, TIMD4, FGF-23, GDF-15, PSP-D and SPON1, biomarkers broadly associated with inflammation and remodeling mechanistic pathways, were strong but indiscriminate predictors of a variety of individual CV events.<\/jats:p>","DOI":"10.1038\/s41598-022-12385-0","type":"journal-article","created":{"date-parts":[[2022,5,20]],"date-time":"2022-05-20T20:08:55Z","timestamp":1653077335000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":40,"title":["Inflammation and remodeling pathways and risk of cardiovascular events in patients with ischemic heart failure and reduced ejection fraction"],"prefix":"10.1038","volume":"12","author":[{"given":"Nicolas","family":"Girerd","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John","family":"Cleland","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stefan D.","family":"Anker","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"William","family":"Byra","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carolyn S. P.","family":"Lam","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David","family":"Lapolice","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mandeep R.","family":"Mehra","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dirk J.","family":"van Veldhuisen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emmanuel","family":"Bresso","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zohra","family":"Lamiral","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Barry","family":"Greenberg","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Faiez","family":"Zannad","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2022,5,20]]},"reference":[{"key":"12385_CR1","doi-asserted-by":"publisher","first-page":"169","DOI":"10.1002\/ejhf.211","volume":"17","author":"SL Kristensen","year":"2015","unstructured":"Kristensen, S. 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F.Z. and N.G. are supported by public grants overseen by the European Commission (EUFP7) and the French National Research Agency (ANR) as part of the second \u2018Investissements d\u2019Avenir\u2019 programme FIGHT-HF (ANR-15-RHU-0004); programme HOMAGE under grant agreement N 305507; and project FIBROTARGETS grant HEALTH-2013- 602904. S.D.A. reports receiving fees from Abbott, Bayer, Boehringer Ingelheim, Cardiac Dimension, Cordio, Impulse Dynamics, Novartis, Occlutech, Servier, and Vifor Pharma, and grant support from Abbott and Vifor Pharma. M.R.M. reports personal fees from Janssen Research & Development LLC as a member of the steering committee of the COMMANDER HF trial and consulting fees during the conduct of the study and personal fees from Abbott, Medtronic, Portola Pharmaceuticals, Bayer, Mesoblast, Baim Institute for Clinical Research, Xogenex, NupulseCV and FineHeart outside the submitted work. J.G.F.C. reports personal fees from Janssen Research & Development LLC as a member of the steering committee of the COMMANDER HF trial and research grants and honoraria for speaking, committees, and advisory boards from Amgen, AstraZeneca, Bayer, Bristol-Myers Squibb, GlaxoSmithKline, Johnson & Johnson, Medtronic, MyoKardia, Novartis, Philips Healthcare, Pharmacosmos, Pharma Nord, Sanofi, Laboratoires Servier, Stealth BioTherapeutics, Torrent Pharmaceuticals, and Vifor Pharma. C.S.P.L. reports personal fees from Janssen Research & Development LLC during the conduct of the study; research support from Boston Scientific, Bayer, Roche Diagnostics, AstraZeneca, Medtronic, and Vifor Pharma; personal fees from serving on the advisory board\/steering committee\/executive committee\/clinical end points committee for Boston Scientific, Bayer, Roche Diagnostics, AstraZeneca, Medtronic, Vifor Pharma, Novartis, Amgen, Merck, Janssen Research & Development LLC, Menarini, Boehringer Ingelheim, Novo Nordisk, Abbott Diagnostics, Corvia Medical, Stealth BioTherapeutics, Jana Care, Biofourmis, Applied Therapeutics Inc, WebMD Global LLC, Radcliffe Group Ltd, Takeda Pharmaceutical Company, and Darma Laboratories outside the submitted work; and support from a Clinician Scientist Award from the National Medical Research Council of Singapore. D.J.v.V. reports personal fees from Johnson & Johnson and Bayer during the conduct of the study and reports receiving board membership fees from Janssen Research & Development LLC as a member of the steering committee of the COMMANDER HF trial. W.M. B. reports other support from Janssen Research & Development LLC during the conduct of the study and is employed by and is a shareholder of Johnson & Johnson. B.G. reports personal fees from Janssen Research & Development LLC as a member of the steering committee of the COMMANDER HF trial and consulting fees from Bayer during the conduct of the study; consulting fees from Janssen Research & Development LLC, Bayer, Novartis, Mesoblast, Ionis Pharmaceuticals, Zensun USA, and Cellular Dynamics outside the submitted work; speaker fees from Novartis and Otsuka Pharmaceutical outside the submitted work; and personal fees from AstraZeneca, Actelion, Amgen, EBR Systems, Impulse Dynamics, MyoKardia, Rocket Pharma, Sanofi, and Viking Therapeutics outside the submitted work. F.Z. reports personal fees from Janssen Research & Development LLC and Bayer during the conduct of the study; personal fees from AstraZeneca, Boehringer Ingelheim, LivaNova, GE Healthcare, Amgen, Novartis, Quantum Genomics, Cardior Pharmaceuticals, CardioRenal, CVCT, Merck, CVRx, Vifor Fresenius Medical Care Renal Pharma, NovoNordisk, and MundiPharma outside the submitted work; fees for serving on a steering committee or a safety and data monitoring board from Actelion, Amgen, Bayer, Boehringer Ingelheim, Boston Scientific, CVRx, GE Healthcare, Janssen Research & Development LLC, Novartis, and ResMed; and consulting fees from AstraZeneca, Cardior Pharmaceuticals, CardioRenal, Quantum Genomics, and Vifor Fresenius Medical Care Renal Pharma. No other authors have any competing-interests.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"8574"}}