{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,11]],"date-time":"2026-09-11T14:08:52Z","timestamp":1789135732646,"version":"build-2803163510"},"reference-count":13,"publisher":"American Chemical Society (ACS)","issue":"9","license":[{"start":{"date-parts":[[2026,8,25]],"date-time":"2026-08-25T00:00:00Z","timestamp":1787616000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Institute of iBiMED (UID 4501- Instituto de Biomedicina- Aveiro)"},{"name":"Instruct-ERIC"},{"name":"CardioNIR project? CARDIOvascular Near-InfraRed spectroscopy probing? 2021"},{"name":"Portuguese Foundation for Science and Technology (FCT), European Union, QREN, FEDER, COMPETE"},{"name":"CEITEC Proteomics Core Facility, Brno, Czech Republic, an Instruct-ERIC centre"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2026,9,11]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Levosimendan is intermittently administered in selected patients with advanced heart failure, but data on prolonged exposure and associated circulating molecular profiles remain limited. We conducted a retrospective observational study of 41 patients with heart failure with reduced ejection fraction, including eight patients exposed to \u226522 intermittent levosimendan infusions and 33 nonexposed controls followed in the same specialist heart failure setting. Baseline clinical characteristics, follow-up outcomes, and plasma proteomic profiles were assessed using label-free data-independent acquisition mass spectrometry. Patients exposed to prolonged intermittent levosimendan were older and had more advanced heart failure at baseline, including lower left ventricular ejection fraction and higher NT-proBNP concentrations. During clinical follow-up from the first specialist cardiology observation to plasma sampling, cardiovascular hospitalization occurred in 3\/8 levosimendan-exposed patients and 1\/33 controls, while cardiovascular death occurred in 2\/8 and 0\/33, respectively; these outcomes are reported descriptively because of baseline imbalance, retrospective treatment allocation, and the small exposed-group size. These outcomes are reported descriptively because of baseline imbalance and the small exposed-group size. Plasma proteomic analysis identified cross-sectional differences between groups. Control patients showed higher representation of immune and inflammatory proteins, whereas levosimendan-exposed patients showed higher abundance of proteins related to antioxidant defense, redox regulation, coagulation\/hemostasis, and metabolic adaptation, including GPX3, SELENOP, PROS1, F2, AHSG, and ALDOA. These findings define an exploratory plasma proteomic phenotype associated with prolonged intermittent levosimendan exposure in real-world advanced heart failure. Prospective controlled studies with baseline and serial proteomic sampling are required to determine whether these molecular differences reflect treatment-associated adaptation or underlying clinical differences.<\/jats:p>","DOI":"10.1021\/acsptsci.6c00195","type":"journal-article","created":{"date-parts":[[2026,8,31]],"date-time":"2026-08-31T21:31:43Z","timestamp":1788211903000},"page":"2513-2524","source":"Crossref","is-referenced-by-count":0,"title":["Cross-Sectional Plasma Proteomic Phenotypes Associated\nwith Prolonged Intermittent Levosimendan Exposure in Advanced Heart\nFailure"],"prefix":"10.1021","volume":"9","author":[{"given":"Jose\u0301","family":"Mesquita Bastos","sequence":"first","affiliation":[{"name":"Servic\u0327o de Cardiologia da Unidade de Sau\u0301de Local Regia\u0303o Aveiro , ,","place":["Aveiro, Portugal, 3814-501"]},{"name":"University of Aveiro , , ,","place":["Aveiro, Portugal, 3810-193"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ines","family":"Cruz","sequence":"additional","affiliation":[{"name":"Servic\u0327o de Cardiologia da Unidade de Sau\u0301de Local Regia\u0303o Aveiro , ,","place":["Aveiro, Portugal, 3814-501"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luis","family":"Santos","sequence":"additional","affiliation":[{"name":"Servic\u0327o de Cardiologia da Unidade de Sau\u0301de Local Regia\u0303o Aveiro , ,","place":["Aveiro, Portugal, 3814-501"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3636-5805","authenticated-orcid":true,"given":"Rui","family":"Vitorino","sequence":"additional","affiliation":[{"name":"University of Aveiro , , ,","place":["Aveiro, Portugal, 3810-193"]},{"name":"Cardiovascular R&D Centre \u2212 RISE , , ,","place":["Porto, Portugal, 4200-319"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"316","published-online":{"date-parts":[[2026,8,25]]},"reference":[{"issue":"6","key":"2026091109132750000_cit1","doi-asserted-by":"publisher","first-page":"775","DOI":"10.1007\/s40256-024-00675-z","article-title":"The Efficacy and Safety of Levosimendan\nin Patients with Advanced Heart Failure: An Updated Meta-Analysis\nof Randomized Controlled Trials","volume":"24","author":"Elsaeidy","year":"2024","journal-title":"Am. J. Cardiovasc\nDrugs"},{"issue":"10","key":"2026091109132750000_cit2","doi-asserted-by":"publisher","first-page":"722","DOI":"10.1016\/j.jchf.2021.05.009","article-title":"Advanced\nHeart Failure\nEpidemiology and Outcomes: A Population-Based Study","volume":"9","author":"Dunlay","year":"2021","journal-title":"JACC Heart Fail."},{"issue":"8","key":"2026091109132750000_cit3","doi-asserted-by":"publisher","DOI":"10.1161\/CIR.0000000000000950","article-title":"Heart Disease\nand Stroke Statistics-2021 Update: A Report From the American Heart\nAssociation","volume":"143","author":"Virani","year":"2021","journal-title":"Circulation"},{"issue":"6","key":"2026091109132750000_cit4","doi-asserted-by":"publisher","first-page":"617","DOI":"10.1007\/s10557-018-6838-2","article-title":"Levosimendan\nin Acute and Advanced\nHeart Failure: an Expert Perspective on Posology and Therapeutic Application","volume":"32","author":"Bouchez","year":"2018","journal-title":"Cardiovasc. Drugs Ther."},{"issue":"4","key":"2026091109132750000_cit5","doi-asserted-by":"publisher","first-page":"515","DOI":"10.1016\/S1388-9842(02)00041-7","article-title":"The effectiveness\nand relative effectiveness of intravenous inotropic drugs acting through\nthe adrenergic pathway in patients with heart failure-a meta-regression\nanalysis","volume":"4","author":"Thackray","year":"2002","journal-title":"Eur. J. Heart Fail."},{"issue":"21","key":"2026091109132750000_cit6","doi-asserted-by":"publisher","first-page":"6408","DOI":"10.3390\/jcm11216408","article-title":"Use of Levosimendan\nin Patients with Advanced Heart Failure: An Update","volume":"11","author":"Masarone","year":"2022","journal-title":"J. Clin. Med."},{"issue":"2","key":"2026091109132750000_cit7","doi-asserted-by":"publisher","first-page":"144","DOI":"10.1097\/FJC.0000000000001506","article-title":"Repeated Levosimendan Infusions in\nthe Management of Advanced Heart Failure: Review of the Evidence and\nMeta-analysis of the Effect on Mortality","volume":"83","author":"Silvetti","year":"2024","journal-title":"J.\nCardiovasc. Pharmacol."},{"issue":"1","key":"2026091109132750000_cit8","doi-asserted-by":"publisher","first-page":"5","DOI":"10.1002\/ejhf.3024","article-title":"Focused Update of the 2021 ESC Guidelines\nfor the diagnosis and treatment of acute and chronic heart failure:\nDeveloped by the task force for the diagnosis and treatment of acute\nand chronic heart failure of the European Society of Cardiology (ESC)\nWith the special contribution of the Heart Failure Association (HFA)\nof the ESC","volume":"26","author":"McDonagh","year":"2024","journal-title":"Eur. J. Heart Fail."},{"issue":"10","key":"2026091109132750000_cit9","doi-asserted-by":"publisher","first-page":"1309","DOI":"10.1016\/j.amjcard.2004.01.073","article-title":"Effects of\nlevosimendan on circulating pro-inflammatory cytokines and soluble\napoptosis mediators in patients with decompensated advanced heart\nfailure","volume":"93","author":"Parissis","year":"2004","journal-title":"Am. J. Cardiol."},{"key":"2026091109132750000_cit10","doi-asserted-by":"publisher","first-page":"100290","DOI":"10.1016\/j.jmccpl.2025.100290","article-title":"Innovations\nin heart failure management: The role of cutting-edge biomarkers and\nmulti-omics integration","volume":"11","author":"Bastos","year":"2025","journal-title":"J. Mol. Cell Cardiol\nPlus"},{"issue":"1","key":"2026091109132750000_cit11","doi-asserted-by":"publisher","first-page":"73","DOI":"10.1007\/s40256-020-00416-y","article-title":"Levosimendan Can Improve\nthe Level of B-Type Natriuretic Peptide and the Left Ventricular Ejection\nFraction of Patients with Advanced Heart Failure: A Meta-analysis\nof Randomized Controlled Trials","volume":"21","author":"Cui","year":"2021","journal-title":"Am. J. Cardiovasc\nDrugs"},{"issue":"11","key":"2026091109132750000_cit12","doi-asserted-by":"publisher","DOI":"10.1097\/ccm.0000000000001269","article-title":"Anti-Inflammatory Profile of Levosimendan\nin Cecal Ligation-Induced Septic Mice and in Lipopolysaccharide-Stimulated\nMacrophages","volume":"43","author":"Wang","year":"2015","journal-title":"Crit. Care Med."},{"issue":"8","key":"2026091109132750000_cit13","doi-asserted-by":"publisher","first-page":"804","DOI":"10.1016\/j.ejheart.2006.03.003","article-title":"Long-term\neffects of levosimendan infusion on inflammatory\nprocesses and sFas in patients with severe heart failure","volume":"8","author":"Trikas","year":"2006","journal-title":"Eur. J. Heart Fail"}],"container-title":["ACS Pharmacology &amp; Translational Science"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/pubs.acs.org\/doi\/pdf\/10.1021\/acsptsci.6c00195","content-type":"application\/pdf","content-version":"vor","intended-application":"unspecified"},{"URL":"https:\/\/pubs.acs.org\/aptsfn\/article-pdf\/9\/9\/2513\/67392760\/acsptsci.6c00195.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/pubs.acs.org\/aptsfn\/article-pdf\/9\/9\/2513\/67392760\/acsptsci.6c00195.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,9,11]],"date-time":"2026-09-11T13:29:56Z","timestamp":1789133396000},"score":1,"resource":{"primary":{"URL":"https:\/\/pubs.acs.org\/aptsfn\/article\/9\/9\/2513\/5328220\/Cross-Sectional-Plasma-Proteomic-Phenotypes"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,8,25]]},"references-count":13,"journal-issue":{"issue":"9","published-online":{"date-parts":[[2026,8,25]]},"published-print":{"date-parts":[[2026,9,11]]}},"URL":"https:\/\/doi.org\/10.1021\/acsptsci.6c00195","relation":{},"ISSN":["2575-9108"],"issn-type":[{"value":"2575-9108","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,8,25]]}}}