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Nitric oxide (NO) is a key contributor to vascular health, and several NO-related metabolites are associated with cardiovascular outcomes. However, it remains unknown whether differences in circulating NO-related metabolite concentrations exist between men and women with HFpEF.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>In this cross-sectional analysis of a multicentre randomized controlled intervention trial (OptimEx-Clin), plasma concentrations of NO-related amino acids (L-arginine, L-homoarginine (hArg), L-ornithine, L-lysine, L-citrulline), asymmetric and symmetric dimethylarginines (ADMA, SDMA), and functional metabolite ratios were assessed in 171 patients with HFpEF. Analyses were stratified by sex and age, and further adjusted for relevant clinical covariates using multivariable regression models. A principal component analysis (PCA) was performed to explore sex-related metabolite patterns.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      The comparison of NO-related metabolites in 58 men and 113 women with HFpEF showed significant sex differences for SDMA (\u03b2-coefficient [95% CI]; -0.11 [-0.20 to -0.03] \u00b5mol\/L,\n                      <jats:italic>p<\/jats:italic>\n                      \u2009=\u20090.010) and hArg (-0.24 [-0.46 to -0.01] \u00b5mol\/L,\n                      <jats:italic>p<\/jats:italic>\n                      \u2009=\u20090.043) in unadjusted models; both with lower concentrations in women. While the association with hArg was attenuated after multivariable adjustment, higher SDMA concentrations in men were observed in five out of six tested models. No other significant sex differences were observed neither in single metabolites nor in composite metabolite ratios. The PCA of all measured metabolites did not demonstrate a clear separation between women and men in the overall metabolite profile.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>In HFpEF, sex-related differences in circulating NO-related metabolites were limited and metabolite-specific, with SDMA showing the most consistent sex-associated difference with higher concentrations in men. The substantial overlap of metabolic profiles between women and men showed no distinct patterns of circulating metabolites linked to endothelial function in patients with HFpEF.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Registry<\/jats:title>\n                    <jats:p>ClinicalTrials.gov, TRN: NCT02078947.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1186\/s13293-026-00940-7","type":"journal-article","created":{"date-parts":[[2026,6,15]],"date-time":"2026-06-15T07:54:16Z","timestamp":1781510056000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Circulating nitric oxide pathway metabolites in heart failure with preserved ejection fraction: a sex-stratified cross-sectional analysis"],"prefix":"10.1186","volume":"17","author":[{"given":"Sophia Marie-Theres","family":"Dinges","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Edzard","family":"Schwedhelm","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Flavia","family":"Baldassarri","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bernhard","family":"Haller","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andreas B.","family":"Gevaert","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rainer","family":"B\u00f6ger","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ephraim B.","family":"Winzer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Frank","family":"Edelmann","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ulrik","family":"Wisl\u00f8ff","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Volker","family":"Adams","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Burkert","family":"Pieske","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emeline M.","family":"Van Craenenbroeck","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Martin","family":"Halle","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Susanna M.","family":"Hofmann","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stephan","family":"Mueller-Stegner","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,6,15]]},"reference":[{"key":"940_CR1","doi-asserted-by":"crossref","unstructured":"Deng Y, Zhang J, Ling J, Hu Q, Song T, Xu Y, et al. 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All participants provided written informed consent.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval and consent to participate"}},{"value":"Not applicable.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent for publication"}},{"value":"A.B.G. reported lecture\/travel fees paid to his institution by Abbott, AstraZeneca, Boehringer-Ingelheim, Johnson and Johnson, Novartis, and Novo Nordisk, as well as grants paid to his institution by Abbott and Boehringer-Ingelheim, all outside the submitted work. F.E. reported personal fees from Astra Zeneca, Bayer, Berlin Chemie, Boehringer-Ingelheim, CVRx, Medtronic, Merck, MSD, Novartis, Pfizer, PharmaCosmos, Resmed, Servier and Vifor Pharma, non-financial support from Novartis, and grants from Astra Zeneca, Boehringer-Ingelheim, Servier and Thermo Fisher outside the submitted work. E.B.W. reports grants from Boehringer-Ingelheim, and personal fees from Amgen, AstraZeneca, Bayer, Bristol-Myers Squibb, Boehringer-Ingelheim, CVRx, Daiichi-Sankyo, Pfizer, Lilly, Novartis, and Novo Nordisk outside the submitted work. B.P. reported institutional grants from Astra-Zeneca, Bayer Healthcare and Boston Scientific; personal fees for Steering Committee, consulting, and speaker services from Bayer Healthcare, MSD, Astra-Zeneca, Boehringer-Ingelheim, Novartis, Boston Scientific and Abbott outside the submitted work. B.P. holds minor shares in ICTS GmbH (Imaging in Clinical Trials Services). E.M.V.C. reported consultancy fees paid to institution by Bristol-Myers Squibb, Novartis, Pfizer, Astra Zeneca and Boehringer-Ingelheim. M.H. reported honoraria for lectures from Abbott, Amgen, Astra-Zeneca, Boehringer-Ingelheim, Bristol-Myers Squibb, Daiichi-Sankyo, Lilly, Medi, Novartis, Pfizer and Roche, consulting fees from Medical Park, and being the past-president of the European Association of Preventive Cardiology (presidency 2020\u20132022) outside the submitted work. S.M. reported personal fees from Bristol-Myers Squibb (consulting services), WIP \u2014 Scientific Institute of Private Health Insurance (lecture), and the German Cardiac Society (lecture), outside the submitted work. No other potential conflicts of interest were reported.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"120"}}