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We aimed to investigate the determinants and prognostic impact of circulating \u03b2-OHB levels in patients with advanced HF and reduced ejection fraction (HFrEF).<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods and results<\/jats:title>\n                    <jats:p>A total of 867 patients with advanced HFrEF (age 57\u2009\u00b1\u200911\u2009years, 83% male, 45% diabetic, 60% New York Heart Association class III), underwent clinical and echocardiographic examination, circulating metabolite assessment, and right heart catheterization (n\u2009=\u2009383). The median \u03b2-OHB level was 64 (interquartile range [IQR] 33\u2013161) \u03bcmol\/L (normal 0\u201374\u2009\u03bcmol\/L). \u03b2-OHB levels correlated with increased markers of lipolysis (free fatty acids [FFA]), higher natriuretic peptides, worse pulmonary haemodynamics, and lower humoral regulators of ketogenesis (insulin\/glucagon ratio). During a median follow-up of 1126 (IQR 410\u20131781) days, there were 512 composite events, including 324 deaths, 81 left ventricular assist device implantations and 107 urgent cardiac transplantations. In univariable Cox regression, increased \u03b2-OHB levels (T3 vs. T1: hazard ratio [HR] 1.39, 95% confidence interval [CI] 1.13\u20131.72, p\u2009=\u20090.002) and elevated FFA levels (T3 vs. T1: HR 1.39, 95% CI 1.09\u20131.79, p\u2009=\u20090.008) were both predictors of a worse prognosis. In multivariable Cox analysis evaluating the simultaneous associations of FFA and \u03b2-OHB levels with outcomes, only FFA levels remained significantly associated with adverse outcomes.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>In patients with advanced HFrEF, increased plasma \u03b2-OHB correlate with FFA levels, worse right ventricular function, greater neurohormonal activation and other markers of HF severity. The association between plasma \u03b2-OHB and adverse outcomes is eliminated after accounting for FFA levels, suggesting that increased \u03b2-OHB is a consequence reflecting heightened lipolytic state, rather than a cause of worsening HF.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/ejhf.3324","type":"journal-article","created":{"date-parts":[[2024,6,10]],"date-time":"2024-06-10T04:08:36Z","timestamp":1717992516000},"page":"1931-1940","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["Circulating Beta-Hydroxybutyrate Levels in Advanced Heart Failure with Reduced Ejection Fraction: Determinants and Prognostic Impact"],"prefix":"10.1093","volume":"26","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2958-943X","authenticated-orcid":false,"given":"Luca","family":"Monzo","sequence":"first","affiliation":[{"name":"Institute for Clinical and Experimental Medicine (IKEM) , Prague ,","place":["Czech 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