Circulating beta‐hydroxybutyrate levels in advanced heart failure with reduced ejection fraction: Determinants and prognostic impact

Abstract Aims Patients with heart failure (HF) display metabolic alterations, including heightened ketogenesis, resulting in increased beta‐hydroxybutyrate (β‐OHB) formation. We aimed to investigate the determinants and prognostic impact of circulating β‐OHB levels in patients with advanced HF and reduced ejection fraction (HFrEF). Methods and results A total of 867 patients with advanced HFrEF (age 57 ± 11 years, 83% male, 45% diabetic, 60% New York Heart Association class III), underwent clinical and echocardiographic examination, circulating metabolite assessment, and right heart catheterization ( n = 383). The median β‐OHB level was 64 (interquartile range [IQR] 33–161) μmol/L (normal 0–74 μmol/L). β‐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 410–1781) 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 β‐OHB levels (T3 vs. T1: hazard ratio [HR] 1.39, 95% confidence interval [CI] 1.13–1.72, p = 0.002) and elevated FFA levels (T3 vs. T1: HR 1.39, 95% CI 1.09–1.79, p = 0.008) were both predictors of a worse prognosis. In multivariable Cox analysis evaluating the simultaneous associations of FFA and β‐OHB levels with outcomes, only FFA levels remained significantly associated with adverse outcomes. Conclusions In patients with advanced HFrEF, increased plasma β‐OHB correlate with FFA levels, worse right ventricular function, greater neurohormonal activation and other markers of HF severity. The association between plasma β‐OHB and adverse outcomes is eliminated after accounting for FFA levels, suggesting that increased β‐OHB is a consequence reflecting heightened lipolytic state, rather than a cause of worsening HF.