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

AimsPatients with heart failure (HF) display metabolic alterations, including heightened ketogenesis, resulting in increased beta-hydroxybutyrate (beta-OHB) formation. We aimed to investigate the determinants and prognostic impact of circulating beta-OHB levels in patients with advanced HF and reduced ejection fraction (HFrEF).Methods and resultsA 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 beta-OHB level was 64 (interquartile range [IQR] 33-161) mu mol/L (normal 0-74 mu mol/L). beta-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 beta-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 beta-OHB levels with outcomes, only FFA levels remained significantly associated with adverse outcomes.ConclusionsIn patients with advanced HFrEF, increased plasma beta-OHB correlate with FFA levels, worse right ventricular function, greater neurohormonal activation and other markers of HF severity. The association between plasma beta-OHB and adverse outcomes is eliminated after accounting for FFA levels, suggesting that increased beta-OHB is a consequence reflecting heightened lipolytic state, rather than a cause of worsening HF.Summary of the study design and key findings. In the central panel, (+) and (-) means that the variable is directly or inversely associated with beta-hydroxybutyrate (beta-OHB) levels, respectively. The gold arrow means that free fatty acid (FFA) levels are the only variable that remained associated with beta-OHB levels in the multivariable model. HFrEF, heart failure with reduced ejection fraction; HOMA-IR, homeostasis model assessment of insulin resistance; LV, left ventricular; RHC, right heart catheterization; RV, right ventricular; TG, triglycerides. Parts of the figure were created using Biorender.com. image