Circulating Beta-Hydroxybutyrate Levels in Advanced Heart Failure with Reduced Ejection Fraction: Determinants and Prognostic Impact

Luca Monzo; Barry A. Borlaug; Jan Beneš; Martin Kotrč; Katerina Kroupova; A Jabor; Janka Franeková; Vojtěch Melenovský

doi:10.1002/ejhf.3324

June 10, 2024European Journal of Heart FailureOpen Access

Circulating Beta-Hydroxybutyrate Levels in Advanced Heart Failure with Reduced Ejection Fraction: Determinants and Prognostic Impact

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Why the study?

Patients with HF display metabolic alterations including heightened ketogenesis and increased beta-hydroxybutyrate (beta-OHB) formation, but the determinants and prognostic impact of circulating beta-OHB levels in advanced HFrEF were unclear.

Are elevated circulating beta-hydroxybutyrate (β-OHB) levels independently associated with adverse outcomes in patients with advanced HFrEF?

Structured PICO

Are elevated circulating beta-hydroxybutyrate (β-OHB) levels independently associated with adverse outcomes in patients with advanced HFrEF?

P

Population

867 patients with advanced HFrEF, mean age 57 ± 11 years, 83% male, 45% diabetic, 60% NYHA class III.

I

Intervention

Circulating beta-hydroxybutyrate (β-OHB) levels

O

Outcome

Composite of death, left ventricular assist device implantation, and urgent cardiac transplantationcomposite

Elevated beta-hydroxybutyrate levels in advanced HFrEF reflect a heightened lipolytic state rather than independently causing worsening heart failure, as their prognostic value is lost when adjusting for free fatty acids.

Implication

Higher β-OHB signals higher event risk in advanced HFrEF; leaves open whether ketogenesis modulation improves outcomes.

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.