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Circulating beta-hydroxybutyrate levels in advanced heart failure with reduced ejection fraction: Determinants and
Luca Monzo1,2, Jan Kovar1, Barry A Borlaug3
1Institute for Clinical and Experimental Medicine (IKEM), Prague, Czech Republic.
Insights
In advanced heart failure with reduced ejection fraction (HFrEF), elevated beta-hydroxybutyrate (β-OHB) levels correlate with free fatty acids (FFA). However, FFA, not β-OHB, predicts adverse outcomes, suggesting β-OHB reflects lipolysis rather than causing HF worsening.
Area of Science:
- Cardiology
- Metabolic Medicine
- Biochemistry
Background:
- Heart failure with reduced ejection fraction (HFrEF) is associated with metabolic dysregulation.
- Increased ketogenesis and beta-hydroxybutyrate (β-OHB) are observed in HFrEF patients.
- The clinical significance of β-OHB in advanced HFrEF requires further investigation.
Purpose of the Study:
- To examine the determinants of circulating β-OHB levels in advanced HFrEF.
- To assess the prognostic impact of β-OHB on clinical outcomes in HFrEF.
- To clarify the relationship between β-OHB, lipolysis, and HF severity.
Main Methods:
- Study included 867 patients with advanced HFrEF.
- Clinical, echocardiographic, and metabolite assessments were performed.
- Right heart catheterization was utilized in a subset of patients.
- Follow-up assessed composite events, including mortality and device implantation.
Main Results:
- Median β-OHB was 64 μmol/L, with higher levels correlating with increased free fatty acids (FFA), natriuretic peptides, and worse hemodynamics.
- Univariable analysis showed both β-OHB and FFA predicted worse prognosis.
- Multivariable analysis revealed FFA, but not β-OHB, remained an independent predictor of adverse outcomes.
Conclusions:
- In advanced HFrEF, elevated β-OHB is linked to lipolysis and HF severity markers.
- The prognostic association of β-OHB is attenuated after adjustment for FFA.
- Increased β-OHB appears to be a marker of heightened lipolysis rather than an independent driver of HF progression.
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.
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