Association of beta-hydroxybutyrate with development of heart failure: Sex differences in a Dutch population cohort

Jose L. Flores-Guerrero*, Berend Daan Westenbrink, Margery A. Connelly, James D. Otvos, Dion Groothof, Irina Shalaurova, Erwin Garcia, Gerjan Navis, Rudolf A. de Boer, Stephan J. L. Bakker, Robin P. F. Dullaart

*Corresponding author for this work

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Background In the failing heart, energy metabolism is shifted towards increased ketone body oxidation. Nevertheless, the association of beta-hydroxybutyrate (beta-OHB) with development of heart failure (HF) remains unclear. We investigated the association between plasma beta-OHB and the risk of HF in a prospective population-based cohort.

Design Plasma beta-OHB concentrations were measured in 6134 participants of the PREVEND study. Risk of incident HF with reduced (HFrEF) or preserved (HFpEF) ejection fraction was estimated using multivariable-adjusted Cox regression models.

Results During median follow-up for 8.2 years, 227 subjects were diagnosed with HF (137 with HFrEF; 90 with HFpEF). Cox regression analyses revealed a significant association of higher beta-OHB concentrations with incident HF (HR per 1 standard deviation increase, 1.40 (95% CI: 1.21-1.63; P <.001), which was largely attributable to HFrEF. In women, the hazard ratio (HR) for HFrEF per 1 standard deviation increase in beta-OHB was 1.73 (95% confidence interval (CI): 1.17-2.56, P = .005) in age, BMI, type 2 diabetes, hypertension, myocardial infarction, smoking, alcohol consumption, total cholesterol, HDL-C, triglycerides, glucose, eGFR and UAE adjusted analysis. In men, in the same fully adjusted analysis, the HR was 1.14 (CI: 0.86-1.53, P = .36) (P <.01 for sex interaction). In N-terminal pro-brain natriuretic peptide (NT-proBNP)-stratified analysis, the age-adjusted association with HF was significant in women with higher NT-proBNP levels (P = .008).

Conclusions This prospective study suggests that high plasma concentrations of beta-OHB are associated with an increased risk of HFrEF, particularly in women. The mechanisms responsible for the sex differences of this association warrant further study.

Original languageEnglish
Article number13468
Pages (from-to)1-11
Number of pages11
JournalEuropean Journal of Clinical Investigation
Publication statusPublished - 18-Dec-2020


  • beta&#8208
  • hydroxybutyrate
  • heart failure
  • ketone bodies
  • sex differences
  • RISK

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