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

Research output: Contribution to journalArticleAcademicpeer-review

24 Citations (Scopus)


Background: In the failing heart, energy metabolism is shifted towards increased ketone body oxidation. Nevertheless, the association of beta-hydroxybutyrate (β-OHB) with development of heart failure (HF) remains unclear. We investigated the association between plasma β-OHB and the risk of HF in a prospective population-based cohort. Design: Plasma β-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 β-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 β-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 β-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 numbere13468
JournalEuropean Journal of Clinical Investigation
Issue number5
Publication statusPublished - May 2021
Externally publishedYes

Bibliographical note

Funding Information:
This work was supported by The Dutch Kidney Foundation which supported the infrastructure of the PREVEND program from 1997 to 2003 (Grant E.033). The University Medical Center Groningen supported the infrastructure from 2003 to 2006. Dade Behring, Ausam, Roche, and Abbott financed laboratory equipment and reagents by which various laboratory determinations could be performed. β‐OHB were measured at LabCorp, Morrisville USA at no cost. Dr Flores‐Guerrero acknowledges support from the National Council of Science and Technology (CONACYT).

Publisher Copyright:
© 2020 The Authors. European Journal of Clinical Investigation published by John Wiley & Sons Ltd on behalf of Stichting European Society for Clinical Investigation Journal Foundation


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