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

Abstract

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 populationbased 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. K E Y W O R D Sbeta-hydroxybutyrate, heart failure, ketone bodies, sex differences 2 of 11 | FLORES-GUERRERO Et aL.*P values represent the significance of difference across the tertiles of plasmatic β-OHB. P values were determined using a one-way analysis of variance for normally distributed data, Kruskal-Wallis test for skewed distributed data, and chi-square test for categorical data.

Ketone bodies: from enemy to friend and guardian angel

“…Circulating ketone body concentrations were increased in patients with heart failure, in correlation with cardiac use. The concentrations of βOHB in circulation were also increased in persons with incident heart failure [115]. Circulating levels of ketone bodies and their myocardial use were also found increased in persons with type 2 diabetes [14].…”

Heart Failure with Reduced Ejection Fraction—Does Sex Matter?

“…One showed similar levels of N-terminal pro-BNP [ 6 ] between men and women, whilst another study showed women tended to have a higher BNP [ 26 ]. Although the implications are unknown currently, one paper discovered that high plasma concentrations of beta hydroxybuturate were associated with increased risk of HFrEF particularly in women [ 27 ].…”

A Pilot Study on the 1H-NMR Serum Metabolic Profile of Takotsubo Patients Reveals Systemic Response to Oxidative Stress

“…We found values higher than normal for nine TTS patients, reaching a maximum of almost 3 mM in 3HB and 1 mM in AcAc. In contrast, healthy subjects show concentrations of KB as low as 19 μM, which can increase to approximately 120 μM after an overnight fast [ 38 ]. Our TTS patients were studied in the nonfasting state upon admission, thereby enhancing the significance of the high KB levels observed.…”