Abstract
BackgroundIn 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.DesignPlasma 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.ResultsDuring 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).ConclusionsThis 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.
Highlights
Heart failure (HF) is a global pandemic
Considering the possible implications of ketone body metabolism in the failing heart, the present study aimed to explore the longitudinal association of β-OHB with incidence of preserved and reduced ejection fraction HF in participants enrolled in the Prevention of Renal and Vascular End-stage Disease (PREVEND), a prospective Dutch population-based cohort study
The Cox regression analysis restricted to women showed that higher β-OHB concentrations were associated with an increased risk of HF after adjustment for total cholesterol, high-density lipoprotein cholesterol (HDL-C), triglycerides, leucine, glucose, estimated glomerular filtration rate (eGFR) and Urinary albumin excretion (UAE) (HR: 1.47, 95% CI: 1.11-1.94, P = .006)
Summary
Heart failure (HF) is a global pandemic. In the US, the prevalence of HF is expected to increase by 46% from 2012 to 2030.1 it is clinically relevant to better understand the metabolic abnormalities underlying this complex clinical syndrome. Risk of incident HF with reduced (HFrEF) or preserved (HFpEF) ejection fraction was estimated using multivariable-adjusted Cox regression models. 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. 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. Conclusions: This prospective study suggests that high plasma concentrations of β-OHB are associated with an increased risk of HFrEF, in women. The mechanisms responsible for the sex differences of this association warrant further study
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