K. Saadeh, AO. Papacosta, LT. Lennon and SG. Wannamethee (2026). Ketone bodies and incident heart failure: 20-year results from the prospective British Regional Heart Study. ESC heart failure, 13(1). https://doi.org/10.1093/eschf/xvag015

PubMed 41711718

[Abstract]
INTRODUCTION: Ketone bodies (KBs), acetoacetate, and β-hydroxybutyrate, are an important fat-derived alternative energy source for the heart and have been implicated in the pathogenesis of cardiovascular disease. The study aimed to determine the relationship between total KB (acetoacetate + β-hydroxybutyrate) and KB ratio (acetoacetate:β-hydroxybutyrate) with incident heart failure (HF) in older men.

METHODS: Three thousand four hundred fifty-nine men without prevalent myocardial infarction or HF from the prospective cohort British Regional Heart Study were included in the analysis. Ketone body levels were measured by nuclear magnetic resonance spectroscopy. Participants were followed up for a median 15.9 years.

RESULTS: Three hundred seventy-five men developed HF. Total KB was not significantly associated with incident HF {age-adjusted standardized hazard ratios [HRs] [95% confidence interval (CI)] 0.94 [0.84-1.04], P = .231 for trend}. However, KB ratio was significantly associated with incident HF (age-adjusted standardized HR (95% CI) 1.12 [1.01-1.24], P = .023 for trend). Risk tended to increase with increasing levels of KB ratio from 0.35 with risk significantly raised when the KB ratio was above 0.55 (top decile) even after adjustment for traditional cardiovascular risk factors, inflammatory markers, and NT-pro-BNP [HR (95% CI) for KB ratio >0.55 vs <0.18 (bottom quartile) = 1.60 (1.13-2.27), P = .008]. The increased risk associated with elevated KB ratio was more evident in the younger men (age <70 years). When examined by levels of NT-pro-BNP, elevated KB ratio was significantly associated with increased HF risk only in the presence of elevated NT-pro-BNP (>83 pg/ml; above the median) [age-adjusted HR = 1.87 (1.25-2.81)]. Weaker associations were seen in those without raised NT-pro-BNP [HR = 1.23 (0.66-2.27)].

CONCLUSION: Elevated KB ratio is associated with a significantly increased risk of HF and may serve as a biomarker of HF incidence particularly when NT-pro-BNP is also elevated.