Circulating Ketone Bodies and Incident Cardiovascular Outcomes and Mortality: Insights From the UK Biobank

Background Ketone bodies (KB) are endogenous energy sources synthesized by the liver in response to metabolic stress. Their associations with atherosclerotic cardiovascular disease (ASCVD), heart failure (HF), and mortality and their potential beneficial or harmful effects have yet to be determined. This study aimed to examine the association between KB and incident cardiovascular outcomes and mortality in a large general population cohort free from ASCVD and HF at baseline. Methods This analysis included 90 987 participants (mean age 56.4 ± 8.1 years; 54.7% women) from the UK Biobank without prevalent ASCVD or HF. KB were measured by nuclear magnetic resonance spectroscopy. The primary outcomes were ASCVD, HF, and all‐cause death. Secondary outcomes were myocardial infarction, ischemic stroke, peripheral artery disease, and CVD death. All outcomes were defined based on International Classification of Diseases, Ninth Revision ( ICD‐9 ) and Tenth Revision ( ICD‐10 ) codes. Multivariable‐adjusted Cox proportional hazards models examined the association of total KB with incident cardiovascular outcomes and mortality. Results At a median follow‐up of 13.4 years, higher levels of total KB (per 10‐fold increase) were associated with a greater risk of incident ASCVD, HF, and all‐cause mortality (hazard ratio [HR], 1.31 [95% CI, 1.18–1.46], 1.44 [95% CI, 1.24–1.6]7, and 1.51 [95% CI, 1.38–1.66]), respectively. Participants also demonstrated a 37% (95% CI, 11%–69%) increased risk of stroke and 69% (95% CI, 43%–100%) increased risk of CVDdeath. There was no significant association between KB and incident myocardial infarction. Conclusions Elevation in endogenous KB in a population free from CVD at baseline is associated with an increased risk of ASCVD, HF, stroke, and mortality.