Circulating ketone bodies and incident cardiovascular outcomes and mortality: Insights from the UK Biobank

Authors: CHEVLI, PARAG - Wake Forest University School Of Medicine; MIRZAI, SAEID - Wake Forest University School Of Medicine; KAZIBWE, RICHARD - Wake Forest University School Of Medicine; KINGSLEY, JEFF - Wake Forest University School Of Medicine; WOOD, ALEXIS - Children'S Nutrition Research Center (CNRC); YEBOAH, JOSEPH - Wake Forest University School Of Medicine; SLIPCZUK, LEANDRO - Albert Einstein College Of Medicine; MEHTA, ANURAG - Virginia Commonwealth University; BHATIA, HARPEET - University Of California, San Diego; PANDEY, AMBARISH - University Of Texas Southwestern Medical Center; SHAPIRO, MICHAEL D - Wake Forest University School Of Medicine

Submitted to: Journal of the American Heart Association
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 12/9/2025
Publication Date: 2/20/2026
Citation: Chevli, P.A., Mirzai, S., Kazibwe, R., Kingsley, J., Wood, A.C., Yeboah, J., Slipczuk, L., Mehta, A., Bhatia, H.S., Pandey, A., Shapiro, M. 2026. Circulating ketone bodies and incident cardiovascular outcomes and mortality: Insights from the UK Biobank. Journal of the American Heart Association. 15. Article e042582. https://doi.org/10.1161/JAHA.125.042582.
DOI: https://doi.org/10.1161/JAHA.125.042582

Interpretive Summary: Cardiovascular disease remains a leading cause of death worldwide, and identifying early biological markers of risk is critical for prevention. Ketone bodies are molecules produced by the liver during periods of metabolic stress, such as fasting or low carbohydrate intake, and they are sometimes viewed as beneficial alternative fuel sources for the heart. In this large study of more than 90,000 adults from the UK Biobank who were free of heart disease at baseline, researchers examined whether higher blood levels of ketone bodies predicted future cardiovascular events and death. Over more than 13 years of follow-up, individuals with higher ketone levels had significantly greater risks of atherosclerotic cardiovascular disease, heart failure, stroke, cardiovascular death, and all-cause mortality, even after accounting for traditional risk factors such as blood pressure, cholesterol, diabetes, and body weight. These findings suggest that elevated circulating ketone bodies may signal underlying metabolic stress or early disease processes rather than protection. This research is important for clinicians, researchers, and policymakers because it highlights ketone bodies as a potential early biomarker of cardiovascular risk and underscores the need to better understand how metabolic pathways influence chronic disease development and prevention.

Technical Abstract: 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. 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. 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 CVD death. There was no significant association between KB and incident myocardial infarction. Elevation in endogenous KB in a population free from CVD at baseline is associated with an increased risk of ASCVD, HF, stroke, and mortality.