Ketone body ratio as a predictor of heart failure incidence: findings from a 15-year longitudinal cohort study

Abstract Background Heart failure (HF) is a major public health concern. It is a leading cause of morbidity and mortality and increases significantly with age. Ketone bodies (KB), acetoacetate and β-hydroxybutyrate, act as an alternative energy substrate for myocardial metabolism, especially during metabolic stress. Studies have demonstrated that the myocardium of patients with heart failure show increased KB use and that KB can influence haemodynamic parameters in the failing heart including improving systolic function. KB ratio is a marker of mitochondrial redox state (NAD+/NADH). However, its potential as a predictor of HF incidence has not been studied. Purpose To assess the association between total KB levels (acetoacetate + β-hydroxybutyrate), individual KB components, and KB ratio (acetoacetate: β-hydroxybutyrate) with incident HF in a cohort of older men. Methods The prospective cohort from the British Regional Heart Study included 3459 men aged 60-79 years without prevalent myocardial infarction (MI) or HF. Serum KB levels were quantified by nuclear magnetic resonance spectroscopy and participants were followed up for a median 15.9 years. HF events were identified via primary care and national health records. Cox proportional hazards models were used to investigate associations, adjusting for established cardiovascular risk factors and inflammatory markers. Results 375 participants (10.8%) developed incident HF during follow-up (6.82 cases per 1,000 person-years). Total KB levels did not show a significant association with HF incidence (HR 0.88 0.72–1.08, p=0.231). However, higher KB ratio was significantly associated with increased HF incidence (HR 2.67 1.11–6.41, p=0.028). Stratified analysis showed a stronger association in younger individuals (70 years) and those who developed HF with reduced ejection fraction. Diabetic status did not appear to alter the relationship. Restricted cubic spline analysis demonstrated a linear increase in HF risk beyond a KB ratio of 0.35, suggesting a potential threshold for increased susceptibility. Neither total KB nor KB ratio were associated with incident MI (Total KB HR 0.86 0.67–1.09, p=0.213; KB Ratio HR 0.87 0.68–1.11, p=0.261). Conclusion This study provides novel evidence that higher KB ratio, reflecting mitochondrial redox potential (NAD+/ NADH), rather than total KB, is significantly associated with increased risk of HF incidence independent of established cardiovascular risk factors and inflammatory markers in older adults. The association appears stronger in younger individuals and those developing HFrEF. Therefore, KB ratio may serve as an early biomarker for HF risk stratification and a target for future metabolic interventions in HF prevention and management.