Abstract

Background: Lipoprotein(a) [Lp(a)] is an independent risk factor for atherosclerotic cardiovascular disease (ASCVD). Recent epidemiological studies have revealed an association between ketone bodies (KB) and adverse cardiovascular outcomes, offering a unique insight into metabolic health and its impact on mortality risk. Elevated levels of both Lp(a) and KB may synergistically amplify pathological processes, including endothelial dysfunction, inflammation, and oxidative stress, through their involvement in shared pathophysiological pathways, thereby exacerbating disease progression beyond the impact of each biomarker individually. Methods: Utilizing data from the UK Biobank, KB were measured by nuclear magnetic resonance spectroscopy and serum Lp(a) concentrations were measured using an immunoturbidimetric assay. Four groups were created as follows: Group 1: Lp(a)<125 nmol/L and Total KB<75 th percentile (<94 μmol/L); Group 2: Lp(a)≥125 nmol/L and Total KB<75 th percentile; Group 3: Lp(a)<125 nmol/L and Total KB≥75 th percentile; and Group 4: Lp(a)≥125 nmol/L and Total KB≥75th percentile. Multivariable-adjusted Cox proportional hazard models were used to examine the association of Lp(a) and total KB with incident cardiovascular outcomes and mortality. Results: A total of 72,704 UK Biobank participants (mean age 56 y, SD=8, 55% women) without prevalent CVD or HF with a median follow up of 13.4 years were included. In the fully adjusted model, compared with those in the reference group (Group 1), participants in Group 2, Group 3, and Group 4 demonstrated a 14%, 17%, and 38%, increased risk of incident ASCVD events, respectively (p<0.01 for all). However, those with Lp(a) ≥ 125 nmol/L and total KB < 75th percentile demonstrated no increased risk of HF, all-cause mortality, stroke, or CVD mortality. Participants with elevated levels of both Lp(a) and KB had significantly increased risk of all outcomes (Table). There was no evidence for a statistically significant interaction between Lp(a) and KB on any outcome. Conclusion: Consistent with prior literature, Lp(a) was associated with atherosclerotic outcomes. However, elevated KB was associated with all outcomes, irrespective of Lp(a) levels.