Remnant cholesterol and its role in patients with coronary atherosclerosis evaluated by coronary CT

Abstract Background Remnant cholesterol (RC) is an emerging factor contributing to residual risk in patients with ischemic heart disease. However, the relationship between RC and coronary atherosclerotic plaque burden remains scarcely explored. Purpose This study aimed to investigate whether elevated levels of RC represent an independent or interactive risk factor in relation to coronary atherosclerotic burden in individuals undergoing primary prevention, as well as its impact on the incidence of major cardiovascular events during follow-up. Methods This was a retrospective cohort study involving 296 patients who underwent a coronary CT between 2017 and 2019. Clinical and biochemical data were collected and the cumulative incidence of MACE was assessed until 2024. RC was estimated indirectly. Coronary atherosclerotic plaque burden was quantified using coronary artery calcium score (CACS), Segment Involvement Score (SIS), and CAD-RADS classification, including visual plaque burden. Kaplan-Meier survival models and multivariable Cox regression analyses were performed. In addition, a four-way mediation analysis adjusted for potential confounders was conducted to explore whether RC acts as a mediator or as an effect modifier in the relationship between plaque burden and MACE. Results The median age was 64.4 years; 58.8% were women. Elevated RC was observed in 23.6% of the patients. The 5-year cumulative incidence of MACE was 13.3%. The highest quartile of remnant cholesterol was significantly associated with MACE in the Kaplan–Meier analysis (log-rank p = 0.02) and in the unadjusted Cox model (HR: 3.10; 95% CI: 1.20–8.00; p = 0.019). However, this association was attenuated after adjusting for any atherosclerosis quantification scale. The four-way mediation analysis showed a significant interaction between RC and CAD-RADS score on MACE (crude interaction effect: β = 0.10; 95% CI: 0.02–0.17; p = 0.015) that persisted when adjusted for potential confounding factors: β = 0.12; 95% CI: 0.04–0.20; p = 0.004. This suggested a role as an effect modifier, particularly a relationship of positive reference interaction. Similar findings were observed for SIS, CACS and visual plaque burden. Conclusion Elevated levels of RC are associated with a higher risk of 5 year-MACE in patients evaluated by coronary CT. Beyond its direct effect it seems to act as an effect modifier, enhancing the impact of coronary atherosclerosis on cardiovascular risk, independently of traditional risk factors.