Estimated cumulative LDL-C exposure and severity of coronary artery lesions in patients with acute coronary syndrome: a retrospective observational cross-sectional analysis

Background Atherosclerotic cardiovascular disease dominated by coronary atherosclerosis is the leading cause of global mortality and disability. Low-density lipoprotein cholesterol (LDL-C) is a well-established pathogenic driver, yet most existing studies rely on single cross-sectional LDL-C testing. Estimated cumulative LDL-C exposure, calculated as a single fasting LDL-C measurement multiplied by age and serving as a proxy for lifelong lipid burden, remains insufficiently characterized regarding its association with coronary lesion severity. Methods This retrospective observational cross-sectional analysis enrolled 871 patients with acute coronary syndrome (ACS) undergoing coronary angiography between January and September 2024. Estimated cumulative LDL-C exposure was calculated as fasting LDL-C measured within 24 h of admission (mmol/L) multiplied by age (years) and stratified into quartiles. Least absolute shrinkage and selection operator (LASSO) regression was used for variable screening. Multiple linear regression, restricted cubic spline (RCS), subgroup interaction, and receiver operating characteristic (ROC) curve analyses were performed to quantify associations and predictive performance. Results Estimated cumulative LDL-C exposure was positively associated with the square root of the SYNTAX score ( β = 0.0098, P < 0.001). In covariate-adjusted ROC analyses, the model containing estimated cumulative LDL-C exposure showed slightly higher discrimination than the model containing age and LDL-C as separate additive terms (AUC 0.860 vs. 0.853; DeLong P = 0.0160), although the absolute difference was small (ΔAUC = 0.007). RCS analysis identified a nonlinear association ( P for nonlinearity = 0.026) with a point of maximum estimated slope at approximately 170.2 mmol·year/L; however, the 95% confidence interval was wide (56.6–177.9 mmol·year/L), and this value should not be interpreted as a validated threshold. Subgroup interaction tests revealed stronger associations in male patients and smokers (sex P = 0.036; smoking P = 0.047 both after FDR correction). Conclusions Estimated cumulative LDL-C exposure was independently associated with greater coronary lesion severity in patients with acute coronary syndrome. The estimated cumulative LDL-C exposure model showed modestly better fit and discrimination than the age + LDL-C model, although this finding should be interpreted cautiously because age is mathematically embedded in the exposure definition. These findings are consistent with the cumulative LDL-C exposure hypothesis and support its potential value in assessing coronary lesion burden.