ASCVD Risk Stratification Using Apolipoprotein B and the LDL-C to Total Cholesterol Ratio

Background and Aims Low-density lipoprotein cholesterol (LDL-C) is causal for atherosclerotic cardiovascular disease (ASCVD), yet substantial risk heterogeneity persists across the LDL-C distribution. We tested whether LDL-related susceptibility is better explained by a dual-axis structure integrating ApoB-defined particle burden with LDL cholesterol composition captured by the LDL-C/total cholesterol (LDL-C/TC) ratio. Methods We analyzed six US cohorts of adults without cardiovascular disease or receiving lipid-lowering therapy at baseline. ApoB and the LDL-C/TC ratio were dichotomized at 90 mg/dL and 0.60, respectively, to define four phenotypes. Incident ASCVD was assessed using multivariable Cox proportional hazards models, with prespecified subgroup analyses by age, sex, and clinical risk groups. Results Among 9,238 ARIC participants (2,038 ASCVD events; median follow-up 25.6 years), ApoB and the Martin/Hopkins LDL-C/TC ratio showed stronger per–SD associations with ASCVD (adjusted hazard ratios [HRs] 1.20 and 1.27) than LDL-C levels. Cross-classification of ApoB and the LDL-C/TC ratio identified four phenotypes. Dual-normal participants exhibited the lowest ASCVD incidence, whereas the dual-elevated phenotype showed the highest risk (HR 1.67). Among discordant phenotypes, the low-ApoB/high-ratio group was associated with modestly higher risk (HR 1.28), while the high-ApoB/low-ratio phenotype demonstrated borderline associations. Conclusions LDL-related atherogenic risk is more coherently explained by a dual-axis framework integrating ApoB-defined particle burden with LDL cholesterol composition captured by the LDL-C/TC ratio. This structure reveals composition-driven vulnerability not apparent from ApoB or contemporary risk scores and supports a scalable strategy in which routine ratio interpretation, coupled with selective ApoB testing, may enhance ASCVD risk stratification within preventive paradigms.