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.