The hidden atherogenic burden of lipoprotein(a): Reclassification by risk-weighted apoB in a multicenter registry.
BACKGROUND AND AIMS Apolipoprotein B (apoB) is the preferred marker of atherogenic particle burden, but it assumes that all apoB-containing lipoproteins confer the same cardiovascular risk. Mendelian randomization studies suggest that triglyceride-rich lipoproteins (TRLs) and lipoprotein(a) [Lp(a)] are more atherogenic per apoB particle than LDL. Risk-weighted apoB (RW-apoB) captures these differences in a single metric. We assessed the reclassification produced by RW-apoB versus measured apoB in the GAELp(a) registry, a real-world Lp(a)-enriched cohort. METHODS This post-hoc analysis of the GAELp(a) registry included 1861 adults with available apoB, Lp(a) expressed in nmol/L, and fasting triglycerides (TG) < 250 mg/dL. RW-apoB was calculated as: 11.65 × TG (mmol/L) + 0.215 × Lp(a) (nmol/L) + 0.736 × apoB (mg/dL). Reclassification was defined as the change in percentile rank between RW-apoB and measured apoB (Δ percentile). Analyses were stratified across five Lp(a) categories. A complementary analysis without TG truncation was performed in 1966 participants to evaluate the contribution of each RW-apoB component. RESULTS Mean apoB was 89.9 ± 27.6 mg/dL, whereas mean RW-apoB was 103.7 ± 36.3 mg/dL. Overall, 60.0% of participants were reclassified by ≥ 10 percentile points. In individuals with Lp(a) < 75 nmol/L, measured apoB slightly overestimated weighted atherogenic burden (median Δ percentile: -13.2). Conversely, apoB progressively underestimated weighted atherogenic burden with increasing Lp(a), reaching an RW-apoB/apoB ratio of 1.91 and median Δ percentile of +34.7 at Lp(a) ≥300 nmol/L. The reclassification pattern was virtually identical in the no-truncation analysis (60.0%), with Lp(a)-not TRL-identified as the primary driver of discordance between RW-apoB and measured apoB. CONCLUSIONS Conventional apoB substantially underestimated weighted atherogenic burden in individuals with elevated Lp(a), with discordance increasing at higher concentrations. These findings support particle-specific weighting approaches for apoB-based cardiovascular risk assessment.