Direct Lp(a)-C measurements provide evidence for Apo(a) isoform-dependent cholesterol composition of Lp(a)

Lipoprotein(a) [Lp(a)] carries cholesterol [Lp(a)-C], yet the cholesterol composition of Lp(a) particles and its relationship to apolipoprotein(a) [apo(a)] isoform size remains incompletely defined. Prior estimates of Lp(a)-C have relied on fixed-percentage assumptions rather than direct biochemical measurement, limiting insight into particle-level heterogeneity. We developed a direct immunocapture assay using the monoclonal antibody LPA4 to quantify Lp(a)-C in plasma and applied it to 94 individuals spanning a wide range of Lp(a) concentrations and apo(a) isoform sizes. Lp(a)-C was strongly correlated with Lp(a) molar concentration (R = 0.925, P < 0.001) and inversely associated with apo(a) isoform size (R = -0.745, P < 0.001). Across tertiles of the predominant apo(a) isoform size, smaller isoforms (12-17 KIV repeats) had higher Lp(a)-C (8.3 ± 4.3 mg/dl; 11.0 ± 3.4%), mid-range isoforms (18-23 KIV) were intermediate (5.0 ± 3.2 mg/dl), whereas larger isoforms (>24 KIV) showed lower Lp(a)-C (3.0 ± 1.5 mg/dl) (P < 0.001), normalized to plasma volume (not particle concentration). In contrast, particle-normalized metrics demonstrated the opposite pattern: both the Lp(a)-C/Lp(a) molar ratio and Lp(a)-C/Lp(a)-apoB mass ratio increased progressively with apo(a) isoform size (P < 0.001), indicating greater cholesterol content per Lp(a) particle among larger isoforms. These findings demonstrate a dissociation between circulating Lp(a)-C concentration, which primarily reflects particle number, and cholesterol content per particle, which varies systematically with apo(a) isoform size. Direct measurement of Lp(a)-C identifies compositional heterogeneity not captured by conventional estimation methods and may provide a framework for future studies of isoform-dependent variation in Lp(a) structure and function.