Association of Elevated Lipoprotein(a) Levels with HDL Subfraction Distribution and Antioxidant Function

Low levels of high-density lipoprotein cholesterol (HDL-C) are strongly associated with increased cardiovascular risk. However, under various pathological conditions, high-density lipoprotein (HDL) particles may undergo structural and functional modifications, leading to a progressive loss of antioxidant capacity and a shift from a cardioprotective to a proatherogenic phenotype. In this cross-sectional study, we investigated differences in HDL particle distribution and antioxidant function between individuals with elevated lipoprotein(a) [Lp(a)] levels (≥30 mg/dL) and those with low Lp(a) levels (<10 mg/dL). Serum low-density lipoprotein (LDL) and HDL subfractions were analyzed in twenty subjects with high Lp(a) and ten low-Lp(a) controls using non-denaturing polyacrylamide gel electrophoresis (PAGE, Lipoprint system). Enzymatic activities of paraoxonase-1 (PON1) and HDL-associated lipoprotein-associated phospholipase A2 (HDL-Lp-PLA2) were measured. Electrophoretic analysis revealed a significant increase in small HDL (S-HDL) in the high-Lp(a) group compared to the controls (34.1 ± 13.2% vs. 21.5 ± 2.7%, p = 0.01), alongside a reduction in large HDL (L-HDL) (19.6 ± 9.9% vs. 33.4 ± 3.8%, p < 0.001). Furthermore, the high Lp(a) group exhibited significantly lower HDL-PON1 activity (55 ± 12 vs. 67 ± 7 U/mL, p < 0.001) and HDL-Lp-PLA2 activity (2.6 ± 1.0 vs. 3.6 ± 1.2 nmol/min/mL, p < 0.02) compared with the controls. These findings suggest that markedly elevated Lp(a) levels are associated with a shift toward a more proatherogenic HDL subfraction profile and impaired antioxidant functionality, which may reflect mechanisms linked to increased atherosclerotic cardiovascular disease (ASCVD) risk.