Abstract 4139560: Lipoprotein(a) [Lp(a)]-Enriched Plasma Undergoes More Rapid Oxidation than Small Dense LDL-Enriched Plasma that is Inhibited by Eicosapentaenoic Acid (EPA)

Background: Elevated Lp(a) levels are associated with increased cardiovascular (CV) risk, along with small dense LDL (sdLDL). Lp(a) contains oxidized phospholipid that may “seed” lipid oxidation reactions compared to other lipoproteins. The omega-3 fatty acid EPA delivered as icosapent ethyl (4 g/d) reduced CV events in high-risk patients, including those with elevated Lp(a) (REDUCE-IT). EPA has conjugated double bonds that trap lipid free radicals. We compared rates of oxidation for Lp(a)-enriched and sdLDL-enriched LDL with potential inhibition by EPA at a pharmacologic concentration. Methods: Lp(a) and sdLDL were enriched to 66% of total ApoB-containing particles from patients with elevated levels following isopycnic centrifugation. Lp(a), sdLDL and LDL were matched for total protein (50 µg/mL) and incubated at 37°C for 30 min with EPA (50 µM). Samples then underwent copper sulfate-induced oxidation (20 µM) monitored by formation of malondialdehyde (MDA) for 3 h. We normalized rates of oxidation to total available lipid in the samples. Results: After 0.5 h, Lp(a)-enriched plasma underwent the most rapid oxidation – 60% of total lipid oxidation ( p <0.001 vs other fractions) – followed by sdLDL-enriched plasma (30% of total oxidation) then pure LDL (17% of total oxidation). All samples underwent complete oxidation by 2 h. Initially (t = 0 h), Lp(a) enriched plasma contained more oxidized lipid than all other fractions ( p <0.05). The relative antioxidant activity of EPA was greatest in the Lp(a) enriched samples; EPA inhibited oxidation of Lp(a)-enriched, sdLDL-enriched, and pure LDL by 50%, 46% and 47% ( p <0.001), respectively, at 2 h. The antioxidant activity of EPA in samples persisted at all time points. Conclusions: Lp(a)-enriched plasma underwent rapid oxidation attributed to oxidized phospholipid content and followed by sdLDL and LDL. Oxidation was disproportionately inhibited by EPA in Lp(a) enriched plasma due to free radical scavenging mechanism associated with its multiple conjugated double bonds. The high lipid oxidation rates for Lp(a) inhibited by EPA may contribute to the benefit observed in REDUCE-IT, including in subjects with elevated Lp(a) levels.