Abstract 4143799: Dose-Dependent Inhibition of Lp(a) Oxidation by Eicosapentaenoic Acid (EPA) Compared to a Fibrate and Statin due to Lipid Interactions and Antioxidant Properties

Background: Elevated Lp(a) levels are an independent and causal risk factor for cardiovascular (CV) disease. Levels of oxidized Lp(a) were more predictive of CV events and endothelial dysfunction than non-oxidized forms in patients. The omega-3 fatty acid EPA reduced CV events in high-risk patients, including those with elevated Lp(a) (REDUCE-IT). EPA inhibits lipid oxidation due to scavenging activity and lipophilicity. We compared the effects of a pharmacologic concentration of EPA on oxidation rates for Lp(a) versus LDL compared to a fibrate and statin, along with lipid affinity. Methods: Lp(a) was enriched to 66% of total ApoB-containing particles from patients with elevated levels by isopycnic centrifugation. Samples of Lp(a) and LDL (50 µg/ml) were incubated at 37°C for 30 min with EPA at various concentrations (10 – 100 µM) compared to equimolar fenofibric acid or rosuvastatin (10 µM). Samples then underwent copper sulfate-induced oxidation (20 µM) monitored by formation of malondialdehyde (MDA). Lipid affinity of each agent was measured by UV/Vis spectroscopy using lipid vesicles containing phosphatidylcholine and cholesterol at a 0.3:1 ratio. Drug concentrations in vesicles versus buffer were measured and compared to standard curves. Results: Lp(a) enriched ApoB particles underwent time-dependent oxidation by 51-fold, peaking after 2 h (4.13 ± 0.10, p<0.001). EPA significantly inhibited Lp(a) oxidation in a dose and time-dependent manner; after 2 h, EPA inhibited oxidation from 31 to 69% ( p <0.001) at 5 concentrations while fenofibric acid and rosuvastatin lacked antioxidant activity. Similar distinct antioxidant effects of EPA were observed in non-modified LDL. The antioxidant activity EPA correlated with higher lipid affinity that was significantly greater than fenofibric acid and rosuvastatin ( p <0.001). Conclusions: EPA inhibited oxidation of Lp(a) enriched plasma in a dose-dependent fashion due to potent scavenging mechanism and high lipid affinity. The fibrate or statin tested did not exert similar antioxidant effects. The potent antioxidant actions of EPA may contribute to reduced events in REDUCE-IT, including in subjects with elevated Lp(a).