Abstract
Introduction: Oxidized LDL triggers inflammation during the initiation and progression of atherosclerotic plaque. The omega-3 fatty acid (n3-FA) EPA administered as icosapent ethyl (IPE), reduced cardiovascular (CV) events in REDUCE-IT due, in part, to potential antioxidant and anti-thrombotic activity. By contrast, mixed n3-FA containing docosahexaenoic acid (DHA) have failed to reduce CV events in similar high-risk patients (STRENGTH). Some have raised concerns over the relationship between these discordant outcomes and placebo choice (mineral oil) as well as DHA content. We compared the effects of these compounds on oxidation of LDL where such ingested fatty acids are concentrated and transported. Methods: LDL was isolated from human plasma by isopycnic centrifugation, separated into test samples of 100 μg/mL, and incubated at 37°C for 30 min with pharmaceutical grade mineral oil, EPA, DHA or vehicle at equimolar levels (10 μM). All samples were then subjected to copper sulfate-induced oxidation (20 μM) monitored by formation of malondialdehyde (MDA). Ascorbic acid at equimolar levels served as a control. Results: LDL oxidation increased 30-fold (0.28±0.03 vs 8.72±0.54 μM; p <0.001) after 4 h and the rate was unaffected by addition of mineral oil. By contrast, EPA significantly inhibited LDL oxidation; after 4 h, EPA inhibited MDA levels by 75% compared with vehicle (8.72±0.54 vs 2.20±0.36 μM; p <0.001). While DHA exhibited antioxidant activity at 2 hours at a level less than EPA (1.15±0.54 vs 3.00±1.08 μM; p <0.05), it exhibited no antioxidant activity after 4 h. Like DHA, ascorbic acid also reduced LDL oxidation only up to 2 h. Conclusions: These data support sustained LDL antioxidant effects for EPA compared with DHA, ascorbic acid, or mineral oil. The longer-term antioxidant actions of EPA may contribute to reduced events in outcome trials compared to mixed n3-FA formulations, independent of placebo selection.
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