Short‐Term, High‐Dose Fish Oil Supplementation Increases the Production of Omega‐3 Fatty Acid–Derived Mediators in Patients With Peripheral Artery Disease (the OMEGA‐PAD I Trial)

Abstract

BackgroundPatients with peripheral artery disease (PAD) experience significant morbidity and mortality. The OMEGA-PAD I Trial, a randomized, double-blinded, placebo-controlled trial, addressed the hypothesis that short-duration, high-dose n-3 polyunsaturated fatty acids (n-3 PUFA) oral supplementation improves endothelial function and inflammation in PAD.Methods and ResultsEighty patients with stable claudication received 4.4 g of fish oil or placebo for 1 month. The primary end point was endothelial function as measured by brachial artery flow-mediated vasodilation. Secondary end points included biomarkers of inflammation, n-3 polyunsaturated fatty acids metabolome changes, lipid profile, and walking impairment questionnaires. Although there was a significant increase in FMD in the fish oil group following treatment (0.7±1.8% increase from baseline, P=0.04), this response was not different then the placebo group (0.6±2.5% increase from baseline, P=0.18; between-group P=0.86) leading to a negative finding for the primary endpoint. There was, however, a significant reduction in triglycerides (fish oil: −34±46 mg/dL, P<0.001; placebo −10±43 mg/dL, P=0.20; between-group differential P-value: 0.02), and an increase in the omega-3 index of 4±1% (P<0.001) in the fish oil group (placebo 0.1±0.9%, P=0.49; between-group P<0.0001). We observed a significant increase in the production of pathway markers of specialized pro-resolving mediators generated from n-3 polyunsaturated fatty acids in the fish oil group.ConclusionsHigh-dose, short-duration fish oil supplementation did not lead to a different response in the primary end point of endothelial function between the treatment and placebo group, but improved serum triglycerides and increased the production of downstream n-3 polyunsaturated fatty acids–derived products and mediators in patients with PAD.Clinical Trial RegistrationURL: https://www.clinicaltrials.gov/. Unique identifier: NCT01310270.

Resolution of vascular injury: Specialized lipid mediators and their evolving therapeutic implications

“…It has been well established that oral supplementation with omega-3 fatty acids or diets rich in their marine sources increase both plasma and cell-membrane levels of EPA and DHA (Grenon, Owens et al 2015, Wang, Hjorth et al 2015). Unfortunately, the relationship between blood levels of these n-3 fatty acids and the downstream biochemical pathways producing SPM is poorly understood.…”

“…The physiological impact of oral supplementation of n-3 PUFA for each individual is variable depending on baseline characteristics such as prior dietary intake and hereditary metabolic factors (von Schacky 2014). Recently, the OMEGA-PAD-I Trial demonstrated the effects of short-term n-3 fatty acid supplementation on altering biochemical SPM pathways in PAD patients (Grenon, Owens et al 2015). In this study, eighty subjects were randomized to either 4.4g of fish oil, corresponding to 2.6g of EPA and 1.8g of DHA daily, or placebo for one month.…”

n-3 Fatty acid supplementation and proresolving mediators of inflammation

“…Subsequent studies have examined the effect of n-3 fatty acids supplementation in relation to plasma SPM formation in healthy volunteers [21,23 & ,26]; patients suffering from chronic headaches [22]; mild hypertriglyceridemia [27]; chronic renal disease [24 && ]; and peripheral artery disease [28].…”

“…The effect of n-3 fatty acid supplements on SPMs and other lipid mediators was studied in 80 patients with peripheral artery disease [28]. The study was a randomized double blind trial that gave patients either 4.4 g/day n-3 fatty acids or placebo for 1 month with endothelial function as the primary outcome [28].…”

“…The study was a randomized double blind trial that gave patients either 4.4 g/day n-3 fatty acids or placebo for 1 month with endothelial function as the primary outcome [28]. Assessment of a number of SPMs in plasma using a lipidomic approach showed plasma 18-HEPE was significantly increased after n-3 fatty acids compared with the placebo group.…”