NATURE REVIEWS | CARDIOLOGY VOLUME 6 | DECEMBER 2009 | 753 Mid America Heart Institute and University of Missouri-Kansas City, Kansas City, MO, USA (J. H. Lee, J. H. O’Keefe). Ochsner Medical Center, New Orleans, LA, USA (C. J. Lavie). Cardiovascular Health Research Center, Sanford Research/USD and Sanford School of Medicine of the University of South Dakota, Sioux Falls, SD, USA (W. S. Harris). Correspondence: J. H. O’Keefe, Mid America Heart Institute and University of Missouri-Kansas City, 4330 Wornall Road, Suite 2000, Kansas City, MO 64111, USA jhokeefe@cc-pc.com Omega-3 fatty acids: cardiovascular benefits, sources and sustainability John H. Lee, James H. O’Keefe, Carl J. Lavie and William S. Harris Abstract | The evidence for the cardioprotective nature of omega-3 fatty acids is abundant, and currently available data indicate that patients with known coronary heart disease should consume at least 1 g daily of long-chain omega-3 fatty acids from either oily fish or fish-oil supplements, and that individuals without disease should consume at least 250–500 mg daily. However, this area of research poses two questions. Firstly, which is the best source of omega-3 fatty acids—fish or fish-oil supplements? Secondly, are recommendations for omega-3 supplementation warranted in view of the rapid depletion of world fish stocks? The argument that eating fish is better than taking fish-oil supplements stems from the fact that several important nutrients, such as vitamin D, selenium, and antioxidants, are missing from the supplements. However, three major prevention trials have clearly indicated that omega-3 fatty acid capsules confer cardiovascular benefits and, therefore, that both are cardioprotective. Sustainable sources of omega-3 fatty acids will need to be identified if long-term cardiovascular risk reduction is to be achieved at the population level. Lee, J. H. et al. Nat. Rev. Cardiol. 6, 753–758 (2009); published online 27 October 2009; doi:10.1038/nrcardio.2009.188 Introduction Omega‑3 fatty acids come in several forms but eicosapen‑ taenoic acid (EPA) and docosahexaenoic acid (DHA) have been most widely investigated with regard to their cardiovascular benefits. Both forms are abundantly avail‑ able in oily fish (Table 1) and in supplements provided by numerous companies. Many epidemiological studies and randomized control trials have established the beneficial effects of omega‑3 fatty acids on cardiovascular health. 1–3 In response to this abundance of evidence, the AHA has, for the first time, endorsed a nutritional supplement for the secondary prevention of cardiovascular events in patients with documented coronary heart disease (CHD); 2 they recommend the consumption of omega‑3 in the form of oily fish, but cite supplements as another option. However, some studies have indicated a less robust relationship between omega‑3 fatty acids and reduction in cardio‑ vascular risk. 4 Furthermore, some researchers argue that wild fish populations are collapsing and blanket recom‑ mendations to increase omega‑3 fatty acids from marine sources will only exacerbate this problem. 5 In this Review, we will examine the currently available evidence on the importance of omega‑3 fatty acids for cardioprotection, address whether the benefits are best conferred by con‑ suming fish or supplementing with fish oils, and discuss possible future sources of omega‑3 fatty acids. Omega-3 and cardiovascular health Thousands of epidemiological, observational, and experimental studies and randomized controlled trials conducted over the last three decades have established the positive cardiovascular effects of the long‑chain omega‑3 fatty acids DHA and EPA. 1,3 These benefits seem to result primarily from DHA and EPA enrichment of membrane phospholipids, 6 which leads to improved arterial and endothelial function, 7 reduced platelet aggre‑ gation, 8 improved autonomic tone, 9,10 increased arrhyth‑ mic thresholds 11 and reduced blood pressure (Box 1, Figure 1). 10,12–14 Omega‑3 fatty acids may also reduce insulin resistance 15 and suppress production of pro‑ inflammatory cytokines (interleukin‑6, interleukin‑1β, and tumor necrosis factor). 16 In patients with heart failure, doses of omega‑3 fatty acids of 8 g daily or more improve body composition and have anti‑inflammatory effects. 17,18 Omega‑3 fatty acids also have favorable effects on lipid profiles, and the AHA recommends 2–4 g daily of DHA and EPA for patients with high triglyceride levels. 2 In a meta‑analysis by Harris and colleagues, in which data from 25 trials that evaluated the correlation between in vivo omega‑3 fatty acid levels and risk of CHD were analyzed, the number of CHD events was inversely related to levels of DHA in phospholipids. 19 These markers are closely related to the amount of DHA in the myo‑ cardium. 19,20 This study did not, however, demonstrate a statistically significant relationship between plasma EPA level and risk of CHD, but interpretation of this finding is difficult since DHA and EPA are almost always con‑ sumed together. A randomized controlled trial conducted in the late 1980s (the Diet and Reinfarction Trial [DART]) demonstrated that 2‑year all‑cause mortality was reduced by 29% in patients who receive omega‑3 fatty acids after a Competing interests J. H. O’Keefe declares an association with the following companies: Cardiotabs LLC and GlaxoSmithKline. C. J. Lavie declares an association with the following company: GlaxoSmithKline. W. S. Harris declares an association with the following companies: GlaxoSmithKline, Monsanto, and OmegaQuant Analytics. See the article online for full details of the relationships. J. H. Lee declares no competing interests. REVIEWS © 2009 Macmillan Publishers Limited. All rights reserved