A Revolution in Omega-3 Fatty Acid Research

Deepak L. Bhatt, MD, MPH; Matthew J. Budoff, MD; R. Preston Mason, PHD


J Am Coll Cardiol. 2020;76(18):2098-2101. 

Decades of observational research have supported an association between omega-3 fatty acid (OM3FA) intake and a lower rate of cardiovascular events.[1] However, with the exception of GISSI-P (Gruppo Italiano per lo Studio della Sopravvivenza nell'Infarto Miocardico Prevenzione), multiple randomized trials of mixtures of largely low doses of omega-3 fatty acids provided neutral overall results.[2] Particular subgroups or secondary endpoints did show promise, but certainly nothing definitive.[2] Then came REDUCE-IT (Reduction of Cardiovascular Events with Icosapent Ethyl–Intervention Trial), which proved in a large cardiovascular outcome trial in the statin era that a high dose of a purified ethyl ester of eicosapentaenoic acid (EPA) in patients at elevated cardiac risk significantly reduced a variety of ischemic endpoints, including death from cardiovascular causes, in a largely Western population.[3–9] This followed the earlier randomized, but open-label, JELIS (Japan EPA Lipid Intervention Study), which had also found significant benefit in a mixed primary and secondary prevention population, in this case with a medium dose of a purified ethyl ester in a Japanese population (with higher baseline levels of EPA).[10] The benefits appeared to be largely related to achieved levels of EPA. The EVAPORATE (Effect of Vascepa on Progression of Coronary Atherosclerosis in Persons With Elevated Triglycerides on Statin Therapy) trial showed significant, favorable effects on measures of plaque volume and composition on noninvasive computed tomography with icosapent ethyl versus placebo, echoing what had been observed with EPA in the open-label CHERRY (Combination Therapy of Eicosapentaenoic Acid and Pitavastatin for Coronary Plaque Regression Evaluated by Integrated Backscatter Intravascular Ultrasonography) trial, which had used invasive intravascular ultrasound.[11–13] Thus, the case for EPA provision by means of prescription-grade medication is now firmly established.

In this issue of the Journal, Lázaro et al.[14] evaluated the dietary impact of OM3FAs in 944 consecutive patients with ST-segment elevation myocardial infarction (STEMI). They examined the proportion of EPA in serum phosphatidylcholine (PC), which estimates the amount of recent dietary EPA consumption. They found that the serum-PC EPA levels at the time of STEMI were associated with a significantly lower incidence of major adverse cardiovascular events at 3-year follow-up. They also found that serum-PC alpha-linolenic acid (ALA) levels were associated with a lower incidence of all-cause mortality.

The study by Lázaro et al.[14] enrolled patients with STEMI. However, the results likely apply to all patients with atherosclerosis or who are at high risk for it. Interestingly, in a recent study of coronary artery calcification, low levels of EPA and another omega-3 fatty acid called docosahexaenoic acid (DHA) were associated with early-onset coronary atherosclerosis, which was independent of age, sex, or statin use.[15]

The biology of OM3FAs is complex, and our understanding is rapidly evolving.[16] Certain essential OM3FAs such as ALA are obtained in the diet from plant sources (e.g., chia seeds, flax seeds, and walnuts). As indicated in Figure 1, the conversion of ALA to DHA is complex and requires 7 independent enzymatic steps that include EPA and docosapentaenoic acid as intermediaries. By contrast, EPA and DHA can be directly obtained from marine sources (such as oily fish) to avoid the multiple biosynthesis steps required of ALA. Indeed, the conversion of ALA to EPA and DHA is inefficient, especially in a population consuming a typical Western diet of processed foods, animal fats, and refined seed oils high in OM6FAs. Therefore, direct dietary intake of OM3FAs from foods rich in EPA and DHA is more efficient, but in patients with cardiovascular disease, even these sources are highly inadequate to achieve consistent therapeutic levels associated with the beneficial outcomes reported in REDUCE-IT. The OM3FA dietary supplements, while very popular, remain unproven with respect to reducing cardiovascular risk due to quality concerns and lack of regulation. Oxidation of these highly unsaturated OM3FAs during commercial processing may compromise any potential benefit, as demonstrated by independent laboratory studies.[17]

Figure 1.

Pathway for Biosynthetic Conversion of ALA to EPA and DHA
Alpha(α)-linolenic acid (ALA) is enzymatically converted to the omega-3 fatty acids (OM3FAs), eicosapentaenoic acid (EPA), docosapentaenoic acid (DPA), and docosahexaenoic acid (DHA), by a series of endoplasmic reticulum and peroxisomal proteins. The final product in this pathway is DHA that is synthesized by peroxisomal β-oxidation to remove the 2-carbon acetyl-CoA from its precursor. This pathway requires Δ5-desaturase and Δ6-desaturase encoded by the FADS1 and FADS2 genes, respectively. The fatty acid elongation steps are carried out by elongases that are encoded by the ELOVL1 and ELOVL2 genes. Specialized pro-resolving mediators (SPMs) comprise chemical mediators designated E series resolvins, derived from EPA, and D series resolvins, protectins, and maresins generated from DPA and DHA. The OM3FAs are converted to SPMs and other bioactive lipids (eicosanoids, docosanoids) by various enzymes including cyclooxygenase (COX), lipoxygenase (LOX), and cytochrome P450 (CYP). These products mediate gene expression, cell signaling, and potent anti-inflammatory effects. There are dietary sources for ALA that are plant-based (such as chia seeds, flax seeds, and walnuts), whereas EPA and DHA can be obtained from marine sources (such as oily fish).

For those with fish or seafood allergy, or who for religious or ethical reasons are vegetarian or vegan and extend this to prohibit consumption of marine-derived products, ALA may provide a suitable alternative. However, as noted in the previous text, the conversion of ALA to EPA is very inefficient with a rate of only approximately 5% to 20%, with higher, estrogen-dependent rates only among healthy younger women. Thus, ALA may not be a sufficient substitute for direct dietary sources of EPA and related long chain fatty acids. Beyond the implications for drug development, lessons learned from this study likely also apply to dietary guidance. Walnuts, flax seeds, and chia seeds are some examples of foods rich in ALA content. Nuts, such as walnuts, have been associated with cardiovascular benefits in multiple studies, and within the world of nutritional epidemiology, the results are extremely robust. Indeed, certain observations from this study by Lázaro et al.[14] could be confounded by other beneficial elements of foods that also happen to be rich in ALA and EPA.

REDUCE-IT has ushered in a new era in cardiovascular prevention, with what will likely be the first of several therapeutics.[18] Ongoing research will examine the potential of higher doses of EPA than what was used in REDUCE-IT, as well as investigation of noncardiovascular applications. We are witnessing a resurgence in OM3FA research—basic science, nutritional, epidemiology, and randomized trials. Cardiovascular benefits of other active metabolites and derivatives of EPA, and different OM3FAs such as docosapentaenoic acid and ALA, will also be explored in the years to come.[19] Although such research is ongoing, based on findings such as from Lázaro et al.,[14] it makes sense to counsel patients to increase their intake of foods rich in OM3FAs such as EPA and ALA in place of less healthy sources of calories, as well as to implement use of prescription EPA in patients who have approved indications.