Sheikh et al. Cardiovasc Diabetol (2019) 18:84 https://doi.org/10.1186/s12933-019-0887-0 Cardiovascular Diabetology REVIEW Open Access Cardiovascular, electrophysiologic, and hematologic efects of omega-3 fatty acids beyond reducing hypertriglyceridemia: as it pertains to the recently published REDUCE-IT trial Omar Sheikh1* , Anthony G. Vande Hei2, Ayman Battisha3, Tarek Hammad1, Son Pham1 and Robert Chilton1 Abstract Heart disease continues to afect health outcomes globally, accounting for a quarter of all deaths in the United States. Despite the improvement in the development and implementation of guideline-directed medical therapy, the risk of adverse cardiac events remains substantially high. Historically, it has been debated whether omega-3 polyunsaturated fatty acids provide clinical beneft in cardiac disease. The recently published REDUCE-IT trial demonstrated a statisti- cally signifcant absolute risk reduction of 4.8% in its primary endpoint (cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, coronary revascularization, or unstable angina) with the use of icosapent ethyl, which is a highly purifed eicosapentaenoic acid (EPA) ethyl ester. However, the mechanism of action of omega-3 fatty acids is not commonly discussed. Moreover, the use of EPA was not without risk, as the incidence of atrial fbrillation was increased along with a trend towards increased bleeding risk. Thus, our aim is to help explain the function of purifed EPA ethyl ester, especially at the molecular level, which will ultimately lead to a better understanding of their clinically observable efects. Keywords: Omega-3 polyunsaturated fatty acids, Hypertriglyceridemia, Hyperlipidemia, Diabetes mellitus Background their ability to reduce the incidence of adverse cardiovas- Te decline in coronary artery disease (CAD)-related cular events. Te Cochrane group reported similar fnd- mortality over the last four to fve decades was regarded ings, demonstrating no signifcant beneft [4]. Te lack as a major breakthrough [1]; however, multiple rebutting of evidence has led physicians away from recommend- reports from recent years that demonstrate an increasing ing omega-3 fatty acids and towards dietary modifca- trend towards higher mortality rates from CAD in speci- tions, exercise, and weight loss. By contrast, Yokoyama fed patient populations exist [2, 3]. Despite advance- et al. [5] reported that eicosapentaenoic acid (EPA) sig- ments in prevention and treatment strategies, current nifcantly reduces major adverse cardiovascular events by data illustrate that heart disease accounts for a quarter of 19% when used for secondary prevention of cardiovascu- all deaths in the United States. lar disease. Te recently published landmark REDUCE- Omega-3 fatty acids are not commonly utilized in the IT trial [6] examined the use of EPA in addition to statin clinical setting because of the lack of uniform evidence of therapy in patients with hypertriglyceridemia to further explore its role in the appropriate clinical setting. Multiple factors associated with omega-3 fatty acids *Correspondence: [email protected] 1 Cardiology Division, University Texas Health Science Center at San and inconsistent results of published studies have been Antonio, 7403 Wurzbach Road, San Antonio, TX 78229, USA reported, which include, but are not limited to, dos- Full list of author information is available at the end of the article age, preparation, studied population, clinical setting © The Author(s) 2019. This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creat iveco mmons .org/licen ses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creat iveco mmons .org/ publi cdoma in/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Sheikh et al. Cardiovasc Diabetol (2019) 18:84 Page 2 of 12 (primary vs. secondary prevention), and background Basic science of omega‑3 fatty acids therapy [7]. Furthermore, their cellular mechanism of Biochemistry action and how they produce their clinical effects are Molecular and interventional studies have demonstrated not commonly discussed. Thus, in this discussion, we the benefts of omega-3 fatty acids in the primary and aimed to review the composition of omega-3 polyun- secondary prevention of cardiovascular disease. Tese saturated fatty acids, their multiple pharmaco–physi- benefts arise from multiple, complex interactions, ologic pathways, and their resultant effects on the including infammatory mediators, lipid metabolism, cardiovascular system. alteration of cardiac ion channels, cell membrane chem- istry and physiology, down-stream cell signaling path- ways, and anti-thrombotic pathways, to name a few. To Overview of the REDUCE‑IT trial gain further understanding, it is critical to understand Utilizing 473 participating sites across a total of 11 the basic science regarding omega-3 fatty acids. countries, Bhatt et al. [6] randomized patients into Omega-6 and omega-3 fatty acids are polyunsatu- two groups: the intervention group, which received 2 g rated fatty acids (PUFA) that represent the two classes of of icosapent ethyl twice daily and the placebo group. essential fatty acids, and they must be derived from diet The inclusion criteria were as follows: patients aged as humans cannot synthesize them in sufcient quanti- ≥ 45 years with known cardiovascular disease, those ties. Te diference between them is based on the loca- aged ≥ 50 years with diabetes mellitus and at least one tion of the fatty acid’s double bond from the methyl end. additional risk factor, and those with a fasting triglyc- Omega-6 fatty acids, most notably arachidonic acid (AA), eride level of 135–499 mg/dL and a low-density lipo- have their frst double bond between the ffth and sixth protein cholesterol (LDL-C) level of 41–100 mg/dL. carbons, and omega-3 fatty acids, such as EPA and doc- However, an amendment to the inclusion criteria was osahexaenoic acid (DHA), have their frst double bond made in 2013; the lower limit of acceptable triglycer- between the third and fourth carbons. ide level increased from 135 mg/dL to 200 mg/dL. A Omega-3 fatty acids are derived from a-linoleic acid total of 8179 patients underwent randomization, and (ALA), which is found in plant oils and marine oils, and 70.7% of whom were enrolled on the basis of second- omega-6 fatty acids from linoleic acid, which is com- ary prevention. Between the two treatment arms, the monly found in vegetable oils. Once ALA is consumed, distribution of patients with diabetes was 58%, and the it is metabolized by a desaturase, elongase, and another median triglyceride level was 216 mg/dL. desaturase enzyme, which results in EPA formation. EPA Patients were followed for an average of 4.9 years; undergoes further enzymatic action and eventual peroxi- the median change in triglyceride level from baseline somal β-oxidation to yield DHA [8, 9]. Te EPA deriva- to 1 year was a decrease of 18.3% in the icosapent ethyl tive has specifcally shown promise in the REDUCE-IT group and an increase of 2.2% in the placebo group. trial. The median LDL-C level increased from baseline by Trough enzymatic conversion, PUFA could form 20 3.1% in the icosapent ethyl group and by 10.2% in the carbon atom molecules called eicosanoids (eicosa = 20). placebo group. Specifcally, eicosanoids are produced from membrane The primary endpoint of the study was a composite phospholipids by the action of phospholipases and could of cardiovascular death, nonfatal myocardial infarc- form prostaglandin(s)/thromboxane via cyclooxygenase tion (MI), nonfatal stroke, coronary revascularization, (COX1/2) and leukotrienes/lipoxins via lipoxygenase. AA or unstable angina. Secondary endpoints included (omega-6) usually produces pro-infammatory eicosa- cardiovascular death, nonfatal MI, or nonfatal stroke. noids, named two-series prostanoids (prostaglandin E2, The primary outcome of interest occurred in 17.2% of PGD2, PGI2 thromboxane A2) and four-series leukot- patients in the icosapent ethyl group and in 22.0% in rienes (LTB4, LTE4). Tese pro-infammatory mediators the placebo group (p < 0.001), with a number needed to produce a wide array of actions, such as vasodilatation, treat (NNT) of 21 over a median of 4.9 years. Second- vasoconstriction, leukocyte activation, platelet aggrega- ary endpoints were observed in 11.2% of patients in tion, and production of reactive oxygen species. PGE2 the icosapent ethyl group and in 14.8% in the placebo specifcally causes fever and increases vascular perme- group (p < 0.001). With regard to adverse events, the ability to allow for chemotaxis of leukocytes and the rate of atrial fibrillation (AF) was statistically higher formation of edema [10]. By contrast, EPA-derived in the icosapent ethyl group (5.3%) than in the placebo eicosanoids are generally anti-infammatory, includ- group (3.9%), as was peripheral edema (6.5% vs. 5.0%), ing three-series prostanoids and fve-series leukotrienes with a trend toward increased rate of serious bleeding (the series dictates where the double bond lies) [11– (2.7% vs. 2.1%; p = 0.06) in the intervention group. 13]. EPA has a variety of mechanisms to produce their Sheikh et al. Cardiovasc Diabetol (2019) 18:84 Page 3 of 12 anti-infammatory efect, including the regulation of have two structural forms: resolvin E and D. Resolvin E is transcription factors that are responsible for the infam- formed by the action of 5-lipoxygenase on EPA-derived matory cascade, such as NF-κB, which regulates the tran- mediators and inhibits neutrophil chemotaxis, specif- scription of genes for infammatory cytokines, i.e., Il-1β. cally transendothelial migration. Protectins and resolvins Moreover, EPA competes with AA for cell membrane derived from DHA both play a role in blocking t-cell and phospholipid synthesis, with preferential splitting of EPA neutrophil migration, respectively.