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CardioNerds Tommy Das (Program Director of the CardioNerds Academy and cardiology fellow at Cleveland Clinic), Rick Ferraro (Director of CardioNerds Journal Club and cardiology fellow at the Johns Hopkins Hospital), and CardioNerds Healy Honor Roll Ambassador Dr. Justice Oranefo (UConn cardiology fellow) discuss omega-3 fatty acids acid with Dr. Ty Gluckman, preventive cardiologist and medical director of the Center for Cardiovascular Analytics, Research, and Data Science (CARDS) at the Providence St. Joseph Heart Institute in Portland, Oregon. Audio editing by CardioNerds Academy Intern, Christian Faaborg-Andersen.

In the recent years, purified omega 3 fatty acids and its esters have emerged as a potential new tool in our arsenal for management of hypertriglyceridemia and atherosclerotic coronary artery disease. In this episode we review the sources and basic structure of these compounds, as well as their metabolic effects as it pertains to cardiovascular disease. Using hypothetical patient cases, we also discuss scenarios in which these therapies can be useful.

This episode is part of the CardioNerds Lipids Series which is a comprehensive series lead by co-chairs Dr. Rick Ferraro and Dr. Tommy Das and is developed in collaboration with the American Society For Preventive Cardiology (ASPC).

Relevant disclosures: None

Pearls • Notes • References • Guest Profiles • Production Team

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Pearls

1. Omega 3 (n-3) fatty acids are a class of polyunsaturated fatty acids [PUFA]. The most studied n-3 fatty acids include eicosapentaenoic acid [EPA], docosahexaenoic acid [DHA] and alpha linoleic acid [ALA]. ALA is found in certain vegetable oils while EPA and DHA are abundant in fish sources.
2. Cardiovascular benefits of n-3 fatty acids include blood pressure reduction, enhanced diastolic function, triglyceride reduction, and immunomodulatory properties.
3. Inflammation plays a major role in the atherogenic process and plaque rupture. Inflammatory marker hs-CRP is a risk enhancing factor for predicting future ASCVD risk. Ongoing trials are investigating therapy that target the inflammatory process in treatment of atherosclerotic heart disease.
4. Prevention and management of ASCVD require aggressive lifestyle modifications and medical therapy addressing risk factors and underlying inflammatory conditions.
5. Purified forms of n-3 fatty acids are approved for the treatment of severe hypertriglyceridemia and as an adjunct therapy to statins for reduction of coronary events in high-risk individuals.

Show notes

1. What are omega 3 (n-3) fatty acids? What are the natural sources of n-3 fatty acids?

• n-3 fatty acids are class of polyunsaturated fatty acids [PUFA]. PUFA are types of unsaturated fats that have more than one double bond in their backbone. PUFAs are important constituents of the phospholipids of all cell membranes.
• The most studied n-3 fatty acids include eicosapentaenoic acid [EPA], docosahexaenoic acid [DHA] and alpha linoleic acid [ALA].
• ALA is found in certain vegetable oils including walnuts, flaxseeds, chia seeds. EPA and DHA are abundant in cold water fish oils such as salmon, mackerel, tuna sardines. Interestingly, farm raised fish usually have higher levels of EPA and DHA than wild caught fish; however, this depends on what the fish are fed. Another important class of PUFAs are omega 6 (n-6) fatty acids, found in vegetable oils (1,2). 

2. What are the metabolic effects of omega 3 fatty acids?

• Multiple early studies have demonstrated the anti-inflammatory properties of n-3 fatty acids.
• The typical Western diet with a high arachidonic acid (an n-6 fatty acid) content promotes atherogenesis leading to the high incidence of CAD in this population.
• Supplementation with diets rich in DHA and EPA has been associated with reduced arachidonic acid content as well as reduced markers of inflammation. The relative dietary ratios of n-6:n-3 fatty acids have major implications for cardiovascular health.
• Anti-inflammatory mechanism of n-3 fatty acids include cell membrane stabilization, anti-oxidant properties, reduced leukocyte chemotaxis. (1-3).
• Other studied cardiovascular benefits of n-3 fatty acids include triglyceride lowering properties (11, 12), blood pressure and heart rate reduction (13, 14), improved endothelial function and antithrombotic properties (15, 16).
• Importantly, EPA and DHA are distinct molecules (different hydrocarbon length and number of double bonds) with different biologic effects. EPA assumes an extended conformation in cellular membranes, allowing it to neutralize reactive oxygen species, facilitate membrane stabilization, and limit oxidation of LDL cholesterol more easily. In contrast, DHA has a longer carbon chain and has one additional double bond, resulting in less membrane stabilization. DHA also inhibits formation of Dihomo-γ-linolenic acid (DGLA), which is important for production of anti-inflammatory eicosanoids and thus can also increase levels of LDL cholesterol.

3. What role does inflammation play in coronary artery disease?

• The impact of inflammation in the pathogenesis of atherosclerosis and plaque rupture has been well studied. Inflammatory mediators such CRP, IL-6, and myeloperoxidase have been found to be associated with increased cardiovascular risk.
• The JUPITER trial demonstrated the benefit of statin therapy in patients with elevated hsCRP. Subsequent trials targeting inflammation in the management of CAD have shown promise. Examples include the LoDoCo which investigated colchicine therapy and the CANTOS trial with investigated the IL-1 beta inhibitor canakinumab.
• The pathogenic role of inflammation and potential therapeutic role of anti-inflammatory therapy remain key areas of interest and multiple pharmacologic agents are undergoing investigation. (6, 7, 8, 17, 18).
• Check out the #CardsJC on the LoDoCo 2 trial for more on Colchicine in the management of CAD. Table 1 below summarizes notable trials of anti-inflammatory therapies for ASCVD.

4. What is the role for n-3 fatty acids in management of coronary artery disease?

• While a diet rich in n-3 fatty acids is associated with a lower risk of cardiovascular events, supplementation with over-the-counter fish oil containing supplements have not demonstrated significant cardiovascular benefits.
• Purified forms of high dose n-3 fatty acid esters consisting of EPA and/or DHA have shown mixed results as therapies for ASCVD.
• In the JELIS trial, patients with hypercholesterolemia treated with high dose icosapent ethyl (an EPA ester) in addition to pravastatin 10mg/day or simvastatin 5mg/day experienced reduced incidence of cardiac events and reduced LDL with greater benefit seen in patients with impaired glucose metabolism.
• The REDUCE-IT trial showed similar results in patients with atherosclerotic disease and high risk patients with elevated fasting triglycerides.
• Interestingly, the STRENGTH trial, in which patients were treated with combination EPA+DHA, did not show a benefit in the treatment arm.
• Icosapent ethyl is currently indicated as an adjunct therapy in addition to maximally tolerated statin therapy in patients with triglyceride levels ≥150 mg/dL and either established cardiovascular disease or type 2 diabetes mellitus plus ≥2 risk factors for cardiovascular disease to reduce incidence of cardiac events. (19 – 21).
• Check out the #CardsJC on the STRENGTH trial for an overview of relevant trial data. Table 2 below summarizes notable trials of omega-3 fatty acids for ASCVD.

5. What is the role of n-3 fatty acids in management of hypertriglyceridemia?

• In the approach to hypertriglyceridemia, be sure to identify and treat secondary causes (alcoholism, hypothyroidism, uncontrolled diabetes, etc) before instituting pharmacotherapy. Enjoy the CardioNerds “Causes of Hypertriglyceridemia” infographic developed by Dr. Teodora Donisan.
• The 2021 ACC expert consensus decision pathway on the management of ASCVD in patients with hypertriglyceridemia provides guidelines and algorithmic strategies to management of hypertriglyceridemia in several patient populations (22).
• The triglyceride reducing properties of n-3 fatty acids have been demonstrated on several trials including the EVOLVE trial (11). One should note that while several therapies reduce triglycerides, the potential benefits from n-3 fatty acids likely extend beyond triglyceride reduction.

References – Triglycerides

1. MOZAFFARIAN, D. & WU, J.H.Y., 2011. Omega-3 Fatty Acids and Cardiovascular Disease: Effects on Risk Factors, Molecular Pathways, and Clinical Events. Journal of the American College of Cardiology, 58(20), pp.2047–2067.
2. Calder, Philip C, 2010. Omega-3 fatty acids and inflammatory processes. Nutrients, 2(3), pp.355–374.
3. Raphael, William & Sordillo, Lorraine M, 2013. Dietary polyunsaturated fatty acids and inflammation: The role of phospholipid biosynthesis. International journal of molecular sciences, 14(10), pp.21167–21188.
4. Schwalfenberg, G., 2006. Omega-3 fatty acids: their beneficial role in cardiovascular health. Canadian family physician, 52(6), pp.734–740.
5. Hansson, Göran K, 2005. Mechanisms of disease: Inflammation, atherosclerosis, and coronary artery disease. The New England journal of medicine, 352(16), pp.1626–1695.
6. Ridker, Paul M et al., 2008. Rosuvastatin to Prevent Vascular Events in Men and Women with Elevated C-Reactive Protein. The New England journal of medicine, 359(21), pp.2195–2207.
7. Ridker, Paul M et al., 2017. Antiinflammatory Therapy with Canakinumab for Atherosclerotic Disease. The New England journal of medicine, 377(12), pp.1119–1131.
8. Tardif, Jean-Claude et al., 2019. Efficacy and Safety of Low-Dose Colchicine after Myocardial Infarction. The New England journal of medicine, 381(26), pp.2497–2505.
9. Xin, Wei, Wei, Wei & Li, Xiaoying, 2012. Effects of fish oil supplementation on inflammatory markers in chronic heart failure: a meta-analysis of randomized controlled trials. BMC cardiovascular disorders, 12(1), p.77.
10. Li, Kelei et al., 2014. Effect of marine-derived n-3 polyunsaturated fatty acids on C-reactive protein, interleukin 6 and tumor necrosis factor α: A meta-analysis. PloS one, 9(2), p.e88103.
11. Skulas-Ray, Ann C et al., 2019. Omega-3 Fatty Acids for the Management of Hypertriglyceridemia: A Science Advisory From the American Heart Association. Circulation (New York, N.Y.), 140(12), pp.CIR0000000000000709–e691.
12. Bhatt, Deepak L et al., 2019. Cardiovascular Risk Reduction with Icosapent Ethyl for Hypertriglyceridemia. The New England journal of medicine, 380(1), pp.11–22.
13. Geleijnse, J.M. et al., 2002. Blood pressure response to fish oil supplementation : metaregression analysis of randomized trials. Journal of hypertension, 20(8), pp.1493–1499.
14. Mozaffarian, D. et al., 2005. Effect of fish oil on heart rate in humans. A meta-analysis of randomized controlled trials. Circulation (New York, N.Y.), 112(13), pp.1945–1952.
15. Dangardt, F. et al., 2010. Omega-3 fatty acid supplementation improves vascular function and reduces inflammation in obese adolescents. Atherosclerosis, 212(2), pp.580–585.
16. Goodfellow, J. et al., 2000. Dietary supplementation with marine omega-3 fatty acids improve systemic large artery endothelial function in subjects with hypercholesterolemia. Journal of the American College of Cardiology, 35(2), pp.265–270.
17. Nidorf, S.M. et al., 2020. Colchicine in Patients with Chronic Coronary Disease. The New England journal of medicine, 383(19), pp.1838–1847.
18. Nidorf, Stefan M., MD, MBBS et al., 2013. Low-Dose Colchicine for Secondary Prevention of Cardiovascular Disease. Journal of the American College of Cardiology, 61(4), pp.404–410.
19. Yokoyama, Mitsuhiro, Dr et al., 2007. Effects of eicosapentaenoic acid on major coronary events in hypercholesterolaemic patients (JELIS): a randomised open-label, blinded endpoint analysis. The Lancet (British edition), 369(9567), pp.1090–1098.
20. Bhatt, D.L. et al., 2019. Cardiovascular Risk Reduction with Icosapent Ethyl for Hypertriglyceridemia. The New England journal of medicine, 380(1), pp.11–22.
21. Nicholls, S.J. et al., 2020. Effect of High-Dose Omega-3 Fatty Acids vs Corn Oil on Major Adverse Cardiovascular Events in Patients at High Cardiovascular Risk: The STRENGTH Randomized Clinical Trial. JAMA : the journal of the American Medical Association, 324(22), pp.2268–2280.
22. Virani, S.S. et al., 2021. 2021 ACC Expert Consensus Decision Pathway on the Management of ASCVD Risk Reduction in Patients With Persistent Hypertriglyceridemia. Journal of the American College of Cardiology, 78(9), pp.960–993.

Guest Profiles

CardioNerds Lipids Production Team