Does fish oil and EPA supplementation provide cardioprotection?
The drive towards healthy aging has prompted people in incorporating fish/fish oil supplements in their diet due to its richness in omega-3 fatty acids, which is touted to have several health benefits related to depression, stroke, diabetes mellitus, cancer and Alzheimer’s disease1.
The interest of researchers grew in fish and fish oil, after a study by Bang and colleagues2 that suggested the decreased incidence of ischemic heart disease in Greenland Eskimos due to higher dietary intake of fish (rich in polyunsaturated fatty acids such as eicosapentaenoic and docosahexaenoic acids) than Danes. Since then several studies suggest a possible association between fish/fish oil intake and cardiovascular diseases prevention. In fact, in view of the rising evidence, WHO and many countries recommend dietary supplementation of omega-3 fatty acids in the form of fish or fish oil supplements3.
Marine-derived omega-3 fatty acids, such as EPA (eicosapentaenoic acid) and DHA (docosahexaenoic acid) are anti-inflammatory precursors. The potential mechanisms of omega-3 fatty acids in cardioprotection include anti-inflammation, vasodilation and improved endothelial function, stabilization of atherosclerotic plaque, hypotriglyceridemia, anti-thrombosis, anti-arrhythmia, cardiac remodeling, and improved exercise tolerance and cognitive function4. Conversely, arachidonic acid (an omega-6 fatty acid) is principally considered proinflammatory4,5.
EPA competes with AA (arachidonic acid) for cyclooxygenase and lipoxygenase enzymes, thus reducing the inflammatory effect of AA by reduced production of its highly inflammatory eicosanoids6. Therefore, the ratio of EPA to AA can be considered a measurement of chronic inflammation; the higher the ratio, the lower is the inflammation and vice versa5.
A study performed on 88 obese Japanese patients with dyslipidemia showed a positive correlation of treatment with highly purified EPA (1.8 g/day) for 3 months. The result showed an increased in EPA:AA ratio and vascular function along with a decrease in arterial stiffness and inflammation. This study highlights the cardioprotective role of EPA by statistically significant reduction in metabolic variables, such as A1C levels, total cholesterol, triglycerides, C-reactive protein and cardio-ankle vascular index (a marker for arterial stiffness), and elevation of EPA:AA ratio and adiponectin levels7.
Higher EPA:AA ratio has been associated with decreased prevalence of coronary artery disease; however, this cannot be said for DHA:AA ratio8. The Hisayama study9 is one such prospective study executed in a total of 3103 Japanese people ≥40 years of age followed through for an average of 5.1 years. In individuals with HS-CRP (high-sensitivity C-reactive protein) ≥1.0 mg/l, with every 0.20 decrement in the serum EPA:AA ratio, the risk of cardiovascular disease and coronary artery disease increased by 1.52 and 2.23 times, respectively. However, no significant association was noted for DHA:AA ratio.
Apart from coronary artery disease, EPA:AA ratio has also been associated with acute coronary syndrome, myocardial infarction, stroke, chronic heart failure, and peripheral artery and vascular disease10-14. These studies emphasize the role of EPA not only in coronary artery disease, but in overall cardioprotection.
However, there are other studies that failed to see any beneficial effect of omega-3 fatty acids in cardiovascular disease, neither in primary nor secondary prevention15,16.
Although, there have been conflicting evidence regarding the role of omega-3 fatty acid in cardioprotection, consumption of a healthy diet with serving of fatty fish (200-400 g) every week is still recommended. In individuals with insufficient intake of fish, fish oil supplements in the form of EPA and DHA (0.3-1.0g/d) is recommended3,4. Therefore, fish/fish oil supplement is not only implicated in cardioprotection, but also for health conscious individuals to reap its benefits for healthy aging.
- de Magalhães JP, Müller M, Rainger GE, Steegenga W. Fish oil supplements, longevity and aging. Aging (Albany NY). 2016;8(8):1578–1582.
- Bang HO, Dyerberg J, and Sinclair HM. The composition of the Eskimo food in north western Greenland. The American Journal of Clinical Nutrition. 1980;33(12): 2657–2661.
- Kris-Etherton PM, Harris WS, Appel LJ.Fish Consumption, Fish Oil, Omega-3 Fatty Acids, and Cardiovascular Disease. Circulation. 2002;106(21):2747–2757.
- Goel A, Pothineni NV, Singhal M, Paydak H, Saldeen T, Mehta JL. Fish, Fish Oils and Cardioprotection: Promise or Fish Tale?. Internal Journal of Molecular Sciences. 2018;19(12):3703.
- Nelson JR, Raskin S. The eicosapentaenoic acid: arachidonic acid ratio and clinical utility in cardiovascular disease. Postgraduate Medicine. 2019;131(4):268-77.
- Calder PC. N-3 polyunsaturated fatty acids, inflammation, and inflammatory diseases. The American Journal of Clinical Nutrition. 2006;83(6):1505S-1519S.
- Ito R, Satoh-Asahara N, Yamakage H, Sasaki Y, Odori S, Kono S, Wada H, Suganami T, Ogawa Y, Hasegawa K, Shimatsu A. An increase in the EPA/AA ratio is associated with improved arterial stiffness in obese patients with dyslipidemia. Journal of Atherosclerosis and Thrombosis. 2014;21(3):248-60.
- Tani S, Takahashi A, Nagao K, Hirayama A. Association of fish consumption-derived ratio of serum n-3 to n-6 polyunsaturated fatty acids and cardiovascular risk with the prevalence of coronary artery disease. International Heart Journal. 2015;56(3):260-268.
- Ninomiya T, Nagata M, Hata J, Hirakawa Y, Ozawa M, Yoshida D, Ohara T, Kishimoto H, Mukai N, Fukuhara M, Kitazono T, Kiyohara Y. Association between ratio of serum eicosapentaenoic acid to arachidonic acid and risk of cardiovascular disease: the Hisayama Study. Atherosclerosis. 2013;231(2):261-7.
- Serikawa T, Miura S, Okabe M, Hongo H, Tokutome M, Yoshikawa T, Takesue K, Adachi S, Osaka K, Matsukawa R, Yanagi D, Nozoe M, Kozai T, Hironaga K, Saku K, Yamamoto Y. Ratio of eicosapentaenoic acid to arachidonic acid is a critical risk factor for acute coronary syndrome in middle-aged older patients as well as younger adult patients. Journal of Cardiology. 2014;63(1):35–40.
- Ueeda M, Doumei T, Takaya Y, Ohnishi N, Takaishi A, Hirohata S, Miyoshi T, Shinohata R, Usui S, Kusachi S. Association of serum levels of arachidonic acid and eicosapentaenoic acid with prevalence of major adverse cardiac events after acute myocardial infarction. Heart Vessels. 2011;26(2):145–152.
- Tanaka K, Ishikawa Y, Yokoyama M, Origasa H, Matsuzaki M, Saito Y, Matsuzawa Y, Sasaki J, Oikawa S, Hishida H, Kita T, Kitabatake A, Nakaya N, Sakata T, Shimada K, Shirato K; JELIS Investigators, Japan. Reduction in the recurrence of stroke by eicosapentaenoic acid for hypercholesterolemic patients: subanalysis of the JELIS trial. Stroke. 2008;39(7):2052–2058.
- Watanabe S, Yoshihisa A, Kanno Y, Takiguchi M, Yokokawa T, Sato A, Miura S, Shimizu T, Abe S, Sato T, Suzuki S, Oikawa M, Sakamoto N, Yamaki T, Sugimoto K, Kunii H, Nakazato K, Suzuki H, Saitoh SI, Takeishi Y. Associations with eicosapentaenoic acid to arachidonic acid ration and mortality in hospitalized heart failure patients. Journal of Cardiac Failure. 2016;22(12):962–969.
- Okada K, Kotani K, Ishibashi S. Ankle-brachial index and eicosapentaenoic acid/arachidonic acid ratio in smokers with type 2 diabetes mellitus. Tobacco Induced Diseases. 2016;14:2.
- Manson JE, Cook NR, Lee IM, Christen W, Bassuk SS, Mora S, Gibson H, Albert CM, Gordon D, Copeland T, D’Agostino D, Friedenberg g, Ridge C, Bubes V, Giovannucci EL, Willett WC, Buring JE; VITAL Research Group. Marine n-3 Fatty Acids and Prevention of Cardiovascular Disease and Cancer. The New England Journal of Medicine. 2019;380(1):23-32.
- ORIGIN Trial Investigators, Bosch J, Gerstein HC, Dagenais GR, Diaz R, Dyal L, Jung H, Maggiono AP, Probstfield J, Ramachandran A, Riddle MC, Ryden LE, Yusuf S. n-3 fatty acids and cardiovascular outcomes in patients with dysglycemia. The New England Journal of Medicine. 2012;367(4):309-318.