Fish, Fish Oils and Cardioprotection: Promise or Fish Tale?

Akshay Goel, Naga Venkata Pothineni, Mayank Singhal, Hakan Paydak, Tom Saldeen, Jawahar L Mehta, Akshay Goel, Naga Venkata Pothineni, Mayank Singhal, Hakan Paydak, Tom Saldeen, Jawahar L Mehta

Abstract

Fish and commercially available fish oil preparations are rich sources of long-chain omega-3 polyunsaturated fatty acids. Eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) are the most important fatty acids in fish oil. Following dietary intake, these fatty acids get incorporated into the cell membrane phospholipids throughout the body, especially in the heart and brain. They play an important role in early brain development during infancy, and have also been shown to be of benefit in dementia, depression, and other neuropsychiatric disorders. Early epidemiologic studies show an inverse relationship between fish consumption and the risk of coronary heart disease. This led to the identification of the cardioprotective role of these marine-derived fatty acids. Many experimental studies and some clinical trials have documented the benefits of fish oil supplementation in decreasing the incidence and progression of atherosclerosis, myocardial infarction, heart failure, arrhythmias, and stroke. Possible mechanisms include reduction in triglycerides, alteration in membrane fluidity, modulation of cardiac ion channels, and anti-inflammatory, anti-thrombotic, and anti-arrhythmic effects. Fish oil supplements are generally safe, and the risk of toxicity with methylmercury, an environmental toxin found in fish, is minimal. Current guidelines recommend the consumption of either one to two servings of oily fish per week or daily fish oil supplements (around 1 g of omega-3 polyunsaturated fatty acids per day) in adults. However, recent large-scale studies have failed to demonstrate any benefit of fish oil supplements on cardiovascular outcomes and mortality. Here, we review the different trials that evaluated the role of fish oil in cardiovascular diseases.

Keywords: cardiovascular disease; docosahexaenoic acid (DHA); eicosapentaenoic acid (EPA); fish oil; omega-3 fatty acids.

Conflict of interest statement

The authors declare no conflicts of interest.

Figures

Figure 1
Figure 1
Structure and metabolism of major polyunsaturated fatty acids (PUFAs).
Figure 2
Figure 2
Pleiotropic cardioprotective effects of ω-3 PUFAs.

References

    1. Bauer U.E., Briss P.A., Goodman R.A., Bowman B.A. Prevention of chronic disease in the 21st century: Elimination of the leading preventable causes of premature death and disability in the USA. Lancet. 2014;384:45–52. doi: 10.1016/S0140-6736(14)60648-6.
    1. Bang H.O., Dyerberg J., Nielsen A. Plasma lipid and lipoprotein pattern in Greenlandic West-coast Eskimos. Lancet. 1971;297:1143–1146. doi: 10.1016/S0140-6736(71)91658-8.
    1. Bang H.O., Dyerberg J., Sinclair H.M. The composition of the Eskimo food in north western Greenland. Am. J. Clin. Nutr. 1980;33:2657–2661. doi: 10.1093/ajcn/33.12.2657.
    1. Burr M.L., Gilbert J.F., Holliday R.A., Elwood P.C., Fehily A.M., Rogers S., Sweetnam P.M., Deadman N.M. Effects of changes in fat, fish, and fibre intakes on death and myocardial reinfarction: Diet and reinfarction trial (DART) Lancet. 1989;334:757–761. doi: 10.1016/S0140-6736(89)90828-3.
    1. Yang B., Saldeen T.G., Nichols W.W., Mehta J.L. Dietary fish oil supplementation attenuates myocardial dysfunction and injury caused by global ischemia and reperfusion in isolated rat hearts. J. Nutr. 1993;123:2067–2074.
    1. GISSI-Prevenzione Investigators Dietary supplementation with n-3 polyunsaturated fatty acids and vitamin E after myocardial infarction: Results of the GISSI-Prevenzione trial. Lancet. 1999;354:447–455. doi: 10.1016/S0140-6736(99)07072-5.
    1. Whelton S.P., He J., Whelton P.K., Muntner P. Meta-analysis of observational studies on fish intake and coronary heart disease. Am. J. Cardiol. 2004;93:1119–1123. doi: 10.1016/j.amjcard.2004.01.038.
    1. He K., Song Y., Daviglus M.L., Liu K., Van Horn L., Dyer A.R., Greenland P. Accumulated evidence on fish consumption and coronary heart disease mortality: A Meta-analysis of cohort studies. Circulation. 2004;109:2705–2711. doi: 10.1161/01.CIR.0000132503.19410.6B.
    1. Yokoyama M., Origasa H., Matsuzaki M., Matsuzawa Y., Saito Y., Ishikawa Y., Oikawa S., Sasaki J., Hishida H., Itakura H., et al. Effects of eicosapentaenoic acid on major coronary events in hypercholesterolaemic patients (JELIS): A randomised open-label, blinded endpoint analysis. Lancet. 2007;369:1090–1098. doi: 10.1016/S0140-6736(07)60527-3.
    1. Tavazzi L., Maggioni A.P., Marchioli R., Barlera S., Franzosi M.G., Latini R., Lucci D., Nicolosi G.L., Porcu M., Tognoni G. Effect of n-3 polyunsaturated fatty acids in patients with chronic heart failure (the GISSI-HF trial): A randomised, double-blind, placebo-controlled trial. Lancet. 2008;372:1223–1230.
    1. Kris-Etherton P.M., Harris W.S., Appel L.J. Fish consumption, fish oil, omega-3 fatty acids, and cardiovascular disease. Circulation. 2002;106:2747–2757. doi: 10.1161/01.CIR.0000038493.65177.94.
    1. Clarke T.C., Black L.I., Stussman B.J., Barnes P.M., Nahin R.L. Trends in the Use of Complementary Health Approaches among Adults: United States, 2002–2012. National Center for Health Statistics; Hyattsville, MD, USA: 2015. pp. 1–16.
    1. Rauch B., Schiele R., Schneider S., Diller F., Victor N., Gohlke H., Gottwik M., Steinbeck G., Del Castillo U., Sack R., et al. OMEGA, a randomized, placebo-controlled trial to test the effect of highly purified omega-3 fatty acids on top of modern guideline-adjusted therapy after myocardial infarction. Circulation. 2010;122:2152–2159. doi: 10.1161/CIRCULATIONAHA.110.948562.
    1. Kromhout D., Giltay E.J., Geleijnse J.M. n–3 Fatty acids and cardiovascular events after myocardial infarction. N. Engl. J. Med. 2010;363:2015–2026. doi: 10.1056/NEJMoa1003603.
    1. Galan P., Kesse-Guyot E., Czernichow S., Briancon S., Blacher J., Hercberg S. Effects of B vitamins and omega 3 fatty acids on cardiovascular diseases: A randomised placebo controlled trial. BMJ. 2010;341:c6273. doi: 10.1136/bmj.c6273.
    1. ORIGIN Trial Investigators n–3 Fatty acids and cardiovascular outcomes in patients with dysglycemia. N. Engl. J. Med. 2012;367:309–318. doi: 10.1056/NEJMoa1203859.
    1. Risk and Prevention Study Collaborative Group N–3 fatty acids in patients with multiple cardiovascular risk factors. N. Engl. J. Med. 2013;368:1800–1808. doi: 10.1056/NEJMoa1205409.
    1. Bowen K.J., Harris W.S., Kris-Etherton P.M. Omega-3 fatty acids and cardiovascular disease: Are there benefits? Curr. Treat. Opt. Cardiovasc. Med. 2016;18:69. doi: 10.1007/s11936-016-0487-1.
    1. Dennis E.A., Norris P.C. Eicosanoid storm in infection and inflammation. Nat. Rev. Immunol. 2015;15:511. doi: 10.1038/nri3859.
    1. Saini R.K., Keum Y.S. Omega-3 and omega-6 polyunsaturated fatty acids: Dietary sources, metabolism, and significance—A review. Life Sci. 2018;203:255–267. doi: 10.1016/j.lfs.2018.04.049.
    1. Dietary Guidelines Advisory Committee . Scientific Report of the 2015 Dietary Guidelines Advisory Committee. US Department of Health and Human Services; Washington, DC, USA: 2015.
    1. Burke M.F., Burke F.M., Soffer D.E. Review of cardiometabolic effects of prescription omega-3 fatty acids. Curr. Atheroscler. Rep. 2017;19:60. doi: 10.1007/s11883-017-0700-z.
    1. Kromhout D., Yasuda S., Geleijnse J.M., Shimokawa H. Fish oil and omega-3 fatty acids in cardiovascular disease: Do they really work? Eur. Heart J. 2011;33:436–443. doi: 10.1093/eurheartj/ehr362.
    1. Endo J., Arita M. Cardioprotective mechanism of omega-3 polyunsaturated fatty acids. J. Cardiol. 2016;67:22–27. doi: 10.1016/j.jjcc.2015.08.002.
    1. Yagi S., Fukuda D., Aihara K.I., Akaike M., Shimabukuro M., Sata M. N-3 polyunsaturated fatty acids: Promising nutrients for preventing cardiovascular disease. J. Atheroscler. Thromb. 2017;24:999–1010. doi: 10.5551/jat.RV17013.
    1. Calder P.C. The role of marine omega-3 (n-fatty acids in inflammatory processes, atherosclerosis and plaque stability. Mol. Nutr. Food Res. 2012;56:1073–1080. doi: 10.1002/mnfr.201100710.
    1. De Winther M.P., Kanters E., Kraal G., Hofker M.H. Nuclear factor κB signaling in atherogenesis. Arter. Thromb. Vasc. Biol. 2005;25:904–914. doi: 10.1161/01.ATV.0000160340.72641.87.
    1. Omura M., Kobayashi S., Mizukami Y., Mogami K., Todoroki-Ikeda N., Miyake T., Matsuzaki M. Eicosapentaenoic acid (EPA) induces Ca2+-independent activation and translocation of endothelial nitric oxide synthase and endothelium-dependent vasorelaxation. FEBS Lett. 2001;487:361–366. doi: 10.1016/S0014-5793(00)02351-6.
    1. Ishida T., Naoe S., Nakakuki M., Kawano H., Imada K. Eicosapentaenoic acid prevents saturated fatty acid-induced vascular endothelial dysfunction: Involvement of long-chain acyl-CoA synthetase. J. Atheroscler. Thromb. 2015;22:1172–1185. doi: 10.5551/jat.28167.
    1. Jain A.P., Aggarwal K.K., Zhang P.Y. Omega-3 fatty acids and cardiovascular disease. Eur. Rev. Med. Pharmacol. Sci. 2015;19:441–445.
    1. Haglund O., Mehta J.L., Saldeen T. Effects of fish oil on some parameters of fibrinolysis and lipoprotein(a) in healthy subjects. Am. J. Cardiol. 1994;74:189–192. doi: 10.1016/0002-9149(94)90100-7.
    1. Niki T., Wakatsuki T., Yamaguchi K., Taketani Y., Oeduka H., Kusunose K., Ise T., Iwase T., Yamada H., Soeki T., et al. Effects of the addition of eicosapentaenoic acid to strong statin therapy on inflammatory cytokines and coronary plaque components assessed by integrated backscatter intravascular ultrasound. Circ. J. 2016;80:450–460. doi: 10.1253/circj.CJ-15-0813.
    1. Thies F., Garry J.M., Yaqoob P., Rerkasem K., Williams J., Shearman C.P., Gallagher P.J., Calder P.C., Grimble R.F. Association of n-3 polyunsaturated fatty acids with stability of atherosclerotic plaques: A randomised controlled trial. Lancet. 2003;361:477–485. doi: 10.1016/S0140-6736(03)12468-3.
    1. Swann P.G., Venton D.L., Le Breton G.C. Eicosapentaenoic acid and docosahexaenoic acid are antagonists at the thromboxane A2/prostaglandin H2 receptor in human platelets. FEBS Lett. 1989;243:244–246. doi: 10.1016/0014-5793(89)80137-1.
    1. Atakisi O., Atakisi E., Ozcan A., Karapehlivan M., Kart A. Protective effect of omega-3 fatty acids on diethylnitrosamine toxicity in rats. Eur. Rev. Med. Pharmacol. Sci. 2013;17:467–471.
    1. Christensen J.H., Schmidt E.B. Autonomic nervous system, heart rate variability and n-3 fatty acids. J. Cardiovasc. Med. 2007;8:19–22. doi: 10.2459/01.JCM.0000289276.10675.a1.
    1. Yagi S., Soeki T., Aihara K.I., Fukuda D., Ise T., Kadota M., Bando S., Matsuura T., Tobiume T., Yamaguchi K., et al. Low serum levels of eicosapentaenoic acid and docosahexaenoic acid are risk factors for cardiogenic syncope in patients with Brugada syndrome. Int. Heart J. 2017;58:720–723. doi: 10.1536/ihj.16-278.
    1. Heydari B., Abdullah S., Pottala J.V., Shah R., Abbasi S., Mandry D., Francis S.A., Lumish H., Ghoshhajra B.B., Hoffmann U., et al. Effect of Omega-3 Acid Ethyl Esters on Left Ventricular Remodeling After Acute Myocardial Infarction Clinical Perspective: The OMEGA-REMODEL Randomized Clinical Trial. Circulation. 2016;134:378–391. doi: 10.1161/CIRCULATIONAHA.115.019949.
    1. Endo J., Sano M., Isobe Y., Fukuda K., Kang J.X., Arai H., Arita M. 18-HEPE, an n-3 fatty acid metabolite released by macrophages, prevents pressure overload–induced maladaptive cardiac remodeling. J. Exp. Med. 2014;211:1673–1687. doi: 10.1084/jem.20132011.
    1. Duda M.K., O’shea K.M., Stanley W.C. ω-3 polyunsaturated fatty acid supplementation for the treatment of heart failure: Mechanisms and clinical potential. Cardiovasc. Res. 2009;84:33–41. doi: 10.1093/cvr/cvp169.
    1. Da Boit M., Hunter A.M., Gray S.R. Fit with good fat? The role of n-3 polyunsaturated fatty acids on exercise performance. Metabolism. 2017;66:45–54. doi: 10.1016/j.metabol.2016.10.007.
    1. Yagi S., Akaike M., Ise T., Ueda Y., Iwase T., Sata M. Renin–angiotensin–aldosterone system has a pivotal role in cognitive impairment. Hypertens. Res. 2013;36:753. doi: 10.1038/hr.2013.51.
    1. Yagi S., Hara T., Ueno R., Aihara K.I., Fukuda D., Takashima A., Hotchi J., Ise T., Yamaguchi K., Tobiume T., et al. Serum concentration of eicosapentaenoic acid is associated with cognitive function in patients with coronary artery disease. Nutr. J. 2014;13:112. doi: 10.1186/1475-2891-13-112.
    1. Burr M.L., Ashfield-Watt P.A., Dunstan F.D., Fehily A.M., Breay P., Ashton T., Zotos P.C., Haboubi N.A., Elwood P.C. Lack of benefit of dietary advice to men with angina: Results of a controlled trial. Eur. J. Clin. Nutr. 2003;57:193. doi: 10.1038/sj.ejcn.1601539.
    1. Estruch R., Ros E., Salas-Salvadó J., Covas M.I., Corella D., Arós F., Gómez-Gracia E., Ruiz-Gutiérrez V., Fiol M., Lapetra J., et al. Primary prevention of cardiovascular disease with a Mediterranean diet. N. Engl. J. Med. 2013;368:1279–1290. doi: 10.1056/NEJMoa1200303.
    1. Bonds D.E., Harrington M., Worrall B.B., Bertoni A.G., Eaton C.B., Hsia J., Robinson J., Clemons T.E., Fine L.J., Chew E.Y. Effect of long-chain ω-3 fatty acids and lutein+ zeaxanthin supplements on cardiovascular outcomes: Results of the Age-Related Eye Disease Study 2 (AREDSrandomized clinical trial. JAMA Intern. Med. 2014;174:763–771. doi: 10.1001/jamainternmed.2014.328.
    1. Rizos E.C., Ntzani E.E., Bika E., Kostapanos M.S., Elisaf M.S. Association between omega-3 fatty acid supplementation and risk of major cardiovascular disease events: A systematic review and meta-analysis. JAMA. 2012;308:1024–1033. doi: 10.1001/2012.jama.11374.
    1. Macchia A., Grancelli H., Varini S., Nul D., Laffaye N., Mariani J., Ferrante D., Badra R., Figal J., Ramos S., et al. Omega-3 fatty acids for the prevention of recurrent symptomatic atrial fibrillation: Results of the FORWARD (Randomized Trial to Assess Efficacy of PUFA for the Maintenance of Sinus Rhythm in Persistent Atrial Fibrillation) trial. J. Am. Coll. Cardiol. 2013;61:463–468. doi: 10.1016/j.jacc.2012.11.021.
    1. Mariani J., Doval H.C., Nul D., Varini S., Grancelli H., Ferrante D., Tognoni G., Macchia A. N-3 polyunsaturated fatty acids to prevent atrial fibrillation: Updated systematic review and meta-analysis of randomized controlled trials. J. Am. Heart Assoc. 2013;2:e005033. doi: 10.1161/JAHA.112.005033.
    1. The ASCEND Study Collaborative Group Effects of n-3 fatty acid supplements in diabetes mellitus. N. Engl. J. Med. 2018;379:1540–1550. doi: 10.1056/NEJMoa1804989.
    1. A Study of AMR101 to Evaluate Its Ability to Reduce Cardiovascular Events in High Risk Patients with Hypertriglyceridemia and on Statin. [(accessed on 13 October 2018)];2016 Available online: .
    1. Manson J.E., Cook N.R., Lee I.M., Christen W., Bassuk S.S., Mora S., Gibson H., Albert C.M., Gordon D., Copeland T., et al. Marine n− 3 fatty acids and prevention of cardiovascular disease and cancer. N. Engl. J. Med. 2018 doi: 10.1056/NEJMoa1811403.
    1. US National Institutes of Health . Outcomes Study to Assess STatin Residual Risk Reduction With EpaNova in HiGh CV Risk PatienTs With Hypertriglyceridemia (STRENGTH) US National Institutes of Health; Bethesda, MD, USA: 2015.
    1. Benes L.B., Bassi N.S., Kalot M.A., Davidson M.H. Evolution of Omega-3 Fatty Acid Therapy and Current and Future Role in the Management of Dyslipidemia. Cardiol. Clin. 2018;36:277–285. doi: 10.1016/j.ccl.2017.12.009.
    1. Davidson M.H., Johnson J., Rooney M.W., Kyle M.L., Kling D.F. A novel omega-3 free fatty acid formulation has dramatically improved bioavailability during a low-fat diet compared with omega-3-acid ethyl esters: The ECLIPSE (Epanova® compared to Lovaza® in a pharmacokinetic single-dose evaluation) study. J. Clin. Lipidol. 2012;6:573–584. doi: 10.1016/j.jacl.2012.01.002.
    1. Offman E., Marenco T., Ferber S., Johnson J., Kling D., Curcio D., Davidson M. Steady-state bioavailability of prescription omega-3 on a low-fat diet is significantly improved with a free fatty acid formulation compared with an ethyl ester formulation: The ECLIPSE II study. Vasc. Health Risk Manag. 2013;9:563. doi: 10.2147/VHRM.S50464.

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