1932

Abstract

The long-chain omega-3 fatty acids, eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), are found in seafood, supplements, and concentrated pharmaceutical preparations. Prospective cohort studies demonstrate an association between higher intakes of EPA+DHA or higher levels of EPA and DHA in the body and lower risk of developing cardiovascular disease (CVD), especially coronary heart disease and myocardial infarction, and of cardiovascular mortality in the general population. The cardioprotective effect of EPA and DHA is due to the beneficial modulation of a number of risk factors for CVD. Some large trials support the use of EPA+DHA (or EPA alone) in high-risk patients, although the evidence is inconsistent. This review presents key studies of EPA and DHA in the primary and secondary prevention of CVD, briefly describes potential mechanisms of action, and discusses recently published RCTs and meta-analyses. Potential adverse aspects of long-chain omega-3 fatty acids in relation to CVD are discussed.

Loading

Article metrics loading...

/content/journals/10.1146/annurev-pharmtox-051921-090208
2023-01-20
2024-05-09
Loading full text...

Full text loading...

/deliver/fulltext/pharmtox/63/1/annurev-pharmtox-051921-090208.html?itemId=/content/journals/10.1146/annurev-pharmtox-051921-090208&mimeType=html&fmt=ahah

Literature Cited

  1. 1.
    Brenner RR. 2003. Hormonal modulation of Δ6 and Δ5 desaturases: case of diabetes. Prostaglandins Leukot. Essent. Fatty Acids 68:151–62
    [Google Scholar]
  2. 2.
    Childs CE. 2020. Sex hormones and n-3 fatty acid metabolism. Proc. Nutr. Soc. 79:219–24
    [Google Scholar]
  3. 3.
    Hernández MC, Rojas P, Carrasco F, Basfi-Fer K, Valenzuela R et al. 2020. Fatty acid desaturation in red blood cell membranes of patients with type 2 diabetes is improved by zinc supplementation. J. Trace Elements Med. Biol. 62:126571
    [Google Scholar]
  4. 4.
    Koletzko B, Reischl E, Tanjung C, Gonzalez-Casanova I, Ramakrishnan U et al. 2019. FADS1 and FADS2 polymorphisms modulate fatty acid metabolism and dietary impact on health. Annu. Rev. Nutr. 39:21–44
    [Google Scholar]
  5. 5.
    Arterburn LM, Hall EB, Oken H. 2006. Distribution, interconversion, and dose response of n−3 fatty acids in humans. Am. J. Clin. Nutr. 83:1467S–76S
    [Google Scholar]
  6. 6.
    Baker EJ, Miles EA, Burdge GC, Yaqoob P, Calder PC. 2016. Metabolism and functional effects of plant-derived omega-3 fatty acids in humans. Progress Lipid Res 64:30–56
    [Google Scholar]
  7. 7.
    Metherel AH, Irfan M, Klingel SL, Mutch DM, Bazinet RP. 2019. Compound-specific isotope analysis reveals no retroconversion of DHA to EPA but substantial conversion of EPA to DHA following supplementation: a randomized control trial. Am. J. Clin. Nutr. 110:823–31
    [Google Scholar]
  8. 8.
    Calder PC. 2018. Very long-chain n-3 fatty acids and human health: fact, fiction and the future. Proc. Nutr. Soc. 77:52–72
    [Google Scholar]
  9. 9.
    Browning LM, Walker CG, Mander AP, West AL, Madden J et al. 2012. Incorporation of eicosapentaenoic and docosahexaenoic acids into lipid pools when given as supplements providing doses equivalent to typical intakes of oily fish. Am. J. Clin. Nutr. 96:748–58
    [Google Scholar]
  10. 10.
    Stark KD, Van Elswyk ME, Higgins MR, Weatherford CA, Salem N Jr. 2016. Global survey of the omega-3 fatty acids, docosahexaenoic acid and eicosapentaenoic acid in the blood stream of healthy adults. Progress Lipid Res 63:132–52
    [Google Scholar]
  11. 11.
    Troesch B, Eggersdorfer M, Laviano A, Rolland Y, Smith AD et al. 2020. Expert opinion on benefits of long-chain omega-3 fatty acids (DHA and EPA) in aging and clinical nutrition. Nutrients 12:2555
    [Google Scholar]
  12. 12.
    Djuricic I, Calder PC. 2021. Beneficial outcomes of omega-6 and omega-3 polyunsaturated fatty acids on human health: an update for 2021. Nutrients 13:2421
    [Google Scholar]
  13. 13.
    Salem N Jr., Eggersdorfer M. 2015. Is the world supply of omega-3 fatty acids adequate for optimal human nutrition?. Curr. Opin. Clin. Nutr. Metab. Care 18:147–54
    [Google Scholar]
  14. 14.
    Ho QT, Bank MS, Azad AM, Nilsen BM, Frantzen S et al. 2021. Co-occurrence of contaminants in marine fish from the North East Atlantic Ocean: implications for human risk assessment. Environ. Int. 157:106858
    [Google Scholar]
  15. 15.
    Alfio VG, Manzo C, Micillo R. 2021. From fish waste to value: an overview of the sustainable recovery of omega-3 for food supplements. Molecules 26:1002
    [Google Scholar]
  16. 16.
    Innes JK, Calder PC. 2020. Marine omega-3 (n-3) fatty acids for cardiovascular health: an update for 2020. Int. J. Mol. Sci. 21:1362
    [Google Scholar]
  17. 17.
    Calder PC. 2004. n–3 Fatty acids and cardiovascular disease: evidence explained and mechanisms explored. Clin. Sci. 107:1–11
    [Google Scholar]
  18. 18.
    De Caterina R. 2011. n–3 Fatty acids in cardiovascular disease. N. Engl. J. Med. 364:2439–50
    [Google Scholar]
  19. 19.
    Kris-Etherton PM, Harris WS, Appel LJ. 2002. Fish consumption, fish oil, omega-3 fatty acids, and cardiovascular disease. Circulation 106:2747–57
    [Google Scholar]
  20. 20.
    Saravanan P, Davidson NC, Schmidt EB, Calder PC. 2010. Cardiovascular effects of marine omega-3 fatty acids. Lancet 376:540–50
    [Google Scholar]
  21. 21.
    London B, Albert C, Anderson ME, Giles WR, Van Wagoner DR et al. 2007. Omega-3 fatty acids and cardiac arrhythmias: prior studies and recommendations for future research: a report from the National Heart, Lung, and Blood Institute and Office of Dietary Supplements Omega-3 Fatty Acids and their Role in Cardiac Arrhythmogenesis Workshop. Circulation 116:e320–35
    [Google Scholar]
  22. 22.
    Hu FB, Bronner L, Willett WC, Stampfer MJ, Rexrode KM et al. 2002. Fish and omega-3 fatty acid intake and risk of coronary heart disease in women. JAMA 287:1815–21
    [Google Scholar]
  23. 23.
    Zhang Y, Zhuang P, He W, Chen J, Wang W et al. 2018. Association of fish and long-chain omega-3 fatty acids intakes with total and cause-specific mortality: prospective analysis of 421 309 individuals. J. Intern. Med. 284:399–417
    [Google Scholar]
  24. 24.
    Li Z-H, Zhong W-F, Liu S, Kraus VB, Zhang Y-J et al. 2020. Associations of habitual fish oil supplementation with cardiovascular outcomes and all cause mortality: evidence from a large population based cohort study. BMJ 368:m456
    [Google Scholar]
  25. 25.
    Djoussé L, Akinkuolie AO, Wu JH, Ding EL, Gaziano JM. 2012. Fish consumption, omega-3 fatty acids and risk of heart failure: a meta-analysis. Clin. Nutr. 31:846–53
    [Google Scholar]
  26. 26.
    Tavazzi L, Maggioni AP, Marchioli R, Barlera S, Franzosi MG et al. 2008. 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 372:1223–30
    [Google Scholar]
  27. 27.
    Chowdhury R, Warnakula S, Kunutsor S, Crowe F, Ward HA et al. 2014. Association of dietary, circulating, and supplement fatty acids with coronary risk: a systematic review and meta-analysis. Ann. Intern. Med. 160:398–406
    [Google Scholar]
  28. 28.
    Alexander DD, Miller PE, Van Elswyk ME, Kuratko CN, Bylsma LC. 2017. A meta-analysis of randomized controlled trials and prospective cohort studies of eicosapentaenoic and docosahexaenoic long-chain omega-3 fatty acids and coronary heart disease risk. Mayo Clin. Proc. 92:15–29
    [Google Scholar]
  29. 29.
    Del Gobbo LC, Imamura F, Aslibekyan S, Marklund M, Virtanen JK et al. 2016. ω-3 polyunsaturated fatty acid biomarkers and coronary heart disease: pooling project of 19 cohort studies. JAMA Intern. Med. 176:1155–66
    [Google Scholar]
  30. 30.
    Harris WS, Del Gobbo L, Tintle NL. 2017. The Omega-3 Index and relative risk for coronary heart disease mortality: estimation from 10 cohort studies. Atherosclerosis 262:51–54
    [Google Scholar]
  31. 31.
    Harris WS, Tintle NL, Imamura F, Qian F, Ardisson Korat AV et al. 2021. Blood n-3 fatty acid levels and total and cause-specific mortality from 17 prospective studies. Nat. Commun. 12:2329
    [Google Scholar]
  32. 32.
    Sci. Advis. Comm. Nutr., Comm. Toxic 2004. Advice on fish consumption: benefits and risks Rep., TSO London:
  33. 33.
    ISSFAL (Int. Soc. Study Fat. Acids Lipids) 2004. Recommendations for intake of polyunsaturated fatty acids in healthy adults Policy Statement, ISSFAL Washington, DC:
  34. 34.
    French Agency Food Environ. Occup. Health Saf 2003. The omega-3 fatty acids and the cardiovascular system: nutritional benefits and claims Rep., AFSSA, Maisons-Alfort, France
  35. 35.
    FAO (Food Agric. Organ. United Nations) 2010. Fat and fatty acids in human nutrition: report of an expert consultation Rep., FAO, Rome
  36. 36.
    Harris W. 2001. Omega-3 long-chain PUFA and triglyceride lowering: minimum effective intakes. Eur. Heart J. Suppl. 3:D59–61
    [Google Scholar]
  37. 37.
    Innes JK, Calder PC. 2018. The differential effects of eicosapentaenoic acid and docosahexaenoic acid on cardiometabolic risk factors: a systematic review. Int. J. Mol. Sci. 19:532
    [Google Scholar]
  38. 38.
    Allaire J, Couture P, Leclerc M, Charest A, Marin J et al. 2016. A randomized, crossover, head-to-head comparison of eicosapentaenoic acid and docosahexaenoic acid supplementation to reduce inflammation markers in men and women: the Comparing EPA to DHA (ComparED) study. Am. J. Clin. Nutr. 104:280–87
    [Google Scholar]
  39. 39.
    Woodman RJ, Mori TA, Burke V, Puddey IB, Watts GF, Beilin LJ. 2002. Effects of purified eicosapentaenoic and docosahexaenoic acids on glycemic control, blood pressure, and serum lipids in type 2 diabetic patients with treated hypertension. Am. J. Clin. Nutr. 76:1007–15
    [Google Scholar]
  40. 40.
    Mori TA, Burke V, Puddey IB, Watts GF, O'Neal DN et al. 2000. Purified eicosapentaenoic and docosahexaenoic acids have differential effects on serum lipids and lipoproteins, LDL particle size, glucose, and insulin in mildly hyperlipidemic men. Am. J. Clin. Nutr. 71:1085–94
    [Google Scholar]
  41. 41.
    Skulas-Ray AC, Wilson PW, Harris WS, Brinton EA, Kris-Etherton PM et al. 2019. Omega-3 fatty acids for the management of hypertriglyceridemia: a science advisory from the American Heart Association. Circulation 140:e673–91
    [Google Scholar]
  42. 42.
    Barter PJ, Ballantyne CM, Carmena R, Cabezas MC, Chapman MJ et al. 2006. Apo B versus cholesterol in estimating cardiovascular risk and in guiding therapy: report of the thirty-person/ten-country panel. J. Intern. Med. 259:247–58
    [Google Scholar]
  43. 43.
    Sniderman AD. 2005. Apolipoprotein B versus non-high-density lipoprotein cholesterol: and the winner is…. Circulation 112:3366–67
    [Google Scholar]
  44. 44.
    Jiang J, Li K, Wang F, Yang B, Fu Y et al. 2016. Effect of marine-derived n-3 polyunsaturated fatty acids on major eicosanoids: a systematic review and meta-analysis from 18 randomized controlled trials. PLOS ONE 11:e0147351
    [Google Scholar]
  45. 45.
    AbuMweis S, Jew S, Tayyem R, Agraib L. 2018. Eicosapentaenoic acid and docosahexaenoic acid containing supplements modulate risk factors for cardiovascular disease: a meta-analysis of randomised placebo-control human clinical trials. J. Hum. Nutr. Diet. 31:67–84
    [Google Scholar]
  46. 46.
    Li K, Huang T, Zheng J, Wu K, Li D. 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:e88103
    [Google Scholar]
  47. 47.
    Oppedisano F, Macrì R, Gliozzi M, Musolino V, Carresi C et al. 2020. The anti-inflammatory and antioxidant properties of n-3 PUFAs: their role in cardiovascular protection. Biomedicines 8:306
    [Google Scholar]
  48. 48.
    Gao L-G, Cao J, Mao Q-X, Lu X-C, X-l Zhou, Fan L 2013. Influence of omega-3 polyunsaturated fatty acid-supplementation on platelet aggregation in humans: a meta-analysis of randomized controlled trials. Atherosclerosis 226:328–34
    [Google Scholar]
  49. 49.
    Wang Q, Liang X, Wang L, Lu X, Huang J et al. 2012. Effect of omega-3 fatty acids supplementation on endothelial function: a meta-analysis of randomized controlled trials. Atherosclerosis 221:536–43
    [Google Scholar]
  50. 50.
    Xin W, Wei W, Li X 2012. Effect of fish oil supplementation on fasting vascular endothelial function in humans: a meta-analysis of randomized controlled trials. PLOS ONE 7:e46028
    [Google Scholar]
  51. 51.
    Miller PE, Van Elswyk M, Alexander DD 2014. Long-chain omega-3 fatty acids eicosapentaenoic acid and docosahexaenoic acid and blood pressure: a meta-analysis of randomized controlled trials. Am. J. Hypertens. 27:885–96
    [Google Scholar]
  52. 52.
    Hidayat K, Yang J, Zhang Z, Chen GC, Qin LQ et al. 2018. Effect of omega-3 long-chain polyunsaturated fatty acid supplementation on heart rate: a meta-analysis of randomized controlled trials. Eur. J. Clin. Nutr. 72:805–17
    [Google Scholar]
  53. 53.
    Burr ML, Gilbert J, Holliday RA, Elwood P, Fehily A et al. 1989. Effects of changes in fat, fish, and fibre intakes on death and myocardial reinfarction: diet and reinfarction trial (DART). Lancet 334:757–61
    [Google Scholar]
  54. 54.
    GISSI-Prevenzione Investig 1999. Dietary supplementation with n-3 polyunsaturated fatty acids and vitamin E after myocardial infarction: results of the GISSI-Prevenzione trial. Lancet 354:447–55
    [Google Scholar]
  55. 55.
    Marchioli R, Barzi F, Bomba E, Chieffo C, Di Gregorio D et al. 2002. Early protection against sudden death by n-3 polyunsaturated fatty acids after myocardial infarction: time-course analysis of the results of the Gruppo Italiano per lo Studio della Sopravvivenza nell'Infarto Miocardico (GISSI)-Prevenzione. Circulation 105:1897–903
    [Google Scholar]
  56. 56.
    Yokoyama M, Origasa H, Matsuzaki M, Matsuzawa Y, Saito Y et al. 2007. Effects of eicosapentaenoic acid on major coronary events in hypercholesterolaemic patients (JELIS): a randomised open-label, blinded endpoint analysis. Lancet 369:1090–98
    [Google Scholar]
  57. 57.
    Rauch B, Schiele R, Schneider S, Diller F, Victor N et al. 2010. 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 122:2152–59
    [Google Scholar]
  58. 58.
    Galan P, Kesse-Guyot E, Czernichow S, Briancon S, Blacher J, Hercberg S. 2010. Effects of B vitamins and omega 3 fatty acids on cardiovascular diseases: a randomised placebo controlled trial. BMJ 341:c6273
    [Google Scholar]
  59. 59.
    Kromhout D, Giltay EJ, Geleijnse JM. 2010. n-3 Fatty acids and cardiovascular events after myocardial infarction. N. Engl. J. Med. 363:2015–26
    [Google Scholar]
  60. 60.
    ORIGIN Trial Investig 2012. n-3 Fatty acids and cardiovascular outcomes in patients with dysglycemia. N. Engl. J. Med 367:309–18
    [Google Scholar]
  61. 61.
    Risk Prev. Study Collab. Group 2013. n-3 Fatty acids in patients with multiple cardiovascular risk factors. . N. Engl. J. Med. 368:1800–8
    [Google Scholar]
  62. 62.
    ASCEND Study Collab. Group 2018. Effects of n-3 fatty acid supplements in diabetes mellitus. N. Engl. J. Med. 379:1540–50
    [Google Scholar]
  63. 63.
    Manson JE, Cook NR, Lee I-M, Christen W, Bassuk SS et al. 2019. Marine n-3 fatty acids and prevention of cardiovascular disease and cancer. N. Engl. J. Med. 380:23–32
    [Google Scholar]
  64. 64.
    Bhatt DL, Steg PG, Miller M, Brinton EA, Jacobson TA et al. 2019. Cardiovascular risk reduction with icosapent ethyl for hypertriglyceridemia. N. Engl. J. Med. 380:11–22
    [Google Scholar]
  65. 65.
    Jo S-H, Han SH, Kim S-H, Eckel RH, Koh KK 2021. Cardiovascular effects of omega-3 fatty acids: hope or hype?. Atherosclerosis 322:15–23
    [Google Scholar]
  66. 66.
    Budoff MJ, Bhatt DL, Kinninger A, Lakshmanan S, Muhlestein JB et al. 2020. Effect of icosapent ethyl on progression of coronary atherosclerosis in patients with elevated triglycerides on statin therapy: final results of the EVAPORATE trial. Eur. Heart J. 41:3925–32
    [Google Scholar]
  67. 67.
    Nicholls SJ, Lincoff AM, Garcia M, Bash D, Ballantyne CM et al. 2020. Effect of high-dose omega-3 fatty acids versus corn oil on major adverse cardiovascular events in patients at high cardiovascular risk: the STRENGTH randomized clinical trial. JAMA 324:2268–80
    [Google Scholar]
  68. 68.
    Calder PC, Deckelbaum RJ. 2021. Omega-3 fatty acids: new studies, new data, new questions. Curr. Opin. Clin. Nutr. Metab. Care 24:109–13
    [Google Scholar]
  69. 69.
    Kalstad AA, Myhre PL, Laake K, Tveit SH, Schmidt EB et al. 2021. Effects of n-3 fatty acid supplements in elderly patients after myocardial infarction: a randomized, controlled trial. Circulation 143:528–39
    [Google Scholar]
  70. 70.
    Bucher HC, Hengstler P, Schindler C, Meier G. 2002. n-3 Polyunsaturated fatty acids in coronary heart disease: a meta-analysis of randomized controlled trials. Am. J. Med. 112:298–304
    [Google Scholar]
  71. 71.
    Studer M, Briel M, Leimenstoll B, Glass TR, Bucher HC. 2005. Effect of different antilipidemic agents and diets on mortality: a systematic review. Arch. Intern. Med. 165:725–30
    [Google Scholar]
  72. 72.
    Zhao Y-T, Chen Q, Sun Y-X, Li X-B, Zhang P et al. 2009. Prevention of sudden cardiac death with omega-3 fatty acids in patients with coronary heart disease: a meta-analysis of randomized controlled trials. Ann. Med. 41:301–10
    [Google Scholar]
  73. 73.
    Marik PE, Varon J. 2009. Omega-3 dietary supplements and the risk of cardiovascular events: a systematic review. Clin. Cardiol. 32:365–72
    [Google Scholar]
  74. 74.
    Kotwal S, Jun M, Sullivan D, Perkovic V, Neal B. 2012. Omega 3 fatty acids and cardiovascular outcomes: systematic review and meta-analysis. Circ. Cardiovasc. Q. Outcomes 5:808–18
    [Google Scholar]
  75. 75.
    Abdelhamid AS, Brown TJ, Brainard JS, Biswas P, Thorpe GC et al. 2018. Omega-3 fatty acids for the primary and secondary prevention of cardiovascular disease. Cochrane Database Syst. Rev. 11:CD003177
    [Google Scholar]
  76. 76.
    Bernasconi AA, Wiest MM, Lavie CJ, Milani RV, Laukkanen JA. 2021. Effect of omega-3 dosage on cardiovascular outcomes: an updated meta-analysis and meta-regression of interventional trials. Mayo Clin. Proc. 96:304–13
    [Google Scholar]
  77. 77.
    Hu Y, Hu FB, Manson JE. 2019. Marine omega-3 supplementation and cardiovascular disease: an updated meta-analysis of 13 randomized controlled trials involving 127 477 participants. J. Am. Heart Assoc. 8:e013543
    [Google Scholar]
  78. 78.
    Rizos EC, Markozannes G, Tsapas A, Mantzoros CS, Ntzani EE. 2021. Omega-3 supplementation and cardiovascular disease: formulation-based systematic review and meta-analysis with trial sequential analysis. Heart 107:150–58
    [Google Scholar]
  79. 79.
    Mach F, Baigent C, Catapano AL, Koskinas KC, Casula M et al. 2020. 2019 ESC/EAS guidelines for the management of dyslipidaemias: lipid modification to reduce cardiovascular risk. Eur. Heart J. 41:111–88
    [Google Scholar]
  80. 80.
    American Diabetes Association 2020. 10. Cardiovascular disease and risk management: Standards of Medical Care in Diabetes—2020. Diabetes Care 43:Suppl. 1S111–34
    [Google Scholar]
  81. 81.
    Orringer CE, Jacobson TA, Maki KC. 2019. National Lipid Association scientific statement on the use of icosapent ethyl in statin-treated patients with elevated triglycerides and high or very-high ASCVD risk. J. Clin. Lipidol. 13:860–72
    [Google Scholar]
  82. 82.
    Siscovick DS, Barringer TA, Fretts AM, Wu JH, Lichtenstein AH et al. 2017. Omega-3 polyunsaturated fatty acid (fish oil) supplementation and the prevention of clinical cardiovascular disease: a science advisory from the American Heart Association. Circulation 135:e867–84
    [Google Scholar]
  83. 83.
    Jairoun AA, Shahwan M, Zyoud SH. 2020. Fish oil supplements, oxidative status, and compliance behaviour: regulatory challenges and opportunities. PLOS ONE 15:e0244688
    [Google Scholar]
  84. 84.
    Albert BB, Cameron-Smith D, Hofman PL, Cutfield WS. 2013. Oxidation of marine omega-3 supplements and human health. BioMed. Res. Int. 2013.464921
    [Google Scholar]
  85. 85.
    Shahidi F, Zhong Y. 2010. Lipid oxidation and improving the oxidative stability. Chem. Soc. Rev. 39:4067–79
    [Google Scholar]
  86. 86.
    GOED (Glob. Organ. EPA DHA Omega-3) 2019. GOED voluntary monograph, version 7 GOED, Salt Lake City, UT
  87. 87.
    EFSA Panel Biol. Hazards (BIOHAZ) 2010. Scientific opinion on fish oil for human consumption. Food hygiene, including rancidity. EFSA J 8:1874
    [Google Scholar]
  88. 88.
    Ottestad I, Vogt G, Retterstøl K, Myhrstad MC, Haugen J-E et al. 2012. Oxidised fish oil does not influence established markers of oxidative stress in healthy human subjects: a randomised controlled trial. Br. J. Nutr. 108:315–26
    [Google Scholar]
  89. 89.
    Goodnight SJ, Harris WS, Connor WE. 1981. The effects of dietary omega 3 fatty acids on platelet composition and function in man: a prospective, controlled study. Blood 58:880–85
    [Google Scholar]
  90. 90.
    Von Schacky C, Fischer S, Weber PC. 1985. Long-term effects of dietary marine omega-3 fatty acids upon plasma and cellular lipids, platelet function, and eicosanoid formation in humans. J. Clin. Investig. 76:1626–31
    [Google Scholar]
  91. 91.
    DiNicolantonio JJ, OKeefe J. 2019. Importance of maintaining a low omega-6/omega-3 ratio for reducing platelet aggregation, coagulation and thrombosis. Open Heart 6:e001011
    [Google Scholar]
  92. 92.
    Woodman RJ, Mori TA, Burke V, Puddey IB, Barden A et al. 2003. Effects of purified eicosapentaenoic acid and docosahexaenoic acid on platelet, fibrinolytic and vascular function in hypertensive type 2 diabetic patients. Atherosclerosis 166:85–93
    [Google Scholar]
  93. 93.
    Din JN, Harding SA, Valerio CJ, Sarma J, Lyall K et al. 2008. Dietary intervention with oil rich fish reduces platelet-monocyte aggregation in man. Atherosclerosis 197:290–96
    [Google Scholar]
  94. 94.
    Harris WS. 2007. Expert opinion: omega-3 fatty acids and bleeding—cause for concern?. Am. J. Cardiol. 99:S44–46
    [Google Scholar]
  95. 95.
    Akintoye E, Sethi P, Harris WS, Thompson PA, Marchioli R et al. 2018. Fish oil and perioperative bleeding: insights from the OPERA randomized trial. Circ. Cardiovasc. Q. Outcomes 11:e004584
    [Google Scholar]
  96. 96.
    Kapoor K, Alfaddagh A, Al Rifai M, Bhatt DL, Budoff MJ et al. 2021. Association between omega-3 fatty acid levels and risk for incident major bleeding events and atrial fibrillation: MESA. J. Am. Heart Assoc. 10:e021431
    [Google Scholar]
  97. 97.
    Jeansen S, Witkamp RF, Garthoff JA, van Helvoort A, Calder PC. 2018. Fish oil LC-PUFAs do not affect blood coagulation parameters and bleeding manifestations: analysis of 8 clinical studies with selected patient groups on omega-3-enriched medical nutrition. Clin. Nutr. 37:948–57
    [Google Scholar]
  98. 98.
    Fradet S, Pelletier JF, Singbo N, Lacombe L, Toren P et al. 2022. Effects of omega-3 fatty acids supplementation on perioperative blood loss and complications after radical prostatectomy. Clin. Nutr. ESPEN 47:221–26
    [Google Scholar]
  99. 99.
    Curfman G. 2021. Omega-3 fatty acids and atrial fibrillation. JAMA 325:1063
    [Google Scholar]
  100. 100.
    Albert CM, Cook NR, Pester J, Moorthy MV, Ridge C et al. 2021. Effect of marine omega-3 fatty acid and vitamin D supplementation on incident atrial fibrillation: a randomized clinical trial. JAMA 325:1061–73
    [Google Scholar]
  101. 101.
    Lombardi M, Carbone S, Del Buono MG, Chiabrando JG, Vescovo GM et al. 2021. Omega-3 fatty acids supplementation and risk of atrial fibrillation: an updated meta-analysis of randomized controlled trials. Eur. Heart J. Cardiovasc. Pharmacother. 7:e69–70
    [Google Scholar]
  102. 102.
    Gencer B, Djousse L, Al-Ramady OT, Cook NR, Manson JE, Albert CM. 2021. Effect of long-term marine ɷ-3 fatty acids supplementation on the risk of atrial fibrillation in randomized controlled trials of cardiovascular outcomes: a systematic review and meta-analysis. Circulation 144:1981–90
    [Google Scholar]
  103. 103.
    Fatkin D, Cox CD, Martinac B. 2022. Fishing for links between omega-3 fatty acids and atrial fibrillation. Circulation 145:1037–39
    [Google Scholar]
  104. 104.
    Schuchardt JP, Hahn A. 2013. Bioavailability of long-chain omega-3 fatty acids. Prostaglandins Leukot. Essent. Fatty Acids 89:1–8
    [Google Scholar]
/content/journals/10.1146/annurev-pharmtox-051921-090208
Loading
/content/journals/10.1146/annurev-pharmtox-051921-090208
Loading

Data & Media loading...

  • Article Type: Review Article
This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error