Вклад жирных кислот в развитие сердечно-сосудистых заболеваний

Нарушение обмена жирных кислот (ЖК) может являться значимым фактором, потенциирующим развитие и прогрессирование атеросклероза и связанных с ним сердечно-сосудистых заболеваний (ССЗ). Тем не менее большинство исследований сосредоточены на изучении влияния классификационных групп ЖК. Поэтому цель настоящей лекции – представить как про-, так и антиатерогенные функции каждой жирной кислоты.
В настоящей работе рассмотрены современные сведения о влиянии насыщенных (миристиновой (С 14:0), пальмитиновой (С 16:0), стеариновой (С 18:0)), мононенасыщенных (пальмитолеиновой (С 16:1), олеиновой (С 18:1)) и полиненасыщенных (линолевой (С 18:2, омега-6), альфа-линоленовой (С 18:3, омега-3), дигомо-гамма-линоленовой (С 20:3, омега-6), арахидоновой (С 20:4, омега-6), эйкозапентаеновой (С 20:5, омега-3), докозагексаеновой (С 22:6, омега-3)) жирных кислот на ССЗ. Накопленные данные расширяют представления о роли ЖК в метаболических процессах, что позволит перейти от фундаментальнопоисковых работ к практическим аспектам применения данных веществ в лечении ССЗ. В перспективе эти результаты могут быть использованы при интерпретации и прогнозировании изменений метаболических нарушений липидов при ССЗ.

1. Бойцов С.А., Драпкина О.М., Шляхто Е.В., Конради А.О., Баланова Ю.А., Жернакова Ю.В. и др. Исследование ЭССЕ-РФ (Эпидемиология сердечно-сосудистых заболеваний и их факторов риска в регионах Российской Федерации). Десять лет спустя. Кардиоваскулярная терапия и профилактика. 2021;20(5):3007. DOI: 10.15829/1728-8800-2021-3007.

2. Латфуллин И.А. Ишемическая болезнь сердца: основные факторы риска, лечение. Казань: Казанский (Приволжский) федеральный университет, 2017:426.

3. Бадейникова К.К., Мамедов М.Н. Ранние маркеры атеросклероза: предикторы развития сердечно-сосудистых осложнений. Профилактическая медицина. 2023;26(1):103–108. DOI: 10.17116/profmed202326011103.

4. Сергиенко И.В., Аншелес А.А. Патогенез, диагностика и лечение атеросклероза: практические аспекты. Кардиологический вестник. 2021;16(1):64–72. DOI: 10.17116/Cardiobulletin20211601164.

5. The top-10 causes of death in the world (fact sheet). World Health Organization., 2020. https://www.who.int/ru/newsroom/fact-sheets/detail/the-top-10-causes-of-death

6. Kotlyarov S., Kotlyarova A. Involvement of Fatty Acids and Their Metabolites in the Development of Inflammation in Atherosclerosis. Int. J. Mol. Sci. 2022;23(3):1308. DOI: 10.3390/ijms23031308.

7. Chen X., Liu L., Palacios G., Gao J., Zhang N., Li G. et al. Plasma metabolomics reveals biomarkers of the atherosclerosis. J. Sep. Sci. 2010;33(17-18):2776–2783. DOI: 10.1002/jssc.201000395.

8. Kotlyarov S., Kotlyarova A. Clinical significance of polyunsaturated fatty acids in the prevention of cardiovascular diseases. Front. Nutr. 2022;9:998291. DOI: 10.3389/fnut.2022.998291.

9. Ghosh A., Gao L., Thakur A., Siu P.M., Lai C.W.K. Role of free fatty acids in endothelial dysfunction. J. Biomed. Sci. 2017;24(1):50. DOI: 10.1186/s12929-017-0357-5.

10. Зотов В.А., Бессонов В.В., Рисник Д.В. Методические аспекты исследования жирных кислот в биологических образцах. Прикладная биохимия и микробиология. 2022;58(1):90–104. DOI: 10.31857/S0555109922010111.

11. Гизингер О. А. Роль короко- и среднецепочечных жирных кислот в реакциях гомеостатического регулирования. Терапевт. 2021;9:45–51. DOI: 10.33920/MED-12-2109-05.

12. Sacks F.M., Lichtenstein A.H., Wu J.H.Y., Appel L.J., Creager M.A., Kris-Etherton P.M. et al. Dietary fats and cardiovascular disease: a presidential advisory from the American Heart Association. Circulation. 2017;136(3):e1–e23. DOI: 10.1161/CIR.0000000000000510.

13. Annevelink C.E., Sapp P.A., Petersen K.S., Shearer G.C., Kris-Etherton P.M. Diet-derived and diet-related endogenously produced palmitic acid: Effects on metabolic regulation and cardiovascular disease risk. J. Clin. Lipidol. 2023;17(5):577–586. DOI: 10.1016/j.jacl.2023.07.005.

14. Carta G., Murru E., Banni S., Manca C. Palmitic acid: physiological role, metabolism and nutritional implications. Front. Physiol. 2017;8:902. DOI: 10.3389/fphys.2017.00902.

15. Fatima S., Hu X., Gong R.H., Huang C., Chen M., Wong H.L.X. et al. Palmitic acid is an intracellular signaling molecule involved in disease development. Cell Mol. Life Sci. 2019;76(13):2547–2557. DOI: 10.1007/s00018-019-03092-7.

16. Innis S.M. Fatty acids and early human development. Early Hum. Dev. 2007;83(12):761–766. DOI: 10.1016/j.earlhumdev.2007.09.004.

17. Титов В.Н., Ариповский А.В., Каба С.И., Колесник П.О., Веждел М.И., Ширяева Ю.К. Индивидуальные жирные кислоты в плазме крови, эритроцитах и липопротеинах. Сравнение результатов больных ишемической болезнью сердца и добровольцев. Клиническая лабораторная диагностика. 2012;7:3–8.

18. Domínguez-López I., Arancibia-Riveros C., Casas R., Tresserra-Rimbau A., Razquin C., Martínez-González M.Á. et al. Changes in plasma total saturated fatty acids and palmitic acid are related to pro-inflammatory molecule IL-6 concentrations after nutritional intervention for one year. Biomed. Pharmacother. 2022;150:113028. DOI: 10.1016/j.biopha.2022.113028.

19. Kleber M.E., Delgado G.E., Dawczynski C., Lorkowski S., März W, von Schacky C. Saturated fatty acids and mortality in patients referred for coronary angiography-The Ludwigshafen Risk and Cardiovascular Health study. J. Clin. Lipidol. 2018;12(2):455–463.e3. DOI: 10.1016/j.jacl.2018.01.007.

20. Lee Y., Lai H.T.M., de Oliveira Otto M.C., Lemaitre R.N., McKnight B., King I.B. et al. Serial Biomarkers of De Novo Lipogenesis Fatty Acids and Incident Heart Failure in Older Adults: The Cardiovascular Health Study. J. Am. Heart Assoc. 2020;9(4):e014119. DOI: 10.1161/JAHA.119.014119.

21. Chei C.L., Yamagishi K., Kitamura A., Kiyama M., Sankai T., Okada T. et al. Serum Fatty Acid and Risk of Coronary Artery Disease - Circulatory Risk in Communities Study (CIRCS). Circ. J. 2018;82(12):3013–3020. DOI: 10.1253/circj.CJ-18-0240.

22. Mensink R.P. Effects of saturated fatty acids on serum lipids and lipoproteins: a systematic review and regression analysis. Geneva: World Health Organization, 2016:72.

23. Praagman J., de Jonge E.A., Kiefte-de Jong J.C.,Beulens J.W., Sluijs I., Schoufour J.D. et al. Dietary saturated fatty acids and coronary heart disease risk in a dutch middle-aged and elderly population. Arterioscler. Thromb. Vasc. Biol. 2016;36(9):2011–2018. DOI: 10.1161/ATVBAHA.116.307578.

24. Zong G., Li Y., Wanders A.J., Alssema M., Zock P.L., Willett W.C. et al. Intake of individual saturated fatty acids and risk of coronary heart disease in US men and women: two prospective longitudinal cohort studies. BMJ. 2016;355:i5796. DOI: 10.1136/bmj.i5796.

25. Yuan S., Bäck M., Bruzelius M., Mason A.M., Burgess S., Larsson S. Plasma Phospholipid Fatty Acids, FADS1 and Risk of 15 Cardiovascular Diseases: A Mendelian Randomisation Study. Nutrients. 2019;11(12):3001. DOI: 10.3390/nu11123001.

26. Khaw K.T., Friesen M.D., Riboli E., Luben R., Wareham N. Plasma phospholipid fatty acid concentration and incident coronary heart disease in men and women: the EPIC-Norfolk prospective study. PLoS Med. 2012;9(7):e1001255. DOI: 10.1371/journal.pmed.1001255.

27. Lai H.T.M., de Oliveira Otto M.C., Lee Y., Wu J.H.Y., Song X., King I.B. et al. Serial Plasma Phospholipid Fatty Acids in the De Novo Lipogenesis Pathway and Total Mortality, Cause-Specific Mortality, and Cardiovascular Diseases in the Cardiovascular Health Study. J. Am. Heart Assoc. 2019;8(22):e012881. DOI: 10.1161/JAHA.119.012881.

28. Van Rooijen M.A., Plat J., Blom W.A.M., Zock P.L., Mensink R.P. Dietary stearic acid and palmitic acid do not differently affect ABCA1-mediated cholesterol efflux capacity in healthy men and postmenopausal women: A randomized controlled trial. Clin. Nutr. 2021;40(3):804-811. DOI: 10.1016/j.clnu.2020.08.016.

29. Praagman J., Beulens J.W., Alssema M., Zock P.L., Wanders A.J., Sluijs I. et al. The association between dietary saturated fatty acids and ischemic heart disease depends on the type and source of fatty acid in the European Prospective Investigation into Cancer and Nutrition-Netherlands cohort. Am. J. Clin. Nutr. 2016;103(2):356–365. DOI: 10.3945/ajcn.115.122671.

30. Zazula R., Moravec M., Pehal F., Nejtek T., Protuš M., Müller M. Myristic acid serum levels and their significance for diagnosis of systemic inflammatory response, sepsis, and bacteraemia. J. Pers. Med. 2021;11(4):306. DOI: 10.3390/jpm11040306.

31. Rioux V., Catheline D., Legrand P. In rat hepatocytes, myristic acid occurs through lipogenesis, palmitic acid shortening and lauric acid elongation. Animal. 2007;1(6):820–826. DOI: 10.1017/S1751731107000122.

32. Noto D., Fayer F., Cefalù A.B., Altieri I., Palesano O., Spina R. et al. Myristic acid is associated to low plasma HDL cholesterol levels in a Mediterranean population and increases HDL catabolism by enhancing HDL particles trapping to cell surface proteoglycans in a liver hepatoma cell model. Atherosclerosis. 2016;246:50–56. DOI: 10.1016/j.atherosclerosis.2015.12.036.

33. Ebbesson S.O., Voruganti V.S., Higgins P.B., Fabsitz R.R., Ebbesson L.O., Laston S. et al. Fatty acids linked to cardiovascular mortality are associated with risk factors. Int. J. Circumpolar. Health. 2015;74:28055. DOI: 10.3402/ijch.v74.28055.

34. Hooper L., Martin N., Jimoh O.F., Kirk C., Foster E., Abdelhamid A.S. Reduction in saturated fat intake for cardiovascular disease. Cochrane Database Syst. Rev. 2020;8(8):CD011737. DOI: 10.1002/14651858.CD011737.pub3.

35. Legrand-Poels S., Esser N., L’homme L., Scheen A., Paquot N., Piette J. Free fatty acids as modulators of the NLRP3 inflammasome in obesity/type 2 diabetes. Biochem. Pharmacol. 2014;92(1):131–141. DOI: 10.1016/j.bcp.2014.08.013.

36. Frigolet M.E., Gutiérrez-Aguilar R. The role of the novel lipokine palmitoleic acid in health and disease. Adv. Nutr. 2017;8(1):173S–181S. DOI: 10.3945/an.115.011130.

37. Rocha D.M., Bressan J., Hermsdorff H.H. The role of dietary fatty acid intake in inflammatory gene expression: a critical review. Sao Paulo Med. J. 2017;135(2):157–168. DOI: 10.1590/1516-3180.2016.008607072016.

38. Takenouchi Y., Seki Y., Shiba S., Ohtake K., Nobe K., Kasono K. Effects of dietary palmitoleic acid on vascular function in aorta of diabetic mice. BMC Endocr. Disord. 2022;22(1):103. DOI: 10.1186/s12902-022-01018-2.

39. Cao H., Gerhold K., Mayers J.R., Wiest M.M., Watkins S.M., Hotamisligil G.S. Identification of a lipokine, a lipid hormone linking adipose tissue to systemic metabolism. Cell. 2008;134(6):933–944. DOI: 10.1016/j.cell.2008.07.048.

40. Guo X., Li H., Xu H., Halim V., Zhang W., Wang H. et al. Palmitoleate induces hepatic steatosis but suppresses liver inflammatory response in mice. PLoS One. 2012;7(6):e39286. DOI: 10.1371/journal.pone.0039286.

41. Mozaffarian D., de Oliveira Otto M.C., Lemaitre R.N., Fretts A.M., Hotamisligil G., Tsai M.Y. et al. trans-Palmitoleic acid, other dairy fat biomarkers, and incident diabetes: the Multi-Ethnic Study of Atherosclerosis (MESA). Am. J. Clin. Nutr. 2013;97(4):854–861. DOI: 10.3945/ajcn.112.045468.

42. Luan D., Wang D., Campos H., Baylin A. Adipose tissue palmitoleic acid is inversely associated with nonfatal acute myocardial infarction in Costa Rican adults. Nutr. Metab. Cardiovasc. Dis. 2018;28(10):973–979. DOI: 10.1016/j.numecd.2018.05.004.

43. De Souza C.O., Vannice G.K., Rosa Neto J.C., Calder P.C. Is palmitoleic acid a plausible nonpharmacological strategy to prevent or control chronic metabolic and inflammatory disorders? Mol. Nutr. Food Res. 2018;62(1). DOI: 10.1002/mnfr.201700504.

44. Chan K.L., Pillon N.J., Sivaloganathan D.M., Costford S.R., Liu Z., Théret M. et al. Palmitoleate reverses high fat-induced proinflammatory macrophage polarization via AMP-activated protein kinase (AMPK). J. Biol. Chem. 2015;290(27):16979–16988. DOI: 10.1074/jbc.M115.646992.

45. Souza C.O., Teixeira A.A., Biondo L.A., Silveira L.S., Calder P.C., Rosa Neto J.C. Palmitoleic acid reduces the inflammation in LPS-stimulated macrophages by inhibition of NFκB, independently of PPARs. Clin. Exp. Pharmacol. Physiol. 2017;44(5):566–575. DOI: 10.1111/1440-1681.

46. Guasch-Ferré M., Hu F.B., Martínez-González M.A., Fitó M., Bulló M., Estruch R. et al. Olive oil intake and risk of cardiovascular disease and mortality in the PREDIMED Study. BMC Med. 2014;12:78. DOI: 10.1186/1741-7015-12-78.

47. Steffen B.T., Duprez D., Szklo M., Guan W., Tsai M.Y. Circulating oleic acid levels are related to greater risks of cardiovascular events and all-cause mortality: The Multi-Ethnic Study of Atherosclerosis. J. Clin. Lipidol. 2018;12(6):1404–1412. DOI: 10.1016/j.jacl.2018.08.004.

48. Bock M., von Schacky C., Scherr J., Lorenz E., Lechner B., Krannich A. et al. De novo lipogenesis-related monounsaturated fatty acids in the blood are associated with cardiovascular risk factors in HFpEF patients. J. Clin. Med. 2023;12(15):4938. DOI: 10.3390/jcm12154938.

49. Würtz P., Havulinna A.S., Soininen P., Tynkkynen T., Prieto-Merino D., Tillin T. et al. Metabolite profiling and cardiovascular event risk: a prospective study of 3 population-based cohorts. Circulation. 2015;131(9):774–785. DOI: 10.1161/CIRCULATIONAHA.114.013116.

50. Lin Y.T., Salihovic S., Fall T., Hammar U., Ingelsson E., Ärnlöv J. et al. Global plasma metabolomics to identify potential biomarkers of blood pressure progression. Arterioscler. Thromb. Vasc. Biol. 2020;40(8):e227–e237. DOI: 10.1161/ATVBAHA.120.314356.

51. Mika A., Sikorska-Wiśniewska M., Małgorzewicz S., Stepnowski P., Dębska-Ślizień A., Śledziński T. et al. Potential contribution of monounsaturated fatty acids to cardiovascular risk in chronic kidney disease. Pol. Arch. Intern. Med. 2018;128(12):755–763. DOI: 10.20452/pamw.4376.

52. Lands B. A critique of paradoxes in current advice on dietary lipids. Prog. Lipid. Res. 2008;47(2):77–106. DOI: 10.1016/j.plipres.2007.12.001.

53. Alvheim A.R., Malde M.K., Osei-Hyiaman D., Lin Y.H., Pawlosky R.J., Madsen L. et al. Dietary linoleic acid elevates endogenous 2-AG and anandamide and induces obesity. Obesity (Silver Spring). 2012;20(10):1984–1894. DOI:10.1038/oby.2012.38.

54. Maroon J.C., Bost J.W. Omega-3 fatty acids (fish oil) as an anti-inflammatory: an alternative to nonsteroidal anti-inflammatory drugs for discogenic pain. Surg. Neurol. 2006;65(4):326–331. DOI: 10.1016/j.surneu.2005.10.023.

55. Garg P.K., Guan W., Nomura S., Weir N., Karger A.B., Duprez D. et al. Plasma ω-3 and ω-6 PUFA Concentrations and Risk of Atrial Fibrillation: The Multi-Ethnic Study of Atherosclerosis. J. Nutr. 2021;151(6):1479–1486. DOI: 10.1093/jn/nxab016.

56. Marklund M., Wu J.H.Y., Imamura F., Del Gobbo L.C., Fretts A., de Goede J. et al. Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Fatty Acids and Outcomes Research Consortium (FORCE). Biomarkers of dietary omega-6 fatty acids and incident cardiovascular disease and mortality. Circulation. 2019;139(21):2422–2436. DOI: 10.1161/CIRCULATIONAHA.118.038908.

57. Das U.N. Essential fatty acids and their metabolites could function as endogenous HMG-CoA reductase and ACE enzyme inhibitors, anti-arrhythmic, anti-hypertensive, anti-atherosclerotic, anti-inflammatory, cytoprotective, and cardioprotective molecules. Lipids Health Dis. 2008;7:37. DOI: 10.1186/1476-511X-7-37.

58. Edel A.L., Patenaude A.F., Richard M.N., Dibrov E., Austria J.A., Aukema H.M. et al. The effect of flaxseed dose on circulating concentrations of alpha-linolenic acid and secoisolariciresinol diglucoside derived enterolignans in young, healthy adults. Eur. J. Nutr. 2016;55(2):651–663. DOI: 10.1007/s00394-015-0885-2.

59. Abdelhamid A.S., Brown T.J., Brainard J.S., Biswas P., Thorpe G.C., Moore H.J. et al. Omega-3 fatty acids for the primary and secondary prevention of cardiovascular disease. Cochrane Database Syst. Rev. 2018;11(11):CD003177. DOI: 10.1002/14651858.CD003177.pub4.

60. Yue H., Qiu B., Jia M., Liu W., Guo X.F., Li N. et al. Effects of α-linolenic acid intake on blood lipid profiles: a systematic review and meta-analysis of randomized controlled trials. Crit. Rev. Food Sci. Nutr. 2021;61(17):2894–2910. DOI: 10.1080/10408398.2020.1790496.

61. Pan A., Chen M., Chowdhury R., Wu J.H., Sun Q., Campos H. et al. α-Linolenic acid and risk of cardiovascular disease: a systematic review and meta-analysis. Am. J. Clin. Nutr. 2012;96(6):1262–1273. DOI: 10.3945/ajcn.112.044040.

62. Sala-Vila A., Guasch-Ferré M., Hu F.B., Sánchez-Tainta A., Bulló M., Serra-Mir M. et al. Dietary α-Linolenic Acid, Marine ω-3 Fatty Acids, and Mortality in a Population With High Fish Consumption: Findings From the PREvención con DIeta MEDiterránea (PREDIMED) Study. J. Am. Heart Assoc. 2016;5(1):e002543. DOI: 10.1161/JAHA.115.002543.

63. Kromhout D., Giltay E.J., Geleijnse J.M.; Alpha Omega Trial Group. n-3 fatty acids and cardiovascular events after myocardial infarction. N. Engl. J. Med. 2010;363(21):2015–2026. DOI: 10.1056/NEJMoa1003603.

64. Zelniker T.A., Morrow D.A., Scirica B.M., Furtado J.D., Guo J., Mozaffarian D. et al. Plasma omega-3 fatty acids and the risk of cardiovasculareEvents in patients after an acute coronary syndrome in MERLIN-TIMI 36. J. Am. Heart Assoc.2021;10(8):e017401. DOI: 10.1161/JAHA.120.017401.

65. Winnik S., Lohmann C., Richter E.K., Schäfer N., Song W.L., Leiber F. et al. Dietary α-linolenic acid diminishes experimental atherogenesis and restricts T cell-driven inflammation. Eur. Heart J. 2011;32(20):2573–2584. DOI: 10.1093/eurheartj/ehq501.

66. Abedi E., Sahari M.A. Long-chain polyunsaturated fatty acid sources and evaluation of their nutritional and functional properties. Food Sci. Nutr. 2014;2(5):443–463. DOI: 10.1002/fsn3.121.

67. Borow K.M., Nelson J.R., Mason R.P. Biologic plausibility, cellular effects, and molecular mechanisms of eicosapentaenoic acid (EPA) in atherosclerosis. Atherosclerosis. 2015;242(1):357–366. DOI: 10.1016/j.atherosclerosis.2015.07.035.

68. Budoff M. Triglycerides and triglyceride-rich lipoproteins in the causal pathway of cardiovascular disease. Am. J. Cardiol. 2016;118(1):138–145. DOI: 10.1016/j.amjcard.2016.04.004.

69. Gdula-Argasińska J., Czepiel J., Woźniakiewicz A., Wojtoń K., Grzywacz A., Woźniakiewicz M. et al. n-3 Fatty acids as resolvents of inflammation in the A549 cells. Pharmacol. Rep. 2015;67(3):610–615. DOI: 10.1016/j.pharep.2015.01.001.

70. Nelson J.R., Wani O., May H.T., Budoff M. Potential benefits of eicosapentaenoic acid on atherosclerotic plaques. Vascul. Pharmacol. 2017;91:1–9. DOI: 10.1016/j.vph.2017.02.004.

71. Itakura H., Yokoyama M., Matsuzaki M., Saito Y., Origasa H., Ishikawa Y. et al. Relationships between plasma fatty acid composition and coronary artery disease. J. Atheroscler. Thromb. 2011;18(2):99–107. DOI: 10.5551/jat.5876.

72. Bhatt D.L., Steg P.G., Miller M., Brinton E.A., Jacobson T.A., Ketchum S.B. et al. Cardiovascular risk reduction with icosapent ethyl for hypertriglyceridemia. N. Engl. J. Med. 2019;380(1):11–22. DOI: 10.1056/NEJMoa1812792.

73. Cawood A.L., Ding R., Napper F.L., Young R.H., Williams J.A., Ward M.J. et al. Eicosapentaenoic acid (EPA) from highly concentrated n-3 fatty acid ethyl esters is incorporated into advanced atherosclerotic plaques and higher plaque EPA is associated with decreased plaque inflammation and increased stability. Atherosclerosis. 2010;212(1):252–259. DOI: 10.1016/j.atherosclerosis.2010.05.022.

74. Singh S., Arora R.R., Singh M., Khosla S. Eicosapentaenoic acid versus docosahexaenoic acid as options for vascular risk prevention: a fish story. Am. J. Ther. 2016;23(3):e905–910. DOI: 10.1097/MJT.0000000000000165.

75. Honda K.L., Lamon-Fava S., Matthan N.R., Wu D., Lichtenstein A.H. Docosahexaenoic acid differentially affects TNFα and IL-6 expression in LPS-stimulated RAW 264.7 murine macrophages. Prostaglandins Leukot. Essent. Fatty Acids. 2015;97:27–34. DOI: 10.1016/j.plefa.2015.03.002.

76. Peris-Martínez C., Piá-Ludeña J.V., Rog-Revert M.J., Fernández-López E., Domingo J.C. Antioxidant and Anti-Inflammatory Effects of Oral Supplementation with a Highly-Concentrated Docosahexaenoic Acid (DHA) Triglyceride in Patients with Keratoconus: A Randomized Controlled Preliminary Study. Nutrients. 2023;15(5):1300. DOI: 10.3390/nu15051300.

77. So J., Wu D., Lichtenstein A.H., Tai A.K., Matthan N.R., Maddipati K.R. et al. EPA and DHA differentially modulate monocyte inflammatory response in subjects with chronic inflammation in part via plasma specialized pro-resolving lipid mediators: A randomized, double-blind, crossover study. Atherosclerosis. 2021;316:90–98. DOI: 10.1016/j.atherosclerosis.2020.11.018.

78. Klingel S.L., Metherel A.H., Irfan M., Rajna A., Chabowski A., Bazinet R.P. et al. EPA and DHA have divergent effects on serum triglycerides and lipogenesis, but similar effects on lipoprotein lipase activity: a randomized controlled trial. Am. J. Clin. Nutr. 2019;110(6):1502–1509. DOI: 10.1093/ajcn/nqz234.

79. Allaire J., Couture P., Leclerc M., Charest A., Marin J., Lépine M.C. et al. 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. 2016;104(2):280–287. DOI: 10.3945/ajcn.116.131896.

80. Metherel A.H., Irfan M., Klingel S.L., Mutch D.M., Bazinet R.P. 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. 2019;110(4):823–831. DOI: 10.1093/ajcn/nqz097.

81. Allaire J., Harris W.S., Vors C., Charest A., Marin J., Jackson K.H et al. Supplementation with high-dose docosahexaenoic acid increases the Omega-3 Index more than high-dose eicosapentaenoic acid. Prostaglandins Leukot. Essent. Fatty Acids. 2017;120:8–14. DOI: 10.1016/j.plefa.2017.03.008.

82. Lee J.B., Notay K., Klingel S.L., Chabowski A., Mutch D.M., Millar P.J. Docosahexaenoic acid reduces resting blood pressure but increases muscle sympathetic outflow compared with eicosapentaenoic acid in healthy men and women. Am. J. Physiol. Heart Circ. Physiol. 2019;316(4):H873–H881. DOI: 10.1152/ajpheart.00677.2018.

83. Rontoyanni V.G., Hall W.L., Pombo-Rodrigues S., Appleton A., Chung R., Sanders T.A. A comparison of the changes in cardiac output and systemic vascular resistance during exercise following high-fat meals containing DHA or EPA. Br. J. Nutr. 2012;108(3):492–499. DOI: 10.1017/S0007114511005721.

84. Rousseau-Ralliard D., Moreau D., Guilland J.C., Raederstorff D., Grynberg A. Docosahexaenoic acid, but not eicosapentaenoic acid, lowers ambulatory blood pressure and shortens interval QT in spontaneously hypertensive rats in vivo. Prostaglandins Leukot. Essent. Fatty Acids. 2009;80(5–6):269–277. DOI: 10.1016/j.plefa.2009.03.003.

85. Choque B., Catheline D., Rioux V., Legrand P. Linoleic acid: between doubts and certainties. Biochimie. 2014;96:14–21. DOI: 10.1016/j.biochi.2013.07.012.

86. Hajihashemi P., Feizi A., Heidari Z., Haghighatdoost F. Association of omega-6 polyunsaturated fatty acids with blood pressure: A systematic review and meta-analysis of observational studies. Crit. Rev. Food Sci. Nutr. 2023;63(14):2247–2259. DOI: 10.1080/10408398.2021.1973364.

87. Harris W.S., Mozaffarian D., Rimm E., Kris-Etherton P., Rudel L.L., Appel L.J. et al. Omega-6 fatty acids and risk for cardiovascular disease: a science advisory from the American Heart Association Nutrition Subcommittee of the Council on Nutrition, Physical Activity, and Metabolism; Council on Cardiovascular Nursing; and Council on Epidemiology and Prevention. Circulation. 2009;119(6):902–907. DOI: 10.1161/CIRCULATIONAHA.108.191627.

88. Hooper L., Al-Khudairy L., Abdelhamid A.S., Rees K., Brainard J.S., Brown T.J. et al. Omega-6 fats for the primary and secondary prevention of cardiovascular disease. Cochrane Database Syst. Rev. 2018;7(7):CD011094. DOI: 10.1002/14651858.CD011094.pub3.

89. Miura K., Stamler J., Nakagawa H., Elliott P., Ueshima H., Chan Q. et al. Relationship of dietary linoleic acid to blood pressure. The International Study of Macro-Micronutrients and Blood Pressure Study [corrected]. Hypertension. 2008;52(2):408–414. DOI: 10.1161/HYPERTENSIONAHA.108.112383.

90. Zhao J.V., Schooling C.M. Effect of linoleic acid on ischemic heart disease and its risk factors: a Mendelian randomization study. BMC Med. 2019;17(1):61. DOI: 10.1186/s12916-019-1293-x.

91. Cole R.M., Angelotti A., Sparagna G.C., Ni A., Belury M.A. Linoleic Acid-Rich Oil Alters Circulating Cardiolipin Species and Fatty Acid Composition in Adults: A Randomized Controlled Trial. Mol. Nutr. Food Res. 2022;66(15):e2101132. DOI: 10.1002/mnfr.202101132.

92. Gallagher H., Williams J.O., Ferekidis N., Ismail A., Chan Y.H., Michael D.R. et al. Dihomo-γ-linolenic acid inhibits several key cellular processes associated with atherosclerosis. Biochim. Biophys. Acta Mol. Basis Dis. 2019;1865(9):2538–2550. DOI: 10.1016/j.bbadis.2019.06.011.

93. Takai S., Jin D., Kawashima H., Kimura M., Shiraishi-Tateishi A., Tanaka T. et al. Anti-atherosclerotic effects of dihomo-gamma-linolenic acid in ApoE-deficient mice. J. Atheroscler. Thromb. 2009;16(4):480–489. DOI: 10.5551/jat.no430.

94. Sergeant S., Rahbar E., Chilton F.H. Gamma-linolenic acid, Dihommo-gamma linolenic, Eicosanoids and Inflammatory Processes. Eur. J. Pharmacol. 2016;785:77–86. DOI: 10.1016/j.ejphar.2016.04.020.

95. Hadj Ahmed S., Kaoubaa N., Kharroubi W., Zarrouk A., Najjar M.F., Batbout F. et al. Association of plasma fatty acid alteration with the severity of coronary artery disease lesions in Tunisian patients. Lipids Health Dis. 2017;16(1):154. DOI: 10.1186/s12944-017-0538-y.

96. Nilsen D.W.T., Myhre P.L., Kalstad A., Schmidt E.B., Arnesen H., Seljeflot I. Serum levels of dihomo-gamma (γ)-linolenic acid (DGLA) are inversely associated with linoleic acid and total death in elderly patients with a recent myocardial infarction. Nutrients. 2021;13(10):3475. DOI: 10.3390/nu13103475.

97. Ouchi S., Miyazaki T., Shimada K., Sugita Y., Shimizu M., Murata A. et al. Decreased circulating dihomo-gamma-linolenic acid levels are associated with total mortality in patients with acute cardiovascular disease and acute decompensated heart failure. Lipids Health Dis. 2017;16(1):150. DOI: 10.1186/s12944-017-0542-2.

98. Nagai T., Honda Y., Sugano Y., Nishimura K., Nakai M., Honda S et al. Circulating omega-6, but not omega-3 polyunsaturated fatty acids, are associated with clinical autcomes in patients with acute decompensated heart failure. PLoS One. 2016;11(11):e0165841. DOI: 10.1371/journal.pone.0165841.

99. Sonnweber T., Pizzini A., Nairz M., Weiss G., Tancevski I. Arachidonic acid metabolites in cardiovascular and metabolic diseases. Int. J. Mol. Sci. 2018;19(11):3285. DOI: 10.3390/ijms19113285.

100. Zhang Y., Liu Y., Sun J., Zhang W., Guo Z., Ma Q. Arachidonic acid metabolism in health and disease. Med. Comm. (2020). 2023;4(5):e363. DOI: 10.1002/mco2.363.

101. Yang L., Mäki-Petäjä K., Cheriyan J., McEniery C., Wilkinson I.B. The role of epoxyeicosatrienoic acids in the cardiovascular system. Br. J. Clin. Pharmacol. 2015;80(1):28–44. DOI: 10.1111/bcp.12603.

102. De Goede J., Verschuren W.M., Boer J.M., Verberne L.D., Kromhout D., Geleijnse J.M. N-6 and N-3 fatty acid cholesteryl esters in relation to fatal CHD in a Dutch adult population: a nested case-control study and meta-analysis. PLoS One. 2013;8(5):e59408. DOI: 10.1371/journal.pone.0059408.

103. Takahashi J., Sakai K., Sato T., Takatsu H., Komatsu T., Mitsumura H. et al. Serum arachidonic acid levels is a predictor of poor functional outcome in acute intracerebral hemorrhage. Clin. Biochem. 2021;98:42–47. DOI: 10.1016/j.clinbiochem.2021.09.012.

104. Zhang T., Zhao J.V., Schooling C.M. The associations of plasma phospholipid arachidonic acid with cardiovascular diseases: A Mendelian randomization study. EBio Medicine. 2021;63:103189. DOI: 10.1016/j.ebiom.2020.103189.

105. Nielsen M.S., Schmidt E.B., Stegger J., Gorst-Rasmussen A., Tjonneland A., Overvad K. Adipose tissue arachidonic acid content is associated with the risk of myocardial infarction: a Danish case-cohort study. Atherosclerosis. 2013;227(2):386–390. DOI: 10.1016/j.atherosclerosis.2012.12.035.