farmacología
farmacología cardiovascular 60 | mayo de 2024servó regresión de la placa en el 50% de los sujetos con EPAmás estatinas frente al 24% en el grupo de estatinas solas(55). Por el contrario, cuando se utilizó una mezcla de ácidosgrasos omega-3 (EPA + DHA) en diversos ensayos clínicos, nose observaron los beneficios (56-57).Se han revisado las posibles diferencias mecanísticas entreEPA y DHA: la longitud más corta y posiblemente el menornúmero de dobles enlaces de EPA permite una mayor intercalaciónde EPA en la bicapa de membrana de las células delmúsculo liso vascular, lo que resulta en más efectos antioxidantesy menos fluidez/inestabilidad de la membrana, inhibiendoasí la formación excesiva de colesterol en la membranacelular. Por el contrario, una mayor longitud de hidrocarburodel DHA provoca una intercalación deficiente en la bicapa dela membrana celular, y conduce a la formación de cristales decolesterol, que pueden dañar los macrófagos y la integridadde la membrana celular. En un modelo murino reciente sedemostró que el EPA reducía el espesor de la íntima-media delas placas ricas en macrófagos y estaba más concentrado enlas placas de capa delgada que en las de capa gruesa, mientrasque el DHA se distribuía más uniformemente en ambostipos de placas. Estas diferencias pueden, al menos en parte,explicar los hallazgos dispares entre los desenlaces CV observadosen los ensayos clínicos de EPA puro (IPE) y ensayos similarespero que usaron ácidos grasos omega-3 que contienenDHA y EPA (58-61).ConclusionesHemos revisado las características del icosapento de etilo, ycomprobamos que presenta características diferentes al restode las estrategias basadas en omega-3 para la reducción deeventos CV. La elevación en los niveles de EPA en sangrepresenta diversos efectos pleiotrópicos que podrían explicarlos beneficios del tratamiento con el éster purificado IPE enaltas dosis y por largo plazo, más allá de la reducción de losniveles de triglicéridos.Referencias bibliográficas• 1. Fan W, Philip S, Granowitz C, et, al. Hypertriglyceridemia in statin-treated US adults: the National Health and Nutrition Examination Survey. J ClinLipidol. 2019;13:100–108.• 2. Budoff M. Triglycerides and triglyceride-rich lipoproteins in the causal pathway of cardiovascular disease. Am J Cardiol. 2016;118(1):138–145.• 3. Toth PP, Granowitz C, Hull M, et al. High triglycerides are associated with increased cardiovascular events, medical costs, and resource utilization:a real-world administrative claims analysis of statin-treated patients with high residual cardiovascular risk. J Am Heart Assoc. 2018;7(15):e008740.• 4. GISSI Prevenzione Investigators. Dietary supplementation with n-3 polyunsaturated fatty acids and vitamin E after myocardial infarction: results ofthe GISSI-Prevenzione trial. Gruppo Italiano per lo studio della Sopravvivenza nell’Infarto miocardico. Lancet. 1999;354(9177):447–455.• 5. Rauch B, Schiele R, Schneider S, et al. OMEGA, a randomized, placebo-controlled trial to test the effect of highly purified omega-3 fatty acids ontop of modern guideline-adjusted therapy after myocardial infarction. Circulation. 2010;122(21):2152–2159.• 6. ASCEND Study Collaborative Group, Bowman L, Mafham M, et al. Effects of n-3 fatty acid supplements in diabetes mellitus. N Engl J Med2018;379(16):1540–1550.• 7. Manson JE, Cook NR, Lee IM, et al. Marine n-3 fatty acids and prevention of cardiovascular disease and cancer. N Engl J Med. 2019;380(1):23–32.• 8. ORIGIN Trial Investigators. n-3 Fatty acids and cardiovascular outcomes in patients with dysglycemia. N Engl J Med. 2012;367(4):309–318.• 9. Kalstad AA, Myhre PL, Laake K, et al. Effects of n-3 fatty acid supplements in elderly patients after myocardial infarction: a randomized controlledtrial. Circulation. 2020;143(6):528–539.• 10. Nicholls SJ, Lincoff AM, Garcia M, et al. Effect of high-dose omega-3 fatty acids vs corn oil on major adverse cardiovascular events in patients athigh cardiovascular risk: the STRENGTH randomized clinical trial. JAMA. 2020;324(22):2268–2280.• 11. Yokoyama M, Origasa H, Matsuzaki M, et al. Effects of eicosapentaenoic acid on major coronary events in hypercholesterolaemic patients (JELIS):a randomised open-label, blinded endpoint analysis. Lancet. 2007;369(9567):1090–1098.• 12. Saito Y, Yokoyama M, Origasa H, et al. Effects of EPA on coronary artery disease in hypercholesterolemic patients with multiple risk factors:sub-analysis of primary prevention cases from the Japan EPA Lipid Intervention Study (JELIS). Atherosclerosis. 2008;200(1):135–140.• 13. Bhatt DL, Steg G, and Miller M, et al. Cardiovascular risk reduction with icosapent ethyl for hypertriglyceridemia N Engl J Med 2019 380(1):11–22.• 14. Peterson BE, Bhatt DL, Steg PG, et al. Reduction in revascularization with icosapent ethyl: insights from REDUCE-IT revascularization analyses.Circulation. 2021;143(1):33–44.• 15. Bhatt DL, Brinton EA, Miller M, et al. Substantial cardiovascular benefit from icosapent ethyl in patients with diabetes: REDUCE-IT DIABETES[abstract]. Diabetes. 2020;69(suppl 1):4–LB.• 16. Majithia A, Bhatt DL, Friedman AN, et al. Benefits of icosapent ethyl across the range of kidney function in patients with established cardiovasculardisease or diabetes: REDUCE-IT RENAL. Circulation. 2021;144(22):1750–1759.• 17. Bhatt DL, Steg PG, Miller M, et al. Reduction in first and total ischemic events with icosapent ethyl across baseline triglyceride tertiles. J Am CollCardiol. 2019;74(8):1159–1161.• 18. Bhatt DL, Miller M, Steg G, et al. editors EPA levels and cardiovascular outcomes in the reduction of cardiovascular events with icosapent ethyl-interventiontrial [oral presentation]. Chicago, IL: Annual Scientific Session of the American College of Cardiology; Mar 28-30 2020.• 19. Nelson JR, Budoff MJ, Wani OR, et al., EPA’s pleiotropic mechanisms of action: a narrative review. Postgrad Med. 2021;133(6):651–664.• 20. Gryglewski RJ, Salmon JA, Ubatuba FB, et al. Effects of all cis-5,8,11,14,17 eicosapentaenoic acid and PGH3 on platelet aggregation. Prostaglandins.1979;18(3):453–478.• 21. Li XL, Steiner M. Fish oil: a potent inhibitor of platelet adhesiveness. Blood. 1990;76(5):938–945.• 22. Kramer HJ, Stevens J, Grimminger F, et al. Fish oil fatty acids and human platelets: dose-dependent decrease in dienoic and increase in trienoicthromboxane generation. Biochem Pharmacol. 1996;52(8):1211–1217.• 23. Dyerberg J, Bang HO, Stoffersen E, et, al. Eicosapentaenoic acid and prevention of thrombosis and atherosclerosis? Lancet. 1978;2(8081):117–119.• 24. Yamada H, Yoshida M, Nakano Y, et al. In vivo and in vitro inhibition of monocyte adhesion to endothelial cells and endothelial adhesion moleculesby eicosapentaenoic acid. Arterioscler Thromb Vasc Biol. 2008;28(12):2173–2179.EDITORIAL SCIENS // 13
• 25. Satoh-Asahara N, Shimatsu A, Sasaki Y, et al. Highly purified eicosapentaenoic acid increases interleukin-10 levels of peripheral blood monocytesin obese patients with dyslipidemia. Diabetes Care. 2012;35(12):2631–2639.• 26. Jaudszus A, Gruen M, Watzl B, et al. Evaluation of suppressive and pro-resolving effects of EPA and DHA in human primary monocytes and T-helpercells. J Lipid Res. 2013;54(4):923–935.• 27. Kawashima A, Harada T, Imada K, et al. Eicosapentaenoic acid inhibits interleukin-6 production in interleukin-1beta-stimulated C6 glioma cellsthrough peroxisome proliferator-activated receptor-gamma. Prostaglandins Leukot Essent Fatty Acids. 2008;79(1–2):59–65.• 28. Allam-Ndoul B, Guenard F, Barbier O, et al. Effect of n-3 fatty acids on the expression of inflammatory genes in THP-1 macrophages. Lipids HealthDis. 2016;15:69.• 29. Albracht-Schulte K, Gonzalez S, Jackson A, et al. Eicosapentaenoic acid improves hepatic metabolism and reduces inflammation independent ofobesity in high-fat-fed mice and in HepG2 cells. Nutrients. 2019;11(3):599.• 30. Mo Z, Tang C, Li H, et al. Eicosapentaenoic acid prevents inflammation induced by acute cerebral infarction through inhibition of NLRP3 inflammasomeactivation. Life Sci. 2020;242:117133.• 31. Miller M, Ballantyne CM, Bays HE, et al. Effects of icosapent ethyl (eicosapentaenoic acid ethyl ester) on atherogenic lipid/lipoprotein, apolipoprotein,and inflammatory parameters in patients with elevated high-sensitivity C-reactive protein (from the ANCHOR study). Am J Cardiol.2019;124(5):696–701.• 32. Nishio R, Shinke T, Otake H, et al. Stabilizing effect of combined eicosapentaenoic acid and statin therapy on coronary thin-cap fibroatheroma.Atherosclerosis. 2014;234(1):114–119.• 33. Brinton EA, Ballantyne CM, Bays HE, et al. Effects of icosapent ethyl on lipid and inflammatory parameters in patients with diabetes mellitus-2,residual elevated triglycerides (200–500 mg/dL), and on statin therapy at LDL-C goal: the ANCHOR study. Cardiovasc Diabetol. 2013;12(1):100.• 34. Arita M, Ohira T, Sun YP, et al. Resolvin E1 selectively interacts with leukotriene B4 receptor BLT1 and ChemR23 to regulate inflammation. JImmunol. 2007;178(6):3912–3917.• 35. Oh SF, Dona M, Fredman G, et al. Resolvin E2 formation and impact in inflammation resolution. J Immunol. 2012;188(9):4527–4534.• 36. Isobe Y, Arita M, Matsueda S, et al. Identification and structure determination of novel anti-inflammatory mediator resolvin E3, 17,18-dihydroxyeicosapentaenzic acid. J Biol Chem. 2012;287(13):10525–10534.• 37. Golzari MH, Hosseini S, Koohdani F, et al. The Effect of Eicosapentaenoic Acid on the Serum Levels and Enzymatic Activity of Paraoxonase 1 inthe Patients With Type 2 Diabetes Mellitus. Acta Med Iran. 2017;55(8):486–495.• 38. Golzari MH, Javanbakht MH, Ghaedi E, et al. Effect of eicosapentaenoic acid supplementation on paraoxonase 2 gene expression in patients withtype 2 diabetes mellitus: a randomized double-blind clinical trial. Clin Nutr Res. 2019;8(1):17–27.• 39. Mason RP, Sherratt SCR, Jacob RF. Eicosapentaenoic acid inhibits oxidation of apoB-containing lipoprotein particles of different size in vitro whenadministered alone or in combination with atorvastatin active metabolite compared with other triglyceride-lowering agents. J Cardiovasc Pharmacol.2016;68(1):33–40.• 40. Sherratt SCR, Mason RP. Eicosapentaenoic acid inhibits oxidation of high density lipoprotein particles in a manner distinct from docosahexaenoicacid. Biochem Biophys Res Commun. 2018;496(2):335–338.• 41. Sherratt SCR, Juliano RA, Mason RP. Eicosapentaenoic acid (EPA) has optimal chain length and degree of unsaturation to inhibit oxidation ofsmall dense LDL and membrane cholesterol domains as compared to related fatty acids in vitro. Biochimica et Biophysica Acta (BBA) - Biomembranes.2020;1862(7):183254.• 42. Okuda Y, Kawashima K, Sawada T, et al. Eicosapentaenoic acid enhances nitric oxide production by cultured human endothelial cells. BiochemBiophys Res Commun. 1997;232(2):487–491.• 43. Fukumoto K, Takemoto Y, Yoshikawa J, et al. Increase in EPA/AA ratio predicts improvement in endothelial function in purified eicosapentaenoicacid-treated patients [abstract P6205]. Eur Heart J. 2019;40(suppl 1):3816.• 44. Yamakawa K, Shimabukuro M, Higa N, et al. Eicosapentaenoic acid supplementation changes fatty acid composition and corrects endothelialdysfunction in hyperlipidemic patients. Cardiol Res Pract. 2012;2012:754181.• 45. Sasaki J, Miwa T, Odawara M. Administration of highly purified eicosapentaenoic acid to statin-treated diabetic patients further improves vascularfunction. Endocr J. 2012;59(4):297–304.• 46. Toyama K, Nishioka T, Isshiki A, et al. Eicosapentaenoic acid combined with optimal statin therapy improves endothelial dysfunction in patientswith coronary artery disease. Cardiovasc Drugs Ther. 2014;28(1):53–59.• 47. Mason RP, Dawoud H, Jacob RF, et al. Eicosapentaenoic acid improves endothelial function and nitric oxide bioavailability in a manner that isenhanced in combination with a statin. Biomed Pharmacother. 2018;103:1231–1237.• 48. Tanaka N, Irino Y, Shinohara M, et al. Eicosapentaenoic acid-enriched high-density lipoproteins exhibit anti-atherogenic properties. Circ J.2018;82(2):596–601.• 49. Itoh M, Suganami T, Satoh N, et al. Increased adiponectin secretion by highly purified eicosapentaenoic acid in rodent models of obesity andhuman obese subjects. Arterioscler Thromb Vasc Biol. 2007;27(9):1918–1925.• 50. Budoff MJ, Bhatt DL, Kinninger A, et al. Effect of icosapent ethyl on progression of coronary atherosclerosis in patients with elevated triglycerideson statin therapy: final results of the EVAPORATE trial. Eur Heart J. 2020;41(40):3925–3932.• 51. Nelson JR, Wani O, May HT, et al. Potential benefits of eicosapentaenoic acid on atherosclerotic plaques. Vascul Pharmacol. 2017;91:1–9.• 52. Xiao YF, Gomez AM, Morgan JP, et al. Suppression of voltage-gated L-type Ca2+ currents by polyunsaturated fatty acids in adult and neonatal ratventricular myocytes. Proc Natl Acad Sci U S A. 1997;94(8):4182–4187.• 53. Xiao YF, Ke Q, Wang SY, et al. Single point mutations affect fatty acid block of human myocardial sodium channel alpha subunit Na+ channels.Proc Natl Acad Sci U S A. 2001;98(6):3606–3611.• 54. Den Ruijter HM, Berecki G, Verkerk AO, et al. Acute administration of fish oil inhibits triggered activity in isolated myocytes from rabbits andpatients with heart failure. Circulation. 2008;117(4):536–544.• 55. Ando K, Watanabe T, Daidoji H, et al. Abstract 12007: combination therapy of eicosapentaenoic acid and pitavastatin for coronary plaque regressionevaluated by integrated backscatter intravascular ultrasonography: a randomized controlled trial. Circulation. 2015;132(suppl_3):A12007.• 56. Alfaddagh A, Elajami TK, Ashfaque H, et al. Effect of eicosapentaenoic and docosahexaenoic acids added to statin therapy on coronary arteryplaque in patients with coronary artery disease: a randomized clinical trial. J Am Heart Assoc. 2017;6(12).• 57. Nakao K, Noguchi T, Miura H, et al. Effect of eicosapentaenoic acid/docosahexaenoic acid on coronary high-intensity plaques detected usingnon-contrast T1-weighted imaging: a randomized trial. SSRN. 2022 Jan 4; Online Ahead of Print. DOI:10.2139/ssrn.4000233• 58. Mason RP, Libby P, Bhatt DL. Emerging mechanisms of cardiovascular protection for the omega-3 fatty acid eicosapentaenoic acid. ArteriosclerThromb Vasc Biol. 2020;40(5):1135–1147.• 59. Mason RP, Jacob RF, Shrivastava S, et al. Eicosapentaenoic acid reduces membrane fluidity, inhibits cholesterol domain formation, and normalizesbilayer width in atherosclerotic-like model membranes. Biochim Biophys Acta. 2016;1858(12):3131–3140.• 60. Mason RP. New insights into mechanisms of action for omega-3 fatty acids in atherothrombotic cardiovascular disease. Curr Atheroscler Rep.2019;21(2):1–11.• 61. Sato T, Horikawa M, Takei S, et al. Preferential incorporation of administered eicosapentaenoic acid into thin-cap atherosclerotic plaques. ArteriosclerThromb Vasc Biol. 2019;39(9):1802–1816.14 // EDITORIAL SCIENS
