Utilidad terapéutica de los ácidos grasos omega-3. Volumen 6, Número Supl.D, Junio 2006   

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Farmacología de los ácidos grasos omega-3


Rev Esp Cardiol 2006; 6: 3 - 19
ISSN : 1579-2242

El consumo de ácidos grasos omega-3, como el ácido eicosapentanoico (EPA) y el ácido docosahexanoico (DHA), derivados de alimentos marinos y de plantas ha demostrado, en estudios epidemiológicos y clínicos, que reduce la incidencia de mortalidad coronaria y la muerte por arritmias. Recientemente, un suplemento que contiene una concentración del 90% de ácidos omega-3 (EPA y DHA) en forma de etil ésteres (Omacor®) ha sido autorizado como tratamiento adjunto a la dieta para reducir la hipertrigliceridemia en pacientes adultos y, también, como tratamiento adjunto a la dieta y a otros tratamientos en la prevención secundaria del infarto de miocardio. En este artículo, en primer lugar, revisamos la estructura química, las acciones farmacológicas y los mecanismos por los cuales los ácidos grasos n-3 y, en particular, el Omacor®, pueden reducir el riesgo de muerte cardiovascular. A continuación, se analizan las propiedades farmacocinéticas, la seguridad y las recomendaciones de diversos organismos para administrar suplementos de EPA+DHA u Omacor® en los pacientes con enfermedades cardiovasculares.


Palabras clave: Ácidos grados omega-3. Dieta. Cardiopatía isquémica. EPA. DHA.
 

Pharmacology of Omega-3 Polyinsaturated Fatty Acids

Epidemiological and clinical trials have shown that the consumption of omega-3 polyunsaturated fatty acids, such as eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), derived from seafood and plant sources reduces the incidence of fatal coronary artery disease and death due to arrhythmia. Recently, a food supplement containing a 90% concentration of omega-3 fatty acids (i.e., EPA and DHA) in the form of ethyl esters (Omacor®) has been licensed for use as an adjunct to dietary modification for the reduction of hypertriglyceridemia in adults and as an adjuvant to standard medical treatment for the secondary prevention of myocardial infarction. In this article, we review firstly the chemical structure of omega-3 fatty acids, and the pharmacological actions and mechanisms through which they may reduce the risk of cardiovascular disease. Thereafter, we discuss the pharmacokinetics, safety profile, and the recommendations made in several guidelines concerning the use of EPA+DHA supplements or Omacor® in patients with cardiovascular disease.


Keywords: Omega-3 fatty acids. Diet. Coronary artery disease. EPA. DHA.
 

INTRODUCCION

Las enfermedades cardiovasculares representan la primera causa de muerte en el mundo y, según las previsiones de la Organización Mundial de la Salud, esta situación se agravará en los próximos años como consecuencia de la adopción de los hábitos de vida occidentales en los países en vías de desarrollo1 . En particular, la cardiopatía isquémica representa una de las primeras causas de mortalidad, tanto en los países desarrollados como en los países en vías de desarrollo. En España, en el año 2002, la cardiopatía isquémica causó 68.500 infartos de miocardio, con una mortalidad prehospitalaria del 40% y del 24,9% en el primer mes que siguió al ingreso hospitalario; de los 33.500 pacientes hospitalizados con diagnóstico de angina inestable, el 4,5% fallecía en los 3 meses siguientes2 . La elevada morbimortalidad de la cardiopatía isquémica hace que incluso una pequeña reducción pueda tener un considerable impacto en la salud de nuestra población.

En 1976, investigadores daneses observaron que la incidencia y la mortalidad por cardiopatía isquémica era mucho menor en la población esquimal, que consumía una gran cantidad de grasas de origen marino (hasta 10-12 g/día), muy ricas en ácidos grasos poliinsaturados omega-3 (AGPI n-3), que en la de población danesa que habitaba en la isla, que consumía principalmente AGPI n-63,4 . De hecho, el cociente ácidos grasos poliinsaturados/saturados era de 0,84 en la población esquimal y de 0,24 en los daneses. Por tanto, estos investigadores relacionaron la baja incidencia de cardiopatía isquémica con la ingesta de AGPI n-3 procedentes de los aceites de pescado.

Desde entonces, numerosos estudios experimentales, epidemiológicos y de intervención5-15 han demostrado que la ingesta de una dieta rica en AGPI n-3 reduce la mortalidad coronaria y la muerte súbita cardiaca16 y que, en las zonas geográficas donde los AGPI n-3 predominan en la dieta, la incidencia de enfermedades cardiovasculares aterotrombóticas disminuye. En los últimos años se ha demostrado que los AGPI n-3 presentan múltiples efectos protectores cardiovasculares, ya que reducen las concentraciones plasmáticas de triglicéridos y presentan propiedades antiarrítmicas, antiinflamatorias, antiaterogénicas y antitrombóticas16 (tabla 1).

Las concentraciones de AGPI n-3 en el organismo están determinadas por la dieta, principalmente a través de la ingesta de aceites de pescado, por alimentos (leche o huevos) suplementados o con suplementos artificiales (nutracéuticos) que pueden adquirirse sin receta y que aportan cantidades muy variables de AGPI n-3. Muy recientemente se ha comercializado un nuevo fármaco, Omacor® , que contiene AGPI n-3 purificados y concentrados en forma etil ésteres, que permiten alcanzar las concentraciones recomendadas por las sociedades científicas en los pacientes. En este capítulo analizaremos las características estructurales, el mecanismo de acción y las propiedades farmacodinámicas y farmacocinéticas, su seguridad y las aplicaciones terapéuticas de los AGPI n-3 y, en particular, del Omacor® .

ESTRUCTURA QUIMICA DE LOS ACIDOS OMEGA-3

El organismo humano sintetiza numerosos ácidos grasos denominados no esenciales, mientras que otros deben incorporarse al organismo a través de la dieta, razón por la que se denominan esenciales. Estos últimos incluyen los AGPI de las familias omega-3 (n-3) y omega-6 (n-6), números que hacen referencia a la localización que ocupa el primer doble enlace en estos ácidos grasos, contando a partir del carbono situado en el extremo metilo de la cadena (omega terminal o n) (fig. 1). En el ser humano, los AGPI n-3 y n-6 son importantes para mantener la estructura de las membranas celulares, facilitar la absorción de las vitaminas liposolubles (A, D, E y K), regular el metabolismo del colesterol y producir eicosanoides, que regulan múltiples procesos celulares (tono vascular y bronquial, motilidad gastrointestinal y uterina, protección gástrica, diuresis, coagulación sanguínea, temperatura corporal, fenómenos algésicos, inflamatorios e inmunitarios). Sin embargo, los mamíferos no son capaces de introducir dobles enlaces antes del noveno carbono de la cadena de ácido graso, razón por la que deben obtener a través de la dieta las concentraciones adecuadas de AGPI n-3 y n-6.

Fig. 1. Estructura de los ácidos grasos poliinsaturados (AGPI) omega-3 y omega-6.

Los AGPI n-6 se originan a partir del ácido linoleico, que contiene 18 átomos de carbono y 2 dobles enlaces (C18:2), del que derivan los ácidos gamma-linolénico y araquidónico (AA, C20:4) (fig. 2). El AA liberado a partir de los fosfolípidos de la membrana por acción de la fosfolipasa A2 recibe la acción de ciclooxigenasas, lipoxigenasa y epoxigenasa o citocromo P450, y se convierte, respectivamente, en prostaglandinas (E2, F2 * , D2, H2 e I2) y tromboxanos de la serie 2 (A2 y B2), leucotrienos de la serie 4 (LTB4) y ácidos epoxieicosatrienoicos, que actúan como mensajeros celulares y aumentan la agregación plaquetaria, la frecuencia cardiaca y presentan propiedades vasoconstrictoras y proinflamatorias. El ácido linoleico se encuentra en verduras, frutas, frutos secos, cereales y semillas, así como en los aceites de cártamo, girasol, maíz, soja, onagra, calabaza y germen de trigo.

Los principales AGPI n-3 de cadena larga (>= 20C) se originan a partir del alfalinolénico (C18:3), que tiene la capacidad de convertirse en el organismo en ácido eicosapentaenoico (EPA, C20:5) y ácido docosahexanoico (DHA C22:6). De hecho, el DHA y los AGPI n-6 (ácidos linoleico y araquidónico) son los principales AGPI presentes en los fosfolípidos de las membranas celulares (fig. 2). Las principales fuentes de alfalinolénico son las nueces y, especialmente, los aceites vegetales de linaza, colza, soja y lino



Referencias Bibliográficas:
1. World Health Organization.. The World Health Report 2003: Shaping the Future. Geneva: World Health Organization; 2003.
2. Marrugat J, Elosúa R, Martí H. . Epidemiology of ischaemic heart disease in Spain: estimation of the number of cases and trends from 1997 to 2005. Rev Esp Cardiol. 2002;55:337-46. [Medline]
[Descargar cita] [Artículo]
3. Bang HO, Dyerberg J, Hjoorne N.. The composition of food consumed by Greenland Eskimos. Acta Med Scand. 1976;200:69-73. [Medline]
[Descargar cita]
4. Bang HO, Dyerberg J, Sinclair HM.. The composition of the Eskimo food in north western Greenland. Am J Clin Nutr. 1980; 33:2657-61. [Medline]
[Descargar cita]
5. Kromhout D, Bosschieter EB, Le Lezenne Coulander C.. The inverse relation between fish consumption and 20-year mortality from coronary heart disease. N Engl J Med. 1985;312:1205-9. [Medline]
[Descargar cita]
6. Burr ML, Fehily AM, Gilbert JF, Rogers S, Holliday RM, Sweetnam PM, et al.. Effects of changes in fat, fish, and fibre intakes on death and myocardial reinfarction: diet and reinfarction trial (DART). Lancet. 1989;2:757-61. [Medline]
[Descargar cita]
7. Dolecek TA.. Epidemiological evidence of relationships between dietary polyunsaturated fatty acids and mortality in the multiple risk factor intervention trial. Proc Soc Exp Biol Med. 1992;200: 177-82. [Medline]
[Descargar cita]
8. Daviglus ML, Stamler J, Orencia AJ, Dyer AR, Liu K, Greenland P, et al.. Fish consumption and the 30-year risk of fatal myocardial infarction. N Engl J Med. 1997;336:1046-53. [Medline]
[Descargar cita]
9. Siscovick DS, Raghunathan TE, King I, Weinmann S, Wicklund KG, Albright J, et al.. Dietary intake and cell membrane levels of long-chain n-3 polyunsaturated fatty acids and the risk of primary cardiac arrest. JAMA. 1995;274:1363-7. [Medline]
[Descargar cita]
10. Albert CM, Hennekens CH, O'Donnell CJ, Ajani UA, Carey VJ, Willett WC, et al.. Fish consumption and risk of sudden cardiac death. JAMA. 1998;279:23-8. [Medline]
[Descargar cita]
11. Albert CM, Campos H, Stampfer MJ, Ridker PM, Manson JE, Willett WC, et al.. Blood levels of long-chain n-3 fatty acids and risk of sudden death. N Engl J Med. 2002;346:1113-8. [Medline]
[Descargar cita]
12. Hu FB, Bronner L, Willett WC, Stampfer MJ, Rexrode KM, Albert CM, et al.. Fish and omega-3 fatty acid intake and risk of coronary heart disease in women. JAMA. 2002;287:1815-21. [Medline]
[Descargar cita]
13. Hu FB, Cho E, Rexrode KM, Albert CM, Manson JE.. Fish and long-chain o-3 fatty acid intake and risk of coronary heart disease and total mortality in diabetic women. Circulation. 2003;107: 1852-7. [Medline]
[Descargar cita]
14. De Lorgeril M, Salen P, Martin JL, Monjaud I, Delaye J, Mamelle N.. Mediterranean diet, traditional risk factors, and the rate of cardiovascular complications after myocardial infarction: final report of the Lyon Diet Heart Study. Circulation. 1999;99:779-85. [Medline]
[Descargar cita]
15. Gruppo Italiano per lo Studio della Sopravivenza nell'Infarto myocardio.. Dietary supplementation with n-3 polyunsaturated fatty acids and vitamin E after myocardial infarction: results of the GISSI-Prevenzione trial. Lancet. 1999;354:447-55. [Medline]
[Descargar cita]
16. Harrison N, Abhyankar B.. The mechanism of action of omega-3 fatty acids in secondary prevention post-myocardial infarction. Curr Med Res Opin. 2005;21:95-100. [Medline]
[Descargar cita]
17. Rupp H, Turcani M, Ohkubo T, Maisch B, Brilla CG.. Dietary linolenic acid-mediated increase in vascular prostacyclin formation. Mol Cell Biochem. 1996;162:59-64. [Medline]
[Descargar cita]
18. Davis BC, Kris-Etherton PM.. Achieving optimal essential fatty acid status in vegetarians: current knowledge and practical implications. Am J Clin Nutr. 2003;78 Suppl:S640-6.

19. Kris-Etherton PM, Harris WS, Appel LJ; for the Nutrition Commettee.. Fish consumption, fish oil, omega-3 fatty acids, and cardiovascular disease. Circulation. 2002;106:2747-57. [Medline]
[Descargar cita]
20. Williams LK.. Balancing the risks and benefits of fish consumption. Ann Intern Med. 2005;142:946-9. [Medline]
[Descargar cita]
21. Simopoulos AP.. Essential PUFAs in health and chronic disease. Am J Clin Nutr. 1999;70:S560­9.

22. Kris-Etherton PM, Taylor DS, Yu-Poth S, Huth P, Moriarty K, Fishell V, et al.. Polyunsaturated PUFAs in the food chain in the United States. Am J Clin Nutr. 2000;71:S179-88.

23. Harris WS, Park Y, Isley WL.. Cardiovascular disease and long-chain omga-3 fatti acids. Curr Opin Lipidol. 2003;14:9-14. [Medline]
[Descargar cita]
24. Breivik H, ThorstadO.. Removal of organic environmental pollutants from fish oil by short-path distillation. Lipid Technology. 2005;17:55-8.

25. Jacobs MN, Santillo D, Johnston PA, Wyatt CL, French MC.. Organochlorine residues in fish oil dietary supplements: comparison with industrial grade oils. Chemosphere. 1998;37:1709-21. [Medline]
[Descargar cita]
26. Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults.. Executive Summary of the Third Report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, And Treatment of High Blood Cholesterol In Adults (Adult Treatment Panel III). JAMA. 2001;285:2486-97. [Medline]
[Descargar cita]
27. Van de Werf F, Ardissino D, Betriu A, Cokkinos DV, Falk E, Fox KA, et al.. Task Force on the Management of Acute Myocardial Infarction of the European Society of Cardiology. Management of acute myocardial infarction in patients presenting with ST-segment elevation. The Task Force on the Management of Acute Myocardial Infarction of the European Society of Cardiology. Eur Heart J. 2003;24:28-66. [Medline]
[Descargar cita]
28. Hokanson JE, Austin MA.. Plasma triglyceride level is a risk factor for cardiovascular disease independent of high-density lipoprotein cholesterol level: a meta-analysis of population-based prospective studies. J Cardiovasc Risk. 1996;3:213-9. [Medline]
[Descargar cita]
29. Borthwick L, on behalf of the UK Study Group.. The effects of an omega-3 ethyl ester concentrate on blood concentrations in patients with hyperlipidaemia. Clin Drug Invest. 1998;15:1-8.

30. Pownall HJ, Brauchi D, Kilinc C, Osmundsen K, Pao Q, Payton-Ross C, et al.. Correlation of serum triglyceride and its reduction by omega-3 fatty acids with lipid transfer activity and the neutral lipid compositions of high-density and low-density lipoproteins. Atherosclerosis. 1999;143:285-97. [Medline]
[Descargar cita]
31. Calabresi L, Villa B, Canavesi M, Sirtori CR, James RW, Bernini F, et al.. An omega-3 polyunsaturated fatty acid concentrate increases plasma high-density lipoprotein 2 cholesterol and paraoxonase levels in patients with familial combined hyperlipidemia. Metabolism. 2004;53:153-8. [Medline]
[Descargar cita]
32. Roche HM, Gibney MJ.. Postprandial triacylglycerolaemia: the effect of low-fat dietary treatment with and without fish oil supplementation. Eur J Clin Nutr. 1996;50:617-24. [Medline]
[Descargar cita]
33. Halminski MA, Marsh JB, Harrison EH.. Differential effects of fish oil, safflower oil and palm oil on fatty acid oxidation and glycerolipid synthesis in rat liver. J Nutr. 1991;121:1554-61. [Medline]
[Descargar cita]
34. Park Y, Harris WS.. Omega-3 fatty acid supplementation accelerates chylomicron triglyceride clearance. J Lipid Res. 2003; 44:455-63. [Medline]
[Descargar cita]
35. Willumsen N, Skorve J, Hexeberg S, Rustan AC, Berge RK.. The hypotriglyceridemic effect of eicosapentaenoic acid in rats is reflected in increased mitochondrial fatty acid oxidation followed by diminished lipogenesis. Lipids. 1993;28:683-90. [Medline]
[Descargar cita]
36. Bucher HC, Hengstler P, Schindler C, Meier G.. N-3 polyunsaturated fatty acids in coronary heart disease: a meta-analysis of randomized controlled trials. Am J Med. 2002;112:298-304. [Medline]
[Descargar cita]
37. Garaulet M, Pérez-Llamas F, Pérez-Ayala M, Martínez P, De Medina FS, Tebar FJ, et al.. Site-specific differences in the fatty acid composition of abdominal adipose tissue in an obese population from a Mediterranean area Relation with dietary fatty acids, plasma lipid profile, serum insulin, and central obesity. Am J Clin Nutr. 2001;74:585-91. [Medline]
[Descargar cita]
38. Bao DQ, Mori TA, Burke V, Puddey IB, Beilin LJ.. Effects of dietary fish and weight reduction on ambulatory blood pressure in overweight hypertensives. Hypertension. 1998;32:710-7. [Medline]
[Descargar cita]
39. Kriketos AD, Robertson RM, Sharp TA, Drougas H, Reed GW, Storlien LH et al.. Role of weight loss and polyunsaturated fatty acids in improving metabolic fitness in moderately obese, moderately hypertensive subjects. J Hypertens. 2001;19:1745-54. [Medline]
[Descargar cita]
40. Nettleton JA, Katz R.. N-3 long-chain polyunsaturated fatty acids in type 2 diabetes: a review. J Am Diet Assoc. 2005;105: 428-40. [Medline]
[Descargar cita]
41. Schraer CD, Mayer AM, Vogt AM, Naylor J, Brown TL, Hastie J, et al.. The Alaska Native diabetes program. Int J Circumpolar Health. 2001;60:487-94. [Medline]
[Descargar cita]
42. Montori VM, Farmer A, Wollan PC, Dinneen SF.. Fish oil supplementation in type 2 diabetes: a quantitative systematic review. Diabetes Care. 2000;23:1407-15. [Medline]
[Descargar cita]
43. Farmer A, Montori V, Dinneen S, Clar C.. Fish oil in people with type 2 diabetes mellitus. Cochrane Database Syst Rev. 2001;(3):CD003205. [Medline]
[Descargar cita]
44. Chan DC, Watts GF, Mori TA, Barrett PH, Redgrave TG, Beilin LJ.. Randomized controlled trial of the effect of n-3 fatty acid supplementation on the metabolism of apolipoprotein B-100 and chylomicron remnants in men with visceral obesity. Am J Clin Nutr. 2003;77:300-7. [Medline]
[Descargar cita]
45. Friedberg CE, Janssen MJ, Heine RJ, Grobbee DE.. Fish oil and glycemic control in diabetes: a meta-analysis. Diabetes Care. 1998;21:494-500. [Medline]
[Descargar cita]
46. American Diabetes Association. . Evidence-based nutrition principles and recommendations for the treatment and prevention of diabetes and related complications. Diabetes Care. 2002;25 Suppl 1:S50-60.

47. American Heart Association Web site.. Fish and omega-3 fatty acids: AHA Recommendation [accedido Ago 2005]. Disponible en: www.americanheart.org/presenter.jhtml?identifier=4632

48. Chan DC, Watts GF, Barrett PH, Beilin LJ, Mori TA.. Effect of atorvastatin and fish oil on plasma high-sensitivity C-reactive protein concentrations in individuals with visceral obesity. Clin Chem. 2002;48:877-83. [Medline]
[Descargar cita]
49. Durrington PN, Bhatnagar D, Mackness MI, Morgan J, Julier K, Khan MA, et al.. An omega-3 polyunsaturated fatty acid concentrate administered for one year decreased triglycerides in simvastatin treated patients with coronary heart disease and persisting hypertriglyceridaemia. Heart. 2001;85:544-8. [Medline]
[Descargar cita]
50. Nordøy A, Hansen J-B, Brox J, Svensson B.. Effects of atorvastatin and omega-3 fatty acids on LDL subfractions and postprandial hyperlipemia in patients with combined hyperlipemia. Nutr Metab Cardiovasc Dis. 2001;11:7-16. [Medline]
[Descargar cita]
51. Stalenhoef AF, De Graaf J, Wittekoek ME, Bredie SJ, Demacker PN, Kastelein JJ.. The effect of concentrated n-3 fatty acids versus gemfibrozil on plasma lipoproteins, low density lipoprotein heterogeneity and oxidizability in patients with hypertriglyceridemia. Atherosclerosis. 2000;153:129-38. [Medline]
[Descargar cita]
52. Howe PR.. Dietary fats and hypertension: focus on fish oil. Ann N Y Acad Sci. 1997;827:339-52. [Medline]
[Descargar cita]
53. Morris MC, Sacks F, Rosner B.. Does fish oil lower blood pressure? A meta-analysis of controlled trials. Circulation. 1993;88: 523-33. [Medline]
[Descargar cita]
54. Appel LJ, Miller ER 3rd, Seidler AJ, Whelton PK.. Does supplementation of diet with 'fish oil' reduce blood pressure? A meta-analysis of controlled clinical trials. Arch Intern Med. 1993;153: 1429-38. [Medline]
[Descargar cita]
55. Yosefy C, Viskoper JR, Laszt A, Priluk R, Guita E, Varon D, et al.. The effect of fish oil on hypertension, plasma lipids and hemostasis in hypertensive, obese, dyslipidemic patients with and without diabetes mellitus. Prostaglandins Leukot Essent Fatty Acids. 1999;61:83-7. [Medline]
[Descargar cita]
56. Goode GK, Garcia S, Heagerty AM.. Dietary supplementation with marine fish oil improves in vitro small artery endothelial function in hypercholesterolemic patients: a double-blind placebo-controlled study. Circulation. 1997;96:2802-7. [Medline]
[Descargar cita]
57. Leeson CP, Mann A, Kattenhorn M, Deanfield JE, Lucas A, Muller DP.. Relationship between circulating n-3 fatty acid concentrations and endothelial function in early adulthood. Eur Heart J. 2002;23:216-22. [Medline]
[Descargar cita]
58. Nestel P, Shige H, Pomeroy S, Cehun M, Abbey M, Raederstorff D.. The n-3 fatty acids eicosapentaenoic acid and docosahexaenoic acid increase systemic arterial compliance in humans. Am J Clin Nutr. 2002;76:326-30. [Medline]
[Descargar cita]
59. Engler MM, Engler MB, Malloy M, Chiu E, Besio D, Paul S, et al.. Docosahexaenoic acid restores endothelial function in children with hyperlipidemia: results from the EARLY study. Int. J. Clin Pharmacol Ther. 2004;42:672-9.

60. Shimokawa H, Jules Y, Lam T, Chesebro JH, Bowie EJW, Vanhoutte PM.. Effects of dietary supplementation with cod-liver oil on endothelium-dependent responses in porcine coronary arteries. Circulation. 1987;76:898-905. [Medline]
[Descargar cita]
61. Harris WS, Rambjor GS, Windsor SL, Diederich D.. N-3 fatty acids and urinary excretion of nitric oxide metabolites in humans. Am J Clin Nutr. 1997;65:459-64. [Medline]
[Descargar cita]
62. Mori TA, Woodman RJ, Burke V, Puddey IB, Croft KD, Beilin LJ.. Effect of eicosapentaenoic acid and docosahexaenoic acid on oxidative stress and inflammatory markers in treated-hypertensive type 2 diabetic subjects. Free Radical Bio Med. 2003;35: 772-81.

63. Mori TA, Beilin LJ, Burke V, Morris J, Ritchie J.. Interactions between dietary fat, fish, and fish oils and their effects on platelet function in men at risk of cardiovascular disease. Arterioscler Thromb Vasc Biol. 1997;17:279-86. [Medline]
[Descargar cita]
64. Agren JJ, Vaisanen S, Hanninen O, Muller AD, Hornstra G.. Hemostatic factors and platelet aggregation after a fish-enriched diet or fish oil or docosahexaenoic acid supplementation. Prostaglandins Leukot Essent Fatty Acids. 1997;57:419-21. [Medline]
[Descargar cita]
65. Knapp HR.. Dietary fatty acids in human thrombosis and hemostasis. Am J Clin Nutr. 1997;65 5 Suppl:S1687-98.

66. Bayon Y, Croset M, Daveloose D, Guerbette F, Chirouze V, Viret J, et al.. Effect of specific phospholipid molecular species incorporated in human platelet membranes on thromboxane A2/prostaglandin H2 receptors. J Lipid Res. 1995;36:47-56. [Medline]
[Descargar cita]
67. Barcelli U, Glas-Greenwalt P, Pollak VE.. Enhancing effect of dietary supplementation with omega-3 fatty acids on plasma fibrinolysis in normal subjects. Thromb Res. 1985; 39:307-12. [Medline]
[Descargar cita]
68. Mehta J, Lawson D, Saldeen TJ. . Reduction in plasminogen activator inhibitor-1 (PAI-1) with omega-3 polyunsaturated fatty acid (PUFA) intake. Am Heart J. 1988;116:1201-6. [Medline]
[Descargar cita]
69. Weiner BH, Ocene IS, Levine PH, Cuenoud HF, Fisher M, Johnson BF, et al.. Inhibition of atherosclerosis by cod-liver oil in a hyperlipidemic swine model. N Engl J Med. 1986;315:841-6. [Medline]
[Descargar cita]
70. Davis BC, Kris-Etherton PM.. Achieving optimal essential fatty acid status in vegetarians: current knowledge and practical implications. Am J Clin Nutr. 2003;78 3 Suppl:S640-6.

71. Mortensen A, Hansen BF, Hansen JF, Frandsen H, Bartnikowska E, Andersen PS, et al.. Comparison of the effects of fish oil and olive oil on blood lipids and aortic atherosclerosis in Watanabe heritable hyperlipidaemic rabbits. Br J Nutr. 1998;80:565-573. [Medline]
[Descargar cita]
72. Von Schacky C, Angerer P, Kothny W, Theisen K, Mudra H.. The effect of dietary omega-3 fatty acids on coronary atherosclerosis: a randomized, double-blind, placebo-controlled trial. Ann Intern Med. 1999;130:554-62. [Medline]
[Descargar cita]
73. Maresta A, Balduccelli M, Varani E, Marzilli M, Galli C, Heiman F, et al.. ESPRIT Investigators. Prevention of post-coronary angioplasty restenosis by omega-3 fatty acids: main results of the Esapent for Prevention of Restenosis Italian Study (ESPRIT). Am Heart J. 2002;143:E5. [Medline]
[Descargar cita]
74. Erkkila AT, Lichtenstein AH, Mozaffarian D, Herrington DM.. Fish intake is associated with a reduced progression of coronary artery atherosclerosis in postmenopausal women with coronary artery disease. Am J Clin Nutr. 2004;80:626-32. [Medline]
[Descargar cita]
75. Thies F, Garry JM, Yaqoob P, Rerkasem K, Williams J, Shearman CP, et al.. Association of n-3 polyunsaturated fatty acids with stability of atherosclerotic plaques: a randomised controlled trial. Lancet. 2003;361:477-85. [Medline]
[Descargar cita]
76. Calder PC.. Polyunsaturated fatty acids, inflammation, and immunity. Lipids. 2001;36:1007-24. [Medline]
[Descargar cita]
77. Mori TA, Beilin LJ.. Omega-3 fatty acids and inflammation. Curr Atheroscler Rep. 2004;6:461-7. [Medline]
[Descargar cita]
78. Tremoli E, Mosconi C, Maderna P, Colli S, Stragliotto E, Sirtori CR, et al.. Effects of EPA and DHA ethylesters on plasma fatty acids and on platelets, PMN and monocytes in healthy volunteers. Adv Prostaglandin Thromboxane Leukot Res. 1991;21A: 233-6. [Medline]
[Descargar cita]
79. De Caterina R, Liao JK, Libby P.. Fatty acid modulation of endothelial activation. Am J Clin Nutr. 2000;71 Suppl:S213-23.

80. De Caterina R, Zampolli A.. n-3 fatty acids: antiatherosclerotic effects. Lipids. 2001;36 Suppl:S69-78.

81. Chen H, Li D, Chen J, Roberts GJ, Saldeen T, Mehta JL.. EPA and DHA attenuate ox-LDL-induced expression of adhesion molecules in human coronary artery endothelial cells via protein kinase B pathway. J Mol Cell Cardiol. 2003;35:769-75. [Medline]
[Descargar cita]
82. Mayer K, Meyer S, Reinholz-Muhly M, Maus U, Merfels M, Lohmeyer J, et al.. Short-time infusion of fish oil-based lipid emulsions, approved for parenteral nutrition, reduces monocyte proinflammatory cytokine generation and adhesive interaction with endothelium in humans. J Immunol. 2003;171:4837-43. [Medline]
[Descargar cita]
83. Kielar ML, Jeyarajah DR, Penfield JG, Lu CY.. Docosahexaenoic acid decreases IRF-1 mRNA and thus inhibits activation of both the IRF-E and NFkappa d response elements of the iNOS promoter. Transplantation. 2000;69:2131-7. [Medline]
[Descargar cita]
84. Babcock TA, Kurland A, Helton WS, Rahman A, Anwar KN, Espat NJ.. Inhibition of activator protein-1 transcription factor activation by omega-3 fatty acid modulation of mitogen-activated protein kinase signaling kinases. JPEN J Parenter Enteral Nutr. 2003;27:176-80. [Medline]
[Descargar cita]
85. Zhao Y, Joshi-Barve S, Barve S, Chen LH.. Eicosapentaenoic acid prevents LPS-induced TNF-alpha expression by preventing NF-*B activation. J Am Coll Nutr. 2004;23:71-8. [Medline]
[Descargar cita]
86. Ait-Said F, Elelamy I, Werts C, Gomard MT, Jacquemin C, Couetil JP, et al.. Inhibition by eicosapentaenoic acid of IL-1beta-induced PGHS-2 expression in human microvascular endothelial cells: involvement of lipoxygenase-derived metabolites and p38 MAPK pathway. Biochim Biophys Acta. 2003;1631: 77-84. [Medline]
[Descargar cita]
87. Endres S, Von Schacky C.. n-3 polyunsaturated fatty acids and human cytokine synthesis. Curr Opin Lipidol. 1996;7:48-52. [Medline]
[Descargar cita]
88. Lo CJ, Chiu KC, Fu M, Lo R, Helton S.. Fish oil decreases macrophage tumor necrosis factor gene transcription by altering the NF kappa B activity. J Surg Res. 1999;82:216-21. [Medline]
[Descargar cita]
89. Kaminski WE, Jendraschak E, Kiefl R, Von Schacky C.. Dietary omega-3 fatty acids lower levels of platelet-derived growth factor mRNA in human mononuclear cells. Blood. 1993;81:1871-9. [Medline]
[Descargar cita]
90. Von Schacky C.. Dietary omega-3 fatty acids and human growth factor and cytokine gene expression. Eur Heart J. 2001;3 Suppl D:D50-2.

91. Jump DB.. The biochemistry of n-3 polyunsaturated fatty acids. J Biol Chem. 2002;277:8755-8. [Medline]
[Descargar cita]
92. Xu HE, Lambert MH, Montana VG, Parks DJ, Blanchard SG, Brown PJ et al.. Molecular recognition of fatty acids by peroxisome proliferator-activated receptors. Mol Cell. 1999;3:397-403. [Medline]
[Descargar cita]
93. Marx N, Sukhova GK, Collins T, Libby P, Plutzky J.. PPAR-* activators inhibit cytokine-induced vascular cell adhesion molecule-1 expression in human endothelial cells. Circulation. 1999; 99:3125-31. [Medline]
[Descargar cita]
94. Ou J, Tu H, Shan B, Luk A, DeBose-Boyd RA, Bashmakov Y, et al.. Unsaturated fatty acids inhibit transcription of the sterol regulatory element-binding protein-1c (SREBP-1c) gene by antagonizing ligand-dependent activation of the LXR. Proc Natl Acad Sci USA. 2001;98:6027-32. [Medline]
[Descargar cita]
95. Mishra A, Chaudhary A, Sethi S.. Oxidized omega-3 fatty acids inhibit NF-kappaB activation via a PPARalpha-dependent pathway. Arterioscler Thromb Vasc Biol. 2004;24:1621-7. [Medline]
[Descargar cita]
96. López-García E, Schulze MB, Manson JE, Meigs JB, Albert CM, Rifai N, et al.. Consumption of (n-3) fatty acids is related to plasma biomarkers of inflammation and endothelial activation in women. J Nutr. 2004;134:1806-11. [Medline]
[Descargar cita]
97. Hjerkinn EM, Seljeflot I, Ellingsen I, Berstad P, Hjermann I, Sandvik L, et al.. Influence of long-term intervention with dietary counseling, long-chain n-3 fatty acid supplements, or both on circulating markers of endothelial activation in men with long-standing hyperlipidemia. Am J Clin Nutr. 2005;81:583-9. [Medline]
[Descargar cita]
98. Moyad MA.. An introduction to dietary/supplemental omega-3 fatty acids for general health and prevention. Part II. Urologic Oncology. 2005;23:36-48. [Medline]
[Descargar cita]
99. Singh RB, Niaz MA, Sharma JP, Kumar R, Rastogi V, Moshiri M.. Randomized, double-blind, placebo-controlled trial of fish oil and mustard oil in patients with suspected acute myocardial infarction: the Indian experiment of infarct survival-4. Cardiovasc Drugs Ther. 1997;11:4859-1.

100. Mozaffarian D, Lemaitre RN, Kuller LH, Burke GL, Tracy RP, Siscovick DS.. Cardiovascular Health Study. Cardiac benefits of fish consumption may depend on the type of fish meal consumed: the Cardiovascular Health Study. Circulation. 2003;107: 1372-7. [Medline]
[Descargar cita]
101. Mozaffarian D, Psaty BM, Rimm EB, Lemaitre RN, Burke GL, Lyles MF, et al.. Fish intake and risk of incident atrial fibrillation. Circulation. 2004;110:368-73. [Medline]
[Descargar cita]
102. McLennan PL.. Myocardial membrane fatty acids and the antiarrhythmic actions of dietary fish oil in animal models. Lipids. 2001;36 Suppl:S111-4.

103. Whelton SP, He J, Whelton PK, Muntner P.. Meta-analysis of observational studies on fish intake and coronary heart disease. Am J Cardiol. 2004;93:1119-23. [Medline]
[Descargar cita]
104. Rissanen T, Voutilainen S, Nyyssonen K, Lakka TA, Salonen JT.. Fish oil-derived fatty acids, docosahexaenoic acid and docosapentaenoic acid, and the risk of acute coronary events: the Kuopio ischaemic heart disease risk factor study. Circulation. 2000;102:2677-9. [Medline]
[Descargar cita]
105. Eritsland J, Arnesen H, Gronseth K, Fjeld NB, Abdelnoor M.. Effect of dietary supplementation with n-3 fatty acids on coronary artery bypass graft patency. Am J Cardiol. 1996;77:31-6. [Medline]
[Descargar cita]
106. Marchioli R, Barzi F, Bomba E, Chieffo C, Di Gregorio D, Di Mascio R, et al.. GISSI-Prevenzione Investigators. 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 Sopravivenza nell'Infarto Miocardico (GISSI)-Prevenzione. Circulation. 2002;105: 1897-903. [Medline]
[Descargar cita]
107. McLennan PL, Abeywardena MY, Charnock JS.. Dietary fish oil prevents ventricular fibrillation following coronary artery occlusion and reperfusion. Am Heart J. 1988;116:709-17. [Medline]
[Descargar cita]
108. Hock CE, Beck LD, Bodine RC, Reibel DK.. Influence of dietary n-3 fatty acids on myocardal ischemia and reperfusion. Am J Physiol. 1990;259:H1518-26. [Medline]
[Descargar cita]
109. Yang B, Saldeen TG, Nichols WW, Mehta JL.. Dietary fish oil supplementation attenuates myocardial dysfunction and injury caused by global ischemia and reperfusion in isolated rat hearts. J Nutr. 1993;123:2067-74. [Medline]
[Descargar cita]
110. Billman GE, Hallaq H, Leaf A.. Prevention of ischemia-induced ventricular fibrillation by -3 fatty acids. Proc Natl Acad Sci USA. 1994;91:4427-30. [Medline]
[Descargar cita]
111. Charnock JS.. Dietary fats and cardiac arrhythmia in primates. Nutrition. 1994;10:161-9. [Medline]
[Descargar cita]
112. McLennan PL, Bridle TM, Abeywardena MY, Charnock JS.. Dietary lipid modulation of ventricular fibrillation threshold in the marmoset monkey. Am Heart J. 1992;123:1555-61. [Medline]
[Descargar cita]
113. Kang JX, Leaf A.. Prevention of fatal cardiac arrhythmias by polyunsaturated fatty acids. Am J Clin Nutr. 2000;71 1 Suppl:S 202-7.

114. Pepe S, McLennan PL.. Cardiac membrane fatty acid composition modulates myocardial oxygen consumption and postischemic recovery of contractile function. Circulation. 2002;105: 2303-8. [Medline]
[Descargar cita]
115. Mozaffarian D, Bryson CL, Lemaitre RN, Burke GL, Siscovick DS.. Fish intake and risk of incident heart failure. Mozaffarian D. J Am Coll Cardiol. 2005;45:2015-21. [Medline]
[Descargar cita]
116. Calo L, Bianconi L, Colivicchi F, Lamberti F, Loricchio ML, De Ruvo E, et al.. N-3 Fatty acids for the prevention of atrial fibrillation after coronary artery bypass surgery: a randomized, controlled trial. J Am Coll Cardiol. 2005;45:1723-8. [Medline]
[Descargar cita]
117. Stein PK, Kleiger RE.. Insights from the study of heart rate variability. Annu Rev Med. 1999;50:249-61 [Medline]
[Descargar cita]
118. Christensen JH, Korup E, Aaroe J, Toft E, Moller J, Rasmussen K, et al.. Fish consumption, n-3 fatty acids in cell membranes, and heart rate variability in survivors of myocardial infarction with left ventricular dysfunction. Am J Cardiol. 1997;79:1670-3. [Medline]
[Descargar cita]
119. Villa B, Calabresi L, Chiesa G, Rise P, Galli C, Sirtori CR.. Omega-3 fatty acid ethyl esters increase heart rate variability in patients with coronary disease. Pharmacol Res. 2002;45:475. [Medline]
[Descargar cita]
120. Grimsgaard S, Bonaa KH, Hansen JB, Myhre ES.. Effects of highly purified eicosapentaenoic acid and docosahexaenoic acid on hemodynamics in humans. Am J Clin Nutr. 1998;68:52-9. [Medline]
[Descargar cita]
121. Kang JX, Leaf A.. Evidence that free polyunsaturated fatty acids modify Na+ channels by directly binding to the channel proteins. Proc Natl Acad Med Sci USA. 1996;93:3542-6.

122. Kang JX.. The importance of omega-6/omega-3 fatty acid ratio in cell function. The genetransfer of omega-3 fatty acid desaturase. World Rev Nutr Diet. 2003;92:23-36. [Medline]
[Descargar cita]
123. Leaf A.. The electrophysiological basis for the antiarrhythmic actions of polyunsaturated fatty acids. Eur Heart J. 2001;3 Suppl D:D98-105.

124. Xiao YF, Gómez AM, Morgan JP, Lederer WJ, Leaf A.. Suppression of voltage-gated L-type Ca2+ currents by polyunsaturated fatty acids in adult and neonatal rat ventricular myocytes. Proc Natl Acad Sci U S A. 1997;94:4182-7. [Medline]
[Descargar cita]
125. Xiao YF, Kang JX, Morgan JP, Leaf A.. Blocking effects of polyunsaturated fatty acids on Na+ channels of neonatal rat ventricular myocytes. Proc Natl Acad Sci U S A. 1995;92:11000-4. [Medline]
[Descargar cita]
126. Xiao Y-F, Wright SN, Wang GK, Morgan JP, Leaf A.. N-3 fatty acids suppress voltage-gated Na+ currents in HEK293t cells transfected with the á-subunit of the human cardiac Na+ channel, Proc Natl Acad Sci U S A. 1998;95:2680-5.

127. De Caterina R, Madonna R, Zucchi R, La Rovere MT.. Antiarrhythmic effects of omega-3 fatty acids: from epidemiology to bedside. Am Heart J. 2003;146:420-30. [Medline]
[Descargar cita]
128. Madsen T, Skou HA, Hansen VE, Fog L, Christensen JH, Toft E, et al.. C-reactive protein, dietary n-3 fatty acids, and the extent of coronary artery disease. Am J Cardiol. 2001; 88:1139-42 [Medline]
[Descargar cita]
129. Jump DB, Clarke SD.. Regulation of gene expression by dietary fat. Annu Rev Nutr. 1999,19:63-90.

130. Joy CB, Mumby-Croft R, Joy LA. . Polyunsaturated fatty acid supplementation for schizophrenia. Cochrane Database Syst Rev. 2003;(2):CD001257. [Medline]
[Descargar cita]
131. Kromann N, Green A.. Epidemiological studies in the Upernavik district, Greenland Incidence of some chronic diseases, 1950-1974. Acta Med Scand. 1980;208:401-6. [Medline]
[Descargar cita]
132. Pedersen HA, Mulvad G, Seidelin KN, Malcom GT, Boudreau DA.. N-3 fatty acids as a risk factor for haemorrhagic stroke. Lancet. 1999;353:812-3. [Medline]
[Descargar cita]
133. He K, Rimm EB, Merchant A, Rosner BA, Stampfer MJ, Willett WC, et al.. Fish consumption and risk of stroke in men. JAMA. 2002;288:3130-6. [Medline]
[Descargar cita]
134. Iso H, Rexrode KM, Stampfer MJ, Manson JE, Colditz GA, Speizer FE, et al.. Intake of fish and omega-3 fatty acids and risk of stroke in women. JAMA. 2001;285:304-12. [Medline]
[Descargar cita]
135. Mozaffarian D, Longstreth WT Jr, Lemaitre RN, Manolio TA, Kuller LH, Burke GL, Siscovick DS.. Fish consumption and stroke risk in elderly individuals: the cardiovascular health study. Arch Intern Med. 2005;165:200-6. [Medline]
[Descargar cita]
136. Farrer LA, Bowirrat A, Friedland RP, Waraska K, Korczyn AD, Baldwin CT.. Identification of multiple loci for Alzheimer disease in a consanguineous Israeli-Arab community. Hum. Mol Genet. 2003;12:415-22.

137. Sparks DL, Martin TA, Grss DR, Hunsaker JC 3rd.. Link between heart disease, cholesterol, and Alzheimer's disease: a review. Microsc Res Tech. 2000;50:287-90. [Medline]
[Descargar cita]
138. Zuijdgeest-van-Leeuwen SD, Dagnelie PC, Rietveld T, Van den Berg JW, Wilson JH.. Incorporation and washout of orally administered n-3 fatty acid ethyl esters in different plasma lipid fractions. Br J Nutr. 1999;82:481-8. [Medline]
[Descargar cita]
139. Rupp H.. Risk stratification by the EPA+DHA level and the EPA/AA ratio. Focus on Anti-inflammatory and Antiarrhythmogenic effects of long-chain omega-3 fatty acids. Herz. 2004;29: 673-85. [Medline]
[Descargar cita]
140. Luley C, Wieland H, Grünwald J.. Bioavailability of omega-3 fatty acids: ethylester preparations are as suitable as triglyceride preparationhs. Akt Ernährungsmed. 1990:15:123-5.

141. Hilbert G, Lillemark L, Balchen S, Hojskov CS.. Reduction of organochlorine contaminants from fish oil during refining. Chemosphere. 1998;37:1241-52. [Medline]
[Descargar cita]
142. US Food and Drug Administration.. US Environmental Protection Agency. What You Need to Know About Mercury in Fish and Shellfish: 2004 EPA and FDA Advice for Women Who Might Become Pregnant, Women Who Are Pregnant, Nursing Mothers, Young Children. March 2004. EPA 823-F-04-009.

143. US Food and Drug Administration.. Letter responding to health claim petition dated June 23, 2003 (Wellness petition): omega-3 fatty acids and reduced risk of coronary heart disease. Disponible en: http://frwebgate.access.gpo.gov/cgibin/getdoc.cgi?dbname=1997_register&doci;

144. Mataix J, Aranceta J.. Aceites y grasas. En: Sociedad Española de Nutrición Comunitaria. Guías alimentarias para la población española. Madrid: 2001; p. 121-32.





Rev Esp Cardiol 2006; 6: 3 - 19
ISSN : 1579-2242