Información del artículo
El consumo de alimentos ricos en ácidos grasos omega-3 o la ingesta de complementos que contienen estos compuestos reducen la morbimortalidad cardiovascular. El beneficio clínico de estos compuestos es independiente de la reducción de colesterol pues, aunque disminuyen significativamente las concentraciones de triglicéridos de forma dependiente de la dosis, no modifican prácticamente los concentraciones de colesterol unido a lipoproteínas de baja densidad. Además, los resultados del estudio GISSI indican que la reducción de la mortalidad cardiovascular puede deberse principalmente a sus efectos antiarrítmicos. La necesidad de controlar las concentraciones de triglicéridos y de colesterol en pacientes con hiperlipidemia combinada plantea la cuestión de si la administración de estos compuestos junto con las estatinas, que mejora el perfil lipídico en estos pacientes, también puede incrementar la reducción de la mortalidad cardiovascular. En este artículo se revisan los mecanismos a través de los cuales ejercen su efecto clínico los ácidos grasos omega-3 y se analiza en qué medida su acción «farmacológica» complementa la actividad hipolipidemiante de las estatinas y puede ser aditiva sobre los efectos pleiotrópicos de estos fármacos. De hecho, los resultados parciales del estudio JELIS (Japan EPA Lipid Intervention Study) señalan que el tratamiento combinado con ambos podría aumentar la protección cardiovascular y reducir la mortalidad.
Palabras clave:
Ácidos grasos omega-3
Estatinas
Hipercolesterolemia
Efectos pleiotrópicos
Estudios clínicos
Abreviaturas:
AGPI
ALA
CI
COX
DART
DHA
EPA
FMD
GISSI
HDL
IAM
ICAM-I
IECA
JELIS
LDL
LOX
LTB5
NCEP
NO
PAI-1
RR
4S
TFPI
TNT
TXA3
VCAM-I
VLDL
Omega-3 polyunsaturated fatty acids reduce cardiovascular morbidity and mortality. The clinical benefit of these compounds is independent of the reduction in cholesterol level because they decrease the triglyceride level significantly in a dose-dependent manner while having practically no effect on the low-density lipoprotein cholesterol level. In addition, the results of the GISSI study indicate that the reduction in cardiovascular mortality associated with these compounds may be principally due to their antiarrhythmic properties. The need to control both triglyceride and cholesterol levels in patients suffering mixed hyperlipidemia raises the question of whether combined administration of these compounds with statins (a combination known to improve the lipid profile in these patients) further reduces cardiovascular mortality. In this article, we review the mechanisms responsible for the clinical effects of omega-3 fatty acids and discuss the extent to which their «pharmacological» action complements the lipid-lowering effects of statins and could supplement the pleiotropic effects of these drugs. In fact, early results of the Japan EPA Lipid Intervention Study (JELIS) suggest that combined treatment with omega-3 fatty acids and statins could increase cardiovascular protection and reduce mortality.
Key words:
Omega-3 fatty acids
Statins
Hypercholesterolemia
Pleiotropic effects
Clinical trials
El Texto completo está disponible en PDF
Bibliografía
[1.]
S. Yusuf, S. Hawken, S. Ounpuu, T. Dans, A. Avezum, F. Lanas, INTERHEART Study Investigators, et al.
Effect of potentially modifiable risk factors associated with myocardial infarction in 52 countries (the INTERHEART study): case-control study.
Lancet, 364 (2004), pp. 937-952
[2.]
Martínez-González J, Badimon L. Influence of statin use on endothelail function: from bench to clinics. Curr Pharm Design. 2006. En prensa.
[3.]
Randomised trial of cholesterol lowering in 4444 patients with coronary heart disease: the Scandinavian Simvastatin Survival Study (4S) Lancet. 1994;344:1383-9.
[4.]
H.O. Bang, J. Dyerberg, N. Hjoorne.
The composition of food consumed by Greenland Eskimos.
Acta Med Scand, 200 (1976), pp. 69-73
[5.]
H.O. Bang, J. Dyerberg, H.M. Sinclair.
The composition of the Eskimo food in north western Greenland.
Am J Clin Nutr, 33 (1980), pp. 2657-2661
[6.]
D. Kromhout, E.B. Bosschieter, C. De Lezenne Coulander.
The inverse relation between fish consumption and 20-year mortality from coronary heart disease.
N Engl J Med, 312 (1985), pp. 1205-1209
[7.]
M.L. Burr, A.M. Fehily, J.F. Gilbert, S. Rogers, R.M. Holliday, P.M. Sweetnam, et al.
Effects of changes in fat, fish, and fibre intakes on death and myocardial reinfarction: diet and reinfarction trial (DART).
Lancet, 2 (1989), pp. 757-761
[8.]
M. De Lorgeril, P. Salen, J.L. Martin, I. Monjaud, J. Delaye, N. Mamelle.
Mediterranean diet, traditional risk factors, and the rate of cardiovascular complications after myocardial infarction: final report of the Lyon Diet Heart Study.
Circulation, 99 (1999), pp. 779-785
[9.]
C.M. Albert, C.H. Hennekens, C.J. O’Donnell, U.A. Ajani, V.J. Carey, W.C. Willett, et al.
Fish consumption and risk of sudden cardiac death.
JAMA, 279 (1998), pp. 23-28
[10.]
F.B. Hu, L. Bronner, W.C. Willett, M.J. Stampfer, K.M. Rexrode, C.M. Albert, et al.
Fish and omega-3 fatty acid intake and risk of coronary heart disease in women.
JAMA, 287 (2002), pp. 1815-1821
[11.]
F.B. Hu, E. Cho, K.M. Rexrode, C.M. Albert, J.E. Manson.
Fish and long-chain omega-3 fatty acid intake and risk of coronary heart disease and total mortality in diabetic women.
Circulation, 107 (2003), pp. 1852-1857
[12.]
C.M. Albert, H. Campos, M.J. Stampfer, P.M. Ridker, J.E. Manson, et al.
Blood levels of long-chain n-3 fatty acids and the risk of sudden death.
N Engl J Med, 346 (2002), pp. 1113-1118
[13.]
N. Harrison, B. Abhyankar.
The mechanism of action of omega-3 fatty acids in secondary prevention post-myocardial infarction.
Curr Med Res Opin, 21 (2005), pp. 95-100
[14.]
K. He, Y. Song, M.L. Daviglus, K. Liu, L. Van Horn, A.R. Dyer, et al.
Accumulated evidence on fish consumption and coronary heart disease mortality: a meta-analysis of cohort studies.
Circulation, 109 (2004), pp. 2705-2711
[15.]
Gruppo Italiano per lo Studio della Sopravvivenza nell’Infarto miocardico (GISSI).
Dietary supplementation with n-3 polyunsaturated fatty acids and vitamin E after myocardial infarction: results of the GISSI-Prevenzione trial.
Lancet, 354 (1999), pp. 447-455
[16.]
R. Marchioli, F. Barzi, E. Bomba, C. Chieffo, D. Di Gregorio, R. Di Mascio, The GISSI-Prevenzione Investigators, et al.
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 (2002), pp. 1897-1903
[17.]
H. Rupp, C.N. Verboom, B. Jager.
Saving lives post-MI: highly purified omega-3 PUFAs fotr the prevention of sudden death.
J Clin Basic Cardiol, 5 (2002), pp. 209-214
[18.]
J.X. Kang, A. Leaf.
Antiarrhythmic effects of polyunsaturated fatty acids. Recent studies.
Circulation, 94 (1996), pp. 1774-1780
[19.]
A. Leaf.
The electrophysiological basis for the antiarrhythmic actions of polyunsatured fatty acids.
Eur Heart J Suppl, (2001), pp. D98-D105
[20.]
W.S. Harris.
N-3 fatty acids and serum lipoproteins: human studies.
Am J Clin Nutr, (1997), pp. S1645-S1654
[21.]
L.H. Storlien, A.J. Hulbert, P.L. Else.
Polyunsaturated fatty acids, membrane function and metabolic diseases such as diabetes and obesity.
Curr Opin Clin Nutr Metab Care, 1 (1998), pp. 559-563
[22.]
P.L. McLennan, M.Y. Abeywardena, J.S. Charnock.
Influence of dietary lipids on arrhythmias and infarction after coronary artery ligation in rats.
Can J Physiol Pharmacol, 63 (1985), pp. 1411-1417
[23.]
Y.F. Xiao, A.M. Gomez, J.P. Morgan, W.J. Lederer, A. Leaf.
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, 94 (1997), pp. 4182-4187
[24.]
J.H. Chiu, R.H. Abdelhadi, M.K. Chung, H.S. Gurm, N.F. Marrouche, W.I. Saliba, et al.
Effect of statin therapy on risk of ventricular arrhythmia among patients with coronary artery disease and an implantable cardioverter-defibrillator.
Am J Cardiol, 95 (2005), pp. 490-491
[25.]
F. Marin, D.A. Pascual, V. Roldan, J.M. Arribas, M. Ahumada, P.L. Tornel, et al.
Statins and postoperative risk of atrial fibrillation following coronary artery bypass grafting.
Am J Cardiol, 97 (2006), pp. 55-60
[26.]
W.S. Harris, H.N. Ginsberg, N. Arunakul, N.S. Shachter, S.L. Windsor, M. Adams, et al.
Safety and efficacy of Omacor in severe hypertriglyceridemia.
J Cardiovasc Risk, 4 (1997), pp. 385-391
[27.]
L. Calabresi, B. Villa, M. Canavesi, C.R. Sirtori, R.W. James, F. Bernini, 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, 53 (2004), pp. 153-158
[28.]
M. Studer, M. Briel, B. Leimenstoll, T.R. Glass, H.C. Bucher.
Effect of different antilipidemic agents and diets on mortality: a systematic review.
Arch Intern Med, 165 (2005), pp. 725-730
[29.]
J.C. LaRosa, S.M. Grundy, D.D. Waters, C. Shear, P. Barter, J.C. Fruchart, Treating to New Targets (TNT) Investigators, et al.
Intensive lipid lowering with atorvastatin in patients with stable coronary disease.
N Engl J Med, 352 (2005), pp. 1425-1435
[30.]
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, 285 (2001), pp. 2486-2497
[31.]
G. De Backer, E. Ambrosioni, K. Borch-Johnsen, C. Brotons, R. Cifkova, J. Dallongeville, et al.
Third Joint Task Force of European and Other Societies on Cardiovascular Disease Prevention in Clinical Practice. European guidelines on cardiovascular disease prevention in clinical practice. Third Joint Task Force of European and Other Societies on Cardiovascular Disease Prevention in Clinical Practice.
Eur Heart J, 24 (2003), pp. 1601-1610
[32.]
D. Bhatnagar, M.I. Mackness, P.N. Durrington.
Treatment of mixed hyperlipidaemia using a combination of omega-3 fatty acids and HMG-CoA reductase inhibitor.
Eur Heart J Supp, (2001), pp. D53-D58
[33.]
C. Contacos, P.J. Barter, D.R. Sullivan.
Effect of pravastatin and omega-3 fatty acids on plasma lipids and lipoproteins in patients with combined hyperlipidemia.
Arterioscler Thromb, 13 (1993), pp. 1755-1762
[34.]
A. Nordoy, K.H. Bonaa, H. Nilsen, R.K. Berge, J.B. Hansen, O.C. Ingebretsen.
Effects of Simvastatin and omega-3 fatty acids on plasma lipoproteins and lipid peroxidation in patients with combined hyperlipidaemia.
J Intern Med, 243 (1998), pp. 163-170
[35.]
A. Nordoy, K.H. Bonaa, P.M. Sandset, J.B. Hansen, H. Nilsen.
Effect of omega-3 fatty acids and simvastatin on hemostatic risk factors and postprandial hyperlipemia in patients with combined hyperlipemia.
Arterioscler Thromb Vasc Biol, 20 (2000), pp. 259-265
[36.]
P.N. Durrington, D. Bhatnagar, M.I. Mackness, J. Morgan, K. Julier, M.A. Khan, 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, 85 (2001), pp. 544-548
[37.]
A. Nordoy, J.B. Hansen, J. Brox, B. Svensson.
Effects of atorvastatin and omega-3 fatty acids on LDL subfractions and postprandial hyperlipemia in patients with combined hyperlipemia.
Nutr Metab Cardiovasc Dis, 11 (2001), pp. 7-16
[38.]
L. Tavazzi, G. Tognoni, M.G. Franzosi, R. Latini, A.P. Maggioni, R. Marchioli, GISSI-HF Investigators, et al.
Rationale and design of the GISSI heart failure trial: a large trial to assess the effects of n-3 polyunsaturated fatty acids and rosuvastatin in symptomatic congestive heart failure.
Eur J Heart Fail, 6 (2004), pp. 635-641
[39.]
J.G. Cleland, N. Freemantle, A.P. Coletta, A.L. Clark.
Clinical trials update from the American Heart Association: REPAIR-AMI, ASTAMI, JELIS, MEGA, REVIVE-II, SURVIVE, and PROACTIVE.
Eur J Heart Fail, 8 (2006), pp. 105-110
[40.]
M.Y. Abeywardena, J.S. Charnock.
Dietary lipid modification of myocardial eicosanoids following ischemia and reperfusion in the rat.
Lipids, 30 (1995), pp. 1151-1156
[41.]
K. Vanschoonbeek, M.A. Feijge, M. Paquay, J. Rosing, W. Saris, C. Kluft, et al.
Variable hypocoagulant effect of fish oil intake in humans: modulation of fibrinogen level and thrombin generation.
Arterioscler Thromb Vasc Biol, 24 (2004), pp. 1734-1740
[42.]
J. Mehta, D. Lawson, T.J. Saldeen.
Reduction in plasminogen activator inhibitor-1 (PAI-1) with omega-3 polyunsaturated fatty acid (PUFA) intake.
Am Heart J, 116 (1988), pp. 1201-1206
[43.]
J. Alfon, T. Royo, X. García-Moll, L. Badimon.
Platelet deposition on eroded vessel walls at a stenotic shear rate is inhibited by lipid-lowering treatment with atorvastatin.
Arterioscler Thromb Vasc Biol, 19 (1999), pp. 1812-1817
[44.]
L. Casani, S. Sánchez-Gómez, G. Vilahur, L. Badimon.
Pravastatin reduces thrombogenicity by mechanisms beyond plasma cholesterol lowering.
Thromb Haemost, 94 (2005), pp. 1035-1041
[45.]
L. Mussoni, C. Banfi, L. Sironi, M. Arpaia, E. Tremoli.
Fluvastatin inhibits basal and stimulated plasminogen activator inhibitor 1, but induces tissue type plasminogen activator in cultured human endothelial cells.
Thromb Haemost, 84 (2000), pp. 59-64
[46.]
M. Zeman, A. Zak, M. Vecka, E. Tvrzicka, A. Pisarikova, B. Stankova.
N-3 fatty acid supplementation decreases plasma homocysteine in diabetic dyslipidemia treated with statin-fibrate combination.
J Nutr Biochem, (2005),
[47.]
L. Badimon, J. Martínez-González.
Endothelium and vascular protection: an update.
Rev Esp Cardiol, (2002), pp. 17-26
[48.]
L. Badimon, Martínez-González.
Endothelial dysfunction.
Rev Esp Cardiol, 6 (2006), pp. 21A-30A
[49.]
C.P. Leeson, A. Mann, M. Kattenhorn, J.E. Deanfield, A. Lucas, D.P. Muller.
Relationship between circulating n-3 fatty acid concentrations and endothelial function in early adulthood.
Eur Heart J, 23 (2002), pp. 216-222
[50.]
M.M. Engler, M.B. Engler, M. Malloy, E. Chiu, D. Besio, S. Paul, et al.
Docosahexaenoic acid restores endothelial function in children with hyperlipidemia: results from the EARLY study.
Int J Clin Pharmacol Ther, 42 (2004), pp. 672-679
[51.]
J. Goodfellow, M.F. Bellamy, M.W. Ramsey, C.J. Jones, M.J. Lewis.
Dietary supplementation with marine omega-3 fatty acids improve systemic large artery endothelial function in subjects with hypercholesterolemia.
J Am Coll Cardiol, 35 (2000), pp. 265-270
[52.]
Y. Okuda, K. Kawashima, T. Sawada, K. Tsurumaru, M. Asano, S. Suzuki, et al.
Eicosapentaenoic acid enhances nitric oxide production by cultured human endothelial cells.
Biochem Biophys Res Commun, 232 (1997), pp. 487-491
[53.]
E. Lopez-Garcia, M.B. Schulze, J.E. Manson, J.B. Meigs, C.M. Albert, N. Rifai, et al.
Consumption of (n-3) fatty acids is related to plasma biomarkers of inflammation and endothelial activation in women.
J Nutr, 134 (2004), pp. 1806-1811
[54.]
E.M. Hjerkinn, I. Seljeflot, I. Ellingsen, P. Berstad, I. Hjermann, L. Sandvik, 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, 81 (2005), pp. 583-589
[55.]
A. Mishra, A. Chaudhary, S. Sethi.
Oxidized omega-3 fatty acids inhibit NF-kappaB activation via a PPARalpha-dependent pathway.
Arterioscler Thromb Vasc Biol, 24 (2004), pp. 1621-1627
[56.]
F. Thies, J.M. Garry, P. Yaqoob, K. Rerkasem, J. Williams, C.P. Shearman, et al.
Association of n-3 polyunsaturated fatty acids with stability of atherosclerotic plaques: a randomised controlled trial.
Lancet, 361 (2003), pp. 477-485
[57.]
J.W. Elrod, D.J. Lefer.
The effects of statins on endothelium, inflammation and cardioprotection.
Drug News Perspect, 18 (2005), pp. 229-236
Copyright © 2006. Sociedad Española de Cardiología
