The Journal of Membrane Biology

, Volume 206, Issue 2, pp 117–128

Antiarrhythmic Mechanisms of n-3 PUFA and the Results of the GISSI-Prevenzione Trial

  • R. Marchioli
  • G. Levantesi
  • A. Macchia
  • A.P. Maggioni
  • R.M. Marfisi
  • M.G. Silletta
  • L. Tavazzi
  • G. Tognoni
  • F. Valagussa


The purpose of this paper is twofold: on the one hand, to confirm the positive results on n-3 PUFA from the overall results Gruppo Italiano per lo Studio della Sopravvivenza nell’Infarto Miocardico (GlSSI)-Prevenzione trial; on the other, to summarize and describe how the results of an important trial can help generate hypotheses either on mechanisms of action or on differential results in particular subgroups of patients, as well as test the pathophysiological hypotheses that have accompanied in the years the story of the hypothesized mechanisms of action of a drug. GISSI-Prevenzione was conceived as a pragmatic population trial on patients with recent myocardial infarction and it was conducted in the framework of the Italian public health system. In GISSI-Prevenzione, 11,323 patients were enrolled in a clinical trial aimed at testing the effectiveness of n-3 polyunsaturated fatty acids (PUFA) and vitamin E. Patients were invited to follow Mediterranean dietary habits, and were treated with up-to-date preventive pharmacological interventions. Long-term n-3 PUFA at 1 g daily, but not vitamin E at 300 mg daily, was beneficial for death and for combined death, non-fatal myocardial infarction, and stroke. All the benefit, however, was attributable to the decrease in risk for overall (−20%), cardiovascular (−30%), and sudden death (−45%). At variance from the orientation of a scientific scenario largely dominated by the “cholesterol-heart hypothesis”, GISSI-Prevenzione results indicate n-3 PUFA (virtually devoid of any cholesterol-lowering effect) as a relevant pharmacological treatment for secondary prevention after myocardial infarction.


Coronary disease Prevention and control n-3 polyunsaturated fatty acids Sudden death 


  1. 1.
    Albert C.M., Campos H., Stampfer M.J., Ridker P.M., Manson J.M., Willett W.C., Ma J. 2002. Blood levels of long-chain n-3 fatty acids and the risk of sudden death. N. Engl. J. Med. 346:1113–1118PubMedGoogle Scholar
  2. 2.
    Albert C.M., Hennekens C.H., O’Donnell C.J., et al. 1998. Fish consumption and risk of sudden cardiac death. JAMA 279:23–28PubMedGoogle Scholar
  3. 3.
    Albert M.A., Danielson E., Rifai N., et al, for the PRINCE Investigators. 2001. Effects of statin therapy on C-reactive protein levels: the pravastatin inflammation/CRP evaluation (PRINCE): a randomized trail and cohort study. JAMA 286:64–70PubMedGoogle Scholar
  4. 4.
    Arita M., Bianchini F., Aliberti J., Sher A., Chiang N., Hong S., et al. 2005. Stereochemical assignment, anti-inflammatory properties, and receptor for the omega-3 lipid mediator resolvin El. EJM 201:713–722Google Scholar
  5. 5.
    Arita M., Yoshida M., Hong S., Tjonahen E., Glickman J.N., Petasis N.A., et al. 2005. Resolvin El, an endogenous lipid mediator derived from omega-3 eicosapentaenoic acid, protects against 2,4,6-trinitrobenzene sulfonic acid-induced colitis. PNAS 102:767l–7676CrossRefGoogle Scholar
  6. 6.
    Armitage, J., for A Study of Cardiovascular Events in Diabetes (ASCEND) Investigators. European Society of Cardiology Congress, München, 2004 (personal communication)Google Scholar
  7. 7.
    Ascherio A., Rimm E.B., Stampfer M.J., Giovannucci E.L., Willett W.C. 1995. Dietary intake of marine n-3 fatty acids, fish intake and the risk of coronary disease among men. N. Engl. J. Med. 332:977–982CrossRefPubMedGoogle Scholar
  8. 8.
    Bang H.O., Dyerberg J., Hjørne N. 1976. The composition of food consumed by Greenland Eskimos. Acta Med. Scand. 200:69–73PubMedGoogle Scholar
  9. 9.
    Bigger J.T., Fleiss J.L., Rolnitzky L.M., Steinman R.C. 1993. Frequency domain measures of heart period variability to assess risk late after myocardial infarction. J. Am. Coll. Cardiol. 21:729–736PubMedGoogle Scholar
  10. 10.
    Bigger J.T., Fleiss J.L., Steinman R.C., Rolnitzky L.M., Kleiger R.E., Rottman J.N. 1992. Frequency domain measures of heart period variability and mortality after myocardial infarction. Circulation 85:164–171PubMedGoogle Scholar
  11. 11.
    Billman G.E., Kang J.X., Leaf A. 1999. Prevention of ischemia-induced ventricular arrhythmias by dietary pure n-3 polyunsaturated fatty acids in dogs. Circulation 99:2452–2457PubMedGoogle Scholar
  12. 12.
    Burr M.L., Ashfield-Watt P.A., Dunstan F.D., Fehily A.M., Breay P., Ashton T., Zotos P.C., Haboubi N.A., Elwood P.C. 2003. Lack of benefit of dietary advice to men with angina: results of a controlled trial. Eur. J. Clin. Nutr. 57:193–200CrossRefPubMedGoogle Scholar
  13. 13.
    Burr M.L., Fehily A.M., Gilbert J.F., Rogers S., Holliday R.M., Sweetnam P.M., Elwood P.C., Deadman N.M. 1989. Effects of changes in fat, fish, and fibre intakes on death and myocardial reinfarction: diet and reinfarction trial (DART). Lancet 2:757–761PubMedGoogle Scholar
  14. 14.
    Calder P.C. 2001. Polyunsaturated fatty acids, inflammation, and immunity. Lipids 6:1007–1024Google Scholar
  15. 15.
    Calò L., Bianconi L., Colivicchi F., Lamberti F., Loricchio M.L., de Ruvo E., Meo A., Pandori C., Staibano M., Santini M. 2005. N-3 fatty acids for the prevention of atrial fibrillation after coronary artery bypass surgery: A randomized, controlled trial. J. Am. Coll. Cardiol. 45:1723–1728PubMedGoogle Scholar
  16. 16.
    Christensen J.H., Christensen M.S., Dyerberg J., Schmidt E.B. 1999. Heart rate variability and fatty acid content of blood cell membranes: a dose-response study with n-3 PUFAs. Am. J. Clin. Nutr. 70:331–337PubMedGoogle Scholar
  17. 17.
    Christensen J.H., Gustenhoff P., Korup E., Aarøe J., Toft E., Møller J., Rasmussen K., Dyerberg J., Schmidt E.B. 1996. Effect of fish oil on heart rate variability in survivors of myocardial infarction: a double blind randomised controlled trial. B.M.J. 312:677–678Google Scholar
  18. 18.
    Christensen J.H., Riahi S., Schmidt E.B., Mølgaard. H., Pedersen A.K., Heath F., et al. 2005. n-3 fatty acids and ventricular arrhythmias in patients with ischaemic heart disease and implantable cardioverter defibrillators. Europace 7:338–344CrossRefPubMedGoogle Scholar
  19. 19.
    Christensen J.H., Gustenhoff P., Eilersen E., et al. 1995. n-3 Fatty acids and ventricular extra systoles in patients with ventricular tachyarrhythmias. Nutr. Res. 15:1–8Google Scholar
  20. 20.
    Christensen J.H., Korup E., Aaroe J., et al. 1997. 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. 79:1670–1673PubMedGoogle Scholar
  21. 21.
    CIBIS Investigators. 1999. Cardiac Insufficiency Bisoprolol Study II (CIBIS-II): a randomised trial. Lancet 353:9–13Google Scholar
  22. 22.
    Dagenais G.R., Marchioli R., Yusuf S., Tognoni G. 2000. Beta-carotene, vitamin C, and vitamin E and cardiovascular diseases. Curr. Cardiol. Rep. 2:293–9PubMedGoogle Scholar
  23. 23.
    De Caterina R., Basta G. 2001. n-3 Fatty acids and the inflammatory response — biological background. Eur. Heart J. 3:D42–D49Google Scholar
  24. 24.
    Endres S., Ghorbani R., Kelley V.E., et al. 1989. The effect of dietary supplementation with n-3 polyunsaturated fatty acids on the synthesis of interleukin-1 and tumor necrosis factor by mononuclear cells. N. Engl. J. Med. 320:265–271PubMedGoogle Scholar
  25. 25.
    Eritsland J., Arnesen H., Gronseth K., Fjeld N.B., Abdelnoor M. 1996. Effect of dietary supplementation with n-3 fatty acids on coronary artery bypass graft patency. Am. J. Cardiol. 77:31–36CrossRefPubMedGoogle Scholar
  26. 26.
    Flower R.J., Perretti M. 2005. Controlling inflammation: a fat chance? JEM 201:671–674Google Scholar
  27. 27.
    GISSI Prevenzione Investigators. Gruppo Italiano per lo Studio della Sopravvivenza nell’Infarto miocardico. 1999. Dietary supplementation with n-3 polyunsaturated fatty acids and vitamin E after myocardial infarction: results of the GISSI-Prevenzione trial. Lancet 354:447–455Google Scholar
  28. 28.
    Gruppo Italiano Studio Sulla Sopravvivenza nell’Infarto Miocardico (GISSI). 1993. I1 Protocollo Dello Studio Gissi-Prevenzione: Studio di Intervento Preventive Sulle Componenti Aterosclerotica e Trombotica Del Rischio Post-Infarto. G. Ital. Cardiol. 23:1053–1061Google Scholar
  29. 29.
    Hamazaki K., Itomura M., Huan M., Nishizawa H., Sawazaki S., Tanouchid M., et al. 2005. Effect of n-3 fatty acid-containing phospholipids on blood catecholamine concentrations in healthy volunteers: a randomized, placebo-controlled, double-blind trial. Nutrition 2:705–710Google Scholar
  30. 30.
    Harbige L.S. 2003. Fatty acids, the immune response, and auto-immunity: a question of n-6 essentiality and the balance between n-6 and n-3. Lipids 38:323–34lPubMedGoogle Scholar
  31. 31.
    Hu F.B., Bronner L., Willett W.C., Stampfer M.J., Rexrode K.M., Albert C.M., Hunter D., Manson J.E. 2002. Fish and omega-3 fatty acid intake and risk of coronary heart disease in women. JAMA 287:1815–1821CrossRefPubMedGoogle Scholar
  32. 32.
    Jahangiri A., Leifert W.R., Patten G.S., McMurchie E.J. 2000. Termination of asynchronous contractile activity in rat atrial myocytes by n-3 polyunsaturated fatty acids. Mol. Cell. Biochem. 206:33–41CrossRefPubMedGoogle Scholar
  33. 33.
    Johansen O., Brekke M., Seljeflot I., Abdelnoor M., Arnesen H. 1999. N-3 fatty acids do not prevent restenosis after coronary angioplasty: results from the CART study. Coronary Angioplasty Restenosis Trial. J. Am. Coll. Cardiol. 33:1619–1626CrossRefPubMedGoogle Scholar
  34. 34.
    Jula A., Marniemi J., Ronnemaa T., Virtanen A., Huupponen R. 2005. Effects of diet and simvastatin on fatty acid composition in hypercholesterolemic men a randomized controlled trial. Arterioscler. Thromb. Vase. Biol. 25:web-published ahead of print, DOI: 10.1161/01.ATV.0000177812.84927.faGoogle Scholar
  35. 35.
    Kang J.X., Leaf A. 1996. Antiarrhythmic effects of polyunsaturated fatty acids: Recent studies. Circulation 94:1774–1780PubMedGoogle Scholar
  36. 36.
    Kang J.X., Leaf A. 1994. Effects of long-chain polyunsaturated fatty acids on the contraction of neonatal rat cardiac myocytes. Proc. Natl. Acad. Sci. USA 91:9886–9890PubMedGoogle Scholar
  37. 37.
    Kang J.X., Leaf A. 1995. Prevention and termination of the β-adrenergic agonist-induced arrhythmias by free polyunsaturated fatty acids in neonatal rat cardiac myocytes. Biochem-Biophys. Res. Commun. 208:629–636CrossRefPubMedGoogle Scholar
  38. 38.
    Kang J.X., Xiao Y.-F., Leaf A. 1995. Free, long-chain, polyunsaturated fatty.acids reduce membrane electrical excitability in neonatal rat cardiac myocytes. Proc. Natl. Acad. Sci. USA 92:3997–4001PubMedGoogle Scholar
  39. 39.
    Kaul U., Sanghvi S., Bahl V.K., Dev V., Wasir H.S. 1992. Fish oil supplements for prevention of restenosis after coronary angioplasty. Intern. J. Cardiol. 35:87–89Google Scholar
  40. 40.
    Kleiger R.E., Miller J.P., Bigger J.T., Moss A.J., the Multicenter Post-Infarction Research Group. 1987. Decreased heart rate variability and its association with increased mortality after acute myocardial infarction. Am. J. Cardiol. 59:256–262CrossRefPubMedGoogle Scholar
  41. 41.
    Kromann N., Green A. 1980. Epidemiologic Studies in the Upernavik District, Greenland. Incidence of some chronic disease (1950–1974). Acta Med. Scand. 208:401–406PubMedGoogle Scholar
  42. 42.
    Leaf A., for the Fatty Acid Antiarrhythmia Trial (FAAT) Investigators. 2004. European Society of Cardiology Congress, München (personal communication)Google Scholar
  43. 43.
    Leaf A., Jorgensen M.B., Jacobs A.K., Cote G., Schoenfeld D.A., Scheer J., et al. 1994. Do fish oils prevent restenosis after coronary angioplasty?. Circulation 90:2248–2257PubMedGoogle Scholar
  44. 44.
    Leaf A., Kang J.X., Xiao Y-F., Billman G.E. 2003. Clinical prevention of sudden cardiac death by n-3 polyunsaturated fatty acids and mechanism of prevention of arrhythmias by n-3 fish oils. Circulation 107:2646–2652CrossRefPubMedGoogle Scholar
  45. 45.
    Macchia A., Levatesi G., Franzosi M.G., Geraci E., Maggioni A.P., Marfisi R.M., Nicolosi G.L., Schweiger C., Tavazzi L., Tognoni G., Valagussa F., Marchioli R., on behalf of GISSI-Prevenzione Investigators. 2005. Left ventricular systolic dysfunction, total mortality, and sudden death in patients with myocardial Infarction treated with n-3 Polyunsaturated Fatty Acids. Eur. J. Heart Fail. 7:904–909PubMedGoogle Scholar
  46. 46.
    Madsen T., Skou H.A., Hansen V.E., Fog L., Christensen J.H., Toft E., Schmidt E.B. 2001. C-reactive protein, dietary n-3 fatty acids, and the extent of coronary heart disease. Am. J. Cardiol. 88:1139–1142CrossRefPubMedGoogle Scholar
  47. 47.
    Maggioni A.P., Tavazzi L., Marchioli R., Tognoni G., Avanzini F., Roncaglioni M.C. on the behalf of the GISSI-Group. 2001. Perspectives on n-3 PUFA: primary prevention, antiarrhythmic effects, congestive heart failure. Eur. Heart J. 3: D106–D109Google Scholar
  48. 48.
    Marchioli R., Barzi F., Bomba E., Chieffo C., Di Gregorio D., Di Mascio R., Franzosi M.G., Geraci E., Levatesi G., Maggioni A.P., Mantini L., Marfisi R.M., Mastrogiuseppe G., Mininni N., Nicolosi G.L., Santini. M., Schweiger C., Tavazzi L., Tognoni G., Tucci C., Valagussa F., GISSI-Prevenzione Investigators. 2002. Early protection against sudden death by n-3 polyunsaturated fatty acids after myocardial infarction: time-course analysis of the results of the Gruppo Italiano per lo Studio della Sopravivenza nell’Infarto Miocardico (GlSSI)-Prevenzione. Circulation 105:1897–1903CrossRefPubMedGoogle Scholar
  49. 49.
    Marchioli, R., Valagussa, F. 2000. Evidence and perspectives on n-3 polyunsaturated fatty acids in cardiovascular disease. Proceedings of the “Consensus Meeting: Clinical effect, Biological Background, and Research Priorities on n-3 Fatty acids”, Research Centre of the Italian National Association of Hospital Cardiologists (ANMCO), Florence, Italy, 17–19 FebruaryGoogle Scholar
  50. 50.
    Marchioli R. 1999. Antioxidant vitamins and prevention of cardiovascular disease: Laboratory, epidemiological, and clinical trial data. Pharmacol. Res. 40:227–238CrossRefPubMedGoogle Scholar
  51. 51.
    Marchioli R. 2001. Treatment with n-3 polyunsaturated fatty acids after myocardial infarction: results of GISSI-Prevenzione Trial. Eur. Heart J. Suppl. 3:D85–D97Google Scholar
  52. 52.
    Marchioli R., Di Pasquale A., for the Ricercatori GISSI Prevenzione. 1993. Il Quadro di Riferimento Biochimico, Farmacologico, Epidemiologico del Gissi-Prevenzione. G. Ital. Cardiol. 23:933–964PubMedGoogle Scholar
  53. 53.
    Maresta A., Balduccelli M., Varani E., Marzilli M., Galli C., Heiman F., Lavezzari M., Stragliotto E., De Caterina R., ESPRIT Investigators. 2002. Prevention of postcoronary angioplasty restenosis by omega-3 fatty acids: main results of the Esapent for Prevention of Restenosis Italian Study (ESPRIT). Am. Heart J. 143:E5CrossRefPubMedGoogle Scholar
  54. 54.
    McLennan P.L. 1993. Relative effects of dietary saturated, monounsaturated, and polyunsaturated fatty acids on cardiac arrhythmias in rats. Am. J. Clin. Nutr. 57:207–212PubMedGoogle Scholar
  55. 55.
    McLennan P.L., Bridle T.M., Abeywardena M.Y., Charnok J.S. 1992. Dietary lipid modulation of ventricular fibrillation threshold in the marmoset monkey. Am. Heart J. 123:1555–1561CrossRefPubMedGoogle Scholar
  56. 56.
    MERIT-HF Study Group. 1999. Effect of metoprolol CR/XL in chronic heart failure: Metoprolol CR/XL Randomized Intervention Trial in Congestive Heart Failure (MERIT-HF). Lancet 353:2001–2007Google Scholar
  57. 57.
    Metra M., Nodali S., D’Aloia A., Bontempi L., Boldi E., Cas L.D. 2000. A rationale for the use of (β-blockers as standard treatment for heart failure. Am. Heart J. 139:511–521PubMedGoogle Scholar
  58. 58.
    Meydani M., Natiello F., Goldin B., et al. 1991. Effect of long-term fish oil supplementation on vitamin E status and lipid peroxidation in women. J. Nutr. 121:484–491PubMedGoogle Scholar
  59. 59.
    Mori T.A., Chem C.P., Beilin L.J. 2004. Omega-3 fatty acids and inflammation. Curr. Atheroscler. Rep. 6:461–467PubMedGoogle Scholar
  60. 60.
    Mozaffarian D., Lemaitre R.N., Kuller L.H., Burke G.L., Tracy R.P., Siscovick D.S. 2003. Cardiovascular Health Study. Cardiac benefits of fish consumption may depend on the type of fish meal consumed: the Cardiovascular Health Study. Circulation 107:1372–1377CrossRefPubMedGoogle Scholar
  61. 61.
    Mozaffarian D., Psaty B.M., Rimm E.B., Lemaitre R.N., Burke G.L., Lyles M.F., Lefkowitz D., Siscovick D.S. 2004. Fish intake and risk of incident atrial fibrillation. Circulation 110:368–373CrossRefPubMedGoogle Scholar
  62. 62.
    Natvig H., Borchgrevink C.F., Dedichen J., Owren P.A., Schiotz E.H., Westlund K. 1968. A controlled trial of the effect of linolenic acid on incidence of coronary heart disease. The Norwegian vegetable oil experiment of 1965–66. Scand. J. Clin. Lab. Invest. 105:1–20Google Scholar
  63. 63.
    Nilsen D.W., Albrektsen G., Landmark K., Moen S., Aarsland T., Woie L. 2001. Effects of a high-dose concentrate of n-3 fatty acids or corn oil introduced early after an acute myocardial infarction on serum triacylglycerol and HDL cholesterol. Am. J. Clin. Nutr. 74:50–56PubMedGoogle Scholar
  64. 64.
    O’Keefe J.H. Jr., Magalski A., Stevens T.L., et al. 2000. Predictors of improvement in left ventricular ejection fraction with carvedilol for congestive heart failure. J. Nucl. Cardiol. 7:3–7PubMedGoogle Scholar
  65. 65.
    Packer M., Bristow M.R., Cohn J.N., et al. 1996. The effect of carvedilol on morbidity and mortality in patients with chronic heart failure. U.S. Carvedilol Heart Failure Study Group. N. Engl. J. Med. 334:1349–1355CrossRefPubMedGoogle Scholar
  66. 66.
    Pepe S., McLennan P.L. 2002. Cardiac membrane fatty acid composition modulates myocardial oxygen consumption and postischemic recovery of contractile function. Circulation 105:2303–2308CrossRefPubMedGoogle Scholar
  67. 67.
    Peskind E.R., Wingerson D., Murray S., Pascualy M., Dobie D.J., Le Corre P., et al. 1995. Effects of Alzheimer’s disease and normal aging on cerebrospinal fluid norepinephrine responses to yohimbine and clonidine. Arch. Gen. Psychiatry 52:774–782PubMedGoogle Scholar
  68. 68.
    Raitt M.H., Connor W.E., Morris C., Kron J., Halperin B., Chugh S.S., et al. 2005. Fish oil supplementation and risk of ventricular tachycardia and ventricular fibrillation in patients with implantable defibrillators: A randomized controlled trial. JAMA 293:2884–2891CrossRefPubMedGoogle Scholar
  69. 69.
    Ridker P.M., Rifai N., Clearfiled N., et al, for the Air Force/Texas Coronary Atherosclerosis Prevention Study Investigators. 2001. Measurement of C-reactive protein for the targeting of statin therapy in the primary prevention of acute coronary events. N. Engl. J. Med. 344:1959–1965CrossRefPubMedGoogle Scholar
  70. 70.
    Ridker P.M., Rifai N., Pfeffer M.A., et al. For the Cholesterol And Recurrent Events (CARE) Investigators. 1999. Long-term effects of pravastatin on plasma concentration of C-reactive protein. Circulation 100:230–235PubMedGoogle Scholar
  71. 71.
    Rise’ P., Ghezzi S., Galli C. 2003. Relative potencies of statins in reducing cholesterol synthesis and enhancing linoleic acid metabolism. Eur. J. Pharmacol. 467:73–75Google Scholar
  72. 72.
    Sacks F.M., Stone P.H., Gibson C.M., Silverman D.I., Rosner B., Pasternak RC. 1995. Controlled trial of fish oil for regression of human coronary atherosclerosis. HARP Research Group. J. Am. Coll. Cardiol. 25:1492–1498CrossRefPubMedGoogle Scholar
  73. 73.
    Sellmayer A., Witzgall H., Lorenz R.L., Weber P.C. 1995. Effects of dietary fish oil on ventricular premature complexes. Am. J. Cardiol. 76:974–977CrossRefPubMedGoogle Scholar
  74. 74.
    Simopoulos A.P. 1991. Omega-3 fatty acids in health and disease and growth and development. Am. J. Clin. Nutr. 54:438–463PubMedGoogle Scholar
  75. 75.
    Simopoulos A.P. 1997. Omega-3 fatty acids in the prevention- management of cardiovascular disease, Can. J. Physiol. Pharmacol. 75:234–239Google Scholar
  76. 76.
    Siscovick D.S., Raghunathan T.E., King I., et al. 1995. Dietary intake and cell membrane levels of long-chain ω-3 polyunsaturated fatty acids and the risk of primary cardiac arrest. J. Am. Med. Assoc. 274:1363–1367CrossRefGoogle Scholar
  77. 77.
    Stein P.K., Kleiger R.E. 1999. Insights from the study of heart rate variability. Annu. Rev. Med. 50:249–261PubMedGoogle Scholar
  78. 78.
    Steinberg D., Parthasarathy S., Carew T.E., Khoo J.C., Witztum J.L. 1989. Beyond cholesterol: Modifications of low-density lipoprotein that increase its atherogenicity. N. Engl J. Med. 320:915–924PubMedGoogle Scholar
  79. 79.
    Svensson T.H. 1987. Peripheral, autonomic regulation of locus coeruleus noradrenergic neurons in brain: putative implications for psychiatry and psychopharmacology. Psychopharmacol. (Berl) 92:1–7Google Scholar
  80. 80.
    Tavazzi L., Tognoni G., Franzosi M.G., Latini R., Maggioni A.P., Marchioli R., Nicolosi G.L., Porcu M. on behalf of GISSI-HF Investigators. 2004. 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. 6:635–641PubMedGoogle Scholar
  81. 81.
    The Heart Outcomes Prevention Evaluation study investigators. 2000. Vitamin E supplementation and cardiovascular events in high-risk patients. N. Engl. J. Med. 342:154–60Google Scholar
  82. 82.
    Thies F., Garry J.M.C., Yaqoob P., Rerkasem K., Williams J., Shearman C.P., et al. 2003. Association of n-3 polyunsaturated fatty acids with stability of atherosclerotic plaques: a randomised controlled trial. Lancet 361:477–485CrossRefPubMedGoogle Scholar
  83. 83.
    von Schacky C., Angerer P., Kothny W., Theisen K., Mudra H. 1999. The effect of dietary omega-3 fatty acids on coronary atherosclerosis. A randomized, double-blind, placebo-controlled trial. Ann. Intern. Med. 130(7):554–562Google Scholar
  84. 84.
    Weisser B., Struck A., Gobel B.O., Vetter H., Dusing R. 1990. Fish oil and baroreceptor function in man. Klin. Wochenschr. 68:49–52PubMedGoogle Scholar
  85. 85.
    Willerson J.T., Ridker P.M. 2004. Inflammation as a cardiovascular risk factor. Circulation 109:II2–II10PubMedGoogle Scholar
  86. 86.
    Xiao Y.-F., Wright S.N., Wang G.K., Morgan J.P., Leaf A. 2000. Coexpression with β 1-subunit modifies the kinetics and fatty acid block of hH1α Na+ channels. Am. J. Physiol. Heart Circ. Physiol. 279:H35–H46PubMedGoogle Scholar
  87. 87.
    Xiao Y.-F., Gomez A.M., Morgan J.P., Lederer W.J., Leaf A. 1997. Suppression of voltage-gated L-type Ca2+ currents by polyunsaturated fatty acids in adult and neonatal rat cardiac myocytes. Proc. Natl. Acad. Sci. USA 94:4182–4187PubMedGoogle Scholar
  88. 88.
    Xiao Y.-F., Kang J.X., Morgan J.P., Leaf A. 1995. Blocking effects of polyunsaturated fatty acids on Na+ channels of neonatal rat ventricular myocytes. Proc. Natl. Acad. Sci. USA 92:1100–1104Google Scholar
  89. 89.
    Xiao Y.-F., Wright S.N., Wang J.K., Morgan J.P., Leaf A. 1998. n-3 Fatty acids suppress voltage-gated Na+ currents in Hek293t cells transfected with the subunit of the human cardiac Na+ channel. Proc. Natl. Acad. Sci. USA 95:2680–2685PubMedGoogle Scholar
  90. 90.
    Yuan J.M., Ross R.K., Gao Y.T., Yu M.C. 2001. Fish and shellfish consumption in relation to death from myocardial infarction among men in Shanghai, China. Am. J. Epidemiol. 154:809–816CrossRefPubMedGoogle Scholar
  91. 91.
    Zampelas A., Panagiotakos D.B., Pitsavos C., Das U.N., Chrysohoou C., Skoumas Y., Stefanadis C. 2005. Fish consumption is associated with decreased levels of inflammatory markers related to cardiovascular disease: The ATTICA Study. Am. Coll. Cardiol. 46:120–124Google Scholar

Copyright information

© Springer Science+Business Media, Inc. 2005

Authors and Affiliations

  • R. Marchioli
    • 1
  • G. Levantesi
    • 1
  • A. Macchia
    • 1
  • A.P. Maggioni
    • 2
  • R.M. Marfisi
    • 1
  • M.G. Silletta
    • 1
  • L. Tavazzi
    • 3
  • G. Tognoni
    • 1
  • F. Valagussa
    • 2
  1. 1.Consorzio Mario Negri SudChietiItaly
  2. 2.Centro Studi ANMCOFirenzeItaly
  3. 3.IRCCS Policlinico San MatteoPaviaItaly

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