High dietary methionine intake increases the risk of acute coronary events in middle-aged men

Published:November 08, 2005DOI:


      Background and aim

      Homocysteine, a methionine metabolite, is suggested to be a risk factor for cardiovascular diseases (CVD). To date, the effects of dietary intake of methionine, the key amino acid in homocysteine metabolism, on CVD have not been studied. Our aim was to examine the effects of dietary methionine intake on the risk of acute coronary events.

      Methods and results

      We examined the effects of dietary methionine intake, assessed with 4-d food record, on acute coronary events in a prospective cohort study consisting of 1981 coronary disease free men from eastern Finland, aged 42–60 years at baseline in 1984–89, in the Kuopio Ischaemic Heart Disease Risk Factor (KIHD) Study. During an average follow-up time of 14.0 years, 292 subjects experienced an acute coronary event. In a Cox proportional hazards model adjusting for age, examination years, BMI, urinary nicotine metabolites and protein intake (excluding methionine) the relative risks of acute coronary event in the three highest quarters of dietary methionine intake were 1.31 (95% CI: 0.92, 1.86), 1.31 (95% CI: 0.88, 1.96) and 2.08 (95% CI: 1.31, 3.29) as compared with the lowest quarter. Further adjustments did not change the results. However, opposite association was observed with total protein intake, which tended to decrease the risk.


      The main finding of this study is that long-term, moderately high dietary methionine intake may increase the risk of acute coronary events in middle-aged Finnish men free of prior CHD. More prospective research is needed to confirm the role of dietary methionine in the development of CVD, and whether its effects are independent of homocysteine.


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        • Selhub J.
        Homocysteine metabolism.
        Annu Rev Nutr. 1999; 19: 217-246
        • Nygard O.
        • Vollset S.E.
        • Refsum H.
        • Brattstrom L.
        • Ueland P.M.
        Total homocysteine and cardiovascular disease.
        J Intern Med. 1999; 246: 425-454
        • Mangoni A.A.
        • Jackson S.H.D.
        Homocysteine and cardiovascular disease: current evidence and future prospects.
        Am J Med. 2002; 112: 556-565
        • The Homocysteine Studies Collaboration
        Homocysteine and risk of ischemic heart disease and stroke. A meta-analysis.
        J Am Med Assoc. 2002; 288: 2015-2022
        • Salonen J.T.
        Is there a continuing need for longitudinal epidemiologic research? The Kuopio Ischaemic Heart Disease Risk Factor Study.
        Ann Clin Res. 1988; 20: 46-50
      1. Salo-Väänänen P. Determination of protein content in foods by the amount of total nitrogen and amino acids (Elintarvikkeiden proteiinipitoisuuden määrittäminen niiden typpi- ja aminohappopitoisuuksien avulla). In Finnish. University of Helsinki, Department of applied chemistry and microbiology. EKT-series 1050; 1996.

        • Voutilainen S.
        • Rissanen T.H.
        • Virtanen J.
        • Lakka T.A.
        • Salonen J.T.
        Low dietary folate intake is associated with an excess incidence of acute coronary events: the Kuopio Ischaemic Heart Disease Risk Factor (KIHD) Study.
        Circulation. 2001; 103: 2674-2680
        • Willett W.C.
        • Stampfer M.
        Implications of total energy intake for epidemiological analyses.
        in: Willett W. Nutritional Epidemiology. Oxford University Press, New York, NY1998: 273-301
        • Tuomilehto J.
        • Arstila M.
        • Kaarsalo E.
        • Kankaanpaa J.
        • Ketonen M.
        • Kuulasmaa K.
        • et al.
        Acute myocardial infarction (AMI) in Finland – baseline data from the FINMONICA AMI register in 1983–1985.
        Eur Heart J. 1992; 13: 577-587
        • Møller J.
        • Rasmussen K.
        Homocysteine in plasma: stabilisation with fluoride.
        Clin Chem. 1995; 41: 785-789
        • Rasmussen K.
        Solid phase sample excretion for rapid determination of methylmalonic acid in serum and urine by a stable-isotope-dilution method.
        Clin Chem. 1989; 35: 260-264
        • Salonen J.T.
        • Nyyssonen K.
        • Korpela H.
        • Tuomilehto J.
        • Seppanen R.
        • Salonen R.
        High stored iron levels are associated with excess risk of myocardial infarction in eastern Finnish men.
        Circulation. 1992; 86: 803-811
        • Salonen J.T.
        • Salonen R.
        • Seppanen K.
        • Rauramaa R.
        • Tuomilehto J.
        HDL, HDL2, and HDL3 subfraction, and the risk of acute myocardial infarction: a prospective population study in eastern Finnish men.
        Circulation. 1991; 84: 129-139
        • Lakka T.A.
        • Venalainen J.M.
        • Rauramaa R.
        • Salonen R.
        • Tuomilehto J.
        • Salonen J.T.
        Relation of leisure-time physical activity and cardiorespiratory fitness to the risk of acute myocardial infarction in men.
        N Engl J Med. 1994; 330: 1549-1554
        • Puhakainen E.V.
        • Barlow R.D.
        • Salonen J.T.
        An automated colorimetric assay for urine nicotine metabolites: a suitable alternative to cotinine assays for the assessment of smoking status.
        Clin Chim Acta. 1987; 170: 255-262
        • Rimm E.B.
        • Willett W.C.
        • Hu F.B.
        • Sampson L.
        • Colditz G.A.
        • Manson J.E.
        • et al.
        Folate and vitamin B6 from diet and supplements in relation to risk of coronary heart disease among women.
        J Am Med Assoc. 1998; 279: 359-364
        • Haulrik N.
        • Toubro S.
        • Dyerberg J.
        • Stender S.
        • Skov A.R.
        • Astrup A.
        Effect of protein and methionine intakes on plasma homocysteine concentrations: a 6-mo randomized controlled trial in overweight subjects.
        Am J Clin Nutr. 2002; 76: 1202-1206
        • Mennen L.I.
        • de Courcy G.P.
        • Guilland J.C.
        • et al.
        Homocysteine, cardiovascular disease risk factors, and habitual diet in the French Supplementation with Antioxidant Vitamins and Minerals Study.
        Am J Clin Nutr. 2002; 76: 1279-1289
        • Stolzenberg-Solomon R.Z.
        • Miller III, E.R.
        • Maguire M.G.
        • Selhub J.
        • Appel L.J.
        Association of dietary protein intake and coffee consumption with serum homocysteine concentrations in an older population.
        Am J Clin Nutr. 1999; 69: 467-475
        • Jacques P.F.
        • Bostom A.G.
        • Wilson P.W.F.
        • Rich S.
        • Rosenberg I.H.
        • Selhub J.
        Determinants of plasma total homocysteine concentration in the Framingham Offspring cohort.
        Am J Clin Nutr. 2001; 73: 613-621
        • Shimakawa T.
        • Nieto F.J.
        • Malinow M.R.
        • Chambless L.E.
        • Schreiner P.J.
        • Szklo M.
        Vitamin intake: a possible determinant of plasma homocyst(e)ine among middle-aged adults.
        Ann Epidemiol. 1997; 7: 285-293
        • Ward M.
        • McNulty H.
        • Pentieva K.
        • McPartlin J.
        • Strain J.J.
        • Weir D.G.
        • et al.
        Fluctuations in dietary methionine intake do not alter plasma homocysteine concentration in healthy men.
        J Nutr. 2000; 130: 2653-2657
        • Christen W.G.
        • Ajani U.A.
        • Glynn R.J.
        • Hennekens C.H.
        Blood levels of homocysteine and increased risks of cardiovascular disease: causal or casual?.
        Arch Intern Med. 2000; 160: 422-434
        • Voutilainen S.
        • Virtanen J.K.
        • Rissanen T.H.
        • et al.
        Serum folate and homocysteine and incidence of acute coronary events: the Kuopio Ischaemic Heart Disease Risk Factor Study.
        Am J Clin Nutr. 2004; 80: 317-323
        • Troen A.M.
        • Lutgens E.
        • Smith D.E.
        • Rosenberg I.H.
        • Selhub J.
        The atherogenic effect of excess methionine intake.
        Proc Natl Acad Sci USA. 2003; 100: 15089-15094
        • Ambrosi P.
        • Rolland P.H.
        • Bodard H.
        • et al.
        Effects of folate supplementation in hyperhomocysteinemic pigs.
        J Am Coll Cardiol. 1999; 34: 274-279
        • Toborek M.
        • Kopieczna-Grzebieniak E.
        • Drozdz M.
        • Wieczorek M.
        Increased lipid peroxidation as a mechanism of methionine-induced atherosclerosis in rabbits.
        Atherosclerosis. 1995; 115: 217-224
        • Hu F.B.
        • Stampfer M.J.
        • Manson J.E.
        • et al.
        Dietary protein and risk of ischemic heart disease in women.
        Am J Clin Nutr. 1999; 70: 221-227
        • Iso H.
        • Stampfer M.J.
        • Manson J.E.
        • et al.
        Prospective study of fat and protein intake and risk of intraparenchymal hemorrhage in women.
        Circulation. 2001; 103: 856-863
        • Shimamoto T.
        • Komachi Y.
        • Inada H.
        • et al.
        Trends for coronary heart disease and stroke and their risk factors in Japan.
        Circulation. 1989; 79: 503-515
        • Liu L.
        • Ikeda K.
        • Sullivan D.H.
        • Ling W.
        • Yamori Y.
        Epidemiological evidence of the association between dietary protein intake and blood pressure: a meta-analysis of published data.
        Hypertens Res. 2002; 25: 689-695
        • Halton T.L.
        • Hu F.B.
        The effects of high protein diets on thermogenesis, satiety and weight loss: a critical review.
        J Am Coll Nutr. 2004; 23: 373-385
        • Karkeck J.M.
        Improving the use of dietary survey methodology.
        J Am Diet Assoc. 1987; 87: 869-871
        • Willett W.
        Nutritional epidemiology: issues and challenges.
        J Epidemiology. 1987; 16: S312-S317