Preventing Coronary Heart Disease
1998; Lippincott Williams & Wilkins; Volume: 97; Issue: 5 Linguagem: Inglês
10.1161/01.cir.97.5.421
ISSN1524-4539
AutoresGilbert S. Omenn, Shirley A.A. Beresford, Arno G. Motulsky,
Tópico(s)Pregnancy and preeclampsia studies
ResumoHomeCirculationVol. 97, No. 5Preventing Coronary Heart Disease Free AccessEditorialPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessEditorialPDF/EPUBPreventing Coronary Heart Disease B Vitamins and Homocysteine Gilbert S. Omenn, Shirley A. A. Beresford and Arno G. Motulsky Gilbert S. OmennGilbert S. Omenn From the School of Public Health and Community Medicine (G.S.O.), Departments of Epidemiology (S.A.A.B.) and of Medicine and Genetics (A.G.M.), University of Washington, Seattle, Wash. , Shirley A. A. BeresfordShirley A. A. Beresford From the School of Public Health and Community Medicine (G.S.O.), Departments of Epidemiology (S.A.A.B.) and of Medicine and Genetics (A.G.M.), University of Washington, Seattle, Wash. and Arno G. MotulskyArno G. Motulsky From the School of Public Health and Community Medicine (G.S.O.), Departments of Epidemiology (S.A.A.B.) and of Medicine and Genetics (A.G.M.), University of Washington, Seattle, Wash. Originally published10 Feb 1998https://doi.org/10.1161/01.CIR.97.5.421Circulation. 1998;97:421–424The list of preventable and reversible risk factors for atherosclerotic cardiovascular disease continues to grow. Cigarette smoking, high blood pressure, physical inactivity, elevated cholesterol, underlying lipoprotein abnormalities, lipoprotein(a), diabetes, overweight, male gender, and age are well-established risk factors. During the 1990s, there have been many reports associating elevated plasma homocysteine levels with arteriosclerotic cardiovascular disease and consistent evidence that dietary and supplemental folic acid can reduce homocysteine levels.12The article by Robinson and colleagues3 in this issue of Circulation presents further evidence of the importance of homocysteine and suggestive evidence that plasma folate and plasma pyrixodal-l-phosphate (vitamin B6) are protective factors. Their study is part of the European Concerted Action Project,4 which examined 750 patients younger than age 60 with diagnoses within the previous 12 months of coronary, cerebrovascular, or peripheral vascular disease and 800 healthy control subjects. The patient groups were young (47 years for cases and 44 years for control subjects) and heterogeneous, with nonfatal clinical events or symptoms of arteriosclerotic cardiovascular disease supported by ECG, angiographic, or Doppler evidence; the study involved 19 centers in nine European countries. Men in the highest quintile for fasting total homocysteine (tHcy), compared with the remainder of the population, had an estimated relative risk of 2.2 (95% confidence interval [CI], 1.6 to 2.9), with a striking dose-response relationship and a more-than-multiplicative interaction with cigarette smoking and high blood pressure on vascular disease risk4 ; the corresponding estimated relative risk for coronary heart disease was similar (2.0; 95% CI 1.6 to 2.8). (tHcy is the sum of homocysteine and homocysteinyl moieties of oxidized disulfides, homocystine, and cysteine- homocysteine.)Robinson and colleagues3 examined three B vitamins in detail to determine their effects on fasting and post–methionine-loading tHcy levels and any independent effects on cardiovascular disease risk. The results should be considered preliminary. Low folate and low vitamin B6 levels were statistically significantly more frequent among patients than among control subjects; a similar tendency for plasma B12 was not statistically significant. The inverse association with disease for folate was in part accounted for by increased tHcy levels, but the association for vitamin B6 was not. Relative risks for the top quintile of fasting tHcy and for high postload tHcy were 1.69 (CI, 1.26 to 2.26) and 1.62 (CI, 1.22 to 2.16), respectively, compared with all other quintiles, after adjustment for the vitamin effects. These relative risks are similar to the weighted means of other studies; it should be noted that one must scrutinize reported results for the choice of comparison groups and the units of change in homocysteine when comparing estimated relative risks between studies.2The findings regarding folate and B6 by Robinson et al3 would be stronger if they better matched the metabolic roles of the vitamins in homocysteine metabolism. Homocysteine is formed from the sulfur-containing essential amino acid methionine. Homocysteine can be transsulfurated to cysteine via two B6-dependent reactions or remethylated to methionine via B12- and folate-dependent reactions. Because fasting levels are more influenced by remethylation and post–methionine-load levels are more influenced by transsulfuration, one would expect folate (and B12) to be acting primarily on fasting levels and B6 to be primarily acting on postload levels. Both measures of tHcy were investigated in the 1550 study participants, but no such differential effects of folate and B6 were found.In one of several reports since the meta-analyses by our group,25 Verhoef et al6 found relative risks of 1.3 (CI, 1.0 to 1.6) for each 1 SD increase (5 μmol/L) in fasting tHcy in a comparison of 131 patients with 88 less severely affected patients with coronary artery disease and 101 population control subjects. Within patients and within control subjects, there was the expected inverse relationship between each of the three B vitamins and tHcy levels; but, contrary to expectations, pyridoxal-5-phosphate and folate levels were not lower in patients compared with the combined control groups. Among men who had received routine examinations in London, tHcy was strongly associated with death from ischemic heart disease (estimated relative risk, 2.9; CI, 2.0 to 4.1, after adjustment for apolipoprotein B and blood pressure).7 Nygard et al8 reported mortality results for 587 patients with angiographically confirmed coronary artery disease. After a median follow-up of 4.6 years, 64 had died (50 from cardiovascular causes). There was a striking graded relationship between plasma tHcy and overall mortality (eg, 25% of those with tHcy levels of ≥15 μmol/L had died compared with 4% of those with levels of 15 μmol/L compared with levels of 20 μmol/L.18 Despite several reports that the TT genotype is increased among patients with premature vascular disease,16 no such association could be demonstrated in 2029 patients with coronary heart disease when compared with 1639 control subjects across seven different independent studies (A.G. Motulsky, unpublished data, 1997). It is noteworthy that homozygotes for the TT variant had a 21% reduction in tHcy levels after supplementation with 1000 μg of folic acid compared with lesser reductions among heterozygotes (13%) and the more common homozygotes for the CC variant (7%).16 It is likely, therefore, that genetic variants in MTHFR and other enzymes related to folic acid metabolism (eg, methionine synthase) will require individuals to have different nutritional and supplement needs.19 Nutritional needs and intervention dosages must be tailored to the underlying pathophysiology, a general challenge we still face in national guidelines for screening and treatment of elevated serum cholesterol values.What Kinds of Prevention Trials Are Needed and May Be Feasible?Cardiovascular researchers have led the way with large-scale randomized trials of interventions for patients with specific clinical conditions (secondary prevention) and for healthy populations with risk factors for developing cardiovascular end points (primary prevention trials). The homocysteine hypothesis should be well suited to a direct test with folic acid as the intervention. However, as with all trials, the choice of the study population, choice of the agent or combination of agents, determination of an adequate and safe dose, and parameters of the design (incidence rates for the end points, size of effect expected, duration of intervention and follow-up, and allowance for nonadherence and for competing causes of death) must all be taken into account. Potential study populations include cardiac patients and healthy populations, and genotyped and high tHcy subgroups of each. Many investigators around the world are considering such trials; pilot trials will be needed. The lesson learned from the randomized trials in Finland and the United States that tested the seemingly compelling hypothesis that β-carotene would reduce lung cancer and coronary heart disease incidence and found that this vitamin/chemical instead increased lung cancer incidence and cardiovascular mortality20 is that statistical associations do not prove cause-and-effect relationships and do not rule out adverse effects. Associations should not be described as "effects."Potential trials are complicated by the introduction of folate fortification of grains and by increasing recommendations for the use of folic acid supplements in the general population and in cardiac patients. The Beta-Carotene and Retinol Efficacy Trial (CARET) faced a similar dilemma when β-carotene was being added to cereals and multivitamins and was highly promoted before the trial results were obtained. It may prove impossible to mount a sufficiently powerful trial. In that case, the stronger the biochemical, pathophysiological, nutritional, and genetic information about the cascade from dietary intake and genetic variation to circulating levels of folate and tHcy, the more persuasive will be the current inference of benefit. In CARET, we are analyzing the full cascade, from food frequency questionnaire estimates of folate intake and polymerase chain reaction analyses of genetic variation in the MTHFR enzyme to serum folate and B12 levels, tHcy concentrations, and observed fatal cardiovascular end points (G.S. Omenn, M.R. Malinow et al, unpublished data).The Vitamins in Stroke Prevention (VISP) trial is recruiting 3600 patients with nondisabling strokes to receive a multivitamin combination containing 2.5 mg of folic acid, 25 mg of B6, and 0.4 mg of B12 versus a multivitamin with 20 mg of folic acid, 0.2 mg of B6, and 6 mg of B12, with a primary end point of recurrent stroke and secondary end points of death from cardiovascular disease or myocardial infarction. The trial is based on a pilot study of homocysteine lowering in patients with acute stroke.21 In addition, a protocol has been announced for a nested case-control study among 30 000 patients receiving drugs for heart disease or high blood pressure in general practices in Norway.22What Should Clinicians Do With Present Knowledge?Because we interpret the totality of the current evidence linking folic acid, homocysteine, and cardiovascular disease risk as remaining strong with respect to the potential benefits of increasing folic acid intake on a population-wide basis, we recommend that everyone consume ≥400 μg of folic acid/d. Potentially pregnant women should take more to maximize the protective effect against neural tube closure defects. Screening for tHcy levels would be useful for individual risk profiles and for targeting efforts at adherence or recommendations for higher doses. Common multivitamins contain 2 to 3 mg of B6 and 6 to 9 μg of B12. We have no recommendation on B6 because definitive evidence of an inverse association with tHcy levels and of an optimal dose does not exist. As noted above, we recommended2 and urged the Food and Drug Administration to mandate inclusion of sufficient B12 in folic acid capsules (200 to 1000 μg) to ensure adequate absorption by passive mechanisms even in the absence of intrinsic factor. Inclusion of B12 in the fortified grains deserves consideration, as well; if it is not included, B12 should be prescribed, especially to protect older individuals with various degrees of B12 deficiency.13Reprint requests to Gilbert S. Omenn, MD, PhD, Executive Vice President for Medical Affairs, The University of Michigan, Ann Arbor, MI 48109-0624.The opinions expressed in this editorial are not necessarily those of the editors or of the American Heart Association. References 1 Malinow MR. Homocyst(e)inemia: a common and easily reversible risk factor for occlusive atherosclerosis. Circulation.1990; 81:2004–2006.CrossrefMedlineGoogle Scholar2 Boushey CJ, Beresford SAA, Omenn GS, Motulsky AG. A quantitative assessment of plasma homocysteine as a factor for vascular disease: probable benefits of increasing folic acid intakes. JAMA.1995; 472:1049–1057.Google Scholar3 Robinson K, Arheart K, Refsum H, Brattström L, Boers G, Ueland P, Rubba P, Palma-Reis R, Meleady R, Daly L, Witteman J, Graham I. The European Comac Group. Low circulating folate and vitamin B6 concentrations: risk factors for stroke, peripheral vascular disease, and coronary artery disease. Circulation. 1998:97:437–443.Google Scholar4 Graham IM, Daly LE, Refsum HM, Robinson K, Brattström L, Ueland P, Palma-Reis R, Boers G, Sheahan R, Israelsson B, Uiterwaal CS, Meleady R, McCaster D, Verhoef P, Witteman J, Rubba P, Bellet H, Wautrecht JC, de Valk HW, Sales Lúis AC, Parrot-Rouland FM, Tan KS, Higgins I, Garcon D, Medrano JS, Condito M, Evans AE, Andria G. Plasma homocysteine as a risk factor for vascular disease: the European Concerted Action Project. JAMA.1997; 277:1775–1781.CrossrefMedlineGoogle Scholar5 Beresford SAA, Boushey CJ. Homocysteine, folic acid, and cardiovascular disease risk. In Bendich A, Deckelbaum RJ, eds. Preventive Nutrition: The Comprehensive Guide for Health Professionals. Totowa, NJ: Humana Press; 1997:193–224.Google Scholar6 Verhoef P, Kok FJ, Kruyssen ACM, Schouten EG, Witteman JCM, Grobbee DE, Ueland PM, Refsum H. Plasma total homocysteine, B vitamins, and risk of coronary atherosclerosis. Arterioscler Thromb Vasc Biol.1997; 17:989–995.CrossrefMedlineGoogle Scholar7 Wald NUJ, Watt HC, Law MR. Homocysteine and ischaemic heart disease: results of a prospective study with implications on prevention. Arch Int Med. In press.Google Scholar8 Nygard O, Nrdrehaug JE, Refsum H, Ueland PM, Farstad M, Vollset SE. Plasma homocysteine levels and mortality in patients with coronary artery disease. N Engl J Med.1997; 337:230–236.CrossrefMedlineGoogle Scholar9 Chasan-Taber KL, Selhub J, Rosenberg IH, Malinow MR, Terry P, Tishler PV, Willett W, Hennekens CH, Stampfer MJ. A prospective study of folate and vitamin B6 and risk of myocardial infarction in US physicians. J Am Coll Nutr.1996; 15:136–143.CrossrefMedlineGoogle Scholar10 Evans RW, Shaten BJ, Hempel JD, Cutler JA, Kuller LH. Homocyst(e)ine and risk of cardiovascular disease in the Multiple Risk Factor Intervention Trial. Arterioscler Thromb Vasc Biol..1997; 17:1947–1953.CrossrefMedlineGoogle Scholar11 Selhub J, Jacques PF, Wilson PWF, Rush D, Rosenberg IH. Vitamin status and intake as primary determinants of homocysteinemia in an elderly population. JAMA.1993; 270:2693–2698.CrossrefMedlineGoogle Scholar12 Morbidity and Mortality Weekly Report. Recommendations for the use of folic acid to reduce the number of cases of spina bifida and other neural tube defects. MMWR.1992; 41:1–7.Google Scholar13 Savage DG, Lindenbaum J. Folate-cobalamin interactions. In: Bailey LB, ed. Folate in Health and Disease. New York, NY: Marcel Dekker; 1995:237–285.Google Scholar14 McCully KS. Vascular pathology of homocysteinemia. Am J Pathol.1969; 56:111–128.MedlineGoogle Scholar15 Motulsky AG. Nutritional ecogenetics: homocysteine-related arteriosclerotic vascular disease, neural tube defects, and folic acid. Am J Hum Genet.1996; 58:17–20.MedlineGoogle Scholar16 Malinow MR, Nieto FJ, Kruger WD, Duell PB, Hess DL, Gluckman RA, Block PC, Holzgang CR, Anderson PH, Seltzer D, Upson B, Lin QR. The effects of folic acid supplementation on plasma total homocysteine are modulated by multivitamin use and methylenetetrahydrofolate reductase genotypes. Arterioscler Thromb Vasc Biol.1997; 17:1157–1162.CrossrefMedlineGoogle Scholar17 Harmon DL, Woodside JV, Yarnell JWG, McMaster D, Young IS, McCrum EE, Gey KF, Whitehead AS, Evans AE. The common 'thermolabile' variant of methylene tetrahydrofolate reductase is a major determinant of mild hyperhomocysteinaemia. Q J Med.1996; 89:571–577.CrossrefGoogle Scholar18 Guttormsen AB, Ueland PM, Nesthus I, Nygard O, Schneede J, Vollset SE, Refsum H. Determinants and vitamin responsiveness of intermediate hyperhomocysteinemia (>40 μmol/L): the Hordaland Homocysteine Study. J Clin Invest.1996; 98:2174–2183.CrossrefMedlineGoogle Scholar19 Molloy A, Sean D, Mills JL, Kirke PN, Whitehead AS, Ramsbottom D, Conley MR, Weir DG, Scott JH. Thermolabile variant of 5,10-methylenetetrahydrofolate reductase associated with low red-cell folates: implications for folate intake recommendations. Lancet.1997; 349:1591–1593.CrossrefMedlineGoogle Scholar20 Omenn GS, Goodman GE, Thornquist MD, Balmes J, Cullen MR, Glass A, Keogh JP, Meyskens FL Jr, Valanis B, Williams. JH Jr, Barnhart S, Hammar S. Effects of a combination of beta-carotene and vitamin A on lung cancer incidence, total mortality, and cardiovascular mortality in smokers and asbestos-exposed workers. N Engl J Med.1996; 334:1150–1155.CrossrefMedlineGoogle Scholar21 Howard VJ, Chambless LE, Malinow MR, Lefkowitz D, Toole JF. Results of a homocyst(e)ine lowering pilot study in acute stroke patients. Stroke.1997; 28:234.Google Scholar22 Aursnes I. Protocol for a nested case-control study with folic acid in hyperhomocysteinemia. Can J Cardiol. 1997;13(suppl B):315B. Abstract.Google Scholar eLetters(0) eLetters should relate to an article recently published in the journal and are not a forum for providing unpublished data. Comments are reviewed for appropriate use of tone and language. Comments are not peer-reviewed. Acceptable comments are posted to the journal website only. Comments are not published in an issue and are not indexed in PubMed. Comments should be no longer than 500 words and will only be posted online. 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