a Scientific and Technical Institute of Nutrition and Food (ISTNA), INSERM U557, INRA U1125, 5 Rue du Vertbois, 75003 Paris, France. E-mail: s_debree{at}vcnam.cnam.fr
b National Institute of Public Health and the Environment (RIVM), PO Box 1, NL-3720 BA Bilthoven, The Netherlands.
c University Medical Centre St Radboud, Laboratory of Pediatrics and Neurology, PO Box 9109 NL-6500 HB Nijmegen, The Netherlands.
SirsRecently an elegant meta-analysis of the relation between elevated concentrations of the total plasma homocysteine concentration (tHcy) and cardiovascular disease (CVD) was published in this journal.1 The authors conclude that prospective studies, which compared with case-control studies have a stronger methodological design, indicate only weak support for a causal relation between tHcy and coronary heart disease (CHD). While this is generally true, a distinction should be made among prospective studies that excluded and included subjects with CVD at baseline. Neglecting this difference may result in discarding tHcy as a risk factor for CHD in general, whereas we consider it potentially important in subjects with a high baseline risk of CVD.
Figure 1 gives an overview of all prospective studies that provided a relative risk (RR) estimate for CHD for each 5 µmol/l increase in tHcy (or for a difference in tHcy quartiles2 or quintiles.3 Except for one study,4 the studied populations were not selected on the basis of their risk of CHD. The RR of studies that included (or did not report on exclusion of 5,6) subjects with baseline CVD were more often statistically significant as compared to studies that excluded subjects with pre-existing CVD. The observation of a more often statistically significantly positive, or stronger, RR is strengthened by findings of studies that performed separate analyses in high-risk subjects (e.g. with a history of myocardial infarction, stroke, angina pectoris, diabetes, or hypertension).3,7,8 Moreover, in elderly populations the number of subjects with silent, pre-clinical, CVD is probably larger; of the five prospective studies with elderly populations in Figure 1
(average age >60 years)6,811 only one8 did not show a significant association between the tHcy concentration and the risk of CHD. Finally, prospective studies performed in high-risk populations consistently show that the tHcy concentration is a strong predictor of cardiovascular mortality and morbidity (including CHD) in subjects with CHD,12 diabetes,13,14 renal insufficiency,15,16 peripheral artery disease,17 and systemic lupus erythematosus.18
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Thus, the available evidence seems to indicate that the tHcy concentration is a risk factor that provokes the acute event in subjects with a high risk of CVD, as suggested by some researchers.4,21 Intuitively it may seem unlikely to have a risk factor that operates only to predict disease in high-risk and not in low-risk subjects, however, elevated tHcy concentrations interact multiplicatively with conventional CVD risk factors that characterize high-risk subjects, like hypercholesterolaemia, hypertension and smoking.22 In addition, as elevated tHcy concentrations may interfere with normal coagulation and fibrinolysis,23 the stimulation of thrombosis in high-risk subjects that already have a certain degree of atherosclerosis, may be the crucial factor triggering vascular occlusion. This notion is supported by the results of a Norwegian prospective study in CHD patients.12 They found that the tHcy concentration was strongly associated with mortality, but not with the extent of coronary atherosclerosis. Furthermore, young patients with inborn errors of homocysteine metabolism that received effective treatment to lower their very high tHcy concentrations, still have a tHcy concentration well above the normal range (i.e. >30 µmol/l).24 The fact that these patients do not suffer from CVD events might be the results of the absence of other CVD risk factors in these young individuals. Thus, in subjects without conventional risk factors for CVD, an elevated tHcy concentration may be relatively harmless.
The concomitant presence of CVD and a high tHcy concentration could also mean that elevations in the tHcy concentration are merely a marker of the degree of the underlying vascular disease. The latter seems, however, less likely given the recent finding, provided by a double-blind randomized placebo-controlled intervention trial, that lowering the tHcy concentration significantly reduced the rate of restenosis in coronary angioplasty patients.25 In addition, causality can also be inferred by the association between the 677 C > T variant of the MTHFR gene and the risk of CVD, as this genotype is present from birth onwards and will not change over the years. The 677TT variant of this genotype leads to an approximately 25% higher tHcy concentration compared with 677CC subjects.26 A meta-analysis performed in 1998, with almost 6000 cases and almost 7000 controls showed that the 677TT genotype is associated with an overall odds ratio (OR) for CVD of 1.12 (95% CI: 0.921.37).26 Although this OR is line with an increased risk of CVD for those with the 677TT genotype, the results was non-statistically significant, which is most likely attributable to a power problem. A more definite answer to the question whether this genotype is related to an increased risk of CHD will be provided by the largest meta-analysis performed to date (~11 000 CHD cases and ~13 000 controls),27 that will be published shortly. Ongoing intervention trials will be able to indicate whether a lower tHcy concentration, achieved through vitamin supplementation (folic acid, vitamin B6 and B12), prevents CVD in high-risk subjects.28
In conclusion, as tHcy may trigger an acute event in subjects with an unfavourable CVD risk profile, the overall estimate of the association between the tHcy concentration and the risk of CHD may be underestimated when epidemiological studies that included and excluded subjects with pre-existing CVD are evaluated together.
Acknowledgments
This work was financially supported by a grant of the Netherlands Heart Foundation (grant no. 96.147). HJ Blom is established investigator of the Netherlands Heart Foundation (grant no. D97.021).
References
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2 Voutilainen S, Lakka TA, Hamelahti P, Lehtimaki T, Poulsen HE, Salonen JT. Plasma total homocysteine concentration and the risk of acute coronary events: the Kuopio Ischaemic Heart Disease Risk Factor Study. J Intern Med 2000;248:21722.[CrossRef][ISI][Medline]
3 Knekt P, Reunnanen A, Alfthan G et al. Hyperhomocystinemia. A risk factor or a consequence of coronary heart disease? Arch Intern Med 2001;161:158994.
4 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; 17:194753.
5 ABrook R, Tavendale R, Tunstall-Pedoe H. Homocysteine and coronary risk in the general population: analysis from the Scottish Heart Health Study and Scottish MONICA surveys. Eur Heart J 1998; 19(Suppl.):8.[ISI][Medline]
6 Bostom AG, Silbershatz H, Rosenberg IH et al. Nonfasting plasma total homocysteine levels and ll-cause and cardiovascular disease mortality in elderly Framingham men and women. Arch Intern Med 1999; 159:107780.
7 de Bree A. Dietary, lifestyle and genetic determinants of homocysteine and its relation with coronary heart disease [Dissertation, ISBN 90-9015334-9]. Katholieke Universiteit Nijmegen, 2001.
8 Stehouwer CDA, Weijenberg MP, van den BM, Jakobs C, Feskens EJM, Kromhout D. Serum homocysteine and risk of coronary heart disease and cerebrovascular disease in elderly menA 10-year follow-up. Arterioscler Thromb Vasc Biol 1998;18:1895901.
9 Bots ML, Launer LJ, Lindemans J et al. Homocysteine and short-term risk of myocardial infarction and stroke in the elderly: the Rotterdam Study. Arch Intern Med 1999;159:3844.
10 Vollset SE, Refsum H, Tverdal A et al. Plasma total homocysteine and cardiovascular and noncardiovascular mortality: the Hordalans Homocysteine Study. Am J Clin Nutr 2001;74:13036.
11 Kark JD, Selhub J, Adler B et al. Nonfasting plasma total homocysteine level and mortality in middle-aged and elderly men and women in Jerusalem. Ann Intern Med 1999;131:32130.
12 Nygard O, Nordrehaug 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;337:163233.
13 Stehouwer CD, Gall MA, Hougaard P, Jakobs C, Parving HH. Plasma homocysteine concentration predicts mortality in non-insulin-dependent diabetic patients with and without albuminuria. Kidney Int 1999;55:30814.[CrossRef][ISI][Medline]
14 Kark JD, Selhub J, Bostom A, Adler B, Rosenberg IH. Plasma homocysteine and all-cause mortality in diabetes. Lancet 1999;353:193637.[Medline]
15 Bostom AG, Shemin D, Verhoef P et al. Elevated fasting total plasma homocysteine levels and cardiovascular disease outcomes in maintenance dialysis patientsA prospective study. Arterioscler Thromb Vasc Biol 1997;17:255458.
16 Moustapha A, Naso A, Nahlawi M et al. Prospective study of hyperhomocysteinemia as an adverse cardiovascular risk factor in end-stage renal disease. Circulation 1998;97:13841.
17 Taylor LM Jr, DeFrang RD, Harris EJ Jr, Porter JM. The association of elevated plasma homocyst(e)ine with progression of symptomatic peripheral arterial disease. J Vasc Surg 1991;13:12836.[CrossRef][ISI][Medline]
18 Petri M, Roubenoff R, Dallal GE, Nadeau MR, Selhub J, Rosenberg IH. Plasma homocysteine as a risk factor for atherothrombotic events in systemic lupus erythematosus. Lancet 1996;348:112024.[CrossRef][ISI][Medline]
19 Stampfer MJ, Malinow MR, Willett WC et al. A prospective study of plasma homocyst(e)ine and risk of myocardial infarction in US physicians. JAMA 1992;268:87781.[Abstract]
20 Chasan Taber L, Selhub J, Rosenberg IH et al. A prospective study of folate and vitamin B6 and risk of myocardial infarction in US physicians. J Am Coll Nutr 1996;15:13643.[Abstract]
21 Refsum H, Ueland PM. Recent data are not in conflict with homocysteine as a cardiovascular risk factor. Curr Opin Lipidol 1998;9:53339.[CrossRef][ISI][Medline]
22 Graham IM, Daly LE, Refsum HM et al. Plasma homocysteine as a risk factor for vascular disease: The European concerted action project. JAMA 1997;277:177581.[Abstract]
23 Thambyrajah J, Townend JN. Homocysteine and atherothrombosismechanisms for injury. Eur Heart J 2000;21:96774.
24 Yap S, Naughten ER, Wilcken B, Wilcken DE, Boers GH. Vascular complications of severe hyperhomocysteinemia in patients with homocystinuria due to cystathionine beta-synthase deficiency: effects of homocysteine-lowering therapy. Semin Thromb Hemost 2000; 26:33540.[CrossRef][ISI][Medline]
25 Schnyder G, Roffi M, Pin R et al. Decreased rate of coronary restenosis after lowering of plasma homocysteine levels. N Engl J Med 2001; 345:1593600.
26 Brattstrom L, Wilcken DE, Ohrvik J, Brudin L. Common methylenetetrahydrofolate reductase gene mutation leads to hyperhomocysteinemia but not to vascular disease: the result of a meta-analysis. Circulation 1998;98:252026.
27 Klerk M, Schouten EG, Blom HJ, Kok FJ, Verhoef P. A pooled analysis on MTHFR C677T polymorphism and risk of coronary heart disease. 3rd International Conference on Homocysteine Metabolism, 15 July 2001 Sorrento, Naples, Italy Abstracts Book, No. 63 2001;65.
28 Clarke R, Armitage J. Vitamin supplements and cardiovascular risk: review of the randomized trials of homocysteine-lowering vitamin supplements. Semin Thromb Hemost 2000;26:34148.[CrossRef][ISI][Medline]
29 Alfthan G, Pekkanen J, Jauhiainen M et al. Relation of serum homocysteine and lipoprotein(a) concentrations to atherosclerotic disease in a prospective Finnish population based study. Atherosclerosis 1994;106:919.[ISI][Medline]
30 Arnesen E, Refsum H, Bonaa KH, Ueland PM, Forde OH, Nordrehaug JE. Serum total homocysteine and coronary heart disease. Int J Epidemiol 1995;24:70409.[Abstract]
31 Folsom AR, Nieto FJ, McGovern PG et al. Prospective study of coronary heart disease incidence in relation to fasting total homocysteine, related genetic polymorphisms, and B vitamins: The atherosclerosis risk in communities (ARIC) study. Circulation 1998; 98:20410.
32 Wald NJ, Watt HC, Law MR, Weir DG, McPartlin J, Scott JM. Homocysteine and ischemic heart disease: Results of a prospective study with implications regarding prevention. Arch Intern Med 1998;158:86267.
33 Ridker PM, Manson JE, Buring JE, Shih J, Matias M, Hennekens CH. Homocysteine and risk of cardiovascular disease among postmenopausal women. JAMA 1999;281:181721.
34 Ubbink JB, Fehily AM, Pickering J, Elwood PC, Vermaak WJH. Homocysteine and ischaemic heart disease in the Caerphilly cohort. Atherosclerosis 1998;140:34956.[CrossRef][ISI][Medline]
35 Whincup PH, Refsum H, Perry IJ et al. Serum total homocysteine and coronary heart disease: prospective study in middle aged men. Heart 1999;82:44854.
SirsWe thank Dr de Bree and her colleagues for their interest in our work. Although much has been learned about homocysteine, its role as a risk factor for cardiovascular disease (CVD) continues to be debated.13 Dr de Bree and colleagues argued that homocysteine may predict CVD best in those with pre-existing CVD. In this view, homocysteine serves as a marker for atherosclerosis rather than as a causative agent of incident CVD.4
Since we submitted our manuscript,5 additional nested case-control studies4,69 and cohort studies1013 that met our study criteria have been published. Two of the three nested case-control studies from Finland found that homocysteine was significantly associated only with an increased risk for ischaemic heart disease (IHD) among men or women with baseline heart disease but not among those free of baseline heart disease.4,8 An additional Finnish study and one from Sweden failed to find a significant association of homocysteine with IHD.6,9 Furthermore, a 10-year follow-up of the Caerphilly study using a nested case-control study design also did not report a significant association between homocysteine and coronary heart disease as had an earlier report of 5 years of follow-up using a cohort design.7 In contrast, three cohort studies reported significant associations of homocysteine with IHD.10,12,13 In the fourth cohort study, homocysteine was not associated with stroke among all participants but was associated with stroke among participants whose stroke occurred before age 65 years.11 In addition, another nested case-control study found a significant association between homocysteine and sudden cardiac death.14
Using studies that we included in our analyses and more recently published studies, Dr de Bree and colleagues separated prospective studies into those that excluded participants with baseline CVD and those that included CVD. A visual inspection of their Figure suggests that studies that included baseline CVD were more likely to produce significant associations between homocysteine and CVD than were studies that excluded participants with baseline CVD. Their presentation of the data helps to illustrate a potential source of heterogeneity in the data. A study of Finnish women that Dr de Bree and colleagues the authors did not consider also found that homocysteine predicted risk for major coronary events only among women with histories of heart disease at baseline.8 Also, Kark and colleagues repeated their analyses after eliminating participants with prevalent CVD and diabetes and reported that the multivariate association persisted undiminished (data not shown).10
Because Dr de Bree and colleagues did not present summary odds ratios (OR) for the two sets of studies, a quantitative comparison of these two sets is more difficult to perform. However, all risk estimates per 5 µmol/l change of homocysteine for the six studies that included baseline CVD appear to be below 1.5, and a summary OR appears to be similar to the summary OR (1.23; 95% CI: 1.071.41) that we estimated for nested case-control studies.5
Whether homocysteine predicts CVD risk better in the short-term than in the long-term is unclear. Several authors have found that homocysteine better predicted risk for the events occurring during the earlier stages of their studies than during the later stages.4,15 However, others have not found this effect.16,17 Nevertheless, positive results have been reported for studies with reasonably long follow-up periods,18,19 and negative results have been reported for studies with much shorter follow-up periods.20
An additional point that Dr de Bree and her colleagues make is that studies of older populations are more likely to produce significant findings. However, a number of prospective studies have found significant associations in younger but not older age groups as well,15,16,21,22 or found no age-related difference.18,23
The magnitude and the relation (linear or non-linear) between risk factors and any disease are always important. Considerable uncertainty about the magnitude of the risk estimates continues to exist. One of the principal messages from our meta-analysis was that the magnitude of the risk estimates varied in function of study design. Such estimates are important because they are used to determine population-attributable fractions and thus the societal burden of a risk factor. In concert with other information, such as the ease and cost-effectiveness of reducing the impact of risk factors, policy makers can render more informed decisions regarding the allocation of resources to disease prevention.
We concur with Dr de Bree and colleagues about the importance of looking for groups, such as people with pre-existing CVD, in which homocysteine may better predict risk for future adverse events. Additional studies may help to clarify the view that homocysteine may better predict the risk for future IHD among people at high risk for coronary heart disease than among those without pre-existing heart disease. Although determination of whether homocysteine is a risk factor for IHD and other adverse events in the general population rather than in specific subgroups is clearly important, the fortification of the US food supply with folic acid and the subsequent drop in homocysteine concentration24 may to some degree make this debate moot in the US. The discussion about the role of homocysteine in CVD most likely will continue until the results from trials of homocysteine lowering through vitamin supplementation clarify this issue.
References
1 Dudman NP. An alternative view of homocysteine. Lancet 1999;354:207274.[CrossRef][ISI][Medline]
2 Ueland PM, Refsum H, Beresford SA, Vollset SE. The controversy over homocysteine and cardiovascular risk. Am J Clin Nutr 2000; 72:32432.
3 Mangoni AA, Jackson SH. Homocysteine and cardiovascular disease: current evidence and future prospects. Am J Med 2002;112:55665.[CrossRef][ISI][Medline]
4 Knekt P, Reunanen A, Alfthan G et al. Hyperhomocystinemia: a risk factor or a consequence of coronary heart disease? Arch Intern Med 2001;161:158994.
5 Ford ES, Smith SJ, Stroup DF, Steinberg KK, Mueller PW, Thacker SB. Homocyst(e)ine and cardiovascular disease: a systematic review of the evidence with special emphasis on case-control studies and nested case-control studies. Int J Epidemiol 2002;31:5970.
6 Voutilainen S, Lakka TA, Hamelahti P, Lehtimaki T, Poulsen HE, Salonen JT. Plasma total homocysteine concentration and the risk of acute coronary events: the Kuopio Ischaemic Heart Disease Risk Factor Study. J Intern Med 2000;248:21722.[CrossRef][ISI][Medline]
7 Fallon UB, Ben-Shlomo Y, Elwood P, Ubbink JB, Smith GD. Homocysteine and coronary heart disease in the Caerphilly cohort: a 10 year follow up. Heart 2001;85:15358.
8 Knekt P, Alfthan G, Aromaa A et al. Homocysteine and major coronary events: a prospective population study amongst women. J Intern Med 2001;249:46165.[CrossRef][ISI][Medline]
9 Thogersen AM, Nilsson TK, Dahlen G et al. Homozygosity for the C677>T mutation of 5,10-methylenetetrahydrofolate reductase and total plasma homocyst(e)ine are not associated with greater than normal risk of a first myocardial infarction in northern Sweden. Coron Artery Dis 2001;12:8590.[CrossRef][ISI][Medline]
10 Kark JD, Selhub J, Adler B et al. Nonfasting plasma total homocysteine level and mortality in middle-aged and elderly men and women in Jerusalem. Ann Intern Med 1999;131:32130.
11 Fallon UB, Elwood P, Ben-Shlomo Y, Ubbink JB, Greenwood R, Smith GD. Homocysteine and ischaemic stroke in men: the Caerphilly study. J Epidemiol Community Health 2001;55:9196.
12 Vollset SE, Refsum H, Tverdal A et al. Plasma total homocysteine and cardiovascular and noncardiovascular mortality: the Hordaland Homocysteine Study. Am J Clin Nutr 2001;74:13036.
13 Ridker PM, Shih J, Cook TJ et al. Plasma homocysteine concentration, statin therapy, and the risk of first acute coronary events. Circulation 2002;105:177679.
14 Albert CM, Ma J, Rifai N, Stampfer MJ, Ridker PM. Prospective study of C-reactive protein, homocysteine, and plasma lipid levels as predictors of sudden cardiac death. Circulation 2002;105:259599.
15 Stampfer MJ, Malinow MR, Willett WC et al. A prospective study of plasma homocyst(e)ine and risk of ischemic stroke. Stroke 1994;25:192430.[Abstract]
17 Verhoef P, Kok FJ, Kruyssen DA et al. Plasma total homocysteine, B vitamins, and risk of coronary atherosclerosis. Arterioscler Thromb Vasc Biol 1997;17:98995.
18 Perry IJ, Refsum H, Morris RW, Ebrahim SB, Ueland PM, Shaper AG. Prospective study of serum total homocysteine concentration and risk of stroke in middle-aged British men. Lancet 1995;346:139598.[ISI][Medline]
19 Wald NJ, Watt HC, Law MR, Weir DG, McPartlin J, Scott JM. Homocysteine and ischemic heart disease: results of a prospective study with implications regarding prevention. Arch Intern Med 1998;158:86267.
20 Folsom AR, Nieto FJ, McGovern PG et al. Prospective study of coronary heart disease incidence in relation to fasting total homocysteine, related genetic polymorphisms, and B vitamins: the Atherosclerosis Risk in Communities (ARIC) study. Circulation 1998;98:20410.
21 Arnesen E, Refsum H, Bonaa KH, Ueland PM, Forde OH, Nordrehaug JE. Serum total homocysteine and coronary heart disease. Int J Epidemiol 1995;24:70409.[Abstract]
22 Chasan-Taber L, Selhub J, Rosenberg IH et al. A prospective study of folate and vitamin B6 and risk of myocardial infarction in US physicians. J Am Coll Nutr 1996;15:13643.[Abstract]
23 Bots ML, Launer LJ, Lindemans J et al. Homocysteine and short-term risk of myocardial infarction and stroke in the elderly: the Rotterdam Study. Arch Intern Med 1999;159:3844.
24 Jacques PF, Selhub J, Bostom AG, Wilson PW, Rosenberg IH. The effect of folic acid fortification on plasma folate and total homocysteine concentrations. N Engl J Med 1999;340:144954.