Correspondence

Plasma Homocysteine Levels and Mortality in Patients with Coronary Artery Disease

N Engl J Med 1997; 337:1631-1633November 27, 1997

Article

To the Editor:

Nygård et al. (July 24 issue)1 nicely demonstrate an association between elevated plasma homocysteine levels and increased mortality in patients with angiographically confirmed coronary artery disease. It is important to mention that fasting plasma homocysteine levels, as used in this study, identify only some of the patients with disturbances in homocysteine metabolism. Approximately twice as many patients are identified with the additional use of a methionine-loading test.2,3 One could speculate that the effect seen by Nygård et al. would have been even more pronounced if the patients had been further characterized with a methionine-loading test. Homocysteine may be an even stronger risk factor for mortality in patients with coronary artery disease than was shown in this study.

It is known that plasma homocysteine levels can be decreased and even normalized in a large proportion of patients through treatment with folic acid, vitamin B₆ , and betaine,4,5 even though it is not known whether such lowering slows the rate of progression of arteriosclerotic disease or decreases thromboembolic events.

Stephan Moll, M.D.
Humboldt Universität Charité, 13122 Berlin, Germany

5 References

1
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;337:230-236
Full Text | Web of Science | Medline

2
Falcon CR, Cattaneo M, Panzeri D, Martinelli I, Mannucci PM. High prevalence of hyperhomocyst(e)inemia in patients with juvenile venous thrombosis. Arterioscler Thromb 1994;14:1080-1083
CrossRef | Medline

3
Cattaneo M, Martinelli I, Mannucci PM. Hyperhomocysteinemia as a risk factor for deep-vein thrombosis. N Engl J Med 1996;335:974-975[Erratum, N Engl J Med 1997;336:1399.]
Full Text | Web of Science | Medline

4
Malinow MR. Hyperhomocyst(e)inemia: a common and easily reversible risk factor for occlusive atherosclerosis. Circulation 1990;81:2004-2006[Erratum, Circulation 1990;82:1547.]
CrossRef | Web of Science | Medline

5
Franken DG, Boers GH, Blom HJ, Trijbels FJ, Kloppenborg PW. Treatment of mild hyperhomocysteinemia in vascular disease patients. Arterioscler Thromb 1994;14:465-470
CrossRef | Medline

To the Editor:

The article by Nygård et al. reports increased mortality in patients with coronary artery disease who have elevated homocysteine levels. The authors also describe no correlation between folate levels and mortality, although folate is known to lower homocysteine levels.1 Folate levels were measured in serum, where they correlate less with tissue levels than do folate concentrations in red cells. Perhaps a more accurate estimate of total-body folate would have been obtained if folate had been evaluated in red cells. This value could have been used to select the patients whose homocysteine levels would decrease after the start of folate supplementation.

David Farhadi, M.D.
Hospital of the University of Pennsylvania, Philadelphia, PA 19104

1 References

1
Ubbink JB, Vermaak WJ, van der Merwe A, Becker PJ. Vitamin B-12, vitamin B-6, and folate nutritional status in men with hyperhomocysteinemia. Am J Clin Nutr 1993;57:47-53
Web of Science | Medline

To the Editor:

Nygård and colleagues have reported that the homocysteine concentration is a strong independent predictor of mortality in patients with angiographically confirmed coronary artery disease. The authors referred to the prothrombotic effects of homocysteine but did not include hemostatic variables in their multivariate analyses. In a previous case–control study we found a strong positive correlation between homocysteine and fibrinogen. Therefore, the association between homocysteine and coronary artery disease was not independent.1 We have extended this study and analyzed the relation between homocysteine, clinical data, hemostatic variables, lipid risk factors, and coronary anatomy in 348 men and 117 women, 32 to 85 years old, who underwent coronary angiography. Homocysteine was significantly correlated with age, the presence and number of stenosed coronary vessels, and concentrations of apolipoprotein A-II, fibrinogen, the fibrin-split product d-dimer, and C-reactive protein. Age and the concentrations of apolipoprotein A-II, fibrinogen, d-dimer, and C-reactive protein also had significant associations with both the presence and the number of stenosed coronary vessels. In a multivariate model, d-dimer concentration (β = 0.192, P = 0.028) but not age or concentrations of homocysteine, apolipoprotein A-II, fibrinogen, and C-reactive protein was independently associated with the presence of coronary artery disease. In an alternative model that did not include the d-dimer concentration, age (β = 0.219, P<0.001) and the fibrinogen concentration (β = 0.116, P = 0.035) were independently associated with coronary artery disease, but the homocysteine, apolipoprotein A-II, and C-reactive protein levels were not.

Various prospective studies in the population and in patients with manifest coronary artery disease have identified hemostatic and inflammatory markers, including concentrations of fibrinogen and C-reactive protein, as risk factors for future coronary events.2-4 Therefore, because of the strong correlations between homocysteine concentration and hemostatic variables and because of the prothrombotic properties of homocysteine in vitro, it seems essential that hemostatic risk factors be included in studies evaluating the possible role of homocysteine as an independent risk factor for coronary morbidity and mortality.

Arnold von Eckardstein, M.D.
Gerd Assmann, M.D.
Westphalian Wilhelms University of Münster, D-48129 Münster, Germany

4 References

1
von Eckardstein A, Malinow MR, Upson B, et al. Effects of age, lipoproteins, and hemostatic parameters on the role of homocyst(e)inemia as a cardiovascular risk factor in men. Arterioscler Thromb 1994;14:460-464
CrossRef | Medline

2
Ernst E, Resch KL. Fibrinogen as a cardiovascular risk factor: a meta-analysis and review of the literature. Ann Intern Med 1993;118:956-963
Web of Science | Medline

3
Thompson SG, Kienast J, Pyke SDM, Haverkate F, van de Loo JCW. Hemostatic factors and the risk of myocardial infarction or sudden death in patients with angina pectoris. N Engl J Med 1995;332:635-641
Full Text | Web of Science | Medline

4
Heinrich J, Balleisen L, Schulte H, Assmann G, van de Loo J. Fibrinogen and factor VII in the prediction of coronary risk: results from the PROCAM study in healthy men. Arterioscler Thromb 1994;14:54-59[Erratum, Arterioscler Thromb 1994;14:1392.]
CrossRef | Medline

Author/Editor Response

The authors reply:

To the Editor: The methionine-loading test is performed by measuring the concentration of homocysteine after the patient ingests a standard dose of methionine, which is believed to stress the homocysteine degradation pathway dependent on cystathionine beta-synthase. Although there is a strong correlation between fasting and post-loading homocysteine concentrations and both measurements have similarly strong associations with cardiovascular disease, the information obtained from the two tests is not identical.1,2 We agree with Dr. Moll that the measurement of post-loading total homocysteine could shed further light on the role of total homocysteine in the prediction of cardiovascular disease. However, the methionine-loading test is a cumbersome procedure, and routine testing may be impractical.

The serum folate concentration is responsive to folate intake and is believed to indicate short-term folate status, whereas the red-cell folate concentration may reflect the average folate status during the lifetime of the erythrocyte. However, the methods of determining folate levels are seriously flawed, causing considerable analytic imprecision.3,4 Although we are not convinced that the concentration of folate in red cells is superior to that in serum or plasma as a marker of folate status, we agree with Dr. Farhadi that measurement of red-cell folate would have given additional information relevant to our study.

Drs. von Eckardstein and Assmann suggest that the observed association between plasma total homocysteine levels and subsequent mortality may have been confounded by hemostatic factors. The platelet count was included in the multivariate model, and lipoprotein(a) showed no significant association with mortality. We also measured fibrinogen in our patients but found no association with homocysteine (r = 0.06), and its inclusion in the multivariate model did not affect the homocysteine–mortality relation.

Ottar Nygård, M.D.
Helga Refsum, M.D.
Per Magna Ueland, M.D.
Mikael Farstad, M.D.
Stein Emil Vollset, M.D., Dr.P.H.
University of Bergen

Jan Erik Nordrehaug, M.D.
Haukeland University Hospital, 5021 Bergen, Norway

4 References

1
Mansoor MA, Bergmark C, Svardal AM, Lonning PE, Ueland PM. Redox status and protein binding of plasma homocysteine and other aminothiols in patients with early-onset peripheral vascular disease: homocysteine and peripheral vascular disease. Arterioscler Thromb Vasc Biol 1995;15:232-240
CrossRef | Web of Science | Medline

2
Graham IM, Daly LE, Refsum HM, et al. Plasma homocysteine as a risk factor for vascular disease: the European Concerted Action Project. JAMA 1997;277:1775-1781
CrossRef | Web of Science | Medline

3
Lindenbaum J, Allen RH. Clinical spectrum and diagnosis of folate deficiency. In: Bailey LB, ed. Folate in health and disease. New York: Marcel Dekker, 1995:43-73.

4
Gunter EW, Bowman BA, Caudill SP, Twite DB, Adams MJ, Sampson EJ. Results of an international round robin for serum and whole-blood folate. Clin Chem 1996;42:1689-1694
Web of Science | Medline