Homocysteine and Coronary Heart Disease

ABSTRACT

Children with homocystinuria have markedly elevated plasma homocysteine concentrations and increased risks of stroke and coronary heart disease (CHD). Supplementation with folic acid, vitamin B₆, and vitamin B₁₂ lower homocysteine levels and such therapy is remarkably effective in delaying the occurrence of vascular events in affected individuals. The relevance, if any, of moderately elevated homocysteine levels to cardiovascular disease in the general population is uncertain. The results of retrospective studies of homocysteine and risk of cardiovascular disease (where blood is collected after the onset of disease) indicate that CHD or stroke patients invariably have higher homocysteine levels than age-matched controls. In contrast, the results of prospective studies (where blood is collected before onset of disease) show much weaker associations of homocysteine with cardiovascular disease. This article examines the background, epidemiological evidence relating homocysteine with vascular disease, and effects of vitamin supplements on homocysteine concentrations. Large-scale clinical trials of folic acid-based vitamin supplements are currently in progress to test whether lowering blood homocysteine levels can reduce the risks of CHD and stroke.

KEYWORD

Homocysteine - coronary heart disease - stroke

REFERENCES

• 1 Jacobsen D W. Practical chemistry of homocysteine and other thiols. In: Carmel R, Jacobsen DW, eds. Homocysteine in Health and Disease Cambridge: Cambridge University Press 2001 0: 9-20
• 2 Wilcken D EL, Wilcken B. Historical overview and recent perspectives. In: Carmel R, Jacobsen DW, eds. Homocysteine in Health and Disease Cambridge: Cambridge University Press 2001 :
• 3 Wilcken D E, Wilcken B. The natural history of vascular disease in homocystinuria and the effects of treatment.  J Inherit Metab Dis . 1997;  20 295-300
• 4 McCully K S. Homocysteine and vascular disease.  Nat Med . 1996;  2 386-389
• 5 Finkelstein J D, Martin J J. Methionine metabolism in mammals; distribution of homocysteine between competing pathways.  J Biol Chem . 1984;  259 9508-9513
• 6 Ueland P M, Refsum H, Stabler S P. Total homocysteine in plasma or serum: methods and clinical applications.  Clin Chem . 1993;  39 1764-1779
• 7 Nexo E, Engebaak F, Ueland P M. Evaluation of novel assays in clinical chemistry: quantification of plasma total homocysteine.  Clin Chem . 2000;  46 1150-1156
• 8 Vollset S E, Refsum H, Nygard O, Ueland P M. Lifestyle factors associated with hyperhomocysteinemia. In: Carmel R, Jacobsen DW, eds. Homocysteine in Health and Disease Cambridge: Cambridge University Press 2001 : 341-355
• 9 Clarke R, Woodhouse P, Ulvik A. Variability and determinants of total homocysteine concentrations in an elderly population.  Clin Chem . 1998;  44 102-107
• 10 Frost P, Blom H J, Milos R. A candidate genetic risk factor for vascular disease: a common mutation in merthylenetetrahydrofolate reductase.  Nat Genet . 1995;  10 111-113
• 11 Jacques P F, Bostom A G, Williams R R. Relation between folate status, a common mutation between methylenetetrahydrofolate reductase, and plasma homocysteine concentrations.  Circulation . 1996;  93 7-9
• 12 Hustad S, Ueland P M, Vollset S E. Riboflavin as a determinant of plasma total homocysteine: effect modification by methylenetetrahydrofolate reductase C677T polymorphism.  Clin Chem . 2000;  46 1065-1071
• 13 Leclerc D, Campeau E, Goyette P. Human methionine synthase: cDNA cloning and identification of mutations in patients of the cblG complement group of folate/cobalamin disorders.  Hum Mol Denet . 1996;  5 1867-1874
• 14 Wilson A, Platt R, Wu Q. A common variant in methionine synthase reductase combined with low cobalamin (vitamin B-12) increases risk for spina bifida.  Mol Genet & Metab . 1999;  67 317-323
• 15 Selhub J, Jacques P F, Wilson P W, Rush D, Rosenberg I H. Vitamin status and intake as primary determinants of homocysteinemia in an elderly population.  JAMA . 1993;  270 2693-2698
• 16 Homocysteine Lowering Trialists' Collaboration. Lowering blood homocysteine with folic acid based supplements: meta-analysis of randomised trials.  Br Med J . 1998;  316 894-898
• 17 Boushey C, Beresford S AA, Omenn G S, Motulsky A G. A quantitative assessment of plasma homocysteine as a risk factor for vascular disease: probable benefits of increasing folic acid intakes.  JAMA . 1995;  274 1049-1057
• 18 Danesh J, Lewington S. Plasma homocysteine and coronary heart disease.  J Cardiovasc Risk . 1998;  5 229-232
• 19 Ueland P M, Refsum H, Beresford S AA, Vollset S E. The controversy over homocysteine and cardiovascular risk.  Am J Clin Nutr . 2000;  72 324-332
• 20 Clarke R, Lewington S, Donald A. Underestimation of the importance of homocysteine as a risk factor for cardiovascular disease in epidemiological studies.  J Cardiovasc Risk . 2001;  8 363-369
• 21 Brattstrom L, Wilcken D EL. Homocysteine and cardiovascular disease: cause or effect?.  Am J Clin Nutr . 2000;  72 315-323
• 22 Clarke R, Collins R. Can dietary supplements with folic acid or vitamin B-6 reduce cardiovascular risk?.  <~>Design of clinical trials to test the homocysteine hypothesis of vascular disease. J Cardiovasc Risk . 1998;  5 249-255