Editorials

Heart attacks and homocysteine

It is now accepted that an elevated plasma concentration of homocysteine is a risk factor for atherosclerotic vascular disease affecting the coronary, cerebral, and peripheral arteries.¹ Prospective data^{2 3 4} confirm the findings of casecontrol studies^{5 6 7 8} and indicate that an elevated plasma homocysteine concentration precedes the development of disease and that there is a dose-response effect.

A 5 µmol/l increase in plasma homocysteine concentration has been estimated to raise the risk of coronary heart disease by as much as an increase in serum cholesterol concentration of 0.5 mmol/l.¹ Data from the European Union concerted action project, a case-control study of 750 patients with vascular disease and 800 controls, indicate that a plasma homocysteine concentration above 12 µmol/l (the top fifth of the control distribution) doubles the risk of myocardial infarction and cerebral or peripheral vascular disease in both men and women.⁹ Additional patients at high risk can be identified by stressing the methionine pathway by means of a methionine loading test, analogous to a glucose tolerance test. Both genetic and nutritional factors influence homocysteine concentrations; since simple nutrient supplementation with folic acid can reduce homocysteine concentrations in almost all subjects, these observations may have substantial public health implications.

Homocysteine is a sulphur amino acid produced by demethylation of the essential amino acid methionine. It may be irreversibly degraded by cystathionine ß-synthase. This enzyme requires vitamin B6 as a cofactor. Alternatively, homocysteine may be remethylated to conserve methionine, a process requiring several enzymes. Of these, methionine synthase requires methylcobalamin as a cofactor and methyltetrahydrofolate as a co-substrate. Production of methyltetrahydrofolate requires both an adequate supply of folate and the enzyme methylene tetrahydrofolate reductase. Dysfunctional enzymes or inadequate amounts of nutrients may therefore lead to an elevated concentration of intracellular homocysteine, which is then exported to the plasma.

Homocystinuria occurs when plasma homocysteine concentrations are sufficiently high to be excreted in the urine as the disulphide homocystine. Classically, it is caused by homozygous deficiency of cystathionine ß-synthase.¹⁰ Rarer causes are homozygous deficiency in methylene tetrahydrofolate reductase and defects in cobalamin metabolism. The observation that such distinct conditions share both an elevated plasma homocysteine concentration and the development of precocious vascular disease led McCully to formulate the homocysteine theory of atherosclerosis.¹¹ A commoner genetic defect is the presence of the thermolabile variant of methylene tetrahydrofolate reductase, which reduces but does not abolish enzyme activity. This mutation occurs in perhaps 5-7% of normal subjects and is associated with increased risk of vascular disease in some studies,^{12 13} though not all.^{14 15}

Deficiency of the nutrients which regulate homocysteine metabolism may be a more common cause of mildly raised plasma homocysteine concentrations than genetic defects,¹⁶ although interaction effects seem likely.¹⁷ Concentrations of both folate and vitamin B12 relate inversely to plasma homocysteine,¹⁸ and a raised plasma homocysteine concentration is a sensitive marker for even low normal intakes of folate and vitamin B12.¹⁹ It follows that current reference ranges for plasma nutrient concentrations and recommended daily intakes may need revision.

Despite sound epidemiological evidence for a strong, graded, and independent relation between homocysteine and coronary heart disease, the mechanism of how homocysteine may be atherogenic remains unclear. Experimental evidence of the capacity of homocysteine to damage vascular endothelium; to interact with platelets, low density lipoprotein cholesterol, and clotting factors; and to impair nitric oxide function has been reported.²⁰ Many such experiments have used species of homocysteine not prevalent in vivo and at artificially high concentrations. Many require replication and extension.

The demonstration that a raised plasma homocysteine concentration is a powerful risk factor for vascular disease is of little value unless homocysteine concentration can be reduced and there is a resulting reduction in risk. Only then can the relation be judged to be causal beyond reasonable doubt. Dietary supplementation with folic acid reduces plasma homocysteine concentrations by about 30% in almost all subjects. The effect of vitamin B12 is modest, except in deficient subjects. Vitamin B6 has more effect on lowering homocysteine concentrations unmasked by methionine loading than on basal concentrations, but the clinical importance of this observation is uncertain. A meta-analysis of dose finding studies, particularly with regard to folic acid, is under way. The optimal dose is uncertain but may be around 1 mg.

Since homocysteine is unequivocally linked with vascular disease and since plasma homocysteine concentration can be reduced simply and cheaply with folic acid, it is now a matter of urgency to ascertain whether reducing plasma homocysteine concentration reduces coronary risk. Estimates of the effect of folate supplementation or food fortification on the risk of coronary heart disease have been reported, but hard evidence of benefit accruing from reducing plasma homocysteine concentration is not yet available. Were folic acid a patentable new product, it is likely that such trials would already be under way. As it is, the most likely next step will be the addition of a homocysteine lowering component to one of the large secondary prevention trials of lipid or blood pressure treatment currently being planned. Only when the results of such trials are available will it be possible to decide whether homocysteine deserves its place as a major causal risk factor for coronary disease.

Professor of epidemiology and preventive medicine Royal College of Surgeons in Ireland, Dublin 2, Ireland

Research fellow Adelaide Hospital, Dublin 8, Ireland

Ian Graham, Raymond Meleady 

1. Boushey C, Beresford SAA, Omenn G, Motulsky A. A quantitative assessment of plasma homocysteine as a risk factor for vascular disease. Probable benefits of increasing folic acid intakes. JAMA 1995;274:1049-57. [Abstract]
2. Stampfer MJ, Malinow R, Willet WC, Newcomer L, Upson B, Ullman D, et al. A prospective study of plasma homocyst(e)ine and risk of myocardial infarction in US physicians. JAMA 1992;268:877-81. [Abstract]
3. 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;346:1395-8. [Medline]
4. Arnesen E, Refsum H, Bonaa KH, Ueland PM, Forde OH, Nordrehaug JE. Serum total homocysteine and coronary heart disease. Int J Epidemiol 1995;24:704-9. [Abstract/Free Full Text]
5. Clarke R, Daly L, Robinson K, Naughten E, Cahalane S, Fowler B, et al. Hyperhomocysteinemia: an independent risk factor for vascular disease. N Engl J Med 1991;324:1149-55. [Abstract]
6. Pancharuniti N, Lewis CA, Sauberlich HE, Perkins LL, Go RCP, Alvarez J, et al. Plasma homocyst(e)ine, folate, and vitamin B12 concentrations and risk for early-onset coronary artery disease. Am J Clin Nutr 1994;59:940-8. [Abstract/Free Full Text]
7. Robinson K, Mayer EL, Miller DP, Green R, van Lente F, Gupta A, et al. Hyperhomocysteinemia and low pyridoxal phosphate; common and independent risk factors for coronary artery disease. Circulation 1995;92:2825-30. [Abstract/Free Full Text]
8. Wu LL, Wu J, Hunt SJ, James BC, Vincent GM, Williams RR, et al. Plasma homocyst(e)ine as a risk factor for early familial coronary artery disease. Clin Chem 1994;40:552-61. [Abstract/Free Full Text]
9. Graham I. Interactions between homocysteinemia and conventional risk factors in vascular disease. Eur Heart J 1994;15(suppl):530.
10. Mudd SH, Levy HL, Skovby F. Disorders of transsulphuration. In: Scriver CR, Beaudet AL, Sly WS, Valle D, eds. The metabolic basis of inherited disease. 6th ed. Vol 1. New York: McGraw Hill, 1989: 693-734.
11. McCully KS, Wilson RB. Homocysteine theory of arteriosclerosis. Atherosclerosis 1975;22:215-27. [Medline]
12. Kang SS, Zhou J, Wong PWK, Kowalisyn J, Strokosch G. Intermediate homocysteinemia: a thermolabile variant of methylenetetrahydrofolate reductase. Am J Hum Genet 1988;43:414-21. [Medline]
13. Engbersen AMT, Franken DG, Boers GHJ, Stevens EBM, Trijbels FJM, Blom HJ. Thermolabile 5, 10-methylenetetrahydrofolate reductase as a cause of mild hyperhomocysteinemia. Am J Hum Genet 1995;56:142-50. [Medline]
14. Adams M, Smith PD, Martin D, Thompson JR, Lodwick D, Samani NJ. Genetic analysis of thermolabile methylenetetrahydrofolate reductase as a risk factor for myocardial infarction. Q J Med 1996;89:437-44. [Abstract]
15. Wilcken DEL, Wang XL, Sim AS, McCredie M. Distribution in healthy and coronary populations of the methylenetetrahydrofolate reductase (MTHFR) C(sub 677)T mutation. Arterioscler Thromb Vasc Biol 1996;16:878-82. [Abstract/Free Full Text]
16. Daly L, Robinson K, Tan KS, Graham IM. Hyperhomocysteinaemia: a metabolic risk factor for coronary heart disease determined by both genetic and environmental influences? Q J Med 1993;86:685-9.
17. Jacques PF, Bostom AG, Williams RR, Ellison RC, Eckfeldt JH, Rosenberg IH, et al. Relation between folate status, a common mutation in methylenetetrahydrofolate reductase, and plasma homocysteine concentrations. Circulation 1996;93:7-9. [Abstract/Free Full Text]
18. 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;270:2693-8. [Abstract]
19. Joosten E, van den Berg A, Reizler R, Naurath HJ, Lindenbaum J, Stabler SP, et al. Metabolic evidence that deficiencies of vitamin B-12 (cobalamin), folate, and vitamin B-6 occur commonly in elderly people. Am J Clin Nutr 1993;58:468-76. [Abstract/Free Full Text]
20. Ueland PM, Refsum H, Brattstrom L. Plasma homocysteine and cardiovascular disease. In: Francis RB, ed. Atherosclerotic cardiovascular disease, hemostasis and endothelial function. New York: Marcell Dekker, 1992:183-235.