Heart attacks and homocysteineBMJ 1996; 313 doi: https://doi.org/10.1136/bmj.313.7070.1419 (Published 07 December 1996) Cite this as: BMJ 1996;313:1419
- Ian Graham,
- Raymond Meleady
- Professor of epidemiology and preventive medicine Royal College of Surgeons in Ireland, Dublin 2, Ireland
- Research fellow Adelaide Hospital, Dublin 8, Ireland
Time for a randomised controlled trial of plasma homocysteine reduction
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 data2 3 4 confirm the findings of casecontrol studies5 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.