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Homocysteine and heart disease

There is a growing recognition that high levels of homocysteine are associated with heart disease. This started in the late 1960s when a pathologist in Boston encountered two children with homocystinuria, who, despite being very young, had advanced atherosclerosis, though the plaques contained no lipid. The pathologist concerned, Kilmer McCully, was given a hard time for putting forward the suggestion of a possible link between homocysteine and the formation of atheromatous plaque [1].

Basis of homocysteine theory

Homocysteine is a curious sulphur-containing amino acid formed during methionine metabolism. It can dimerise to homocystine, or form disulphide bonds with proteins to form so-called 'protein-bound' homocysteine. In plasma about 80% of homocysteine is protein bound.

Metabolism of homocysteine is by pathways which re-methylate it (and which require vitamin B12 and folic acid), or by a trans-sulphuration pathway which requires vitamin B6. Homocysteine in blood (and elsewhere) is a product of how much methionine is eaten, mainly in protein (with about three times more methionine in animal than plant protein), and how much is metabolised (and metabolism may be affected by amounts of B vitamins and folate available).

What homocysteine does to arteries

Too much homocysteine and the result is atherosclerosis. Evidence for this comes from a variety of sources:

Homocysteine, the epidemiology

There is a growing amount of evidence associating high homocysteine levels ('normal values' are usually regarded as being below about 14 μmol/L) with death from heart disease. A classic study (Figure 1) showed that high homocysteine levels in a population were associated with higher levels of cardiovascular disease mortality [2].

In the BUPA prospective study of 21,500 men aged 35 to 64 years, homocysteine in stored samples was compared in 229 men without a history of ischaemic heart disease and who subsequently died of ischaemic heart disease over a mean follow-up of 8.7 years, and 1126 age-matched controls [3]. This study showed that men in the highest quartile of plasma homocysteine levels (over 15 μmol/L) were nearly three times more likely to die of ischaemic heart disease, even after adjusting for factors like apolipoprotein levels and blood pressure (odds ratio 2.9, 95% confidence interval 2.0 to 4.1).

The BUPA study also contained data from other prospective and retrospective studies which examined homocysteine levels and fatal or nonfatal cardiac events. There was considerable consistency, with an odds ratio of ischaemic heart disease for each 5 μmol/L increase in serum homocysteine of 1.8 (1.5 to 2.2) in a total of about 2,300 subjects.

Another prospective examination of the relationship between plasma homocysteine and mortality was carried out in 587 patients with angiographically confirmed coronary artery disease [4]. Over a median follow up of 4.6 years 64 patients died. For those patients whose plasma homocysteine was <9 μmol/L, only 3.8% died, compared with 25% of those with plasma homocysteine ≥15 μmol/L (Table).

Mortality over four years in 587 patients with coronary artery disease [4]
Homocysteine (µmol/L) Mortality (%)
<9 3.8
9-14.9 8.6
≥15 24.7

Homocysteine and vitamins

Serum homocysteine concentrations have been correlated with plasma vitamin concentration and vitamin intake in 1160 adult survivors, aged 67 to 96 years, from the Framingham study [5]. Homocysteine was higher in men and women aged over 80 years, but after adjusting for age, sex and levels of other vitamins, there was a strong inverse correlation between plasma homocysteine and folate. Individuals with the lowest plasma folate were twelve times more likely to have an elevated homocysteine concentration (defined as being above 14 μmol/L) after adjusting for age, sex and other B vitamins.

The mean serum homocysteine concentration and the proportion of individuals with elevated plasma homocysteine (>14 μmol/L) was correlated with B vitamin intake (Figure 2). The quintile with the lowest B vitamin intake had a prevalence of homocysteinaemia of 53%. Similar results were found for a vitamin index expressing serum concentrations of B vitamins.

That there is a relationship between increased intake of vitamins, especially B vitamins, and heart disease was confirmed in the Nurses' Health Study [6]. In 14 years of follow up from 1980 there were 658 nonfatal and 281 fatal cases of coronary heart disease in over 80,000 women who gave detailed information on diet and vitamin supplements at entry. After controlling for cardiovascular risk factors, the incidence of heart disease in those with the highest intake of folate was 31% lower than those with the lowest intake. For vitamin B6 those with the highest intake had a 33% lower risk of disease. For women in the highest quintile for both folate and vitamin B6, the risk of heart disease was reduced by 45% (95% confidence interval 26% to 59%).

Therapeutic implications

There are few randomised controlled trials of interventions to reduce homocysteine concentrations in blood and correlation of that with clinical outcome. All we have is an observation [7] that treatment with folate and B vitamins stops the increase in atherosclerotic plaque area in patients with unexplained atherosclerosis which might have a genetic cause and who have homocysteine concentrations of >14 μmol/L.


Homocysteine is clearly important, and the epidemiological evidence linking high levels of homocysteine in blood to increased rates of heart disease is becoming impressive. A homocysteine industry is starting to develop, in which new and easier methods for analysing this amino acid are being developed and marketed. Right now assays aren't so easy, but before long we will probably be seeing people comparing their homocysteine level just as they now discuss their cholesterol or PSA. Another screening test to worry about for someone!

The nutritional advice seems to be not much different from anything else we have seen before. Eat lots of fruit and vegetables, don't be too liberal with animal protein, avoid refined carbohydrates and take alcohol in moderation. There is definitely a school of thought, though, that folate and B vitamin intakes should be supplemented - 'eat right and take a multivitamin' seems to be the emerging consensus.


  1. Kilmer McCully: pioneer of the homocysteine theory. Lancet 1998 352: 1364.
  2. G Alfthan, A Aro, KF Gey. Plasma homocysteine and cardiovascular disease mortality. Lancet 1997 349: 397.
  3. NJ Wald, HC Watt, MR Law et al. Homocysteine and ischaemic heart disease. Archives of Internal Medicine 1998 158: 862-7.
  4. O Nygård, JE Nordrehaug, H Refsum et al. Plasma homocysteine and mortality in patients with coronary artery disease. New England Journal of Medicine 1997 337: 230-6.
  5. J Selhub, PF Jacques, PW Wilson et al. Vitamin status and intake as primary determinants of homocysteinaemia in an elderly population. JAMA 1993 270: 2693-8.
  6. EB Rimm, WC Willett, FB Hu et al. Folate and vitamin B6 from diet and supplements in relation to risk of coronary heart disease among women. JAMA 1998 279: 359-64.
  7. JC Peterson, JD Spence. Vitamins and progression of atherosclerosis in hyper-homocyst(e)inaemia. Lancet 1998 351: 263.

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