24 . 01 . 2020

The Impact of Homocysteine on Cardiovascular Disease

Homocysteine ​​is an amino acid derived from cellular metabolism that has a direct toxic action on the vascular endothelium. In this article, we investigate the efficacy of homocysteine-lowering interventions ​​in cardiovascular disease prevention.

In 1962, Kilmer McCully, an American researcher, proposed the theory that high levels of homocysteine ​​were at the origin of atherosclerotic disease. This theory was based on the observation of advanced atherosclerosis in the autopsy of two children with homocystinuria (a genetic condition that leads to very high levels of homocysteine), as well as on several animal experiments. Initially, McCully was looked at with skepticism by the scientific community, but in the 1990s, his theory gained more acceptance, and several studies aimed at testing his hypothesis took place.

What is homocysteine?

Homocysteine ​​is an amino acid, not directly involved in protein synthesis, which is an intermediary in the metabolism of methionine, itself an essential amino acid. Methionine from the diet (meat, fish, and eggs are the main sources) is metabolized to homocysteine, through a group of intracellular reactions, with the formation of S-Adenosylmethionine, which functions as the primary donor of methyl groups in the body. The resulting homocysteine ​​can then be remethylated to methionine or converted to cysteine ​​via transsulfuration. For these homocysteine ​​metabolic pathways to take place, adequate levels of three vitamins are required: folic acid, vitamin B12, and vitamin B6.


Fig.1 – Methionine-homocysteine cycle.


What is the normal homocysteine ​range?

For most laboratories, levels ​​between 5 and 15 micromoles/liter (µmol / L) are considered normal. However, values ​​below 12 µmol / L are considered ideal.

At high concentrations, homocysteine ​​can have the following toxic effects on the endothelium:

  •  increased oxidative stress;
  • increased inflammation;
  • decreased vascular elasticity, due to activation of metalloproteinases and increased collagen synthesis;
  • antagonism of the vasodilator effect of nitric oxide (NO)

All of these mechanisms lead to endothelial dysfunction, a recognized atherosclerosis promoting factor.

Is increased homocysteine ​​associated with a higher incidence of cardiovascular disease?

Following the line of reasoning exposed here, a clear association between high levels of homocysteine ​​and the incidence of cardiovascular disease would be expected. Initially, retrospective studies suggested a strong association, however prospective studies did not confirm it.

A 2002 meta-analysis suggested that decreasing homocysteine ​​by 25% would result in a 10% lower risk of coronary heart disease. In contrast, a 2012 study, in which data from 19 previous studies were analyzed, concluded that moderate homocysteine ​​elevation did not have a significant effect on the incidence of cardiovascular disease.

What do the homocysteine-lowering trials say?

The homocysteine hypothesis has been around long enough to be tested. A 2017 systematic review from the Cochrane Library analyzed 15 randomized controlled trials, involving about 70,000 patients in total. In these clinical trials, folic acid and vitamin B12 had been administered to some patients, with a subsequent reduction in serum homocysteine ​​levels, while others received placebo. According to this systematic review, the homocysteine-lowering intervention:

  • had no significant effect on the incidence of coronary heart disease or deaths by all causes.
  • contributed to a 10% reduced stroke risk.

The theory of homocysteine ​​as a promoter of atherosclerosis seems to have lost strength over time. This is yet another example that what is true today may be false tomorrow.

However, we must not fall into the extreme of ignoring homocysteine, but rather include it in a careful and comprehensive metabolic assessment of our patients. It may be that this marker does not have an exclusively causal effect on the atherosclerotic process, but rather is a sign of other biochemical imbalances.



Martí-Carvajal AJ, Solà I, Lathyris D, Dayer M. Homocysteine-lowering interventions for preventing cardiovascular events. Cochrane Database Syst Rev. 2017;2017(8).

Clarke R, Bennett DA, Parish S, et al. Homocysteine and coronary heart disease: Meta-analysis of MTHFR case-control studies, avoiding publication bias. PLoS Med. 2012;9(2).

Clarke R, Halsey J, Bennett D, Lewington S. Homocysteine and vascular disease: Review of published results of the homocysteine-lowering trials. J Inherit Metab Dis. 2011;34(1):83-91.

Cianciolo G, De Pascalis A, Di Lullo L, Ronco C, Zannini C, La Manna G. Folic acid and homocysteine in chronic kidney disease and cardiovascular disease progression: Which comes first? CardioRenal Med. 2017;7(4):255-266.