Homocysteine and Risk of Ischemic Heart Disease and Stroke

Abstract & Commentary

Synopsis: This meta-analysis suggests that elevated homocysteine levels are only a modest independent predictor of ischemic heart disease and stroke risk in healthy populations.

Source: The homocysteine studies collaboration. Homocysteine and risk of ischemic heart disease and stroke: A meta-analysis. JAMA. 2002;288:2015-2022.

The theory that an elevated blood concentration of the amino acid homocysteine may be a risk factor for ischemic heart disease (IHD) was suggested by the observation that children with homocystinuria and markedly elevated homocysteine levels suffered from premature IHD. Epidemiological data using case-controlled studies supported this theory. However, results from more recent prospective observational studies varied in the significance of the association.

In order to examine the effect of homocysteine level and IHD and stroke risk, this collaborative meta-analysis sought to combine individual participant data from all relevant observational studies to produce a better estimate of the association of total plasma homocysteine levels with IHD and stroke, while controlling for other cardiovascular risk factors.

Medline was searched from January 1966 to January 1999 for observational studies of the association between IHD or stroke and homocysteine concentrations. Additional studies were identified by examining the references and by communicating with relevant researchers. Data from 30 prospective or retrospective studies involving a total of 5073 IHD events and 1113 stroke events were included in the meta-analysis. Statistical adjustments were made between studies to control for known cardiovascular risk factors. Combined odds ratios for the association of IHD and stroke with blood homocysteine concentrations were obtained by using conditional logistic regression.

Stronger associations were observed in retrospective studies of homocysteine measure in blood collected after the onset of disease than in prospective studies among individuals without a history of cardiovascular disease when the blood was collected. After adjusting for cardiovascular risk factors and regression dilution bias in the prospective studies, a 25% lower usual homocysteine level was associated with an 11% (odds ratio [OR], 0.89; 95% confidence interval [CI], 0.83-0.96), lower IHD risk and 19% lower stroke risk (OR, 0.81; 95% CI, 0.69-0.95).

Comment by Martin S. Lipsky, MD

This meta-analysis suggests that elevated homocysteine has only a modest independent effect as a predictor of IHD and stroke risk in healthy populations. The effect they found was weaker than initially reported in earlier retrospective studies. In an accompanying editorial, Wilson1 notes that as although it appears likely that homocysteine will not be as important in determining cardiovascular risk as cholesterol, smoking, diabetes mellitus, and hypertension but it is still significant. As this meta-analysis notes, even though the risk reduction is modest, if the association of homocysteine with IHD is causal then the benefits for the general population by lowering homocysteine levels could be substantial.

At this time, the results support the recommendation that all of us should eat our fruits and veggies or at the very least to live like our mothers told us to. It also substantiates that there may be benefit to recommending those individuals at high risk for IHD and stroke supplement their diets with folic acid in order to lower their homocysteine level. Even though it is not clear whether lowering homocysteine will result in reducing the risk for IHD, the negligible risks for taking vitamin supplementation make it prudent to continue this practice until definitive data form a large randomized trial of the effects on vascular disease on lowering homocysteine with folic acid are available.

Dr. Lipsky, Professor and Chair, Department of Family Medicine, Northwestern University Medical School, Chicago, IL, is Associate Editor of Internal Medicine Alert.


1. Wilson P. JAMA. 2002;288:2042-2043.