Slightly or even moderately increased levels of plasma homocysteine, as seen in patients with heterozygous cystathione deficiency, do not seem to indicate an increased risk of coronary artery disease (CAD). The homozygous form of this condition, associated with greater than 100-fold levels of plasma homocysteine, often indicates severe peripheral vascular disease, but patients have an incidence of CAD equal to that in an otherwise healthy population. Many observational studies, however, have found a significant association between elevated homocysteine levels and CAD. However, persons with elevated homocysteine levels may have less healthy lifestyles, which is itself a risk factor for CAD. Cleophas and associates performed a meta-analysis of case-control and cohort studies examining the relationship between homocysteine level and CAD risk.

Thirty-three studies were uncovered in a search of the literature (22 case-control and 11 cohort studies), involving a total of more than 16,000 patients. The observational study data were highly heterogeneous and demonstrated a considerable publication bias. Prospective longitudinal studies provided more robust evidence and were analyzed separately. These results were also heterogeneous, with five of the 11 cohort studies failing to demonstrate a significant association between elevated homocysteine levels and CAD.

There is increasing evidence that acute elevation of serum homocysteine levels by oral methionine loading increases plasma oxidation markers and impairs human endothelial function. Therefore, homocystinemia in acute conditions may contribute to endothelial dysfunction and atherogenesis in humans. The role of homocysteine in the long-term progression of atherosclerosis and CAD maybe overshadowed by other risk factors such as hypertension, diabetes and lipid levels. The relationship between homocystinemia and other risk factors or protective mechanisms in different subjects needs further study. The observational studies that demonstrated significant correlation between high levels of homocysteine and increased risk of CAD did not control for unhealthy lifestyles. Lifestyle may be the important factor that is related to homocysteine levels in an as yet uncertain manner.

The authors conclude that although the data thus far demonstrate a strong association between homocystinemia and CAD, they do not support the contention that the relationship is causative. Interventional studies with homocysteine-lowering therapy are currently in progress. Homocysteine may not be as harmful to the heart as it appears to be, but it may be an important indicator for an unhealthy lifestyle, making it an important variable in assessing patients for CAD risk.