Plasma homocysteine as a cardiovascular risk factor: causal, consequential, or of no consequence?

Elevated plasma total homocysteine may be causally related to the risk of atherosclerotic cardio-vascular diseases. Many significant studies indicate an effect by elevated homocysteine on cardiovascular disease occurrence, progression, and recurrence that is independent of traditional risk factors. However, recent data have cast doubt on the veracity of the relationship between elevated plasma total homocysteine and the incidence of cardiovascular disease. In general, a stronger relationship has been found in cross-sectional and retrospective case-control studies than in nested case-control or prospective studies. The issues of study design, bias, and confounding are critical to an analysis of this putative relationship, and their effects can only be avoided by randomized controlled trials of homocysteine-lowering therapy (folic acid). While awaiting the outcome of these trials, there may already be sufficient evidence to prescribe homocysteine-lowering therapy in subjects deemed to be at high risk of cardiovascular disease.