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 a therosclerotic cardiovascular diseases. Many significant studies indicate a n effect by elevated homocysteine on cardiovascular disease occurrence, pro gression, and recurrence that is independent of traditional risk factors. H owever, recent data have cast doubt on the veracity of the relationship bet ween elevated plasma total homocysteine and the incidence of cardiovascular disease. In general, a stronger relationship has been found in cross-secti onal 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 ca n 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.