Plasma total homocysteine: instigator or indicator of cardiovascular disease?

Cardiovascular disease (CVD) is a major cause of morbidity and mortality in developed countries. However, traditional risk factors cannot fully account for this. In the last 20 years, there has been an explosion of interest in plasma total homocysteine (tHcy) as a potential modifiable risk factor for CVD. Recent meta-analyses of epidemiological studies support the concept that increased tHcy concentrations are associated with CVD. This has led to the 'homocysteine hypothesis', which states that lowering plasma tHcy using folic acid and other B-vitamins will reduce the risk of CVD. In experimental studies, homocysteine has been shown to cause oxidative stress, endothelial cell dysfunction and promote thrombogenesis. However, data from recent large randomized controlled trials have shown that there is no clinical benefit to lowering plasma tHcy concentrations with folic acid and other B-vitamins. This lack of effect of tHcy lowering strongly suggests that homocysteine is not an instigator but merely an indicator of CVD.