Hyperhomocysteinaemia and atherothrombosis

Homocysteine (Hcy) is a sulfhydryl amino acid derived from the metabolic co nversion of methionine that is dependent on vitamins (folic acid, B-12 and B-6) as cofactors or cosubstrates. In 1969, McCully first reported the pres ence of severe atherosclerotic lesions in patients with severe hyperhomocys teinaemia and hypothesized the existence of a pathogenic link between hyper homocysteinaemia and atherogenesis. Several case-control and cross-sectiona l studies confirmed the initial hypothesis of McCully, showing that also mo derate hyperhomocysteinaemia is associated with a heightened risk of occlus ive arterial disease. Less consistent results have been reported by prospec tive cohort studies of subjects who were healthy at the time of their enrol lment, whereas prospective cohort studies of patients with overt coronary a rtery disease or other risk conditions consistently confirmed the associati on between moderate hyperhomocysteinaemia and the risk of cardiovascular mo rbidity and mortality. More recently, an association between moderate hyper homocysteinaemia and heightened risk of venous thromboembolism has been doc umented, suggesting that hyperhomocysteinaemia might be involved not only i n atherogenesis, but also in thrombogenesis. The mechanisms by which hyperh omocysteinaemia might contribute to atherogenesis and thrombogenesis are in completely understood. The mainstay of treatment of hyperhomocysteinaemia i s folic acid, alone or in combination with vitamins B-12 and B-6. Although it is quite clear that vitamins effectively reduce the plasma levels of tot al Hcy, we do not yet know whether they will decrease the risk of vascular disease. The results of ongoing randomized, placebo-controlled, double-blin ded trials on the effects of vitamins on thrombotic risk will help in defin ing whether the relationship between hyperhomocysteinaemia and thrombosis i s causal, and will potentially have a dramatic impact on the prevention of thromboembolic events.