Impaired homocysteine metabolism and atherothrombotic disease

Based on recent retrospective, prospective, and experimental studies, mild to moderate elevation of fasting or postmethionine-load plasma homocysteine is accepted as an independent risk factor for cardiovascular disease and t hrombosis in both men and women. Hyperhomocysteinemia results from an inhib ition of the remethylation pathway or from an inhibition or a saturation of the transsulfuration pathway of homocysteine metabolism. The involvement o f a high dietary intake of methionine-rich animal proteins has not yet been investigated and cannot be ruled out. However, folate deficiency, either a ssociated or not associated with the thermolabile mutation of the N-5.10-me thylenetetrahydrofolate reductase, and vitamin B, deficiency, perhaps assoc iated with cystathionine p-synthase defects or with methionine excess, are believed to be major determinants of the increased risk of cardiovascular d isease related to hyperhomocysteinemia. Recent experimental studies have su ggested that moderately elevated homocysteine levels are a causal risk fact or for atherothrombotic disease because they affect both the vascular wall structure and the blood coagulation system The oxidant stress that results from impaired homocysteine metabolism, which modifies the intracellular red ox status, might play a central role in the molecular mechanisms underlying moderate hyperhomocysteinemia-mediated vascular disorders. Because folate supplementation can efficiently reduce plasma homocysteine levels, both in the fasting state and after methionnine loading, results from further prosp ective cohort studies and from on-going interventional trials will determin e whether homocysteine-lowering therapies can contribute to the prevention and reduction of cardiovascular risk. Additionally, these studies will prov ide unequivocal arguments for the independent and causal relationship betwe en hyperhomocysteinemia and atherothrombotic disease.