title: Homocysteine, methylenetetrahydrofolate reductase, folate status and atherothrombosis: A mechanistic and clinical perspective.
abstract: Observational studies consistently reported an association between plasma total homocysteine concentrations and the risk of vascular events. In contrast, data from randomized trials largely support the hypothesis that mild elevations in homocysteine level have a modest effect on cardiovascular risk. A substantial body of evidence suggests that platelet activation is, at least in part, a transducer of the effects of high homocysteine in promoting atherothrombosis. The larger treatment effect recorded in several supplementation trials by subjects not on antiplatelet agents may support this hypothesis and justify, at least in part, the success of folate therapy in primary prevention. Circulating folate and homocysteine levels as well as MTHFR genotype, while emerging as major predictors of the risk of vascular events and of the efficacy of folic acid therapy, have also proved to be determinants of an interindividual variability in the degree of lipid peroxidation and platelet activation, and of the extent of their downregulation by folic acid. This may justify a variability in folate requirements, to be further characterized with dose-finding studies using biochemical endpoints. The combination of low-dose aspirin and low-dose folate would appear to be ideally suited for the primary prevention of both coronary and cerebrovascular events, and additional clinical trials should assess the efficacy and safety of these agents.
authors.affiliation: Center of Excellence on Aging, "G. d'Annunzio" University Foundation and Department of Medicine and Aging, University of Chieti "G. d'Annunzio" School of Medicine, Italy. Electronic address: f.santilli@unich.it.
authors.forename: Francesca
authors.initials: F
authors.lastname: Santilli
authors.affiliation: Center of Excellence on Aging, "G. d'Annunzio" University Foundation and Department of Medicine and Aging, University of Chieti "G. d'Annunzio" School of Medicine, Italy.
authors.forename: Giovanni
authors.initials: G
authors.lastname: Davì
authors.affiliation: Department of Pharmacology, Catholic University School of Medicine, Rome, Italy.
authors.forename: Carlo
authors.initials: C
authors.lastname: Patrono
mesh_terms: D001241:Aspirin / Q000008:administration & dosage; D050197:Atherosclerosis / Q000235:genetics / Q000473:pathology / Q000517:prevention & control*; D004359:Drug Therapy, Combination; D005492:Folic Acid / Q000008:administration & dosage / Q000097:blood / Q000627:therapeutic use; D005838:Genotype; D006710:Homocysteine / Q000097:blood*; D006801:Humans; D042965:Methylenetetrahydrofolate Reductase (NADPH2) / Q000235:genetics; D011322:Primary Prevention / Q000379:methods; D016032:Randomized Controlled Trials as Topic; D013927:Thrombosis / Q000235:genetics / Q000473:pathology / Q000517:prevention & control*
chemical_list: D006710:Homocysteine; D005492:Folic Acid; D042965:Methylenetetrahydrofolate Reductase (NADPH2); D001241:Aspirin
keywords: Ascorbic acid (PubChem CID: 9888239); Atherothrombosis; Cobalamin (PubChem CID: 5460183); Cytosine (PubChem CID: 597); Folate; Folic acid (PubChem CID: 6037); Homocysteine; Homocysteine (PubChem CID: 91552); Methylenetetrahydrofolate reductase polymorphism; Platelets; Pyridoxine (PubChem CID: 1054); S-adenosyl-methionine (PubChem CID: 34756); Selenium (PubChem CID: 6326970); Thymidine (PubChem CID: 5789); Trinitroglycerin (PubChem CID: 4510)