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Metabolism of Homocysteine and its Relationship with Cardiovascular Disease

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Hyperhomocysteinemia, or the rise of plasmatic homocysteine levels above 15 μg/dL, is accepted nowadays as an independent risk factor for cardiovascular disease in men and women. Homocysteine (Hcy) is a non-protein forming aminoacid (aa) derivated from the loss of the methyl group, found within methionine. Methionine regenerates by retrieving the methyl radical from 5-methyltetrahydrofolate (5-MTHF) creating tetrahydrofolate (THF) which will then regenerate to 5-MTHF through the action of methylentetrahydrofolate reductase (MTHFR). This process is called remethylation. Alternatively, Hcy can follow the transsulfuration route, where through cystationine-β-syntetase (CBS), it irreversibly converted into cystationine, a precursor of cysteine, glutathione, and other substances that are finally excreted in the urine. Hyperhomocysteinemia results from inhibition of the remethylation route, or inhibition or saturation of the transsulfuration pathway. Main factors causally associated increased plasmatic Hcy are mutations of the enzymes MTHFR and CBS; varying nutritional and health states; demographic factors; and, others. The most accepted hypotheses about Hcy action in cardiovascular disease are direct endothelial and vessel wall damage; oxidative stress generation; and, stimulation of a procoagulant and proinflammatory state of blood components. Since hyperhomocysteinemia can be effectively treated with folic acid, prospective trials are underway to determine if folate therapy is required to lower Hcy levels in plasma. These studies also attempt to address the impact, if any, of folate therapy in the reduction of cardiovascular risk, and to demonstrate if hyperhomocysteinemia is actually an independent risk factor that can be effectively treated.

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Correspondence to María T. Collados.

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Aguilar, B., Rojas, J. & Collados, M. Metabolism of Homocysteine and its Relationship with Cardiovascular Disease. J Thromb Thrombolysis 18, 75–87 (2004).

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