Metabolism of Homocysteine and its Relationship with Cardiovascular Disease

Abstract

Hyperhomocysteinemia, or the rise of plasmatic homocysteine levels above 15 mug/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-beta-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.

Elevated Homocysteine Is Associated With Reduced Regional Left Ventricular Function

“…Increased Hcy levels can promote endothelial dysfunction of coronary resistance vessels. 49,50 Investigators have also emphasized the critical role of Hcy as a source of increased oxidative stress, a factor known to promote myocardial damage. 50 In addition to indirect effects on myocardial performance, Hcy may have direct effect on the myocardium.…”

“…49,50 Investigators have also emphasized the critical role of Hcy as a source of increased oxidative stress, a factor known to promote myocardial damage. 50 In addition to indirect effects on myocardial performance, Hcy may have direct effect on the myocardium. Short-term exposure of isolated papillary muscle to Hcy decreases the rate of rise and duration of action potentials, without detectable changes in the resting membrane potential or the early phase of repolarization.…”

C677T methylenetetrahydrofolate reductase gene polymorphism as a risk factor involved in venous thromboembolism: A population-based case-control study

“…Mild or moderate hyperhomocysteinemia is a known risk factor for venous thrombophilia as a single disorder or in combined defects (1,2). Hyperhomocysteinemia occurs due to a combination of genetic and environmental factors (3,4). Several mutations or combined defects affecting the homocysteine (Hcy) pathway have been reported (5,6).…”

Cerebral Venous Sinus Thrombosis: Incidence and Hyperhomocysteinemia as a Risk Factor in Japanese Patients

“…Raised levels are found in some chronic diseases such as DM, and malignancy; after the administration of certain drugs such as oral contraceptives, AEDs, and methotrexate; and in patients of older age, male sex, postmenopausal status, heavy smoking history, etc. Folate and vitamin deficiencies can also occur because of chronic alcoholism, or low intake and disturbed digestive absorption of green or yellow vegetables and other foods containing these vitamins [22][23][24]. There were 9 cases of hyper-Hcy in our study.…”