Role of homocysteine in the development of cardiovascular disease.

It is well known that neuronal damage following a stroke has been attributed to the over stimulation of excitatory amino acids such as glutamate and aspartate through activation of NMDA receptors. The brain is exposed to most of the constituents of plasma including homocysteine as a result of the disruption of the blood-brain barrier after stroke, head trauma and stress. The question, therefore, arises as to whether or not homocysteine is able to selectively stimulate the release of excitatory amino acids in stroke. This review article will address the importance of homocysteine in nervous system specifically how these amino acids may trigger the release of catecholamines. Our data will thus strengthen the view that a mechanism for the association of hyperhomocysteinemia with increased brain lesion in stroke. As hypothalamus also controls the cardiac function via sympathetic system, the contractility of heart will be compromised. Homocysteine is also known to mediate cardiovascular problems by its adverse effects on cardiovascular endothelium and smooth muscle cells with resultant alterations in subclinical arterial structure and function. The present review will thus summarize both central and peripheral effects of homocysteine and will highlight some of the controversies associated with hyperhomocysteinemia-induced cardiovascular problems.

The role of folic acid fortification in neural tube defects: a review.

The worldwide prevalence of neural tube defects (NTDs) has fallen noticeably during the past 30 years, but the specific etiology and causative mechanism of NTDs remain unknown. Since introduction of mandatory fortification of grains with folic acid, a further decrease in NTD prevalence has been reported in North America and other countries with large variations among ethnic subgroups. However, a significant portion of NTDs still persists. Population data suggest that women of childbearing age may not yet be adequately targeted, while the general population may be overfortified with folic acid. While an excessive folate intake may be associated with adverse effects, there remains uncertainty about the minimum effective folate intake and status required for NTD prevention, and the safe upper folate level. Besides folate, several other lifestyle and environmental factors as well as genetic variations may influence NTD development, possibly by affecting one-carbon metabolism and thus epigenetic events. In conclusion, mandatory folic acid fortification plays a significant part in the reduction of NTD prevalence, but possibly at a cost and with a portion of NTDs remaining. More effective preventive strategies require better understanding of the etiology of this group of birth defects.

[Homocysteine, vitamin B-12, folic acid and the cognitive decline in the elderly]. / Homocystéine, vitamine B12 et acide folique dans le déclin cognitif chez les personnes âgées.

Hyperhomocysteinemia is a risk factor for neurological diseases, but the underlying pathophysiology has not been adequately explained. Mild hyperhomocysteinemia, which is sometimes associated with a low plasma level of vitamin B9, B12 and folic acid, is responsible in the toxicity in neural cell by activating NMDA receptor. Indeed, even if vitamin supplementation has clearly proven its efficiency on lowering plasma levels of homocysteine, recent studies do not show any positive effect of vitamin therapy on cognitive function. The hypothesis that this therapy is inefficient has been recently reinforced by two randomized trials on the effects of vitamin supplementation. Several hypotheses still need to be explored: Mechanisms of homocysteine toxicity and that of total uselessness of vitamin supplementation; the possible need to complete the actual data with further, more powerful studies in order to prove the role of homocysteine in the development of neurodegenerative diseases and a clinical effect of vitamin therapy.

Role of homocysteine in end-stage renal disease.

Patients on dialysis have a substantially higher mortality rate compared with the general population. Dialysis is usually associated with an increased plasma level of homocysteine (Hcy). Hcy is viewed as a nontraditional marker of the prognosis of cardiovascular disease (CVD) in the general population and in patients with chronic kidney disease. The effects of Hcy-lowering therapy in patients with end-stage renal disease (ESRD) remain controversial. We searched multiple databases including PubMed, MEDLINE, and OVID, and conducted a systematic review of the literature. Possible therapeutic measures were also surveyed. Our review shows that effective normalization of plasma Hcy level may decrease CVD-related morbidity and mortality in nondiabetic ESRD patients. Hyperglycemia in association with diabetes mellitus makes ESRD patients resistant to Hcy-lowering therapy. Folic acid fortification may attenuate the beneficial effects of Hcy-lowering therapy. Supraphysiological doses of folic acid and vitamin B supplementation might be needed in ESRD patients with diabetes or high Hcy levels. The response to Hcy-lowering therapy may be influenced by differences within and between populations in sex, genotype, nutrition, and mandatory fortification. Treatment resistance found mainly in diabetic ESRD patients but not in nondiabetic ESRD patients that may need other therapeutic approaches.

Homocysteine mediated decrease in bone blood flow and remodeling: role of folic acid.

Deficiencies in folate lead to increased serum concentrations of homocysteine (Hcy), which is known as hyperhomocysteinemia (HHcy), is associated with bone disorders. Although, Hcy accumulates collagen in bone and contribute to decrease in bone strength. The mechanism of Hcy induced bone loss and remodeling is unclear. Therefore, the present study was aimed to determine the role of folic acid (FA) in genetically HHcy-associated decrease in bone blood flow and remodeling. Wild type (WT) and cystathionine-ß-synthase heterozygous (CBS+/-) mice were used in this study and supplemented with or without FA (300 mg/kg, Hcy reducing agent) in drinking water for 6 weeks. The tibial bone blood flow was measured by laser Doppler and ultrasonic flow probe method. The tibial bone density (BD) was assessed by dual energy X-ray absorptiometry. The bone homogenates were analyzed for oxidative stress, NOX-4 as oxidative marker and thioredoxin-1 (Trx-1) as anti-oxidant marker, bone remodeling (MMP-9) and bio-availability of nitric oxide (eNOS/iNOS/NO) by Western blot method. The results suggested that there was decrease in tibial blood flow in CBS+/- mice. The BD was also reduced in CBS+/- mice. There was an increase in NOX-4, iNOS, MMP-9 protein as well as MMP-9 activity in CBS+/- mice and decrease in Trx-1, eNOS protein levels, in part by decreasing NO bio-availability in CBS+/- mice. Interestingly, these effects were ameliorated by FA and suggested that FA supplementation may have therapeutic potential against genetically HHcy induced bone loss.

The homocysteine controversy.

Mild to moderate hyperhomocysteinemia has been identified as a strong predictor of cardiovascular disease, independent from classical atherothrombotic risk factors. In the last decade, a number of large intervention trials using B vitamins have been performed and have shown no benefit of homocysteine-lowering therapy in high-risk patients. In addition, Mendelian randomization studies failed to convincingly demonstrate that a genetic polymorphism commonly associated with higher homocysteine levels (methylenetetrahydrofolate reductase 677 C>T) is a risk factor for cardiovascular disease. Together, these findings have cast doubt on the role of homocysteine in cardiovascular disease pathogenesis, and the homocysteine hypothesis has turned into a homocysteine controversy. In this review, we attempt to find solutions to this controversy. First, we explain that the Mendelian randomization analyses have limitations that preclude final conclusions. Second, several characteristics of intervention trials limit interpretation and generalizability of their results. Finally, the possibility that homocysteine lowering is in itself beneficial but is offset by adverse side effects of B vitamins on atherosclerosis deserves serious attention. As we explain, such side effects may relate to direct adverse effects of the B-vitamin regimen (in particular, the use of high-dose folic acid) or to proinflammatory and proproliferative effects of B vitamins on advanced atherosclerotic lesions.

Homocysteine and vascular disease: review of published results of the homocysteine-lowering trials.

Moderately elevated homocysteine levels have been associated with a higher risk of cardiovascular disease in observational studies, but whether these associations are causal is uncertain. Randomized trials of dietary supplementation with B vitamins were set up to assess whether lowering homocysteine levels could reduce the risk of vascular disease. This review is based on a meta-analysis of published results of eight homocysteine-lowering trials for preventing vascular disease. The eight trials comprised a total of 37,485 individuals and provided comparisons of the effects of B vitamins on 5,074 coronary heart disease (CHD) events, 1,483 stroke events, 2,692 incident cancer events, and 5,128 deaths. Our meta-analysis assessed the effects of lowering homocysteine levels by about 25% for about 5 years. Allocation to B vitamins had no beneficial effects on any cardiovascular events, with hazard ratios (95% confidence intervals) of 1.01 (0.96-1.07) for CHD and 0.96 (0.87-1.07) for stroke. Moreover, allocation to B vitamins had no significant adverse effects on cancer [1.08 (0.99-1.17)], or for death from any cause [1.02 (0.97-1.07)]. Thus, supplementation with B vitamins had no statistically significant effects on the risks of cardiovascular events, total mortality rates, or cancer. A meta-analysis based on individual participant data from all available trials will assess the effects of lowering homocysteine levels on a broader range of outcomes, overall and in all relevant subgroups. However, available evidence does not support the routine use of B vitamins to prevent cardiovascular disease.

Anti-inflammatory strategies for homocysteine-related cardiovascular disease.

Homocysteine may induce vascular damage for atherosclerosis. Vitamin/folate supplementation has been proposed to reduce the cardiovascular disease risk. Nevertheless, there is no randomized clinical trial clearly proving the efficacy of reducing the homocysteine as a means of lowering the incidence of cardiovascular disease. Homocysteine induces oxidative stress leading to endothelial dysfunction. In addition, homocysteine-induced oxidative stress favors lipid peroxidation and induces production of inflammatory factors, thus accelerating atherosclerosis. In this paper, we reviewed the available evidence concerning the association between homocysteine and cardiovascular disease, with the objective of discussing the pertinence of screening, treatment, and prevention of hyperhomocysteinemia-related cardiovascular disease. Our previous findings also indicated the significant role of mononuclear cells activation in homocysteine-induced endothelial dysfunction; treatment with statins attenuated homocysteine-induced endothelial adhesiveness, indicating the novel endothelial protection effects of statins in the presence of homocysteine. Since inflammation and oxidative stress are critical to homocysteine-induced vascular damage, the improvement of endothelial dysfunction and the inhibition of mononuclear cell activation by anti-inflammatory and/or antioxidative drugs/agents may serve as the potential therapeutic strategy for hyperhomocysteinemia-related cardiovascular disease.

Homocysteine and heart failure: an overview.

An elevated plasma level of homocysteine (HCY) is associated with increased risk of thrombotic and atherosclerotic vascular disease. Several studies and recent patents have demonstrated that hyper-homocysteinemia (HHCY) is an independent risk factor for vascular disease. An elevated homocysteine level has been also reported to be a risk factor for the development of congestive heart failure (CHF) in individuals free of myocardial infarction. Animal studies showed that experimental HHCY induces systolic and diastolic dysfunction, as well as an increased BNP expression. Moreover, hyperhomocysteinemic animals exhibit an adverse cardiac remodeling characterized by accumulation of interstitial and perivascular collagen. The mechanisms leading from an elevated HCY level to reduced pump function and adverse cardiac remodeling are a matter of speculation. Existing data indicate that direct effects of HCY on the myocardium, as well as nitric oxide independent vascular effects, are involved. Preliminary data from small intervention trials have initiated the speculation that HCY lowering therapy by micronutrients may improve clinical as well as laboratory markers of CHF. In conclusion, HHCY might be a potential etiological factor in CHF. Future studies need to explore the exact pathomechanisms of HHCY in CHF. Moreover, larger intervention trials are needed to clarify whether modification of plasma HCY by B-vitamin supplementation improves the clinical outcome in CHF patients.

RETRACTED: Phytoestrogen alpha-zearalanol inhibits homocysteine-induced endothelin-1 expression and oxidative stress in human umbilical vein endothelial cells.

This article has been retracted: please see Elsevier Policy on Article Withdrawal (https://www.elsevier.com/about/our-business/policies/article-withdrawal). This article has been retracted at the request of the Editor-in-Chief. After an institutional investigation into the work of Dr. Jun Ren, University of Wyoming subsequently conducted an examination of other selected publications of Dr. Ren's under the direction of the HHS Office of Research Integrity. Based on the findings of this examination, the University of Wyoming recommended this article be retracted due to data irregularities in Figures 3 and 5 that significantly affect the results and conclusions reported in the manuscript.

[Review of the role of hyperhomocysteinemia and B-vitamin deficiency in neurological and psychiatric disorders--current evidence and preliminary recommendations]. / Hyperhomocysteinämie und B-Vitaminmangel bei neurologischen und psychiatrischen Erkrankungen--Aktueller Kenntnisstand und vorläufige Empfehlungen.

Elevated concentration of total homocysteine (Hcy) in plasma (> 12 micromol/l) is a risk factor for several diseases of the central nervous system. Epidemiological studies have shown a dose-dependent relationship between concentrations of Hcy and the risk for neurodegenerative diseases. Hcy is a marker for B-vitamin deficiency (folate, B12, B6). Hyperhomocysteinemia (HHcy) causes hypomethylation which is an important mechanism that links Hcy to dementia. Supplementation with vitamins B aims at reducing the risk of neurodegenerative diseases. Current evidence suggests that Hcy-lowering treatment has a positive effect for the secondary and primary prevention of stroke. HHcy is very common in patients with Parkinson disease particularly those who receive L-dopa treatment. Furthermore, a positive association has been reported between HHcy and multiple sclerosis. Moreover, HHcy and vitamin B deficiency are reported to have a causal role in depression, and epilepsy. In addition several anti-epileptic drugs cause secondary HHcy. Therefore, sufficient intakes of the vitamins are recommended for patients who have already developed neuropsychiatric diseases. Vitamin B deficiency should be suspected in children with development disorders, failure to thrive and unexplained neurological manifestations. Elderly people are also an important at-risk group where vitamin B deficiency and HHcy have been linked to neurodegenerative diseases. Treatment with folate, B12, and B6 can improve cerebral function. Preventive vitamin B supplementation and sufficient intake seem very important for secondary and primary prevention of neuropsychiatric disorders, especially in subjects with a low intake or status of the vitamins.

Homocysteine and abdominal aortic aneurysms.

There is evidence to suggest that increased levels of homocysteine play a significant role in vascular disease. It has been suggested that lowering homocysteine levels by dietary folate supplementation may reduce the risk of stroke and coronary heart disease. It is plausible that homocysteine may also play a role in the pathogenesis of abdominal aortic aneurysms (AAA) and that patients with this disease may benefit from folate supplementation. Our objective was to review the published work with regard to the role of homocysteine in the pathogenesis of AAA. Searches were carried out in published work in English with the keywords 'abdominal aortic aneurysm' and 'homocysteine'. There is evidence from in vitro and animal model studies that activation of metalloproteinases by homocysteine can influence aortic wall structure. Several case-control studies report an association between increased levels of homocysteine and the presence of an AAA. There are conflicting genotypic data concerning the association between methylenetetrahydrofolate reductase gene variants and AAA. Although there is evidence for an association between homocysteine and AAA, it is not strong enough to conclude that it plays a causal role in the pathogenesis of AAA. Further research is needed, given the potential benefit that simple vitamin supplementation may have for patients with AAA.

Deficiencias nutritivas en niños vegetarianos / Nutritional deficiencies in vegetarian children

Presentamos a cuatro niños vegetarianos, de edades comprendidas entre 1 y 3 años, con múltiples deficiencias nutritivas. En sus dietas se incluían pequeñas cantidades de leche y de huevos (lacto-ovo-vegetarianos) pero no tomaban carne, pescado ni suplementos vitamínicos. En la encuesta nutricional encontramos una ingesta insuficiente de energía, calcio, hierro y vitamina B12. Todos los niños tenían una talla normal, pero con puntuaciones Z bajas (entre -0,77 y -1,28) y un peso muy disminuido (puntuación Z entre - 1,92 y -2,38). Un niño tenía raquitismo clínico con hipocalcemia y déficit de vitamina D. Otro niño tenía raquitismo clínico con niveles normales de vitamina D, sugiriendo que la causa del raquitismo era la deficiencia en calcio. Los datos de laboratorio mostraron en todos lo niños una anemia por déficit de vitamina B12 entre 102 y 130 pg/ml, niveles normales, 180-900 pg/mL ) con VCM elevado, homocisteína sérica elevada y ferritina sérica muy baja, indicando el déficit de hierro. Todos los niños tuvieron una buena respuesta al tratamiento con suplementos nutricionales de vitaminas, calcio, hierro y una modificación parcial de sus dietas, de acuerdo con los padres (AU)

We report four vegetarian children aged between 1 and 3 years old with multiple nutritional deficiencies. Their diets included milk eggs in small amount (lacto-ovo-vegetarian) but not received meat, fish or supplementary vitamins. In the dietary recall we found an inadequate intake of energy, calcium, iron and vitamin B12. All children had normal height but in lower Z-score (between -0.77 an -1.28) and greatly decreased weight (Z-score between -1.92 and -2.38). One children had clinical rickets with hypocalcemia and vitamin D deficiency. Another children had clinical rickets with normal vitamin D levels. This suggests that the calcium deficiency was the cause of rickets. Laboratory data revealed in all children a vitamin B12 deficiency anemia (vitamin b 12 levels between 102 and 130 pg/ml, normal range 180-900 pg/ml) with high MCV, high homocysteine serum levels and low ferritin serum levels. All children responded well to nutritional supplementation with vitamins, calcium, iron and moderate adjustment of diets by mutual agreement with the parents (AU)

The effect of diet on endothelial function.

Endothelial dysfunction is an early precursor to atherosclerosis. Lifestyle interventions, including diet, have been shown to affect endothelial function. High-fat diets have been shown to impair endothelial function, and diets such as the Mediterranean diet have been associated with improved endothelial function. This review discusses the effects of diet, dietary supplements such as folic acid, polyphenols, and antioxidant vitamins on endothelial function. We provide a summary of the current data linking diet with endothelial function and explore controversies within this field.

Elevated prenatal homocysteine levels as a risk factor for schizophrenia.

CONTEXT: Elevated prenatal homocysteine level is a plausible risk factor for schizophrenia because of its partial antagonism of N-methyl-D-aspartate receptors under physiologic glycine concentrations and its association with abnormal placental function and pregnancy complications. OBJECTIVE: We examined whether elevated maternal levels of homocysteine during the third trimester were associated with adult schizophrenia risk. DESIGN: Nested case-control study of a large birth cohort, born from 1959 through 1967 and followed up for schizophrenia from 1981 through 1997. SETTING: Population-based birth cohort and health plan. PARTICIPANTS: Cases (n = 63) were diagnosed with schizophrenia and other spectrum disorders (mostly schizophrenia and schizoaffective disorder). Controls (n = 122) belonged to the birth cohort; had not been diagnosed with a schizophrenia spectrum or major affective disorder; and were matched to cases on date of birth, sex, length of time in the cohort, and availability of maternal serum samples. MAIN MEASURES: Archived maternal serum samples were assayed for homocysteine levels during pregnancies of cases and matched controls. RESULTS: In a model that tested for a threshold effect of third-trimester homocysteine levels, an elevated homocysteine level was associated with a greater than 2-fold statistically significant increase in schizophrenia risk (odds ratio, 2.39; 95% confidence interval, 1.18-4.81; P = .02). CONCLUSIONS: These findings indicate that elevated third-trimester homocysteine levels may be a risk factor for schizophrenia. Elevated third-trimester homocysteine levels may elevate schizophrenia risk through developmental effects on brain structure and function and/or through subtle damage to the placental vasculature that compromises oxygen delivery to the fetus. If future studies both replicate this association and support a causal link, then the use of folic acid supplementation would merit evaluation as a strategy for prevention of schizophrenia in offspring.

Biochemistry of homocysteine in health and diseases.

The amino acid homocysteine (Hcy), formed from methionine has profound importance in health and diseases. In normal circumstances, it is converted to cysteine and partly remethylated to methionine with the help of vit B12 and folate. However, when normal metabolism is disturbed, due to deficiency of cystathionine-beta-synthase, which requires vit B6 for activation, Hcy is accumulated in the blood with an increase of methionine, resulting into mental retardation (homocystinuria type I). A decrease of cysteine may cause eye diseases, due to decrease in the synthesis of glutathione (antioxidant). In homocystinurias type II, III and IV, there is accumulation of Hcy, but a decrease of methionine, thus, there is no mental retardation. Homocysteinemia is found in Marfan syndrome, some cases of type I diabetes and is also linked to smoking and has genetic basis too. In hyperhomocysteinemias (HHcys), clinical manifestations are mental retardation and seizures (type I only), ectopia lentis, secondary glaucoma, optic atrophy, retinal detachment, skeletal abnormalities, osteoporosis, vascular changes, neurological dysfunction and psychiatric symptoms. Thrombotic and cardiovascular diseases may also be encountered. The harmful effects of homocysteinemias are due to (i) production of oxidants (reactive oxygen species) generated during oxidation of Hcy to homocystine and disulphides in the blood. These could oxidize membrane lipids and proteins. (ii) Hcy can react with proteins with their thiols and form disulphides (thiolation), (iii) it can also be converted to highly reactive thiolactone which could react with the proteins forming -NH-CO- adducts, thus affecting the body proteins and enzymes. Homocystinuria type I is very rare (1 in 12 lakhs only) and is treated with supplementation of vit B6 and cystine. Others are more common and are treated with folate, vit B12 and in selected cases as in methionine synthase deficiency, methionine, avoiding excess. In this review, the role of elevated Hcy levels in cardiovascular, ocular, neurologial and other diseases and the possible therapeutic measures, in addition to the molecular mechanisms involved in deleterious manifestations of homocysteinemia, have been discussed.

[The role of increased levels of homocysteine in the development of cardiovascular diseases].

INTRODUCTION: Homocysteine is a sulphur amino acid produced by demethylation of the essential amino acid methionine. Dysfunction of certain enzymes or insufficient intake of nutrients may cause increase of intracellular homocysteine, which is then exported into plasma. ETIOPATHOGENESIS OF CARDIOVASCULAR DISEASES ACCOMPANIED WITH HIGHER LEVEL OF HOMOCYSTEINE: McCully's theory suggests that high levels of homocysteine are associated with cardiovascular diseases, arteriosclerosis and endothelial dysfunction. Harmful effects of homocysteine are associated with LDL cholesterol oxidation, increased production of collagen, lower availability of nitric oxide as well as prothrombotic activity. REDUCTION OF HOMOCYSTEINE LEVELS: The most recent researches show that hyperhomocysteinemia is responsible for about 10% of total risk of cardiovascular diseases. Vitamin B12 plays a major role in the remethylation of homocysteine. Reducing the homocysteine concentration in blood by 3 mol/l (with daily intake of 0.8 mg of folic acid) reduces the risk of ishemic heart diseases by 16%, vein thrombosis by 25%, and stroke by 24%. A six-month therapy with folic acid (1 mg/d), vitamin B12 (400g/d) and vitamin B6 (10mg/d), reduces the frequency of cardiovascular occurrences after successful PTCA. Plasma homocysteine concentration over 12/l doubles the risk of myocardial infarction. CONCLUSION: A lack of folates, vitamin B6 and vitamin B12 increases the level of homocysteine and thus increases the risk of cardiovascular diseases. Changes in lifestyle and diet, as well as intake of food supplements, are of great importance in reducing homocysteine levels in plasma and therefore in reducing the occurrence and acceleration of arteriosclerosis.

Vitamins and minerals 4: overview of folate and the B vitamins.

Many studies have suggested that elevated homocysteine levels are an independent risk factor for cardiovascular disease, stroke and Alzheimer's disease. Lower levels of the three water-soluble vitamins--folate (folic acid), vitamin B6 and vitamin B12--are primary determinants of high blood homocysteine levels. In the fourth of an occasional series on vitamins, minerals and supplements, June Thompson looks at the role folate, in particular, may play in reducing homocysteine in the body and in protecting the body from some other diseases.

The effects of sulfur amino acid intake on immune function in humans.

No direct data exist on the influence of supranormal intakes of sulfur amino acids on immune function in humans. However 3 major products of sulfur amino acids, glutathione (GSH), homocysteine (Hcy), and taurine (Tau), influence, mainly, inflammatory aspects of the immune response in vitro and in vivo. Methionine intakes above approximately 1 g/d transiently raise plasma Tau, Hcy, and GSH. Tau and GSH ameliorate inflammation. Hcy has the opposite effect. A biphasic relation, between cellular GSH and CD4+ and CD8+ numbers occurs in healthy men. How changes in sulfur amino acid intake influence this phenomenon is unknown. In animals, high Tau intakes are antiinflammatory. How immune function in humans is affected is unknown. A positive relation between plasma neopterin (a marker of a Th-1-type immune response) and Hcy indicates that Hcy may play a part in inflammatory aspects of Parkinson's disease and aging. In vitro, Hcy, at concentrations seen following consumption of approximately 6 g L-methionine/d in adults, increases the interactions among T lymphocytes, monocytes, and endothelium. Whether a similar phenomenon occurs in vivo is unknown. Polymorphisms in the methylenetetrahydrofolate reductase gene are associated with raised plasma Hcy in young but not old subjects. The relation of this observation to immune function is unknown. The relationships among Hcy, inflammatory aspects of disease, and in vitro alterations in immune cell behavior create a cautionary note about supplementation of diets with l-methionine to raise intake above approximately 1 g/d. Studies directly linking methionine intake, genetics, plasma Hcy, Tau, and GSH and immune function are needed.

Homocyst(e)ine and stroke.

Homocyst(e)ine elevation is associated with a two- to threefold fold increased risk of ischemic stroke. Although most commonly associated with large-artery atherosclerosis and venous thrombosis, hyperhomocysteinemia may contribute to stroke by other mechanisms as well. Levels of homocysteine are determined by genetic regulation of the enzymes involved in homocyst(e)ine metabolism and by levels of the vitamin cofactors (folate, B (6), and B (12)) associated with those reactions. Emerging evidence suggests that genetic variation within this pathway, such as the methyleneterahydrofolate reductase and cystathionine beta-synthase and nicotinamide N-methyltransferase genes, increases the risk of ischemic stroke. The introduction of grain folate fortification in 1998 has reduced homocyst(e)ine concentrations in the U.S. population. However, it is important to screen for vitamin B (12) deficiency and be cognizant that vitamin B (6) levels may be low in the elderly and in individuals with inflammatory disorders. The Vitamin Intervention in Stroke Prevention study failed to prove that high-dose supplementation with folate, B (6), and B (12) reduced the risk of recurrent stroke or myocardial infarction at 2 years; however, there is an ongoing clinical trial evaluating the potential benefit of vitamin supplementation.