Effects of folic acid and combinations of folic acid and vitamin B-12 on plasma homocysteine concentrations in healthy, young women

BACKGROUND: Elevated plasma homocysteine concentrations are considered to be a risk factor for vascular disease and fetal malformations such as neural tube defects. Recent studies have shown that plasma homocysteine can be lowered by folic acid in amounts corresponding to 1-2 times the recommended dietary allowance. Preliminary evidence indicates that vitamin B-12 may be beneficial when included in supplements or in a food-fortification regimen together with folic acid. OBJECTIVE: We aimed to compare the homocysteine-lowering potential of a folic acid supplement with that of 2 supplements containing different doses of vitamin B-12 in addition to folic acid. DESIGN: Female volunteers of childbearing age (n = 150) received a placebo for 4 wk followed by a 4-wk treatment with either 400 microg folic acid, 400 microg folic acid + 6 microg vitamin B-12, or 400 microg folic acid + 400 microg vitamin B-12. RESULTS: Significant reductions (P < 0.001) in plasma homocysteine were observed in all groups receiving vitamin treatment. The effect observed with the combination of folic acid + 400 microg vitamin B-12 (total homocysteine, -18%) was significantly larger than that with a supplement containing folic acid alone (total homocysteine, -11%) (P < 0.05). Folic acid in combination with a low vitamin B-12 dose (6 microg) affected homocysteine as well (-15%). CONCLUSIONS: These results suggest that the addition of vitamin B-12 to folic acid supplements or enriched foods maximizes the reduction of homocysteine and may thus increase the benefits of the proposed measures in the prevention of vascular disease and neural tube defects.     

Homocysteine: a new risk factor for atherosclerosis

The accumulating evidence for the role of homocysteine as a risk factor for atherosclerosis is persuasive. A high plasma homocysteine concentration induces pathologic changes in the arterial wall and thus is strongly associated with an increased risk of atherosclerosis, manifested as cardiovascular, cerebrovascular and peripheral vascular events. Studies are being conducted to determine whether lowering homocysteine levels prevents occlusive events. At present, testing for elevated homocysteine concentrations should be considered in patients with premature atherosclerosis or a strong family history of atherosclerosis, since hyperhomocysteinemia is a common risk factor in these patients. Treatment of hyperhomocysteinemia is straightforward and associated with minimal risk. This disorder is usually correctable with vitamin supplements containing folic acid.     

Chronic heart failure in the United States: a manifestation of coronary artery disease

BACKGROUND: Hyperhomocysteinemia occurs in renal failure and may increase the risk for cardiovascular disease, possibly by damaging the endothelium. Folic acid and betaine are required in two separate homocysteine conversion pathways and may therefore lower plasma homocysteine. OBJECTIVE: To study the therapeutic role of betaine and the effect on endothelial function of long-term homocysteine-lowering therapy with folic acid, in peritoneal dialysis (PD) patients. PATIENTS AND DESIGN: Thirty PD patients were randomized to a 12-week treatment with 5 mg folic acid and 4 g betaine daily, or to 5 mg folic acid alone daily. They were then rerandomized to treatment with 1 or 5 mg folic acid daily for 40 weeks. MEASUREMENTS: At baseline and after 52 weeks, endothelial function was assessed by determination of endothelium-dependent vasodilatation and biochemical markers. RESULTS: Plasma total homocysteine (tHcy) was elevated at baseline: 42.6 (5.8) micromol/L. Only 1 patient (3%) had a normal plasma homocysteine (i.e., < or = 15 micromol/L) before therapy. Normalization of plasma homocysteine occurred in 39% of the patients at 12 weeks. Betaine had no additional homocysteine-lowering effect. Plasma tHcy levels were similar during treatment with 1 or 5 mg folic acid daily. Endothelial function was impaired at baseline and had not improved after 52 weeks of treatment. CONCLUSIONS: Peritoneal dialysis patients have hyperhomocysteinemia, which can be normalized with folic acid alone in about 40% of patients. Betaine does not further lower plasma homocysteine. A maintenance dose of 1 or 5 mg folic acid daily results in equivalent plasma homocysteine levels. Long-term reduction in plasma homocysteine did not result in improvement of endothelial function as assessed by our methods.     

Homocysteine: relations to ischemic cardiovascular diseases

Homocysteine, a sulfur-containing amino acid, is an intermediate metabolite of methionine. Patients with homocystinuria and severe hyperhomocysteinemia develop premature arteriosclerosis and arterial thrombotic events, and venous thromboembolism. Studies suggest that moderate hyperhomocysteinemia can be considered as an independent risk factor in the development of premature cardiovascular disease. In vitro, homocysteine has toxic effects on endothelial cells. Homocysteine can promote lipid peroxidation and damage vascular endothelial cells. Moreover, homocysteine interferes with the natural anticoagulant system and the fibrinolytic system. Homocysteinemia should be known in patients with premature vascular diseases, especially in subjects with no risk factors. Folic acid, vitamin B6 can lower homocysteine levels.     

Treatment of mild hyperhomocysteinemia in vascular disease patients

Mild hyperhomocysteinemia is recognized as a risk factor for premature arteriosclerotic disease. A few vitamins and other substances have been reported to reduce blood homocysteine levels, but normalization of elevated blood homocysteine concentrations with any of these substances has not been reported. Therefore, we screened 421 patients suffering from premature peripheral or cerebral occlusive arterial disease by oral methionine loading tests for the presence of mild hyperhomocysteinemia. Thirty-three percent of patients with peripheral and 20% of patients with cerebral occlusive arterial disease were identified with mild hyperhomocysteinemia (14% of the men, 34% of the premenopausal women, and 26% of the postmenopausal women). Mildly hyperhomocysteinemic patients were administered vitamin B6 250 mg daily. After 6 weeks methionine loading tests were again assessed to evaluate the effect of treatment. Patients with nonnormalized homocysteine concentrations were further treated with vitamin B6 250 mg daily and/or folic acid 5 mg daily and/or betaine 6 g daily, solely or in any combination. Vitamin B6 treatment normalized the afterload homocysteine concentration in 56% of the treated patients (71% of the men, 45% of the premenopausal women, and 88% of the postmenopausal women). Further treatment resulted in a normalization of homocysteine levels in 95% of the remaining cases. Thus, mild hyperhomocysteinemia, which is frequently encountered in patients with premature arteriosclerotic disease, can be reduced to normal in virtually all cases by safe and simple treatment with vitamin B6, folic acid, and betaine, each of which is involved in methionine metabolism.     

Vitamin nutrition status and homocysteine: an atherogenic risk factor

In an epidemiologic survey, a marginal status of folic acid, vitamin B12, and vitamin B6 was shown to be associated with hyperhomocysteinemia. In a case-control study, a low plasma folate concentration was associated with increased coronary heart disease risk. This phenomenon appears to be mediated by folate's effect on homocysteine metabolism. Both studies offer further perspectives on homocysteine as an atherogenic risk factor.     

Disordered methionine/homocysteine metabolism in premature vascular disease. Its occurrence, cofactor therapy, and enzymology

Mild homocysteinemia occurs surprisingly often in patients with premature vascular disease. We studied the possible enzymatic sources of this mild hyperhomocysteinemia and the control of homocysteine levels in plasma by treatment of patients with the cofactors and cosubstrates of homocysteine catabolism. We assessed homocysteine metabolism in 131 patients who had premature disease in their coronary, peripheral, or cerebrovascular circulation by using a standard oral methionine-load test. Impaired homocysteine metabolism occurred in 28 patients. We assayed levels of the primary enzymes of homocysteine catabolism in cultured skin fibroblast extracts from 15 of these 28 patients. The patients' cystathionine beta-synthase levels (3.68 +/- 2.52 nmol/h per milligram of cell protein, mean +/- SD) were markedly depressed compared with those from 31 healthy adult control subjects (7.61 +/- 4.49, P < .001). The patients' levels of 5-methyltetrahydrofolate: homocysteine methyltransferase were normal. While betaine: homocysteine methyltransferase was not expressed in skin fibroblasts, 24-hour urinary betaine and N,N-dimethylglycine measurements were consistent with normal or enhanced remethylation of homocysteine by betaine: homocysteine methyltransferase in the 13 patients tested. When treated daily with choline and betaine, pyridoxine, or folic acid, there was a normalization of the postmethionine plasma homocysteine level in 16 of 19 patients. Our results indicate that mild homocysteinemia in premature vascular disease may be caused by either a folate deficiency or deficiencies in cystathionine beta-synthase activity. It does not necessarily involve deficiencies of either 5-methyltetrahydrofolate:homocysteine methyltransferase or betaine:homocysteine methyltransferase. Effective treatment regimens are also defined.     

Antibacterial activity of bovine lactoferrin and its peptides against enterohaemorrhagic Escherichia coli O157:H7

OBJECTIVES: To assess the long term effects of small increases in dietary folic acid on the concentration of plasma homocysteine, an independent risk factor for occlusive vascular disease, in a general population. DESIGN: A randomized double-blind placebo-controlled intervention study. SUBJECTS: One hundred and nineteen healthy volunteers, whose intake of fortified or supplemental folic acid was low, were recruited by letter from the patient register of a large inner-city group general practice. METHODS: Volunteers were randomized to receive unfortified cereals, or cereals fortified with 200 microg of folic acid per portion, with or without other vitamins. Blood samples were taken presupplement and at 4, 8 and 24 weeks on treatment and analysed for plasma homocysteine, cysteine and vitamin B12 and serum and red cell folate. Ninety-four subjects completed the study providing blood samples on all four occasions. RESULTS: There were no significant changes in any measured parameter in those eating unfortified cereals. Overall, folic acid fortification of cereals led to significant increases (P < 0.001) in serum folate (66%), and red cell folate (24%), and a decrease in plasma homocysteine (10%; P < 0.001). There were no changes in vitamin B12 or cysteine. The homocysteine decrease persisted until the end of the study and was primarily seen in those who initially had the highest plasma homocysteine or the lowest serum folate. CONCLUSIONS: If homocysteine is found to be a causative risk factor in occlusive vascular disease, food fortification with physiological levels of folic acid should have a significant impact on the prevalence of the disease in the general population.     

Cerebral vascular complication of hyperhomocysteinemia. Controlling thromboembolic complications with folates

BACKGROUND: Young patients who experience cardiovascular events may have raised levels of homocysteine. There may be several causes for this hyperhomocysteinemia. CASE REPORT: Cerebrovascular disease occurred in a 40-year-old female smoker with hyperhomocysteinemia. This patient subsequently had several episodes of thromboembolism involving the brain and lower limb arteries. Prothrombin concentration was difficult to control with antivitamin K anticoagulants. Investigations to identify a genetic cause of hyperhomocysteinemia revealed that she was homozygous for the C677T mutation on the methylenetetrahydrofolate reductase gene. There was no G1691A mutation of the factor V gene, a risk factor for familial thrombosis. Supplementation with folic acid successfully halted episodes of thromboembolism (follow-up 2 years) and prothrombin levels stabilized under treatment. DISCUSSION: The C677T mutation, which is common in the general population (15.7%), cannot explain the effect of folate supplementation alone. Other mutations affecting homocysteine metabolism could have a potentializing effect on vascular events.     

Acute methionine load-induced hyperhomocysteinemia enhances platelet aggregation, thromboxane biosynthesis, and macrophage-derived tissue factor activity in rats

A moderate elevation of plasma homocysteine is a risk factor for atherosclerosis and arterial and veinous thrombosis. However, the mechanisms leading to vascular disorders are poorly understood because studies that have investigated the potential atherothrombogenicity of hyperhomocysteinemia in vivo are scarce. Using a rat model, we were the first to show that dietary folic acid deficiency, a major cause of basal hyperhomocysteinemia, is associated with enhanced macrophage-derived tissue factor and platelet activities. We proposed that an homocysteine-induced oxidative stress may account for this hypercoagulable state. To determine the true thrombogenicity of moderate hyperhomocysteinemia and better understand its etiology, we have carried out an acute methionine load in control and folate-deficient animals. When rats were fed the control diet, a transient fourfold increase in plasma homocysteine levels was observed 2 h after the methionine administration. As with prolonged dietary folic acid deficiency, this methionine load potentiated the platelet aggregation in response to thrombin and ADP as well as the thrombin-induced thromboxane synthesis. It also stimulated the basal and lipopolysaccharide-induced tissue factor activity of peritoneal macrophages. These prothrombotic effects were associated with an increased lipid peroxidation characterized by an elevation of plasma conjugated dienes, lipid hydroperoxides, and thiobarbituric acid-reactive substances. When rats were fed a folic acid-deficient diet, the methionine load did not cause any further increase in plasma homocysteine concentration, platelet activation, macrophage tissue factor-dependent coagulation, or lipoperoxidation. Altogether, our data showed that the prethrombotic state due to both the altered remethylation and transsulfuration pathways resulted from the moderate elevation of circulating homocysteine. We conclude that moderate hyperhomocysteinemia plays a role in the development of a thrombogenic state that might be mediated by the occurrence of oxidative stress.     

Plasma homocysteine concentrations in patients with type 1 diabetes

OBJECTIVE: To determine the plasma concentration of total homocysteine (tHcy), a recognized risk factor for vascular disease, in patients with type 1 diabetes and to examine the relationships with age, sex, duration of diabetes, microvascular complications and neuropathy, and folic acid concentration. RESEARCH DESIGN AND METHODS: Plasma tHcy and folic acid concentrations were measured in a randomly selected cohort of type 1 diabetic patients (n = 119), well characterized as regards microvascular complications, and in a matched control group (n = 51). RESULTS: Plasma tHcy was higher in male than in female control subjects (geometric mean [95% CI]: 9.3 [8.0-10.9] vs. 6.1 [5.2-7.2] micromol/l, P < 0.001), as previously described, but there was no sex difference in diabetic patients. Plasma tHcy significantly correlated with age in patients (r = 0.348, P < 0.01) but not in control subjects (r = 0.007, P = 0.96). Male patients without microvascular complications had lower plasma tHcy concentrations than did male control subjects (6.2 [5.1-7.5] vs. 9.3 [8.0-10.9] micromol/l, P < 0.001), but values in female patients without complications were similar to those of female control subjects. Plasma folic acid concentration was higher in diabetic patients than in control subjects. The expected negative association between plasma tHcy and folic acid was stronger in control subjects than in patients. CONCLUSIONS: Subnormal tHcy concentrations in male patients, the absence of a sex difference, and the positive association with age indicate that homocysteine metabolism differs between type 1 diabetic patients and control subjects. Homocysteine is unlikely to be of pathogenic significance in patients, particularly male subjects, with early microvascular disease and/or neuropathy.     

Plasma homocysteine, a risk factor for cardiovascular disease, is lowered by physiological doses of folic acid

Elevated plasma homocysteine, an independent risk factor for cardiovascular disease (CVD) can be lowered by administration of pharmacological doses of folic acid. The effect of lower doses in apparently normal subjects is currently unknown but is highly relevant to the question of food fortification. Healthy male volunteers (n = 30) participated in a chronic intervention study (26 weeks). Folic acid supplements were administered daily at doses increasing from 100 micrograms (6 weeks), to 200 micrograms (6 weeks), to 400 micrograms (14 weeks). Fasting blood samples collected before, during and 10 weeks post intervention were analysed for plasma homocysteine, serum and red-cell folate levels. Results, expressed as tertiles of baseline plasma homocysteine concentration, showed significant (p < or = 0.001) homocysteine lowering in the top (10.90 +/- 0.83 mumol/l) and middle (9.11 +/- 0.49 mumol/l) tertiles only. In the low tertile, where the mean baseline homocysteine level was 7.07 +/- 0.84 mumol/l, no significant response was observed. Of the three folic acid doses, 200 micrograms appeared to be as effective as 400 micrograms, while 100 micrograms was clearly not optimal. There is thus a minimal level of plasma homocysteine below which folic acid has no further lowering effect, probably because an optimal folate status has been reached. A dose as low as 200 micrograms/day of folic acid is effective in lowering plasma homocysteine concentrations in apparently normal subjects. Any public health programme for lowering homocysteine levels, with the goal of diminishing CVD risk, should not be based on unnecessarily high doses of folic acid.     

The role of hyper-homocysteinemia in the etiology of some vascular diseases

About 5% of population have a highly, while other 15% a moderately elevated plasma homocysteine level. Hyperhomocysteinemia may be responsible about 10-20% of coronary artery, 40% of cerebrovascular and 60% of peripheral vascular diseases. There in an inverse relationship between folate, cobalamin and pyridoxine intake or blood level and plasma homocysteine level. In addition, the intake of these three B vitamins can reduce high plasma homocysteine level. Folate-folic acid seems to be the most important in homocysteine reduction due to the compensation of thermolabile methylenetetrahydrofolate reductase insufficiency, however, a milder impact of cobalamin any pyridoxine (mainly following a methionine load test) is also proved. There are possibilities to reduce risk associated with elevated homocysteine: e. g. dietary supplementation or food fortification. In Hungary bread enriched by folic acid, cobalamin and pyriodixine might reduce rate of vascular diseases due to hyperhomocysteinemia.     

Treatment of hyperhomocysteinemia in renal transplant recipients. A randomized, placebo-controlled trial

BACKGROUND: Stable renal transplant recipients have an excess prevalence of hyperhomocysteinemia, which is a risk factor for arteriosclerosis. OBJECTIVE: To determine the effect of treatment with 1) vitamin B6 or 2) folic acid plus vitamin B12 on fasting and post-methionine-loading plasma total homocysteine levels in renal transplant recipients. DESIGN: Block-randomized, placebo-controlled, 2 x 2 factorial study. SETTING: University-affiliated transplantation program. PATIENTS: 29 clinically stable renal transplant recipients. INTERVENTION: Patients were randomly assigned to one of four regimens: placebo (n = 8); vitamin B6, 50 mg/d (n = 7); folic acid, 5 mg/d, and vitamin B12, 0.4 mg/d (n = 7); or vitamin B6, 50 mg/d, folic acid, 5 mg/d, and vitamin B12, 0.4 mg/d (n = 7). MEASUREMENTS: Fasting and 2-hour post-methionine-loading plasma total homocysteine levels. RESULTS: Vitamin B6 treatment resulted in a 22.1% reduction in geometric-mean post-methionine-loading increases in plasma total homocysteine levels (P = 0.042), and folic acid plus vitamin B12 treatment caused a 26.2% reduction in geometric-mean fasting plasma total homocysteine levels (P = 0.027). These results occurred after adjustment for age; sex; and pretreatment levels of total homocysteine, B vitamins, and creatinine. CONCLUSIONS: Vitamin B6 should be added to the combination of folic acid and vitamin B12 for effective reduction of both post-methionine-loading and fasting plasma total homocysteine levels in renal transplant recipients.     

High plasma homocysteine: a risk factor for vascular disease in the elderly

Homocysteine is an intermediate compound formed during the metabolism of methionine. Several studies have shown that plasma homocysteine concentrations rise with age. Overt or borderline deficiencies of folate, vitamin B12 or B6 and possibly age-related kidney dysfunction are the major causes of homocysteine elevation in the elderly population. Multiple case-control and prospective studies have shown that a high plasma homocysteine concentration is an independent risk factor for cardiovascular diseases; this association persists in the elderly. Supplementation with folic acid either alone or with vitamins B12 and B6 can lower plasma homocysteine. Intervention studies to assess the effects (if any) of such treatment on prognosis are now in progress in patients with vascular disease.     

Folate intake in Europe: recommended, actual and desired intake

OBJECTIVES: To evaluate possible inconsistencies between recommended, actual and desired folate intake in European adult populations. DESIGN: Review of dietary recommendations, of food consumption surveys, and of intervention and observational studies relating folate intake to the risk of neural tube defects and plasma homocysteine levels. RESULTS: In Europe, mean dietary folate intake in adults is 291 micrograms/d (range 197-326) for men and 247 micrograms/d (range 168-320) for women. The recommended intakes vary between 200-300 micrograms/d (men) and 170-300 micrograms/d (women). However, women with a previous pregnancy affected by a neural tube defect (NTD), are recommended to take 4000 micrograms/d of supplemental folic acid when planning a subsequent pregnancy. For those without a history of NTD, the use of 400 micrograms/d of supplemental folic acid is the best option to prevent the occurrence of NTDs. A daily dose of 650 micrograms supplemental folic acid normalises elevated plasma homocysteine levels, which is a risk factor for cardiovascular diseases. A dietary folate intake of at least 350 micrograms/d is desired to prevent an increase in plasma homocysteine levels of the adult population in general. CONCLUSIONS: Mean dietary folate intake in Europe is in line with recommendations, but the desired dietary intake of > 350 micrograms/d is only reached by a small part of studied European populations. It is considered unethical to investigate whether supplements with a dose lower than 400 micrograms/d of folic acid are also protective against NTDs. However, research to establish the lowest effective dose of dietary folate/supplemental folic acid to optimise homocysteine levels and research on the bioavailability of folate is required. This will enable the choice of a strategy to achieve desired folate intakes in the general population. In the meantime, consumption of plant foods like vegetables, fruits, and cereals should be stimulated to reach the desired level of 350 micrograms of dietary folate per day.     

An Arabidopsis mutant missing one acid phosphatase isoform

BACKGROUND: A high plasma homocysteine concentration is a risk factor for atherosclerosis and thrombosis, which are major causes of morbidity and mortality in heart transplant patients. High homocysteine concentrations may be caused by lower folate and vitamin B6 levels. We hypothesized that these patients might have high homocysteine concentrations and low levels of folate and vitamin B6, which could contribute to the development of vascular complications. METHODS: Total fasting plasma homocysteine was measured in 189 cardiac transplant recipients and in healthy controls, as were concentrations of folate, vitamin B12, vitamin B6, and creatinine. RESULTS: Homocysteine concentrations were higher in recipients than controls (19.1+/-13.0 vs. 11.0+/-3.0 micromol/L, P<0.01), and hyperhomocysteinemia (>90th percentile for controls, 14.6 micromol/L) was seen in 68% of recipients (P<0.01). Folate and vitamin B6 concentrations were lower (5.9+/-4.2 vs. 7.9+/-4.2 pmol/L and 40+/-25 vs. 84+/-77 nmol/L, respectively; P<0.01 for both). Folate and vitamin B6 deficiencies were seen in 10.8% and 17.91% of recipients, respectively (P<0.01). Hyperhomocysteinemia was more frequent in patients with vascular complications after transplantation than in those without (79.2% vs. 63.8%, P<0.05). CONCLUSIONS: Elevated plasma homocysteine and deficiencies of folate and vitamin B6 are common in transplant recipients. A high homocysteine concentration was more common in patients with vascular complications. Prospective studies are now required to evaluate the role of these abnormalities as risk factors for the atherothrombotic complications of transplantation.     

Hyperhomocysteinemia and venous thrombosis: a meta-analysis

Hyperhomocysteinemia is an established risk factor for atherosclerosis and vascular disease. Until the early nineties the relationship with venous thrombosis was controversial. At this moment ten case-control studies on venous thrombosis are published. We performed a metaanalysis of these reports. We performed a MEDLINE-search from 1984 through June 1997 on the keywords "homocysteine" or "hyperhomocysteinemia" and "venous thrombosis", which yielded ten eligible case-control studies. We found a pooled estimate of the odds ratio of 2.5 (95% CI 1.8-3.5) for a fasting plasma homocysteine concentration above the 95th percentile or mean plus two standard deviations calculated from the distribution of the respective control groups. For the post-methionine increase in homocysteine concentration we found a pooled estimate of 2.6 (95% CI 1.6-4.4). These data from case-control studies support hyperhomocysteinemia as a risk factor for venous thrombosis. Further research should focus on the pathophysiology of this relationship and on the clinical effects of reducing homocysteine levels by vitamin supplementation.     

Correlation between total homocysteine and cyclosporine concentrations in cardiac transplant recipients

Increased circulating total homocysteine (tHcy) has been implicated as an independent risk factor for atherosclerotic disease. In cardiac transplant patients, accelerated coronary atherosclerosis is an important cause of late allograft failure; however, studies of tHcy in this at-risk group are limited. We sampled a cohort of 72 subjects 3.95+/-3.14 (mean +/- SD) years after transplantation and found that all had tHcy concentrations above our upper reference limit (15.0 micromol/L). The mean tHcy in the transplant group (25.4+/-7.1 micromol/L) was significantly greater than in our reference group (9.0+/-4.3 micromol/L; n = 457; P <0.001). We also examined the effect of age, gender, time since transplant, serum folate and cobalamin, total protein, urate, creatinine, albumin, and trough whole blood cyclosporine concentrations. In a multiple linear regression model, only creatinine (mean 144+/-52 micromol/L; P = 0.021) and trough cyclosporine concentrations (191+/-163 microg/L; P = 0.015) were independent positive predictors of tHcy, whereas serum folate (8.35+/-7.43 nmol/L; P = 0.018) and time since transplant (P = 0.049) were significant negative predictors. We conclude that hyperhomocysteinemia is a common characteristic of cardiac transplant recipients. Our analysis suggests that folate and renal glomerular dysfunction are important contributory factors; however, whole blood cyclosporine concentrations may also predict the degree of hyperhomocysteinemia in this population and therefore influence interpretation of any apparent response to treatment.     

Open or closed? A world of difference: a history of homocysteine research

This article presents the research of the Nijmegen homocysteine team on birth defects and vascular disease. Hyperhomocysteinemia was found in women who gave birth to offspring with neural tube defects (NTDs) and other birth defects and in women with vascular disease. Elevated homocysteine levels in the blood plasma can be explained by lack of B vitamins (folic acid), mutation of the 5,10-methylenetetrahydrofolate reductase (MTHFR) genes, or both. Genetic mutations were found on the first chromosome (677 C T and 1298 A-C) and can explain up to 50% of the protective effect of folic acid against NTDs. The inborn error of methionine-homocysteine metabolism was also found in cases with recurrent early pregnancy loss, schisis, congenital heart defects, and vascular problems such as placental abruption, infarcts, and fetal growth retardation. One of the most exciting medical findings of recent years is that folic acid can prevent NTDs. This might also hold true for other birth defects and vascular disease.