Reduction In tHcy Research Articles

Optimal folic acid dosage in lowering homocysteine: Precision Folic Acid Trial to lower homocysteine (PFAT-Hcy)

BackgroundWhile folic acid (FA) is widely used to treat elevated total homocysteine (tHcy), promoting vascular health by reducing vascular oxidative stress and modulating endothelial nitric oxide synthase, the optimal daily dose and individual variation by MTHFR C677T genotypes have not been well studied. Therefore, this study aimed to explore the efficacy of eight different FA dosages on tHcy lowering in the overall sample and by MTHFR C677T genotypes.MethodsThis multicentered, randomized, double-blind, controlled clinical trial included 2697 eligible hypertensive adults with elevated tHcy (≥ 10 mmol/L) and without history of stroke and cardiovascular disease. Participants were randomized into eight dose groups of FA combined with 10 mg enalapril maleate, taken daily for 8 weeks of treatment.ResultsThe intent to treat analysis included 2163 participants. In the overall sample, increasing FA dosage led to steady tHcy reduction within the FA dosing range of 0–1.2 mg. However, a plateau in tHcy lowering was observed in FA dose range of 1.2–1.6 mg, indicating a ceiling effect. In contrast, FA doses were positively and linearly associated with serum folate levels without signs of plateau. Among MTHFR genotype subgroups, participants with the TT genotype showed greater efficacy of FA in tHcy lowering.ConclusionsThis randomized trial lent further support to the efficacy of FA in lowering tHcy; more importantly, it provided critically needed evidence to inform optimal FA dosage. We found that the efficacy of FA in lowering tHcy reaches a plateau if the daily dosage exceeds 1.2 mg, and only has a small gain by increasing the dosage from 0.8 to 1.2 mg.ClinicalTrials.gov IdentifierNCT03472508 (Registration Date: March 21, 2018).

The effect of diet-induced weight loss on circulating homocysteine levels in people with obesity and type 2 diabetes

Background/aimsHaving type 2 diabetes (T2D) in combination with being overweight results in an additional increase in cardiovascular disease (CVD) risk. In addition, T2D and obesity are associated with increased levels of total homocysteine (tHcy), possibly contributing to the CVD risk. Weight loss dieting has positive effects on several CVD risk factors, but whether it affects tHcy remains unclear. Therefore, the aim of this study was to determine the effect of a calorie restricted diet on tHcy in overweight people with T2D.MethodsIn this post-hoc analysis of the POWER study, adults with T2D and a BMI greater than 27 kg/m² were included from the outpatient diabetes clinic of the Erasmus Medical Center, Rotterdam. The patients were subjected to a very low-calorie diet with fortified meal replacements for 20 weeks. Before and after this intervention, blood samples were collected to measure tHcy and other CVD risk factors like glycaemic and lipid parameters.Results161 overweight participants with T2D were included, with a mean age of 54 years (range 26–74), mean weight of 104.6 ± 19.9 kg and mean HbA1c of 62.7 ± 14.3 mmol/mol. At baseline, men displayed higher tHcy than women, and tHcy level was positively correlated with body weight and triglyceride levels, while it was negatively correlated with renal function and HDL cholesterol. During the intervention, bodyweight was reduced by a mean of 9.7% (from 104.6 ± 19.9 to 94.5 ± 18.1 kg p < 0.001), and all measured glycaemic and lipid blood parameters improved significantly. However, tHcy remained unchanged (from 12.1 ± 4.1 to 12.1 ± 4.2 umol/L, p = 0.880). The change in tHcy during the intervention was negatively associated with the change in weight and BMI (p = 0.01 and p = 0.008, respectively). People who lost < 10 kg (n = 92) had a mean tHcy change of -0.47 umol/L, while people who lost more than ≥ 10 kg (n = 69) had a mean tHcy change of 0.60 umol/L (p = 0.021).ConclusionIn conclusion, our data show that a calorie restricted diet does not affect tHcy in people with T2D and obesity, despite the use of meal replacements fortified with folic acid and vitamin B12. Our data showed a negative correlation between change in tHcy levels and weight loss, suggesting that people who lost more weight (> 10 kg) showed an increase in tHcy. Future studies should explore the potential increase in tHcy induced by weight loss dieting and target the question if tHcy reduction strategies during weight loss could be clinically beneficial.

Effect of Patent Foramen Ovale Closure After Stroke on Circulatory Biomarkers.

To determine the influence of patent foramen ovale (PFO) closure on circulatory biomarkers. Consecutive patients with PFO-related stroke were prospectively enrolled and followed with serial sampling of cardiac atrial and venous blood pre- and post-PFO closure over time. Candidate biomarkers were identified by mass spectrometry in a discovery cohort first, and lead candidates were validated in an independent cohort. Patients with PFO-related stroke (n = 254) were recruited and followed up to 4 years (median 2.01; interquartile range 0.77-2.54). Metabolite profiling in the discovery cohort (n = 12) identified homocysteine as the most significantly decreased factor in intracardiac plasma after PFO closure (false discovery rate 0.001). This was confirmed in a validation cohort (n = 181), where intracardiac total homocysteine (tHcy) was immediately reduced in patients with complete closure, but not in those with residual shunting, suggesting association of PFO shunting with tHcy elevation (β 0.115; 95% confidence interval [CI] 0.047-0.183; p = 0.001). tHcy reduction was more dramatic in left atrium than right (p < 0.001), suggesting clearance through pulmonary circulation. Long-term effect of PFO closure was also monitored and compared to medical treatment alone (n = 61). Complete PFO closure resulted in long-term tHcy reduction in peripheral blood, whereas medical therapy alone showed no effect (β -0.208; 95% CI -0.375∼-0.058; p = 0.007). Residual shunting was again independently associated with persistently elevated tHcy (β 0.184; 95% CI 0.051-0.316; p = 0.007). PFO shunting may contribute to circulatory tHcy elevation, which is renormalized by PFO closure. PFO is not just a door for clots, but may itself enhance clot formation and injure neurovasculature by clot-independent mechanisms. Biomarkers such as tHcy can potentially serve as cost-effective measures of residual shunting and neurovascular risk for PFO stroke.

ORAL N-ACETYLCYSTEINE LOWERS PLASMA HOMOCYSTEINE IN ADULTS ON A BACKGROUND OF ANABOLIC RESISTANCE TRAINING

Lowering high plasma levels of homocysteine (tHcy) by folate/vitamin-B-supplementation only unsufficiently protects against cardiovascular diseases and dementia. To enhance therapeutic options, we evaluated whether the significant tHcy-lowering effect of oral N-acetylcysteine (NAC) in sedentary adults (-11.71% [12]) is still detectable on a background of anabolic resistance training (RT) which moderately decreases tHcy itself. Reanalysing a previous randomized controlled double-blinded clinical trial, we compared the effect of oral NAC (8 weeks 1.8 g/d, n=9) to that of placebo (n=8) on postabsorptive tHcy in healthy middle-aged subjects (tHcy 11.82±0.69 µM) undergoing 8 weeks of supervised progressive RT. NAC (+RT) led to a significantly greater reduction of tHcy (-13.97±5.81%) than placebo (+RT) (-3.85±4.81%) as confirmed by ANOVA (P&lt;0.05) adjusting for methionine plasma levels and gain in strength. This add-on effect of NAC (~-10%) suggests that combining cysteine supplementation with RT may offer a novel (additional) option to lower tHcy in an aging population.

Effect of long-term low-dose folic acid supplementation on degree of total homocysteine-lowering: major effect modifiers.

We sought to examine the potential modifiers in the association between long-term low-dose folic acid supplementation and the reduction of serum total homocysteine (tHcy) among hypertensive patients, using data from the China Stroke Primary Prevention Trial (CSPPT). This analysis included 16 867 participants who had complete data on tHcy measurements at both the baseline and exit visit. After a median treatment period of 4·5 years, folic acid treatment significantly reduced the tHcy levels by 1·6 μmol/l (95 % CI 1·4, 1·8). More importantly, after adjustment for baseline tHcy and other important covariates, a greater degree of tHcy reduction was observed in certain subgroups: males, the methylenetetrahydrofolate reductase (MTHFR) 677TT genotype, higher baseline tHcy levels (≥12·5 (median) v. <12·5 μmol/l), lower folate levels (<8·0 (median) v. ≥8·0 ng/ml), estimated glomerular filtration rate (eGFR) <60 ml/min per 1·73 m2 (v. 60-<90 and ≥90 ml/min per 1·73 m2), ever smokers and concomitant use of diuretics (P for all interactions <0·05). The degree of tHcy reduction associated with long-term folic acid supplementation can be significantly affected by sex, MTHFR C677T genotypes, baseline folate, tHcy, eGFR levels and smoking status.

No association between hyperhomocysteinemia and vascular access thrombosis in chronic hemodialysis.

PURPOSE. Hyperhomocysteinemia, recognized as a risk factor for cardiovascular diseases, has also been related with controversy to vascular access thrombosis in hemodialysis. Our objective was to determine if such an association could be found in our hemodialysis population. METHODS. The survey was conducted in a cohort of 165 chronic hemodialysis patients. Their vascular access history was considered from hemodialysis initiation until November 1999, including the number of vascular accesses created (either native or synthetic fistulae), focussing on vascular access thrombotic events, and excluding primary vascular access dysfunction. Diabetes, hemoglobin, erythropoietin dose, anticoagulation, and methyltetrahydrofolate reductase (MTHFR) status were considered. Serum total homocysteine (tHcy) measures were sampled for all patients in June 1998 and repeated yearly. Patients had not been supplemented routinely with hydrosoluble vitamins until June 1998, after which all received DiaVite (R&D Laboratories, CA, USA) daily. RESULTS. Median survival of native fistulae was significantly longer (81 months, 95%CI 35-127) than for synthetic fistulae (31 months, 95%CI 27-51). Median vascular access survival was reduced for diabetics vs non diabetics (28 vs 57 months) (p<0.05), whereas sex, age and smoking had no impact. No correlation was found between tHcy concentration and the number of vascular access thrombotic events; homozygotes for MTHFR had higher tHcy but no more vascular access thrombotic events. The 38 patients with a mean vascular access survival of less than 12 months (63 months) were compared to the 127 patients with a mean vascular access survival of >= 12 months (3925 months) (p<0.05): no difference in their respective tHcy concentrations before and after DiaVite introduction was found (3113 and 208 vs 3417 and 226 mol/L), but the first group presented more numerous synthetic fistulae (p<0.0001), lower hemoglobin levels, and higher erythropoietin doses. CONCLUSIONS. No significant association between hyperhomocysteinemia and vascular access thrombosis could be found in our population. DiaVite introduction allowed a significant reduction in tHcy, but had no impact on vascular access survival, except for a slight but not significant reduction in the prevalence of vascular access thrombotic events during the year on DiaVite. Potential benefits of approaches to reduce tHcy for vascular access time-life prolongation remain to be demonstrated.

Association between percent decline in serum total homocysteine and risk of first stroke.

To examine whether a change in serum total homocysteine (tHcy) levels is associated with first stroke risk in a post hoc analysis of the China Stroke Primary Prevention Trial (CSPPT). We analyzed 16,867 participants of the CSPPT with tHcy measurements at both baseline and exit visits. The primary outcome was first stroke. The secondary outcome was a composite of cardiovascular events consisting of cardiovascular death, myocardial infarction, and stroke. The percent decline in tHcy was calculated as [(baseline tHcy - exit tHcy)/baseline tHcy × 100]. Over the median treatment duration of 4.5 years, participants who developed a first stroke had a significantly lower percent decline in tHcy (β = -5.7; 95% confidence interval [CI] -8.8 to -2.6) compared to their counterparts. A 20% tHcy decline was associated with a reduction in stroke risk of 7% (hazard ratio [HR] 0.93; 95% CI 0.90-0.97). When percent decline in tHcy was assessed as tertiles, a significantly lower stroke risk was found in those in tertiles 2-3 (HR 0.79; 95% CI 0.64-0.97) compared with participants in tertile 1. Similar results were observed for the composite of cardiovascular events. The beneficial effect associated with greater tHcy reduction was observed across strata for age, sex, treatment group (with vs without folic acid), MTHFR C677T genotypes, baseline tHcy and serum folate levels, and blood pressure control. Percent lowering in tHcy was significantly associated with a reduction in first stroke risk in Chinese adults with hypertension, and if further confirmed, may serve as a useful indicator for folic acid treatment efficacy on stroke prevention. NCT00794885.

The c.797 G>A (p.R266K) cystathionine β-synthase mutation causes homocystinuria by affecting protein stability.

Mutations in the cystathionine beta-synthase (CBS) gene are the cause of classical homocystinuria, the most common inborn error in sulfur metabolism. The c.797 G>A (p.R266K) mutation in CBS was originally described in several Norwegian pyridoxine responsive CBS deficient patients, and heterologous gene expression studies have shown that the protein has near wild-type levels of enzyme activity. Here, we characterize a transgenic mouse lacking endogenous Cbs and expressing p.R266K human CBS protein from a zinc inducible metallothionein promoter (Tg-R266K Cbs-/- ). Unlike mice expressing other mutant CBS alleles, the Tg-R266K transgene is unable to efficiently rescue neonatal lethality of Cbs-/- on a C57BL/6J background. On a C3H/HeJ background, zinc-induced Tg-R266K Cbs-/- mice express CBS mRNA, but have very low levels of CBS protein and enzyme activity, resulting in extreme elevations in serum total homocysteine (tHcy). Treatment with pyridoxine did not have any appreciable effect on tHcy, indicating this allele is not pyridoxine responsive in mice. However, treatment with the proteasome inhibitor bortezomib resulted in an 97% reduction in tHcy and a 2381% increase in liver CBS activity. These studies show that the p.R266K mutation causes increased proteasomal degradation in vivo, and that treatments that stabilize the protein can be used to reverse its effect.

Folic acid therapy reduces serum uric acid in hypertensive patients: a substudy of the China Stroke Primary Prevention Trial (CSPPT)1–3

Background: The effect of folic acid supplementation on uric acid (UA) concentrations is still inconclusive.Objective: We aimed to test the efficacy of folic acid therapy in reducing serum UA in hypertensive patients.Design: A total of 15,364 hypertensive patients were randomly assigned to a double-blind daily treatment with a single tablet that contained 10 mg enalapril and 0.8 mg folic acid (n = 7685) or 10 mg enalapril alone (n = 7679). The main outcome was the change in serum UA, which was defined as UA at the exit visit minus that at baseline. Secondary outcomes were as follows: 1) controlled hyperuricemia (UA concentration <357 µmol/L after treatment) and 2) new-onset hyperuricemia in participants with normal UA concentrations (<357 µmol/L).Results: After a median of 4.4 y of treatment, the mean ± SD UA concentration increased by 34.7 ± 72.5 µmol/L in the enalapril-alone group and by 30.7 ± 71.8 µmol/L in the enalapril–folic acid group, which resulted in a mean group difference of −4.0 µmol/L (95% CI: −6.5, −1.6 µmol/L; P = 0.001). Furthermore, compared with enalapril alone, enalapril–folic acid treatment showed an increase in controlled hyperuricemia (30.3% compared with 25.6%; OR: 1.31; 95% CI: 1.01, 1.70) and a decrease in new-onset hyperuricemia (15.0% compared with 16.3%; OR: 0.89; 95% CI: 0.79, 0.99). A greater beneficial effect was observed in subjects with hyperuricemia (P-interaction = 0.07) or higher concentrations of total homocysteine (tHcy) (P-interaction = 0.02) at baseline. Furthermore, there was a significant inverse relation (P < 0.001) between the reduction of tHcy and the change in UA concentrations.Conclusions: Enalapril–folic acid therapy, compared with enalapril alone, can significantly reduce the magnitude of the increase of UA concentrations in hypertensive adults. This trial was registered at clinicaltrials.gov as NCT00794885.

Abstract TP443: Homocysteine Level in PFO Related Stroke Patients With Respect to Medical Therapy vs PFO Closure

Background: Homocysteine is an independent risk factor of ischemic stroke by promoting vascular endothelial dysfunction and thrombotic process through oxidative stress. We previously found that PFO closure may reduce total homocysteine level (tHcy) in plasma. Here, we compare the effect of PFO closure and medical treatment in reducing mild homocysteinemia in PFO-related stroke patients. Method: 28 PFO-related stroke patients with mildly elevated tHcy (&gt;12 μmol/l) were prospectively recruited in accordance with IRB. 14 received PFO closure and 14 were treated by medical therapy (antiplatelet/anticoagulant) alone. None of the patients were on folate or vitamin B supplementation. Plasma was collected at baseline and 1 year follow-up after treatment. tHcy level was determined by selected reaction monitoring using mass spectrometry. Result: Compared to medical therapy, PFO closure resulted in a lower tHcy level during follow-up (PFO closure: 11.13 ± 3.94 μmol/L, medical therapy: 15.48 ± 3.55 μmol/L, p = 0.006), with no difference at baseline (PFO closure: 17.77 ± 4.39 μmol/L, medical therapy: 16.47 ± 7.50 μmol/L, p = 0.575). Mild hyperhomocysteinemia patients post PFO closure had a significant reduction of tHcy by 37.34% (p = 0.0005), with 71.43% of the patients (10 of 14) having tHcy levels back to normal (&lt;12 μmol/l), while most of medically treated patients (13 of 14) stayed abnormal (p = 0.4820) (χ2-test, adjusted p = 0.002). Conclusion: We found that compared with routine medical therapy, PFO closure reduced tHcy level in patients with mild hyperhomocysteinemia. Since PFO stroke patients tend to be younger, the life-time risk of even mildly elevated tHcy may be relevant for future thrombotic risk. Understanding the mechanism of PFO-related tHcy changes is important in optimizing medical treatment (e.g. folate replacement); studies are ongoing.

Abstract W P398: PFO Closure Reduces High Homocysteine Level in Atrial Blood of Stroke Patients

Background: PFO allows venous clots to bypass pulmonary filtration, leading to strokes. We previous found in metabolite screening that PFO endovascular closure lower markers of oxidative stress and homocysteine levels in peripheral venous blood. Here we study changes of homocysteine during endovascular closure in cardiac atrial blood to better understand the central metabolism of PFO in circulation. Method: PFO stroke patients are propectively recruited according to IRB approval with plasma sampled from left (LA) and right (RA) atria pre- and post- PFO closure (n=97). Total homocysteine (tHCY) level was measured by selected reaction monitoring using mass spectrometry. Result: tHCY level decreased significantly in both RA and LA post PFO closure (Fig. 1A, p = 0.0014; RA: reduced by 8.54% Fig. 1B, p = 0.0304; LA: reduced by 9.90% Fig. 1C, p = 0.0470). Notably, tHCY reduction was skewed towards patients with higher tHCY levels before PFO closure (Fig. 1D and E, Kolmogorov-Smirnov test, RA: p = 0.0413; LA: p = 0.0010), such that more patients with higher tHCY level had a more significant reduction in tHCY levels compared to those with lower/normal levels. Conclusion: We found that PFO closure efficiently reduced tHCY level in both venous and arterial systems of stroke patients with high tHCY level. This effect is more pronounced in patients with higher levels suggesting PFO closure may help change the pathophysiology of hyperhomocysteinemia; further studies are ongoing to understand the underlying mechanism.

One year B-vitamins increases serum and whole blood folate forms and lowers plasma homocysteine in older Germans.

We aimed to study the effect of long-term supplementation of B-vitamins on folate forms in serum and whole blood (WB) in elderly German subjects. 59 participants (mean age 67 years) were randomized to daily receive either vitamin D3 (1200 IU), folic acid (500 μg), vitamin B12 (500 μg), vitamin B6 (50 mg), and calcium carbonate (456 mg) or vitamin D3 plus calcium carbonate. Serum and WB folate forms were measured before and after 6 and 12 months. B-vitamins supplementation for 6 months led to higher concentrations of 5-methyltetrahydrofolate (5-methylTHF) in serum (mean 49.1 vs. 19.6 nmol/L) and WB (1332 vs. 616 nmol/L). Also non-methyl-folate concentrations in serum and WB were higher after 6 months with B-vitamins supplementation. Unmetabolized folic acid (UFA) increased after supplementation. tHcy concentration was lowered after 1 year of B-vitamin supplementation (mean 13.1 vs. 9.6 μmol/L). A stronger reduction of tHcy after 1 year was found in participants who had baseline level >12.5 μmol/L (mean 17.0 vs. 11.9 μmol/L) compared to those with baseline tHcy lower than this limit (mean 9.1 vs. 7.4 μmol/L). In contrast, the increases in serum and WB 5-methylTHF were comparable between the two groups. One year B-vitamins supplementation increased the levels of 5-methylTHF and non-methyl-folate in serum and WB, normalized tHcy, but caused an increase in the number of cases with detectable UFA in serum. Lowering of tHcy was predicted by baseline tHcy, but not by baseline serum or WB 5-methylTHF.

Folic acid supplementation on homocysteine levels in children taking antiepileptic drugs: A randomized controlled trial.

Objectives:To assess the level of homocysteine (tHcy) in children taking AEDs and to study whether daily oral supplementation of folic acid for 1 month will reduce the tHcy level.Materials and Methods:This was a double-blinded, randomized control trial conducted in Institute of Maternal and Child Health, Kozhikode, India. Totally 60 children were recruited and of them, 48 were enrolled. Of these children, 32 were assigned to the experimental group and 16 to the control group. Baseline data collection and tHcy estimation were done. One mg folic acid tablets were given to the experimental group and placebo tablets to the control group for 30 days. tHcy levels were re-estimated after 1 month follow-up. Statistical significance was tested by χ2 test, and paired and unpaired t-tests, as appropriate. Correlation was tested by Pearson correlation test and P value less than 0.05 was taken as the cut-off for statistical significance.Results:Baseline plasma tHcy concentrations in both groups were comparable [11.90 (6.3) and 13.02 (2.4) μmol/l, respectively]. During the follow-up period, no increase in seizure episodes or no serious adverse reactions were noticed in either group. The reduction of tHcy in the experimental group was 1.92 μmol/l (P = 0.04) and in the control group, there was an increase of 1.05 μmol/l (P = 0.16).Conclusions:In children on AED treatment, folic acid supplementation may reduce tHcy level and thus reduce CVD risk.

An Encapsulated Juice Powder Concentrate Improves Markers of Pulmonary Function and Cardiovascular Risk Factors in Heavy Smokers

Objective: Cigarette smoking is associated with reduced pulmonary function and increased risk factors for cardiovascular disease. This randomized placebo-controlled double-blind study evaluated the effects of two different combinations of mixed fruit and vegetable juice powder concentrate (Juice Plus+, NSA, Collierville, TN) on heavy smokers. Methods: At baseline (T 0) and after 3 months’ supplementation (T 1), pulmonary function parameters and cardiovascular risk factors—that is, plasma total homocysteine (tHcy) with related B vitamins and cysteine (tCys) concentrations—were assessed in 75 apparently healthy smokers (aged 49.2 ± 10.6 years, >20 cigarettes/d, duration ≥10 years) randomized into 3 groups: placebo (P), fruit/vegetable (FV) and fruit/vegetable/berry (FVB). Results: T 0: most smokers showed abnormalities in tHcy and tCys concentrations. T 1: respiratory function was unchanged in P and slightly, but not significantly, improved in FV, whereas FVB showed a significant improvement in forced expiratory flow at 25% (FEF25; p < 0.0001 vs P and FV) and significant improvement in CO diffusion lung/alveolar volume (DLCO/VA). FV and FVB (50%) showed significant reduction in tHcy and tCys compared to T 0 ( p < 0.0001) and P ( p < 0.0001). Conclusions: At T 1, both supplemented groups, but to a greater extent the FVB group, showed improvements in some pulmonary parameters, cardiovascular risk factors, and folate status. The beneficial effects of Juice Plus+ supplementation could potentially help smokers, even if smoking cessation is advisable.

Hydroxocobalamin dose escalation improves metabolic control in cblC

Cobalamin C (cblC), a combined form of methylmalonic acidaemia and hyperhomocysteinaemia, is recognized as the most frequent inborn error of intracellular cobalamin metabolism. This condition can be detected by expanded newborn screening and can have an acute neonatal presentation that is life-threatening if not suspected and promptly treated. Intramuscular (IM) hydroxocobalamin (OHCbl) is the main treatment for patients with cblC, but formal dosing guidelines do not exist. A clinical improvement and a decrease of plasma methylmalonic acid (MMA) and total homocysteine (tHcy) levels, and an increase in methionine are typically observed after its initiation. It is well recognized that despite treatment, long-term complications such as developmental delay and progressive visual loss, may still develop. We describe the biochemical response of a 13-year-old boy with worsening metabolic parameters despite strict adherence to a conventional treatment regimen. We progressively increased the OHCbl dose from 1 to 20 mg IM per day and observed a dose-dependent response with an 80% reduction of plasma MMA (25 to 5.14 micromol/L; normal range <0.27 micromol/L), a 55% reduction of tHcy (112 to 50 micromol/L; normal range: 0-13 micromol/L) and a greater than twofold increase in methionine (17 to 36 micromol/L; normal range: 7-47 micromol/L). This suggests that higher OHCbl doses might be required to achieve an optimal biochemical response in cblC patients, but it is unknown whether it may slow or eliminate other complications. Future clinical trials to determine the benefits of higher-dose OHCbl therapy in patients with cblC and other disorders of intracellular cobalamin metabolism should be planned.

Ethnicity Does Not Affect the Homocysteine-Lowering Effect of B-Vitamin Therapy in Singaporean Stroke Patients

Increased total homocysteine (tHcy) is a risk factor for stroke. This study examines whether the efficacy of B-vitamins in reducing tHcy is modified by ethnicity in a Singaporean ischemic stroke population. 505 patients (419 Chinese, 41 Malays and 45 Indians) with ischemic stroke were randomized to receive placebo or B-vitamins. Fasting blood samples collected at baseline and 1 year were assayed for tHcy. MTHFR polymorphisms were genotyped. Ethnicity did not independently determine tHcy at baseline. The magnitude of tHcy reduction by B-vitamin treatment was consistent across ethnic groups (Chinese -3.8+/-4.5, Malay -4.9+/-4.2, and Indian -3.3+/-3.6 micromol/L) despite ethnic differences in MTHFR genotype and baseline folic acid (FA) and vitamin B(12) (vitB(12)) concentrations. Ethnicity does not appear to affect the tHcy-lowering effect of B-vitamins, despite differences in dietary intake and prevalence of MTHFR polymorphisms. This suggests that the effect of B-vitamins in lowering tHcy is generalizable across Asian populations. However, due to relatively small numbers of non-Chinese studied, confirmation in other populations is required.

Plasma Aβ, homocysteine, and cognition

Amyloid-beta protein (Abeta) plays a key role in Alzheimer disease (AD) and is also implicated in cerebral small vessel disease. Serum total homocysteine (tHcy) is a risk factor for small vessel disease and cognitive impairment and correlates with plasma Abeta levels. To determine whether this association results from a common pathophysiologic mechanism, we investigated whether vitamin supplementation-induced reduction of tHcy influences plasma Abeta levels in the Vitamin Intervention in Stroke Prevention (VISP) study. Two groups of 150 patients treated with either the high-dose or low-dose formulation of pyridoxine, cobalamin, and folic acid in a randomized, double-blind fashion were selected among the participants in the VISP study without recurrent stroke during follow-up and in the highest 10% of the distribution for baseline tHcy levels. Concentrations of plasma Abeta with 40 (Abeta40) and 42 (Abeta42) amino acids were measured at baseline and at the 2-year visit. tHcy levels significantly decreased with vitamin supplementation in both groups. tHcy were strongly correlated with Abeta40 but not Abeta42 concentrations. There was no difference in the change in Abeta40, Abeta42 (p = 0.40, p = 0.35), or the Abeta42/Abeta40 ratio over time (p = 0.86) between treatment groups. Abeta measures were not associated with cognitive change. This double-blind randomized controlled trial of vitamin therapy demonstrates a strong correlation between serum tHcy and plasma Abeta40 concentrations in subjects with ischemic stroke. Treatment with high dose vitamins does not, however, influence plasma levels of Abeta, despite their effect on lowering tHcy. Our results suggest that although tHcy is associated with plasma Abeta40, they may be regulated by independent mechanisms.

Long-term Effects of Folic Acid Fortification and B-vitamin Supplementation on Total Folate, Homocysteine, Methylmalonic Acid and Cobalamin in Older Adults

To investigate the long-term effects of the Canadian folic acid fortification program in older adults' whole blood cell folate (folate) and cobalamin (Cbl) status, including homocysteine (tHcy) and methylmalonic acid (MMA), with and without voluntary B-vitamin intake, from 1997 to 2004. Cohort of community-dwelling volunteer older adults. Clinical and biochemical data, including intake of B-vitamin supplements, were obtained at 2- to 2.5-year intervals and divided in 4 periods. Random coefficients (mixed effects) models were used to estimate the linear trend in folate and to compare levels of biochemical parameters between periods. All models were estimated by restricted maximum likelihood as implemented in PROC MIXED of SAS V8.2. Folate levels increased continuously at a yearly rate of 234 ng/mL (95% CI 213-254; p < 0.001) and had not plateaued by the last period when 84% of subjects without B-vitamins had elevated folate. Homocysteine did not remain suppressed. Elevated tHcy was as prevalent in the last study period as in the first. No significant deficits of Cbl or increases of MMA were observed, but MMA levels tended to increase with time in subjects without B-vitamins. B-vitamin supplements significantly affected all results, reducing tHcy and MMA levels. In this population, fortification with folic acid has resulted in cumulative increases of folate with no long-term reduction in tHcy or changes in Cbl or MMA. Possible deleterious effects of cumulative increases of folate, and beneficial effects of B-vitamin supplements in reducing tHcy and MMA, should be investigated.

Effect of weight reduction on concentration of plasma total homocysteine in obese Japanese men

To test whether weight reduction would lower tHcys concentration, and whether adding exercise training to dietary weight reduction would further reduce tHcys concentration over diet alone. A randomized, controlled, prospective, 14-week weight-loss intervention. Forty-eight obese Japanese men aged 27-66 years were assigned to 2 subgroups depending on the type of treatment: diet alone (DA) and diet plus exercise training (DE). Concentration of tHcy was measured in frozen plasma samples by an HPLC method. Body weight decreased significantly for both groups: DA -7.8 ± 3.2 kg and DE -9.1 ± 3.6 kg. A significant decrease was found in tHcys concentration of the DE group (-2.3 ± 5.0 μmol/L) but not of the DA (-0.3 ± 2.7 μmol/L). For subjects with hyperhomocysteinemia (≥15 μmol/L, n = 17), tHcys concentration decreased from 20.1 ± 7.0 to 13.9 ± 3.0 μmol/L (p < 0.01) for the DE group (n = 8) but did not change for the DA group (16.6 ± 1.9 μmol/L → 15.4 ± 2.3 μmol/L, n = 9). Furthermore, to consider a statistical phenomenon "regression to the mean", we excluded two subjects with the highest two tHcys values of the DE group. The DE group (n = 7) still displayed a significant reduction after the exclusion. A weight reduction with diet alone did not improve tHcy levels. Adding aerobic exercise training to a dietary weight-reduction program may be effective for a reduction in tHcy.

Acute effects of haemodialysis on biochemical modulators of endothelial function

To assess the acute effects of haemodialysis (HD) on biochemical factors modulating endothelial function. Academic medical centre. Forty patients (age 63.5 +/- 2.2 years, mean +/- SEM) undergoing HD. Folic acid (F), homocysteine (tHcy), asymmetric dimethylarginine (ADMA), high-sensitivity C-reactive protein (CRP) and malondialdehyde (MDA) were measured pre-HD, 1 h after commencing HD and within the last hour of HD (end-HD). Endothelium-dependent and -independent vasodilatation were measured by applanation tonometry (changes in augmentation index, AIx, postinhaled salbutamol and postsublingual nitroglycerin) in conjunction with biochemical measurements. Marked reductions in serum F (616 +/- 73 vs. 273 +/- 30 nmol L(-1), P < 0.001), tHcy (16.3 +/- 0.7 vs. 11.2 +/- 0.5 micromol L(-1), P < 0.001) and ADMA (0.64 +/- 0.02 vs. 0.47 +/- 0.02 micromol L(-1), P < 0.001) occurred end-HD, whereas CRP and MDA levels did not significantly change. There was no significant change in endothelium-dependent vasodilatation, whereas endothelium-independent vasodilatation improved end-HD (-23.1 +/- 1.9 vs. -17.3 +/- 1.3%, P = 0.018). Regression analysis showed that both higher ADMA (P = 0.029) and lower F levels (P = 0.040) end-HD were determinants of reduced endothelium-dependent vasodilatation end-HD (R(2) = 0.23). HD is associated with significant reductions in F, tHcy and ADMA serum concentrations. The lack of significant effects of HD on endothelium-dependent vasodilatation could be secondary to the concomitant loss of factors either enhancing (F) or impairing (ADMA) endothelial function.