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B Vitamins and the Risk of Total Mortality and Cardiovascular Disease in End-Stage Renal Disease: Results of a Randomized Controlled Trial Effects of folic acid treatment on homocysteine levels and vascular disease in hemodialysis patients. Homocysteine and risk of cardiovascular disease among postmenopausal women. Folic Acid-Based Intervention in Non-ST Elevation Acute Coronary Syndromes Homocysteine-Lowering Therapy and Risk for Venous Thromboembolism Homocysteine-Lowering Therapy and Stroke Risk, Severity, and Disability: Additional Findings From the HOPE 2 Trial B-Vitamin Therapy for Kidney Transplant Recipients Lowers Homocysteine and Improves Selective Cognitive Outcomes in the Randomized FAVORIT Ancillary Cognitive Trial. Effect of folic acid and B vitamins on risk of cardiovascular events and total mortality among women at high risk for cardiovascular disease: a randomized trial. Homocysteine-Lowering Treatment With Folic Acid, Cobalamin, and Pyridoxine Does Not Reduce Blood Markers of Inflammation, Endothelial Dysfunction, or Hypercoagulability in Patients With Previous Transient Ischemic Attack or Stroke: A Randomized Substudy of the VITATOPS Trial A prospective cohort study of predictive value of homocysteine in patients with type 2 diabetes and coronary artery disease. Effect of Homocysteine-Lowering Treatment With Folic Acid and B Vitamins on Risk of Type 2 Diabetes in Women Randomized, placebo-controlled trial of intramuscular vitamin B12 for the treatment of hyperhomocysteinaemia in dialysis patients. Mortality and cardiovascular events in patients treated with homocysteine-lowering B vitamins after coronary angiography: a randomized controlled trial. Plasma folate and total homocysteine levels are associated with the risk of myocardial infarction, independently of each other and of renal function. Effects of homocysteine-lowering with folic acid plus vitamin B12 vs placebo on mortality and major morbidity in myocardial infarction survivors: a randomized trial. Stabilization of homocysteine in unseparated blood over several days: a solution for epidemiological studies. Homocysteine-lowering therapy does not affect inflammatory markers of atherosclerosis in patients with stable coronary artery disease. Coronary blood flow in patients with stable coronary artery disease treated long term with folic acid and vitamin B12 Prospective study of hyperhomocysteinemia as an adverse cardiovascular risk factor in end-stage renal disease. Effect of homocysteine-lowering therapy with folic acid, vitamin B12, and vitamin B6 on clinical outcome after percutaneous coronary intervention: the Swiss Heart study: a randomized controlled trial. Effect of folic acid and antioxidant vitamins on endothelial dysfunction in patients with coronary artery disease. Plasma total homocysteine: instigator or indicator of cardiovascular disease? Uremic hyperhomocysteinemia: a randomized trial of folate treatment for the prevention of cardiovascular events. Effect of homocysteine lowering on mortality and vascular disease in advanced chronic kidney disease and end-stage renal disease: a randomized controlled trial. Effects of 2-year vitamin B12 and folic acid supplementation in hyperhomocysteinemic elderly on arterial stiffness and cardiovascular outcomes within the B-PROOF trial No effect of folic acid supplementation in the course of 1 year on haemostasis markers and C-reactive protein in older adults. Interactions between the single nucleotide polymorphisms in the homocysteine pathway (MTHFR 677C>T, MTHFR 1298 A>C, and CBSins) and the efficacy of HMG-CoA reductase inhibitors in preventing cardiovascular disease in high-risk patients of hypertension: the GenHAT study Folate Improves Endothelial Function in Patients with Coronary Heart Disease Design and statistical issues in the homocysteinemia in kidney and end stage renal disease (HOST) study Rationale and design of the Folic Acid for Vascular Outcome Reduction In Transplantation (FAVORIT) trial. Preventing Alzheimer’s disease-related gray matter atrophy by B-vitamin treatment Glutathione peroxidase-1 and homocysteine for cardiovascular risk prediction: results from the AtheroGene study. Hyperhomocysteinemia predicts total and cardiovascular mortality in high-risk women Controlled trials of very high dose folic acid, vitamins B12 and B6, intravenous folinic acid and serine for treatment of hyperhomocysteinemia in ESRD. Breakfast cereal fortified with folic acid, vitamin B-6, and vitamin B-12 increases vitamin concentrations and reduces homocysteine concentrations: a randomized trial. The effect of folic acid supplementation on plasma homocysteine in an elderly population. Homocysteine-lowering vitamins do not lower plasma S-adenosylhomocysteine in older people with elevated homocysteine concentrations. The content of docosahexaenoic acid in serum phospholipid is inversely correlated with plasma homocysteine levels in patients with end-stage renal disease. Effects of B vitamins and omega 3 fatty acids on cardiovascular diseases: a randomised placebo controlled trial Randomized trial of folic acid for prevention of cardiovascular events in end-stage renal disease. Plasma homocysteine levels and mortality in patients with coronary artery disease. Methionine synthase D919G polymorphism is a significant but modest determinant of circulating homocysteine concentrations. Homocysteine lowering with folic acid supplements in children: Effects on blood pressure Use of Framingham risk score and new biomarkers to predict cardiovascular mortality in older people: population based observational cohort study Effect of dietary patterns on serum homocysteine: results of a randomized, controlled feeding study. [The assessment of the influence of natural coffee and its modified form on the level of homocysteine, vitamin B6 and folic acid in healthy volunteers]. The SU.FOL.OM3 Study: a secondary prevention trial testing the impact of supplementation with folate and B-vitamins and/or Omega-3 PUFA on fatal and non fatal cardiovascular events, design, methods and participants characteristics Serum Homocysteine and Long-Term Risk of Myocardial Infarction and Sudden Death in Patients with Coronary Heart Disease Serum Total Homocysteine Concentrations in the Third National Health and Nutrition Examination Survey (19911994): Population Reference Ranges and Contribution of Vitamin Status to High Serum Concentrations Homocysteine and cognitive performance in the Framingham offspring study: age is important. Aged garlic extract supplemented with B vitamins, folic acid and L-arginine retards the progression of subclinical atherosclerosis: a randomized clinical trial. Homocysteine lowering effect of different multivitamin preparations in patients with end-stage renal disease. Hormone Replacement Therapy Does Not Affect Plasma Homocysteine in Postmenopausal Women with Coronary Artery Disease Effect of multivitamin supplementation
on the homocysteine and methylmalonic
acid blood concentrations in women
over the age of 60 years Multivitamin/mineral supplementation improves plasma B-vitamin status and homocysteine concentration in healthy older adults consuming a folate-fortified diet. Secondary prevention with folic acid: effects on clinical outcomes. Effect of short-term folate and vitamin B supplementation on blood homocysteine level and carotid artery wall thickness in chronic hemodialysis patients. Prospective study of coronary heart disease incidence in relation to fasting total homocysteine, related genetic polymorphisms, and B vitamins: the Atherosclerosis Risk in Communities (ARIC) study. VITATOPS, the VITAmins TO Prevent Stroke Trial: Rationale and Design of a Randomised Trial of B-Vitamin Therapy in Patients with Recent Transient Ischaemic Attack or Stroke (NCT00097669) (ISRCTN74743444) Risk stratification and prognostic implication of plasma biomarkers in nondiabetic patients with stable coronary artery disease: the role of high-sensitivity C-reactive protein. The effect of homocysteine-lowering with B-vitamins on osteoporotic fractures in patients with cerebrovascular disease: substudy of VITATOPS, a randomised placebo-controlled trial Efficacy of multivitamin supplementation containing vitamins B6 and B12 and folic acid as adjunctive treatment with a cholinesterase inhibitor in Alzheimer's disease: a 26-week, randomized, double-blind, placebo-controlled study in Taiwanese patients. Mesna as a nonvitamin intervention to lower plasma total homocysteine concentration: implications for assessment of the homocysteine theory of atherosclerosis. Total homocysteine is associated with nephropathy in non-insulin-dependent diabetes mellitus. Metformin increases total serum homocysteine levels in non-diabetic male patients with coronary heart disease. Hyperhomocysteinaemia: a significant risk factor for cardiovascular disease in renal transplant recipients. B vitamins in patients with recent transient ischaemic attack or stroke in the VITAmins TO Prevent Stroke (VITATOPS) trial: a randomised, double-blind, parallel, placebo-controlled trial The responsiveness of plasma homocysteine to small increases in dietary folic acid: a primary care study Homocysteine-Lowering by B Vitamins Slows the Rate of Accelerated Brain Atrophy in Mild Cognitive Impairment: A Randomized Controlled Trial Cardiovascular effects of milk enriched with omega-3 polyunsaturated fatty acids, oleic acid, folic acid, and vitamins E and B6 in volunteers with mild hyperlipidemia. Endothelial Dysfunction, Oxidative Stress, and Risk of Cardiovascular Events in Patients With Coronary Artery Disease
Background — Kidney transplant recipients , like other patients with chronic kidney disease , experience excess risk of cardiovascular disease and elevated total homocysteine concentrations . Observational studies of patients with chronic kidney disease suggest increased homocysteine is a risk factor for cardiovascular disease . The impact of lowering total homocysteine levels in kidney transplant recipients is unknown . Methods and Results — In a double-blind controlled trial , we r and omized 4110 stable kidney transplant recipients to a multivitamin that included either a high dose ( n=2056 ) or low dose ( n=2054 ) of folic acid , vitamin B6 , and vitamin B12 to determine whether decreasing total homocysteine concentrations reduced the rate of the primary composite arteriosclerotic cardiovascular disease outcome ( myocardial infa rct ion , stroke , cardiovascular disease death , resuscitated sudden death , coronary artery or renal artery revascularization , lower-extremity arterial disease , carotid endarterectomy or angioplasty , or abdominal aortic aneurysm repair ) . Mean follow-up was 4.0 years . Treatment with the high-dose multivitamin reduced homocysteine but did not reduce the rates of the primary outcome ( n=547 total events ; hazards ratio [ 95 confidence interval]=0.99 [ 0.84 to 1.17 ] ) , secondary outcomes of all-cause mortality ( n=431 deaths ; 1.04 [ 0.86 to 1.26 ] ) , or dialysis-dependent kidney failure ( n=343 events ; 1.15 [ 0.93 to 1.43 ] ) compared to the low-dose multivitamin . Conclusions — Treatment with a high-dose folic acid , B6 , and B12 multivitamin in kidney transplant recipients did not reduce a composite cardiovascular disease outcome , all-cause mortality , or dialysis-dependent kidney failure despite significant reduction in homocysteine level . Clinical Trial Registration — http://www . clinical trials.gov . Unique identifier : NCT00064753 BACKGROUND In observational studies , lower homocysteine levels are associated with lower rates of coronary heart disease and stroke . Folic acid and vitamins B6 and B12 lower homocysteine levels . We assessed whether supplementation reduced the risk of major cardiovascular events in patients with vascular disease . METHODS We r and omly assigned 5522 patients 55 years of age or older who had vascular disease or diabetes to daily treatment either with the combination of 2.5 mg of folic acid , 50 mg of vitamin B6 , and 1 mg of vitamin B12 or with placebo for an average of five years . The primary outcome was a composite of death from cardiovascular causes , myocardial infa rct ion , and stroke . RESULTS Mean plasma homocysteine levels decreased by 2.4 micromol per liter ( 0.3 mg per liter ) in the active-treatment group and increased by 0.8 micromol per liter ( 0.1 mg per liter ) in the placebo group . Primary outcome events occurred in 519 patients ( 18.8 percent ) assigned to active therapy and 547 ( 19.8 percent ) assigned to placebo ( relative risk , 0.95 ; 95 percent confidence interval , 0.84 to 1.07 ; P=0.41 ) . As compared with placebo , active treatment did not significantly decrease the risk of death from cardiovascular causes ( relative risk , 0.96 ; 95 percent confidence interval , 0.81 to 1.13 ) , myocardial infa rct ion ( relative risk , 0.98 ; 95 percent confidence interval , 0.85 to 1.14 ) , or any of the secondary outcomes . Fewer patients assigned to active treatment than to placebo had a stroke ( relative risk , 0.75 ; 95 percent confidence interval , 0.59 to 0.97 ) . More patients in the active-treatment group were hospitalized for unstable angina ( relative risk , 1.24 ; 95 percent confidence interval , 1.04 to 1.49 ) . CONCLUSIONS Supplements combining folic acid and vitamins B6 and B12 did not reduce the risk of major cardiovascular events in patients with vascular disease . ( Clinical Trials.gov number , NCT00106886 ; Current Controlled Trials number , IS RCT N14017017 . ) BACKGROUND Epidemiological studies suggest that mild to moderate elevation in plasma homocysteine concentration is associated with increased risk of atherothrombotic cardiovascular ( CV ) disease . Simple , inexpensive and nontoxic therapy with folic acid and vitamins B6 and B12 reduces plasma homocysteine levels by approximately 25 % to 30 % and may reduce CV events . Therefore , a large , r and omized clinical trial -- the Heart Outcomes Prevention Evaluation (HOPE)-2 study --is being conducted to evaluate this therapy in patients at high risk for CV events . OBJECTIVES To evaluate whether long-term therapy with folic acid and vitamins B6 and B12 reduces the risk of major CV events in a high-risk population . The primary study outcome is the composite of death from CV causes , myocardial infa rct ion and stroke . METHODS A total of 5522 patients aged 55 years or older with pre-existing CV disease or with diabetes and additional risk factor(s ) at 145 centres in 13 countries were r and omly assigned to daily therapy with combined folic acid 2.5 mg , vitamin B6 50 mg and vitamin B12 1 mg , or to placebo . Follow-up will average five years , to be completed by the end of 2005 . RESULTS The patients ' baseline characteristics confirmed their high-risk status . Baseline homocysteine levels varied between countries and regions . HOPE-2 is one of the largest trials of folate and vitamins B6 and B12 and is expected to significantly contribute to the evaluation of the role of homocysteine lowering in CV prevention BACKGROUND Homocysteine is a risk factor for cardiovascular disease . We evaluated the efficacy of homocysteine-lowering treatment with B vitamins for secondary prevention in patients who had had an acute myocardial infa rct ion . METHODS The trial included 3749 men and women who had had an acute myocardial infa rct ion within seven days before r and omization . Patients were r and omly assigned , in a two-by-two factorial design , to receive one of the following four daily treatments : 0.8 mg of folic acid , 0.4 mg of vitamin B12 , and 40 mg of vitamin B6 ; 0.8 mg of folic acid and 0.4 mg of vitamin B12 ; 40 mg of vitamin B6 ; or placebo . The primary end point during a median follow-up of 40 months was a composite of recurrent myocardial infa rct ion , stroke , and sudden death attributed to coronary artery disease . RESULTS The mean total homocysteine level was lowered by 27 percent among patients given folic acid plus vitamin B12 , but such treatment had no significant effect on the primary end point ( risk ratio , 1.08 ; 95 percent confidence interval , 0.93 to 1.25 ; P=0.31 ) . Also , treatment with vitamin B6 was not associated with any significant benefit with regard to the primary end point ( relative risk of the primary end point , 1.14 ; 95 percent confidence interval , 0.98 to 1.32 ; P=0.09 ) . In the group given folic acid , vitamin B12 , and vitamin B6 , there was a trend toward an increased risk ( relative risk , 1.22 ; 95 percent confidence interval , 1.00 to 1.50 ; P=0.05 ) . CONCLUSIONS Treatment with B vitamins did not lower the risk of recurrent cardiovascular disease after acute myocardial infa rct ion . A harmful effect from combined B vitamin treatment was suggested . Such treatment should therefore not be recommended . ( Clinical Trials.gov number , NCT00266487 . ) Rationale Epidemiological studies suggest that elevated homocysteine is linked to stroke and heart disease . However , the results of lowering homocysteine levels in reducing the risk of stroke recurrence are controversial . Aims The study aims to evaluate whether homocysteine-lowering therapy with folic acid and vitamins B6 and B12 reduces recurrent stroke events and other combined incidence of recurrent vascular events and vascular death in ischemic stroke patients of low folate regions . Design This is a multicenter , r and omized , double-blinded , placebo-controlled trial . Patients ( n = 8000 , α = 0·05 , β = 0·10 ) within one-month of ischemic stroke ( large-artery atherosclerosis or small-vessel occlusion ) or hypertensive intracerebral haemorrhage with plasma homocysteine level ⩾15 μmol/l will be enrolled . Eligible patients will be r and omized by a web-based , r and om allocation system to receive multivitamins ( folic acid 0·8 mg , vitamin B610 mg , and vitamin B12 500 μg ) or matching placebo daily with a median follow-up of three-years . Study Outcomes Patients will be evaluated at six monthly intervals . The primary outcome event is the composite event ‘ stroke , myocardial infa rct ion , or death from any vascular cause ’ , whichever occurs first . Secondary outcome measures include nonvascular death , transient ischemic attack , depression , dementia , unstable angina , revascularization procedures of the coronary , and cerebral and peripheral circulations . Discussion This is the first multicenter r and omized trial of secondary prevention for ischemic stroke in a Chinese population with a higher homocysteine level but without folate food fortification BACKGROUND Elevated plasma homocysteine levels are reported to be associated with higher rates of vascular diseases . Plasma homocysteine increases in chronic kidney disease ( CKD ) and could contribute to the increased cardiovascular risk in CKD . METHODS Participants aged 55 years or older with CKD , defined as estimated GFR<60 ml/min and at high cardiovascular risk , were r and omly assigned to the combination of folic acid , 2.5 mg , vitamin B6 , 50 mg and vitamin B12 , 1 mg ( n = 307 ) or placebo ( n = 312 ) daily for 5 years . The primary outcome was a composite of death from cardiovascular causes , myocardial infa rct ion and stroke . RESULTS Mean baseline plasma homocysteine was 15.9 + /- 7.3 micromol/l in the active treatment group and 15.7 + /- 5.7 micromol/l in placebo group and decreased to 11.9 + /- 3.3 micromol/l ( P < 0.001 ) on active treatment ( 15.5 + /- 4.5 on placebo ) . Primary outcome events occurred in 90 participants ( 29.3 % ) on active therapy and in 80 ( 25.6 % ) on placebo ( relative risk , 1.19 ; 95 % confidence interval , 0.88 - 1.61 ; P = 0.25 ) . There were no significant treatment benefits on death from cardiovascular causes ( 1.24 ; 0.84 - 1.83 ) , myocardial infa rct ion ( 1.10 ; 0.76 - 1.61 ) and stroke ( 1.00 ; 0.54 - 1.85 ) . More participants in the active treatment group were hospitalized for heart failure ( 1.98 ; 1.21 - 3.26 ; P = 0.007 ) and for unstable angina ( 1.70 ; 1.02 - 2.83 ; P = 0.04 ) . Incidence of primary outcome increased with decreasing GFR . CONCLUSIONS Active treatment with B vitamins lowered homocysteine levels  in participants with CKD but did not reduce cardiovascular risk Background — In observational studies , hyperhomocysteinemia has been found to be a risk factor for total mortality and cardiovascular events in patients with end-stage renal disease . These patients have grossly elevated homocysteine levels that can be lowered by supplementation with folic acid and vitamin B12 . We conducted a r and omized clinical trial with B vitamins to reduce homocysteine levels and therefore cardiovascular events and total mortality . Methods and Results — This r and omized , double-blind multicenter study was conducted in 33 dialysis centers in north and east Germany between July 2002 and July 2008 . We r and omly assigned 650 patients with end-stage renal disease who were undergoing hemodialysis to 2 postdialysis treatments : 5 mg folic acid , 50 & mgr;g vitamin B12 , and 20 mg vitamin B6 ( active treatment ) or 0.2 mg folic acid , 4 & mgr;g vitamin B12 , and 1.0 mg vitamin B6 ( placebo ) given 3 times per week for an average of 2 years . The primary outcome was total mortality ; the secondary outcome was fatal and nonfatal cardiovascular events . The primary outcome occurred in 102 patients ( 31 % ) receiving the active treatment and in 92 ( 28 % ) receiving placebo ( hazard ratio , 1.13 ; 95 % confidence interval , 0.85 to 1.50 ; P=0.51 ) . The secondary outcome occurred in 83 patients ( 25 % ) receiving the active treatment and in 98 ( 30 % ) receiving placebo ( hazard ratio , 0.80 ; 95 % confidence interval , 0.60 to 1.07 ; P=0.13 ) . Conclusions — Increased intake of folic acid , vitamin B12 , and vitamin B6 did not reduce total mortality and had no significant effect on the risk of cardiovascular events in patients with end-stage renal disease . Clinical Trial Registration — URL : www.anzctr.org.au . Unique identifier : ACTRN12609000911291 . URL : www.cochrane-renal.org . Unique identifier : CRG010600027 BACKGROUND Cardiovascular disease is the most important cause of morbidity and mortality in hemodialysis patients . These patients frequently have hyperhomocysteinemia , a putative risk factor for cardiovascular disease . Treatment with folate , B6 and B12 partially reduces hyperhomocysteinemia . We conducted a long-term study to evaluate whether 15 mg is more effective than 5 mg oral folic acid as a daily dosage to decrease hyperhomocysteinemia , and to assess whether homocysteine-lowering treatment reduces the risk of cardiovascular disease in hemodialysis patients . MATERIAL / METHODS In a 1-year prospect i ve r and omised trial , 81 chronic hemodialysis patients , matched for age , gender and dialytic age , were divided into three groups : 30 untreated patients , 26 patients receiving 5 mg per day , and 25 patients receiving 15 mg per day . RESULTS There was a significant reduction in hyperhomocysteinemia over time in treated patients as compared to untreated , but there were no significant differences between the two treated groups . Only 12 % of the treated patients reached normal total homocysteine plasma levels . We observed a trend towards a significant difference in survival rate in cardiovascular morbidity between treated and untreated patients . Furthermore , hemodialysis patients with new vascular events showed higher homocysteine levels than patients without events . CONCLUSIONS High-dose folic acid treatment did not improve outcome in hyperhomocysteinemia , and 88 % of treated patients maintained higher than normal homocysteine levels . There was a trend towards a decreased rate of cardiovascular events in treated participants as compared to untreated ones CONTEXT Individuals with elevated levels of homocysteine tend to have higher prevalence of cardiovascular disease . However , prospect i ve studies of homocysteine are inconsistent and data among women are limited . OBJECTIVE To determine whether elevated homocysteine levels in healthy postmenopausal women predict risk of developing cardiovascular disease . DESIGN Prospect i ve , nested case-control study with a mean 3-year follow-up . SETTING The Women 's Health Study , an ongoing US primary prevention trial initiated in 1993 . PARTICIPANTS From a total cohort of 28,263 postmenopausal women with no history of cardiovascular disease or cancer at baseline , 122 women who subsequently experienced cardiovascular events were defined as cases , and 244 age- and smoking status-matched women who remained free of disease during follow-up were defined as controls . MAIN OUTCOME MEASURES Incidence of death due to cardiovascular disease , nonfatal myocardial infa rct ion ( MI ) , stroke , percutaneous transluminal coronary angioplasty , or coronary artery bypass graft by baseline homocysteine level . RESULTS Of the 122 cases , there were 85 events of MI or stroke and 37 coronary revascularizations . Case subjects had significantly higher baseline homocysteine levels than controls ( 14.1 vs 12.4 micromol/L ; P = .02 ) . Subjects with homocysteine levels in the highest quartile had a 2-fold increase in risk of any cardiovascular event ( relative risk [ RR ] , 2.0 ; 95 % confidence interval [ CI ] , 1.1 - 3.8 ) . This effect was largely due to an excess of cases with high levels of homocysteine ; the RR for those with homocysteine levels at or higher than the 95th percentile ( 20.7 micromol/L ) was 2.6 ( 95 % CI , 1.1 - 5.7 ) . Risk estimates were independent of traditional risk factors and were greatest for the end points of MI and stroke ( RR for those with baseline homocysteine levels in the top quartile , 2.2 ; 95 % CI , 1.1 - 4.6 ) . Self-reported multivitamin supplement use at study entry was associated with significantly reduced levels of homocysteine ( P<.001 ) . However , the association between increasing quartile of homocysteine level and risk of MI or stroke remained significant in analyses controlling for baseline multivitamin supplement use ( P = .003 for trend ) , and subgroup analyses limited to women who were ( P = .02 for trend ) or were not ( P = .04 for trend ) taking multivitamin supplements . CONCLUSIONS Among healthy postmenopausal US women , elevated levels of homocysteine moderately increased the risk of future cardiovascular disease . Whether lowering the homocysteine level reduces risk of cardiovascular events requires testing in r and omized controlled trials Homocysteinemia is a risk factor for cardiovascular diseases . Folic acid combined with vitamins B6 and B12 is effective in lowering homocysteine levels . This r and omized placebo-controlled study was design ed to determine the effect of a folic acid-based supplement on secondary prevention of clinical events in non-ST-segment elevation acute coronary syndromes . The study comprised 240 patients with either unstable angina or non-ST-elevation myocardial infa rct ion in the previous 2 weeks who were r and omized to a folate group ( n = 116 ) or a placebo group ( n = 124 ) . The folate group received 1 mg folic acid , 400 μg vitamin B12 , and 10 mg vitamin B6 daily . Clinical outcomes within 6 months were assessed . The composite endpoint of death , nonfatal acute coronary syndrome , and serious re-hospitalization was significantly higher in the folate group ; serious re-hospitalization alone was significantly higher in this group . Advanced age and diabetes increased susceptibility to the composite outcome . Folic acid-based supplementation is not beneficial and may even be harmful in the secondary prevention of cardiovascular events in patients with unstable angina and non-ST-elevation myocardial infa rct ion . Further studies on the safety of such supplements are suggested . Controlled Clinical Trials Registry no. IS RCT N30249553 Context In observational studies , elevated plasma homocysteine levels were associated with venous thromboembolism . A multicenter trial of folic acid and B vitamins to reduce cardiovascular events investigated the effect of homocysteine lowering on venous thromboembolism . Contribution In this trial , 5522 adults were r and omly assigned to receive placebo , or folic acid and vitamins B6 and B12 daily for 5 years . Vitamin therapy decreased homocysteine levels , but the incidence of venous thromboembolism was the same in both groups , even in participants with the highest levels of homocysteine . Caution Venous thromboembolism events were not central ly adjudicated . Implication Decreasing homocysteine levels with supplements containing folic acid and vitamins B6 and B12 does not reduce the incidence of venous thromboembolism . The Editors Observational studies have found an association between elevated total plasma homocysteine levels and venous thromboembolism ( 14 ) . Homocysteine is thought to promote thrombosis through enhanced platelet activation , increased thrombin generation , and impaired fibrinolysis and by causing endothelial dysfunction ( 5 ) . Although homocysteine levels can be decreased by 25 % by using a supplement of folic acid and vitamins B6 and B12 ( 6 ) , whether the risk for venous thromboembolism is reduced as a result is not known . The Heart Outcomes Prevention Evaluation 2 ( HOPE-2 ) evaluated the effect of homocysteine-lowering therapy on the risk for major vascular arterial disease ( 7 ) . In conjunction with the trial , we collected data prospect ively to determine whether decreasing homocysteine levels would reduce the occurrence of symptomatic venous thromboembolism . Methods Design The design of HOPE-2 , a large r and omized , placebo-controlled clinical trial , is described elsewhere ( 7 , 8) . Soon after HOPE-2 began , a decision was made to include venous thromboembolism as a study outcome . A diagnosis of venous thromboembolism was based on prespecified , accepted criteria ( 7 ) . An independent data and safety monitoring board evaluated the safety of the participants and the overall quality and scientific integrity of HOPE-2 . The research ethics review board of each participating center approved the trial , and all participants provided written informed consent . Participants The HOPE-2 included 5522 participants 55 years of age or older who had a history of coronary , cerebrovascular , or peripheral vascular disease ; diabetes mellitus ; and at least 1 additional risk factor for cardiovascular disease , regardless of baseline homocysteine level ( 7 , 8) . Persons taking daily vitamin supplementation that contained more than 0.2 mg of folic acid were excluded . A history of venous thromboembolism or the presence or absence of risk factors for venous thromboembolism did not affect eligibility . A complete list of inclusion and exclusion criteria appears elsewhere ( 7 , 8) . Data on all persons who were enrolled in HOPE-2 are included in the current report . Centers Individuals were recruited from 145 centers in 13 countries , including Canada ( n= 3568 ) , the United States ( n= 414 ) , Brazil ( n= 265 ) , western European countries ( n= 426 ) , and Slovakia ( n= 849 ) . Intervention and R and omization Between January 2000 and December 2000 , participants were r and omly assigned to receive a once-daily supplement containing 2.5 mg of folic acid , 50 mg of vitamin B6 , and 1 mg of vitamin B12 , or matching placebo . R and omization was computer generated , with a block size of 4 ; was stratified by clinical center ; and was performed by having clinical centers call an automated central ized system . Information about block size and whether it was r and om or fixed was kept confidential for all study investigators . The r and omization sequence was concealed , and all study personnel and study participants were masked to treatment allocation . The vitamin and placebo pill formulations were indistinguishable by size , color , weight , taste , or dissolution in water . Changes in blood levels of folate , vitamins B6 and B12 , and homocysteine , which are affected by the study intervention , are not commonly measured in clinical practice , and the results of any such measurements that were performed as part of the study were kept confidential . No request was made to unmask treatment allocation for a participant . Baseline Measurements and Follow-up Baseline demographic data ; medical history ; and medication use , including current anticoagulant therapy , were recorded for all participants at study entry . History of venous thromboembolism was not documented . Baseline homocysteine levels were obtained in 3306 r and omly selected participants ( 60 % of total ) who had fasted overnight . Stratified r and om sampling was used to achieve proportional representation of a subset of participants in countries with folic acid food fortification ( Canada and the United States ) and countries without this st and ard ( all other countries with participating centers ) . Homocysteine was measured by using a fluorescence polarization immunoassay ( Abbott IMx , Abbott Laboratories , Abbott Park , Illinois ) . The distribution of homocysteine was statistically significantly skewed ; thus , these measures were log-transformed and inverse transformations were used to generate geometric mean values . The first evaluation for venous thromboembolism occurred 18 months after r and omization ; at this visit , all participants were assessed for any venous thromboembolism event arising between trial entry and the 18-month visit . Thereafter , venous thromboembolism was assessed routinely every 6 months , to an average follow-up of 5 years . The trial used simple case report forms , which were faxed toll-free to the study coordinating office and were entered into a data base by using optical character recognition ( Data Fax , Clinical Data Fax Systems , Hamilton , Ontario , Canada ) . The data base was fit for quality control assessment s and statistical analyses . At each 6-month interval , participants were assessed in the study clinics . These assessment s were directed primarily to ascertain study end points . Side effects were also evaluated , and adherence to treatment was assessed by interview and pill count . When in-person visits were not possible , participants were contacted by telephone . Outcomes The primary outcome in our study was symptomatic venous thromboembolism , which included deep venous thrombosis or pulmonary embolism ( or both ) . In the original HOPE-2 report ( 8) , venous thromboembolism was included under other outcomes . Diagnosis of deep venous thrombosis required confirmation with duplex leg ultrasonography or venography . Diagnosis of pulmonary embolism required confirmation with ventilationperfusion lung scanning , computed tomographic pulmonary angiography , or conventional pulmonary angiography . When diagnostic testing had indeterminate results or was not done , which rarely occurred , we required oral anticoagulant therapy to be initiated at the same time that new-onset venous thromboembolism was recorded on the case report form . A maximum of 1 episode of venous thromboembolism per participant was counted during follow-up . We subcategorized episodes as unprovoked venous thromboembolism if they occurred in participants who did not have cancer at baseline and occurred 90 days or more after a lower limb fracture or 30 days or more after a hospitalization . We ascertained all events with concealment to r and omization for study participants and assessors . Statistical Analysis Our primary analysis was a comparison of the incidence of venous thromboembolism in the 2 study groups . We prespecified secondary analyses and included comparisons between the groups of rates of venous thromboembolism ( including unprovoked events ) according to subgroups and strata ( Figure 1 ) . Figure 1 . Risk for venous thromboembolism ( VTE ) in prespecified subgroups . We used an intention-to-treat analysis to compare the effect of homocysteine-lowering therapy with that of placebo on the subsequent development of venous thromboembolism . We conducted the time-to-event analysis by using a Cox proportional hazards regression model and expressed unadjusted risk as hazard ratios and 95 % CIs . We examined the proportional hazards assumption by fitting the models with the interaction terms between time and treatment . We estimated a survival curve according to the KaplanMeier procedure and compared treatment groups by using a log-rank test . At each interval clinic visit , follow-up was greater than 99 % . In the rare circumstance that an individual could not be assessed at a clinic visit and could not be contacted by telephone , we considered the individual to be free of venous thromboembolism at that point . Individuals who were lost to follow-up were censored at the time of last contact . The original HOPE-2 was design ed to recruit 5000 participants , with a mean of 5 years of follow-up , to detect a relative risk reduction of 17 % to 20 % and a statistical power of 80 % and 90 % in the primary composite outcome of cardiovascular death , myocardial infa rct ion , and stroke , given an annual event rate of 4 % in the placebo group and a 2-sided P value of 0.05 . We did not estimate a formal sample size . A 2-sided P value less than 0.05 was considered significant for all analyses , which we performed by using SAS , version 9.1 ( SAS Institute , Inc. , Cary , North Carolina ) . Role of the Funding Sources The study was funded by the Canadian Institutes of Health Research and Jamieson Laboratories . The funding sources had no role in the design , conduct , or reporting of the study or in the decision to su bmi t the manuscript for publication . Results Study Participants and Homocysteine Levels Of the 5522 study participants , 2758 were r and omly assigned to receive homocysteine-lowering therapy and 2764 were assigned to receive placebo ( Table 1 ) . A total of 3982 participants ( 72 % ) were from Canada and the United States , where universal food fortification with folic acid was in place before the start of the trial . Adherence to Background and Purpose — Elevated total homocysteine is associated with a higher risk of cerebrovascular disease . It is not known whether lowering homocysteine impacts on stroke risk , both in terms of severity and ischemic vs hemorrhagic stroke subtypes . Our aim was to determine whether vitamin therapy reduces the risk of ischemic and hemorrhagic stroke , as well as stroke-related disability . Methods — We analyzed stroke outcomes among participants of the Heart Outcomes Prevention Evaluation 2 ( HOPE 2 ) trial that r and omized 5522 adults with known cardiovascular disease to a daily combination of 2.5 mg of folic acid , 50 mg of vitamin B6 , and 1 mg of vitamin B12 , or matching placebo  , for 5 years . Results — Among 5522 participants , stroke occurred in 258 ( 4.7 % ) individuals during a mean of 5 years of follow-up . The geometric mean homocysteine concentration decreased by 2.2 & mgr;mol/L in the vitamin therapy group and increased by 0.80 & mgr;mol/L in the placebo group . The incidence rate of stroke was 0.88 per 100 person-years in the vitamin therapy group and 1.15 per 100 person-years in the placebo group ( hazard ratio [ HR ] , 0.75 ; 95 % CI , 0.59–0.97 ) . Vitamin therapy also reduced the risk of nonfatal stroke ( HR , 0.72 ; 95 % CI , 0.54–0.95 ) but did not impact on neurological deficit at 24 hours ( P=0.45 ) or functional dependence at discharge or at 7 days ( OR , 0.95 ; 95 % CI , 0.57–1.56 ) . In subgroup analysis , patients aged younger than 69 years , from regions without folic acid food fortification , with higher baseline cholesterol and homocysteine levels , and those not receiving antiplatelet or lipid-lowering drugs at enrollment had a larger treatment benefit . Conclusions — Lowering of homocysteine with folic acid and vitamins B6 and B12 did reduce the risk of overall stroke , but not stroke severity or disability BACKGROUND Objectives : Elevated plasma total homocysteine ( tHcy ) is associated with increased risk of cardiovascular disease , stroke and dementia . Results of clinical trials using B-vitamins to reduce the cognitive risks attributed to tHcy have been inconsistent . The high prevalence of both hyperhomocysteinemia and cognitive impairment among kidney transplant recipients makes them an important population in which to evaluate the effect of lowering homocysteine on cognitive function . We therefore evaluated whether B-vitamin therapy to lower tHcy would prevent cognitive-decline in a cohort of stable kidney transplant recipients . DESIGN The study was a longitudinal ancillary of the FAVORIT trial , a r and omized , placebo-controlled multi-site trial of high-dose B vitamins to reduce cardiovascular and cerebrovascular events in clinical ly stable kidney transplant recipients with elevated tHcy . PARTICIPANTS 584 participants from 18 sites across North America . INTERVENTION The intervention consisted of a daily multivitamin containing high-doses of folate ( 5.0 mg ) , vitamin B12 ( 1.0 mg ) and vitamin B6 ( 50 mg ) . The placebo consisted of a daily multi-vitamin containing no folate and recommended daily allowances of vitamins B12 and B6 ( 0 mg folate ; 2.0 µg vitamin B12 ; 1.4 mg vitamin B6 ) . MEASUREMENTS Annual neuropsychological assessment for up to 5 years ( mean 3.3 years ) using a st and ardized test battery . Efficacy was analyzed on an intention-to-treat basis using end-of-trial data . Subgroup analyses included stratification for baseline plasma B-vitamin and tHcy concentrations . RESULTS At baseline , cognitive impairment was common with 61 % of participants falling more than one st and ard deviation below published norms for at least one cognitive test . Fewer than 1 % of participants had insufficient plasma folate < 5 ng/ml or vitamin B12 < 148 pmol/L. However , 44.6 % had plasma B6 concentrations < 30 nmol/L. At follow-up , processing speed and memory scores were modestly but significantly better in the B-vitamin supplement group than in controls ( p≤0.05 ) . There was no interaction between baseline tHcy , B-vitamin status and treatment on the cognitive outcomes . CONCLUSIONS High-dose B-vitamin supplementation provided modest cognitive benefit for kidney transplant recipients with elevated baseline tHcy . Since nearly all participants were folate and vitamin B12 sufficient at baseline , the potential cognitive benefits of folate and B12 supplementation in individuals with poor B-vitamin status remains to be determined CONTEXT Recent r and omized trials among patients with preexisting cardiovascular disease ( CVD ) have failed to support benefits of B-vitamin supplementation on cardiovascular risk . Observational data suggest benefits may be greater among women , yet women have been underrepresented in published r and omized trials . OBJECTIVE To test whether a combination of folic acid , vitamin B6 , and vitamin B12 lowers risk of CVD among high-risk women with and without CVD . DESIGN , SETTING , AND PARTICIPANTS Within an ongoing r and omized trial of antioxidant vitamins , 5442 women who were US health professionals aged 42 years or older , with either a history of CVD or 3 or more coronary risk factors , were enrolled in a r and omized , double-blind , placebo-controlled trial to receive a combination pill containing folic acid , vitamin B6 , and vitamin B12 or a matching placebo , and were treated for 7.3 years from April 1998 through July 2005 . INTERVENTION Daily intake of a combination pill of 2.5 mg of folic acid , 50 mg of vitamin B6 , and 1 mg of vitamin B12 . MAIN OUTCOME MEASURES A composite outcome of myocardial infa rct ion , stroke , coronary revascularization , or CVD mortality . RESULTS Compared with placebo , a total of 796 women experienced a confirmed CVD event ( 406 in the active group and 390 in the placebo group ) . Patients receiving active vitamin treatment had similar risk for the composite CVD primary end point ( 226.9/10,000 person-years vs 219.2/10,000 person-years for the active vs placebo group ; relative risk [ RR ] , 1.03 ; 95 % confidence interval [ CI ] , 0.90 - 1.19 ; P = .65 ) , as well as for the secondary outcomes including myocardial infa rct ion ( 34.5/10,000 person-years vs 39.5/10,000 person-years ; RR , 0.87 ; 95 % CI , 0.63 - 1.22 ; P = .42 ) , stroke ( 41.9/10,000 person-years vs 36.8/10,000 person-years ; RR , 1.14 ; 95 % CI , 0.82 - 1.57 ; P = .44 ) , and CVD mortality ( 50.3/10,000 person-years vs 49.6/10,000 person-years ; RR , 1.01 ; 95 % CI , 0.76 - 1.35 ; P = .93 ) . In a blood sub study , geometric mean plasma homocysteine level was decreased by 18.5 % ( 95 % CI , 12.5%-24.1 % ; P < .001 ) in the active group ( n = 150 ) over that observed in the placebo group ( n = 150 ) , for a difference of 2.27 micromol/L ( 95 % CI , 1.54 - 2.96 micromol/L ) . CONCLUSION After 7.3 years of treatment and follow-up , a combination pill of folic acid , vitamin B6 , and vitamin B12 did not reduce a combined end point of total cardiovascular events among high-risk women , despite significant homocysteine lowering . TRIAL REGISTRATION clinical trials.gov Identifier : NCT00000541 Background and Purpose — Epidemiological and laboratory studies suggest that increasing concentrations of plasma homocysteine ( total homocysteine [ tHcy ] ) accelerate cardiovascular disease by promoting vascular inflammation , endothelial dysfunction , and hypercoagulability . Methods — We conducted a r and omized controlled trial in 285 patients with recent transient ischemic attack or stroke to examine the effect of lowering tHcy with folic acid 2 mg , vitamin B12 0.5 mg , and vitamin B6 25 mg compared with placebo on laboratory markers of vascular inflammation , endothelial dysfunction , and hypercoagulability . Results — At 6 months after r and omization , there was no significant difference in blood concentrations of markers of vascular inflammation ( high-sensitivity C-reactive protein [ P=0.32 ] ; soluble CD40L [ P=0.33 ] ; IL-6 [ P=0.77 ] ) , endothelial dysfunction ( vascular cell adhesion molecule-1 [ P=0.27 ] ; intercellular adhesion molecule-1 [ P=0.08 ] ; von Willebr and factor [ P=0.92 ] ) , and hypercoagulability ( P-selectin [ P=0.33 ] ; prothrombin fragment 1 and 2 [ P=0.81 ] ; D-dimer [ P=0.88 ] ) among patients assigned vitamin therapy compared with placebo despite a 3.7-&mgr;mol/L ( 95 % CI , 2.7 to 4.7 ) reduction in total homocysteine ( tHcy ) . Conclusions — Lowering tHcy by 3.7 & mgr;mol/L with folic acid-based multivitamin therapy does not significantly reduce blood concentrations of the biomarkers of inflammation , endothelial dysfunction , or hypercoagulability measured in our study . The possible explanations for our findings are : ( 1 ) these biomarkers are not sensitive to the effects of lowering tHcy ( eg , multiple risk factor interventions may be required ) ; ( 2 ) elevated tHcy causes cardiovascular disease by mechanisms other than the biomarkers measured ; or ( 3 ) elevated tHcy is a noncausal marker of increased vascular risk BACKGROUND Little evidence exists on the role of homocysteine as a predictor of mortality in patients with type 2 diabetes . The aim of this study was to investigate whether elevated plasma homocysteine levels are independently associated with all-cause or cardiovascular mortality in patients with type 2 diabetes and coronary artery disease . METHODS This is a prospect i ve cohort study that included 507 patients with type 2 diabetes and angiographically proven coronary artery disease . Patients were divided into 2 groups according to homocysteine level above or below median value ( 12.4 micromol/L ) : the high homocysteine group ( 255 patients ) and the low homocysteine group ( 252 patients ) . The primary end-point of the study was all-cause mortality . RESULTS There were 103 deaths during a 4-year follow-up : 62 deaths in the high homocysteine group and 41 deaths in the low homocysteine group ( Kaplan-Meier estimates of mortality 25.6 % and 17.4 % , respectively ( odds ratio [ OR ] 1.53 , 95 % confidence interval [ CI ] 1.03 - 2.27 , P=0.031 ) . Sixty-two of 103 deaths ( 60.2 % ) were of cardiovascular origin : 37 deaths ( 14.5 % ) occurred in the high homocysteine group and 25 deaths ( 9.9 % ) occurred in the low homocysteine group ( P=0.115 ) . Cox proportional hazards model showed that plasma homocysteine was not an independent correlate of all-cause ( adjusted hazard ratio [ HR ] 1.10 , 95 % CI 0.89 - 1.33 ; P=0.397 for 5 micromol/L increase in concentration ) or cardiovascular ( adjusted HR 1.04 , 95 % CI 0.80 - 1.36 , P=0.753 , for 5 micromol/L increase in concentration ) mortality . CONCLUSION In patients with type 2 diabetes and coronary artery disease , elevated level of homocysteine is an associate of increased cardiovascular risk but not an independent predictor of cardiovascular mortality OBJECTIVE Homocysteinemia may play an etiologic role in the pathogenesis of type 2 diabetes by promoting oxidative stress , systemic inflammation , and endothelial dysfunction . We investigated whether homocysteine-lowering treatment by B vitamin supplementation prevents the risk of type 2 diabetes . RESEARCH DESIGN AND METHODS The Women 's Antioxidant and Folic Acid Cardiovascular Study ( WAFACS ) , a r and omized , double-blind , placebo-controlled trial of 5,442 female health professionals aged ≥40 years with a history of cardiovascular disease ( CVD ) or three or more CVD risk factors , included 4,252 women free of diabetes at baseline . Participants were r and omly assigned to either an active treatment group ( daily intake of a combination pill of 2.5 mg folic acid , 50 mg vitamin B6 , and 1 mg vitamin B12 ) or to the placebo group . RESULTS During a median follow-up of 7.3 years , 504 women had an incident diagnosis of type 2 diabetes . Overall , there was no significant difference between the active treatment group and the placebo group in diabetes risk ( relative risk 0.94 [ 95 % CI 0.79–1.11 ] ; P = 0.46 ) , despite significant lowering of homocysteine levels . Also , there was no evidence for effect modifications by baseline intakes of dietary folate , vitamin B6 , and vitamin B12 . In a sensitivity analysis , the null result remained for women compliant with their study pills ( 0.92 [ 0.76–1.10 ] ; P = 0.36 ) . CONCLUSIONS Lowering homocysteine levels by daily supplementation with folic acid and vitamins B6 and B12 did not reduce the risk of developing type 2 diabetes among women at high risk for CVD BACKGROUND Plasma homocysteine is elevated in patients with end-stage renal disease ( ESRD ) and is a risk factor for cardiovascular disease . Folic acid has been shown to partially reduce homocysteine levels in dialysis patients . It is not known whether vitamin B12 reduces homocysteine independent of folic acid in patients who are not vitamin B12 deficient . AIM To determine whether 1 mg vitamin B12 lowers homocysteine in stable , chronic , haemodialysis patients independent of folic acid . METHODS Twenty-eight haemodialysis patients were r and omized to receive three doses of 1 mg vitamin B12 or 1 mL saline placebo in a double-blind fashion at 1-month intervals . Fasting plasma total homocysteine , folic acid , red-cell folate , vitamin B12 and haemoglobin levels were determined prior to each dose and 4 weeks after the final injection . The study was powered to detect a 30 % reduction in homocysteine over the 3 months . RESULTS Both the two groups were well matched with respect to total homocysteine levels , folic acid , red-cell folate and vitamin B12 levels . Serum vitamin B12 levels were significantly higher in the treatment group compared to placebo ( 217.7 pmol/L ; 95 % confidence interval ( CI ) 103.0 - 332.5 ; P < 0.001 ) at the end of the trial but homocysteine levels were not significantly different ( 3.08 micromol/L ; 95 % CI -4.44 - 10.61 ; P= 0.406 ) . CONCLUSIONS The administration of intramuscular vitamin B12 over a 3-month period does not result in any reduction of plasma homocysteine levels in haemo-dialysis patients independent of folate status , however reductions of < 30 % can not be excluded by the present study . High-dose folic acid remains the treatment of choice in reducing homocysteine , but whether this results in a reduction in cardiovascular events remains to be determined CONTEXT Observational studies have reported associations between circulating total homocysteine concentration and risk of cardiovascular disease . Oral administration of folic acid and vitamin B(12 ) can lower plasma total homocysteine levels . OBJECTIVE To assess the effect of treatment with folic acid and vitamin B(12 ) and the effect of treatment with vitamin B(6 ) as secondary prevention in patients with coronary artery disease or aortic valve stenosis . DESIGN , SETTING , AND PARTICIPANTS R and omized , double-blind controlled trial conducted in the 2 university hospitals in western Norway in 1999 - 2006 . A total of 3096 adult participants undergoing coronary angiography ( 20.5 % female ; mean age , 61.7 years ) were r and omized . At baseline , 59.3 % had double- or triple-vessel disease , 83.7 % had stable angina pectoris , and 14.9 % had acute coronary syndromes . INTERVENTIONS Using a 2 x 2 factorial design , participants were r and omly assigned to 1 of 4 groups receiving daily oral treatment with folic acid , 0.8 mg , plus vitamin B(12 ) , 0.4 mg , plus vitamin B(6 ) , 40 mg ( n = 772 ) ; folic acid plus vitamin B(12 ) ( n = 772 ) ; vitamin B(6 ) alone ( n = 772 ) ; or placebo ( n = 780 ) . MAIN OUTCOME MEASURES The primary end point was a composite of all-cause death , nonfatal acute myocardial infa rct ion , acute hospitalization for unstable angina pectoris , and nonfatal thromboembolic stroke . RESULTS Mean plasma total homocysteine concentration was reduced by 30 % after 1 year of treatment in the groups receiving folic acid and vitamin B(12 ) . The trial was terminated early because of concern among participants due to preliminary results from a contemporaneous Norwegian trial suggesting adverse effects from the intervention . During a median 38 months of follow-up , the primary end point was experienced by a total of 422 participants ( 13.7 % ) : 219 participants ( 14.2 % ) receiving folic acid/vitamin B(12 ) vs 203 ( 13.1 % ) not receiving such treatment ( hazard ratio , 1.09 ; 95 % confidence interval , 0.90 - 1.32 ; P = .36 ) and 200 participants ( 13.0 % ) receiving vitamin B(6 ) vs 222 ( 14.3 % ) not receiving vitamin B(6 ) ( hazard ratio , 0.90 ; 95 % confidence interval , 0.74 - 1.09 ; P = .28 ) . CONCLUSIONS This trial did not find an effect of treatment with folic acid/vitamin B(12 ) or vitamin B(6 ) on total mortality or cardiovascular events . Our findings do not support the use of B vitamins as secondary prevention in patients with coronary artery disease . TRIAL REGISTRATION clinical trials.gov Identifier : NCT00354081 OBJECTIVES To investigate the relationship between plasma folate , vitamin B12 and total homocysteine concentrations ,  dietary intake of folate and vitamins B12 , B6 and B2  , and the  risk of first acute myocardial infa rct ion ( MI ) .  DESIGN Nested case-referent study with up to 13 years of follow-up . SETTING The population -based Northern Sweden Health and Disease Study , with 73 879 participants at the time of case ascertainment . SUBJECTS A total of 571 MI cases ( 406 men ) and 1569 matched referents . Of the cases , 530 had plasma sample s available , and 247 had dietary B-vitamin intake data . RESULTS Plasma concentrations of folate were inversely associated , and total homocysteine positively associated , with the risk of MI , independently of each other and of a number of established and novel cardiovascular risk factors , including renal function [ multivariate odds ratio for highest vs. lowest quintile of folate 0.52 ( 95 % CI 0.31 - 0.84 ) , P for trend = 0.036 , and homocysteine 1.92 ( 95 % CI 1.20 - 3.09 ) , P for trend = 0.006 ] . For plasma vitamin B12 concentrations , and vitamin B12 , B6 and B2 intake , no clear risk relationship was apparent . Though not statistically significant , the results for folate intake were consistent with those for plasma concentrations . CONCLUSIONS In this large prospect i ve study of a population without m and atory folic acid fortification , both folate and homocysteine were strongly associated with the risk of myocardial infa rct ion , independently of each other and of renal function . Although r and omized trials of folic acid supplementation are needed to determine causality , our findings highlight the potential importance of folate , or sources of folate , in incident cardiovascular disease CONTEXT Blood homocysteine levels are positively associated with cardiovascular disease , but it is uncertain whether the association is causal . OBJECTIVE To assess the effects of reducing homocysteine levels with folic acid and vitamin B(12 ) on vascular and nonvascular outcomes . DESIGN , SETTING , AND PATIENTS Double-blind r and omized controlled trial of 12,064 survivors of myocardial infa rct ion in secondary care hospitals in the United Kingdom between 1998 and 2008 . INTERVENTIONS 2 mg folic acid plus 1 mg vitamin B(12 ) daily vs matching placebo . MAIN OUTCOME MEASURES First major vascular event , defined as major coronary event ( coronary death , myocardial infa rct ion , or coronary revascularization ) , fatal or nonfatal stroke , or noncoronary revascularization . RESULTS Allocation to the study vitamins reduced homocysteine by a mean of 3.8 micromol/L ( 28 % ) . During 6.7 years of follow-up , major vascular events occurred in 1537 of 6033 participants ( 25.5 % ) allocated folic acid plus vitamin B(12 ) vs 1493 of 6031 participants ( 24.8 % ) allocated placebo ( risk ratio [ RR ] , 1.04 ; 95 % confidence interval [ CI ] , 0.97 - 1.12 ; P = .28 ) . There were no apparent effects on major coronary events ( vitamins , 1229 [ 20.4 % ] , vs placebo , 1185 [ 19.6 % ] ; RR , 1.05 ; 95 % CI , 0.97 - 1.13 ) , stroke ( vitamins , 269 [ 4.5 % ] , vs placebo , 265 [ 4.4 % ] ; RR , 1.02 ; 95 % CI , 0.86 - 1.21 ) , or noncoronary revascularizations ( vitamins , 178 [ 3.0 % ] , vs placebo , 152 [ 2.5 % ] ; RR , 1.18 ; 95 % CI , 0.95 - 1.46 ) . Nor were there significant differences in the numbers of deaths attributed to vascular causes ( vitamins , 578 [ 9.6 % ] , vs placebo , 559 [ 9.3 % ] ) or nonvascular causes ( vitamins , 405 [ 6.7 % ] , vs placebo , 392 [ 6.5 % ] ) or in the incidence of any cancer ( vitamins , 678 [ 11.2 % ] , vs placebo , 639 [ 10.6 % ] ) . CONCLUSION Substantial long-term reductions in blood homocysteine levels with folic acid and vitamin B(12 ) supplementation did not have beneficial effects on vascular outcomes but were also not associated with adverse effects on cancer incidence . TRIAL REGISTRATION is rct n.org Identifier : IS RCT N74348595 Increased blood homocysteine is a potentially modifiable risk factor for cardiovascular disease . In a recent meta analysis of individual participant data from prospect i ve epidemiologic studies , a 25 % lower homocysteine concentration was associated with an 11 % lower risk for ischemic heart disease and a 19 % lower risk for stroke ( 1 ) . Blood homocysteine is easily lowered by folic acid supplementation , and several large-scale r and omized trials are currently underway to assess the effects of homocysteine-lowering vitamin supplements on the risk of vascular disease . If such trials demonstrate benefit , there will be increasing interest in homocysteine determinations to assess vascular disease risk . In addition , further large-scale epidemiologic studies may be required to investigate the association between homocysteine and cardiovascular disease in a wider range of population s. These would be facilitated by simple and cost-effective methods for blood collection and analysis . One of the chief constraints in homocysteine measurements is the continuing production and release of homocysteine by red blood cells after venipuncture , which causes an artificial increase in plasma concentration of ∼10 % per hour (2)(3 ) . It has been recommended , therefore , that blood sample s for homocysteine measurements be drawn into tubes containing EDTA , chilled , or placed on ice immediately after collection and that the plasma be separated from the red cells within 1 h. Such procedures can be difficult to implement in large-scale epidemiologic studies or other situations in which sample s have to be collected remotely ( e.g. , in multiple clinics or in people ’s homes ) and transported to a central laboratory . Use of NaF or acidic citrate has been advocated for stabilization of homocysteine in whole blood at ambient temperature OBJECTIVES A high level of total homocysteine ( tHcy ) is a risk marker for cardiovascular disease ( CVD ) , and is related to inflammation . We wanted to test the effect of homocysteine-lowering B-vitamin therapy , as used in the Western Norway B-vitamin Intervention Trial ( WENBIT ) , on inflammatory markers associated with atherosclerosis . DESIGN Single centre , prospect i ve double-blind clinical interventional study , r and omised in a 2 x 2 factorial design . SUBJECTS AND METHODS Ninety patients ( 21 female ) with suspected coronary artery disease ( CAD ) , aged 38 - 80 years , were blindly r and omised into one of four groups of daily oral treatment with ( A ) folic acid ( 0.8 mg)/vitamin B12 ( 0.4 mg)/vitamin B6 ( 40 mg ) , ( B ) folic acid/vitamin B12 , ( C ) vitamin B6 alone or ( D ) placebo . Blood sample s were collected before and after 6 months of treatment . RESULTS Before intervention , median levels of the analytes were : tHcy 11.0 micromol L(-1 ) , neopterin 8.1 nmol L(-1 ) , soluble CD40 lig and ( sCD40L ) 3.9 ng mL(-1 ) , interleukin (IL)-6 1.9 pg mL(-1 ) , C-reactive protein ( CRP ) 1.9 mg L(-1 ) and low-density lipoprotein ( LDL ) cholesterol 3.3 mmol L(-1 ) . tHcy was significantly associated with neopterin ( r = 0.49 , P < 0.001 ) and with IL-6 ( r = 0.29 , P = 0.01 ) , but not with CRP or sCD40L . Neither treatment with folic acid/B12 nor with B6 induced significant changes in any of these inflammatory biomarkers ( P > or= 0.14 ) . In patients receiving folic acid/B12 ( groups A and B ) , tHcy was reduced with 33 % ( P < 0.001 ) . CONCLUSIONS In patients with stable CAD , homocysteine-lowering therapy with B-vitamins does not affect levels of inflammatory markers associated with atherogenesis . Failure to reverse inflammatory processes , may partly explain the negative results in clinical secondary B-vitamin intervention trials Background Plasma concentration of total homocysteine is associated with risk of cardiovascular disease in epidemiological studies . We wanted to examine the effects of B-vitamin therapy , which may lower total homocysteine , on coronary flow and vascular function in patients with established coronary artery disease ( CAD ) . Methods Forty patients with stable CAD , mean ( st and ard deviation ) aged 57.8 ( 9.0 ) years , recruited into the Western Norway B-Vitamin Intervention Trial , were r and omly assigned to daily oral treatment with 0.8 mg of folic acid and 0.4 mg of vitamin B12 or placebo , and 40 mg of vitamin B6 or placebo , using a 2 × 2 factorial design . At baseline , and after 9 and 24 months , coronary blood flow was assessed by coronary angiography and Doppler flow-wire measurements during intracoronary infusion of saline ( basal ) , incremental doses of acetylcholine , adenosine , and nitroglycerin . Results We found a significant increase in basal ( P<0.02 ) and adenosine-induced ( P<0.05 ) coronary blood flow in patients who received folic acid/vitamin B12 for 24 months , compared with placebo or vitamin B6 alone . Folic acid/vitamin B12 or vitamin B6 treatment did not change endothelial-dependent response after acetylcholine infusion or flow-dependent proximal dilatation in response to adenosine-induced maximal hyperemia ( P≥0.45 ) . Conclusion Long-term treatment with a combination of folic acid and vitamin B12  increase basal and adenosine-induced maximal coronary blood flow . This may reflect improved microvascular function in patients with stable CAD BACKGROUND Retrospective and case-control studies show that hyperhomocysteinemia is an independent risk factor for atherosclerosis in patients with end-stage renal disease . We studied prospect ively the association between total homocysteine and cardiovascular outcomes . METHODS AND RESULTS In all , 167 patients ( 93 men , 74 women ; mean age , 56.3+/-14.7 years ) were followed for a mean duration of 17.4+/-6.4 months .  Cardiovascular events and causes of mortality were related to total homocysteine values and other cardiovascular risk factors . Cox regression analysis was used to identify the independent predictors for cardiovascular events and mortality . Fifty-five patients ( 33 % ) developed cardiovascular events and 31 ( 19 % ) died , 12 ( 8 % ) of cardiovascular causes . Total plasma homocysteine values ranged between 7.9 and 315.0 micromol/L. Levels were higher in patients who had cardiovascular events or died of cardiovascular causes ( 43.0+/-48.6 versus 26.9+/-14.9 micromol/L , P=.02 ) . The relative risk ( RR ) for cardiovascular events , including death , increased 1 % per micromol/L increase in total homocysteine concentration ( RR , 1.01 ; CI , 1.00 to 1.01 ; P=.01 ) . CONCLUSIONS These prospect i ve observations confirm that hyperhomocysteinemia is an independent risk factor for cardiovascular morbidity and mortality in end-stage renal disease , with an increased RR of 1 % per micromol/L increase in total homocysteine concentration . Interventional studies are needed to evaluate the possible effects of modifying this risk factor in these patients CONTEXT Plasma homocysteine level has been recognized as an important cardiovascular risk factor that predicts adverse cardiac events in patients with established coronary atherosclerosis and influences restenosis rate after percutaneous coronary intervention . OBJECTIVE To evaluate the effect of homocysteine-lowering therapy on clinical outcome after percutaneous coronary intervention . DESIGN , SETTING , AND PARTICIPANTS R and omized , double-blind placebo-controlled trial involving 553 patients referred to the University Hospital in Bern , Switzerl and , from May 1998 to April 1999 and enrolled after successful angioplasty of at least 1 significant coronary stenosis ( > or = 50 % ) . INTERVENTION Participants were r and omly assigned to receive a combination of folic acid ( 1 mg/d ) , vitamin B12 ( cyanocobalamin , 400 micro g/d ) , and vitamin B6 ( pyridoxine hydrochloride , 10 mg/d ) ( n = 272 ) or placebo ( n = 281 ) for 6 months . MAIN OUTCOME MEASURE Composite end point of major adverse events defined as death , nonfatal myocardial infa rct ion , and need for repeat revascularization , evaluated at 6 months and 1 year . RESULTS After a mean ( SD ) follow-up of 11 ( 3 ) months , the composite end point was significantly lower at 1 year in patients treated with homocysteine-lowering therapy ( 15.4 % vs 22.8 % ; relative risk [ RR ] , 0.68 ; 95 % confidence interval [ CI ] , 0.48 - 0.96 ; P = .03 ) , primarily due to a reduced rate of target lesion revascularization ( 9.9 % vs 16.0 % ; RR , 0.62 ; 95 % CI , 0.40 - 0.97 ; P = .03 ) . A nonsignificant trend was seen toward fewer deaths ( 1.5 % vs 2.8 % ; RR , 0.54 ; 95 % CI , 0.16 - 1.70 ; P = .27 ) and nonfatal myocardial infa rct ions ( 2.6 % vs 4.3 % ; RR , 0.60 ; 95 % CI , 0.24 - 1.51 ; P = .27 ) with homocysteine-lowering therapy . These findings remained unchanged after adjustment for potential confounders . CONCLUSION Homocysteine-lowering therapy with folic acid , vitamin B12 , and vitamin B6 significantly decreases the incidence of major adverse events after percutaneous coronary intervention OBJECTIVES The purpose of this study was to determine whether lowering homocysteine levels with folic acid , with or without antioxidants , will improve endothelial dysfunction in patients with coronary artery disease ( CAD ) . BACKGROUND Elevated plasma homocysteine levels are a risk factor for atherosclerosis . Homocysteine may promote atherogenesis through endothelial dysfunction and oxidative stress . METHODS In a double-blind , placebo-controlled , r and omized trial , we used vascular ultrasound to assess the effect of folic acid alone or with antioxidants on brachial artery endothelium-dependent flow-mediated dilation ( FMD ) .  Seventy-five patients with CAD ( screening homocysteine level > or = 9 micromol/liter ) were r and omized equally to one of three groups : placebo , folic acid alone or folic acid plus antioxidant vitamins C and E. Patients were treated for four months . Plasma folate , homocysteine , FMD and nitroglycerin-mediated dilation were measured before and after four months of treatment . RESULTS Plasma folate , homocysteine and FMD were unchanged in the placebo group . Compared with placebo , folic acid alone increased plasma folate by 475 % ( p < 0.001 ) , reduced plasma homocysteine by 11 % ( p = 0.23 ) and significantly improved FMD from 3.2 + /- 3.6 % to 5.2 + /- 3.9 % ( p = 0.04 ) . The improvement in FMD correlated with the reduction in homocysteine ( r = 0.5 , p = 0.01 ) . Folic acid plus antioxidants increased plasma folate by 438 % ( p < 0.001 ) , reduced plasma homocysteine by 9 % ( p = 0.56 ) and insignificantly improved FMD from 2.6 + /- 2.4 % to 4.0 + /- 3.7 % ( p = 0.45 ) , as compared with placebo . Nitroglycerin-mediated dilation did not change significantly in any group . CONCLUSIONS Folic acid supplementation significantly improved endothelial dysfunction in patients with coronary atherosclerosis . Further clinical trials are required to determine whether folic acid supplementation may reduce cardiovascular events Abstract Cardiovascular disease ( CVD ) is a major cause of morbidity and mortality in developed countries . However , traditional risk factors can not fully account for this . In the last 20 years , there has been an explosion of interest in plasma total homocysteine ( tHcy ) as a potential modifiable risk factor for CVD . Recent meta-analyses of epidemiological studies support the concept that increased tHcy concentrations are associated with CVD . This has led to the ‘ homocysteine hypothesis ’ , which states that lowering plasma tHcy using folic acid and other B-vitamins will reduce the risk of CVD . In experimental studies , homocysteine has been shown to cause oxidative stress , endothelial cell dysfunction and promote thrombogenesis . However , data from recent large r and omized controlled trials have shown that there is no clinical benefit to lowering plasma tHcy concentrations with folic acid and other B-vitamins . This lack of effect of tHcy lowering strongly suggests that homocysteine is not an instigator but merely an indicator of CVD Homocysteine is a risk factor for atherosclerosis in the general population , and serum homocysteine levels are almost universally elevated in chronic renal failure patients . When such patients are treated with dialysis , cardiovascular disease accounts for more than 50 % of their mortality , which , in some proportion , may be pathophysiologically related to the elevated serum homocysteine levels . From April 2003 to March 2005 , we conducted a 2-year , double-blind , r and omized , placebo-controlled trial of 186 patients with end-stage kidney disease due to any cause , who were older than 18 years and stable on hemodialysis . Patients were assigned to receive either oral folic acid 10 mg 3 times a week immediately after every dialysis session under nurse supervision or an identical-appearing placebo for the entire study . On admission , plasma total homocysteine ( tHcy ) levels were above 13.9 micromol/L in 96.7 % of patients ( median 25.0 micromol/L , range 9.3 - 104.0 micromol/L ) . In the placebo group , tHcy levels remained elevated at 6 , 12 , and 24 months , while oral folate significantly decreased tHcy to a median value of 10.5 ( 2.8 - 20.3 ) micromol/L , ( p<0.01 ) . During the study , 38 patients ( folic acid group 17 vs. placebo group 21 ; p=0.47 ) died from cardiovascular disease . Kaplan-Meier life table analysis dealing with the incidence of cardiovascular events , both fatal and nonfatal ( myocardial infa rct ion , arrhythmias , angina , heart failure , cerebrovascular accident ) , showed that 2 years of folic acid treatment and the lowering of the homocysteine blood levels had no effect on cardiovascular events ( p=0.41 ; hazard ratio 1.24 , 95 % CI 0.74 - 2.10 ) . However , the carotid artery intima-media wall thickness measured in a blinded fashion decreased from 1.94 + /- 0.59 mm to 1.67 + /- 0.38 mm ( p<0.01 ) after 2 years of folate therapy . In this short-term study of uremic patients , 2 years of folic acid supplementation normalized the tHcy blood levels in 92.3 % of patients but did not change the incidence of cardiovascular events compared with the control group . However , ultrasonography of the common carotid arteries performed at entry and 24 months later showed a significant decrease in intima-media thickness with folate supplementation . This suggests that early folate supplementation may benefit patients with chronic renal failure by preventing cardiovascular deterioration CONTEXT High plasma homocysteine levels are a risk factor for mortality and vascular disease in observational studies of patients with chronic kidney disease .  Folic acid and B vitamins decrease homocysteine levels in this population but whether they lower mortality is unknown . OBJECTIVE To determine whether high doses of folic acid and B vitamins administered daily reduce mortality in patients with chronic kidney disease . DESIGN , SETTING , AND PARTICIPANTS Double-blind r and omized controlled trial ( 2001 - 2006 ) in 36 US Department of Veterans Affairs medical centers . Median follow-up was 3.2 years for 2056 participants aged 21 years or older with advanced chronic kidney disease ( estimated creatinine clearance < or = 30 mL/min ) ( n = 1305 ) or end-stage renal disease ( n = 751 ) and high homocysteine levels ( > or = 15 micromol/L ) . INTERVENTION Participants received a daily capsule containing 40 mg of folic acid , 100 mg of pyridoxine hydrochloride ( vitamin B6 ) , and 2 mg of cyanocobalamin ( vitamin B12 ) or a placebo . MAIN OUTCOME MEASURES The primary outcome was all-cause mortality . Secondary outcomes included myocardial infa rct ion ( MI ) , stroke , amputation of all or part of a lower extremity , a composite of these 3 plus all-cause mortality , time to initiation of dialysis , and time to thrombosis of arteriovenous access in hemodialysis patients . RESULTS Mean baseline homocysteine level was 24.0 micromol/L in the vitamin group and 24.2 micromol/L in the placebo group . It was lowered 6.3 micromol/L ( 25.8 % ; P < .001 ) in the vitamin group and 0.4 micromol/L ( 1.7 % ; P = .14 ) in the placebo group at 3 months , but there was no significant effect on mortality ( 448 vitamin group deaths vs 436 placebo group deaths ) ( hazard ratio [ HR ] , 1.04 ; 95 % CI , 0.91 - 1.18 ) . No significant effects were demonstrated for secondary outcomes or adverse events : there were 129 MIs in the vitamin group vs 150 for placebo ( HR , 0.86 ; 95 % CI , 0.67 - 1.08 ) , 37 strokes in the vitamin group vs 41 for placebo ( HR , 0.90 ; 95 % CI , 0.58 - 1.40 ) , and 60 amputations in the vitamin group vs 53 for placebo ( HR , 1.14 ; 95 % CI , 0.79 - 1.64 ) . In addition , the composite of MI , stroke , and amputations plus mortality ( P = .85 ) , time to dialysis ( P = .38 ) , and time to thrombosis in hemodialysis patients ( P = .97 ) did not differ between the vitamin and placebo groups . CONCLUSION Treatment with high doses of folic acid and B vitamins did not improve survival or reduce the incidence of vascular disease in patients with advanced chronic kidney disease or end-stage renal disease . TRIAL REGISTRATION clinical trials.gov Identifier : NCT00032435 Introduction : Hyperhomocysteinemia is an important cardiovascular risk indicator in the oldest old , and is associated with elevated arterial stiffness in this age group . Since several intervention trials reported a lack of benefit of B-vitamin supplementation on cardiovascular outcomes , we aim ed to investigate the effect of B-vitamin supplementation on arterial stiffness and atherosclerosis in hyperhomocysteinemic elderly patients . Methods : The B-PROOF study is a double-blind , r and omized controlled trial , including 2919 elderly aged at least 65 years , with hyperhomocysteinemia ( 12–50 & mgr;mol/l ) , treated with B-vitamins ( 500 & mgr;g vitamin B12 and 400 & mgr;g folic acid ) or placebo for 2 years . In a subgroup ( n = 569 ) , the effect of B-vitamins on pulse wave velocity ( PWV ) was investigated as a measurement of arterial stiffness . To measure atherosclerosis , carotid intima – media thickness ( IMT ) measures had been used . Incidents of cardiovascular and cerebrovascular events were determined via structured question naires , and blood pressure was also measured . Results : Compared to placebo , B-vitamin supplementation  lowered serum homocysteine by 3.6 & mgr;mol/l ( P < 0.001 ) . Analysis of covariance showed no effect of supplementation on PWV levels , and this was not different for patients without increased arterial stiffness at baseline . Furthermore , no effect on carotid IMT was observed . Discussion : Vitamin B12 and folic acid supplementation in hyperhomocysteinemic elderly patients have no effect on PWV or carotid IMT . Further research will still be necessary to unravel the effects and pathways of homocysteine-lowering treatment on cardiovascular outcomes Elevated homocysteine levels are associated with an increased cardiovascular disease ( CVD ) risk , but the underlying mechanism is still unclear . High homocysteine might affect the endothelium , and consequently lead to impaired haemostasis . In a r and omized placebo controlled trial among 276 older adults with plasma total homocysteine concentrations above 13 mM at screening , we investigated the effect of homocysteine lowering by folic acid supplementation ( 0.8 mg/day ) for 1 year on markers of endothelial function ( von Willebr and factor ) , coagulation ( tissue factor , factor VIIa , fragments 1 + 2 ) , and fibrinolysis ( fibrin degradation products , tissue-type plasminogen activator ) , and inflammation ( C-reactive protein ) . Despite a 24 % reduction in plasma homocysteine concentration and four-fold increase in serum folate concentration in the folic acid group compared to the placebo group , there was no clear change in any of the haemostasis markers , nor CRP . Although homocysteine is associated with vascular disease risk in the general population , marked lowering of slightly elevated homocysteine concentrations by one-year folic acid supplementation does not influence haemostasis markers Background High homocysteine blood concentrations predispose to coronary artery disease and  statins influence homocysteine levels . Aim To study whether genes that regulate homocysteine metabolism interact with statins to modify the risk of coronary heart disease ( CHD ) and other cardiovascular outcomes . Methods The Genetics of Hypertension Associated Treatment is an ancillary study of the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial ( ALLHAT ) . The genotyped population in the Lipid-Lowering Trial of Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial included 9624 participants r and omly assigned to pravastatin or to usual care . The efficacy of pravastatin in reducing risk of all-cause mortality and CHD was compared among genotype strata ( MTHFR 677 CC , CT , and TT , MTHFR 1298 AA , AC , and CC , CBSins DD and I+ ) by examining an interaction term in a proportional hazards model . Results No evidence existed of a pharmacogenetic effect on statins with the MTHFR 1298 A > C genotype for CHD risk . However , in persons with the CC variant for the MTHFR 677 C > T genotype , a significantly protective effect against CHD [ 0.71 ( 95 % CI 0.58–0.87 ) ] was shown , although in the CT [ 1.25 ( 95 % CI 0.97–1.61 ) ] and TT groups [ 0.80 ( 95 % CI 0.50–1.28 ) ] there were no such effects ( interaction hazard ratio P=0.004 ) . The CBSins , I+ variant was associated with a significantly reduced risk for CHD among those on statin treatment [ 0.58 ( 95 % CI 0.44–0.78 ) ] whereas the DD genotype showed no effect of statin therapy [ 1.01 ( 95 % CI 0.84–1.20 ; P=0.002 for interaction ] . For the endpoint all-cause mortality , no significant differences in efficacy were noted . Conclusion Polymorphisms in genes in the homocysteine pathway ( MTHFR 677 C > T and CBSins ) appear to modify the efficacy of pravastatin  in reducing risk of cardiovascular events Abstract Elevated plasma homocysteine is associated with increased cardiovascular risk but it remains unproven that the effect is directly causal . Folate and homocysteine metabolism are closely linked such that administration of folic acid in doses ranging from 0.2–10 mg/day lowers plasma total homocysteine ( tHcy ) by up to 25 % . Folic acid has been widely advocated as a therapy which may reduce cardiovascular risk , but the clinical benefit remains as yet unproven and the choice of dose remains unclear . The effect of folic acid on endothelial function has been investigated in patients with proven coronary heart disease ( CHD ) by measuring flow-mediated dilatation ( FMD ) in the brachial artery . Oral folic acid ( 5 mg/day ) markedly enhances endothelial function ( FMD ) and lowers homocysteine . Studies of the acute effects of folic acid have shown that this improvement occurs within the first 2–4 hours following the first dose , at which times there was no significant reduction in plasma tHcy . Administration of 5-methyltetrahydrofolate directly into the brachial artery markedly enhances FMD , an effect that is blocked by monomethyl arginine ( LNMMA ) , suggesting that the effects of folate are mediated by nitric oxide . This Review summarises studies which show that pharmacological doses of folate markedly enhance endothelial function in patients with CHD . The discordance with changes in plasma homocysteine suggests that these effects may occur by mechanisms distinct from homocysteine lowering The Homocysteine Study ( HOST ) Veterans Affairs Cooperative Studies Program No. 453 , is a prospect i ve , r and omized , two arm , double blind study of patients with end stage renal disease ( ESRD ) or advanced chronic kidney disease ( ACKD , defined as an estimated creatinine clearance of 30 ml/min or less ) . Its primary objective is to determine whether administration of high doses of three vitamins , folic acid , vitamin B6 and vitamin B12 , to lower the high plasma homocysteine levels , will reduce all cause mortality . The secondary objectives are to examine whether the treatment lowers the incidence of myocardial infa rct ion , stroke , amputation of a lower extremity , a composite of death and the foregoing three events , the plasma homocysteine level , and , in  ESRD patients undergoing hemodialysis , thrombosis of the vascular access . A unique feature of this trial is that after initial evaluation at enrollment and one return visit the follow up is exclusively by phone ( or , if necessary , by mail ) . The subject is contacted every three months throughout the duration of the study from a central location . The study drug is shipped to the patient from a central location rather supplied locally . In a two year enrollment period , 2006 patients are to be enrolled . The duration of the observation period is four to six years . Data will be stored and analyzed at a coordinating center . The study design has the power to detect a reduction in all cause mortality rate of 17 % . Issues related to the unique features of the design of this study are discussed BACKGROUND Patients with chronic kidney disease , including kidney transplant recipients , are at high risk for cardiovascular disease ( CVD ) . In addition to the constellation of traditional CVD risk factors in chronic kidney disease , elevated total homocysteine ( tHcy ) is notably more prevalent among the general population . The Folic Acid for Vascular Outcome Reduction In Transplantation ( FAVORIT ) trial is design ed to evaluate whether lowering tHcy using vitamin supplementation reduces CVD events in renal transplant recipients . METHODS FAVORIT is a multicenter double-blind r and omized controlled clinical trial . Participants are clinical ly stable renal transplant recipients who are 6 months or longer posttransplant with elevated tHcy . Patients are r and omized to a multivitamin that includes either a high-dose or low-dose of folic acid ( 5 or 0 mg ) , vitamin B6 ( 50 or 1.4 mg ) , and vitamin B12 ( 1000 or 2 microg ) . The primary end point is a composite of incident or recurrent CVD outcomes , that is , coronary heart , cerebrovascular , or abdominal aortic/lower extremity arterial events . A sample size of 4000 is estimated to provide 87 % power to detect a 20 % treatment effect . Recruitment is expected to continue until July 2006 , with follow-up through June 2010 . RESULTS From August 2002 through December 2004 , 2234 of the target 4000 patients were enrolled . In accordance with trial design , mean ( SD ) screening tHcy was elevated ( 17.4 + /- 6.2 micromol/L ) , and mean ( SD ) estimated creatinine clearance was consistent with stable renal function ( 58.0 + /- 18.6 mL/min ) . Evaluating baseline results to date , 42 % of the r and omized participants had a history of diabetes mellitus , and 21 % had prevalent CVD . CONCLUSIONS The FAVORIT trial is design ed with sufficient power and follow-up time to detect a clinical ly relevant change in CVD risk between renal transplant recipients receiving a high or low tHcy-lowering folic acid multivitamin . Preliminary screening and baseline data support the trial 's objectives Is it possible to prevent atrophy of key brain regions related to cognitive decline and Alzheimer ’s disease ( AD ) ? One approach is to modify nongenetic risk factors , for instance by lowering elevated plasma homocysteine using B vitamins . In an initial , r and omized controlled study on elderly subjects with increased dementia risk ( mild cognitive impairment according to 2004 Petersen criteria ) , we showed that high-dose B-vitamin treatment ( folic acid 0.8 mg , vitamin B6 20 mg , vitamin B12 0.5 mg ) slowed shrinkage of the whole brain volume over 2 y. Here , we go further by demonstrating that B-vitamin treatment reduces , by as much as seven fold , the cerebral atrophy in those gray matter ( GM ) regions specifically vulnerable to the AD process , including the medial temporal lobe . In the placebo group , higher homocysteine levels at baseline are associated with faster GM atrophy , but this deleterious effect is largely prevented by B-vitamin treatment . We additionally show that the beneficial effect of B vitamins is confined to participants with high homocysteine ( above the median , 11 µmol/L ) and that , in these participants , a causal Bayesian network analysis indicates the following chain of events : B vitamins lower homocysteine , which directly leads to a decrease in GM atrophy , thereby slowing cognitive decline . Our results show that B-vitamin supplementation can slow the atrophy of specific brain regions that are a key component of the AD process and that are associated with cognitive decline . Further B-vitamin supplementation trials focusing on elderly subjets with high homocysteine levels are warranted to see if progression to dementia can be prevented OBJECTIVES This prospect i ve study was design ed to evaluate the effect of joint determination of two important contrary biomarkers -- homocysteine and glutathione peroxidase (GPx)-1 - -on cardiovascular risk stratification . BACKGROUND Homocysteine plasma levels have been associated with cardiovascular risk . Experimental data suggest that antioxidative GPx-1 activity modulates cardiovascular risk associated with homocysteine . METHODS In 643 patients with coronary artery disease , we performed a prospect i ve study to assess the risk of homocysteine plasma levels and GPx-1 activity on long-term cardiovascular risk with a median follow-up of 7.1 years . RESULTS Both homocysteine and GPx-1 were among the strongest univariate predictors of future cardiovascular risk , even after adjustment for cardiovascular confounders . Homocysteine levels were significantly elevated in individuals with future cardiovascular events ( 15.4 vs. 13.4 micromol/l ; p < 0.0001 ) ; GPx-1 activity was lower ( 45.3 + /- 13.1 vs. 50.2 + /- 11.0 U/g hemoglobin ; p < 0.0001 ) . In patients with GPx-1 activity below the median value , homocysteine plasma levels above the median were associated with a 3.2-fold ( 95 % confidence interval 1.8 to 5.6 ; p < 0.0001 ) increase in cardiovascular risk , whereas it lost its independent risk prediction in individuals with increased antioxidative capacity , as reflected by high GPx-1 activity . In contrast to single determination , combined assessment revealed a significant increase in the area under the curve of cardiovascular risk predictive models from 0.72 , including traditional risk factors to 0.75 and also including homocysteine levels and GPx-1 activity . CONCLUSIONS Plasma homocysteine levels and GPx-1 activity are complementary in identifying individuals at high cardiovascular risk . Joint determination of both biomarkers provides substantial information on top of classic risk factors in cardiovascular risk assessment Objective The impact of homocysteine on cardiovascular disease can be more detrimental in women than in men , but it is unknown whether this applies to high-risk women . We therefore investigated the association of hyperhomocysteinemia with coronary artery disease ( CAD ) and cardiovascular mortality in high-risk women referred for CAD , both in the total population and in the hypertensive and normotensive cohorts . Design A prospect i ve study cohort . Setting A tertiary centre . Patients Inclusion criteria : 262 consecutive Caucasian postmenopausal women referred for coronary angiography .  Exclusion criteria : acute myocardial infa rct ion and vitamin supplementation . Main outcome measure(s ) We assessed  total plasma homocysteine ( tHcy ) , folate levels , and the MTHFR677C→T polymorphism . CAD was defined as a modified Duke Index score greater than 0 ; hyperhomocysteinemia as tHcy levels of 15 μmol/l or greater . The primary study outcome was cardiovascular mortality at follow-up . Results Mild/moderate and severe hyperhomocysteinemia was found in 15.1 and 1.6 % of women , respectively , without differences between CAD and non-CAD women . By the ATPIII criteria , 92.2 % of the women were in the highest risk class and 55 % had CAD ; however , no association of tHcy with the CAD score was found . After a median follow-up of 3.6 years , 23 women ( 9.1 % ) had died , 15 ( 6 % ) of cardiovascular causes . Women with high tHcy levels showed the worst all-cause and cardiovascular death-free survival at Kaplan – Meier and Cox regression analysis . Moreover , in the hypertensive cohort only women with hyperhomocysteinemia showed increased cardiovascular mortality . Conclusion Hyperhomocysteinemia is common in high-risk women and adversely affects their prognosis , although it is unrelated to the CAD atherosclerotic burden BACKGROUND Hyperhomocysteinemia is seen in most hemodialysis ( HD ) patients and is an independent risk factor for cardiovascular disease . Homocysteine metabolism via remethylation requires activated folate and vitamin B12 and metabolism via transsulfuration requires serine and vitamin B6 . Prior studies have shown highly variable effects of supplemental B vitamin and folate therapy for hyperhomocysteinemia . We undertook a fully controlled trial with abnormally high doses of folic acid alone or with supplemental vitamin B6 and B12 compared with active folate alone or with serine . METHODS Two prospect i ve studies were undertaken in hemodialysis patients . In the first study ( protocol A ) , hyperhomocysteinemia was treated in 77 patients with 30 or 60 mg folic acid with or without vitamins B6 and B12 for eight weeks and compared with matching placebos . In the second study ( protocol B ) , hyperhomocysteinemia was treated in 37 patients with intravenous folinic acid given alone or with serine and compared with matching placebos . All patients received the st and ard of care treatment with a multivitamin tablet before and throughout the protocol to test the hypothesis that additional therapy is required over and above the routine therapy for maximum reduction in total homocysteine ( tHcy ) . RESULTS Normal volunteers ; The mean ( SD ) tHcy of 128 normal subjects was 6.5 ( 4 ) micromol/L. Protocol A ; Plasma folate increased significantly in the groups given folic acid at both four and eight weeks ( P = 0.0001 at both time points ) . Plasma vitamin B12 was significantly increased at four weeks ( P = 0.0018 ) but not at eight weeks ( P = 0.064 ) in those given Vitamin B12 . However , tHcy did not differ between treatment groups at baseline ( P = 0.63 ) , four weeks ( P = 0.79 ) or eight weeks ( P = 0.74 ) . Protocol B : Plasma folate increased significantly at four weeks in those receiving folinic acid ( P = 0.0001 ) but tHcy was not significantly different between groups ( P = 0.92 ) . In neither study was there any significant change in tHcy comparing before and during any treatment intervention . CONCLUSIONS In our studies high dose oral folic acid , intravenous folinic acid , vitamins B6 and B12 and oral serine were ineffective at lowering tHcy in patients on hemodialysis when given folic acid , folinic acid serine or B vitamins in addition to routine folic acid and B vitamin supplements BACKGROUND High homocysteine and low B vitamin concentrations have been linked to the risk of vascular disease , stroke , and dementia and are relatively common in older adults . OBJECTIVE We assessed the effect of breakfast cereal fortified with folic acid , vitamin B-6 , and vitamin B-12 on vitamin and homocysteine status . DESIGN A r and omized , double-blind trial was conducted in 189 volunteers aged 50 - 85 y. The subjects had no history of hypertension , anemia , asthma , cancer , or cardiovascular or digestive disease and did not regularly consume multiple or B vitamin supplements or highly fortified breakfast cereal . Subjects were r and omly assigned to consume 1 cup ( 0.24 L ) breakfast cereal fortified with 440 microg folic acid , 1.8 mg vitamin B-6 , and 4.8 microg vitamin B-12 or placebo cereal for 12 wk . Blood was drawn at 0 , 2 , 12 , and 14 wk . Methionine-loading tests were conducted at baseline and week 14 . RESULTS Final baseline-adjusted plasma homocysteine concentrations were significantly lower and B vitamin concentrations were significantly higher in the treatment group than in the placebo group ( P < 0.001 ) . The percentage of subjects with plasma folate concentrations < 11 nmol/L decreased from 2 % to 0 % , with vitamin B-12 concentrations < 185 pmol/L from 9 % to 3 % , with vitamin B-6 concentrations < 20 nmol/L from 6 % to 2 % , and with homocysteine concentrations > 10.4 micromol/L ( women ) or > 11.4 micromol/L ( men ) from 6.4 % to 1.6 % . The percentage of control subjects with values beyond these cutoff points remained nearly constant or increased . CONCLUSIONS In this relatively healthy group of volunteers , consumption of 1 cup fortified breakfast cereal daily significantly increased B vitamin and decreased homocysteine concentrations , including post-methionine-load homocysteine concentrations BACKGROUND Increased plasma homocysteine is associated with coronary artery disease , peripheral vascular disease and venous thrombosis . Folic acid is the most effective therapy for reducing homocysteine levels . The lowest effective supplement of folic acid is not known , particularly for the elderly who have the highest prevalence of these conditions . AIM To explore the effects of daily supplements of 0 , 50 , 100 , 200 , 400 and 600 microg folic acid on plasma homocysteine in an elderly population . DESIGN R and omized double-blind placebo-controlled trial . METHODS Participants ( n=368 ) aged 65 - 75 years were r and omly allocated to receive one of the treatments for 6 weeks .  Plasma homocysteine was recorded after 3 weeks and 6 weeks of supplementation . RESULTS Only the 400 microg and 600 microg groups had significantly lower homocysteine levels compared to placebo ( p=0.038 and p<0.001 , respectively ) . Using multiple linear regression and each individual 's total folic acid intake ( diet plus supplement ) , a total daily folic acid intake of 926 microg per day would be required to ensure that 95 % of the elderly population would be without cardiovascular risk from folate deficiency . DISCUSSION A daily folic acid intake of 926 microg is unlikely to be achieved by diet alone . Individual supplementation or fortification of food with folic acid will be required to reach this target Elevated plasma total homocysteine ( tHcy ) is a risk factor for vascular disease but lowering tHcy with B-vitamins , including folate , has generally not reduced vascular events in secondary prevention trials . Elevated plasma S-adenosylhomocysteine ( AdoHcy ) concentration may be a more sensitive indicator of vascular disease than plasma tHcy . However , unlike tHcy , plasma AdoHcy did not correlate with folate concentration in one study indicating that folate supplementation may not lower AdoHcy . Our aim was to determine whether providing B-vitamin supplements to healthy older people with elevated tHcy ( > 13 micromol/l ) affects plasma AdoHcy and S-adenosylmethionine ( AdoMet ) concentrations .  Healthy older participants ( n 276 ; > or = 65 years ) were r and omised to receive a daily supplement containing folate ( 1 mg ) , vitamin B12 ( 500 microg ) and vitamin B6 ( 10 mg ) , or placebo , for 2 years . Of these participants , we selected the first fifty participants in each treatment group and measured plasma AdoHcy and AdoMet . Plasma tHcy was 4.4 ( 95 % CI 3.2 , 5.6 ; P < 0.001 ) micromol/l lower at 2 years in the vitamins group compared with the placebo group . At 2 years , there were no significant differences in plasma AdoMet ( + 4 % ( 95 % CI - 2 , 11 ) ; P = 0.19 ) , AdoHcy ( - 1 % ( 95 % CI - 10 , 8) ; P = 0.61 ) or the AdoMet : AdoHcy ratio ( 0.22 ( 95 % CI - 0.04 , 0.49 ) ; P = 0.10 ) between the two groups . In conclusion , B-vitamin supplementation of older people lowered plasma tHcy but had no effect on plasma AdoMet or AdoHcy concentration . If elevated plasma AdoHcy is detrimental , this may explain why B-vitamins have generally failed to reduce vascular events in clinical trials Patients with end-stage renal disease ( ESRD ) have a high morbidity and mortality from cardiovascular disease . An elevated homocysteine level is an independent predictor of cardiovascular events in patients with ESRD . Interestingly , some studies have found an inverse relationship between the content of marine n-3 polyunsaturated fatty acids ( PUFAs ) and homocysteine levels , but data are ambiguous . In patients with ESRD , we hypothesized that serum phospholipid n-3 PUFA content would inversely correlate with homocysteine levels in plasma and that supplementation with n-3 PUFA would reduce plasma homocysteine levels . In a double-blind , r and omized , controlled design , 206 patients with documented cardiovascular disease and treated with hemodialysis for a minimum of 6 months were r and omized to treatment with daily supplement of 1.7 g n-3 PUFA or placebo ( olive oil ) for 3 months . The content of n-3 PUFA in serum phospholipids and homocysteine levels in plasma were measured at baseline and after 3 months of intervention . A dietary question naire was filled out at baseline , and study participants were divided into groups of low , intermediate , and high fish intake . Docosahexaenoic acid was inversely correlated with homocysteine at baseline ( coefficient = -0.161 ; P = .03 ) . Homocysteine was not related to self-reported fish intake . Supplementation with n-3 PUFA  did not reduce homocysteine levels compared with placebo ( mean ± SD difference , -0.3 ± 7.8 versus 0.3 ± 7.1 ; P = .58 ) . The content of docosahexaenoic acid in serum phospholipids is inversely correlated with plasma homocysteine levels , and supplementation with n-3 PUFA does not reduce homocysteine levels in patients with ESRD Objective To investigate whether dietary supplementation with B vitamins or omega 3 fatty acids , or both , could prevent major cardiovascular events in patients with a history of ischaemic heart disease or stroke . Design Double blind , r and omised , placebo controlled trial ; factorial design . Setting Recruitment throughout France via a network of 417 cardiologists , neurologists , and other physicians . Participants 2501 patients with a history of myocardial infa rct ion , unstable angina , or ischaemic stroke . Intervention Daily dietary supplement containing 5-methyltetrahydrofolate ( 560 μg ) , vitamin B-6 ( 3 mg ) , and vitamin B-12 ( 20 μg ) or placebo ; and containing omega 3 fatty acids ( 600 mg of eicosapentanoic acid and docosahexaenoic acid at a ratio of 2:1 ) or placebo . Median duration of supplementation was 4.7 years . Main outcome measures Major cardiovascular events , defined as a composite of non-fatal myocardial infa rct ion , stroke , or death from cardiovascular disease . Results Allocation to B vitamins lowered plasma homocysteine concentrations by 19 % compared with placebo , but had no significant effects on major vascular events ( 75 v 82 patients , hazard ratio , 0.90 ( 95 % confidence interval 0.66 to 1.23 , P=0.50 ) ) . Allocation to omega 3 fatty acids  increased plasma concentrations of omega 3 fatty acids by 37 % compared with placebo , but also had no significant effect on major vascular events ( 81 v 76 patients , hazard ratio 1.08 ( 0.79 to 1.47 , P=0.64 ) ) . Conclusion This study does not support the routine use of dietary supplements containing B vitamins or omega 3 fatty acids for prevention of cardiovascular disease in people with a history of ischaemic heart disease or ischaemic stroke , at least when supplementation is introduced after the acute phase of the initial event . Trial registration Current Controlled Trials IS RCT N41926726 High serum total homocysteine ( tHcy ) is gaining scrutiny as a risk factor for cardiovascular disease in the general population . The relationship between tHcy and mortality and cardiovascular events in patients with end-stage renal disease ( ESRD ) is unsettled . This r and omized trial evaluates the efficacy of high-dose folic acid in preventing events in ESRD . A total of 510 patients on chronic dialysis were r and omized to 1 , 5 , or 15 mg of folic acid contained in a renal multivitamin with a median follow-up of 24 mo . Mortality , cardiovascular events , and homocysteine levels were assessed . There were 189  deaths  , and 121 patients experienced at least one cardiovascular event . Composite rates of mortality and cardiovascular events among the folic acid groups did not differ ( at 24 mo : 43.7 % in 1 mg group , 38.6 % in 5 mg group , 47.1 % in 15 mg group ; log-rank P = 0.47 ) . Unexpectedly , high baseline tHcy was associated with lower event rates . From lowest to highest quartile , event rates at 24 mo were 54.5 % for Q1 , 41.8 % for Q2 , 41.2 % for Q3 , and 34.7 % for Q4 ( log-rank P = 0.033 ) . In contrast to some studies describing tHcy as a risk factor for mortality and cardiovascular events , this study found a reverse relationship between tHcy and events in ESRD patients . Administration of high-dose folic acid did not affect event rates BACKGROUND Elevated plasma homocysteine levels are a risk factor for coronary heart disease , but the prognostic value of homocysteine levels in patients with established coronary artery disease has not been defined . METHODS We prospect ively investigated the relation between plasma total homocysteine levels and mortality among 587 patients with angiographically confirmed coronary artery disease . At the time of angiography in 1991 or 1992 , risk factors for coronary disease , including homocysteine levels , were evaluated . The majority of the patients subsequently underwent  coronary-artery bypass grafting  ( 318 patients ) or percutaneous transluminal coronary angioplasty ( 120 patients ) ; the remaining 149 were treated medically . RESULTS After a median follow-up of 4.6 years , 64 patients ( 10.9 percent ) had died . We found a strong , grade d relation between plasma homocysteine levels and overall mortality . After four years , 3.8 percent of patients with homocysteine levels below 9 micromol per liter had died , as compared with 24.7 percent of those with homocysteine levels of 15 micromol per liter or higher . Homocysteine levels were only weakly related to the extent of coronary artery disease but were strongly related to the history with respect to myocardial infa rct ion , the left ventricular ejection fraction , and the serum creatinine level . The relation of homocysteine levels to mortality remained strong after adjustment for these and other potential confounders . In an analysis in which the patients with homocysteine levels below 9 micromol per liter were used as the reference group , the mortality ratios were 1.9 for patients with homocysteine levels of 9.0 to 14.9 micromol per liter , 2.8 for those with levels of 15.0 to 19.9 micromol per liter , and 4.5 for those with levels of 20.0 micromol per liter or higher ( P for trend=0.02 ) . When death due to cardiovascular disease ( which occurred in 50 patients ) was used as the end point in the analysis , the relation between homocysteine levels and mortality was slightly strengthened . CONCLUSIONS Plasma total homocysteine levels are a strong predictor of mortality in patients with angiographically confirmed coronary artery disease Elevation in plasma homocysteine concentration has been associated with vascular disease and neural tube defects . Methionine synthase is a vitamin B(12)-dependent enzyme that catalyses the remethylation of homocysteine to methionine . Therefore , defects in this enzyme may result in elevated homocysteine levels . One relatively common polymorphism in the methionine synthase gene ( D919 G ) is an A to G transition at bp 2,756 , which converts an aspartic acid residue believed to be part of a helix involved in co-factor binding to a glycine . We have investigated the effect of this polymorphism on plasma homocysteine levels in a working male population ( n = 607 ) in which we previously described the relationship of the C677 T " thermolabile " methylenetetrahydrofolate reductase ( MTHFR ) polymorphism with homocysteine levels .  We found that the methionine synthase D919 G polymorphism is significantly ( P = 0.03 ) associated with homocysteine concentration , and the DD genotype contributes to a moderate increase in homocysteine levels across the homocysteine distribution ( OR = 1.58 , DD genotype in the upper half of the homocysteine distribution , P = 0.006 ) . Unlike thermolabile MTHFR , the homocysteine-elevating effects of the methionine synthase polymorphism are independent of folate and B(12 ) levels ; however , the DD genotype has a larger homocysteine-elevating effect in individuals with low B(6 ) levels . This polymorphism may , therefore , make a moderate , but significant , contribution to clinical conditions that are associated with elevated homocysteine Abstract Hyperhomocysteinemia is emerging as an independent predictor of cardiovascular disease and hypertension among children . The aim of the study was to examine the effects of oral folic acid on homocysteine and blood pressure .  Folic acid supplementation has been found to reduce homocysteine levels and in some cases blood pressure .  Five hundred and twenty children participated in the study , and 26 of them were found to be hyperhomocysteinemic ; 20 of these children r and omly received 5 mg oral folic acid supplement while the other six children were the controls . Serum homocysteine ( P < 0.001 ) levels as well as systolic ( P < 0.001 ) and diastolic ( P = 0.045 ) blood pressure were statistically significantly decreased in the intervention group compared with the controls , while folic acid levels were statistically significantly increased ( P < 0.001 ) . Total serum homocysteine levels were correlated with age , serum folate , body mass index , and blood pressure . It appears that folic acid may be a safe and effective supplement to reduce homocysteine and possibly blood pressure , which consequently may prevent cardiovascular disease in children in early life Objectives To investigate the performance of classic risk factors , and of some new biomarkers , in predicting cardiovascular mortality in very old people from the general population with no history of cardiovascular disease . Design The Leiden 85-plus Study ( 1997 - 2004 ) is an observational prospect i ve cohort study with 5 years of follow-up . Setting General population of the city of Leiden , the Netherl and s. Participants Population based sample of participants aged 85 years ( 215 women and 87 men ) with no history of cardiovascular disease ; no other exclusion criteria . Main measurements Cause specific mortality was registered during follow-up . All classic risk factors included in the Framingham risk score ( sex , systolic blood pressure , total and high density lipoprotein cholesterol , diabetes mellitus , smoking and electrocardiogram based left ventricular hypertrophy ) , as well as plasma concentrations of the new biomarkers homocysteine , folic acid , C reactive protein , and interleukin 6 , were assessed at baseline . Results During follow-up , 108 of the 302 participants  died ; 32 % ( 35/108 ) of deaths were from cardiovascular causes . Classic risk factors did not predict cardiovascular mortality when used in the Framingham risk score ( area under receiver operating characteristic curve 0.53 , 95 % confidence interval 0.42 to 0.63 ) or in a newly calibrated model ( 0.53 , 0.43 to 0.64 ) . Of the new biomarkers studied , homocysteine had most predictive power ( 0.65 , 0.55 to 0.75 ) . Entering any additional risk factor or combination of factors into the homocysteine prediction model did not increase its discriminative power . Conclusions In very old people from the general population with no history of cardiovascular disease , concentrations of homocysteine alone can accurately identify those at high risk of cardiovascular mortality , whereas classic risk factors included in the Framingham risk score do not . These preliminary findings warrant validation in a separate cohort BACKGROUND Elevated blood levels of homocysteine are associated with an increased risk of atherosclerotic cardiovascular disease . Although numerous studies have assessed the impact of vitamin supplements on homocysteine , the effect of dietary patterns on homocysteine has not been well studied . METHODS AND RESULTS During a 3-week run-in , 118 participants were fed a control diet , low in fruits , vegetables , and dairy products , with a fat content typical of US consumption . During an 8-week intervention phase , participants were then fed 1 of 3 r and omly assigned diets : the control diet , a diet rich in fruits and vegetables but otherwise similar to control , or a combination diet rich in fruits , vegetables , and low-fat dairy products and reduced in saturated and total fat . Between the end of run-in and intervention periods , mean change in homocysteine was + 0.46 micromol/L in the control diet , + 0.21 micromol/L in the fruits and vegetables diet ( P=0.47 compared with control ) , and -0.34 micromol/L in the combination diet ( P=0.03 compared with control , P=0.12 compared with the fruits and vegetables diet ) . In multivariable regression models , change in homocysteine was significantly and inversely associated with change in serum folate ( P=0.03 ) but not with change in serum vitamin B(12 ) ( P=0.64 ) or pyridoxal 5 ' phosphate , the coenzyme form of vitamin B(6 ) ( P=0.83 ) . CONCLUSIONS Modification of dietary patterns can have substantial effects on fasting levels of total serum homocysteine . These results provide additional insights into the mechanisms by which diet might influence the occurrence of atherosclerotic cardiovascular disease UNLABELLED The aim of our investigation was the assessment of the influence of natural coffee and that modified by water and pressure extraction ( 60 % less of 2-methyl isoborneol ) on the level of homocysteine , folic acid and vitamin B6 in healthy volunteers . MATERIAL AND METHODS The study was conducted on 36 healthy volunteers . 20 women and 16 men ; smokers constituted half of the group . The study was conducted as a double blind trial ( coffee without labels ) after r and omization into two groups . Initially for 4 weeks , one group drank natural coffee and the other a modified one . After four weeks there was a 28-day break in drinking coffee , after which the groups swapped roles and another trial lasted for the subsequent 4 weeks . All people examined drank three servings of coffee a day brewed from 13 g of material in 180 ml of boiling water . Throughout the entire experiment the examined subjects did not change their diets and did not take any vitamin supplements . Blood for analysis was drawn four times and the following analyses were carried out . homocysteine , folic acid , vitamin B6 total , LDL and HDL-cholesterol , triglicerides , Lp(a ) and fibrinogen . RESULTS We found a significant increase level of plasma homocysteine from 9.6 to 11.4 micromol/l ( p < 0.001 ) in persons drinking natural , unfiltered coffee .  However drinking modified coffee free from irritants result ed in a tendency towards lowering the level of homocysteine ( from 9.1 to 8.7 micromol/l ) . CONCLUSIONS From the above study it may be concluded that lowering the content of irritants in coffee results in reducing its undesired influence on the homocysteine level . Reduction of natural coffee consumption or its change on coffee with lowering the content of irritants should be recommended to cardiovascular disease persons Background During the last decades , many basic and clinical research have pointed to the role of B vitamins ( folate , vitamins B6 and B12 ) and n-3 fatty acids as nutritional factors that might have a protective effect on the development of cardiovascular diseases ( CVD ) . Methods / design The SU.FOL.OM3 ( SUpplementation with FOlate , vitamin B6 and B12 and /or OMega-3 fatty acids ) trial is a r and omized double-blind , placebo-controlled , secondary -prevention trial design ed to test the efficacy of 5-methyl tetra-hydro-folates ( 5-MTHF ) supplementation , in combination with vitamin B6 and B12 and /or n-3 fatty acids , at nutritional doses , on fatal and non fatal ischemic CVD in a 2 × 2 factorial design . A total of 2501 patients aged between 45 and 80 years who had a past history , in the previous year , of myocardial infa rct ion ( n = 1151 ) or instable angina pectoris ( n = 711 ) or an ischemic stroke ( n = 639 ) were included . Subjects have to be supplemented and followed up for five years . Daily supplementation comprised nutritional doses of 5-MTHF ( 560 μg ) , vitamin B6 ( 3 mg ) and B12 ( 20 μg ) and /or n-3 fatty acids ( 600 mg with an EPA : DHA ratio of 2:1 ) . A factorial design 2 × 2 has been applied to investigate the separate effects of the B-vitamins , and the n-3 fatty acids , as well as their interaction as compared to the placebo . The primary endpoint is a combination of myocardial infa rct ion , ischemic stroke and cardiovascular death . Secondary endpoints are events of the composite endpoint taken separately , total mortality , and other cardiovascular events such as acute coronary syndromes , coronary revascularization , cardiac failure , arrhythmia ... Conclusion Baseline socio-demographic and medical characteristics of participants are totally comparable in the four r and omized groups . Trial registration Current Controlled Trials IS RCT We have prospect ively evaluated the risk of incident coronary events in association with serum total homocysteine in patients with preexisting chronic coronary heart disease . A nested case-control design was used . Total homocysteine concentration was measured in baseline fasting serum sample s from patients with chronic coronary heart disease enrolled in the Bezafibrate Infa rct ion Prevention Study ( n = 3,090 ) who developed coronary events during 6.2 years of follow-up ( n = 69 ) . They were matched for age and gender with controls without subsequent cardiovascular events . Elevated homocysteine levels were associated with 2.5 times higher risk of subsequent coronary events and each 5 µmol/l increment was associated with a 25 % higher risk Homocysteine , a non-protein-forming sulfur amino acid , has attracted attention because elevated concentrations of circulating total homocysteine are associated with an increased risk for vascular disease ( 1 , 2 ) . Homocysteine is also a sensitive functional marker of inadequate cellular folate and vitamin B12 concentrations ( 3 ) . Inadequate status of these vitamins has important health consequences that may be independent of their role in homocysteine metabolism . Low folate concentrations increase a woman 's risk for having a baby with a neural tube defect ( 4 , 5 ) , and an inadequate vitamin B12 concentration is known to produce various neurologic and cognitive effects ( 6 , 7 ) . Persons with low circulating folate or vitamin B12 concentrations have higher fasting total homocysteine concentrations ( 8 - 10 ) , and elevated fasting total homocysteine concentrations are usually normalized by treatment with folic acid and vitamin B12 ( 6 , 11 - 14 ) . However , less is known about the importance of these vitamins as risk factors for high homocysteine concentration in the general population . Only three studies have examined the relation between homocysteine concentration and its vitamin determinants in sample s that were design ed to be representative of U.S. national ( 8) or regional ( 9 , 10 ) population s. One of these studies ( 9 ) reported that approximately two thirds of all cases of moderately elevated total homocysteine concentrations were potentially attributable to low vitamin concentrations , but estimation of the proportion of cases with high homocysteine concentrations that can be attributed to inadequate vitamin status is complicated by the lack of a st and ard definition of a high total homocysteine concentration . In the absence of a definition based on increased risk for an adverse health outcome , such as vascular disease , upper reference limits from sample s of healthy persons without established risk factors for high homocysteine concentrations have been used to define a high total homocysteine concentration ( 10 , 15 - 17 ) . We previously described the distribution of total serum homocysteine concentrations in participants 12 years of age or older from the third National Health and Nutrition Examination Survey ( NHANES III ) , a population -based sample of U.S. residents ( 18 ) . These data present a unique opportunity to develop population reference ranges for serum total homocysteine concentration and to determine the extent to which elevated homocysteine concentrations are associated with low circulating vitamin concentrations in a representative sample of U.S. residents . Methods Participants The NHANES III was developed to obtain nationally representative information on the health and nutritional status of the civilian , noninstitutionalized U.S. population ( 19 , 20 ) . Homocysteine concentrations were measured as part of an NHANES III surplus sera project on serum sample s from participants 12 years of age or older who were seen during phase II of this survey ( 19911994 ) . This project is described in greater detail elsewhere ( 18 ) . Homocysteine concentrations were measured at the Jean Mayer USDA Human Nutrition Research Center on Aging at Tufts University by using the high-performance liquid chromatography method of Araki and Sako ( 21 ) . The interassay coefficient of variation for this assay was 6 % . Folate and vitamin B12 were determined for phase 2 specimens at the Centers for Disease Control and Prevention central laboratory by using a Quanta Phase II radioassay kit ( Bio-Rad Laboratories , Hercules , California ) , and analyses are described in detail in the NHANES III Laboratory Procedures Manual ( 22 ) . The coefficients of variation for folate and vitamin B12 were 6 % and 7 % , respectively . Informed consent was obtained from all respondents . The NHANES III protocol was approved by the National Center for Health Statistics NHANES Institutional Review Board , and measurement of serum homocysteine was approved by the Human Investigations Review Committee at the New Engl and Medical Center . We used the following search strategy , combining Medical Subject Headings ( MeSH terms ) and text words , to identify all population -based studies relating vitamin status to circulating homocysteine concentrations : ( [ homocysteine ( MeSH ] OR homocysteine [ Text Word ] ) AND ( vitamins [ MeSH ] OR vitamin [ Text Word ] ] ) AND ( epidemiologic studies [ MeSH ] OR data collection [ MeSH ] OR survey [ Text Word ] ] . This search identified 137 citations , of which 16 were review s. We selected original studies that 1 ) were design ed to be representative of national , regional , or local population s and 2 ) described the relation between circulating homocysteine concentrations and either intake or circulating concentrations of folate or vitamin B12 . As of 1 March 1999 , 3 articles met our criteria ( 8 - 10 ) . Statistical Analysis We used sample weights in analyses to account for unequal probability of selection and nonresponse and to produce estimates of means and percentiles that were representative of the noninstitutionalized , civilian U.S. population . We used SUDAAN statistical software ( 23 ) to account for the complex survey design in the variance estimates . Because total homocysteine , folate , and vitamin B12 values were skewed , logarithmic transformations were applied . To show the relations between total homocysteine concentrations and vitamin concentrations , we classified participants into age- and sex-specific vitamin decile categories and estimated the geometric mean of the serum total homocysteine concentration within each decile . Analyses were adjusted for ethnicity and serum creatinine concentration . In addition , the relation between total homocysteine and folate concentrations was adjusted for vitamin B12 concentrations , and the relation between total homocysteine and vitamin B12 was adjusted for folate concentrations . We tested the associations between homocysteine and vitamins for interactions with age , sex , and ethnicity . We tested for trend of total homocysteine concentration across vitamin concentrations by using linear regression with the logarithm of the continuous vitamin concentration as the independent variable , adjusting as described above . We showed the trend by using the SYSTAT LOWESS procedure to fit smoothed curves ( 24 ) to the geometric mean total homocysteine concentrations in the vitamin decile categories ( 25 ) . It has been suggested that population reference ranges for the total homocysteine concentration be established in sample s of persons without established risk factors for a high homocysteine concentration ( 10 , 15 - 17 ) . For our reference sample , we included persons whom we assumed to be folate- and vitamin B12-replete ( that is , their serum concentrations of both vitamins were above the 50th percentile ) and had normal serum creatinine concentrations ( < 90 mol/L for women and < 110 mol/L for men ) . Pregnant women were excluded . We used the 5th and the 95th percentiles from the reference sample to estimate population reference ranges . To identify the potential impact of low vitamin concentrations on high total homocysteine concentration , we needed to establish values for high total homocysteine and low vitamin concentrations . We used the sex-specific 95th percentiles in the participants 20 to 39 years of age ( the reference sample ) to define high total homocysteine concentrations for all age groups . We used this reference sample because homocysteine concentrations changed little with age in this group , unlike in the other age groups ( 18 ) . We defined low vitamin concentrations as a folate concentration less than 11 nmol/L ( 26 , 27 ) and a vitamin B12 concentration less than 185 pmol/L ( 28 , 29 ) . We calculated the prevalence of high total homocysteine concentration ; the prevalence ratio for high total homocysteine concentration ; the attributable risk percentage ; and the population attributable risk percentage for persons with low concentrations of folate , vitamin B12 , or both compared with persons who had adequate concentrations of both of these vitamins . The attributable risk percentage estimates the excess cases of high homocysteine concentrations among persons with low vitamin concentrations , whereas the population attributable risk percentage takes into account the prevalence of low vitamin concentrations in the population and estimates the excess of high homocysteine concentrations associated with low vitamin concentrations in the entire population . We used the design effect for total homocysteine concentration , which is the ratio of the complex sampling design variance derived by using SUDAAN software ( 23 ) to the simple r and om sample variance calculated by using SAS software ( 30 ) , to determine the recommended minimum sample size needed to achieve stable estimates of means , proportions , and percentiles according to the National Center for Health Statistics analytic guidelines ( 19 ) . On the basis of an average design effect of approximately 1.4 for our sample , means and medians derived from fewer than 42 participants , 10th and 90th percentiles derived from fewer than 112 participants , and 5th and 95th percentiles derived from fewer than 224 participants were deemed unstable . Sample size for stable estimates of the proportions varied by the magnitude of the proportion , ranging from 42 for proportions of 0.5 to 224 for proportions of 0.05 or 0.95 . We indicate in the text and tables statistics that did not meet the appropriate sample size . We categorized participants into three ethnic groups : non-Hispanic white , non-Hispanic black , and Mexican American . We excluded persons from other ethnic groups ( n=436 ) because their inclusion produced unstable estimates of mean total homocysteine concentration after adjustment for ethnicity . Our analyses are based on 8086 participants with complete data on serum total homocysteine , folate , vitamin B12 , and creatinine concentrations .  Results Table 1 shows selected characteristics of the sample by sex and ethnic group . On average , non-Hispanic white Plasma total homocysteine ( tHcy ) concentrations are associated with deficits in cognitive performance in persons free from dementia . The extent to which age modifies these associations is in need of further investigation in large , community-based , prospect i ve studies combining the following elements : 1 ) multiple cognitive tests ; 2 ) statistical adjustment for the role of the vitamin cofactors folate , vitamin B6 , and vitamin B12 ; and 3 ) adjustment for the presence of risk factors for cardiovascular disease and stroke . Using data collected between 1991 and 2002 , the authors investigated the associations between tHcy and multiple measures of cognitive performance in 2,096 dementia- and stroke-free participants of the Framingham Offspring Study , who were stratified into three age groups ( 40 - 49 years , 50 - 59 years , 60 - 82 years ) , after findings of statistically significant tHcy-by-age interactions for multiple cognitive measures . Regardless of statistical adjustment for age , sex , gender , the vitamin cofactors , and cardiovascular risk factors , statistically significant inverse associations between tHcy and multiple cognitive domains were observed for individuals aged 60 or more years ; no such associations were observed for participants aged less than 60 years . Early preventive interventions may be important , because the inverse association between tHcy and cognitive performance is observed beyond middle age OBJECTIVES Previous studies demonstrated that aged garlic extract reduces multiple cardiovascular risk factors . This study was design ed to assess whether aged garlic extract therapy with supplements ( AGE+S ) favorably affects inflammatory and oxidation biomarkers , vascular function and progression of atherosclerosis as compared to placebo . METHODS In this placebo-controlled , double-blind , r and omized trial ( conducted 2005 - 2007 ) , 65 intermediate risk patients ( age 60+/-9 years , 79 % male ) were treated with a placebo capsule or a capsule containing aged garlic extract ( 250 mg ) plus Vitamin B12 ( 100 microg ) , folic acid ( 300 microg ) , Vitamin B6 ( 12.5 mg ) and l-arginine ( 100 mg ) given daily for a 1 year . All patients underwent  coronary artery calcium scanning ( CAC ) , temperature rebound ( TR ) as an index of vascular reactivity using Digital Thermal Monitoring ( DTM ) , and measurement of lipid profile , autoantibodies to malondialdehyde (MDA)-LDL , apoB-immune complexes , oxidized phospholipids ( OxPL ) on apolipoprotein B-100 ( OxPL/apoB ) , lipoprotein ( a ) [ Lp ( a ) ] , C-reactive protein ( CRP ) , homocysteine were measured at baseline and 12 months . CAC progression was defined as an increase in CAC>15 % per year and an increase in TR above baseline was considered a favorable response . RESULTS At 1 year , CAC progression was significantly lower and TR significantly higher in the AGE+S compared to the placebo group after adjustment of cardiovascular risk factors ( p<0.05 ) . Total cholesterol , LDL-C , homocysteine , IgG and IgM autoantibodies to MDA-LDL and apoB-immune complexes were decreased , whereas HDL , OxPL/apoB , and Lp ( a ) were significantly increased in AGE+S to placebo . CONCLUSION AGE+S is associated with a favorable improvement in oxidative biomarkers , vascular function , and reduced progression of atherosclerosis OBJECTIVE Hyperhomocysteinemia occurs in nearly 100 % of patients with end-stage renal disease ( ESRD ) and is associated with increased morbidity and mortality . Means to reduce elevated homocysteine concentrations is supplementation with folic acid , vitamin B6 , and vitamin B12 . However , doses of vitamins required for optimized treatment are subject of debate . Therefore , the effect of 2 different multivitamin preparations on the homocysteine concentrations in patients with ESRD were compared . DESIGN Patients received 3 times per week either 2 tablets of preparation A ( 800 microg folic acid , 6 microg vitamin B12 , 10 mg vitamin B6 ) , 2 tablets of preparation B ( 160 microg folic acid , no vitamin B12 , 10 mg vitamin B6 ) , or placebo for a period of 12 weeks with control of total homocysteine ( tHcy ) levels at baseline , and at 4 , 8 , and 12 weeks . SETTING The study was performed at the University Hospital of Magdeburg , Germany in patients with ESRD treated with chronic intermittent maintenance hemodialysis . RESULTS Preparation A reduced the tHcy concentration significantly by nearly 50 % , whereas preparation B did not change the tHcy concentration in comparison with placebo . However , tHcy was not normalized in the majority of patients receiving preparation A. CONCLUSION The reduction of tHcy achieved by a multivitamin containing 800 microg folic acid was substantial and even higher than the reduction reported in supplementation studies using higher doses of folic acid alone . Nevertheless , hyperhomocysteinemia in ESRD patients appears relatively refractory to vitamin supplementation , in contrast with results obtained in healthy volunteers Objective : The objective was to evaluate the effect of hormone replacement therapy ( HRT ) on plasma homocysteine levels in postmenopausal women with coronary artery disease ( CAD ) and to investigate associations of homocysteine to other cardiovascular risk factors . Methods : The women in this single-center , controlled , and r and omized study were examined at baseline , and after 3 and 12 months , after they had been recruited consecutively from patients referred for investigational coronary angiography . All analyses were performed examiner blind . They were r and omized to HRT consisting of transdermal application of continuous 17β-estradiol with cyclic medroxyprogesterone acetate ( MPA ) tablets for 14 days every 3rd month , or to a control group . Results : After 3 months of unopposed 17β-estradiol , no significant effect on homocysteine was observed compared to the control group . The absolute decrease of 5 % in median plasma homocysteine levels after 12-month HRT did not reach statistical significance . Plasma homocysteine seemed slightly higher in women with three- or four-vessel disease , but the difference was not significant . With increasing homocysteine levels , free tissue factor pathway inhibitor ( TFPI ) antigen increased , whereas E-selectin decreased . In women with diabetes or elevated blood glucose > 6.0 mmol/l , plasma homocysteine was correlated to body mass index , C-peptide and insulin as well as age . Conclusion : Transdermal application of 17β-estradiol and sequential MPA do not affect plasma homocysteine in women with established CAD . Plasma homocysteine is stable in women with CAD over time , and unless special intervention is undertaken , repetitive measurements are not necessary in this particular group of high-risk individuals . The circulating anticoagulant TEPI is related to plasma homocysteine Summary Background Deficiency of folic acid , vitamin B6 and /or vitamin B12 can result in elevated total plasma homocysteine concentrations ( tHcy ) , which are considered to be a risk factor for vascular disease . Studies have shown that supplementation of the three vitamins can lower tHcy even in subjects with tHcy in the normal range . Aim of the study The aim of this study was to evaluate the effect of a 6 month supplementation with vitamin B6 , B12 and folate on the concentrations of total plasma homocysteine and serum methylmalonic acid ( MMA ) of elderly women . Methods The study was design ed as a r and omized placebo controlled doubleblind trial , and 220 healthy women ( aged 60–91 years ) were involved .  The vitamin and mineral capsule contained pyridoxine ( 3.4 mg ) , folic acid ( 400 µg ) and cobalamin ( 9 µg ) in addition to other micronutrients  . Blood concentrations of folate , cobalamin , tHcy , MMA and the activity coefficient of erythrocyte alpha-aspartic aminotransferase ( alpha-EAST ) were measured at baseline and after 6 months of supplementation . Dietary intake was evaluated at the beginning and the end of the intervention by two 3–day diet records . Results Median concentrations of serum cobalamin , serum folate and erythrocyte folate increased significantly and tHcy and alpha – EAST activity ( indicative of improved status of vitamin B6 ) coefficient decreased significantly in the supplemented group . Median MMA concentration of the supplemented group was significantly lower than that of the placebo group after the intervention . The vitamin supplementation had a greater decreasing effect on the tHcy concentration of volunteers with lower vitamin and higher tHcy initial concentrations . In a linear regression model , baseline tHcy , serum folate , age and alpha – EAST activity coefficient were significantly correlated with the change in tHcy . The change in MMA in the supplement group was significantly associated to the baseline MMA values . Conclusions Our results show that a 6 month supplementation including physiological dosages of B vitamins improves the status of these nutrients and reduces tHcy in presumed healthy elderly women Elevated homocysteine has been identified as an independent risk factor for cardiovascular and cerebrovascular disease . Although multivitamin use has been associated with low plasma homocysteine concentrations in several observational studies , no clinical trials have been conducted using multivitamin/mineral supplements to lower homocysteine . We determined whether a multivitamin/mineral supplement formulated at about 100 % Daily Value will further lower homocysteine concentration and improve B-vitamin status in healthy older adults already consuming a diet fortified with folic acid . In this r and omized , double-blind , placebo-controlled trial , 80 free-living men and women aged 50 - 87 y with total plasma homocysteine concentrations of > or = 8 micromol/L received either a multivitamin/mineral supplement or placebo for 56 d while consuming their usual diet . After the 8-wk treatment , subjects taking the supplement had significantly higher B-vitamin status and lower homocysteine concentration than controls ( P : < 0.01 ) . Plasma folate , pyridoxal phosphate ( PLP ) and vitamin B-12 concentrations were increased 41.6 , 36.5 and 13.8 % , respectively , in the supplemented group , whereas no changes were observed in the placebo group . The mean homocysteine concentration decreased 9.6 % in the supplemented group ( P : < 0.001 ) and was unaffected in the placebo group . There were no significant changes in dietary intake during the intervention . Multivitamin/mineral supplementation can improve B-vitamin status and reduce plasma homocysteine concentration in older adults already consuming a folate-fortified diet OBJECTIVES We sought to conduct a r and omized trial with folic acid 0.5 mg/day in a patient population with stable coronary artery disease ( CAD ) . BACKGROUND Folic acid has favorable effects on vascular endothelium and lowers plasma homocysteine levels . In addition , homocysteine appears to be an independent risk factor for atherosclerotic disease . However , the value of folic acid in secondary prevention had seldom been tested . METHODS In this open-label study , 593 patients were included ; 300 were r and omized to folic acid and 293 served as controls .  Mean follow-up time was 24 months . At baseline all patients had been on statin therapy for a mean of 3.2 years . RESULTS In patients treated with folic acid , plasma homocysteine levels decreased by 18 % , from 12.0 + /- 4.8 to 9.4 + /- 3.5 micromol/l , whereas these levels remained unaffected in the control group ( p < 0.001 between groups ) . The primary end point ( all-cause mortality and a composite of vascular events ) was encountered in 31 ( 10.3 % ) patients in the folic acid group and in 28 ( 9.6 % ) patients in the control group ( relative risk 1.05 ; 95 % confidence interval : 0.63 to 1.75 ) . In a multifactorial survival model with adjustments for clinical factors , the most predictive laboratory parameters were , in order of significance , levels of creatinine clearance , plasma fibrinogen , and homocysteine . CONCLUSIONS Within two years , folic acid does not seem to reduce clinical end points in patients with stable coronary artery disease ( CAD ) while on statin treatment . Homocysteine might therefore merely be a modifiable marker of disease . Thus , low-dose folic acid supplementation should be treated with reservation , until more trial outcomes become available OBJECTIVE Hyperhomocysteinemia is an independent risk factor for atherosclerotic vascular disease in chronic hemodialysis patients . This stratified r and omized controlled trial was design ed to measure the effect of high dose oral vitamin B6 , vitamin B12 , and folic acid on homocysteine levels , and to evaluate the effect on atherosclerosis as measured by Intima-Media Thickness ( IMT ) of carotid arteries . MATERIAL AND METHOD Fifty-four chronic hemodialysis patients with hyperhomocysteinemia were r and omized to receive oral 15 mg folic acid , 50 mg vitamin B6 , and 1 mg vitamin B12 daily ( treatment group ) or oral 5 mg folic acid alone ( control group ) for 6 months . Homocysteine level and IMT were measured in both groups . RESULTS At 6 months , homocysteine levels in the treatment group were significantly reduced from 27.94 + /- 8.54 to 22.71 + /- 3.68 mmol/l ( p = 0.009 ) and were not significantly increased from 26.81 + /- 7.10 to 30.82 + /- 8.76 mmol/l in control group ( p = 0.08 ) . Mean difference between both groups was statistically significant ( p = 0.002 ) . There was no significant difference of IMT of carotid arteries , however , a tendency that the treatment group would have less thickness was observed ( 0.69 + /- 0.29 mm and 0.62 + /- 0.16 mm , p = 0.99 ) . CONCLUSION Treatment of hyperhomocysteinemia in chronic hemodialysis patients with daily oral 15 mg folic acid , 50 mg vitamin B6 , and 1 mg vitamin B12 for 6 months decreases homocysteine levels and tends to reduce IMT of carotid arteries . A long term study for the prevention of atherosclerosis is warranted BACKGROUND Elevated plasma total homocysteine ( tHcy ) , low B-vitamin intake , and genetic polymorphisms related to tHcy metabolism may play roles in coronary heart disease ( CHD ) . More prospect i ve studies are needed . METHODS AND RESULTS We used a prospect i ve case-cohort design to determine whether tHcy-related factors are associated with incidence of CHD over an average of 3.3 years of follow-up in a biracial sample of middle-aged men and women . Age- , race- , and field center-adjusted CHD incidence was associated positively ( P<0.05 ) with tHcy in women but not men , and CHD was associated negatively ( P<0.05 ) with plasma folate ( women only ) , plasma pyridoxal 5'-phosphate ( both sexes ) , and vitamin supplementation ( women only ) . However , after accounting for other risk factors , only plasma pyridoxal 5'-phosphate was associated with CHD incidence ; the relative risk for the highest versus lowest quintile of pyridoxal 5'-phosphate was 0.28 ( 95 % CI=0.1 to 0.7 ) . There was no association of CHD with the C677 T mutation of the methylenetetrahydrofolate reductase gene or with 3 mutations of the cystathionine beta-synthase gene . CONCLUSIONS Our prospect i ve findings add uncertainty to conclusions derived mostly from cross-sectional studies that tHcy is a major , independent , causative risk factor for CHD . Our findings point more strongly to the possibility that vitamin B6 offers independent protection . R and omized trials , some of which are under way , are needed to better clarify the interrelationships of tHcy , B vitamins  , and cardiovascular disease Background Epidemiological studies suggest that raised plasma concentrations of total homocysteine ( tHcy ) may be a common , causal and treatable risk factor for atherothromboembolic ischaemic stroke , dementia and depression . Although tHcy can be lowered effectively with small doses of folic acid , vitamin B12 and vitamin B6 , it is not known whether lowering tHcy , by means of B vitamin therapy , can prevent stroke and other major atherothromboembolic vascular events . Aim To determine whether the addition of B-vitamin supplements ( folic acid 2 mg , B6 25 mg , B12 500 μg ) to best medical and surgical management will reduce the combined incidence of stroke , myocardial infa rct ion ( MI ) and vascular death in patients with recent stroke or transient ischaemic attack ( TIA ) of the brain or eye . Design A prospect i ve , international , multicentre , r and omised , double blind , placebo-controlled clinical trial . Setting One hundred and four medical centres in 20 countries on five continents . Subjects Eight thous and ( 6600 recruited as of 5 January , 2006 ) patients with recent ( 7 months ) stroke ( ischaemic or haemorrhagic ) or TIA ( brain or eye ) . R and omisation R and omisation and data collection are performed by means of a central telephone service or secure internet site . Intervention One tablet daily of either placebo or B vitamins ( folic acid 2 mg , B6 25 mg , B12 500 μg ) . Primary outcome The composite of stroke , MI or death from any vascular cause , whichever occurs first . Outcome and serious adverse events are adjudicated blinded to treatment allocation . Secondary outcomes TIA , unstable angina , revascularisation procedures , dementia , depression . Statistical power With 8000 patients followed up for a median of 2 years and an annual incidence of the primary outcome of 8 % among patients assigned placebo , the study will have at least 80 % power to detect a relative reduction of 15 % in the incidence of the primary outcome among patients assigned B vitamins ( to 6·8%/year ) , applying a two-tailed level of significance of 5 % . Conclusion VITATOPS aims to recruit and follow-up 8000 patients between 1998 and 2008 , and provide a reliable estimate of the safety and effectiveness of folic acid , vitamin B12 , and vitamin B6 supplementation in reducing recurrent serious vascular events among a wide range of patients with TIA and stroke throughout the world STUDY OBJECTIVES To evaluate the implication of plasma biomarkers to future cardiovascular events in nondiabetic patients with stable coronary artery disease ( CAD ) . Design s and setting s : Prospect i ve , follow-up study at a tertiary referral center . Patients and measurement : Serial plasma biomarkers including high-sensitivity C-reactive protein ( hsCRP ) , homocysteine , soluble adhesion molecules , von Willebr and factor , and lipid profiles were determined before coronary angiograms in a series of nondiabetic CAD patients with stable angina . Among them , 75 consecutive patients who received coronary revascularization ( 48 coronary interventions and 27 coronary bypass surgeries ) later and another 75 age- and gender-matched patients who preferred medical treatment were both enrolled . In patients of each group , major cardiovascular events including cardiac death , nonfatal myocardial infa rct ion , new or repeated coronary revascularization , and hospitalization for unstable angina , stroke , or peripheral artery disease were prospect ively followed up for at least 6 months . RESULTS Patients were followed up to 40 months ( median , 18 months ) . The incidences of major cardiovascular events were similar between the two groups . For patients with medical treatment , plasma levels of hsCRP , homocysteine , low-density lipoprotein , and the ratio of total cholesterol ( TC ) to high-density lipoprotein cholesterol ( HDL-C ) were significantly higher in those with cardiovascular events than those without . However , only hsCRP > 0.1 mg/dL ( relative risk [ RR ] , 2.78 ; 95 % confidence interval [ CI ] , 1.21 to 6.41 ; p = 0.016 ) and TC/HDL-C ratio > 4.8 ( RR , 2.42 ; 95 % CI , 1.04 to 5.65 ; p = 0.041 ) were independent predictors by multivariable analysis . For patients with revascularization , basal plasma hsCRP levels were higher in those with cardiovascular events than those without ( p = 0.04 ) . However , no biochemical markers could predict future major cardiovascular events in these patients . CONCLUSIONS In nondiabetic patients with CAD , basal plasma hsCRP levels were increased with future cardiovascular events regardless of different treatment strategies . Both plasma hsCRP level and TC/HDL-C ratio independently predict future cardiovascular events , confirming the role of plasma biomarkers in clinical risk stratification especially in patients with medical treatment Background Homocysteine has been postulated as a novel , potentially reversible risk factor for osteoporosis and related fractures . We evaluated whether homocysteine-lowering therapy with B-vitamins in patients with symptomatic cerebrovascular disease reduced the incidence of osteoporotic fractures . Methods VITAmins To Prevent Stroke ( VITATOPS ) was a prospect i ve r and omised double-blind placebo-controlled trial in which 8,164 patients with recent ( within 7 months ) stroke or transient ischemic attack were r and omly allocated to double-blind treatment with one tablet daily of either placebo ( n = 4,075 ) or B-vitamins ( folic acid 2 mg , vitamin B6 25 mg , vitamin B12 500 μg ; n = 4,089 ) . Patients were review ed every six months . Any osteoporotic fracture and osteoporotic hip fractures were secondary outcome events , and were review ed by a masked adjudication committee . Analysis was by intention to treat . Logistic regression was used to identify independent predictors of fracture . Results Participants had a mean age of 62.6 years ( SD 12.5 years ) and 64 % were male , 42 % of Western European descent and 75 % were functionally independent ( Oxford H and icap Scale of two or less ) . After a median duration of 2.8 years therapy and 3.4 years follow-up , there was no significant difference in the incidence of any osteoporotic fracture between participants assigned B-vitamins ( 67 [ 1.64 % ] ) and placebo ( 78 [ 1.91 % ] ; risk ratio [ RR ] 0.86 , 95 % confidence interval [ CI ] 0.62 - 1.18 ) or the incidence of hip fractures ( 34 [ 0.83 % ] B-vitamins vs. 36 [ 0.88 % ] placebo ; RR 0.94 , 95 % CI 0.59 - 1.5 ) . There was no significant impact of B-vitamin therapy on time to first fracture . Baseline homocysteine levels did not predict any osteoporotic fracture ( p = 0.43 ) . Independent predictors of any osteoporotic fracture were female sex , age > 64 years , Western European ethnicity and use of anti-osteoporosis medication at r and omization ( all p < 0.01 ) . Conclusions Once daily treatment with B-vitamins had no effect on incidence of osteoporotic fractures during a median of 3.4 years follow-up in patients with cerebrovascular disease . A modest effect of B-vitamin therapy is not excluded due to the low numbers of fracture outcome events . Trial registration Clinical trials.gov number : NCT00097669 and is rct n.org number : IS RCT N74743444 BACKGROUND Elevated serum homocysteine levels have been associated with the development of Alzheimer 's dementia ( AD ) . The combined use of a mecobalamin capsule preparation , which contains vitamin B12 0.5 mg with an active methyl base , and an over-the-counter nutritional supplement that contains folic acid 1 mg and pyridoxine hyperchloride 5 mg may be effective as a homocysteine-lowering vitamin regimen . OBJECTIVE The aim of this study was to determine whether oral multivitamin supplementation containing vitamins B6 and B12 and folic acid would improve cognitive function and reduce serum homocysteine levels in patients with mild to moderate AD . METHODS This r and omized , double-blind , placebocontrolled trial was conducted at En Chu Kong Hospital , Taipei , Taiwan . Male and female patients aged > 50 years with mild to moderate AD and normal folic acid and vitamin B12 concentrations were enrolled . All patients received treatment with an acetylcholinesterase inhibitor and were r and omized to receive add-on mecobalamin ( B12 ) 500 mg + multivitamin supplement , or placebos , PO QD for 26 weeks . The multivitamin contained pyridoxine ( B6 ) 5 mg , folic acid 1 mg , and other vitamins and iron .  Serum homocysteine level was measured and cognitive tests were conducted at baseline and after 26 weeks . The primary efficacy outcome was change in cognition , measured as the change in score from baseline to week 26 on the Alzheimer 's Disease Assessment Scale 11-item Cognition subscale . Secondary efficacy outcomes included changes in function in performance of activities of daily living ( ADLs ) and concentrations of homocysteine , B12 , and folic acid . Tolerability was assessed by comparing the 2 study groups with respect to physical examination findings , including changes in vital signs , laboratory test abnormalities , concomitant medication use , and compliance of study medication was assessed using an interview with the patient 's caregiver , as well as the monitoring of adverse events ( AEs ) throughout the study . RESULTS Eighty-nine patients ( 45 men , 44 women ; all Taiwanese ; mean [ SD ] age , 75 [ 7.3 ] years ) were enrolled and r and omized . Overall , there were no significant differences in cognition or ADL function scores between the 2 groups . At week 26 , the mean ( SD ) between-group difference in serum homocysteine concentration versus placebo was -2.25 ( 2.85 ) micromol/L ( P = 0.008 ) , and the mean serum concentrations of vitamin B12 and folic acid were significantly higher ( but within normal range ) in the multivitamin group compared with placebo ( . , + 536.9 [ 694.4 ] pg/mL [ P < 0.001 ] and + 13.84 ng/mL [ 11.17 ] [ P = 0.012 ] at 26 weeks , respectively ) . The 2 most common AEs were muscle pain ( 11.1 % and 6.8 % ) and insomnia ( 8.9 % and 9.1 % ) in the multivitamin and placebo groups , respectively . CONCLUSIONS In this population of patients with mild to moderate AD in Taiwan , a multivitamin supplement containing vitamins B(6 ) and B(12 ) and folic acid for 26 weeks decreased homocysteine concentrations . No statistically significant beneficial effects on cognition or ADL function were found between multivitamin and placebo at 26 weeks Elevated plasma total homocysteine is independently associated with atherosclerosis . Recent r and omized trials show that vitamins lower total homocysteine but do not prevent cardiovascular events , suggesting the need for nonvitamin therapies to evaluate whether a causative relationship exists . Mesna ( sodium 2-mercaptoethanesulfonate ) is a thiol-containing drug capable of liberating homocysteine bound by disulfide bonds to proteins , facilitating its excretion . The effect of oral mesna on total homocysteine has not been evaluated and was the objective of this study . Eleven healthy volunteers received vehicle or 10 mg/kg mesna in r and om order , after which serial blood and urine sample s were collected over 4 hours . Plasma total homocysteine decreased by 24.2 % ( P < .0001 ) following mesna .  Urinary homocysteine excretion was significantly greater with mesna ( 3.9 + /- 2.4 mumol ) compared to vehicle ( 0.4 + /- 0.1 mumol ) , P < .01 . Oral mesna decreases plasma total homocysteine and is a potential nonvitamin treatment for assessing the homocysteine theory of atherosclerosis Non-insulin-dependent diabetes mellitus ( NIDDM ) and hyperhomocysteinemia are both associated with premature vascular disease . We tested the hypothesis that homocysteine is associated with vascular disease and other diabetic complications in patients with NIDDM . The current investigation is a cross-sectional analysis of baseline variables for participants in the Appropriate Blood Pressure Control in Diabetes ( ABCD ) Trial . Men and women aged 40 to 74 years with NIDDM and a mean diastolic blood pressure ( BP ) of 80 mm Hg or higher were eligible . We measured serum levels of total homocysteine ( tHcy ) , cystathionine , and methylmalonic acid ( MMA )  and correlated these values with clinical and other laboratory measures of the complications of diabetes mellitus in 452 subjects .  tHcy was higher in males than in females and correlated with the duration of hypertension and systolic BP . tHcy was significantly correlated with MMA ( r = .35 , P < .0001 ) and cystathionine ( r = .53 , P < .0001 ) levels and inversely correlated with serum B12 ( r = -.23 , P < .0001 ) and folate ( r = -.18 , P < .0001 ) . It was significantly correlated with serum creatinine ( r = .28 , P < .0001 for males and r = .39 , P < .0001 for females ) and inversely correlated with creatinine clearance ( r = -.19 , P < .005 for males and r = -.30 , P < .0001 for females ) . tHcy was not increased in subjects with cardiovascular disease or retinopathy , but it was increased in those with neuropathy ( 10.3 v 9.3 micromol/L , P < .05 ) and macroalbuminuria ( 11.0 v 9.2 micromol/L , P < .005 ) . Of these subjects , 2.2 % met the criteria for vitamin B12 deficiency and 1 % met the criteria for folate deficiency . We conclude that elevations of tHcy in this population appear to be the result of a combination of vitamin deficiency and decreased renal function and do not appear to be a predictor of cardiovascular disease It is known that the metabolism of homocysteine ( Hcy ) depends on the vitamins B6 , B12 and folate , and furthermore that metformin reduces serum vitamin B12 levels . In order to investigate whether metformin treatment affects serum total Hcy ( tHcy ) levels we performed an open , prospect i ve , r and omised study in 60 non-diabetic male patients with cardiovascular disease . After a 4-week run-in period with lovastatin 40 mg day-1 , and diet and lifestyle advice , patients were r and omised into two groups , both continuing the run-in treatment . One group received metformin up to 2000 mg day-1 , whereas the control group got no additional treatment . After 12 and 40 weeks of metformin treatment , tHcy levels increased moderately but significantly by 7.2 % ( p < 0.05 ) and 13.8 % ( p < 0.05 ) in the metformin group relative to the control group , whereas serum vitamin B12 levels decreased by 13.4 % ( p < 0.0005 ) and 17.7 % ( p < 0.0005 ) , respectively . Serum folate levels did not change after 12 weeks , but decreased by 8.0 % after 40 weeks ( p = 0.061 ) relative to the control group . Serum levels of total cysteine and methylmalonic acid ( MMA ) did not change . In conclusion , metformin treatment increased tHcy levels and decreased levels of vitamin B12 and folate . Since MMA levels were unchanged , it remains an open question whether the increase in tHcy levels is secondary to reduced vitamin B12 levels , folate levels or a combination of both Moderate hyperhomocysteinaemia has been shown to constitute an independent risk factor for cardiovascular disease ( CVD ) , a frequent cause of morbidity and mortality in renal transplant recipients ( RTR ) . In these patients few data regarding both total homocysteine levels and their influence on cardiovascular risk have been reported . We therefore studied serum homocysteine levels in deep-frozen sera from 42 kidney transplant recipients with a follow-up of 11 + /- 4.5 years ( mean + /- SD ) after transplantation . Eighteen patients had one or more ischaemic events ( CVD ( + ) ) and 24 patients had none ( CVD ( - ) ) . Serum sample s had been drawn 1 - 6 months prior to the first vascular event in CVD ( + ) patients and serum storage time was comparable in both CVD ( - ) and CVD ( + ) patients . Serum homocysteine levels were measured using a radioenzymatic method .  Mean homocysteine level was significantly higher in 42 RTR males and females ( 15.5 + /- 6.3 , 13.5 + /- 5.5 microM respectively ) compared with 35 control subjects matched for age and sex ( 8.7 + /- 1.9 , 7.5 + /- 1.9 microM , P < 0.001 ) . The difference in serum homocysteine levels between CVD ( + ) and CVD ( - ) RTR nearly reached statistical significance in male patients ( 18.6 + /- 7.8 versus 13.1 + /- 3.4 microM , P < 0.06 ) but not in female patients ( P = NS ) . In the CVD ( + ) group 11/18 patients had homocysteine levels > 14 microM ( the upper limit in healthy controls ) versus 7/24 in the CVD ( - ) group ( P = 0.04 ) . In these patients we simultaneously measured in the same serum sample s , serum triglycerides , and total and HDL cholesterol , and calculated LDL cholesterol . By stepwise discriminant analysis and by logistic regression analysis in this relatively small patient population , only serum triglycerides and homocysteine were selected as risk factors associated with CVD . We conclude that significant hyperhomocysteinaemia is present in renal transplant recipients and represents a potential risk factor for cardiovascular disease in these patients BACKGROUND Epidemiological studies suggest that raised plasma concentrations of total homocysteine might be a risk factor for major vascular events . Whether lowering total homocysteine with B vitamins prevents major vascular events in patients with previous stroke or transient ischaemic attack is unknown . We aim ed to assess whether the addition of once-daily supplements of B vitamins to usual medical care would lower total homocysteine and reduce the combined incidence of non-fatal stroke , non-fatal myocardial infa rct ion , and death attributable to vascular causes in patients with recent stroke or transient ischaemic attack of the brain or eye . METHODS In this r and omised , double-blind , parallel , placebo-controlled trial , we assigned patients with recent stroke or transient ischaemic attack ( within the past 7 months ) from 123 medical centres in 20 countries to receive one tablet daily of placebo or B vitamins ( 2 mg folic acid , 25 mg vitamin B6 , and 0.5 mg vitamin B12 ) . Patients were r and omly allocated by means of a central 24-h telephone service or an interactive website , and allocation was by use of r and om permuted blocks stratified by hospital . Participants , clinicians , carers , and investigators who assessed outcomes were masked to the assigned intervention . The primary endpoint was the composite of stroke , myocardial infa rct ion , or vascular death . All patients r and omly allocated to a group were included in the analysis of the primary endpoint . This trial is registered with Clinical Trials.gov , NCT00097669 , and Current Controlled Trials , IS RCT N74743444 . FINDINGS Between Nov 19 , 1998 , and Dec 31 , 2008 , 8164 patients were r and omly assigned to receive B vitamins ( n=4089 ) or placebo ( n=4075 ) . Patients were followed up for a median duration of 3.4 years ( IQR 2.0 - 5.5 ) . 616 ( 15 % ) patients assigned to B vitamins and 678 ( 17 % ) assigned to placebo reached the primary endpoint ( risk ratio [ RR ] 0.91 , 95 % CI 0.82 to 1.00 , p=0.05 ; absolute risk reduction 1.56 % , -0.01 to 3.16 ) . There were no unexpected serious adverse reactions and no significant differences in common adverse effects between the treatment groups . INTERPRETATION Daily administration of folic acid , vitamin B6 , and vitamin B12 to patients with recent stroke or transient ischaemic attack was safe but did not seem to be more effective than placebo in reducing the incidence of major vascular events . These results do not support the use of B vitamins to prevent recurrent stroke . The results of ongoing trials and an individual patient data meta- analysis will add statistical power and precision to present estimates of the effect of B vitamins . FUNDING Australia National Health and Medical Research Council , UK Medical Research Council , Singapore Biomedical Research Council , Singapore National Medical Research Council , Australia National Heart Foundation , Royal Perth Hospital Medical Research Foundation , and Health Department of Western Australia 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 r and omized 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 r and omized to receive unfortified cereals , or cereals fortified with 200 μg of folic acid per portion , with or without other vitamins . Blood sample s 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 sample s 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 .Sponsorship : We acknowledge , with thanks , financial support from the Kellogg Company of Great Britain Background An increased rate of brain atrophy is often observed in older subjects , in particular those who suffer from cognitive decline . Homocysteine is a risk factor for brain atrophy , cognitive impairment and dementia . Plasma concentrations of homocysteine can be lowered by dietary administration of B vitamins . Objective To determine whether supplementation with B vitamins that lower levels of plasma total homocysteine can slow the rate of brain atrophy in subjects with mild cognitive impairment in a r and omised controlled trial ( VITACOG , IS RCT N 94410159 ) . Methods and Findings Single-center , r and omized , double-blind controlled trial of high-dose folic acid , vitamins B6 and B12 in 271 individuals ( of 646 screened ) over 70 y old with mild cognitive impairment . A subset ( 187 ) volunteered to have cranial MRI scans at the start and finish of the study . Participants were r and omly assigned to two groups of equal size , one treated with folic acid ( 0.8 mg/d ) , vitamin B12 ( 0.5 mg/d ) and vitamin B6 ( 20 mg/d ) , the other with placebo ; treatment was for 24 months . The main outcome measure was the change in the rate of atrophy of the whole brain assessed by serial volumetric MRI scans . Results A total of 168 participants ( 85 in active treatment group ; 83 receiving placebo ) completed the MRI section of the trial . The mean rate of brain atrophy per year was 0.76 % [ 95 % CI , 0.63–0.90 ] in the active treatment group and 1.08 % [ 0.94–1.22 ] in the placebo group ( P = 0.001 ) . The treatment response was related to baseline homocysteine levels : the rate of atrophy in participants with homocysteine > 13 µmol/L was 53 % lower in the active treatment group ( P = 0.001 ) . A greater rate of atrophy was associated with a lower final cognitive test scores . There was no difference in serious adverse events according to treatment category . Conclusions and Significance The accelerated rate of brain atrophy in elderly with mild cognitive impairment can be slowed by treatment with homocysteine-lowering B vitamins . Sixteen percent of those over 70 y old have mild cognitive impairment and half of these develop Alzheimer 's disease . Since accelerated brain atrophy is a characteristic of subjects with mild cognitive impairment who convert to Alzheimer 's disease , trials are needed to see if the same treatment will delay the development of Alzheimer 's disease . Trial Registration Controlled-Trials.com IS RCT OBJECTIVE Results from epidemiologic studies and clinical trials have indicated that consumption of omega-3 fatty acids , oleic acid , and folic acid have beneficial effects on health , including decreased risk of cardiovascular disease . We evaluated the combined effects of these nutrients through the consumption of milk enriched with omega-3 polyunsaturated fatty acids , oleic acid , vitamins E and B6 , and folic acid on risk factors for cardiovascular disease in volunteers with mild hyperlipidemia . METHODS Thirty subjects ages 45 to 65 y ( 51.3 + /- 5.3 y ) were given 500 mL/d of semi-skimmed milk for 4 wk and then 500 mL/d of the enriched milk for 8 wk .  Plasma and low-density lipoproteins were obtained at the beginning of the study and at 4 , 8 , and 12 wk . RESULTS Consumption of enriched milk for 8 wk increased plasma concentrations of docosahexaenoic acid and eicosapentaenoic acid and significantly ( P < 0.05 ) decreased plasma concentrations of triacylglycerol ( 24 % ) , total cholesterol ( 9 % ) , and low-density lipoprotein cholesterol ( 13 % ) . Plasma and low-density lipoprotein oxidation and vitamin E concentration remained unchanged throughout the study . Significant decreases in plasma concentrations of vascular cell adhesion molecule-1 ( 9 % ) and homocysteine ( 17 % ) were found , accompanied by a 98 % increase in plasma concentration of folic acid . CONCLUSIONS Dairy supplementation strategies with omega-3 polyunsaturated fatty acids , oleic acid , and vitamins may be useful for decreasing risk factors for cardiovascular disease Background —Endothelial function is impaired in coronary artery disease and may contribute to its clinical manifestations . Increased oxidative stress has been linked to impaired endothelial function in atherosclerosis and may play a role in the pathogenesis of cardiovascular events . This study was design ed to determine whether endothelial dysfunction and vascular oxidative stress have prognostic impact on cardiovascular event rates in patients with coronary artery disease . Methods and Results —Endothelium-dependent and -independent vasodilation was determined in 281 patients with documented coronary artery disease by measuring forearm blood flow responses to acetylcholine and sodium nitroprusside using venous occlusion plethysmography . The effect of the coadministration of vitamin C ( 24 mg/min ) was assessed in a subgroup of 179 patients .  Cardiovascular events , including death from cardiovascular causes , myocardial infa rct ion , ischemic stroke , coronary angioplasty , and coronary or peripheral bypass operation , were studied during a mean follow-up period of 4.5 years . Patients experiencing cardiovascular events ( n=91 ) had lower vasodilator responses to acetylcholine ( P < 0.001 ) and sodium nitroprusside ( P < 0.05 ) , but greater benefit from vitamin C ( P < 0.01 ) . The Cox proportional regression analysis for conventional risk factors demonstrated that blunted acetylcholine-induced vasodilation ( P = 0.001 ) , the effect of vitamin C ( P = 0.001 ) , and age ( P = 0.016 ) remained independent predictors of cardiovascular events . Conclusions —Endothelial dysfunction and increased vascular oxidative stress predict the risk of cardiovascular events in patients with coronary artery disease . These data support the concept that oxidative stress may contribute not only to endothelial dysfunction but also to coronary artery disease activity
In this third up date of the Cochrane review , there were no differences in effects of homocysteine-lowering interventions in the form of supplements of vitamins B6 , B9 or B12 given alone or in combination comparing with placebo on myocardial infa rct ion , death from any cause or adverse events .
BACKGROUND Cardiovascular disease , which includes coronary artery disease , stroke and peripheral vascular disease , is a leading cause of death worldwide .
Homocysteine is an amino acid with biological functions in methionine metabolism .
A postulated risk factor for cardiovascular disease is an elevated circulating total homocysteine level .
The impact of homocysteine-lowering interventions , given to patients in the form of vitamins B6 , B9 or B12 supplements , on cardiovascular events has been investigated .
This is an up date of a review previously published in 2009 , 2013 , and 2015 .
OBJECTIVES To determine whether homocysteine-lowering interventions , provided to patients with and without pre-existing cardiovascular disease are effective in preventing cardiovascular events , as well as reducing all-cause mortality , and to evaluate their safety .