In fact, get rid of belly fat animals haelth on vitamin B 6 deficient diet were found to hwart atherosclerosis Healfh and Greenberg,coronary artery vitaminns Murray et al. Although fot levels of plasma vitamin B vitamins for heart health due to its decreased B vitamins for heart health have been reported to be associated with high risk of cardiovascular disease Ye and Song, ; Wang et al. Women who plan to become pregnant should make sure to get the recommended mcg per day since many neural tube defects can happen shortly after conception and before a woman even knows she is pregnant. Vitamin A and its precursors, α-carotene or β-carotene, were claimed to exert beneficial effects in the development of different cardiovascular diseases Palace et al.

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Analyses of UK Biobank data were performed under application AMM is supported by EC-Innovative Medicines Initiative BigData Heart. Funders had no roles in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; or the decision to submit the manuscript for publication.

Open Access funding provided by Karolinska Institute. Unit of Cardiovascular and Nutritional Epidemiology, Institute of Environmental Medicine, Karolinska Institutet, Nobelsväg 13, , Stockholm, Sweden. British Heart Foundation Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK.

National Institute for Health Research Cambridge Biomedical Research Centre, University of Cambridge and Cambridge University Hospitals, Cambridge, UK. Department of Medicine, University of Cambridge, Cambridge, UK.

MRC Biostatistics Unit, University of Cambridge, Cambridge, UK. Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK. Unit of Medical Epidemiology, Department of Surgical Sciences, Uppsala University, Uppsala, Sweden.

You can also search for this author in PubMed Google Scholar. Study conception and design: SY and SCL; data acquisition and analysis: SY, AMM, SB, and SCL; drafting the manuscript and figures: SY; reviewing the manuscript: SY, AMM, PC, SB, and S.

The authors read and approved the final manuscript. Correspondence to Susanna C. All studies included in cited genome-wide association studies had been approved by a relevant review board, and participants had provided written informed consent. The present MR analyses were approved by the Swedish Ethical Review Authority Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

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Reprints and permissions. Yuan, S. et al. Homocysteine, B vitamins, and cardiovascular disease: a Mendelian randomization study. BMC Med 19 , 97 Download citation. Received : 10 February Accepted : 29 March Published : 23 April Anyone you share the following link with will be able to read this content:.

Sorry, a shareable link is not currently available for this article. Provided by the Springer Nature SharedIt content-sharing initiative. Skip to main content. Search all BMC articles Search. Download PDF. Research article Open access Published: 23 April Homocysteine, B vitamins, and cardiovascular disease: a Mendelian randomization study Shuai Yuan 1 , Amy M.

Larsson ORCID: orcid. Abstract Background Whether a modestly elevated homocysteine level is causally associated with an increased risk of cardiovascular disease remains unestablished. Results Higher genetically predicted circulating tHcy levels were associated with an increased risk of stroke.

Conclusions This study reveals suggestive evidence that B vitamin therapy and lowering of tHcy may reduce the risk of stroke, particularly subarachnoid hemorrhage and ischemic stroke. Background The B vitamins, including folate and vitamins B6 and B12, play vital roles in the metabolism of homocysteine Fig.

Full size image. Methods Outcome data sources Summary-level data for 12 CVD endpoints were obtained from large genetic consortia [ 21 , 22 , 23 , 24 , 25 , 26 ], the UK Biobank study [ 27 ] and the FinnGen consortium [ 28 ].

Table 1 Information on outcome data sources Full size table. Results We observed suggestive associations of higher genetically predicted circulating tHcy levels with increased risk of any stroke, subarachnoid hemorrhage, and ischemic stroke Fig.

Discussion This MR study investigated the potential causal role of circulating tHcy and B vitamins in a broad range of CVDs and revealed suggestive associations of higher genetically predicted tHcy levels with increased risk of any stroke, subarachnoid hemorrhage, and ischemic stroke.

Conclusions This MR study provides limited evidence in support of a general benefit of lowering tHcy levels in the prevention of a broad range of CVDs in the general population.

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All study investigators, personnel, and participants were unaware of the participants' treatment assignments. Following randomization and annually thereafter, participants were mailed monthly calendar packs containing active agents or placebos.

The participants were followed up annually with questionnaires on adherence, use of nonstudy supplements, and occurrence of major illnesses or adverse events. Written permission for medical records was sought from participants who reported cardiovascular end points or from the next of kin in case of death.

Death certificates were also obtained. An end points committee of physicians who were blinded to randomized treatment assignment adjudicated all primary and secondary cardiovascular outcome events. Study medications and end point ascertainment were continued in a blinded fashion until the scheduled end of the trial, July 31, Follow-up and validation of reported end points were completed in July for a follow-up duration of 7.

At the scheduled end of the trial on July 31, , morbidity and mortality follow-up was If counted in terms of person-time, mortality and morbidity information was complete for Women in WAFACS who provided a baseline blood sample in , prior to the initiation of background dietary folic acid fortification in the US food supply in , were eligible for this preplanned substudy.

From the eligible participants, in the active treatment and in the placebo group provided a blood sample at the end of randomized treatment. These women were randomly selected from participants who were adherent with study medications. Plasma levels of folate chemiluminescence method using the Elecsys autoimmunoanalyzer, Roche Diagnostics, Basel, Switzerland and homocysteine enzymatic assay using the Hitachi analyzer, Roche Diagnostics, Basel, Switzerland were measured in baseline and follow-up samples in a blinded fashion in the same analytical run.

The primary outcome was a combined end point of cardiovascular morbidity and mortality, which included incident MI, stroke, coronary revascularization procedures coronary artery bypass grafting or percutaneous coronary intervention , and cardiovascular mortality.

The individual components of total MI, total stroke, and total coronary heart disease events MI, coronary revascularization, and death from coronary heart disease were prespecified secondary end points. An MI was confirmed if symptoms met World Health Organization criteria and if the event was associated with either diagnostic electrocardiogram changes or elevated cardiac enzymes.

Coronary revascularization was confirmed by medical record review. Confirmed stroke was defined as a new neurologic deficit of sudden onset that persisted for more than 24 hours or until death within 24 hours. Clinical information, computed tomographic scans, and magnetic resonance images were used to distinguish hemorrhagic from ischemic events.

Coronary revascularization was confirmed if a coronary artery bypass grafting or percutaneous coronary intervention was documented in the medical record. Death due to cardiovascular cause was confirmed by examination of autopsy reports, death certificates, medical records, and information obtained from the next of kin or other family members.

Death from any cause was confirmed by the end points committee on the basis of a death certificate. Only confirmed end points were included in these analyses, except for total mortality, which included an additional 43 reported deaths.

Power calculations were performed under the assumption that all 4 agents would have beneficial effects on CVD, which would be additive on the log scale when used in combination. This method affects the power calculations by reducing the incidence in all exposed groups and provides a conservative estimate of the study's power to detect the effects of each agent.

Baseline characteristics were compared by randomized groups using t tests, χ 2 tests for proportions, and tests for trend for ordinal categories. Primary analyses were performed on an intent-to-treat basis, including all randomized participants in each treatment group, as randomized.

For both the primary and secondary analyses, person-time was calculated until the first confirmed end point specified by the analysis or to the end of the trial if no end point occurred.

Kaplan-Meier curves were used to estimate cumulative incidence over time by randomized treatment group, and the log-rank test was used to compare survival curves. The proportionality assumption was tested using an interaction term for treatment with log time, and was met for each of the primary and secondary analyses.

To examine the effect of nonadherence, a post hoc sensitivity analysis censored participants when they stopped taking at least two-thirds of their study medications, reported taking outside supplements, or were missing adherence information. Prespecified subgroup analyses according to antioxidant treatment assignment s , presence or absence of prior CVD, dietary folic acid intake, smoking, diabetes, aspirin, hormone therapy, and multivitamin use were performed using stratified Cox proportional hazards models.

These analyses used baseline exposure assessments and were restricted to participants with nonmissing subgroup data at baseline. Additional exploratory subgroup analyses were conducted to evaluate the consistency of the results.

Tests for effect modification by subgroup used interaction terms between subgroup indicators and randomized assignment, with a test for trend for ordinal subgroup categories.

The raw distributions and median values of plasma homocysteine and folate levels in the blood substudy were compared using the nonparametric Wilcoxon rank sum test. For homocysteine, geometric means were compared after natural logarithmic transformation to compare differences between treatment groups.

Analyses were conducted using SAS version 9 SAS Institute, Cary, North Carolina , using 2-sided tests with a significance level of. In April , female health professionals participating in the WACS trial were randomly assigned to active treatment with folic acid, vitamin B 6 , and vitamin B 12 and participants were assigned to placebo.

Baseline characteristics at the time of randomization in and responses to the dietary questionnaire administered prior to randomization in are displayed in Table 1. The mean age of the population was There were no statistically significant differences in baseline characteristics or in dietary intake of study vitamins between the randomized groups Table 1.

Adherence was assessed through self-report on annual study questionnaires and was defined as taking at least two-thirds of the study pills. There were no serious adverse events reported that were conclusively related to study interventions.

During the 7. Overall, MIs, strokes, coronary revascularization procedures, and cardiovascular deaths occurred in the population over the course of the study. There was no difference in the cumulative incidence of the primary combined end point in the active vs placebo treatment groups at any time during study follow-up Figure 2.

A total of women This corresponded to an overall RR of 1. There remained no evidence for a treatment effect in sensitivity analysis censoring at nonadherence RR, 1.

Among the prespecified secondary cardiovascular outcomes, total coronary heart disease events occurred in participants When analyzed separately, there were no significant differences for each of the components of the primary outcome including MI Also, the risk of death from any cause was similar between the active and placebo treatment groups RR, 0.

There were no significant treatment effects with respect to the primary outcome in any of the prespecified or exploratory subgroups evaluated Table 3.

Also, there was no evidence that either dietary folate intake or multivitamin use modified the treatment effect, although power was limited for these subgroups as well. With respect to the antioxidant vitamins, there was evidence for an interaction between randomized treatment assignment to vitamin C and the combination therapy with folic acid, vitamin B 6 , and vitamin B 12 on the primary end point Table 3.

There were no other significant 2-way or 3-way interactions among the agents for the primary end point. The participants in the blood substudy were similar with respect to all the clinical characteristics outlined in Table 1 , except that smokers 8.

The distributions of baseline and follow-up folate and homocysteine levels among participants in the placebo group and participants in the active group are displayed in Table 4.

Prior to the initiation of fortification and randomization, median folate levels were similar in the active treatment group 8. Median plasma homocysteine levels were also similar at baseline in the active treatment group At the end of study follow-up, the median folate level increased significantly in the placebo group to In comparison, homocysteine levels were significantly reduced in the active treatment group median level, 9.

In order to directly compare the degree of additional homocysteine lowering observed in the active over the placebo group, we computed the difference between treatment groups in the change in the natural logarithm of homocysteine level from baseline to follow-up, adjusting for baseline levels.

The geometric mean homocysteine level was decreased by In this large-scale, placebo-controlled, randomized trial among high-risk women participants, we found no overall effects of a combination of folic acid, vitamin B 6 , and vitamin B 12 on the primary outcome of total CVD events over the largest number of person-years and the longest follow-up period reported to our knowledge 7.

In subgroup analyses, there was no heterogeneity of treatment effect among those above or below the median of folate intake and among women with or without prior vascular disease.

A possible interaction with randomized vitamin C and with nonrandomized angiotensin-converting enzyme inhibitor treatment on the primary outcome was observed; however, due to the large number of comparisons, these results could have been due to chance. These null results for women are consistent with those previously reported in randomized trials composed primarily of men with preexisting vascular disease.

Although there was a significant reduction in the secondary end point of stroke in this trial RR, 0. The HOPE-2 trial also reported an increased risk of hospitalization for unstable angina RR, 1. Smaller studies among patients postcoronary intervention have found both decreased 15 and increased 16 rates of restenosis among patients treated with B-vitamin regimens.

In the present study, we found no evidence for a benefit on stroke or any evidence for harm regarding the primary composite end point or any of the individual secondary end points including coronary revascularization.

Concerns have been raised regarding the power of this trial and other current trials to adequately test the homocysteine hypothesis 17 , 18 ; especially in countries where folic acid fortification of the food supply has taken place.

Although homocysteine levels were unchanged in the placebo group, folic acid fortification likely prevented further elevations in homocysteine levels that would have otherwise taken place due to the aging of the population.

However, such modest plausible reductions in the individual secondary end points of stroke, MI, and cardiovascular death cannot be excluded even in a trial of this size.

First, the study was conducted in a population of health professionals, who were at a relatively low risk of folate deficiency. These participants were allowed to take the RDA of folic acid and B-vitamins and were also exposed to folic acid—fortified grain products during the course of the trial.

Although the blood study suggests that a significant proportion of the participants were folate deficient at the beginning of the trial, this was virtually eliminated over the course of study.

Therefore, we cannot rule out the possibility that this same regimen may have resulted in an even greater reduction in homocysteine levels in a more folate-deficient population, which might have translated into an observable benefit on cardiovascular events.

Alternatively, the optimal dose of these vitamins may actually be lower than the dose tested in this and other trials, and the potential for harm at higher doses has been raised by other studies. Also, morbidity and mortality follow-up rates in this high-risk population were lower than in other trials of primary prevention using similar methodology 23 ; and it is thus plausible that a larger primary prevention population with higher rates of follow-up might have demonstrated a benefit.

However, since the lost to follow-up rates did not differ between the 2 treatment groups in this study, they are unlikely to account for the null findings observed. These remaining issues, along with the hypotheses regarding possible novel drug interactions with vitamin C and angiotensin enzyme-converting inhibitors raised by the subgroup analyses of this study, warrant further investigation in future studies.

In summary, in the WAFACS trial, a combination pill of 2. Our results are consistent with prior randomized trials performed primarily among men with established vascular disease 3 and do not support the use of folic acid and B vitamin supplements as preventive interventions for CVD in these high-risk—fortified populations.

Corresponding Author: Christine M. Albert, MD, MPH, Division of Preventive Medicine, Brigham and Women's Hospital, Commonwealth Ave E, Boston, MA calbert partners.

Author Contributions: Dr Albert had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Acquisition of data : Albert, Gaziano, Zaharris, MacFadyen, Danielson, Buring, Manson. Critical revision of the manuscript for important intellectual content : Albert, Cook, Gaziano, Zaharris, MacFadyen, Danielson, Buring, Manson.

Administrative, technical, or material support : Zaharris, MacFadyen, Danielson, Manson. Financial Disclosures: Dr Gaziano reports receiving investigator-initiated study support of vitamin pills and packaging from Wyeth. Dr Buring reports receiving investigator-initiated study support of vitamin pills and packaging from Natural Source Vitamin E Association.

Dr Manson reports receiving investigator-initiated study support of vitamin pills and packaging from Cognis and BASF. The other authors reported no disclosures. Disclaimer: Dr Gaziano, a JAMA Contributing Editor, was not involved in the editorial review of or decision to publish this article.

Vitamin E and its placebo were supplied by Cognis Corporation LaGrange, Illinois. All other agents and their placebos were supplied by BASF Corporation Mount Olive, New Jersey. Pill packaging was provided by Cognis and BASF.

Role of the Sponsor: Cognis, BASF, and the National Heart, Lung, and Blood Institute did not participate in the design and conduct of the study; collection, management, analysis, and interpretation of the data; and preparation, review, or approval of the manuscript.

Data and Safety Monitoring Board: L. Cohen, R. Collins, T. Colton, D. DeMets, I. Henderson, A. La Croix, R. Prentice, and N. Wenger chair and M. Cotch, F. Ferris, L. Friedman, P. Greenwald, N. Kurinij, M. Perloff, E. Schron, and A. Zonderman ex-officio members. Additional Contributions: We are indebted to the participants in the Women's Antioxidant and Folic Acid Cardiovascular Study for their dedicated and conscientious collaboration; to the entire staff of the Women's Antioxidant and Folic Acid Cardiovascular Study: including Marilyn Chown, BS, MPH, Shamikhah Curry, Margarette Haubourg, Felicia Zangi, Tony Laurinaitis, Geneva McNair, Philomena Quinn, Harriet Samuelson, MA, Ara Sarkissian, MM, and Martin Van Denburgh, BA; and to the following individuals for their assistance in conducting this trial: Michelle Albert, MD, MPH, Tobias Kurth, MD, ScD, I-Min Lee, MBBS, ScD, Aruna Pradhan, MD, MPH, Paul Ridker, MD, MPH, and Jacqueline H.

Suk, MD, MPH, Brigham and Women's Hospital, Boston, Massachusetts; Gavin Blake, MBBS, Mater Misericordiae University Hospital, Dublin, Ireland; Claudia Chae, MD, MPH, Massachusetts General Hospital, Boston; Carlos Kase, MD, Boston University Medical Center, Boston, Massachusetts; and James O.

Taylor, MD, East Boston Neighborhood Health Center, Boston, Massachusetts. full text icon Full Text. Download PDF Top of Article Abstract Methods Results Article Information References. Figure 1. Flow Diagram of the Folic Acid, Vitamin B 6 , and Vitamin B 12 Component of WAFACS.

View Large Download. Figure 2. Cumulative Incidence of Major Cardiovascular Disease by Randomized Folic Acid and B-Vitamin Intervention in WAFACS. Table 1.

Baseline Characteristics of WAFACS and Blood Substudy Participants. Table 2. Relative Risk of Clinical Outcomes According to Treatment Assignment With Folic Acid, Vitamin B 6 , and Vitamin B 12 vs Placebo.

Table 3. Effect of Randomized Treatment Assignment on the Primary Outcome in Prespecified and Exploratory Subgroups.

BMC Medicine volume Improve cholesterol profile vltamins, Article number: 97 Cite Green tea health benefits article. Metrics details. Whether vigamins modestly elevated homocysteine Improve cholesterol profile is causally associated ivtamins an vitamiins risk of cardiovascular disease remains unestablished. We conducted a Mendelian randomization study to assess the associations of circulating total homocysteine tHcy and B vitamin levels with cardiovascular diseases in the general population. Summary-level data for 12 cardiovascular endpoints were obtained from genetic consortia, the UK Biobank study, and the FinnGen consortium.

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What can B Vitamins do for your cardiovascular system? Citamins indicates Women's Antioxidant Cardiovascular Heaet WAFACS, Improve cholesterol profile Antioxidant and Folic Acid Cardiovascular Heary. Improve cholesterol profile Mortality and morbidity information was complete for Potent pre-workout mix WAFACS indicates Women's Antioxidant and Folic Acid Cardiovascular Study. Major cardiovascular disease denotes myocardial infarction, stroke, coronary revascularization, or cardiovascular death. Albert CMCook NRGaziano JM, et al. 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.