Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress
Clinical Collections
Advances in Alzheimer’s

Keynote webinar | Spotlight on medication adherence

LIVE: Thursday 27th June 2024, 18:00-19:30 (CEST)
Join our expert panel to discover why you need to understand the drivers of non-adherence in your patients, and how you can optimize medication adherence in your clinics to drastically improve patient outcomes.
ADVANCED SEARCH
Log in
Top
Nutrition Journal
Published in: Nutrition Journal 1/2023

Open Access 01-12-2023 | Folic Acid | Review

The effects of folic acid supplementation on endothelial function in adults: a systematic review and dose-response meta-analysis of randomized controlled trials

Authors: Mohammad Zamani, Fatemeh Rezaiian, Saeede Saadati, Kaveh Naseri, Damoon Ashtary-Larky, Mohsen Yousefi, Elnaz Golalipour, Cain C. T. Clark, Samira Rastgoo, Omid Asbaghi

Published in: Nutrition Journal | Issue 1/2023

Login to get access

Abstract

Background

Endothelial dysfunction serves as an early marker for the risk of cardiovascular disease (CVD); therefore, it is an attractive site of therapeutic interventions to reduce the risk of CVD. This study was conducted to investigate the effect of folic acid supplementation on endothelial function markers in randomized controlled trials (RCTs).

Methods

PubMed, ISI web of science, and Scopus databases were searched up to July 2022 for detecting eligible studies. A random-effects model was used for meta-analysis, and linear Meta-regression and non-linear dose-response analysis were performed to assess whether the effect of folic acid supplementation was affected by the dose and duration of intervention. Cochrane tools were also used to assess the risk of bias in the included studies.

Results

Twenty-one studies, including 2025 participants (1010 cases and 1015 controls), were included in the present meta-analysis. Folic acid supplementation significantly affected the percentage of flow-mediated dilation (FMD%) (WMD: 2.59%; 95% CI: 1.51, 3.67; P < 0.001) and flow-mediated dilation (FMD) (WMD: 24.38 μm; 95% CI: 3.08, 45.68; P = 0.025), but not end-diastolic diameter (EDD) (WMD: 0.21 mm; 95% CI: − 0.09, 0.52; P = 0.176), and intercellular adhesion molecule (ICAM) (WMD: 0.18 ng/ml; 95% CI: − 10.02, 13.81; P = 0.755).

Conclusions

These findings suggest that folic acid supplementation may improve endothelial function by increasing FMD and FMD% levels.

Trial registration

PROSPERO registration cod: CRD42021289744.
Appendix
Available only for authorised users
Literature
1.
Vanhoutte PM, Shimokawa H, Tang EH, Feletou M. Endothelial dysfunction and vascular disease. Acta Physiol. 2009;196(2):193–222.CrossRef
2.
3.
Lara J, Ashor AW, Oggioni C, Ahluwalia A, Mathers JC, Siervo M. Effects of inorganic nitrate and beetroot supplementation on endothelial function: a systematic review and meta-analysis. Eur J Nutr. 2016;55(2):451–9.PubMedCrossRef
4.
Gallo G, Pierelli G, Forte M, Coluccia R, Volpe M, Rubattu S. Role of oxidative stress in the process of vascular remodeling following coronary revascularization. Int J Cardiol. 2018;268:27–33.PubMedCrossRef
5.
Sena CM, Carrilho F, Seiça RM. Endothelial dysfunction in type 2 diabetes: targeting inflammation. Endothelial Dysfunct. 2018;24:23110.
6.
Strohbach A, Pennewitz M, Glaubitz M, Palankar R, Groß S, Lorenz F, et al. The apelin receptor influences biomechanical and morphological properties of endothelial cells. J Cell Physiol. 2018;233(8):6250–61.PubMedCrossRef
7.
Gori T, Münzel T. Oxidative stress and endothelial dysfunction: therapeutic implications. Ann Med. 2011;43(4):259–72.PubMedCrossRef
8.
Medina-Leyte DJ, Zepeda-García O, Domínguez-Pérez M, González-Garrido A, Villarreal-Molina T, Jacobo-Albavera L. Endothelial dysfunction, inflammation and coronary artery disease: potential biomarkers and promising Therapeutical approaches. Int J Mol Sci. 2021;22(8):3850.PubMedPubMedCentralCrossRef
9.
Sun HJ, Wu ZY, Nie XW, Bian JS. Role of endothelial dysfunction in cardiovascular diseases: the link between inflammation and hydrogen sulfide. Front Pharmacol. 2019;10:1568.PubMedCrossRef
10.
Shafabakhsh R, Milajerdi A, Reiner Ž, Kolahdooz F, Amirani E, Mirzaei H, et al. The effects of catechin on endothelial function: a systematic review and meta-analysis of randomized controlled trials. Crit Rev Food Sci Nutr. 2020;60(14):2369–78.PubMedCrossRef
11.
Konukoglu D, Uzun H. Endothelial dysfunction and hypertension. Hypertension. 2016;956:511–40.
12.
Bonetti PO, Lerman LO, Lerman A. Endothelial dysfunction: a marker of atherosclerotic risk. Arterioscler Thromb Vasc Biol. 2003;23(2):168–75.PubMedCrossRef
13.
Maruhashi T, Kajikawa M, Kishimoto S, Hashimoto H, Takaeko Y, Yamaji T, et al. Diagnostic criteria of flow-mediated vasodilation for Normal endothelial function and nitroglycerin-induced vasodilation for Normal vascular smooth muscle function of the brachial artery. J Am Heart Assoc. 2020;9(2):e013915.PubMedPubMedCentralCrossRef
14.
Chia PY, Teo A, Yeo TW. Overview of the assessment of endothelial function in humans. Front Med (Lausanne). 2020;7:542567.PubMedCrossRef
15.
Vanhoutte PM, Shimokawa H, Feletou M, Tang EH. Endothelial dysfunction and vascular disease - a 30th anniversary update. Acta Physiol (Oxf). 2017;219(1):22–96.PubMedCrossRef
16.
Bentley TG, Weinstein MC, Willett WC, Kuntz KM. A cost-effectiveness analysis of folic acid fortification policy in the United States. Public Health Nutr. 2009;12(4):455–67.PubMedCrossRef
17.
Yang Q, Botto LD, Erickson JD, Berry RJ, Sambell C, Johansen H, et al. Improvement in stroke mortality in Canada and the United States, 1990 to 2002. Circulation. 2006;113(10):1335–43.PubMedCrossRef
18.
Wang L, Li H, Zhou Y, Jin L, Liu J. Low-dose B vitamins supplementation ameliorates cardiovascular risk: a double-blind randomized controlled trial in healthy Chinese elderly. Eur J Nutr. 2015;54(3):455–64.PubMedCrossRef
19.
Asbaghi O, Salehpour S, Rezaei Kelishadi M, Bagheri R, Ashtary-Larky D, Nazarian B, et al. Folic acid supplementation and blood pressure: a GRADE-assessed systematic review and dose-response meta-analysis of 41,633 participants. Crit Rev Food Sci Nutr. 2021:1–16.
20.
Asbaghi O, Ghanavati M, Ashtary-Larky D, Bagheri R, Rezaei Kelishadi M, Nazarian B, et al. Effects of folic acid supplementation on oxidative stress markers: a systematic review and Meta-analysis of randomized controlled trials. Antioxidants (Basel). 2021;10(6):871.PubMedCrossRef
21.
Asbaghi O, Ashtary-Larky D, Bagheri R, Nazarian B, Pourmirzaei Olyaei H, Rezaei Kelishadi M, et al. Beneficial effects of folic acid supplementation on lipid markers in adults: a GRADE-assessed systematic review and dose-response meta-analysis of data from 21,787 participants in 34 randomized controlled trials. Crit Rev Food Sci Nutr. 2021:1–19.
22.
Asbaghi O, Ashtary-Larky D, Bagheri R, Moosavian SP, Olyaei HP, Nazarian B, et al. Folic acid supplementation improves glycemic control for diabetes prevention and management: a systematic review and dose-response Meta-analysis of randomized controlled trials. Nutrients. 2021;13(7):2355.PubMedPubMedCentralCrossRef
23.
Asbaghi O, Ashtary-Larky D, Bagheri R, Moosavian SP, Nazarian B, Afrisham R, et al. Effects of folic acid supplementation on inflammatory markers: a Grade-assessed systematic review and dose-response Meta-analysis of randomized controlled trials. Nutrients. 2021;13(7):2327.PubMedPubMedCentralCrossRef
24.
Cui S, Li W, Wang P, Lv X, Gao Y, Huang G. Folic acid inhibits homocysteine-induced cell apoptosis in human umbilical vein endothelial cells. Mol Cell Biochem. 2018;444(1–2):77–86.PubMedCrossRef
25.
Bajic Z, Sobot T, Skrbic R, Stojiljkovic MP, Ponorac N, Matavulj A, et al. Homocysteine, vitamins B6 and folic acid in experimental models of myocardial infarction and heart failure-how strong is that link? Biomolecules. 2022;12(4):536.PubMedPubMedCentralCrossRef
26.
Li M, Chen J, Li YS, Feng YB, Gu X, Shi CZ. Folic acid reduces adhesion molecules VCAM-1 expession in aortic of rats with hyperhomocysteinemia. Int J Cardiol. 2006;106(2):285–8.PubMedCrossRef
27.
Moens AL, Goovaerts I, Claeys MJ, Vrints CJ. Flow-mediated vasodilation: a diagnostic instrument, or an experimental tool? Chest. 2005;127(6):2254–63.PubMedCrossRef
28.
Yoshida T, Kawano H, Miyamoto S, Motoyama T, Fukushima H, Hirai N, et al. Prognostic value of flow-mediated dilation of the brachial artery in patients with cardiovascular disease. Intern Med. 2006;45(9):575–9.PubMedCrossRef
29.
Lekakis JP, Papamichael CM, Papaioannou TG, Dagre AG, Stamatelopoulos KS, Tryfonopoulos D, et al. Oral folic acid enhances endothelial function in patients with hypercholesterolaemia receiving statins. Eur J Cardiovasc Prev Rehabil. 2004;11(5):416–20.PubMed
30.
Title LM, Cummings PM, Giddens K, Genest JJ Jr, Nassar BA. Effect of folic acid and antioxidant vitamins on endothelial dysfunction in patients with coronary artery disease. J Am Coll Cardiol. 2000;36(3):758–65.PubMedCrossRef
31.
Title LM, Ur E, Giddens K, McQueen MJ, Nassar BA. Folic acid improves endothelial dysfunction in type 2 diabetes--an effect independent of homocysteine-lowering. Vasc Med. 2006;11(2):101–9.PubMedCrossRef
32.
Woo KS, Chook P, Lolin YI, Sanderson JE, Metreweli C, Celermajer DS. Folic acid improves arterial endothelial function in adults with hyperhomocystinemia. J Am Coll Cardiol. 1999;34(7):2002–6.PubMedCrossRef
33.
Thambyrajah J, Landray MJ, McGlynn FJ, Jones HJ, Wheeler DC, Townend JN. Does folic acid decrease plasma homocysteine and improve endothelial function in patients with predialysis renal failure? Circulation. 2000;102(8):871–5.PubMedCrossRef
34.
Thambyrajah J, Landray MJ, Jones HJ, McGlynn FJ, Wheeler DC, Townend JN. A randomized double-blind placebo-controlled trial of the effect of homocysteine-lowering therapy with folic acid on endothelial function in patients with coronary artery disease. J Am Coll Cardiol. 2001;37(7):1858–63.PubMedCrossRef
35.
Woodman RJ, Celermajer DE, Thompson PL, Hung J. Folic acid does not improve endothelial function in healthy hyperhomocysteinaemic subjects. Clin Sci (Lond). 2004;106(4):353–8.PubMedCrossRef
36.
Spoelstra-de MA, Brouwer CB, Terheggen F, Bollen JM, Stehouwer CD, Smulders YM. No effect of folic acid on markers of endothelial dysfunction or inflammation in patients with type 2 diabetes mellitus and mild hyperhomocysteinaemia. Neth J Med. 2004;62(7):246–53.PubMed
37.
Moher D, Liberati A, Tetzlaff J, Altman DG. Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. BMJ. 2009;339:b2535.PubMedPubMedCentralCrossRef
38.
Higgins JP, Altman DG, Gøtzsche PC, Jüni P, Moher D, Oxman AD, et al. The Cochrane Collaboration’s tool for assessing risk of bias in randomised trials. BMJ. 2011;343:d5928.PubMedPubMedCentralCrossRef
39.
DerSimonian R, Kacker R. Random-effects model for meta-analysis of clinical trials: an update. Contemp Clin Trials. 2007;28(2):105–14.PubMedCrossRef
40.
Borenstein M, Hedges LV, Higgins JP, Rothstein HR. Introduction to meta-analysis: John Wiley & Sons; 2011.
41.
Sahebkar A. Are curcuminoids effective C-reactive protein-lowering agents in clinical practice? Evidence from a meta-analysis. Phytother Res. 2014;28(5):633–42.PubMedCrossRef
42.
Guyatt GH, Oxman AD, Vist GE, Kunz R, Falck-Ytter Y, Alonso-Coello P, et al. GRADE: an emerging consensus on rating quality of evidence and strength of recommendations. BMJ. 2008;336(7650):924–6.PubMedPubMedCentralCrossRef
43.
Bellamy MF, McDowell IF, Ramsey MW, Brownlee M, Newcombe RG, Lewis MJ. Oral folate enhances endothelial function in hyperhomocysteinaemic subjects. Eur J Clin Investig. 1999;29(8):659–62.CrossRef
44.
Doshi SN, McDowell IF, Moat SJ, Lang D, Newcombe RG, Kredan MB, et al. Folate improves endothelial function in coronary artery disease: an effect mediated by reduction of intracellular superoxide? Arterioscler Thromb Vasc Biol. 2001;21(7):1196–202.PubMedCrossRef
45.
Pullin CH, Ashfield-Watt PA, Burr ML, Clark ZE, Lewis MJ, Moat SJ, et al. Optimization of dietary folate or low-dose folic acid supplements lower homocysteine but do not enhance endothelial function in healthy adults, irrespective of the methylenetetrahydrofolate reductase (C677T) genotype. J Am Coll Cardiol. 2001;38(7):1799–805.PubMedCrossRef
46.
Doshi SN, McDowell IF, Moat SJ, Payne N, Durrant HJ, Lewis MJ, et al. Folic acid improves endothelial function in coronary artery disease via mechanisms largely independent of homocysteine lowering. Circulation. 2002;105(1):22–6.PubMedCrossRef
47.
Doshi S, McDowell I, Moat S, Lewis M, Goodfellow J. Folate improves endothelial function in patients with coronary heart disease. Clin Chem Lab Med. 2003;41(11):1505–12.PubMedCrossRef
48.
Doshi SN, Moat SJ, Lewis MJ, McDowell IF, Giddings JC, Goodfellow J. Short-term high-dose folic acid does not alter markers of endothelial cell damage in patients with coronary heart disease. Int J Cardiol. 2004;94(2–3):203–7.PubMedCrossRef
49.
Durga J, van Tits LJ, Schouten EG, Kok FJ, Verhoef P. Effect of lowering of homocysteine levels on inflammatory markers: a randomized controlled trial. Arch Intern Med. 2005;165(12):1388–94.PubMedCrossRef
50.
Moat SJ, Madhavan A, Taylor SY, Payne N, Allen RH, Stabler SP, et al. High- but not low-dose folic acid improves endothelial function in coronary artery disease. Eur J Clin Investig. 2006;36(12):850–9.CrossRef
51.
Moens AL, Claeys MJ, Wuyts FL, Goovaerts I, Van Hertbruggen E, Wendelen LC, et al. Effect of folic acid on endothelial function following acute myocardial infarction. Am J Cardiol. 2007;99(4):476–81.PubMedCrossRef
52.
Shirodaria C, Antoniades C, Lee J, Jackson CE, Robson MD, Francis JM, et al. Global improvement of vascular function and redox state with low-dose folic acid: implications for folate therapy in patients with coronary artery disease. Circulation. 2007;115(17):2262–70.PubMedCrossRef
53.
Woo K, Chook P, Yip T, Kwong S, Hu Y, Huang X, et al. Folic acid and vitamin B12 supplementation improves arterial function and structure in subjects with subnormal intake. Heart Lung Circ. 2008;17:S201–S2.CrossRef
54.
Palomba S, Falbo A, Giallauria F, Russo T, Tolino A, Zullo F, et al. Effects of metformin with or without supplementation with folate on homocysteine levels and vascular endothelium of women with polycystic ovary syndrome. Diabetes Care. 2010;33(2):246–51.PubMedCrossRef
55.
Hashemi M, Heshmat-Ghahdarijani K, Zarean E, Baktash F, Mortazavi ZS. Evaluation of the effect of high-dose folic acid on endothelial dysfunction in pre-eclamptic patients: a randomized clinical trial. J Res Med Sci. 2016;21:114.PubMedPubMedCentralCrossRef
56.
Connor SL, Ojeda LS, Sexton G, Weidner G, Connor WE. Diets lower in folic acid and carotenoids are associated with the coronary disease epidemic in central and Eastern Europe. J Am Diet Assoc. 2004;104(12):1793–9.PubMedCrossRef
57.
Eichholzer M, Lüthy J, Gutzwiller F, Stähelin HB. The role of folate, antioxidant vitamins and other constituents in fruit and vegetables in the prevention of cardiovascular disease: the epidemiological evidence. Int J Vitam Nutr Res. 2001;71(1):5–17.PubMedCrossRef
58.
Li Y, Huang T, Zheng Y, Muka T, Troup J, Hu FB. Folic acid supplementation and the risk of cardiovascular diseases: a Meta-analysis of randomized controlled trials. J Am Heart Assoc. 2016;5(8):e003768.PubMedPubMedCentralCrossRef
59.
Taylor SY, Dixon HM, Yoganayagam S, Price N, Lang D. Folic acid modulates eNOS activity via effects on posttranslational modifications and protein-protein interactions. Eur J Pharmacol. 2013;714(1–3):193–201.PubMedPubMedCentralCrossRef
60.
Chalupsky K, Kračun D, Kanchev I, Bertram K, Görlach A. Folic acid promotes recycling of tetrahydrobiopterin and protects against hypoxia-induced pulmonary hypertension by recoupling endothelial nitric oxide synthase. Antioxid Redox Signal. 2015;23(14):1076–91.PubMedPubMedCentralCrossRef
61.
Stanhewicz AE, Kenney WL. Role of folic acid in nitric oxide bioavailability and vascular endothelial function. Nutr Rev. 2017;75(1):61–70.PubMedCrossRef
62.
Zhong Q, Nong Q, Mao B, Pan X, Meng L. Association of Impaired Vascular Endothelial Function with increased cardiovascular risk in asymptomatic adults. Biomed Res Int. 2018;2018:3104945.PubMedPubMedCentralCrossRef
63.
Sitia S, Tomasoni L, Atzeni F, Ambrosio G, Cordiano C, Catapano A, et al. From endothelial dysfunction to atherosclerosis. Autoimmun Rev. 2010;9(12):830–4.PubMedCrossRef
64.
Davignon J, Ganz P. Role of endothelial dysfunction in atherosclerosis. Circulation. 2004;109(23 Suppl 1):Iii27–32.PubMed
65.
Zhang M, Wen J, Wang X, Xiao C. High-dose folic acid improves endothelial function by increasing tetrahydrobiopterin and decreasing homocysteine levels. Mol Med Rep. 2014;10(3):1609–13.PubMedCrossRef
66.
Tyagi N, Sedoris KC, Steed M, Ovechkin AV, Moshal KS, Tyagi SC. Mechanisms of homocysteine-induced oxidative stress. Am J Physiol Heart Circ Physiol. 2005;289(6):H2649–56.PubMedCrossRef
67.
Chernyavskiy I, Veeranki S, Sen U, Tyagi SC. Atherogenesis: hyperhomocysteinemia interactions with LDL, macrophage function, paraoxonase 1, and exercise. Ann N Y Acad Sci. 2016;1363(1):138–54.PubMedPubMedCentralCrossRef
68.
de Bree A, van Mierlo LA, Draijer R. Folic acid improves vascular reactivity in humans: a meta-analysis of randomized controlled trials. Am J Clin Nutr. 2007;86(3):610–7.PubMedCrossRef
69.
Raggi P, Genest J, Giles JT, Rayner KJ, Dwivedi G, Beanlands RS, et al. Role of inflammation in the pathogenesis of atherosclerosis and therapeutic interventions. Atherosclerosis. 2018;276:98–108.PubMedCrossRef
70.
Thayse K, Kindt N, Laurent S, Carlier S. VCAM-1 target in non-invasive imaging for the detection of atherosclerotic plaques. Biology (Basel). 2020;9(11):368.PubMed
71.
Metadata
Title
The effects of folic acid supplementation on endothelial function in adults: a systematic review and dose-response meta-analysis of randomized controlled trials
Authors
Mohammad Zamani
Fatemeh Rezaiian
Saeede Saadati
Kaveh Naseri
Damoon Ashtary-Larky
Mohsen Yousefi
Elnaz Golalipour
Cain C. T. Clark
Samira Rastgoo
Omid Asbaghi
Publication date
01-12-2023
Publisher
BioMed Central
Keyword
Folic Acid
Published in
Nutrition Journal / Issue 1/2023
Electronic ISSN: 1475-2891
DOI
https://doi.org/10.1186/s12937-023-00843-y

Other articles of this Issue 1/2023

Nutrition Journal 1/2023 Go to the issue

Research

Chronotype is associated with eating behaviors, physical activity and overweight in school-aged children

Research

Does the ketogenic diet improve neurological disorders by influencing gut microbiota? A systematic review

Research

Association between dietary approaches to stop hypertension (DASH) diet and hyperuricemia among Chinese adults: findings from a nationwide representative study

Research

Does vitamin D affect strength and speed characteristics and testosterone concentration in elite young track and field athletes in the North European summer?

Research

Healthy Nordic diet and associations with plasma concentrations of metabolites in the choline oxidation pathway: a cross-sectional study from Northern Sweden

Research

Low carbohydrate high fat-diet in real life assessed by diet history interviews
Live Webinar | 27-06-2024 | 18:00 (CEST)

Keynote webinar | Spotlight on medication adherence

Reserve your place

Live: Thursday 27th June 2024, 18:00-19:30 (CEST)

WHO estimates that half of all patients worldwide are non-adherent to their prescribed medication. The consequences of poor adherence can be catastrophic, on both the individual and population level.

Join our expert panel to discover why you need to understand the drivers of non-adherence in your patients, and how you can optimize medication adherence in your clinics to drastically improve patient outcomes.

Prof. Kevin Dolgin
Prof. Florian Limbourg
Prof. Anoop Chauhan
Developed by: Springer Medicine
Obesity Clinical Trial Summary

At a glance: The STEP trials

Read more

A round-up of the STEP phase 3 clinical trials evaluating semaglutide for weight loss in people with overweight or obesity.

Developed by: Springer Medicine

Highlights from the ACC 2024 Congress

Year in Review: Pediatric cardiology

Pediatric Cardiology Video

Watch Dr. Anne Marie Valente present the last year's highlights in pediatric and congenital heart disease in the official ACC.24 Year in Review session.

Year in Review: Pulmonary vascular disease

Cardiopulmonary Comorbidity Video

The last year's highlights in pulmonary vascular disease are presented by Dr. Jane Leopold in this official video from ACC.24.

Year in Review: Valvular heart disease

Valvular Heart Disease Video

Watch Prof. William Zoghbi present the last year's highlights in valvular heart disease from the official ACC.24 Year in Review session.

Year in Review: Heart failure and cardiomyopathies

Heart Failure Video

Watch this official video from ACC.24. Dr. Biykem Bozkurt discusses last year's major advances in heart failure and cardiomyopathies.

ACC 2024 Congress Coverage

Year in Review: Heart failure and cardiomyopathies

Heart Failure Video

Watch this official video from ACC.24. Dr. Biykem Bozkurt discusses last year's major advances in heart failure and cardiomyopathies.

Watch now

Semaglutide benefits people with type 2 diabetes and obesity-related heart failure

16-04-2024 Type 2 Diabetes News

Incentivised to exercise

11-04-2024 Lifestyle Modifications News

New intervention for STEMI-related cardiogenic shock

10-04-2024 Myocardial Infarction News

» View more highlights on the ACC 2024 congress hub page

Image Credits