Folic acid supplementation for stroke prevention: The devil is in the details
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Cerebrovascular disease (CVD) is the second leading cause of death worldwide. In addition to the traditional risk factors such as hypertension, diabetes, and hyperlipidemia, nutritional folate deficiency may be an important risk factor for CVD, especially in low-income countries. Folic acid supplementation has been considered for stroke prevention, but trial results have been variable. Therefore, in general, stroke patients do not receive folic acid supplementation routinely, partly due to the lack of consensus regarding such necessity. To be metabolically active, the synthetic folic acid, which is often taken as a supplement, needs to be enzymatically converted to 5-methyltetrahydrofolate (5-MTHF) by the endogenous enzyme methylenetetrahydrofolate reductase (MTHFR). 5-MTHF promotes homocysteine catabolism while improving endothelial function and reducing superoxide generation. It has been shown that supplementation with synthetic folic acid reduced the incidence of ischemic strokes in individuals with hypertension, but the efficacy of folic acid supplementation in primary prevention of ischemic strokes was markedly reduced in the subset of hypertensive patients with mutations in the MTHFR gene. Furthermore, supplementation with synthetic folic acid may promote accumulation of unmetabolized free folic acid which may increase risk of cancer, immune suppression, and cognitive impairment, especially in patients with mutations in MTHFR. Since MTHFR genotyping is neither feasible nor cost-effective in the vast population of patients at risk of ischemic stroke, supplementation with low-dose 5-MTHF merits examination in large well-designed clinical trials.
- Tong X, Yang Q, Ritchey MD, et al. The burden of cerebrovascular disease in the United States. Prev Chronic Dis. 2019;16:E52. doi: 10.5888/pcd16.180411
- Feigin VL, Owolabi MO, Feigin VL, World Stroke Organization-Lancet Neurology Commission Stroke Collaboration Group. Pragmatic solutions to reduce the global burden of stroke: A World Stroke Organization-Lancet Neurology Commission. Lancet Neurol. 2023;22:1160-1206. doi: 10.1016/S1474-4422(23)00277-6
- Mozaffarian D, Benjamin EJ, Go AS, et al. Heart disease and stroke statistics-2016 update: A report from the American Heart Association. Circulation. 2016;133(4):e38-e360. doi: 10.1161/cir.0000000000000350
- Gorelick PB. New horizons for stroke prevention: PROGRESS and HOPE. Lancet Neurol. 2002;1(3):149-156. doi: 10.1016/s1474-4422(02)00070-4
- Khaku AS, Tadi P. Cerebrovascular disease. In: StatPearls. Treasure Island, FL: StatPearls Publishing LLC.; 2023.
- Yu JG, Zhou RR, Cai GJ. From hypertension to stroke: Mechanisms and potential prevention strategies. CNS Neurosci Ther. 2011;17(5):577-584. doi: 10.1111/j.1755-5949.2011.00264.x
- GBD 2019 Stroke Collaborators. Global, regional, and national burden of stroke and its risk factors, 1990-2019: A systematic analysis for the Global Burden of Disease Study 2019. Lancet Neurol. 2021;20(10):795-820. doi: 10.1016/s1474-4422(21)00252-0
- Schutte AE, Srinivasapura Venkateshmurthy N, Mohan S, Prabhakaran D. Hypertension in low- and middle-income countries. Circ Res. 2021;128(7):808-826. doi: 10.1161/circresaha.120.318729
- Rozen R. molecular biology of methylenetetrahydrofolate reductase (MTHFR): Interrelationships with folic acid, homocysteine and vascular disease. In: Robinson K, editor. Homocysteine and Vascular Disease. Heidelberg: Springer Netherlands; 2000. p. 271-289.
- McRae MP. High-dose folic acid supplementation effects on endothelial function and blood pressure in hypertensive patients: A meta-analysis of randomized controlled clinical trials. J Chiropr Med. 2009;8(1):15-24. doi: 10.1016/j.jcm.2008.09.001
- Antoniades C, Shirodaria C, Warrick N, et al. 5-Methyltetrahydrofolate rapidly improves endothelial function and decreases superoxide production in human vessels: Effects on vascular tetrahydrobiopterin availability and endothelial nitric oxide synthase coupling. Circulation. 2006;114(11):1193-1201. doi: 10.1161/CIRCULATIONAHA.106.612325
- Carboni L. Active folate versus folic acid: The role of 5-MTHF (Methylfolate) in human health. Integr Med (Encinitas). 2022;21(3):36-41.
- Yang Q, Botto LD, Erickson JD, et al. Improvement in stroke mortality in Canada and the United States, 1990 to 2002. Circulation. 2006;113(10):1335-1343. doi: 10.1161/circulationaha.105.570846
- Tian T, Yang KQ, Cui JG, Zhou LL, Zhou XL. Folic acid supplementation for stroke prevention in patients with cardiovascular disease. Am J Med Sci. 2017;354(4):379-387. doi: 10.1016/j.amjms.2017.05.020
- Hsu CY, Chiu SW, Hong KS, et al. Folic acid in stroke prevention in countries without mandatory folic acid food fortification: A meta-analysis of randomized controlled trials. J Stroke. 2018;20:99-109.
- 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. doi: 10.1161/jaha.116.003768
- Lee M, Hong KS, Chang SC, Saver JL. Efficacy of homocysteine-lowering therapy with folic acid in stroke prevention: A meta-analysis. Stroke. 2010;41(6):1205-1212. doi: 10.1161/strokeaha.109.573410
- Cohen E, Margalit I, Shochat T, Goldberg E, Krause I. Sex differences in folate levels: A cross sectional study of a large cohort from Israel. Isr Med Assoc J. 2021;23(1):17-22.
- Ray JG, Vermeulen MJ, Boss SC, Cole DEC. Declining rate of folate insufficiency among adults following increased folic acid food fortification in Canada. Can J Public Health. 2002;93(4):249-253. doi: 10.1007/bf03405010
- Appelros P, Stegmayr B, Terént A. Sex differences in stroke epidemiology: A systematic review. Stroke. 2009;40(4): 1082-1090. doi: 10.1161/strokeaha.108.540781
- Blom HJ, Smulders Y. Overview of homocysteine and folate metabolism. With special references to cardiovascular disease and neural tube defects. J Inherit Metab Dis. 2011;34(1):75-81. doi: 10.1007/s10545-010-9177-4
- Pietrzik K, Bailey L, Shane B. Folic acid and L-5- methyltetrahydrofolate: Comparison of clinical pharmacokinetics and pharmacodynamics. Clin Pharmacokinet. 2010;49(8):535-548. doi: 10.2165/11532990-000000000-00000
- Auton A, Brooks LD, Durbin RM, et al. A global reference for human genetic variation. Nature. 2015;526(7571):68-74. doi: 10.1038/nature15393
- Graydon JS, Claudio K, Baker S, et al. Ethnogeographic prevalence and implications of the 677C>T and 1298A>C MTHFR polymorphisms in US primary care populations. Biomark Med. 2019;13(8):649-661. doi: 10.2217/bmm-2018-0392
- Bennett DA, Parish S, Millwood IY, et al. MTHFR and risk of stroke and heart disease in a low-folate population: A prospective study of 156 000 Chinese adults. Int J Epidemiol. 2023;52:1862-1869. doi: 10.1093/ije/dyad147
- Oxford Population Health. Folic Acid Supplements May Reduce the Risk of Stroke in People with Genetic Predisposition. Oxford. Available from: https://www. ndph.ox.ac.uk/news/folic-acid-supplements-may-reduce-the-risk-of-stroke-in-people-with-genetic-predisposition#:~:text=folic%20acid%20also%20lowers%20 blood,such%20as%20bread%20and%20cereals [Last accessed on 2023 Dec 07].
- Huo Y, Li J, Qin X, et al. Efficacy of folic acid therapy in primary prevention of stroke among adults with hypertension in China: The CSPPT randomized clinical trial. JAMA. 2015;313(13):1325-1335. doi: 10.1001/jama.2015.2274
- Shirodaria C, Antoniades C, Lee J, 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):2262-2270. doi: 10.1161/circulationaha.106.679084
- Sauer J, Mason JB, Choi SW. Too much folate-A risk factor for cancer and cardiovascular disease? Curr Opin Clin Nutr Metab Care. 2009;12(1):30-36. doi: 10.1097/MCO.0b013e32831cec62
- Cheng Y, Liu S, Chen D, et al. Association between serum 5-methyltetrahydrofolate and homocysteine in Chinese hypertensive participants with different MTHFR C677T polymorphisms: A cross-sectional study. Nutr J. 2022;21(1):29. doi: 10.1186/s12937-022-00786-w
- Brown C, Wang J, Jiang H, Elias MF. Homocysteine reduction for stroke prevention: Regarding the recent AHA/ASA 2021 prevention of stroke in patients with stroke and transient ischemic attack. Pharmgenomics Pers Med. 2023;16:895-900. doi: 10.2147/pgpm.S426421
- Cole BF, Baron JA, Sandler RS, et al. Folic acid for the prevention of colorectal adenomas: A randomized clinical trial. JAMA. 2007;297(21):2351-2359. doi: 10.1001/jama.297.21.2351
- Pellis L, Dommels Y, Venema D, et al. High folic acid increases cell turnover and lowers differentiation and iron content in human HT29 colon cancer cells. Br J Nutr. 2008;99(4):703-708. doi: 10.1017/s0007114507824147
- Sawaengsri H, Wang J, Reginaldo C, et al. High folic acid intake reduces natural killer cell cytotoxicity in aged mice. J Nutr Biochem. 2016;30:102-107. doi: 10.1016/j.jnutbio.2015.12.006
- Ebbing M, Bønaa KH, Nygård O, et al. Cancer incidence and mortality after treatment with folic acid and Vitamin B12. JAMA. 2009;302(19):2119-2126. doi: 10.1001/jama.2009.1622
- Reynolds EH. Folic acid, ageing, depression, and dementia. BMJ. 2002;324(7352):1512-1515. doi: 10.1136/bmj.324.7352.1512