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Global Translational Medicine Folic acid for stroke prevention

a biomarker of folate deficiency. However, further studies first stroke was markedly diminished in patients carrying
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are needed to evaluate the potential benefits of folate the CT and TT gene polymorphisms compared with those
supplementation in primary stroke prevention, especially with CC genotype. The authors posit that individuals with
when combined with B vitamins. the TT genotype may require a high dosage of folic acid
Synthetic folic acid is one of the most common supplementation to overcome biologically insufficient
supplements. Clinical pharmacokinetic and levels. However, low-dose folic acid supplementation
(400 µg daily) improved biochemical and physiological
pharmacodynamic studies on synthetic folic acid
supplementation revealed that approximately 86% of indicators of vascular function in patients with coronary
folic acid in the hepatic portal vein is unmetabolized. 12,22 artery disease, and high-dose folic acid supplementation
28,29
Synthetic folic acid must be converted to 5-MTHF to be (5 mg daily) provides no additional benefit. Therefore,
biologically active. Folate metabolism is impaired in we propose supplementation with 5-MTHF to bypass
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patients with mutations in the methylenetetrahydrofolate folate metabolism and overcome deficiency of active folate
reductase (MTHFR) gene encoding MTHFR, which in hypertensive individuals carrying the TT genotype. This
catalyzes conversion of 5,10-methylenetetrahydrofolate could reduce risk of first stroke while avoiding potential
risks associated with synthetic folic acid accumulation
to biologically active folate, 5-MTHF. The most common outlined below. Supplementation with 5-MTHF is
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MTHFR gene mutation characterized by C-to-T supported by is supported by data from a cross-sectional
substitution at bp677 leads to a 60% reduction in MTHFR
enzyme activity and subsequent folate deficiency. Impaired analysis of Chinese hypertensive participants in the Chinese
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folic acid metabolism in individuals with the MTHFR Stroke Primary Prevention Trials that revealed inverse
TT gene polymorphism leads to folic acid accumulation association between serum 5-MTHF and homocysteine
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and folate deficiency and attenuates folate-mediated when 5-MTHF was ≤10 ng/mL. This underscores the
need for higher serum 5-MTHF status in hypertensive
physiologic functions. Approximately one fourth of the patients regardless of MTHFR genotype. Clinical trials are
global population are carriers of MTHFR 677C>T gene urgently needed to evaluate the efficacy of 5-MTHF for
mutation, which occurs in nearly half of Hispanics. 23,24 primary stroke prevention while avoiding potential risks
Unmetabolized folic acid can accumulate and compete associated with synthetic folic acid. Emerging noninvasive
with natural folate for the folate transporter and the folate measures of central nervous system perfusion including
receptor, thereby reducing generation of biologically active
folate. 12 retinal vascular imaging will likely play an important
role in monitoring the effectiveness of stroke prevention
To examine the possible relevance of folic acid for stroke strategies such as fortification or supplementation with
prevention, researchers at the China Kadoorie Biobank synthetic folic acid versus 5-MTHF. 31
Study Group 25,26 analyzed genetic data from 156,253
participants in their study population who had a genetic 3. Potential risks of supplementation with
variant in MTHFR which was associated with higher synthetic folic acid
homocysteine levels. Among the 156,253 participants Supplementation with synthetic folic acid can lead to
studied, 12,240 developed a stroke over a 12 year period. accumulation of unmetabolized free folic acid (UMFA),
Individuals with MTHFR variant had a 13% higher risk especially in patients with CT or TT genotype for
of total stroke (adjusted OR: 1.13, 95% CI: 1.09 – 1.17), MTHFR. UMFA accumulation has been implicated in
suggesting a link between active folate levels and risk of the development of chronic disease including colorectal
stroke.
cancer. In the Aspirin/Folate Polyp Prevention Study
The efficacy of folic acid supplementation in improving using folic acid as a chemopreventive agent, 29,32 subjects
cardiovascular outcomes in hypertensive patients is supplemented with 1 mg daily folic acid had more
variable due to differential expression of the MTHFR gene. advanced lesions and multiple adenomas at 5-year
In the China Stroke Primary Prevention Trial, a total of follow-up. The folic acid group also exhibited a higher rate
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20,702 Chinese hypertensive patients were randomized to of invasive prostate cancer. The effects of supranormal folic
daily treatment with a single-pill combination of enalapril acid supplementation have been attributed to decreased
and 800 µg folic acid versus enalapril alone. Folic acid markers of cell differentiation and increased cell turnover
supplementation led to significant risk reduction in the first associated with high concentrations of folate in colon
stroke (2.7%), first ischemic stroke (2.2%), and composite cancer cells. 29,33 Folic acid supplementation and impaired
cardiovascular events (3.1%) compared to enalapril alone folic acid metabolism have also been associated with
(3.4%, 2.8%, and 3.9%, respectively). However, the efficacy immunosuppression, cancer, and cognitive impairment
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of synthetic folic acid supplementation in reducing risk of or dementia. Therefore, folic acid supplementation poses
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Volume 3 Issue 2 (2024) 3 doi: 10.36922/gtm.2509