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Global Translational Medicine Folic acid for stroke prevention

occur annually in the United States (US), and mortality was statistically significant and could not be accounted
from CVD is increasing significantly among younger for by any changes in other recognized risk factors.
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adults. Deaths and disability due to strokes are expected During the same time period, in the absence of folic acid
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to rise alarmingly over the next 30 years, with an annual fortification, there was no decline in stroke mortality in the
stroke mortality projected to increase by 50% or 3 million United Kingdom. These findings suggest that folic acid
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by 2050 according to a new report from the World Stroke fortification may help to reduce stroke-related mortality.
Organization – Lancet Neurology Commission. Nearly
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85% of strokes are ischemic. High morbidity, impact on 2. Folic acid versus 5-MTHF for prevention
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quality of life, and mortality from ischemic stroke have of ischemic stroke
underlined the importance of preventing this dreaded Patients with cardiovascular disease (CVD) are at increased
complication in patients at risk.
risk of stroke. Tian et al. performed a meta-analysis
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Patients with hypertension are three to four times more of 65,790 patients with CVD and observed a significant
likely to suffer a stroke compared to non-hypertensive reduction in stroke risk after folic acid supplementation
patients. Hypertension remains the leading cause (RR = 0.90; 95% CI: 0.84 – 0.97; P = 0.05). Further
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of ischemic stroke, with 54% of strokes attributable stratified analysis revealed greater beneficial effects in
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to hypertension. Hypertension is the most common populations from regions with no or partly fortified grain.
modifiable risk factor for ischemic stroke globally, followed The authors concluded that in patients with CVD, folic acid
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by diabetes, smoking, obesity, atrial fibrillation, and supplementation reduces stroke risk, especially in patients
illicit drug use. Hypertension increases the susceptibility consuming grain that is either not fortified or only partly
to ischemic stroke by promoting and accelerating fortified. This is consistent with randomized controlled
atherosclerotic plaque formation, vascular smooth muscle trials demonstrating lower risk of future stroke in patients
cell hypertrophy, and remodeling of systemic and cerebral receiving folic acid supplementation in countries without
arteries, leading to arterial occlusion and ischemic injury. 6 mandatory folic acid food fortification. The control
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Strikingly, 86% of global deaths and 89% of global group and the experimental groups were balanced in
disability-adjusted life-years lost due to stroke in 2020 the distribution of patients with comorbid conditions
occurred in low- and middle-income countries (LMICs) including acute myocardial infarction with hypertension,
and continue to grow faster in LMICs than in high-income hyperlipidemia, coronary artery disease, and end-stage
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countries. The factors underlying the differences in renal disease. 15
incidence of stroke in low versus high-income countries Folic acid supplementation has been recommended for
are poorly understood although a good understanding primary stroke prevention in patients with hypertension.
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of these factors is essential to tackle this epidemic. An In a meta-analysis of patients with CVD, folic acid
obvious factor is the relatively poor availability of health- supplementation reduced risk of stroke and overall CVD
care services including medications, which leads to poor by 10% and 4%, respectively. Although epidemiologic
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control of hypertension in LMICs. Another important studies have demonstrated lower serum homocysteine
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factor to consider is folate deficiency, given the important concentrations associated with reduced risk of stroke,
role of folate in vascular health. The biologically active randomized controlled trials of folic acid to reduce
form of folate, 5-methyltetrahydrofolate (5-MTHF) is homocysteine levels have yielded mixed results regarding
essential for homocysteine catabolism. In addition, stroke prevention. Lee et al. performed a meta-analysis
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5-MTHF directly improves endothelial nitric oxide of 13 randomized controlled trials that had enrolled
synthase coupling, thereby improving endothelial function about 39,000 participants and observed a trend toward
while reducing vascular superoxide production. 10,11 a benefit with folic acid supplementation, which was not
Folate is not synthesized in the body and must be statistically significant. The authors concluded that folic
obtained through the diet. Due to difficulty in achieving acid supplementation did not demonstrate a major effect
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adequate dietary intake of naturally occurring folates in averting stroke. In stratified analyses, a significant
in the general population, folic acid fortification of food beneficial effect was seen in trials that disproportionally
and supplementation has become common practices. enrolled male patients. This is consistent with lower folate
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In the US and Canada, folic acid fortification of enriched levels, higher homocysteine levels, and higher incidence of
grain products was fully implemented by 1998. The stroke in men compared to women. 18-20 Folate deficiency or
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slow decline in stroke mortality observed between 1990 impaired folate metabolism likely underlies cardiovascular
and 1997 accelerated markedly in 1998 to 2002 in nearly dysfunction while homocysteine may be an innocent
all population strata. The decline in stroke mortality bystander with hyperhomocysteinemia simply serving as
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Volume 3 Issue 2 (2024) 2 doi: 10.36922/gtm.2509