Folate: An Under-Rated Vitamin!

Abstract & Commentary

By Barbara A. Phillips, MD, MSPH, Professor of Medicine, University of Kentucky; Director, Sleep Disorders Center, Samaritan Hospital, Lexington, KY. Dr. Phillips serves on the speaker’s bureau of Cephalon, Boehringer Ingelheim, Merck, Res Med, and GlaxoSmithKline and is a consultant for Boehringer Ingelheim, Wyeth-Ayerst, and ResMed.

Synopsis: Increased intake of folate in any form is associated with a reduced risk of developing hypertension for women.

Source: Forman JP, et al. Folate intake and the risk of incident hypertension among US women. JAMA. 2005;293: 320-329.

This report comes from 2 different cohorts of women in the Nurses’ Health Study (NHS): the older cohort (NH1) and the younger cohort (NH2). Together, these cohorts yielded 156,063 women aged 25-55 at intake who were followed for 8 years. Dietary folate consumption was assessed with a validated food frequency questionnaire; this instrument correlates well with measured folate.1 Data were also collected about nondietary supplemental folate intake. Hypertension was defined as a diastolic blood pressure higher than 140 mm Hg, or a systolic blood pressure higher than 90 mm Hg, or a diagnosis of hypertension given by a physician. Women with hypertension at the time of enrollment were excluded from analysis. Total folate intake was categorized as less than 200 mg/d, 200-399 mg/d, 400-599 mg/d, 600-799 mg/d, and > 800 mg/d. Relevant confounders such as age, body mass index, smoking status, physical activity, baseline blood pressure, other dietary constituents (such as caffeine, alcohol, sodium, and potassium), analgesic and oral contraceptive use, family history and race were identified and controlled for in the statistical analysis.

During the 8 years of follow-up, 1.14% of the younger cohort and 3.84% of the older follow-up developed incident hypertension. There was an inverse relationship between folate intake and unfavorable lifestyles; eg, those who consumed more folate were less likely to smoke, be obese, drink excess caffeine and alcohol, be physically inactive, and consume inadequate diets. In this cohort, most of the total folate intake consisted of supplements, rather than dietary intake. In the younger (NHS2) group, women who consumed 1000 mg/d of total folate had a 45% reduction in the risk of developing hypertension after adjustment for confounders (P < 0.001) compared with those women who consumed < 200 mg/d. In the older women (NHS1), those who consumed more than 1000 mg/d of folate were 28% less likely to develop hypertension than those in the lowest intake group (P = 0.05). When the analysis was restricted only to those who consumed most of their folate as supplemental rather than dietary, the reduction in the risk of developing hypertension persisted but was statistically significant only for the younger women. When the analysis was redone comparing the risk of hypertension between those who consumed 400 mg/d compared with 1000 mg/d, the protective effect of increased folate persisted. However, the use of multivitamins was not associated with a reduced risk of hypertension, controlling for all other variables.

Commentary

Although there have been 2 small trials suggesting that folate intake is related to reduced risk of hypertension2,3 this is the first prospective study to demonstrate a relationship between folate intake and the risk of incident hypertension. Possible biologic mechanisms for folate’s effect on blood pressure include increased nitric oxide production in endothelial cells4 or reduction of plasma homocysteine.5

The US recommended daily allowance for folate is 400 mg/d,6 and there are probably few people in the United States who consume less than 200 mg/d.7 However, the greatest protective effect in this study was with the highest levels of folate intake (> 1000 mg/d), and there was a significantly reduced chance of developing hypertension for younger women who consumed > 1000 mg/d compared with those who consumed the recommended daily allowance of 400 mg/d. In this population of nurses, few people consumed > 1000 mg/d (251/93,803 in NHS 2, and 240/62,260 in NHS 1). Since it is likely that nurses are somewhat more health-conscious than the US population at large, probably very few of our patients consume the amount of folate (> 1000 mg) that was associated with the greatest benefit in reducing incident hypertension in this study. This suggests that consuming the recommended daily allowance of folate does not provide as much benefit as exceeding it.

Vegetables, of course, are rich in folate. Vegetarian diets have been shown to reduce blood pressure,8 and it is likely that the increased dietary folate of a vegetarian diet is at least part of the explanation for the beneficial effect of such diets on blood pressure. In this study, total intake of folate remained significantly associated with a reduced risk of developing hypertension even after controlling for other known dietary factors such as calcium, magnesium, potassium, and fiber.

This study adds reduced risk of developing hypertension to the list of benefits that have already been associated with increased folate intake. Other likely benefits of folate include improved cognitive function in the elderly,9 reduced risk of cervical and colon cancer,10,11 reduced risk of congenital abnormalities,12 and reduced cardiovascular risk.13

A cautionary note is in order here. The promise of vitamin A reducing lung cancer didn’t pan out,14 and vitamin E has actually been shown to be associated with increased cardiovascular risk.15 However, the current findings about the benefits of high amounts of folate in reducing the risk of hypertension come from a large, well-designed, carefully controlled, prospective trial. They are worth paying attention. For me, this means including increased folate intake along with the other behavioral interventions (weight loss, exercise, reduced sodium, reduced alcohol) that we recommend for hypertension control. Pass the spinach, please.

References

1. Rimm EB, et al. Reproducibility and validity of an expanded self-administered semiquantitative food frequency questionnaire among male health professionals. Am J Epidemiol. 1992;135:1114-1126.

2. van Dijk RA, et al. Long-term homocysteine-lowering treatment with folic acid plus pyridoxine is associated with decreased blood pressure but not with improved brachial artery stiffness; a 2-year, randomized, placebo-controlled trial. Arterioscler Thromb Vasc Biol. 2001;21: 2072-2079.

3. Mangoni AA, et al. Folic acid enhances endothelial function and reduces blood pressure in smokers: a randomized controlled trial. J Intern Med. 2002;252:497-503.

4. Stroes ES, et al. Folic acid reverts dysfunction of endothelial nitric oxide synthase. Circ Res. 2000;86:1129-1134.

5. Jacques PF, et al. The effect of folic acid fortification on plasma folate and total homocysteine concentrations. N Engl J Med. 1999;340: 1449-1454.

6. Recommendations for the use of folic acid to reduce the number of cases of spina bifida and other neural tube defects. MMWR Recomm Rep. 1992;41(RR-14):1-7.

7. Choumenkovitch SF, et al. Folic acid intake from fortification in United States exceeds predictions. J Nutr. 2002;132:2792-2798.

8. Margetts BM, et al. Vegetarian diet in mild hypertension: a randomised controlled trial. Br Med J (Clin Res Ed). 1986;293:1468-1471.

9. D’Anci KE, Rosenberg IH. Folate and brain function in the elderly Curr Opin Clin Nutr Metab Care. 2004;7:659-664.

10. Rampersaud GC, et al. Relationship of folate to colorectal and cervical cancer: review and recommendations for practitioners. J Am Diet Assoc. 2002;102:1273-1282.

11. Larsson SC, et al. A prospective study of dietary folate intake and risk of colorectal cancer. Cancer Epidemiol Biomarkers Prev. 2005;14: 740-743.

12. McDonald SD, et al. The prevention of congenital anomalies with periconceptional folic acid supplementation. J Obstet Gynaecol Can. 2003;25:115-121.

13. Verhaar MC, et al. Folates and cardiovascular disease. Arterioscler Thromb Vasc Biol. 2002;22:6-13.

14. Omenn GS. Human lung cancer chemoprevention strategies: Parker B. Francis lecture. Chest. 2004;125(5 Suppl):123S-127S.

15. Lonn E, HOPE and HOPE-TOO Trial Investigators. Effects of long-term vitamin E supplementation on cardiovascular events and cancer: a randomized controlled trial. JAMA. 2005;293:1338-1347.