January 2011 Issue

To Supplement or Not? — Despite Its Homocysteine Benefit, Folic Acid Is Not Essential for CVD Protection
By Jenna A. Bell, PhD, RD, CSSD
Today’s Dietitian
Vol. 13 No. 1 P. 8

Although hyperhomocysteinemia has been recognized as an independent risk factor for cardiovascular disease (CVD), stroke, and thrombosis, the mechanisms of action and treatment remain hot topics in science.1,2 Elevated homocysteine levels may impair vascular function by adversely affecting endothelial function, producing reactive oxygen species (ROS), and leading to low-density lipid oxidation.3 Because folic acid and B vitamins are required for the remethylation of homocysteine to methionine, supplementation with these vitamins has been shown to lower plasma homocysteine levels.3 Despite this seemingly positive effect, recent research reveals that the decision to prescribe folic acid and B vitamin supplementation is uncertain. 

This article provides an update on the current state of homocysteine and folic acid/B vitamin supplementation to help clarify the uncertainty. The discussion will focus on supplementation because experts agree: Eating a diet with adequate folic acid is beneficial for everyone. 

Causes of Hyperhomocysteinemia
A 2004 review outlines the factors associated with elevated homocysteine levels as follows1:

Age and gender: Plasma homocysteine levels appear to increase with age. Up to the age of 40, men tend to have higher levels than women; but after menopause, women experience levels similar to men.

Genetic: Research has identified a genetic mutation that leads to elevated homocysteine levels. Individuals with this mutation are also more sensitive to folic acid deficiencies.

Vitamin deficiency: The leading cause of hyperhomocysteinemia is vitamin deficiency. Those at risk for vitamin deficiency include the usual suspects: older adults, pregnant women, people with malabsorptive disorders or malignant diseases, and individuals who maintain an imbalanced diet. Alcohol and drug abuse can also contribute to deficiency.

How It Contributes to CVD
Hyperhomocysteinemia has been implicated in CVD development due to its adverse impact on endothelial cells in human blood vessels.1 Homocysteine-mediated oxidative stress contributes to cell injury and subsequent death and is especially detrimental to cells of the cardiovascular system. According to Stanger et al, it alters vascular morphology, stimulates inflammation, activates the endothelium and blood-clotting cascade, and inhibits fibrinolysis. Myriad events contribute to a loss of endothelial antithrombotic function and induce a procoagulant environment.1

More recent evidence with rats shows that chronic hyperhomocysteinemia can alter the antioxidant defense capabilities in the brain and blood and induce oxidative-nitrative stress in the heart.2,4

Does Folic Acid/B Vitamin Supplementation Provide Protection?
Folic acid, vitamin B6, and vitamin B12 deficiency inhibits the breakdown of homocysteine, causing plasma levels to rise.1 Therefore, folic acid supplementation has been shown to lower plasma homocysteine levels.1 Reported online in October 2010 in The American Journal of Clinical Nutrition, a study by Tighe et al showed that a low dose of folic acid (0.2 mg/day) effectively reduced homocysteine levels just as well as higher doses (0.4 and 0.8 mg/day).

Folic acid supplementation has been shown to lower homocysteine levels and ameliorate many of the detrimental effects. Kolling et al found that folic acid prevented homocysteine-induced lipid peroxidation, ROS production, and enzymatic antioxidant defense and nitrite level reduction in rats.2 The researchers assert that if these effects can be replicated in human trials, folic acid supplementation may be a viable adjunct therapy for cardiovascular alterations caused by homocysteine. Similarly, Matte et al found that hyperhomocysteinemia caused DNA damage and disrupted antioxidant defenses in the parietal cortex and blood of rats.4 A coinjection with folic acid squelched these effects.

But despite the beneficial results from the aforementioned studies, recent reports have indicated that the homocysteine-lowering effects may not lead to changes in CVD risk or mortality. In May 2008, Albert et al published results from their randomized trial in The Journal of the American Medical Association. The team sought to test whether a combination of folic acid, vitamin B6, and vitamin B12 reduced the risk of cardiovascular events among women with and without CVD. Participants in the treatment group were given a combination pill of the three vitamins for 7.3 years. At the end of the trial, folic acid, vitamin B6, and vitamin B12 supplementation did not affect cardiovascular events in high-risk women despite the significant homocysteine reductions.

Two recent meta-analyses questioned the efficacy and benefit of B vitamin supplementation to reduce CVD risk. The August 15, 2010, issue of The American Journal of Cardiology published the results of a meta-analysis led by Miller. The group compiled results from randomized controlled trials of folic acid supplementation to prevent CVD events and reported that supplementation did not affect the risk of CVD or stroke. The second meta-analysis performed considered eight large, randomized, placebo-controlled trials involving 37,485 participants. Clarke et al concluded that folic acid supplementation for the purposes of lowering homocysteine levels had no significant effect within five years on cardiovascular events, overall cancer occurrence, or mortality.5

Supplement Only When Warranted
According to the American Heart Association (AHA), despite recognizing hyperhomocysteinemia as a risk factor for CVD, widespread supplementation with folic acid and B vitamins is not warranted. The AHA recommends a diet rich in fruits and vegetables, whole grains, and fat-free or low-fat dairy products. The aim is to achieve the recommended daily value for folic acid (400 mcg/day) from citrus fruits, tomatoes, vegetables, grain products, and fortified foods such as rice and wheat flour. The AHA notes that supplementation should be considered only when the diet is insufficient.

— Jenna A. Bell, PhD, RD, CSSD, is a nutrition writer, blogger, and communications consultant living in Chicago.


1. Stanger O, Herrmann W, Pietrzik K, et al. Clinical use and rational management of homocysteine, folic acid, and B vitamins in cardiovascular and thrombotic diseases. Z Kardiol. 2004;93(6):439-453.

2. Kolling J, Scherer EB, da Cunha AA, da Cunha MJ, Wyse AT. Homocysteine induces oxidative-nitrative stress in heart of rats: Prevention by folic acid. Cardiovasc Toxicol. 2010:Epub ahead of print.

3. Ciaccio M, Bellia C. Hyperhomocysteinemia and cardiovascular risk: Effect of vitamin supplementation in risk reduction. Curr Clin Pharmacol. 2010;5(1):30-36.

4. Matté C, Mackedanz V, Stefanello FM, et al. Chronic hyperhomocysteinemia alters antioxidant defenses and increases DNA damage in brain and blood of rats: Protective effect of folic acid. Neurochem Int. 2009;54(1):7-13.

5. Clarke R, Halsey J, Lewington S, et al. Effects of lowering homocysteine levels with B vitamins on cardiovascular disease, cancer, and cause-specific mortality: Meta-analysis of 8 randomized trials involving 37485 individuals. Arch Intern Med. 2010;170(18):1622-1631.