Folic Acid for the Secondary Prevention of Heart Disease

May 1999; Volume 2: 49-52

By Matthew J. Sorrentino, MD, FACC

Homocystinuria is a rare genetic disease caused by the deficiency of the enzyme cystathionine beta-synthase leading to significantly elevated levels of homocysteine. The condition is associated with serious thromboembolic complications at an early age. Myocardial infarction, pulmonary embolism, and stroke are the most common causes of death in affected individuals.

Study of individuals with this rare disorder has led to speculation that homocysteine and other sulfur-containing amino acids may be a cause of arteriosclerosis. The recognition that folic acid and other B vitamins can lower plasma homocysteine levels suggests that a simple treatment may be available to prevent vascular disease.

Biochemistry and Pathogenesis

Homocysteine is an amino acid produced in the metabolism of protein—usually dietary protein. It has been implicated in atherogenesis. Homocysteine levels are elevated after an acute coronary event. In addition, there is some evidence that endothelial dysfunction may raise homocysteine levels.1 Administration of folic acid will reduce homocysteine levels by enhancing the remethylation of homocysteine to methionine.

Clinical Studies

Retrospective Analyses. An association between elevated plasma homocysteine levels and arteriosclerotic disease was first noted by retrospective case-control studies. Homocysteine levels are frequently elevated in adult patients with atherosclerotic disease. In 1990, Malinow summarized 11 series with more than 2,000 patients showing that homocysteine and other sulfur-containing amino acids values were higher in patients with coronary artery, cerebrovascular, and peripheral vascular disease.2 There was no correlation between homocysteine levels and other cardiovascular risk factors such as cholesterol levels, cigarette smoking, or hypertension. A significant overlap of homocysteine levels was noted, however, with nearly 70-80% of patients having normal values.

Boushey and colleagues extended Malinow’s review with a meta-analysis of studies through June 1994.3 Hyperhomocysteinemia was determined to be an independent risk factor for vascular disease with an odds ratio of 1.7 for coronary artery disease of a 5 µmol/L homocysteine increment. This risk is on the same order as risk for coronary disease by lipid factors.

The risk associated with hyperhomocysteinemia appears to be a graded risk without a threshold below which there is no risk. This suggests a causal relationship between homocysteine and vascular disease. More recently a multicenter case-control study in Europe showed that homocysteine concentrations greater than the 80th percentile for control subjects were associated with an increased risk of atherosclerotic disease.4 Furthermore, low red cell folic acid concentration and low vitamin B6 levels were associated with an increased risk.

Prospective and Additional Meta-Analysis. Results of prospective cohort studies of homocysteine and atherosclerotic disease have not been as conclusive as the retrospective case-control studies. The Atherosclerosis Risk in Communities (ARIC) study was a prospective trial designed to determine if homocysteine-related factors were associated with the incidence of coronary heart disease over a greater than three-year period.5 After adjustment for other risk factors, homocysteine was not independently associated with coronary disease.

Genetic studies have also shown inconsistent results. Brattstrom and colleagues reported a meta-analysis of 13 studies that documented homocysteine levels in relationship to three genotypes and found that although the gene mutations caused a mild increase in homocysteine concentration, there was no increase in cardiovascular risk.6

Prospective vs. Retrospective Analyses. There are a number of reasons why the prospective studies may not have been as conclusive as retrospective analyses. Vascular disease itself may result in higher homocysteine levels. Vascular disease is an inflammatory process and a number of inflammatory markers are elevated in patients with atherosclerotic disease.

Prospective clinical data regarding the benefits of lowering homocysteine levels for the prevention of heart disease are not yet complete. In the European Concerted Action Project, use of vitamin preparations containing folic acid and B vitamins appeared to give protection against the development of vascular disease.7 The Nurses Health Study demonstrated a similar observation.8 Prospective randomized studies are needed to verify these preliminary observations.

Low levels of certain vitamins, such as folic acid, vitamin B6, or B12, may be the primary risk factor for vascular disease and homocysteine levels may be a marker of low vitamin levels. For example, the risk of fatal coronary heart disease was found to be associated with low serum folate levels in men and women in the Nutrition Canada Survey.9

Recent studies have implied that homocysteine may be a risk factor for thrombotic events. Patients with the rare genetic disease homocystinuria with high serum levels of homocysteine frequently have thromboembolic complications. Nygard and colleagues prospectively investigated the relationship between homocysteine levels and mortality in 587 patients with confirmed coronary artery disease and found a strong and graded relationship between homocysteine levels and total mortality.10 This relationship was strengthened when the end point of coronary mortality was used. Acute coronary events are known to be associated with thrombus formation at the site of a ruptured plaque. This result was confirmed in the British United Provident Association Study where homocysteine levels were significantly higher in men who died of coronary heart disease with the association strongest in younger individuals.11

Fortification and Formulation

Homocysteine levels can be reduced by dietary or supplemental folic acid. A diet rich in fruits and vegetables should provide sufficient amounts of folic acid and other B vitamins. (See Table 1 for food sources.)

    Table 1 
    Food Sources of Folate*                                                                           
    Food Serving 
    Size 
    Amount 
    (mcg) 
    %Daily 
    Value‡
    Chicken liver 3.5 oz 770 193
    Breakfast cereals 1/2 to 1 1/2 cup 100-400 25-100
    Braised beef liver 3.5 oz 217 54
    Lentils, cooked 1/2 cup 180 45
    Chickpeas 1/2 cup 141 35
    Asparagus 1/2 cup 132 33
    Spinach, cooked 1/2 cup 131 33
    Black beans 1/2 cup 128 32
    Kidney beans 1/2 cup 115 29
    Baked beans with pork 1 cup 92 23
    Lima beans 1/2 cup 78 20
    Tomato juice 1 cup 48 12
    Brussels sprouts 1/2 cup 47 12
    Orange 1 medium 47 12
    Broccoli, cooked 1/2 cup 39 10

    *Folic acid and folate are interchangeable terms. Folic acid is the synthetic form of folate, which is found naturally in some foods. 

    ‡based on Daily Value for folate of 400 mcg 

    Sources: Pennington, Jean AT, ed. Food Values of Portions Commonly Used. 16th ed. Philadelphia, PA: Lippincott Raven Publishers; 1994. http://www.fda.gov/fdac/features/796_fcht.html and USDA Nutrient Database for Standard Reference, http://www.nal.usda.gov/fnic/foodcomp 
    _________________________________________________________

Unfortunately, the American diet is usually deficient in the foods needed to supply these vitamins adequately. It is estimated that if the American population increased intake of fruits and vegetables by two to three servings a day, folic acid intake would increase about 100 mcg/d with an average decrease in homocysteine levels of about 2 µmol/L.3 Folic acid supplements can bring about further reductions in homocysteine levels. Supplementing the diet with 400 mcg/d of folic acid will decrease homocysteine levels by approximately 6 µmol/L.3

Recently the Food and Drug Administration began fortifying cereal-grain products with folic acid (140 mcg per 100 g of cereal) to help prevent neural tube defects. This fortification began January 1, 1999. Unfortunately, a recent study indicated that cereals fortified to this level would decrease homocysteine levels by only 3.7%, thought to be inadequate to make substantial impact on vascular disease,12 but adequate to reduce the incidence of congenital neural tube defects in newborns.

Folate is commonly available in multivitamins, as part of B-complex supplements, and by itself in a capsule. It is water soluble, and may be taken at any time, once daily. The designation of the United States Pharmacopoeia (USP) on the label may indicate that the manufacturer believes the product meets USP standards for dissolution, purity, disintegration, and strength.

Adverse Effects

Supplementation with folic acid is probably safe. There have been rare cases of exacerbation of vitamin B12 deficiency reported at high doses of folic acid supplementation.13 This may be a concern in elderly patients, and especially elderly vegetarian patients, who may require B12 supplementation. There is some evidence to suggest that many elderly people have early vitamin B12, B6, or folate deficiency despite having normal serum vitamin concentrations.14 Folic acid supplementation may make it more difficult to diagnose vitamin B12 deficiency, when it is present, by simple review of complete blood cell counts.

Drug Interactions

Several drugs may interact with folic acid. Patients treated with the anti-seizure medication phenytoin may have a decrease in phenytoin levels, although at supplement doses of 400 mcg/d, this decrease is unlikely to increase seizure frequency.13 Folic acid may also reduce the efficacy of methotrexate used for rheumatoid arthritis and other medical conditions.

Conclusion

Retrospective studies have shown a clear association between homocysteine levels and atherosclerotic disease, and identified homocysteine as an independent risk factor for heart disease. Prospective studies have been less conclusive but there is growing evidence that homocysteine levels may correlate with the risk of thrombotic complications. In patients with known atherosclerotic disease the desirable homocysteine level is less than 11 µmol/L. Dietary or supplemental folic acid of 400 mcg can lower homocysteine levels 5-6 µmol/L.

Patients who have premature atherosclerosis or high homocysteine levels may require higher doses of folic acid to achieve a full beneficial effect. In these patients it may be desirable to remeasure homocysteine levels six to eight weeks after initiating therapy to see if an adequate reduction has been obtained.

Recommendation

Screening for increased levels of homocysteine is recommended in individuals with premature atherosclerosis or thrombotic complications without clear cause. Families of affected individuals should be screened as well. Patients with known coronary artery disease should have adequate folate intake either through a diet rich in folic acid or with supplements.

Adequate folic acid intake can be achieved with a diet high in fruits and vegetables. Foods rich in folic acid include green leafy vegetables such as spinach and turnip greens; fruits such as oranges; beans such as pinto, garbanzo and kidney; and cereals such as wheat flakes and fortified bran flakes. The current USDA recommendation of five to nine helpings of fruits and vegetables daily should supply an adequate amount of folic acid.

If further supplementation is needed because patients do not eat the recommended number of fruits and vegetables, a capsule containing 400 mcg/d should be adequate for most individuals. In the elderly, supplementation of both vitamin B6 and B12 should also be considered to avoid untoward neurologic reactions in patients with covert B12 deficiency. Higher doses of folic acid should be reserved for those individuals in whom very high homocysteine levels are documented.

References

    1. Woo KS, et al. Hyperhomocyst(e)inemia is a risk factor for arterial endothelial dysfunction in humans. Circulation 1997;96:2542-2544.

    2. Malinow MR. Hyperhomocyst(e)inemia. A common and easily reversible risk factor for occlusive atherosclerosis. Circulation 1990;81:2004-2006.

    3. Boushey CJ, et al. A quantitative assessment of plasma homocysteine as a risk factor for vascular disease. JAMA 1995;274:1049-1057.

    4. Robinson K, et al. Low circulating folate and vitamin B6 concentrations: Risk factors for stroke, peripheral vascular disease, and coronary artery disease. Circulation 1998;97:437-443.

    5. Folsom AR, et al. Prospective study of coronary heart disease incidence in relation to fasting total homocysteine, related genetic polymorphisms, and B vitamins: The Atherosclerosis Risk in Communities (ARIC) study. Circulation 1998;98:204-210.

    6. Brattstrom L, et al. Common methylenetetrahydrofolate reductase gene mutation leads to hyperhomocysteinemia but not to vascular disease: The result of a meta-analysis. Circulation 1998;98:2520-2526.

    7. Graham IM, et al. Plasma homocysteine as a risk factor for vascular disease. The European Concerted Action Project. JAMA 1997;277:1775-1781.

    8. Rimm EB, et al. Folate and vitamin B6 from diet and supplements in relation to risk of coronary heart disease among women. JAMA 1998;279:359-364.

    9. Morrison HI, et al. Serum folate and risk of fatal coronary heart disease. JAMA 1996;275:1893-1896.

    10. Nygard O, et al. Plasma homocysteine levels and mortality in patients with coronary artery disease. N Engl J Med 1997;337:230-236.

    11. Wald NJ, et al. Homocysteine and ischemic heart disease: Results of a prospective study with implications regarding prevention. Arch Intern Med 1998;158: 862-867.

    12. Malinow MR, et al. Reduction of plasma homocyst(e)ine levels by breakfast cereal fortified with folic acid in patients with coronary heart disease. N Engl J Med 1998;338:1009-1015.

    13. Campbell NR. How safe are folic acid supplements? Arch Intern Med 1996;156:1638-1644.

    14. Naurath HJ, et al. Effects of vitamin B12, folate, and vitamin B6 supplements in elderly people with normal serum vitamin concentrations. Lancet 1995;346:85-89.