Homocysteine: Another Risk Factor for Heart Disease?
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Homocysteine: Another Risk Factor for Heart Disease?

Elevated levels of homocysteine, an amino acid found in all humans, may be a risk factor for heart disease. Here we review some fascinating new research highlighting how you can lower your homocysteine levels—and possibly your risk for heart disease—by making some very simple dietary changes.

Homocysteine. Perhaps you've not seen or heard the term. But, at one time you may have discussed your homocysteine level with doctors, friends, and family. Why? Because homocysteine is thought to be another predictor of the risk of developing clogged arteries, heart attack, and stroke.

Homocysteine (pronounced home-oh-sis-teen) is an amino acid. While most amino acids found in the body are building blocks of protein or muscle, homocysteine is not. It is formed as an intermediate step in the production of another amino acid, methionine. The production of methionine requires a number of vitamins; if they are in short supply, the level of homocysteine in the blood rises, causing increased odds of developing plaque in the arteries—a significant risk factor for heart attack and stroke.

Risky Business

The connection between elevated homocysteine levels and cardiovascular disease was first noted more than 25 years ago by Kilmer McCully, MD, a pathologist working at Harvard University. McCully noticed that children with a unique metabolic defect called homocystinuria developed strokes and died. He found that these children had a severe build-up of plaque in their arteries, and theorized a link between the diseased arteries and the high levels of homocysteine that accumulate in the blood of children with homocystinuria. Since then, a growing body of evidence confirms the relationship between elevated homocysteine levels and cardiovascular disease and stroke.

In the October 2002 issue of The Journal of the American Medical Association (JAMA) researchers pooled the evidence from 30 studies, involving 5000 people, in an attempt to gauge the significance of homocysteine levels as a risk factor for heart disease. They found that homocysteine levels were not as important in determining the risk of heart disease as the major risk factors like smoking, family history, hypertension, diabetes, and high cholesterol. However, they still found that people with homocysteine levels 25% lower than usual enjoyed an 11% lower risk of heart disease.

Another study in the December 2002 issue of the British Medical Journal analyzed the results of 72 studies (involving a total of 20,669 people) and observed that high blood homocysteine levels contribute to premature cardiovascular disease. The researchers concluded that lowering homocysteine concentrations in the blood by 3 micrograms per liter of blood—achievable by increasing folic acid intake—would reduce the risk of ischemic heart disease by 11%-20%, deep vein thrombosis 8%-38%, and stroke by 15%-33%. In addition, they found that subjects with abnormal folate metabolism due to a specific mutation were at an increased risk for both moderately elevated homocysteine levels and their associated cardiovascular outcomes.

The identification of homocysteine as a risk factor for heart disease is important because many people who develop narrowed, clogged arteries have none of the more familiar and established risk factors. Although widespread screening of homocysteine levels has not been advocated by clinicians and policymakers, certain people may benefit from testing. For example, young people who already have symptoms of arterial disease, and lack traditional risk factors, may be good candidates for testing.

Right now there are clinical trials in progress to see if adding vitamin B supplements to the diet will prevent atherosclerosis (fat deposits in arteries). Recent studies have shown that homocysteine levels do correlate with calcium deposits in the coronary arteries (which is likely a risk factor for the development of heart disease), but reducing those levels in people who have already had heart attacks may not lower the risk of a recurrent attack. The evidence about homocysteine is conflicting, and new studies should emerge soon. In the meantime you can follow a nutrition plan that assures adequate consumption of B vitamins.

Those Complex B Vitamins

Many factors, including age, gender, smoking and certain diseases and medications, can influence homocysteine status. However, the most important determinants appear to be genetics and diet. Three B-complex vitamins—vitamin B 6, vitamin B 12, and folic acid—are necessary to move homocysteine through the metabolic reaction to form methionine. This lowers homocysteine levels and prevents the toxic effects of homocysteine on the blood vessels. When your diet falls short in these nutrients, homocysteine can build up to high levels.

In 1993, a group of researchers at Tufts University analyzed blood samples drawn from elderly participants in the Framingham Heart Study. The results? One in three participants had homocysteine levels that were too high. About two-thirds of these cases could be traced to a diet low in vitamin B 6 , vitamin B 12, or folate. Canadian researchers also reported that people who had the least amount of folate in their diets were 69% more likely to die of a heart problem than those whose diets were richest in folate.

How Much Is Enough?

While vitamin B 6, vitamin B 12, and folate all play a part in the metabolism of homocysteine, folate seems to have the most impact. Researchers are now scrambling to ascertain how much folate is needed to ward off heart disease. Some experts are recommending 400 micrograms (mcg) a day of folic acid. This is also the amount recommended by public health officials for pregnant women to prevent neural tube defects, such as spina bifida.

In 1999, the Recommended Dietary Allowance (RDA) of folate was increased from 200 mcg per day for men and 180 mcg per day for women, to 400 mcg per day for both men and women, because blood levels of homocysteine fall when this amount of folate is consumed each day.

"Five A Day" Is the Way to Go

What's the best way to keep your homocysteine levels in check? Eat plenty of foods high in folate and vitamins B 6 and B 12 . Piling your plate with fruits, vegetables, and legumes such as lentils and dried beans, will provide hefty amounts of folate. Dark leafy greens, oranges, and orange juice are especially good sources. Perhaps the best way to obtain adequate folic acid is to eat a fortified breakfast cereal; you will get 400 micrograms of folic acid and the RDA for vitamins B 6 and B 12 . If you don't like cereal, try milk, eggs, meat or liver. Five servings of fruits and vegetables will provide enough folate to help prevent heart disease, cancer, and birth defects. Nine fruit and vegetable servings may be even healthier, and is the current goal of many nutritional experts.

Americans are also getting a folate boost from the government. Because of the link between a folate-poor diet and the increased risk of birth defects, the U.S. Food and Drug Administration ruled that wheat flour and bread be fortified with folate beginning in January, 1998. Breakfast cereals can also be fortified with up to 400 micrograms per serving. Researchers from the University of Washington have estimated that fortification of the food supply could save up to 50,000 lives per year, which would otherwise be lost to heart disease.

What About Folate Supplements?

If you get enough folate from your diet, there is no proven benefit to supplementation to prevent heart disease and it is not currently recommended. While it's important to insure adequate folate intake, there is some concern about the relationship between folate and vitamin B12 in the elderly. Elderly people usually absorb less vitamin B12, which can sometimes lead to pernicious anemia. High levels of folate tend to mask the symptoms of a B12 deficiency. If left untreated, pernicious anemia can lead to confusion and lethargy, caused by damage to the nervous system. Further some studies have raised concern that folate supplementation may increase the risk of renarrowing called “restenosis” within coronary arteries that have been stented. Therefore, people should see their health care providers before indiscriminately taking folate supplements and one should not take a folic acid supplement without also taking vitamin B12.

Is Fortification Enough?

Some researchers feel that even with fortification of the food supply, people will still be short of the desired 400 micrograms per day. But remember that it's relatively easy to incorporate folic acid-rich foods into your diet using fruits, vegetables, and legumes. And, it's a win-win proposition! The guidelines for a folate-rich diet are consistent with those for lowering blood cholesterol. What could be better than killing two risk factors with one single dietary intervention?

Folate content of foods
FoodServing size Folate content
Fresh spinach1 cup262
Kidney beans1 cup229
Lentils1/2 cup cooked179
Chick peas1/2 cup cooked145
Asparagus1/2 cup cooked131
Orange juice1 cup109
Broccoli1 cup107
Split peas1/2 cup cooked64


American Heart Association

National Heart, Lung, and Blood Institute National Institutes of Health

American Dietetic Association


BC Health Guide

Heart and Stroke Foundation of Canada


Boushey CJ, et al. A quantitative assessment of plasma homocysteine as a risk factor for vascular disease: probable benefits of increasing folic acid intakes. JAMA. 1995;274:1049-1057.

Mayer EL, Jacobsen DW, and Robinson K. Homocysteine and coronary atherosclerosis. Journal of the American College of Cardiology. 1996;27:517-527.

Selhub J, Jacques PF, Bostom AG, et al. Association between plasma homocysteine concentrations and extracranial carotid-artery stenosis. New England Journal of Medicine. 1993;270:2693-2698.

The Homocysteine Studies Collaboration. Homocysteine and risk of ischemic heart disease and stroke: a meta-analysis. JAMA. 2002;288:2015-2022.

Wald DS, Law M, Morris JK. Homocysteine and cardiovascular disease: evidence on causality from a meta-analysis. BMJ. 2002;325:1202-1206.

Wilson PWF. Homocysteine and Coronary Heart Disease: How Great is the Hazard? JAMA. 2002;288:2042-2043.

Last reviewed May 2008 by Craig Clark, DO, FACC, FAHA, FASE

Please be aware that this information is provided to supplement the care provided by your physician. It is neither intended nor implied to be a substitute for professional medical advice. CALL YOUR HEALTHCARE PROVIDER IMMEDIATELY IF YOU THINK YOU MAY HAVE A MEDICAL EMERGENCY. Always seek the advice of your physician or other qualified health provider prior to starting any new treatment or with any questions you may have regarding a medical condition.

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