An estimated 5%-20% of Americans have elevated homocysteine levels. This amino acid is formed from the breakdown of protein during digestion, and can only be metabolized by the body if certain B vitamins are present. A deficiency of these B vitamins—particularly folate (folic acid)—can lead to elevated blood homocysteine levels. This, in turn, can cause problems in coronary and other arteries by directly damaging the vessel wall and by promoting clot formation. Damaged arteries can eventually lead to the development of atherosclerosis , a hallmark of which is the formation of “plaques” that block blood flow. Atherosclerotic plaques in the coronary arteries increase the risk for heart attack ; whereas plaques in the arteries leading to the brain (cerebrovascular disease) increase the risk of stroke . Elevated homocysteine has been linked to both.

In the past, there has been some controversy over whether homocysteine should be regarded as an independent risk factor for heart disease. An analysis of 72 studies described in the November 23, 2002 issue of the British Medical Journal (BMJ) , lends considerable support to a strong association between homocysteine and cardiovascular disease. The researchers concluded that lowering homocysteine concentrations in the blood significantly reduces the risk of ischemic heart disease, stroke, and even deep vein thrombosis , a serious clotting condition not directly related to atherosclerosis. In addition, they found that homocysteine levels and risk for cardiovascular disease was increased in people with a gene mutation that reduces the activity of methylenetetrahydrofolate reductase (MTHFR), an enzyme involved in folate metabolism.

About the Study

Researchers from England conducted a meta-analysis by pooling the data from 72 studies to arrive at their results. Individually, many of these studies were too small to be statistically reliable. By performing a meta-analysis, researchers in effect create one large study that can often provide meaningful conclusions where smaller, individual studies cannot.

The investigators searched scientific databases to find two different types of studies:

  • Studies that collected blood samples to measure homocysteine levels, waited to see who developed certain diseases, and then made comparisons between those with elevated homocysteine levels and matched controls. (Prospective cohort studies)
  • Studies reporting the prevalence of mutated MTHFR gene in cardiovascular disease cases and controls. (MTHFR studies)

The disease outcomes for the prospective cohort studies included death from ischemic heart disease, non-fatal heart attack, fatal stroke, and non-fatal stroke. The disease outcomes for MTHFR studies included ischemic heart disease identified through angiography (an imaging test to identify atherosclerotic plaques in the coronary arteries), heart attack, deep vein thrombosis, or stroke. All together there were 62 ischemic heart disease studies, 15 stoke studies and 26 deep venous thrombosis studies involving a total of 20,669 cases.

The Findings

The data was adjusted to try and make the study measurements comparable, and further adjustments were made for some other cardiovascular disease risk factors: age, sex, smoking, blood pressure, and serum cholesterol. Overall, the authors found a significant link between elevated homocysteine levels and the three diseases they examined. Specifically, they concluded that lowering homocysteine concentrations 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 MTHFR mutation were at an increased risk for both moderately elevated homocysteine levels and their associated cardiovascular outcomes.

Though these results seem promising, there are limitations to this study. First, in a meta-analysis, people admitted to one trial are likely to differ significantly from those who were enrolled in another. Because of this, it is often not valid to directly compare the experience of individual people. Second, the quality of this meta-analysis is dependent on the quality of all of the studies it contained. Though the authors had exclusion criteria, there did not appear to be an assessment of the quality of the studies that were included.

Third, changes made in adjusting the data to make the study measurements comparable might have affected the study outcomes in ways that are difficult to determine. Fourth, it did not appear that these authors (or all of the authors of the studies used) adjusted for medications, supplements, diet, physical activity, and other factors that could have influenced a person’s chances of having elevated homocysteine levels or being at risk for the three disease outcomes.

Finally, while this study strongly supports a connection between homocysteine levels and cardiovascular disease, it does not directly address whether folic acid supplementation (the only known way to reduce homocysteine levels) can effectively prevent these conditions. However, one study in the May 2002 issue of Stroke found that people who consumed at least 300 micrograms (mcg) of folic acid per day were 20% less likely to have a stroke and 13% less likely to develop cardiovascular disease than their counterparts who consumed less than 136 mcg per day. Other studies have shown beneficial effects at even higher doses of folate.

How Does This Affect You?

This study suggests that keeping your homocysteine levels in the normal range is a good idea. And, other research has shown that adequate folic acid intake can reduce the blood level of homocysteine and decrease the risks associated with it. This does not mean, however, that folate can, or should, necessarily be substituted for cholesterol-lowering and other medications that are commonly prescribed for heart disease. Below are some tips for getting more folic acid into your diet through foods.

Because research has shown that folic acid intake in the early days of pregnancy helps prevent certain birth defects, the federal government has mandated that a number of grain products be fortified with folic acid, including:

  • Rice
  • Pasta
  • Breakfast cereals
  • Most enriched breads
  • Flour
  • Cornmeal

Foods that naturally contain folic acid include:

  • Leafy dark green vegetables
  • Legumes (dried beans and peas)
  • Citrus fruits and juices
  • Most berries