At your last physical, your doctor probably told you to watch your cholesterol, keep your blood pressure low, exercise and refrain from smoking. What he or she probably didn’t tell you is to watch your homocysteine levels—even though it is a significant risk factor for heart disease.

The association between homocysteine and heart disease has long been well-established. However, there is little agreement about what should be done about high homocysteine levels. Doctors disagree about whether or not treating homocysteine actually helps patients with heart disease.

At the heart of the matter is uncertainty about whether lowering homocysteine levels can reverse damage present in those whose blood vessels are damaged. According to Dr. Russell Valentine, a Fellow of the American College of Cardiology, “every study to date has failed to show a link between treating homocysteine and benefit.”

Many studies have shown a connection between high levels of homocysteine and heart disease. A 1992 Harvard study shows heart attack is 3.4 times as likely in men with homocysteine elevated 12 percent above normal levels. A European Journal of Clinical Investigation study showed that 40 percent of stroke victims have elevated homocysteine, up from 6 percent of the general population. 

Both of these studies showed homocysteine to be significant even after all other risk factors were taken into account. In 1995 an American Medical Association review concluded that homocysteine is a strong independent risk factor for stroke.

The American College of Cardiology states that many studies have shown high levels of homocysteine to be as good an indicator of heart problems as cholesterol. However, unlike homocysteine, reducing cholesterol has been strongly linked to better patient outcomes. Thus, the AMA has not provided any definitive recommendations on whether or not to treat homocysteine.

Dr. James Trippi, also a Fellow of the ACC, does testing for homocysteine in his practice. “I think it’s valuable to look for people with an elevated level of homocysteine in the blood,” Trippi says. Trippi believes that lowering homocysteine levels is clinically helpful, especially in treating high-risk patients.

Trippi has a few patients who have no real risk factors other than high levels of homocysteine. “One person had repeated heart attacks and once therapy was started has had no further cardiovascular problems,” Trippi says.

Trippi points out that the treatment for homocysteinemia is simple and believed to be harmless. Vitamins B6, B12 and folic acid are necessary for the body’s enzymes to break down homocysteine properly. Those with moderate levels of homocysteine can usually solve their problems with better diets, and those with high levels may take vitamin supplements.

Trippi believes that homocysteine is probably a strong indicator in only a small number of people. While exceptionally high levels can be dangerous, mild to moderate levels of increased homocysteine may not be a major risk factor for heart disease.

Valentine cautions that treating homocysteine has not been shown to be clinically effective. “For more than 20 years we’ve known of a link between homocysteine and heart disease but at no point has there been a cause and effect relationship (between homocysteine and heart disease) shown,” Valentine says.

Valentine fears that treating homocysteine now could have effects we can’t envision. He cautions that “the science isn’t there yet.” He calls homocysteine a factor on the “bleeding edge” of science, a point at which physicians may be engaging in treatment without sufficient evidence of safety and efficacy.

He points out that vitamin E was once widely prescribed by physicians. It was believed that vitamin E might be helpful to some patients, and that at the very least it was safe. Recent studies have demonstrated that vitamin E may indeed be harmful to patients who take more vitamin E than the body requires.

Valentine also emphasizes that, in most cases, he will treat a patient with a known high level of homocysteine in the same way he would any other patient. Both patients will be told to eat a healthy, balanced diet. “Why measure it if it doesn’t change the treatment?” he asks. 

Homocysteine is an intermediate molecule in the production of methionine and cysteine. These are two of the 20 basic amino acids that are the building blocks for proteins in the human body. When the body cannot finish the process of utilizing homocysteine, it is flushed into the bloodstream and eventually out of the body.

Homocysteine has been shown to have many mechanisms by which it can harm the body. “There are a lot of links at the bench level and that’s why it looks so promising,” according to Valentine.

High blood levels of homocysteine are toxic to the cells lining the arterial walls.  This thin layer of cells is responsible for controlling passage of substances into and out of blood vessels. When they are damaged, the ability of these blood vessels to control what passes through them decreases.

Blood vessels exposed to excess homocysteine also tend to thicken and lose their elasticity. In doing so, they become less able to engage in the motion that helps pump blood through arteries. The cells lining arteries are also responsible for producing the nitrous oxide that helps arteries dilate, so damaging them further reduces blood flow.

Nitrous oxide also is important in minimizing excessive clotting. High levels of homocysteine can lead to clotting when there should be none, which can lead to arterial blockages.

The stiffening of the blood vessels walls is the first step in the series of events that leads to plaque formation. When arterial walls are damaged, plaque is more likely to begin accumulating. Plaque formation, in turn, leads to major cardiac events such as heart attack and stroke.

There is little doubt among physicians that levels of homocysteine predict overall cardiac health. However, the benefits of measuring and treating homocysteine are not well established. The best thing someone can do to avoid high homocysteine is to eat a balanced diet. However, asking your physician is never a bad idea.

There are prospects for better homocysteine therapy in the future.  Valentine speculates, “It may be that our treatment just isn’t powerful enough, and there may be agents that dramatically alter homocysteine levels.” A lack of evidence for homocysteine therapy’s prospects does not mean they are not there. More research is underway, and a clearer role for homocysteine will likely be defined in the future.