Homocysteine is an amino acid produced as a normal byproduct of the breakdown of methionine, which is an essential amino acid acquired mostly from eating meat. Moderate levels of homocysteine are helpful for the growth and maintenance of healthy tissue. However, excess homocysteine levels are associated with various forms of vascular (blood vessel) damage and heart disease.

With a proper nutritional balance, homocysteine is either converted back into methionine or into simple amino acids (cysteine and cystathionine) that are easily flushed from the body through urine. Homocysteine levels can be raised by genetic influences, problems metabolizing certain vitamins, drugs such as fibrates and nicotinic acid, and possibly also by cigarette smoking.

The conversion of homocysteine cannot occur unless the body has enough of three B-vitamins: vitamin B-6, vitamin B-12 and folic acid (the synthetic and more easily absorbed version of folate). Folic acid is the most effective at lowering homocysteine, followed by vitamin B-12. Vitamin B-6 is the least effective. Without these B-vitamins, homocysteine levels will rise. In fact, about 95 percent of patients with folic acid and vitamin B-12 deficiencies have elevated homocysteine levels.

Homocysteine and heart health

Research on homocysteine and heart disease began in 1968, when Dr. Kilmer McCully of Harvard Medical School investigated the early deaths of children with a rare genetic disorder called homocystinuria, which involved high levels of homocysteine. He was surprised to discover these children had severe “hardening of the arteries” (atherosclerosis) and often died from a heart attack or stroke, which is extremely rare among children. Dr. McCully continued to investigate a potential link between excess homocysteine levels and heart disease, even though his conclusions were not initially well received by the medical community.

Research on a possible connection between high homocysteine levels and atherosclerosis was largely abandoned during the 1970s. In the 1980s, however, interest was rekindled as researchers began looking at a possible link between moderately elevated homocysteine levels and heart disease. In contrast to genetic homocystinuria, which is rare, about 5 to 7 percent of the U.S. population has moderately elevated homocysteine levels.

Since then, many studies have been published, often with contradictory results. For example, one study conducted by researchers at Harvard University followed 15,000 people for five years and found that people with the highest homocysteine levels were more than three times as likely to have a heart attack as people with lower homocysteine. However, another study analyzed 15,000 people and found that a low level of vitamin B-6 was related to heart disease, but homocysteine levels were not.

In 2006, researchers published results of clinical trials that examined the effect of folic acid and B vitamins in lowering homocysteine levels and reducing the risk of cardiovascular events. The results found that folic acid and B vitamins lowered homocysteine levels but the treatment did not significantly decrease the risk of death from coronary disease, heart attack or stroke. In addition, individuals who took all three supplements – folic acid, vitamin B6 and B12 – may have a slight increased risk of cardiovascular problems.

In general, studies indicate that elevated homocysteine is somehow associated with heart disease through its influence on arteries and the blood. Homocysteine has been shown to increase damage to the sensitive interior walls of arteries—the same area that is damaged by atherosclerosis. Also, homocysteine increases the blood's tendency to clot, which may increase the risk for heart attack and stroke. However, even while researchers have shown the mechanism by which homocysteine can damage the heart, studies have not shown that treating homocysteine levels necessarily reduces the incidence of heart disease.

Findings like these, which may directly contradict each other, can be frustrating both for patients who want to lower their risk of developing heart disease and physicians who seek to offer the best treatment possible. However, it is worth noting that medical research is an exacting science in which common, clinically observed facts may require years of intensive study to be confirmed and understood.

At this point, most researchers believe that elevated plasma homocysteine levels may confer an increased risk for developing certain forms of heart disease, blood clots and stroke. This means that homocysteine appears to at least partly cause these conditions, independent of other risk factors such as smoking, a family history of heart disease and elevated cholesterol levels. However, it also appears that homocysteine is a less important causal factor than these other, more traditional measures of risk.

Yet there remains considerable debate over the screening and treatment of elevated homocysteine levels. At this point, the American Heart Association does not recommend widespread screening for elevated homocysteine. Rather, only individuals at elevated risk for heart disease are recommended to have their homocysteine levels screened.

Likewise, although there is a clear connection between elevated homocysteine and heart disease and stoke, studies have failed to establish a link between treating homocysteine and a reduced incidence of heart disease. Homocysteine is treated with B-vitamins, such as folic acid, vitamin B-12 and vitamin B-6. Several large, multi-center trials are under way to help physicians better understand the complex interaction between homocysteine, B vitamins and heart disease. In the meantime, individuals should get adequate vitamin B in their diets, and people at elevated risk for heart disease, including older people, may consider taking vitamin B supplements under the supervision of their physician.