Homocysteine and heart disease: theory yet to be tested

Could the amino acid called homocysteine be a more important predictor of heart disease than cholesterol? The idea has some currency since researchers have long known that at least 40% of the people who suffer a heart attack had normal total cholesterol levels. But conventional medical wisdom has long held that a high-saturated fat diet and high blood levels of cholesterol are the major elements in the development of heart disease. Though many physicians in private practice and some at academic medical centers have had their doubts about the importance of cholesterol, the American public has been educated to know your numbers. And testing is a widely accepted part of the routine physical examination of all adults.

In the last few years, however, researchers have directed attention to homocysteine, which comes from the normal breakdown of proteins in the body. Preliminary studies indicate that elevated blood levels of homocysteine are associated with a higher rate of heart disease, stroke, and reduced blood flow to the hands and feet. In 1997, a five-year study of 587 people with heart disease found that their death rate was proportional to their blood levels of homocysteine. Despite these tantalizing links between homocysteine and arteriosclerosis, a direct cause and effect has not been established. Since excess homocysteine is also associated with reduced blood levels of folic acid and vitamins B6 and B12, an increased intake of these three B vitamins could be a major step toward prevention. But most heart specialists advise against this because no clinical trial has proven that lowering the homocysteine levels will reduce a persons risk of heart attack or stroke.

The most recent homocysteine study raised even more questions (Circulation: The Journal of the American Heart Association, 7/21/98). Over an eight-year period, Dr. A.R. Nieto and colleagues at the University of Minnesota Medical School in Minneapolis periodically assessed the blood specimens from 759 initially healthy middle-aged men and women. During the study period, 232 people developed heart disease.

The investigators found that the people with high blood levels of vitamin B6 had the lowest rate of heart disease. But homocysteine levels appeared to be irrelevant. Dr. Nieto and colleagues concluded, Randomized trials, some of which are under way, are needed to better clarify the interrelationship of [homo- cysteine], B vitamins, and cardiovascular disease.

The homocysteine theory dates back to the late 1960s when pathologist Kilmer S. McCully, M.D., studied the arteries of a child who died of a rare in-born error of metabolism called homocystinuria. From this case and several others like it, he found that blood clots and thickening of the artery walls produced premature death from heart attacks and strokes. Homocysteine appeared to cause damage to the inner lining of the arteries.

In his 1997 book entitled The Homocysteine Revolution, Dr. McCully describes how he formulated the theory that homocysteine-induced arteriosclerosis occurs not only in children with a rare disease like homocystinuria but also in the general population where the diet is deficient in vitamin B6, folic acid, and vitamin B12. Deficiencies of these vitamins are produced by losses incurred during processing and preservation of basic foodstuffs, wrote Dr. McCully. The buildup of homocysteine in the blood is caused by dietary, genetic, toxic, hormonal, and aging factors in susceptible people, he believes, and it might also be linked to other degenerative diseases like cancer.

The question of whether high-risk people should have their blood tested for homocysteine or for vitamin B6 was put to Ronald Krauss, M.D., immediate past chairman of the American Heart Associations Nutrition Committee and senior scientist at University of California, Berkeley. We dont recommend homocysteine screening for the general population, he answered, though the test is becoming less expensive and more accessible. We dont have the evidence yet. Homocysteine is not in the same category as cholesterol which has a stronger and more consistent relationship with heart disease. And we have conclusive evidence that cholesterol lowering is beneficial. (For another side of the cholesterol story, see article below.)

In a telephone interview, Dr. Krauss explained that not all the prospective studies consistently show that elevated levels of homocysteine predict the onset of cardiovascular disease or stroke. Beyond that, we are lacking the evidence to show that lowering homocysteine with diet or other means has any beneficial effects thats because the ongoing studies havent been completed. There really isnt an argument for measuring homocysteine, he continued, though the door was left open for physicians to consider the testing and nutritional counseling of people at high risk for cardiovascular disease. [All] people should be consuming the recently revised Recommended Daily Allowances for folic acid, B6 and B12 as part of their daily diet. As Andrew Weill, M.D., put it in the foreword to The Homocysteine Revolution: Eat more fresh fruits and vegetables, more whole grains, less meat and other animal foods, and much less processed foods.

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By Maryann Napoli

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