The observation that many heart attack victims have normal cholesterol levels underscores the need to identify other risk factors for atherosclerosis. Of several substances in the blood that are now thought to predict odds for vascular disease, the amino acid, homocysteine, is the one for which the case is strongest. The findings suggest a simple way to prevent heart attacks because homocysteine levels can be lowered by taking the B vitamin, folic acid. In a 1995 review of work exploring the relationships among homocysteine levels, folic acid and blood vessel disease (JAMA, vol. 274, pp.1049-1057), University of Washington researchers proposed that increasing folic acid intake might prevent as many as 50,000 heart attack deaths a year.

Homocysteine was first named as a suspect in vascular disease over 25 years ago by Dr.Kilmer McCully, then a Harvard pathologist. McCully, who observed severe atherosclerosis in two young children with rare diseases marked by very high homocysteine levels, speculated that minor elevations might account for atherosclerotic disease in adults. Despite early resistance to this startling new theory, subsequent investigations linked homocysteine to an estimated 15 percent of heart attacks.

Among 27 studies of homocysteine and vascular disease cited by the University of Washington review was a Harvard project involving 15,000 physicians (JAMA, vol. 268, pp.877 -81). The research, reported in 1992, showed that although relatively few of the doctors had coronaries, those in the five percent of the group with the highest homocysteine readings had a 3.4 fold increase in heart attack risk. Also cited was a 1995 Tufts University study of over 1,000 elderly men and women, which showed that high homocysteine levels raised odds for significant carotid artery obstruction. (New England Journal of Medicine, vol.332, pp.286-291). A carotid blockage is considered a warning sign of above-average risk for both stroke and coronary artery disease.

The Washington researchers concluded that a 5 u.mol/L increment in homocysteine level raises coronary artery disease risk as much as a 20 mg/dL rise in cholesterol. No one has yet proven how homocysteine causes atherosclerosis, but scientists suspect it may do its harm during one or more steps in the process that transforms a healthy blood vessel into the site of a heart attack. The arteries of animals injected with homocysteine showed changes that may lay the groundwork for the buildup of atherosclerotic plaques. There is also evidence suggesting that homocysteine stimulates proliferation of blood vessel cells that help form plaques and that it encourages clotting.

Folic acid is thought to protect against heart disease because it breaks down homocysteine and allows it to be cleared from the blood stream. The University of Washington review referred to 11 studies of folic acid's effects on homocysteine levels. Among these was the Tufts research, which showed for the first time that inadequate intake of the vitamin is the main determinant of the homocysteine-related increase in the risk of carotid blockage.

New studies suggesting a protective role for folic acid continue to appear. In 1996, Canadian investigators reported that among more than 5,000 men and women who participated in a national nutrition survey, those in the quarter of the group with the lowest folic acid levels were 69 percent more likely to die of a coronary problem than those in the quartile with the greatest stores of the vitamin (JAMA, vol.275,pp.1893-95). There is even evidence that high risk patients have the most to gain. In 1995, a University of Utah study compared over 160 men and women who had evidence of early familial coronary artery disease with a comparable group who did not have the disease. The patients, who had already had either a heart attack, bypass surgery or balloon angioplasty, showed "a considerably greater sensitivity" to the blood's concentration of the B vitamin, according to the researchers (Arteriosclerosis, Thrombosis and Vascular Biology).

Growing evidence that folic acid may prevent heart attacks has led to recommendations that people consume 400 mcg. a day. This amount has been shown to maintain low homocysteine levels and also to prevent neural tube defects in the unborn. But, although 400 mcg. used to be the recommended daily allowance (RDA) for folic acid, the RDA was cut by half several years ago. According to data cited by the University of Washington review, an estimated 88 percent of Americans get less than 400 mcg., providing "ample scope for intervention," say the authors.

One way to insure adequate folic acid intake is to eat five daily servings of fruits and vegetables. People consuming this amount are unlikely to benefit from supplements, according to a JAMA editorial published in 1993 (JAMA, vol.270, pp. 2726 - 27). Among the best natural sources of folic acid are green leafy vegetables, beans and citrus fruits. Because of a government mandate to fortify grain products with the vitamin, as of 1998, it will also be available in foods like bread, pasta and cereal. According to the University of Washington researchers, fortification offers the greatest potential for reducing coronary artery disease. However, other researchers (JAMA, vol 275, pp. 1929 -30) point out that fortification is expected to increase intake of the vitamin by only 100 mcg. and may still leave about three quarters of the population getting less than the desired 400 mcg.

Whether or not to prescribe supplements continues to be debated. Several scientists have called for clinical trials to determine whether giving folic acid actually reduces heart attack risk. An editorial accompanying the Canadian study suggests including vitamins B6 and B12 in the trials, since these vitamins also influence homocysteine levels. An additional reason for giving vitamin B12 is that folic acid supplements can mask vitamin B12 deficiencies, which are not uncommon in the elderly and may cause neurologic damage if left untreated.

While some scientists argue against prescribing supplements before there is direct proof of their benefits, others say that delays may not be desirable for some patients. At a symposium on homocysteine and heart disease, sponsored by the Federation of American Societies of Experimental Biology, Meir Stampfer, M.D., Ph.D. of Harvard, pointed out that "public health considerations often require taking protective action even before all proof is in." The implications of the existing evidence about homocysteine and folate were stressed by the co-chair of the symposium, M.Rene Malinow, of the Oregon Regional Primate Research Center. "Scientists are on the threshhold of the most important extension of the diet/health hypothesis since the discovery of the relationship of cholesterol to heart disease," he said