Homocysteine
Homocysteine and Vascular disease _________________________________ 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.

Homocysteine and Canadian study _______________________________ Canadian research has linked low blood levels of the B vitamin, folic acid, to increased odds for fatal coronary heart disease. A study of more than 5,000 people found that those in the quarter of the group with the lowest folate levels were 69 percent more likely to die of a coronary problem than those in the quartile with the greatest stores of the vitamin. The study underscores the need for clinical trials to determine whether increasing folic acid intake can prevent heart disease, says Meir Stampfer, M.D., Dr. P.H. of the Harvard School of Public Health, in an editorial accompanying the report. The study was published in the June 26, 1996 issue of JAMA (Vol 275, pp. 1893 -1896). The research, led by Howard Morrison, Ph.D., of the Cancer Bureau in Ottawa, Ontario, involved men and women, aged 35 to 79, who reported no history of coronary heart disease. The subjects' blood levels of folic acid were measured from 1970 to 1972. The group was then followed through 1985. During the 15-year period, the researchers identified 165 people who died of coronary heart disease. The data show that as folic acid levels dropped, risk of death rose in a stepwise fashion. Folate appeared most protective in women and in people under age 65. An interesting finding in all age groups was that risk increased even at folic acid levels that are presently considered normal. This observation suggests the need to redefine the norms, note the authors. According to Morrison and his group, the study has two advantages over previous work implicating folate shortages in coronary heart disease. By using subjects who were participants in a national nutrition survey, the researchers were able to link vitamin levels and disease in a representative population sample. Earlier studies of folate and heart disease risk involved either white males or the elderly. The study also correlates low folate levels with actual death from heart disease, rather than with a finding like carotid artery obstruction, which only predicts risk of death. Citing studies that link low folate levels or intake with risk of neural tube defects, cervical dysplasia and rectal cancer, as well as heart disease, the researchers note that about half of U.S. adults consume less than the newly lowered RDA of 200 mcg. An estimated 88 percent ingest less than the amount (400 mcg), which is needed to produce low, stable homocysteine levels. Although the scientists urge bolstering the diet with such folic acid sources as vegetables and legumes, they suggest that some people may need supplements. In his editorial urging clinical trials of folate supplementation, Stampfer says that, because this low cost approach offers no profit incentive, the National Institutes of Health should fund folate trials. "If proven effective, lowering the homocysteine level could prevent tens of thousands of cases of cardiovascular disease each year at very low cost and with few (if any) adverse effects," he says.