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At U.S. and European medical institutions, major clinical trials are underway to answer an intriguing question with big implications: Can B vitamins reverse or slow down deadly vascular disease?

The research has been prompted by more than 200 medical studies establishing elevated homocysteine as a major risk factor for vascular disease, the No.1 killer disease in the United States.

Homocysteine is an amino acid that triggers arterial plaque and bloodclot formation when it reaches toxic levels in the body. This occurs, research suggests, because of a deficiency of two B-complex vitamins, B-6 and folic acid. Homocysteine may not yet be a house-hold word - such as cholesterol - but it appears headed in that direction. According to Kilmer McCully, M.D., it is more important than cholesterol as a risk factor for blood- vessel disorders, including cardiovascular disease, that take the lives of nearly a million Americans each year and affect more than 57 million individuals. McCully, a pathologist at the Veterans Affairs Medical Center in Providence, Rhode Island, is the "father" of the homocysteine theory, a revolutionary explanation of how vascular disease is caused. Years ago, he was forced to leave positions at Harvard and Brown medical schools for promot-ing his ideas, which collided with the prevailing "cholesterol paradigm."

Now, nearly three decades later, his theory has gained worldwide scientific attention, and the once-rejected McCully is gaining celebrity status in the medical community. "Because of my ideas, I was thrown out of two medical schools," he says. "Now, confirmation is coming from an over.”

For decades, we have all heard that the buildup of cholesterol, fat and plaque in the arteries can cause vascular disease and potentially lethal blockages in the body. Blood vessels, primarily those leading to the heart, brain and legs, become hard and stiffen, a process known as arteriosclerosis. Its most common form is atherosclerosis, which occurs when plaques build up on arterial walls to restrict the flow of blood and increase the prospect for clots to block circulation and cause heart attacks, strokes and amputated legs.

The conventional view has incriminated excess dietary consumption of fats and cholesterol as major players in this process. Over the years, the cholesterol menace has spawned massive research, medical technology and the proliferation of low-fat food products. But studies on the impact of dietary cholesterol on disease have been equivocal. Moreover, research has shown that many people die from vascular and cardiovascular disease with normal and even low levels of cholesterol. And studies have also revealed a disturbing risk of illness, including cancer among men, as a result of lowering cholesterol with pharmaceutical drugs.

McCully views the involvement of cholesterol as secondary to that of homocysteine. "In the production of plaques in the artery wall, it is well known that cholesterol becomes damaged by oxidation," he says. "But homocysteine is a potent catalyst for this oxidation reaction and orchestrates all the things in the arterial wall that produce the plaque."

In order to understand why homocysteine may be the most critical risk factor for heart disease, it is helpful to understand how it works in the body.

1) Protein is a basic part of all food. One of the major components of protein is methionine, an essential dietary amino acid needed for proper growth and maintenance of all the cells and tissues in the body.

2) Normally, the liver processes methionine and breaks it down into homocysteine, another amino acid. Some of this homocysteine is then reconverted back into methionine again and used to supply the body's protein needs. The unused homocysteine is passed out in the urine.

3) This process depends on folic acid and vitamin B-6 to run smoothly. The vita-mins are necessary raw materials for specific enzymes that convert methionine and homocysteine.

4) If folic acid and vitamin B-6 are deficient in the diet, this enzymatic process suffers. Homocysteine starts building up in the body and is drawn into the endothelium (inner lining) of arteries. There, the evidence shows, it generates the pathogenic sequence of chemical and oxidative reactions and encourages the formation of blood clots.

Research indicates that elevated homocysteine is not just involved in diseases of the blood vessels. It has been implicated in spontaneous abortion, neural-tube defects, low birth weight, kidney failure, rheumatoid arthritis, alcoholism, osteoporosis, neuropsychiatric disorders, non-insulin dependent diabetes and complications of diabetes. High homocysteine levels have also been found in patients with fibromyalgia and chronic fatigue syndrome.

An intriguing part of McCully's theory is its nutritional implications and the possibility of a simple solution. Many studies have confirmed the association between elevated homocysteine and a deficiency of vitamin B6 and folic acid. The widespread incidence has much to do with modern eating habits and food processing, both of which minimize important nutrients in the diet. "The depletion of vitamin B-6 and folic acid from the diet is, in my opinion, the underlying cause of the disease." says McCully. "Eating refined, white-flour products, white rice, sugar, fats and oils deprives you of critical nutrients and generates all these diseases of modern civilization.

Poor eating habits are another problem. According to the Harvard Health Letter, "On any given day, more than 50 percent of adults fail to eat the three servings of vegetables advised in the Dietary Guidelines for Americans, and only 24 percent consume the recommended two servings of fruit. That's unfortunate because fruits and vegetables are excellent sources of vitamins B-6 and folic acid."

Medical studies have shown that supplementation with vitamin B-6 and folic acid rapidly normalizes homocysteine levels in the blood. The scientific community doesn't know yet whether this translates into actual prevention and improved symptoms for people with vascular disease.

Killian Robinson, M.D., a staff cardiologist at the Cleveland Clinic, has conducted research on homocysteine and says that the medical community is interested in the answer. "Some evidence shows improved endothelial function, that is the function of the lining of the blood-vessel wall, by homocysteine lowering treatment, namely with folic acid supplementation," he says. "The endothelial lining does not appear to function normally in people with higher homocysteine. So if you reduce the level, you may be doing the patient some good. But we need the therapeutic trials to prove that by a simple vitamin treatment you can save a lot of peoples' lives," he adds.

In the search for answers to the homocysteine question, practitioners who have had success with heart disease patients offer some of the strongest clues. John Ellis, M.D., a retired Texas physician known for discovering the healing effect of vitamin B-6 for many people with carpal tunnel syndrome, found that his patients suffered few heart attacks and had very little angina. When Ellis reviewed medical records, he determined that patients who took B-6 for a year or more had nearly 75 percent less risk for developing angina and heart attacks than patients of other doctors in his community who did not take B-6.

Another important clue is the response of individuals with homocysteinuria, a rare and severe genetic disorder associated with high homocysteine levels, premature vascular disease and mild mental retardation. Among these individuals, B-6 alone has been found to reduce the risk of complications, particularly the formation of blood clots, by about 60 percent. In addition, their mental development is enhanced, and they are less likely to become retarded.

With the results of clinical outcome trials still a few years off, McCully's advice is to eat as many whole foods as possible and use a good vitamin supplement. "If you have a family history of heart disease or stroke, or if you have a relative who had a disease like this before the age of 55 or so, you'd better get your homocysteine level checked," advises McCully. "And if it is elevated, you better get it down."

REFERENCES:

Kilmer McCully, M.D., The Homocysteine Revolution (Keats Publishing, 1997)

Rinehart James, and Greenberg, Louis, “Vitamin B6 Deficiency in the Rhesus Monkey With Particular Reference to the Occurrence of Atherosclerosis, Dental Caries and Hepatic Cirrhosis,” American Journal of Clinical Nutrition 1956; 4: 318-25

Kuzuya, Fumio, "Reversibility of Atherosclerosis in Pyridoxine Deficient Monkeys,” Proceedings of the 4th Internatonal Conference of Athenosclerosis, Springer Vedag, Berlin, 1977; 275-7

Nygard, 0.,et al., ”Plasma Homocysteine Levels and Mortality in Patents With Coronary Artery Disease,” New England Journal of Medicine, 1997; 337 (4): 230 6

I.M. Graham, et al., “Plasma Homocysteine as a Risk Factor for Vascular Disease, The European Concerted Action Project,” Journal of the American Association, 1997; 277:1,775-81