BEYOND CHOLESTEROL

By Jeffrey Kluger

Between 1992 and 1996, 64 men and women in Norway quietly died. Their passing was noted by their families but otherwise was largely unremarked. All the deceased, after all, suffered from heart disease, and many had undergone bypass surgery. Deaths like these are not the stuff of headlines.

Last week, however, the dead Norwegians made the evening news. What all of them had in common, in addition to sickly hearts and premature deaths, was elevated levels of an amino acid called homocysteine. The patients were part of a study, published in the current issue of the New England Journal of Medicine, that shows an almost lockstep correlation between high homocysteine levels and coronary-disease mortality. And that paper follows more than 50 less publicized studies since 1992 suggesting similar connections.

What makes this research so compelling is that unlike cholesterol, which everyone knows is associated with coronary problems but can often be treated only by medication and a rigid diet, homocysteine appears to respond to nothing more demanding than eating more vegetables and taking a few more vitamins. Homocysteine is certainly not the lone gunman of heart disease, but the studies strongly suggest that it's at least a co-conspirator--and one that patients can do something about. "This is very convincing," says Dr. Jacob Selhub of Tufts University in Boston. "Homocysteine appears to be a risk factor for heart disease."

To a few doctors, homocysteine is nothing new. As long ago as 1969, Harvard physician Kilmer McCully--now with the Veterans Administration Hospital in Providence, R.I.--was studying the unusual case of an eight-year-old boy who had died of a stroke. McCully found that the boy's bloodstream was fairly awash in excess homocysteine and that his arteries had the sclerotic look of an elderly man's.

Ordinarily pretty harmless stuff, homocysteine is used by the body to help manufacture proteins and carry out cellular metabolism. Too much of it, however, appears to cause blood platelets to clump together and vascular walls to begin to break down. In older patients, a lifetime of this damage may give arteries the scarred and thickened texture that provides circulating cholesterol with a place to stick and grow. In the young boy, accelerated homocysteine production caused by a genetic defect apparently led to accelerated damage. In both instances, however, McCully points to the same chemical culprit. "The underlying cause of heart disease," he says, "is an imbalance in the system that controls homocysteine levels."

Superficially, at least, the New England Journal paper appears to confirm this. The study, conducted at Haukeland University Hospital in Bergen, Norway, surveyed 587 people with a history of heart trouble. The 64 who died during the course of the research were among those with the highest levels of homocysteine in their blood. Overall, the research suggested, people with elevated homocysteine are 4 1/2 times as likely to die of heart disease as those with normal levels.

No one knows for certain what causes some individuals and not others to overproduce homocysteine. But the evidence points to a shortage of vitamin B6, vitamin B12 and folic acid, all of which work to convert the amino acid into a molecular form the body can use. The answer for people concerned about cardiac health would seem to be for them to keep their intake of the protective vitamins high. The Harvard Health Letter has recommended increasing consumption of a range of foods--including leafy green vegetables, beans, peas, grains and certain meats and dairy foods--to keep homocysteine in check. Many researchers agree. "Don't wait for the Messiah," says Selhub. "Start eating more vitamin-rich vegetables now. If you can't, take vitamin supplements."

Not everyone is sold on such a simple prescription. Even if homocysteine is behind some cases of heart disease, it's unlikely to be behind them all, and there's no guarantee that managing the amino acid will decrease the risk of cardiac trouble. Regardless of circulating homocysteine levels, smoking and obesity will still ravage the cardiovascular system, and a poor diet will still choke the blood with fats. Cardiologist Roger Blumenthal of Johns Hopkins University estimates the share of all cardiac cases attributable to homocysteine at fewer than 1 in 5.

What's more, even for patients whose illnesses are caused by elevated amino acids, diet may not be much of a cure. Scientists know cholesterol levels in the blood fluctuate within a limited range; when people eat less fat, the liver simply manufactures more. It's not yet known whether there is a similar set point for homocysteine. "People are jumping the gun if they think they can just take vitamins and skip the traditional health measures like exercising and eating a low-fat diet," says Blumenthal. "All the evidence has yet to come in." Nonetheless, in a field of medicine in which the bad news often surpasses the good, the evidence that came in last week was encouraging indeed.

--Reported by David Bjerklie/New York

With reporting by David Bjerklie/New York