Doubts Raised About Value of Heart Disease Marker

By DONALD G. McNEIL Jr.

evels of homocysteine in the blood — recently promoted as the new cholesterol as a harbinger of coronary disease — may not be very helpful in predicting heart attacks and strokes in healthy people, a study has found.

The report, to be published on Wednesday in the Journal of the American Medical Association, concludes that homocysteine levels are "less strongly related" to the risk of heart attack and stroke "than has been suggested."

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But doctors who think the measurements are useful say the study still endorses that position, if not as strongly as some may have hoped. But they also say that homocysteine's importance was oversold by excited researchers and medical writers in the mid-1990's, when studies found high levels of the substance in the blood of people who had already suffered heart attacks and strokes.

"Why not test for it?" said Dr. Kilmer McCully, who in 1969 was the first to propose that the chemical might somehow cause arteries to clog. He said he had "no major quarrel" with the new study's conclusion, but added: "Even if the test method isn't perfect, it does give some information. And it does show some connection between homocysteine levels and risk."

Homocysteine is an amino acid that builds up in the blood of people who eat lots of animal protein and few leafy vegetables. Researchers suspect it is not just a marker, but may itself damage arterial walls, encouraging plaques to form.

It can be quickly and safely lowered by cutting back on proteins, especially red meat, and taking B vitamins and folic acid, which are found in leafy vegetables, whole grains and virtually all multivitamin tablets.

The study, by a team based at Oxford University and led by Dr. Robert Clarke, was a "meta-analysis," blending data from 30 studies. It encompassed almost 17,000 people who had collectively suffered 5,073 heart attacks and 1,113 strokes.

After making allowances for other risk factors like high blood pressure and smoking, Dr. Clarke's team concluded that people who lower homocysteine levels in their blood by 25 percent cut their heart attack risk by 11 percent and stroke risk by 19 percent.

"That's still a significant association," said Dr. Paul F. Jacques, chief of nutritional epidemiology at the Department of Agriculture's Human Nutrition Research Center on Aging at Tufts University. "It's a modest predictor — but it's all in how you define `modest.' "

The earliest studies, done in the 1970's on patients who had already had a heart attacks or strokes, found a very high co-relation with homocysteine levels. One study found, for example, that the 5 percent of patients with the highest levels had more than three times the risk that others did.

But later studies, which measured homocysteine levels in healthy men and women and then waited five or more years to see which ones developed heart problems, found smaller co-relations, and sometimes none.

"It's amazing how one or two studies can kill the party," Dr. Jacques said.

He and other homocysteine researchers and biostatisticians agreed that the 30 studies that Dr. Clarke had analyzed included all the important ones. Other meta-analyses, such as those of mammograms' ability to detect breast cancer, have provoked angry debate when meta-analysts threw out major studies, saying their data was inadequate.

Dr. Meir J. Stampfer, a leader of the Physicians' Health Study at the Harvard School of Public Health, who made early associations between homocysteine levels and heart disease, found Dr. Clarke's conclusions "more pessimistic than the reality might be."

He cited a study that appeared in the same journal in August: in it, half of 553 heart patients in Switzerland who had had operations to reopen clogged arteries were randomly assigned to receive six months of vitamin B therapy. The group of those who did have the therapy had significantly fewer deaths and heart attacks — 2.6 percent in the group that got vitamins had nonfatal heart attacks versus 4.3 percent in the control group.

Dr. McCully, who is sometimes called the father of homocysteine, said laboratory tests for it are still as crude as cholesterol tests were 50 years ago. He said refinements — the equivalent of HDL and LDL levels with cholesterol — would improve prediction rates.

He said a better test of the homocysteine-heart disease connection would emerge when the results of about 20 new worldwide studies were available. All involve giving vitamins B6, B12 and folic acid to healthy patients and waiting at least five years to see how many develop cardiovascular disease. Some patients are just now reaching the five-year mark.

In the United States, homocysteine levels have been dropping since 1998. In that year, the Food and Drug Administration required all makers of bread and pasta flour to add B vitamins and folic acid to their products. The goal was to eliminate spina bifida among babies born to mothers with vitamin deficiencies, but it may have had a beneficial effect on heart disease, as well. However, typical helpings of bread and pasta do not contain nearly as much as a multivitamin pill does.