The heart health-E vitamin.

Alan Chait is a heart disease researcher at the University of Washington and the former chair of the American Heart Association's Nutrition Committee. Alan Chait takes a vitamin E supplement each day to reduce his risk of heart disease. Does he advise you to do the same?

No. "Even though we have impressive circumstantial data, the evidence isn't strong enough to make a widespread recommendation," says Chait, who adds that his decision to take vitamin E was influenced by his own risk factors.

Why do researchers like Chait have what looks like a double standard? Are they worried about adverse effects or their reputations as scientists? Are they afraid people will take pills instead of eating a healthy diet or seeking needed medical treatment? Or are they simply biased against supplements?

What--if anything--do they know that we don't?

19 CUPS OF SPINACH

Last May, antioxidants hit the news... again. This time, it wasn't cancer, cataracts, or aging that the supplements were supposed to prevent. Instead, as The Washington Post headline put it, "Vitamin E Seen Lowering Heart Disease Risk."

The evidence is mounting that antioxidants-especially vitamin E--can reduce the risk of heart attacks. Indeed, to the average reader, the widespread press reports made vitamin E sound like a sure winner.

Meanwhile, attempts to persuade people not to take vitamin E sounded much weaker.

"Clinical trials could give us definitive answers in just a few years," said researcher Daniel Steinberg of the University of California at San Diego. "If this were the Black Plague and people were going to die in seven days, I'd say okay, but why not sit tight for two or three years?"

That's fine for the pursuit of scientific truth, but it may not be too convincing for a 70-year-old.

And urging people to eat a good diet--which is much-needed advice--doesn't cut the mustard when it comes to vitamin E. Recent studies suggest that it takes at least 100 International Units (IU) a day to reduce the risk of heart disease.

"To get that, you'd have to eat 4 1/2 cups of mashed sweet potatoes, six cups of kale, 19 cups of spinach, two cups of almonds, or almost seven cups of peanuts," says Chait. "And the peanuts contain 5,630 calories and 478 grams of fat."

And that adds to researchers' qualms. "We think vitamin E is safe," notes Chait. But at 100 IU, he says, "we're not talking about a foodstuff. We're talking about a drug."

CLUES FROM TIlE TUBE

In 1980, the workers in Daniel Steinberg's laboratory were stumped.

Arteries start to clog, they surmised, when immune system cells called macrophages gobble up circulating LDL and crawl inside the walls of arteries. (LDL, or low-density lipoproteins, carry "bad" cholesterol.) But when they mixed LDL with macrophages in a test tube, "we couldn't force the macrophages to take up the LDL very quickly," says Steinberg.

Only when the LDL was first mixed with cells from artery walls did the macrophages start biting. "It took us a year to figure out why," he explains. The fats in the LDL were getting oxidized by the cells, just like butter that's exposed to oxygen in air turns rancid. That was clue number one. Since then, scientists have found other clues suggesting that only oxidized LDL triggers the lesions that lead to heart disease (see illustration).

What's more, when researchers mix LDL with an oxidant like copper, the vitamin E that's ordinarily in the LDL gets "used up." Only when the vitamin E, beta-carotene, and other antioxidants in the LDL are depleted do the LDEs fats and other components start to become oxidized.(1)

Compelling. But what happens in a test tube doesn't necessarily happen--or may not happen on a large-enough scale to matter--in people. "The [test-tube] work has built a strong scientific base," says Steinberg, "but its limitations need to be kept in mind."

THE HIDDEN RISK FACTOR

Like detectives hot on the trail of a killer, researchers have sought other pieces of the antioxidant puzzle.

First, they needed evidence that oxidized LDL occurs in people. And they found it...in blood, in the immune system, and in the plaques that clog diseased arteries.

If oxidized LDL causes heart disease, you'd expect people with clogged arteries to have LDL that is easily oxidized. Last year, that's just what a small study from Sweden found.

Jan Regnstrom examined the arteries of 35 young men who had survived heart attacks.(2) Then he measured how long their LDL could resist an oxidant in a test tube.

"The [more susceptible their LDL were to oxidation], the more atherosclerosis was found in their coronary arteries," explains Ishwarlal Jialal of the University of Texas Southwestern Medical Center in Dallas.

Of course, that doesn't prove that having oxidation-prone LDL caused their disease. Whatever makes them susceptible to heart disease might also make their LDL susceptible to oxidation.

But it could explain a mystery that's been puzzling researchers for decades. "We've never understood why most people with heart disease don't have very high cholesterol," says Jialal. Easily oxidized LDL, he adds, "could be the hidden risk factor."

Meanwhile, he and others have shown that antioxidants can make LDL less prone to oxidation...at least when the LDL is studied in test tubes.

At last November's annual meeting of the American Heart Association, Jialal reported that he had given 36 men a daily dose of:

* 800 IU of vitamin E,

* a combination of three antioxidants-800 IU of E, 50,000 IU (30 reg) of beta-carotene, and 1,000 mg of vitamin C--or

* a placebo.

After three months, he measured how susceptible each person's LDL was to oxidation. The triple-antioxidant combo was no better than the E alone.(3) But both doubled the length of time a person's LDL could resist oxidation in a test tube, compared to the placebo.

"It's very clear that vitamin E is the most potent antioxidant for LDL oxidation," says Jialal.

RABBITS & MONKEYS

The scramble for evidence that antioxidants are a shield against heart disease slows down a bit when it comes to animal studies.

"Except for one study on monkeys, we have no experiments on antioxidant vitamins in animals," says Steinberg. "And that study is small and has internal inconsistencies."(4)

And in studies using antioxidants other than vitamins, the results are not always consistent.

"I'm convinced that [the antioxidant drug] probucol slows the progression of atherosclerosis in rabbits and monkeys," says Steinberg. "But I'm not sure it's because probucol acts as an antioxidant."

If antioxidants prevent heart disease, you'd expect probucol plus an ordinary cholestrol-lowering drug to keep arteries clearer than the drug alone. In a recent Swedish trial, it didn't.

NURSES & PHARMACISTS

The news hit like a bombshell. On November 19, 1992, two studies from Harvard University reported almost identical results.(5) The first involved 87,245 healthy female nurses who, in 1980, had filled out questionnaires about their diets and the supplements they were taking. After eight years, the nurses who had reported taking daily supplements containing at least 100 IU of vitamin E were 34 percent less likely to have had a heart attack. Meir Stampfer and his co-workers found no link with vitamin E in foods, perhaps because few of the nurses were getting more than 8 IU of E from their diets.

Meanwhile, Harvard's Eric Rimm tracked 39,910 male pharmacists, veterinarians, and other health professionals for just four years. ("It takes half as long when you're waiting for heart attacks in men," he quips.)

Rimm's description of his results is quite succinct. "Ditto for men, thank you," he joked at a recent conference.

Men who took 100 to 249 IU of vitamin E every day for at least two years had a 37 percent lower risk of heart disease than men who took no vitamin E. (Taking 250 IU or more added no extra benefit.)

That's no small potatoes. "The risk for not taking vitamin E was equivalent to the risk of smoking," says Rimm, if--and that's a big "if"--taking vitamin E caused the lower risk.

It's possible, for example, that people who take supplements lead a healthier lifestyle or do something else that protects them against heart disease. But Stampfer's and Rimm's vitamin-C-takers-who are presumably just as health-conscious as the E-takers--did not have a lower risk.

Still, the vitamin-E-takers were less likely than non-E-takers to have risk factors like cigarette smoking or lack of exercise. Both studies mathematically corrected for those and other "confounders." But, says Steinberg, "it's a bold assumption that we can just throw numbers into a computer to correct for those variables. I'd call that eyewash."

Only one kind of study can eliminate these and other confounders. And that's what most researchers are waiting for.

THE WAITING GAME

"For something that reduces a risk by 20, 30, or 40 percent, we need clinical trials," says Charles Hennekens of the Harvard School of Public Health.

In a trial, researchers don't just observe, they intervene. By randomly dividing people into groups getting either antioxidants or placebos, they eliminate confounders like smoking or exercise. Among the trials Hennekens' team has under way:

* In the Women's Health Study, 41,000 healthy postmenopausal nurses are taking either 600 IU of vitamin E, 83,000 IU (50 mg) of beta-carotene, or 100 mg of aspirin every other day. Results are expected in five to ten years.

* In the Women's Antioxidant and Cardiovascular Disease Study (WACS), women who already have heart disease are taking either 400 IU of vitamin E, 33,000 IU (20 mg) of beta-carotene, or 500 mg of vitamin C every day. Results are due in four years.

Most researchers agree that clinical trials will tell us definitively whether vitamin E prevents heart disease. The question is: Should people take it in the meantime?

"We believe that without data from clinical trials, the evidence is insufficient for use in public policy," said Rimm and Stampfer in The New England Journal of Medicine last November. Yet both take vitamin E themselves.

"The fact that doctors think something is good doesn't mean anything," argues Steinberg. "We used to recommend taking out tonsils by the bucketful."

Some physicians are more comfortable recommending vitamin E for people at high risk. "I treat young people--under 45--with heart disease, and 1 encourage them to take 400 IU a day," says the University of Texas' Jialal. "But as a medical scientist," he adds, "I don't have the evidence to recommend vitamin E to healthy people."

Others are nervous about safety. "We haven't excluded the possibility that there is a small harm," says Hennekens.

Researchers didn't know that aspirin increased the risk of bleeding in some people until his clinical trial showed it, he notes. Studies suggest that vitamin E also makes blood less likely to clot. In fact, that--not oxidized LDL--could explain why vitamin-E-takers have fewer heart attacks. And there's the "magic bullet" problem. "It may give people a false sense of security, a crutch to hang on to," worries the University of Washington's Alan Chair. "Remember how people thought that if they ate a scoop or two of oat bran they didn't have to worry about smoking and other risk factors?"

But what if someone were eating a healthy diet, exercising, not smoking, and wanted take vitamin E? What would these doctors say?

"I wouldn't talk them into it, but I wouldn't talk them out of it," says Jialal. Chait agrees.

Even Steinberg admits, "I'm not the vitamin E police. I'd give my patients the information and let them make their own decision."

1. New England Journal of Medicine 320: 915, 1989.

2. Lancet 339:1183, 1992.

3. Circulation 88 (Suppl.): 1-563, 1993.

4. Journal of the American College of Nutrition 11: 131, 1992.

5. New England Journal of Medicine 328: 1444, 1950, 1993.

THE BOTTOM LINE

* Studies suggest, but haven't proven, that high doses of vitamin E (about 100 IU a day) reduce the risk of heart disease.

* You can't get 100 IU of vitamin E from food without consuming huge amounts of polyunsaturated oils, which add fat to your diet and increase your vitamin E needs.

* Consider taking a supplement of 100 IU of vitamin E a day. There are no known dangers, although it's never been taken by large numbers of people for long periods, so there's no guarantee.

* A typical antioxidant formula--including 200 to 400 IU of vitamin E, 10,000 to 25,000 IU of beta-carotene, and 250 to 500 mg of vitamin C--should cost only about $2.50 to $5 a month. (Don't pay more for other ingredients like zinc and copper--the evidence isn't strong enough.)

* Some of the least expensive antioxidant formulas we found are sold by Puritan's Pride (800-645-1030), Wal-Mart, and drugstores like Peoples, Rite-Aid, CVS, and Eckerd.