The Heart Attackers

IF YOU CARE A WHIT ABOUT YOUR health, you can probably recite your cholesterol level in your sleep. Thanks to the tireless efforts of health officials and drugmakers, Americans can hardly escape the supermarket, let alone the doctor's office, without submitting to a cholesterol check. Five percent of the adult population - some 9 million people - now take cholesterol-lowering drugs in the hope of warding off heart disease, and the potential market swells every time another boomer turns 50. ""Cholesterol consciousness is incredibly high,'' says Dr. James Cleeman, coordinator of the federally sponsored National Cholesterol Education Program. ""Fifteen years ago scientists were the only ones who talked about cholesterol. Today you see the word in the funnies.''

From Cleeman's perspective, this is excellent news. Heart disease is, after all, the nation's No. 1 killer. It claims a half-million lives every year, and high cholesterol is a well-established risk factor. No one denies that excess LDL (the so-called bad cholesterol) can increase the risk of a heart attack, or that cholesterol-lowering therapy can help reduce the risk. But does one blood component warrant so much attention? The fact is, most heart-attack victims have cholesterol levels that would qualify as normal. Moreover, America's heart-attack rate has fallen by half in recent decades, while average cholesterol levels have declined only slightly (chart). So while monitoring cholesterol may be a worthwhile exercise, there is clearly more to staying healthy.

What else should we worry about? Smoking, obesity and high blood pressure all pose well-known hazards - yet roughly a fourth of all heart attacks occur in people with no known risk factors. Fortunately, researchers are now starting to identify other sources of trouble. An avalanche of new studies suggest that an amino acid called homocysteine (pronounced HO-mo-SIS-teen) plays a critical role in destroying our arteries - perhaps as large a role as smoking or cholesterol. Other research suggests that our risk of developing heart disease depends at least partly on the nourishment we receive in the womb and the infections we contract as we age. The most important of the emerging risk factors are subject to our control, and together they could revolutionize the art of prevention.

Arterial disease may kill you in a minute, but it usually develops over a lifetime. And though the root causes are not perfectly understood, the disease process involves several well-known steps. It begins when something injures the lining of an artery and the body tries to repair the damage. Circulating immune cells known as monocytes burrow into the blood-vessel walls, where they mature into macrophages (literally ""big eaters''), gorge themselves on oxidized fatty substances and die (diagram). Eventually, this inflammatory process causes a buildup of tough, fibrous scar tissue that can inhibit blood flow and promote the formation of clots.

According to conventional thinking, high-fat diets trigger this process by causing a buildup of LDL cholesterol in the blood. No one has ever demonstrated that circulating cholesterol is what first injures the arterial wall. But because it collects there, experts have been content to think of it as the primary culprit. Dr. Kilmer McCully, a pathologist at the VA Medical Center in Providence, R.I., has spent three decades advancing a different idea. According to McCully, the initial injury is caused not by cholesterol but by homocysteine, a substance derived from the protein in our diets. If McCully is right, this little-known molecule is what makes our blood vessels vulnerable to cholesterol - and disarming it could be as simple as upping our intake of three B vitamins. That may sound outlandish. But after years of neglect, homocysteine is now inspiring a research explosion, and McCully's ideas are looking more credible every day.

Like cholesterol, homocysteine can be useful. Our bodies derive it from methionine, an amino acid that abounds in animal protein, and use it to build and maintain tissues. During normal metabolism, any excess homocysteine is quickly swept away. With the help of vitamins B6, B12 and folic acid, the liver either converts it back into methionine or breaks it down for excretion. But when that process is disrupted, the consequences can be dire. McCully discovered just how dire back in 1968, while studying a rare genetic disorder called homocystinuria.

CHILDREN BORN WITH THAT condition lack proper levels of the liver enzymes required to process homocysteine, so it reaches astronomical levels in their blood. Kids who go untreated often die of strokes and heart attacks before they reach adulthood, even though their cholesterol levels are normal. McCully discovered during autopsy studies that the young victims' arteries looked a lot like those of elderly heart patients, and that finding raised an intriguing possibility. If severe homocysteine overload can destroy a child's arteries, could milder but more chronic elevations - the kind that anyone might develop from a diet low in vitamin-rich plant foods - foster cardiovascular disease in adults?

It was just a hunch, and the research community was too focused on cholesterol to pay it much heed. But as McCully explored the idea, he found that homocysteine could help explain many of the known risk factors for heart attack and stroke. Smoking and inactivity tend to raise homocysteine levels, for example. And when heart disease runs in a family, the victims often share a minor flaw in one of the genes governing homocysteine metabolism. McCully's hypothesis also squares with what we know about the effects of gender and age. During their reproductive years, women's homocysteine levels are roughly 20 percent lower than men's. But after menopause their homocysteine levels, and their heart-disease risk, rise to male levels. Both sexes experience homocysteine increases in old age, as the body grows less efficient at absorbing B vitamins, and their heart-disease rates rise accordingly.

This is all circumstantial evidence, nothing that would send an amino acid to jail. But there is good reason to suspect that the association between homocysteine and heart disease is more than coincidental. In test-tube studies, the substance not only injures blood-vessel linings but accelerates the buildup of scar tissue and promotes the formation of blood clots. Moreover, researchers have known for years that homocysteine injections produce arterial plaques in animals.

You can't inject people that way, but there are other ways to spot patterns. In a 1992 study of 14,000 male physicians, Harvard researchers found that those with homocysteine levels above the 95th percentile had more than three times the heart-attack risk of those in the bottom 90 percent. Likewise, researchers involved in the Massachusetts-based Framingham Heart Study found in 1995 that people with high homocysteine levels are the most likely to suffer from a dangerous narrowing of the carotid artery, the main vessel feeding the brain. A homocysteine level of less than 14 micromoles per liter of blood is considered normal, but the Framingham researchers found that any reading above 11.4 brought an increase in risk. Scores of scientists are now reporting similar findings. In the past month alone, University of Washington researchers have reported that high homocysteine doubles the risk of heart attack in young women. And scientists in Norway have shown that heart patients with elevated homocysteine are the most likely to die.

That's just the bad news. As they confirm homocysteine's hazards, researchers are also identifying simple ways to avoid them. Some of us are more prone to homocysteine buildup than others (roughly one person in eight inherits a gene that slows disposal of the substance). But almost anyone can control homocysteine by getting enough B vitamins. Blood studies have consistently linked low levels of folic acid to high levels of homocysteine. And a recent European study found that people who reported taking B-vitamin supplements had just half the heart-disease rate of those who didn't.

No one yet has taken the final step, showing in a controlled clinical trial that a specific combination of foods or supplements brings a particular benefit. Meir Stampfer, an epidemiologist at Harvard, is now launching one to see whether a daily folic-acid supplement can help prevent strokes. Until the evidence is definitive, your annual physical isn't likely to include blood tests for homocysteine or B vitamins (though commercial labs will soon offer a full battery). And the government's heart-health promoters say they'll continue to ignore homocysteine in favor of cholesterol until the evidence is definitive.

But that doesn't mean you should. The evidence already in hand suggests that we have nothing to lose, and much to gain, by paying more attention to the vitamin levels in our diets. Unless you're a strict vegetarian, chances are you're getting plenty of B12. Vitamin B6 is also easy to come by, since U.S. food makers pump it into flour. In his new book, ""The Homocysteine Revolution'' (242 pages. Keats. $14.95), McCully speculates that the B6 in processed foods may help explain the sharp drop in heart disease since the 1960s. But folic acid is another story. Experts agree that 400 micrograms a day is probably enough to hold homocysteine in check (and to help women of childbearing age prevent neural-tube defects in their babies). The trouble is, folate is found mostly in beans, grains and greens, which are not America's favorite foods. Nearly half of us fall short of the 200-mcg daily allowance, and only a small minority get 400. Megadoses of folic acid are unnecessary and unwise, but a multivitamin and a few ounces of spinach won't hurt you. And over time, they may well save your life.

Kilmer McCully isn't the only maverick whose novel ideas are gaining currency in heart-disease research. Consider the case of David Barker, an epidemiologist at the University of Southampton, in England. Barker has long argued that our chances of developing heart disease and other chronic ills depend to a surprising degree on what happens to us early in life - not just as kids but as fetuses. He reasons that, like a poorly made car, an undernourished fetus is more likely to break down later. ""We've been obsessed with the breaking-down bit,'' he says, ""and we've forgotten how easy it is to influence people permanently before they're born.''

Barker and others have amassed considerable evidence that smaller-than-average babies run a bigger-than-average risk of developing hypertension, diabetes and heart disease as adults. The possibility first occurred to him back in the early '80s, as he puzzled over Britain's regional disease patterns. Heart-disease mortality is twice as high in some areas as in others, even when dietary and lifestyle differences are taken into account. Looking back in time, Barker noticed that the heart-attack hot spots had been infant-mortality hot spots 70 years earlier. Suspecting that early deprivation might have long-delayed consequences, he gathered data on 16,000 Britons born between 1911 and 1930. His analysis showed that among people who reached full term and weighed from 5.5 to 9.5 pounds at birth, those with the lowest birth weights had the highest average heart-disease rates.

Subsequent studies have brought mixed results, but most tend to support Barker's hypothesis. In the past year alone, he and his colleagues have linked low birth weight to stroke and heart attack in British men, and to cardiovascular disease in men and women from southern India. Large studies conducted in Wales and the United States have turned up the same pattern. When Dr. Gary Curhan of Harvard looked at birth weight and blood pressure in 164,000 female nurses, he found that hypertension was 40 percent more common among those born weighing less than 5 pounds than among those born at 7 to 8.5 pounds. ""It really looks like there's something to this,'' says Harvard epidemiologist Walter Willett.

How could low birth weight foster chronic disease? One theory holds that when a fetus lacks the nutrients it needs, its body resorts to a costly sort of triage. ""The first thing it does is alter its metabolism so it can continue to grow,'' says Barker. That could mean ratcheting up its blood pressure to draw more nutrients through the placenta, or abandoning work on the liver, pancreas and blood vessels to complete construction of the brain. When unborn rats or sheep are deprived of nutrients, they make all these adjustments, and suffer accordingly. Barker draws the lesson that women can protect their kids against heart disease by eating well during pregnancy, but many experts are skeptical. A newborn's size is only modestly related to its mother's diet, says Dr. Nigel Paneth, an epidemiologist at Michigan State University. And even if low birth weight does contribute to heart disease, Barker's own studies show that adult obesity is a stronger predictor.

Low birth weight is fairly rare in this country, but the viruses and bacteria now being linked to arterial disease are not rare at all. Like homocysteine, the infectious suspects have long been eclipsed by cholesterol, but some are starting to look like major offenders. For 17 years, Dr. Joseph Melnick of Houston's Baylor College of Medicine has made a hobby of removing lesions from diseased coronary arteries and testing them for cytomegalovirus (CMV), a common herpes virus. It shows up with surprising frequency - and it's looking less harmless all the time. Scientists have long known that CMV can spell trouble for people receiving heart transplants; infected patients are roughly twice as likely as others to lose their new organs, or their lives, to arterial disease within five years. Transplant patients aren't unique. In a 1996 study, Dr. Stephen Epstein of the National Heart, Lung, and Blood Institute found that CMV infection quintupled the odds that someone having his arteries reamed out by angioplasty would see them close back up within six months. The bug's role is still under investigation, but Epstein says the evidence linking it to cardiovascular disease is as strong today as the evidence for cholesterol was 15 years ago.

The same goes for Chlamydia pneumoniae, an airborne bacterium known mainly as a cause of respiratory illness. In recent years, researchers have amassed a boatload of evidence linking C. pneumoniae to arterial disease (NEWSWEEK, April 28). And British researchers have recently shown that treating infected people with antibiotics may reduce their risk of heart attack. In a study involving 213 male heart-attack survivors, Dr. Sandeep Gupta of St. George's Hospital in London found that patients with evidence of C. pneumoniae infection were up to four times more likely than others to suffer further heart problems over an 18-month period. But the disparity vanished when those patients were given a three-day course of the antibiotic azithromycin. ""We're not yet in a position to say this could prevent first heart attacks,'' he says. ""We can only say this is interesting.''

THERE'S NOT MUCH YOU CAN DO to keep CMV or C. pneumoniae out of your arteries. But a third possible troublemaker - Porphyromonas gingivalis - may be easier to control. P. gingivalis is a bug that inflames our gums, and preliminary evidence suggests that it may also gum up our arteries. As part of the VA Normative Aging Study, Dr. Raul Garcia of the Boston VA Outpatient Clinic followed 1,100 men over a 25-year period. They were all basically healthy at the outset, but they had varying levels of gum disease. And over the course of the study, the men with bad gums suffered nearly twice the heart-attack rate of their fresh-mouthed counterparts - and nearly three times the stroke rate. The bottom line, as Garcia puts it half jokingly: ""Floss or die.'' In truth, no one knows whether P. gingivalis can kill you, but the bacterium has been found in diseased carotid arteries. Researchers now hope to see whether treating gum disease can help prevent heart attacks.

Together, these inquiries are painting an ever-richer picture of America's leading killer. None of the new findings imply that cholesterol doesn't matter, but they suggest it's not our only enemy - or even our worst one. As the homocysteine revolution unfolds, it may turn out that we can accomplish more with nickel-and-dime vitamin supplements than with drugs that cost hundreds of times more. And if the bacterial connections hold up, antibiotics and dental floss may become major weapons in cardiology. But whatever happens, the way we eat and live will count as much as ever.

Does heart disease spread like the flu? Growing evidence suggests that infectious agents play a role. Some suspects:

Chlamydia pneumoniae Causes respiratory illness; may also damage the arteries

Porphyromonas gingivalis People plagued by gum-disease bug have more coronaries

Cytomegalovirus Common herpes virus seems to exacerbate vascular conditions

It kills more Americans than all other illness, including cancer. The root causes are still something of a mystery, but we know how he diesease progresses. And we're learning more about how to prevent it.