Unlocking the heart's secrets
Knowledge gained from the ambitious Framingham Heart Study is extending the lives of millions

BY SUSAN BRINK

In 1948, a healthy American breakfast was fried eggs with ham or bacon and a side of toast slathered with butter. Housewives skimmed the cream from the top of milk bottles to put in coffee. Seventy percent of men smoked. (Fewer than 30 percent of women smoked, but they were just beginning a 40-year climb to catch up.) After the deprivation of the Great Depression and World War II, the best thing a man could do for his family was put meat on the table. And living rooms across the country were beginning to glow in the blue light of television sets, spawning the first generation of couch potatoes.

In that atmosphere, researchers descended on the town of Framingham, Mass., to discover why 1 in 4 men age 55 or older developed heart disease. Many doctors didn't even know what was killing their patients. "When we started, we were getting death certificates saying that patients had died of acute indigestion," says William Kannel, senior investigator and director of the study from 1966 to 1979. Researchers recruited 2,336 men and 2,873 women from the town of about 28,000. They included women not out of a sense of egalitarianism but rather to discover what it was about women that kept them safe from heart disease--that is how little was known about the condition only 50 years ago. In 1971 the Framingham pioneers were joined by 5,135 of their sons, daughters, and sons- and daughters-in-law in a second phase of the study.

Thanks to Framingham, Americans have come to understand that how they live often determines when they'll die. After 50 years, 1,000 research papers, and $43 million, the Framingham Heart Study has shown that smoking is bad for the heart, that high blood pressure is not a normal consequence of aging, and that high cholesterol leads to heart disease. They know that women are at risk for cardiovascular disease, though later in life than men. They know that diabetes is a risk factor (a term coined by the study), that weight affects blood pressure, and that eating too much saturated fat affects cholesterol. They know that age and smoking compound the ill effects of the other risk factors. "All we ever did in Framingham was measure things on people's bodies and then wait to see what happened to them," says William Castelli, director of the study from 1979 to 1995, and now medical director of the Framingham Cardiovascular Institute, where he specializes in the management of risk factors.

Prolonging life. The Framingham Heart Study is one of the most celebrated works of epidemiology in the history of medicine. Before Framingham, epidemiologists did their research by examining medical records and death certificates. Framingham introduced the concept of measuring real people. "It has set the model in epidemiology. It's truly one of the great studies of this century," says Michael DeBakey, renowned heart surgeon and distinguished professor of surgery at Baylor College of Medicine in Houston.

The study is widely credited with contributing to the falling death rate from heart disease. When the heart study began in 1948, the rate of heart disease in the United States was 146.2 cases per 100,000. It climbed to a peak of 220.3 cases per 100,000 in 1963 and has dropped steadily ever since. In 1996, the most recent year reported, it reached a low of 87 cases per 100,000.

The information gathered in Framingham has had a profound effect on behavior and pharmacology. Americans have cut back on cigarettes; in 1994, only 28 percent of men and 23 percent of women smoked. Drugs have been developed to lower high blood pressure and cholesterol. But one lesson of Framingham has yet to produce significant results: the benefits of weight loss and exercise. The population remains fat and sedentary, even in Framingham; nationwide, 55 percent of American adults are overweight. Perhaps the biggest difference since 1948 is that now they know enough to feel guilty.

This groundbreaking research got off to a humble start when Congress, eager to begin its summer recess, rushed through two bills of similar size. One allocated $492,000 to fight Long Island potato bugs; the second gave $500,000 to the National Heart Institute, now called the National Heart, Lung, and Blood Institute, to uncover the cause of heart disease, the country's No. 1 killer. Researchers chose Framingham in part because public-health officials doing surveys on tuberculosis 20 years earlier had found the town's residents cooperative. It was a stable community, and its proximity to Boston, a medical mecca for specialists and consultants, added to its appeal. Framingham's population--working-class residents south of Route 9, professionals to the north--included a mix of people of Polish, Italian, Irish, Jewish, English, Greek, and French-Canadian descent. (Framingham had few minorities in 1948, and the heart study is largely of white people. In response to a 1995 congressional mandate that minorities be represented in medical research, doctors are recruiting blacks, Latinos, American Indians, and Asians and Pacific Islanders from Framingham and nearby communities.)

Push mowers. When the study began, youngsters walked to school or spent a nickel to take the bus across town. Few people formally exercised, though the north siders had a country club for golf. Many of those who worked at the Dennison Manufacturing plant, maker of gummed labels and baggage tags, or at Roxbury Carpet or the General Motors assembly plant, walked to work. Lawn mowers seldom had motors, and they never had seats. Families had one car, so housewives walked to the market or ran outside when the produce truck or the bakery truck wound through their neighborhood.

People had no idea that what they ate threatened their health. "When we were kids, we had the typical Irish diet on a meager income," says Karen Kiley LaChance, 53, a second-generation participant in the study. "Stews, creamed tuna, meatloaf, and always on Sunday we had roast. I remember my mom would pan-fry potatoes, basting them in Crisco. We had gravy on everything. My mother had a deep-fry cooker that would sit on the counter like you'd have a toaster now. She fried everything. My mouth still waters to think of it." Across town, Sandra Merloni, 57, remembers the Italian version of the same sinful food. "We had cappelletti in soup. They're filled with bread crumbs, cheese, and eggs. I remember pepper-and-egg sandwiches fried in oil. And when we had pork, we'd all fight about who got to eat that crispy fat," she says. Rita Hengesch, 81, sums up the consequences of decades of nutritional ignorance. "I always say I killed my first husband with good food." He died in 1973 of a heart attack.

Evelyn Langley, 83, was active in the PTA in Framingham when the project was announced, and she was one of the early volunteers charged with recruiting her neighbors. She knocked on the doors in a 10-block area of her neighborhood, skipping every other house, and had more than one door slammed in her face. "At that time, you had to practically beg people to go on the study. They felt they didn¬t want people to know their private business. Now people would break your arm to get in on it," she says.

Blanketing the town with volunteers and publicity paid off in recruiting, but keeping people in the study posed a different kind of challenge. "Old Dr. Dawber used to go down with the new doctors who were going to examine the patients," says Castelli, referring to Thomas Dawber, the study's first director. "He would say that these people are doing you a favor by letting you examine them, so don't ever lose an opportunity to thank them. That kind of interaction is enough to change the way you talk to patients for the rest of your life."

Poked and probed. The medical probing--every two years for the original group, every four years for their offspring--included taking systolic blood pressure, diastolic blood pressure and a base-line heart rate. Then researchers asked nosy questions about frequency of anxiety, how the subjects slept or didn't sleep, if they experienced nervousness, how often they had headaches, whether they worried, how much alcohol they drank, how many cigarettes they smoked, what education they had, and how they responded to anger. They asked detailed questions about eating habits. Researchers performed 84 medical tests on each volunteer, adding hundreds of other measures as technology advanced. They sent the results of all the tests to each volunteer's personal doctor, but the Framingham researchers never treated a single patient.

The volunteers turned out to be reliable participants. In a rare level of compliance for a long-term study, less than 5 percent of them, and less than 3 percent of their children, have dropped out of the study. Their ranks have been thinned mainly by death: About two thirds of the original group has died.

A major reason participants kept coming back was that they got a kick out of reading about themselves in the newspaper. Kannel cleverly leaked the earliest study results to the local daily, now called the Middlesex News, before the more prestigious Boston Globe got it, so study participants could read it first in their hometown paper. Word of the study soon spread across the country. Morris Shapiro, 90, took his family to the Grand Canyon in 1961, and when they stopped in a small Arizona town because his daughter had an infected toe, the nurse heard "Framingham," and immediately said, "Oh, the heart study." When Karen LaChance was on a ski lift in France on the way to the top of Mont Blanc, a German tourist had the same reaction. In making medical history, they put their town on the map.

Primitive computers. The early researchers, including Dawber, Kannel, and Castelli, made some good guesses about the information they would need, but they didn't have a clear idea of just what they would do with the mountain of data they were beginning to gather. They used pen and paper to record information. Soon, early computers the size of an upright piano were sorting key-punch cards. Statisticians invented methods for analyzing information as they went along--methods that have become standard in epidemiology. It's not surprising that it took about 10 years to publish the first findings. Nor is it surprising that updates have been coming fast and furious ever since.

In 1959, the study found that some heart attacks are "silent," occurring without warning. The world learned from the people in Framingham who died this way--1 in 6 heart-attack victims--that the first and only symptom of a heart attack could be death.

In 1960, the researchers found that cigarette smoking increased the risk of heart disease, giving the U.S. surgeon general ammunition for a 1964 warning that triggered a war against the tobacco industry. When the industry responded by proclaiming the safety of filtered cigarettes, Framingham researchers fired back in 1981 with evidence that filters provide no protection against heart disease.

In 1961, high blood pressure was shown to increase the risk of heart disease. Until then, doctors thought that blood pressure rose as a natural consequence of aging. Today, there are about 60 drugs on the market to control blood pressure. Then, in 1970, Kannel published a landmark study showing that high blood pressure increased the risk of stroke as well as heart disease. Before that, a rule of thumb had been that systolic blood pressure could equal one's age, plus 100. "I was taught that if you were 70, your blood pressure could be 170 and you'd be right on target," says Philip Wolf, professor of neurology at Boston University and principal investigator of the Framingham Heart Study. Later research showed that a systolic pressure of 170 at the age of 70 quadruples the odds of stroke.

In 1967, body measurements of Framingham residents showed that physical activity reduced the risk of heart disease and that obesity increased the risk. Now, any doctor who doesn't recommend diet and exercise would be considered irresponsible.

In 1976, Framingham linked menopause to an increased risk of heart disease in women, uncovering women's mysterious protection--natural estrogen--and showing that the protection didn't last forever. Today, gynecologists routinely recommend hormone replacement therapy to women after menopause.

In 1978, it was discovered that atrial fibrillation, a condition in which the heart beats irregularly because the upper chamber doesn't fully close, increased the risk of stroke fivefold. Until then, the condition had been considered innocuous. Subsequent clinical trials tested anticoagulant drugs like Warfarin and showed that such drugs could prevent strokes in people with atrial fibrillation--though surveys through the early 1990s indicate that the drug is vastly underprescribed for people at risk.

In 1988, good news emerged: High levels of high-density lipoprotein (HDL) actually protect against heart disease.

In 1991, researchers reported that fluctuations in weight (yo-yo dieting is the popular term) posed a heart-disease risk.

This year, the Framingham researchers published a formula that calculates a patient's odds of getting heart disease within the next decade. It uses numbers any physician should be able to provide from a standard checkup. (Work sheet. The News You Can Use section of the U.S. News Web site at www.usnews.com has an interactive version.)

Information from the Framingham participants' lives and deaths has been shared with researchers studying not only heart disease but Alzheimer's disease, osteoporosis, cancer, and arthritis, as well as sleep, hearing, and vision disorders. Volunteers recently have been asked to donate their brains after they die to the Harvard Brain Tissue Resource Center at McLean Hospital, a mental-health hospital in Belmont, Mass., for research on Alzheimer's. Many have already said yes--some joking that, at last, they have the brains to go to Harvard. The data from Framingham have led to the development of drugs to treat hypertension, stroke, and high cholesterol, and the federal government has developed guidelines on how to prevent and treat heart disease.

Dozens of other risk factors may be added to the Framingham list. For example, a high level of homocysteine, an amino acid produced by the body, may contribute to heart disease and stroke by adding to the buildup of fatty substances in the arteries and by making blood vessels less flexible. (A diet high in folic acid and B vitamins reduces homocysteine levels.) Another likely risk factor is Lp(a), a nasty cousin of LDL, the bad cholesterol. Lp(a) may contribute to heart disease by preventing the breakup of clots. And exposure to some infections, including H. pylori (bacteria linked to ulcers), chlamydia (a sexually transmitted disease), and cytomegalovirus (a common virus, thought to be harmless except in people with impaired immunity), may harm blood vessel walls and contribute to heart disease, says Daniel Levy, director of the heart study.

A nation of fatties. As important as the Framingham data are, a chasm exists between what researchers discover about heart health and how doctors and patients respond. Americans steadfastly refuse to follow some of the study's obvious advice, doctors fail to follow treatment guidelines, and nearly three quarters of a million people die of heart disease each year. Framingham participants have as much trouble dieting and exercising as the rest of the population. Fifty years ago, the average weight of the original group of volunteers was 153 pounds; when their children went for their first exams, their average weight was 159. Today, the original group averages 150 pounds and their children average 171 pounds, while height hasn't changed significantly.

Americans are as bad about confronting their cholesterol numbers as they are at conquering their weight problem. Only 11 percent of people surveyed for an NBC Today and Prevention magazine poll even knew their cholesterol levels. Of the estimated 52 million Americans with high levels of LDL, fewer than a third were getting treatment. And those with prescriptions were not filling them, according to a study in the May 13 Journal of the American Medical Association (JAMA). Even when medication was free, or required only a modest copayment, the average patient went without filling a prescription for more than a third of the year. According to JAMA, about half the surviving 7,287 people studied had stopped using the cholesterol-lowering drugs altogether within five years.

Ignoring guidelines. In a survey of 62 percent of all retail pharmacies in the United States, researchers found that physicians were not following national guidelines for treating hypertension. Despite guidelines recommending diuretics and beta blockers as the first line of treatment for most people with high blood pressure, only 11 percent of anti-hypertensive drugs prescribed in 1995 were beta blockers and only 8 percent were diuretics, according to a study published last year in JAMA. People who have already had a heart attack do better with ACE (angiotensin-converting enzyme) inhibitors, several studies have found. But a study in the August issue of the Journal of the American College of Cardiology found that doctors were giving the wrong medication to heart-attack survivors, too. In 1996, only 30 percent of heart-attack patients went home with a prescription for ACE inhibitors.

And it's not only that doctors are prescribing the wrong stuff. Of the 50 million people in America estimated to have high blood pressure, only 34 million know it. Of those who know it, only 27 million seek treatment. And of those seeking treatment, only half get the problem under control--a blood pressure no higher than 140/90, which Framingham pioneer Castelli believes is still too high.

The next generation of studies out of Framingham will likely rob Americans of their last, best rationalization for not changing the way they live. The rationalization goes like this: "Heart disease is in my genes. There's nothing I can do about it." But the secrets hidden in DNA will undoubtedly reveal the opposite, says Christopher O'Donnell, medical officer with the National Heart, Lung, and Blood Institute. What is in the genes--whether a propensity for high blood pressure or an inherited lucky break with a gene providing a high level of HDL, the good cholesterol--is a blueprint that will tell people exactly what they can and should do about it. Genetics-based studies, going on all over the world and begun as part of the Framingham Heart Study in the late 1980s, most likely will not single out for blame either nature or nurture, genes or lifestyle. They will, with crisp genetic data added to the wealth of medical information gathered ploddingly over five decades and across two generations, show which people have the best chance of surviving a careless lifestyle and which ones risk an early death.

Unfortunately, that's not the magic pill that Americans crave. Rather, for cardiovascular disease, even uncovering the deepest genetic secrets will likely mean similar regimens for a healthy heart, only individually tailored: Eat a sensible diet, exercise, quit smoking, and drink only moderately. Just as important, know your blood pressure and cholesterol numbers, and take medication if you can't get them under control through diet and exercise.

Some patients will be told very early that it's crucial for them to eat right and work out; a lucky few will be told they have little to worry about. At Framingham, the DNA of all study participants has been collected, studied, and stored since 1987, creating an unparalleled reservoir of genetic information. "Framingham turned out to be just perfect for genetic analysis," says Richard Myers, a Boston University geneticist who supervises the genetic analysis in the Framingham study. "What we have is not just big families, with parents and children, cousins, aunts, and uncles, but all the information on virtually anything that would be of significance in heart disease. There isn't a missing link." Today, a doctor facing a patient with newly diagnosed hypertension must use evidence compiled from hundreds of studies and distilled into broad guidelines. A properly cared for patient gets diuretics and beta blockers first, for example, then a trial-and-error experiment with other hypertension medications. Exciting research underway now will someday allow doctors to identify which of several blood-pressure-regulating genes a person has inherited and then choose a drug therapy based on a genetic profile.

Protective genes. There may also be some inherited quirks in how individuals respond to cholesterol. Some people on strict cholesterol-lowering diets don't lower their levels of bad cholesterol as well as others, leading researchers to believe that genetic differences influence the effect of diet. The American Journal of Clinical Nutrition reported in March that men who carried an abnormal gene for apolipoprotein E, known as apoE4, had bodies that respond exceptionally quickly to dietary changes. When they ate foods high in saturated fat and cholesterol, their blood-LDL levels rose faster, and when they improved their diets, their levels fell faster than those with no gene abnormality.

Regardless of what new research and technology turns up, O'Donnell cautions that inherited effects will never be more important than lifestyle. "Overweight is as much a contributor to high blood pressure as genes," he says.

The information that continues to pour out of Framingham still allows room to dream. Some of Myers's present work, for example, focuses on a region of a chromosome that may be home to a gene that's shared by people who have high levels of HDL, the good cholesterol. These lucky folks have a low incidence of heart disease, even if they are chain-smoking fatties. Where is the gene, and how does it lead to high levels of protective HDL? And if found, could pharmaceutical companies then create a drug that mimics the gene's protective action? "I don't think we're ever going to get to a point where people are going to stop eating cheeseburgers. So could we make it safe for people to eat cheeseburgers?" asks Myers, laughing at the absurdity of a solution America might finally accept. "Sounds like science fiction, but I don't think it's impossible."

THE NEXT 50 YEARS

Giving the heart a helping hand

Fifty years ago, when the Framingham study began, a heart-attack survivor could look forward to six months of bed rest after discharge from the hospital; after that, chances of an active life were bleak. Today, some patients are up and about within weeks of an attack--many because of advances in cardiac care due at least in part to the study. Here are some key areas of research for the next 50 years:

Sprouting new blood vessels

Some patients' hearts are so damaged from years of disease that blood can't circulate normally. In most cases, the blood vessels involved don't repair themselves. So scientists are exploring ways to promote blood vessel growth, or angiogenesis (the Greek word for "vessel birth"). Doctors hope that in a decade the technology will help a damaged heart develop its own detour around a blocked artery.

At St. Elizabeth's Medical Center in Brighton, Mass., researchers have successfully treated patients with a problem called peripheral vascular disease, in which lack of blood flow to the legs causes gangrene and ulcers. They stimulated blood-vessel growth by injecting a protein called vascular endothelial growth factor into the leg muscle. And Cornell University Medical College researchers are injecting engineered genes into bypass patients that "tell" the blood vessels to grow and compensate for blocked arteries.

Pumping up the heart

Heart failure affects 4 million Americans and leads to 50,000 deaths per year, and it is one of the few cardiac diseases on the upswing. Transplants can help save lives: About 2,300 are performed annually, but as many as 4,000 patients await a donor heart at any given time, and 25 percent die before they get one.

For about 10 years, an invention called the left ventricular assist device, or LVAD, has been helping patients awaiting transplants. Today's LVADs are fist size and are surgically implanted, usually in the abdomen. A tiny electric motor pumps blood through tubes that run from one heart chamber into the circulatory system.

LVADs are not a permanent alternative to surgery, but clinical trials are underway on permanent replacements, known as innovative ventricular assist systems, that could extend the lives of many people who can't undergo transplants because of advanced disease or other reasons.

Another study will examine two new types of artificial heart, past versions of which have proved disappointing. The new models have performed well in animals; researchers will test them using a simulated human system.

Genes and irregular beats

Irregular heartbeat, or arrhythmia, affects millions of Americans and kills more than 350,000 people a year. Researchers at the Howard Hughes Medical Institute at the University of Utah are now uncovering mutated genes in some families that alter the electrochemical balance of the heart, causing a disruption in its normal pace. New genetic tests can pinpoint the genes in individuals, and this information is helping researchers develop new drugs for arrhythmia and isolate other faulty genes.--Mary Brophy Marcus