It turned a whole town into a research lab. It was the first to show the world that high cholesterol and obesity put people at risk for heart disease -- the first, in fact, to coin the very term "risk factor."
And it still hasn't run out of juice. The longest-running heart health study in the world, the 60-year-old Framingham Heart Study, continues to mine its vast data set for causes or signs of heart trouble.
"Framingham has revolutionized our thinking about cardiovascular diseases," says Dr. Bruce Psaty, a cardiovascular disease epidemiologist at the University of Washington in Seattle. "Calling it a landmark study is an understatement."
Six decades on, there is still plenty for Framingham to do. Heart disease remains the top cause of death and serious illness in the U.S. Nearly 2,400 Americans die of cardiovascular disease every day, according to the American Heart Assn. An estimated 80 million have a cardiovascular condition.
Scientists are now seeking genes and additional blood-borne molecules that can predict cardiovascular problems. Others mine Framingham's detailed, long-term data to study noncardiac health concerns such as stroke and dementia -- even how a person's health and happiness affect his or her friends. (See related story.)
In March, Framingham announced a project to search for new biomarkers that indicate risk for cardiovascular disease. The Systems Approach to Biomarker Research, SABRe, will take advantage of the freezers full of blood samples the study has already collected.
"There are thousands of things that could be measured in the blood, most of which we don't even know how to measure," says Dr. Daniel Levy, Framingham study director and a professor at the Boston University School of Medicine.
One goal is to identify people likely to suffer a first heart attack within a few months or a year. That's a large population: According to the American Heart Assn., an estimated 785,000 Americans will have a first heart attack this year, some with little reason to suspect an impending coronary event.
To try to assess risk now, physicians frequently use the Framingham Heart Risk score, which tallies factors such as cholesterol levels and blood pressure to calculate risk for heart disease or cardiac death within the next decade.
But the score isn't perfect. Many people who have a heart attack would not have scored high the day before the event, says Dr. Pieter Muntendam, chief executive of the biotechnology company BG Medicine in Waltham, Mass., which has partnered with Framingham for this project. Other tests, such as CT scans to identify calcium buildup in coronary arteries, are expensive and expose the patient to X-ray radiation.
"The real thing that we need is a diagnostic to identify people at high near-term risk of heart attack," Muntendam says. "Most likely, you could do something very significant for them if you could only find them."
Atherosclerotic plaques build up in the blood vessels over a lifetime, but at some point they may become "soft and smushy," Muntendam says. Pieces of those softened plaques are more likely to break away and clog the circulatory system. That's when treatment is needed, he says.
To try to find a chemical warning sign, BG Medicine will screen Framingham blood samples for about 1,000 potential biomarkers. The company will be interested in substances that increased or decreased in the blood in the year leading up to a person's heart attack.
Muntendam expects to have some results by mid-2010.
Another project, announced in 2007, will sift through DNA for heart risk factors. Called the Single nucleotide polymorphism Health Association Resource, or SHARe, it includes data on 550,000 genetic markers from 9,300 Framingham participants.
Those markers -- single-letter differences among people in their DNA codes -- can act as signposts for genes that influence heart health. The data are freely available to all researchers.
Scientists have already written 25 papers based on SHARe data, and more are coming, says Dr. Christopher O'Donnell, scientific director of the project and a professor at Harvard Medical School. A March paper in Nature Genetics is one example: Scientists found 10 DNA variations associated with changes in a heart characteristic called the QT interval.
The QT interval is the amount of time, after beating, that it takes for the heart to "reset" and be ready to pulse again. Changes in that amount of time -- too short or too long -- are associated with sudden death, says Psaty, who was a co-author on the study.
Psaty notes that a gene search is just the first step. Each gene may make only a small contribution to heart attack risk but, added to other factors, will help to build a picture of who is most at risk.
Certain genes may also indicate how a person will respond to medication, someday helping doctors select the best treatment for a patient, O'Donnell says. Or they may help scientists understand how the cardiovascular system works, ultimately leading to better therapies.
Other SHARe studies have linked DNA changes to gout, cholesterol levels, heart failure and blood pressure.
Although the Framingham study is heart-focused, research using the data goes well beyond the cardiovascular system. Scientists who obtain additional funding can use Framingham data to study such diverse topics as diabetes, lung disease, kidney function, back pain and drinking habits.
Lead Framingham investigator Dr. Philip Wolf of the Boston University School of Medicine has used the study for research on brain health, looking at factors that affect a person's risk for stroke or dementia. In 1991, he and others published the Framingham stroke risk profile, which uses factors such as age and blood pressure to assess how likely a person is to suffer stroke in the near future.
Wolf has also added MRIs to the volley of tests that a Framingham subject may undergo. In a 2004 paper in the journal Neurology, he and others reported that as brain volume decreases, the stroke risk score goes up. This and other studies have shown that some of the same factors that lead to heart disease can also lead to stroke.
"The impact of vascular risk factors on the brain and brain function in normal people is much greater than we had perceived," says Dr. Charles DeCarli of UC Davis, who collaborates with Wolf on the study.
In another, as-yet-unpublished study, DeCarli studied Framingham subjects whose parents suffered dementia. As early as age 52, some people with that family history show signs of "moving off the trajectory of normal aging," he says, with changes in brain structure and thinking ability.
That means people in their 40s and 50s should be thinking about what they can do to maintain brain function, DeCarli says. Some of the strategies used to battle heart disease, such as exercise, may apply. "We need to really be practicing body health for brain health early in life," he says.
Framingham is now on its third generation of subjects, with no sign of stopping, says Dr. Elizabeth Nabel, director of the National Heart, Lung, and Blood Institute, which funds Framingham.
"If we're all here in another decade or so," she says, "we'll look forward to enrolling the fourth generation."
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Key Framingham findings
In 60 years, the Framingham Heart Study has published approximately 1,200 scientific papers. Below are a few landmark discoveries.
* 1960: Smoking increases risk for heart disease.
* 1961: High cholesterol and high blood pressure are risk factors for heart disease.
* 1967: Obesity increases one's chances for heart disease; exercise reduces risk.
* 1970: High blood pressure increases risk of stroke.
* 1976: Risk for heart disease in women increases after menopause.
* 1998: The Framingham Heart Study publishes its cardiovascular risk calculator to estimate a person's chances of developing heart problems within the next decade.
-- Amber Dance