Heartland

It was 1961 and John F. Kennedy was settling into the White House when the Framingham Heart Study first used the phrase “risk factor” to describe now-familiar predictors of cardiovascular disease: high blood pressure, high cholesterol, diabetes, a sedentary lifestyle, family history, and smoking.

From a state of relative ignorance and conjecture about what was causing the country’s epidemic of heart disease, a fundamental understanding would emerge of what continues to place more people on the path to disability and death than any other illness.

Overall, the news is good: It’s even better if you are white, well educated, well off, and male. Across the nation, there are peaks and valleys in the landscape of heart health. Improvements in disease prevalence and mortality accrue for some and erode for others, while a fuller under­standing of the biological and social determinants of disease—who gets sick and who dies—remains uncharted.

Made to Measure

The year of the Framingham Heart Study’s report also witnessed the nation’s first coronary care units; close monitoring of patients who had suffered acute myocardial infarction cut hospital deaths from heart attacks in half. Three years later, a report from the U.S. Surgeon General strongly linked smoking to lung cancer and coronary heart disease, beginning what would become a steep decline in tobacco use.

These turning points signaled a new era of recognition, prevention, and, ultimately, treatment of heart disease and stroke that has transformed cardiovascular medicine to a degree only imagined in that early report from the Framingham study researchers. From 1968 to 2008, the death rate from heart disease dropped nearly 68 percent, while mortality from all other causes declined by a comparatively slight 6 percent.

Other statistics are not so encouraging. Hypertension rates among African Americans, already the highest in the world, are rising. So are the costs: In the United States, deaths related to high blood pressure in African American men are nearly three times higher than those among white men.

Where in the nation you live matters, too. Minnesotans are the least likely to die of cardiovascular disease, while people in Mississippi anchor the opposite end of the mortality curve by an almost two-to-one margin. Risk factors cluster with mortality. People in Colorado are less sedentary than their counterparts in Louisiana—and less likely to die of heart disease. Utah has the lowest proportion of people with high blood pressure, while Alabama has the greatest share of people living with this strong predictor of heart attack.

Risk Analysis

Just as two Harvard professors helped assemble the landmark surgeon general’s report on smoking in 1964, today’s HMS-trained clinicians and scientists are gathering data and using new tools, such as genome sequencing, to probe how and why our number-one killer strikes women and men, black and white, poor and rich so unequally.

Herman Taylor ’80 is one of these investigators. Since 1998 he has directed the Jackson Heart Study, which is both a direct descendant of and a departure from the Framingham study.

“We are in the midst of a fairly dramatic drop-off in deaths, but not everyone is benefiting equally from the advances in cardiovascular care and prevention,” says Taylor, a professor of medicine and Shirley Professor for the Study of Health Disparities at the University of Mississippi Medical Center. “If you look at the African American population within the American population, you see quite different patterns. We’ve got an epidemic that’s essentially unchecked. Here in Mississippi, we are focusing on the epicenter of the epidemic of cardiovascular disease that has persisted into the twenty-first century.”

The Jackson Heart Study has enrolled more than 5,300 participants from all walks of life and has gathered clinical and genetic information from individuals as well as families. The socioeconomic diversity of this study’s population is itself a contrast to that of most populations assembled in early health disparities research, which concentrated disproportionately on the African American poor. Both poor and having poor access to health care, they experienced the worst outcomes, skewing research results toward the negative. Taylor likens it to looking at Appalachia for a view of health in white Americans.

One early result of the more heterogeneous Jackson Heart Study appeared positive: Study participants over age 60 had their high blood pressure under control at levels comparable to those in white people. But there also was bad news: 80 percent of African Americans over age 60 had high blood pressure that needed to be treated, compared to 60 percent of all Americans over that age.

“When you have numbers like that, you’re compelled to look further upstream,” Taylor says. “The temptation is to say African Americans have more heart disease because they have higher levels of risk factors. That’s not an answer. Instead we should ask: Why do they have so many risk factors? and Why are those risk factors more prevalent? Such findings also underscore the urgent need to focus on prevention. Improving our control of blood pressure in patients is critically important and should not be minimized, but it’s far better to keep people from becoming heart patients in the first place.”

Sister Act

African Americans aren’t the only Americans who have historically been underrepresented in research studies. Women, too, have been excluded, or included in numbers too small to generate meaningful findings. These omissions began to be amended after a 1993 federal mandate required that ethnic and racial minorities and women be included in research studies.

When she was head of the National Institutes of Health, Bernadine Healy ’69 launched the Women’s Health Initiative. One of its goals was to more rigorously test assumptions of benefit in women, such as an association between hormone therapy and prevention of heart disease. In 2002, one of the Initiative’s studies of this association was famously halted when hormone use was linked to an increased risk of breast cancer with no improvement in heart disease risk.

C. Noel Bairey Merz ’81 is also cut from the cloth of inclusion, dedicated to changing the model of most studies being done “in men, for men, and by men.” Bairey Merz, professor of medicine at Cedars-Sinai Medical Center and director of the Barbra Streisand Women’s Heart Center at Cedars-Sinai Heart Institute, leads the Women’s Ischemia Syndrome Evaluation (WISE), now in its seventeenth year. WISE is designed to explore differences in heart disease suffered by women.

Before Bairey Merz’s work, a woman could suffer chest pain, produce abnormal scores on a stress test, or even have a heart attack, but if the gold standard for diagnosing heart disease—the coronary angiogram—revealed no blockages in her coronary arteries, the diagnosis was “cardiac syndrome X.”

The WISE project revealed why coronary angiograms, in which a dye is injected into arteries and tracked by X-ray imaging, were not recognizing heart disease in women. The tests are good at revealing chunks of fatty plaque lining blood vessels leading to the heart—the male pattern of ischemic heart disease. They aren’t as good, however, at showing what is now considered a female pattern of plaque deposition: diffuse deposits that narrow the blood vessels in a different but no less deadly fashion. The WISE trial showed that nearly a third of women with obstructive heart disease had this distinct pattern of plaque deposition in their arteries.

“For the past 50 years,” says Bairey Merz, “we’ve gotten pretty good at treating the male-pattern plaque problem, but we do not yet have comparable strategies for seeing diffused plaque.”

Paula Johnson ’84 has called the right to health care and a healthy life the “unfinished work” of the civil rights movement. For all people to reach that goal, we need a better understanding of why some groups have higher rates of risk factors and poorer outcomes for all diseases, including heart disease.

“We cannot assume that what is an effective prevention strategy in men is going to be exactly the same for women,” says Johnson, an HMS associate professor of medicine at Brigham and Women’s Hospital, where she is also executive director of the Connors Center for Women’s Health and Gender Biology. “It’s critically important to look at women and to look at racial and ethnic differences, but you must also look at the intersection of those two together.”

Something to Talk About

The complex biological picture of heart disease may be shaped decades before diagnosis in an environment of stress dating back to childhood, perhaps even before birth. Disorders of pregnancy, such as preeclampsia and gestational diabetes, may relate to children’s heart health, according to Johnson. The lifelong corrosive effects of discrimination, which have been linked to hypertension in the Jackson Heart Study, may worsen the risk for the disease. Among African Americans, coronary heart disease develops earlier, and its course is more severe.

Bairey Merz is cautiously optimistic about progress since 1984, when more women than men died of heart disease. In 2006, the number of women who died of heart disease started to decline; however, female mortality remains higher than that for males.

“At last the problem is out there and people are talking about it,” she says. “We’re all working hard to close the gap and to understand why there are disparities. It’s more than gender. It’s ethnic disparity, racial disparity, and economic disparity. A battle may have been won, but the war is still on.”

Critical Mass

The original Framingham researchers knew heart disease ran in families. Today’s scientists, in Framingham and Jackson, use advanced genomic tools to understand with great precision what might influence that family history. When Elizabeth Nabel, president of Brigham and Women’s Hospital, was director of the National Heart, Lung, and Blood Institute (NHLBI), she made it her mission to support genetic studies of coronary disease. In 2005, the Framingham Heart Study, which now includes three generations of families, began to sequence the genomes of its participants in order to pinpoint genetic alterations that might lead to disease.

To make these discoveries, however, researchers need more numbers than Framingham’s generations can provide. Its 9,000 samples have been analyzed together with data from 60 different cohorts and more than 70,000 patient samples of the international consortium Cohorts for Heart and Aging Research in Genomic Epidemiology. This mass of data allows scientists to detect genomic variants that may have been missed in the first wave of genetic studies.

“There have been improvements in mortality from heart attack and stroke for men and women in the United States,” says Christopher O’Donnell ’87, an HMS associate clinical professor of medicine at Massachusetts General Hospital, senior investigator at NHLBI, and associate director of NHLBI’s Framingham Heart Study, “but there remains a huge opportunity to lower the risk even further. By understanding the heritability—the genetic components—of risk factors and heart disease itself, we might be able to bend the curve even further to completely prevent heart disease.”

Elizabeth Cooney is a science writer in the HMS Office of Communications and External Relations.

Images, top: John Soares, stents courtesy of the Francis A. Countway Library of Medicine.