by Valerie Gregg ell me about your first patient," says Nanette Wenger, smiling encouragingly and nodding politely as the young cardiologist in her charge recounts the history of his new patient at the Grady Memorial Hospital Cardiac Clinics. Then Wenger starts asking questions - one after another, pointed and concise, leading gently to the most important inquiry of all: "What data do we have here?" she asks, reviewing the patient's EKG and x-rays with the cardiology fellow. Wenger - chief of cardiology at Grady, director of the Cardiac Clinics, professor of medicine in Emory School of Medicine's Division of Cardiology, and consultant to the Emory Heart Center - has been asking the right questions and producing groundbreaking answers since the late 1950s, when she was an Emory cardiology fellow herself. Since then, she has promoted gender equity in all areas of scientific inquiry, but most especially in heart disease among women - the number one killer of women in the United States. She has done so passionately, eloquently, and publicly, challenging conventional wisdom with a sharp intelligence, hard work, and, most important, hard evidence. And she's seen results. In 1992, Congress created the Office of Research in Women's Health as part of the National Institutes of Health. It also passed legislation requiring that all government-funded studies of health problems that are common to both men and women include female subjects in adequate numbers and that the studies analyze these problems by gender differences. Industry has adopted these standards as well, with the Food and Drug Administration now requiring data on women and analysis by gender for all new drug applications. "At the same time, there has been a huge amount of public education about heart disease in women recently," says Wenger, who was named the American Heart Association's Physician of the Year for 1998. "I've been writing and speaking about this for 20 years, so the concordance of all these events has been very, very gratifying."

Director of the Cardiac Clinics at Grady since 1960, Wenger was one of the driving forces behind the experimental cardiac rehab program there that has become the model for thousands of similar programs across the nation.

n the past, many presumed the middle-aged male model of heart disease represented all patients, Wenger says. But it left out two populations - women and the elderly. "Many of my women patients with heart disease - most of them past menopause - were totally surprised upon diagnosis. They thought they only had to worry about their husbands, sons, and brothers as far as cardiovascular problems were concerned. As a young cardiologist, Wenger found the shelves empty when she reached for literature about women with heart disease. Thirty years ago, women were rarely recruited as research subjects, and when they were, no one gave much thought to how gender might affect research outcomes. So Wenger began asking questions, gathering evidence, and writing. "There was absolutely no science behind the assumption that what was true for men would apply uniformly to women," she says. "Some of us began asking: 'How much of this predominantly middle-aged male database is applicable to the older woman?' In the scientific literature, the question had not been asked. We knew that women were not included in most studies on cardiovascular disease, and even in those studies that did include women, there was no discussion of gender differences or separate analyses by gender." Scores of research studies and publications have since asserted that men and women are not created equal when it comes to cardiovascular disease. A landmark New England Journal of Medicine review article that Wenger co-authored in 1993 that was based on a conference at the NIH summarized many years of research to show just how dire the situation is. For example: Women are more likely than men to die soon after a heart attack and during hospitalization. They are older and sicker when they do receive treatment, and they more often have co-morbid conditions like diabetes and hypertension. Women are tested and treated less aggressively for chest pain and are less likely to get "clot busting" drugs immediately after suffering heart attacks. Women have different social and emotional considerations than men that should be considered during clinical evaluation. These include caring for children or elderly parents in addition to work responsibilities. Women have been under-represented in studies. Traditional research has excluded women of childbearing age who could become pregnant during the study and elderly women who often have other illnesses along with cardiovascular disease. Women often engage in behaviors that worsen heart disease, such as smoking, and they are less likely to be referred to or to participate in cardiac rehabilitation than male patients.

Legacy building: Wenger collaborates with Sally McNagny, principal investigator of Emory's part of the Women's Health Initiative, the largest study in Emory's history, with 4,000 women enrolled, and the largest in US history, with more than 160,000 women enrolled in 40 centers throughout the country.

hese conclusions have naturally led to more questions. "We now know that the heart of a woman is vulnerable to coronary disease - and much more so after menopause and at an older age," Wenger says. "The next step is educating the public and physicians and establishing treatment guidelines appropriate to older and elderly woman." "Cardiovascular disease in women is an evolving issue because it's often a phenomenon of aging, of postmenopausal women. At the turn of the century, very few women lived much past the age of menopause. Now women live a third of their life after menopause. As the US and worldwide population ages, we will see more women reaching an age where clinical coronary disease is manifest." This consideration led Wenger to more queries about gender differences in diagnoses, outcomes, and management as well as how to educate women and their primary care physicians, including obstetricians and gynecologists. Why are women so much more vulnerable to heart disease after menopause than before? Is it because of hormones, or is it attributable more to other factors related to aging, such as diabetes, hypertension, and high cholesterol? When estrogen levels decrease after menopause, is the cardiovascular system of a woman as vulnerable as that of a man? Wenger looked at questions such as these as principal investigator of the Emory site for the Heart and Estrogen-Progestin Replacement Study (HERS), one of the largest studies ever to examine the hormone/heart disease connection. In the study, almost 3,000 women with coronary disease were randomly given either hormone therapy (estrogen plus progestin) or a placebo and closely monitored for four years. With data collection and analysis now complete, Wenger is excited that "we finally have a scientific database for women. Men and women share so many of the coronary risk factors, but the one that is likely to be unique to women relates to hormones. We need to know whether intervention with hormones is important." One conclusion gleaned from the data so far: hormone therapy does not appear to reduce the risk of recurrent heart attack in postmenopausal women who already had heart disease before beginning hormone replacement. Just as the HERS study has ended, (although a two-year follow-up is planned), Wenger is starting work on an even larger ground-breaking study. She is the co-principal investigator for an international study called RUTH, which will test heart protective qualities of the drug raloxifene in 10,000 women who either have or are at high risk for coronary disease. Raloxifene is one of what Wenger considers a fascinating category of drugs - selective estrogen receptor modulators that have estrogen-like effects on bone and estrogen-antagonist effects on reproductive tissues. Raloxifene is licensed in the United States for prevention of osteoporosis, but, Wenger says, "evidence suggests it may have beneficial effects on cardiovascular disease as well." Here's the most exciting part: Raloxifene fails to stimulate the endometrium or the breast (avoiding the major problem with estrogen of potential increased risk of uterine and breast cancer). "There's no risk of uterine cancer, and there may even be a possibility that raloxifene decreases the risk of breast cancer," Wenger says. "That suggestion is so strong that the NIH is beginning a clinical trial that will compare raloxifene and tamoxifen for the prevention of breast cancer for women at high risk."

t 67, Wenger shows no signs of slowing down. She typically works 12 to 14 hours a day, dividing her time between research duties, seeing patients, and supervising cardiology fellows and residents. In great demand as a speaker both nationally and internationally on women's health, cardiovascular disease in women and the elderly, and cardiac rehabilitation, Wenger has a long list of accolades. She has been at the cutting edge of medicine at every step in her career. At Harvard Medical School, in the sixth class that included women, she was introduced to emerging laboratory and research techniques that were to become the basis for today's clinical practice. In 1956, she was the first woman to be named chief resident in cardiology at Mount Sinai Hospital in New York. Director of the Cardiac Clinics at Grady since 1960, Wenger was one of the driving forces behind the experimental cardiac rehabilitation program there that has become the model for thousands of similar programs across the nation. Her prolific writings and publications - more than 900 scientific articles and book chapters - speak for themselves. "I have not had problems being a woman in medicine because I was always in a setting where my supervisors addressed quality of performance first," she says. "I encountered no problems with promotion at Emory - I was full professor by the time I was 40 - and Emory has always been a very exciting place for me. Over the years I have had the opportunity to train increasing numbers of women as students and residents. Now 40% to 50% of medical school classes are women. We're here to stay."

Dr. Wenger was named 1998 Physician of the Year by the American Heart Association.

he clientele in the waiting room at the Cardiac Clinic at Grady on a typical day - about half men and half women - makes a good case for many of Wenger's research conclusions. Most of the men look to be in their 50s or 60s, while many of the women are obviously older. Just as women and men have differences in how their heart disease should be treated, so do people of different ages, says Wenger. Currently, she is editing a new book on cardiovascular disease in the octogenarian and beyond. "Until the present, very few patients over 80 were included in most research studies," she says. "As people are living longer, we have a sizable number of patients for whose care we have very little scientific evidence. In time we'll have some data. It's amazing what kinds of answers we can get when we just know to ask the right questions." Valerie Gregg is a writer in Atlanta.

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