Cardiovascular disease (CVD) is the leading cause of death in women, a fact not appreciated by about half of the nation’s female population, according to JoAnn E. Manson, MD, MPH, DrPH, chief of the Division of Preventive Medicine at Brigham and Women’s Hospital and the Michael and Lee Bell Professor of Women’s Health at Harvard Medical School.

“Most women think that breast cancer is their greatest health threat in terms of mortality,” she says. “We must get the message out that heart disease is the leading killer of both men and women.”

Dr. Manson has spent much of her career researching heart disease risk factors and preventive interventions that consider sex-based differences between women and men. She says part of the challenge is that for decades, most randomized clinical trials and epidemiologic research were conducted primarily in men.

Even when trials included both sexes, women comprised only about 20% to 30% of study participants, and results among women often were not presented separately. This oversight made it unclear whether intervention results differed between women and men.

“From clot-busting drugs and statins to sleep medications, women see more adverse cardiovascular effects than men,” Dr. Manson says. “We need to study these effects and use those data to adjust doses properly or modify medication choices to maximize benefits and minimize risk.”

Leading the Way via Early CVD Studies

The CVD research paradigm started to change as early as 1976. Then, in the 1990s, the Brigham launched several groundbreaking studies and large-scale randomized clinical trials focused specifically on cardiovascular health in women.

The Brigham has since followed many study participants to gather additional data, detailed medical histories, diet assessments, and biospecimens. These data allow faculty to explore a range of molecular and genetic hypotheses.

Two early and seminal Brigham studies on which Dr. Manson has collaborated are:

• The Nurses’ Health Study (NHS), on which she has led the CVD component for 25 years
• The Women’s Health Study (WHS) trial of aspirin and vitamin E in women, on which she serves as a co-investigator

Both studies still have ongoing follow-up (although the WHS interventions ended in 2005) and have had hundreds of publications. In addition, both are large studies of U.S. female health professionals (>120,000 enrolled in NHS and >39,000 in WHS). Participants in both studies continue to complete annual questionnaires designed to help advance knowledge about preventing CVD, cancer, and many other chronic diseases in women. Collected blood samples also allow for testing of a wide range of biomarker hypotheses related to predicting the risk of disease and uncovering key biological pathways.

Center for the Women’s Health Initiative

The Brigham also was one of the vanguard centers for another large-scale study, the Women’s Health Initiative (WHI), which enrolled 161,808 racially and ethnically diverse postmenopausal women aged 50-79 at 40 clinical centers between 1993 and 1998. WHI evaluated three randomized interventions (menopausal hormone therapy, diet modification, and calcium/vitamin D supplements) for the primary prevention of major chronic disease, including CVD, in older women. The study also evaluated numerous clinical, behavioral, and social factors as predictors of chronic disease and mortality.

“We continue to strive for a better understanding of how conditions that are unique to women, like pregnancy and the transition from pre-menopause to post-menopause, change cardiovascular risk factors,” Dr. Manson says. “Moreover, we are focused on studying widely prescribed interventions that are unique to women, such as estrogen therapy and menopausal hormone therapy, for their balance of benefits and risks, including effects on CVD, cancer, and bone health.”

Since the WHI’s original interventions were completed, the Brigham has continued to leverage study data and biomarker resources to yield novel insights regarding CVD prevention and healthy aging in women. For example, Dr. Manson led a prospective study of WHI data comparing walking with vigorous exercise for the prevention of cardiovascular events in women. The investigators found that both types of activity are associated with substantial reductions in the incidence of cardiovascular events, irrespective of race, age, or body mass index.

Prioritizing Female Representation in Studies Moving Forward

Today, the Division of Preventive Medicine, in concert with other institution divisions and the Brigham’s Connors Center for Women’s Health and Gender Biology, is dedicated to ensuring that women represent at least 50% of participants in relevant clinical trials. Two examples in Preventive Medicine are the VITAL and COSMOS trials, in which the division collaborates closely with investigators throughout the Brigham.

The VITAL (VITamin D and OmegA-3 TriaL) study, in which 50% of participants were women, is a completed 5.3-year, randomized, double-blind, placebo-controlled trial of 25,871 U.S. men and women. It investigated whether taking daily dietary supplements of vitamin D (2,000 IU) or marine omega-3 fatty acids (1 gram/day) reduced the risk of CVD or cancer in people without a prior history of these illnesses. Today, more than 25 ancillary studies, many conducted at the Brigham, are evaluating the effect of vitamin D and omega-3 fatty acids on health outcomes including cognition, autoimmune disease, depression, fracture, and diabetes.

The COSMOS (COcoa Supplement and Multivitamin Outcomes Study) trial, in which 60% of participants were women, is a recently completed, randomized, placebo-controlled, 2×2 factorial trial of a high-quality cocoa flavanol extract and multivitamin supplements in the prevention of CVD and cancer in 21,442 men and women aged 60 and older and 65 and older, respectively.

While the intervention phase ended in 2020, ancillary studies are evaluating the effect of these supplements on cognitive function, diabetes, macular degeneration, cataract, and other outcomes. One of those ancillary studies, recently published in The American Journal of Clinical Nutrition, presents results from a clinic sub-cohort of the COSMOS trial as well as meta-analysis of three cognitive studies within COSMOS. It found a statistically significant benefit of multivitamin-mineral supplementation on memory and slowing of cognitive aging versus placebo.

“Over the years, our studies have provided support for the adage that what’s good for the heart is also good for the brain,” Dr. Manson says.

Pioneering Research Serves as Foundation for Future Breakthroughs

Looking back on her body of work and her leadership of the Division of Preventive Medicine, Dr. Manson says she is proud of the early pioneering research that is still relevant today as well as the division’s most recent research.

For example, Brigham researchers are now using specimens collected through the WHS, WHI, and NHS studies to measure biomarkers and multiomic signatures for risks associated with future heart attacks, stroke, cognitive decline, diabetes, and even cancer.

“Our researchers are combining the laboratory-based approaches of genetics and molecular biology with the techniques of large-scale, population-based epidemiology to discover and validate new risk markers and treatment targets for CVD and other chronic diseases,” Dr. Manson says. “This type of collaborative research is possible thanks to the top-notch scientists and tremendous infrastructure and support we have here at the Brigham.”