Understanding how these factors specifically affect women and teasing out gender differences in prevention and treatment strategies are professional passions of long-time NHLBI grantee JoAnn Manson, M.D., M.P.H., Dr. P.H.
A leading scientist whose career has focused on the influence of gender biology on the development of heart disease and diabetes in women, Dr. Manson is a key researcher for two of the largest women's health projects ever launched in the United States—NIH’s Harvard Nurses' Health Study and the Women's Health Initiative. These groundbreaking research studies provided science-based answers to women’s health questions about nutrition, exercise, aging, obesity, risks and benefits of hormone therapy, risks of smoking, and more.
We recently spoke with Dr. Manson about her latest research projects and how her scientific endeavors extend from her vision of a health care system that provides women with personalized medical care.
Dr. Manson has been principal investigator of the cardiovascular component of the NIH- supported Harvard Nurses' Health Study for the past 15 years (and was previously the Project Director for 12 years). The Nurses’ Health Study (NHS), which began in 1976 and is based at Harvard University and Brigham and Women’s Hospital, is one of the first large scale studies to focus on women’s health, including ways to prevent heart disease, stroke, and cancer. The information provided by the 121,700 nurse-participants led to landmark data showing that diet, physical activity, and other lifestyle factors can prevent heart attacks in women and that biomarkers can uncover biological pathways for heart disease. Also, as a key researcher on the NIH-supported Women's Health Initiative since it was launched in 1993, Dr. Manson and other investigators studied hormone therapy (estrogen plus progestin and estrogen alone) in more than 27,000 women aged 50-79. She is also principal investigator of the ongoing NIH-supported VITamin D and OmegA-3 Trial (VITAL), which is assessing the role of vitamin D and omega-3 fatty acid supplementation in the prevention of cardiovascular disease and cancer. She has also served as PI of several other randomized trials in CVD prevention.
Dr. Manson is chief of the Division of Preventive Medicine and co-director of the Connors Center for Women’s Health and Gender Biology at Brigham and Women’s Hospital. She is also a professor of Medicine and the Michael and Lee Bell endowed professor of Women’s Health at Harvard Medical School. Dr. Manson is one of the 10 most highly cited medical researchers in the world (and the most highly cited woman researcher). She is the recipient of several major research prizes and is an elected member of the Institute of Medicine of the National Academies.
Q: What is the current state of the science regarding the relationship between obesity and future burden of coronary heart disease in women?
A: Obesity is a major risk factor for heart disease and the public health challenge of our time. Coronary heart disease (CHD) remains the leading cause of death in both women and men, and the high prevalence of obesity threatens to reverse some of the gains made in reducing CHD mortality in recent decades. The statistics are staggering. Two out of three U.S. adults are overweight or obese. The clinical and public health consequences of the obesity epidemic are enormous. Our research group has studied the cardiovascular risks of obesity for about 25 years in the Nurses’ Health Study, a nation-wide cohort study. We began by quantifying the risks among mid-life and older women. The evidence is compelling that moderate to severe obesity is strongly linked to increased risk of many serious conditions: coronary heart disease, type 2 diabetes, hypertension, stroke, venous blood clots and pulmonary embolism, atrial fibrillation, heart failure, as well as many non-cardiovascular outcomes including several types of cancer.
The obesity epidemic may portend an enormous future burden of type 2 diabetes and heart disease in women. We have extensively studied the role of dietary factors, physical activity, and other lifestyle factors in relation to body weight, weight gain, and cardiovascular disease risk (see below). Over time, we have become increasingly interested in the role of novel biomarkers in predicting future risk of CHD and their interrelationship with obesity/adiposity.
Q: Why study promising biological markers (biomarkers)?
Biomarkers are objective measurable characteristics of biological processes that can provide insight into the underlying mechanisms or pathways linking risk factors to health outcomes. For example, is obesity related to markers of systemic inflammation, endothelial dysfunction, or thrombosis? Biomarkers also can be helpful for risk prediction -- i.e., determining which individuals are at the highest risk -- and for individualizing and personalizing treatment decisions. Thus, the study of biological markers may inform new prevention strategies and more targeted pharmacologic treatments.
Because the risk of coronary heart disease is closely associated with insulin resistance, abdominal adiposity, and diabetes, the aims of our grant have included the assessment of novel risk factors including hormones and proteins secreted by adipose tissue (“adipokines”), inflammatory markers, and markers of cellular aging in relation to CHD risk. We also have a strong interest in genetic factors associated with obesity and gene-environment interactions linked to increased or decreased risk of CHD. These studies may also help to generate additional testable hypotheses for heart disease research.
Q: How did you become interested in studying adiposity (fat)-related biomarkers?
A: Given my training in internal medicine and the subspecialty of endocrinology, I had a longstanding clinical and research interest in this field. Our Nurses’ Health Study grant on Risk Factors for Cardiovascular Disease in Women, of which I am the principal investigator, provided an opportunity to assess adiposity-related biomarkers as a way to provide insights into why obesity increases cardiovascular disease risk and whether biomarkers can help predict risk. The NHS has archived blood samples collected from more than 32,000 participants in 1989-1990, when the women were ages 43-68, with follow-up for incident cardiovascular disease events over more than two decades.
Fat cells produce hormones and chemicals that can increase inflammation throughout the body. The perception about fat tissue several decades ago was that it was an inactive storage depot for fat with no clear systemic effects. We now know that fat tissue is an active endocrine organ that actively synthesizes and secretes cytokines and hormones that increase systemic inflammation. For example, greater fat mass is associated with higher blood concentrations of tumor necrosis factor-alpha and related receptors (TNF-R1 and R2), interleukin-6 (IL-6), as well as increased hepatic synthesis of C-reactive protein (CRP), all of which are linked to higher CHD risk. We also found that greater adiposity was related to higher levels of vascular cell adhesion molecules (VCAM) and E-selectin, which were also related to increased risk of cardiovascular disease.
Then we moved on to studying adipokines, cell signaling proteins secreted by fat tissue. Although most hormones and chemicals in fat tissue increase insulin resistance and cardiovascular disease, blood levels of adiponectin – a hormone directly synthesized by fat tissue – are inversely related to adiposity and appear to be protective against heart disease. We found that higher levels of total adiponectin, as well as high-molecular weight adiponectin, were related to lower risks of CHD.
Additionally, our research showed that higher blood levels of retinol binding protein-4 (RBP-4) were associated with a three-to-four fold increase in heart disease risk. Although RBP-4 had been linked to type 2 diabetes, this was the first large-scale prospective study to show a link to CHD. We also studied the protein Lp-PLA2 and found that higher levels predicted higher risk of heart disease in women. We’re also studying fatty acid binding protein 4, the lipid binding protein for adipocytes and macrophages.
Q: What are some important findings from the Nurses’ Health Study related to diet and exercise?
A: The impact of lifestyle factors is immense. If you take all modifiable lifestyle factors in aggregate, there is evidence that coronary heart disease is highly preventable. Many heart attacks in women could be prevented by following healthy lifestyles including not smoking, maintaining a healthy weight, eating a diet high in fruits/vegetables and low in trans fats, having low to moderate alcohol intake, and engaging in at least 30 minutes of moderate physical activity per day. The NHS has detailed and frequently-updated information on nutritional, behavioral, and lifestyle variables.
We also found that physical activity lessens, but does not completely eliminate, the adverse relationship between obesity and CHD. These findings speak to the “fit and fat” controversy; our results suggest that “fit and fat” is more healthful than “unfit and fat”, but not as healthful as “fit and lean.” We also found that the typical weight gains of 25-30 pounds that often occur between early and middle adulthood are linked to an almost 80 percent increase in risk of heart attacks!
Regular exercise is critically important to good heart health and it doesn’t have to be vigorous intensity. We found that brisk walking (moderate-intensity exercise) for approximately 30 minutes most days of the week is associated with as great a reduction in heart attack risk as more vigorous exercise in women. Both are linked to close to a 40 percent reduction in risk. We are increasingly interested in conducting pragmatic clinical trials to test interventions for increasing physical activity levels, improving diet, and motivating other behavioral changes.
Our research has also shown associations between higher consumption of sugar sweetened beverages and weight gain and type 2 diabetes. We and others have found that dietary patterns are strongly related to CHD risk, with lower risk found among women following plant-based or Mediterranean diets than western diets high in red meat and processed foods.
Many of these nutritional and lifestyle factors are correlated with telomere lengths – which shorten with age and may serve as a marker of longevity. We found that a healthy weight, regular physical activity, and healthy diet are linked to longer telomeres. Telomeres, found at the ends of chromosomes, shorten each time a cell divides and shorter telomeres have been linked to age-related diseases such as hypertension, diabetes, CHD, and stroke.
Q: What’s next for the Nurses’ Health Study cardiovascular grant?
A: We are now moving into the field of metabolomics – the study of small molecule metabolites that can be proximal risk markers within cells and biological systems. The next phase of the Nurses’ Health Study grant is a collaboration with Dr. Stanley Hazen and colleagues at the Cleveland Clinic looking at the relationship between gut flora metabolites and risk of CHD. In particular, we’ll be studying blood levels of choline, L-carnitine, and trimethylamine N-oxide (TMAO) as predictors of heart disease risk. We and others have found that higher intake of red meat is related to an approximate 40 percent increase in cardiovascular risk. Diet is the primary determinant of gut microbiota metabolites and dietary choline and red meat (L-carnitine) are the major sources from which TMAO is produced.
Q: Besides the Nurses’ Health Study what other NHLBI-funded projects are you involved in?
A: I’m also one of the principal investigators (PI) for the Women’s Health Initiative (WHI), and have served as PI for the Boston site of the WHI since the study began in 1993. We published a comprehensive report on the WHI hormone therapy findings in October 2013 (featured in a recent NHLBI press release). The findings from WHI have transformed clinical practice.
I’m also the PI for the VITamin D and OmegA-3 TriaL (VITAL), a large-scale randomized trial testing whether taking daily dietary supplements of vitamin D (2000 IU/d) or omega-3 fatty acids (1 gm/d) prevents cancer, heart disease, or stroke. The National Heart, Lung, and Blood Institute and the National Cancer Institute (NCI) co-fund this study of 26,000 participants throughout the U.S. ages 50 and older (men and women). This trial has recently completed recruitment and final results are expected in 2017.
Q: What do you hope to accomplish with your research?
A: Our goal is to better understand risk factors for cardiovascular disease in women, as well as gender differences in disease risk and strategies for prevention and treatment. We need to have a better understanding of these gender biology issues, including why women with diabetes have such high cardiovascular disease risk and how lipid-heart disease and sex steroid hormone-heart disease relationships differ between the sexes. We also need to understand why a history of pregnancy-related complications, such as preeclampsia or preterm birth, portend a higher future risk of CHD.
Another goal is improved personalization of health care: individualizing health care and providing appropriate health care to women. By combining clinical information with biomarkers and genomics, we can further individualize and tailor care to patients. Ultimately, this will result in more personalized health care where decision-making is tailored to the individual based on their underlying risk factors, genetic predispositions, and personal preferences and priorities for treatment.
Another great advantage of these large-scale epidemiologic studies (Nurses’ Health Study, WHI, VITAL, and others) is that they provide wonderful opportunities and resources for training young investigators, students in epidemiology, other trainees, and junior faculty members. These studies are national treasures; wonderful opportunities not only to advance science but also to train the next generation of investigators.
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