In Disorders of the Heart and Brain, Does Sex Matter?

Michael Vlessides

September 30, 2020

For Jill M. Goldstein, PhD, sex matters.

A professor of psychiatry and medicine at Harvard Medical School, Goldstein is passionate about the need to develop initiatives focused on sex and gender differences in disorders of the heart and brain. Ask her why and she doesn't hedge.

"Every cell has a sex," she said. "Every cell in a woman's body is different from every cell in a man's body. So we want to raise the awareness that sex is an important factor in disease outcomes."

Women are twice as likely as men to present with major depressive disorder (MDD) and have twice the rate of co-occurrence of MDD and cardiovascular disease, a phenomenon associated with three to five times' greater risk for death from cardiovascular disease. Globally, approximately 2 of every 3 people diagnosed with Alzheimer's disease dementia are women.

In a recent viewpoint article published in JAMA Psychiatry, Goldstein ― along with colleagues Ana Langer, MD, and Jill Lesser, JD ― describe the need for researchers and clinicians to focus on these differences, particularly with respect to the co-occurrence of MDD, cardiovascular disease, and Alzheimer's disease. Doing so, the authors believe, could help stem the tide of what they call this "multimorbidity crisis."

30 Years of Research in Sex Differences

For Goldstein, the quest for sex and gender equality in medicine goes back at least three decades, when she first realized that sex differences were rarely considered, either in the lab or the clinic. Since then, she has dedicated a considerable part of her career to elucidating the differences between men and women in a variety of disorders, including MDD and its comorbidity with cardiometabolic diseases, psychoses, and the risk for dementia. She has published more than 170 articles, chapters, and other original and peer-reviewed works in these areas.

Despite her efforts, substantial gaps and barriers remain, particularly with respect to these particular conditions. For example, most animal studies in neuroscience and cardiovascular disease still use an overwhelming proportion of male samples; few systematic clinical studies have examined sex differences in the brain and heart in MDD.In mixed-sex trials of cardiovascular disease, only one third of participants are women, and only 25% to 33% of such studies report outcomes by sex. Even fewer studies ― including those of Alzheimer's disease, which disproportionately affects women ― are designed on the basis of sex.

"Women have been historically neglected in terms of attention," Langer, professor of the practice of public health at the Harvard T. H. Chan School of Public Health, Boston, Massachusetts, told Medscape Medical News.

Equally troubling for the authors is the fact that researchers tend to examine each of these diseases independently at a single point in time, rather than as co-occurrences throughout life. This approach, they write, prevents a complete understanding of the shared effects of psychological, biological, social, and environmental factors across organs and tissues over an individual's lifetime.

People with both depression and cardiovascular disease have a three- to fivefold increased risk of death from heart disease.... And those people are primarily women.

"People with both depression and cardiovascular disease have a three- to fivefold increased risk of death from heart disease," Goldstein explained. "And those people are primarily women."

Not everyone agrees with Goldstein, including Lise Eliot, PhD, professor and acting discipline chair of neuroscience at Rosalind Franklin University of Medicine and Science in North Chicago, Illinois.

"I've been very unimpressed with studies of human brain-sex differences," Eliot told Medscape Medical News, "because one can find a brain-sex difference that fits with any gender stereotype, particularly when it comes to psychiatric disorders. But these are all disorders that have gender-difference ratios. The paradox is that sex differences are relatively trivial compared to other sources of variance, like environment and genetics."

Eliot went on to explain that gender has played a far more important role in medical outcomes than has sex. "There is a lot of gender bias built into our medical system that is, I think, the basis for a lot of these health disparities," she said. "Psychiatric diagnoses are infused with the gender stereotype. And yet, the drive is to get money to study biologic differences."

Signs of Progress

Although the current state of sex-based research in co-occurring disorders of the heart and brain has a long way to go, there are signs of improvement. Goldstein herself has been integral to these changes throughout her career, though her biggest impact may have come in 2017, when she founded the Innovation Center on Sex Differences in Medicine (ICON). The center ― which boasts world-renowned experts from a variety of fields ― seeks to change the way the world understands heart-brain disorders using sex and gender lenses.

"We really want to try to change how medicine thinks," she said.

ICON's mandate recently took on new significance when the center was designated as a National Institutes of Health (NIH) Specialized Center of Research Excellence on Sex Differences. The NIH grant will fund both basic science and clinical studies of the developmental origins of sex differences in depression and the dysregulation of cardiac function ― efforts, Goldstein hopes, that will ultimately open the door to the development of sex-dependent therapeutic strategies

"We have a number of projects that we're working on," Goldstein said. "For example, we're developing a clinical risk tool to help predict men and women in early mid-life who might be at risk for Alzheimer's disease later on. But the key is, we're developing it in a sex-dependent way."

Her coauthors are equally involved in similar undertakings. Langer currently serves as the director of the Women and Health Initiative at the Harvard T. H. Chan School of Public Health. In that role, she heads an organization that seeks female-driven solutions to women's healthcare needs around the globe. She also serves as the director of global policies and programs for ICON.

"We look at the effect of policies and programs on the health of women and try to come up with ways to identify modifying factors that would allow us to improve the health of women through the life course," Langer explained.

Lesser, on the other hand, is the president of WomenAgainstAlzheimer's, a group that seeks to find, fund, and implement a cure for Alzheimer's disease with respect to the way the disease affects women.

There are other signs of progress as well. In 1993, the National Institutes of Health Revitalization Act was enacted. Part of that legislation mandates that women and minorities ― who had been largely overlooked to that point ― need to be included in sufficient numbers in clinical research to receive NIH funding. The policy was amended to its current form in 2017.

Important advances have also been made in cardiovascular medicine, with women's cardiac health centers becoming more commonplace across the country. For Goldstein, these changes were an important first step in addressing the health differences between women and men. "Heart disease is the number one killer of women in the US," she explained. "Nevertheless, women were getting into treatment later because their symptoms were not the same as the typical male symptoms. And they were dying as a result."

Multidisciplinary efforts for enhancing knowledge around sex differences will require cooperation between academics, industry, advocacy, and policy. Pharmaceutical companies, in particular, can play a big role in this revolution, the authors stress.

"The way it stands, pharmaceutical companies do not incorporate sex into the design of their studies," Goldstein said. "They may do a post hoc analysis to separate their data by sex, but that's not the same as testing a sex effect.

"Nevertheless, I believe there are many molecules sitting in companies' libraries that actually may be more effective in one sex than the other but were thought to be ineffective because the original studies were not designed by sex to test such differences," she added.

Psychiatry's Role

Despite the complexity of revamping the way an entire industry delivers its products and services, Goldstein and her colleagues believe the field of psychiatry is positioned to play an important role in the change, particularly with respect to the multimorbidity of MDD, cardiovascular disease, and Alzheimer's disease. Of these disorders, MDD is often the first to emerge.

"It's very important to understand the shared early origins of these three diseases so we can target them and try to prevent them down the road," Goldstein said. "For example, if we know that sex differences in depression emerge just after puberty and we also know that these differences will place a person at a higher risk for cardiovascular disease later in life, why are we not targeting them earlier?"

The same holds true for Alzheimer's disease. "If we know that hypertension and depression are major independent risk factors for Alzheimer's disease, why are we not targeting them as soon as possible?" she added.

Richard S. Isaacson, MD, director of the Alzheimer's Prevention Clinic at Weill Cornell Medicine in New York City, agrees that this kind of precision medicine is desperately needed when it comes to preventing Alzheimer's disease. "I think we've made tremendous progress in our understanding of how cardiovascular disease and Alzheimer's disease are in some ways inextricably linked," he said. "And I think physicians really have to understand the two are intertwined quite a bit.

"Nevertheless, we have to realize that people may look similar on the outside, but there's a lot of biologic and genetic differences on the inside," he continued. "Precision health is the future of medicine, and that's absolutely the case for Alzheimer's and cardiovascular disease prevention."

Isaacson explained that this understanding has helped shape the way he approaches patients. "In the Alzheimer's Prevention Clinic, I feel like I'm one third neurologist, one third preventive cardiologist, and one third primary care doctor," he said. "And I really believe that, because our panels for Alzheimer's prevention are the same ones that are used by my cardiologist colleagues."

Jordan Smoller, MD, ScD, professor of psychiatry at Harvard Medical School, agrees, yet he recognizes that one specialty cannot tackle the issue of multimorbidity alone. The movement needs financial partners, as well as a pipeline of trained professionals from a variety of fields who prioritize these issues throughout their careers.

Research will also be key, he says, from basic science to translational studies. "Then we need to see if we can actually leverage basic biology and clinical research to develop therapies that account for sex differences," he said. "That's a vitally important area, because it hasn't really happened in any area of medicine to date." silver lining of the COVID-19 outbreak is that it seems to have increased recognition of the associations between sex, gender, and disease outcomes.

According to Smoller, one silver lining of the COVID-19 outbreak is that it seems to have increased recognition of the associations between sex, gender, and disease outcomes. Yet he feels the change may also be due to a confluence of science and culture.

"Often in medicine there's a convergence of factors that really elevate certain questions to become priorities," he explained. "One of them is advances in the science that allow them to be studied in a more fruitful way.

"At a societal level, it's always been controversial to what extent sex and gender play a role," he added. "But it's an issue that has now gathered more interest among a broader field."

"I think the devil is in the details when it comes to cardiovascular health and Alzheimer's disease coexistence," Isaacson added. "There needs to be a deeper dive and more collaborative efforts between preventive cardiologists, neurologists, psychiatrists, and endocrinologists. And we really need to work together to push the needle forward to truly have an impact."

"Things feel very different now than when I first started doing this," said Goldstein. "I think the context is different, and there's even a hunger for this from the public. I think we have a better chance of success now than ever before"

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