The COVID-19 pandemic has been a clarion call to medicine and our healthcare system to attend to the impact of sex and gender on exposure outcomes (i.e., men dying at a higher rate than women), and the impact of comorbidities on exposure outcomes (i.e., consequences of COVID-19 exposure on the heart and brain).

The pandemic is only the most recent indication of the centrality of sex and gender to the causes and consequences of major medical illness and links between the heart and brain.

Heart disease and disorders of the brain, like depression, co-occur substantially (over 20% in the population).

In fact, the co-occurrence of depression and heart disease was slated to be the #1 cause of disability worldwide last year (prior to COVID-19) and will likely be post-COVID as well. Further, women are at twice the risk for this co-occurrence, thus they are more severely affected than men.

People with depression (which has a 2-fold risk for women), who also have heart disease, have a 3-5 fold higher risk of death from heart disease. Thus, unrecognized and untreated depression may be an important contributor to the fact that heart disease is the #1 killer of women in the U.S. and most middle-income countries.

Compounding this, depression and heart disease are independent risk factors for Alzheimer’s disease, another chronic disorder of the brain that has a higher frequency in women, and not only due to women living longer.

With 25-30% of the U.S. population projected to be over 60 years of age by 2050, there is an increasing sense of urgency to find effective early interventions and that could be targeted to the brain and heart. Unfortunately, research and healthcare largely ignore sex differences and typically pursue these diseases within silos by discipline.

Arriving at a Critical Juncture

We are at a critical juncture in medicine: these multi-morbidities demand attention. Jill M. Goldstein, PhD, founder and executive director of the Innovation Center on Sex Differences in Medicine (ICON) and the Helen T. Moershner Endowed MGH Research Institute Chair in Women’s Health, is focused on understanding sex differences in the shared causes of disorders of the heart and brain and leveraging these discoveries into the development of sex-dependent therapies.

Her team demonstrated that some of the same causes of sex differences in depression affected the dysregulation of the heart. Further, the origins of these pathologies, e.g., involving our immune and hormonal systems, occurred in early development, with consequences for the onset of disorders of the heart and brain later in life.

Understanding shared developmental roots of heart and brain pathologies suggests the potential of early interventions to attenuate disability and prevent illness down the road.

For example, sex differences in depression emerge just after puberty, while heart disease onsets later in adulthood. If therapeutics deployed post-puberty for depression were developed to target the heart as well, they may attenuate disability due to potential heart disease in adulthood or even prevent memory decline and Alzheimer’s disease as we age.

Attending to the impact of sex and gender on these diseases will enhance therapeutic strategies for both men and women, creating better healthcare for all.

The Economic Toll of Disease

These multi-morbidities pose an economic threat to this country. Direct and indirect costs (e.g., loss of work productivity due to absence or leaving the job) for depression, heart disease and Alzheimer’s disease separately are estimated to be more than $2 trillion by 2030.

Further, the costs are highest for patients with multi-morbidities, accounting for more than 90% of Medicare spending. Understanding why the illnesses co-occur and how to target multiple organ systems is critical not only for the health of the population but our economic health, given that 17% of the U.S. GDP is associated with healthcare.

The lives and economic productivity of women are particularly affected. Women, as the primary caretakers of their ill relatives, particularly with Alzheimer’s disease (AD), are forced to leave the workforce in the prime of their professional life, with the average age of an AD caretaker being 49 years old.

An Opportunity for New Breakthroughs

National attention to the COVID-19 pandemic provides a unique opportunity to get out of medical silos, incorporate the impact of sex and gender, and drive the scientific and therapeutic breakthroughs we desperately need.

We have already seen how the pandemic has overwhelmed healthcare systems and threatened the U.S. and the world’s economy, and we know COVID-19 will leave secondary consequences for years to come. If left untreated, chronic diseases of the heart and brain will pose a similar risk.

It is urgent to address the preventable disability and premature mortality from these illnesses. We can do so with interdisciplinary and sex- and gender-sensitive tools already at our disposal and, with those waiting to be developed, incorporate them into novel therapeutic strategies.

About the Mass General Research Institute
Research at Massachusetts General Hospital is interwoven through more than 30 different departments, centers and institutes. Our research includes fundamental, lab-based science; clinical trials to test new drugs, devices and diagnostic tools; and community and population-based research to improve health outcomes across populations and eliminate disparities in care.
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