Sex Bias In Cardiovascular Research

Background:

Cardiovascular disease (CVD) is the leading cause of morbidity and mortality in both men and women; however, it doesn’t always present or progress the same way in men and women. In fact, sex is an important biological variable associated with differences in the overall prevalence and disease progression as well as the mechanisms underlying the disease. However, researchers conducting experimental animal studies do not routinely analyze or report on biological sex. In fact, the vast majority of research either uses male animals exclusively or neglects to disaggregate the data by sex when reporting the findings. Hence, the biological basis for sex differences remains largely undescribed, representing a lost opportunity to understand important sex-related differences in basic and developmental factors that influence normal CV function and CVD. Moreover, because studies do not focus on sex differences, researchers are missing potential protective mechanisms that might be at work in only one of the sexes and that could be used as potential targets for novel medical advances. If we instead take into account sex as a biological variable in all research investigations, we may transform our foundational knowledge base and develop new therapeutics and medical technologies that can benefit everyone.

Working Group Discussion:        

The working group heard presentations on existing and emerging scientific evidence showing that sex is a major determinant for the development and progression of CVD. Presentations covered the following main areas:

1. estrogen receptor signaling in cardiovascular function and disease,
2. the role of sex hormones in blood pressure control and cardiovascular disease,
3. sex differences in cardiovascular aging,
4. mouse models for studying sex differences in physiology and disease,
5. the contribution of sex chromosomes to the regulation of blood pressure and cardiovascular function,
6. sex differences in cardiovascular cell therapy and repair, and
7. cardiac responses to pregnancy.

The group also discussed the need for research into the cardiovascular effect of sex-specific clinical conditions, such as early menopause and fetal microchimerism (the persistence of fetal cells in the mother after pregnancy). They also discussed conditions in which sex differences predominate, such as those conditions in which being male or female appears to afford protection against, or increase risk of, developing disease. For example, being male appears to confer protection against pulmonary fibrosis, while being female seems to delay the age of onset of atherosclerosis.

The working group also discussed barriers to promoting sex balance in research, including significant challenges in publishing and peer review of sex differences research. Those in attendance also observed that in the future the working group must identify priority areas, ways to foster awareness and appreciation of sex-based research, and recommendations to increase scientific understanding of this important field.

Working Group Recommendations:

The working group concluded that there is a need to understand the mechanisms by which sex hormones and sex chromosomes modulate and regulate biological processes related to CVD. In order for this to be achieved, experimental research studies in animals of both sexes are necessary. The working group identified five recommendations that should enable and enhance CV research of both sexes:

• Demystify assumptions about the difficulty of studying sex as a biological variable and educate the community about the importance of sex balance in research.
• Develop tools and resources for studying sex differences in CVD.
• Foster basic research on sex differences in health and disease.
• Develop guidelines for sex-based clinical and basic/translational research design that highlight strategic experimental design considerations for researchers who would like to incorporate sex as a variable in their projects.
• Develop metrics for tracking the implementation of the recommendations.

Publication Plans:

The working group plans to prepare a manuscript for publication in a peer-reviewed journal.

NHLBI Contacts and Working Group Organizers:

Martha Lundberg, Ph.D., NHLBI, NIH
Email: martha.lundberg@nih.gov
Telephone: 301-435-0576

Christine Maric-Bilkan, Ph.D., NHLBI, NIH
Email: christine.maric-bilkan@nih.gov
Telephone: 301-435-0486

Working Group Members:

Chairs:

Arthur Arnold, Ph.D., FAHA, FACC, University of California, Los Angeles
Doris Taylor, Ph.D., Texas Heart Institute

Members:

Melinda Dwinell, Ph.D., Medical College of Wisconsin
Susan Howlett, Ph.D., Dalhousie University
Leslie Leinwand, Ph.D., University of Colorado at Boulder
Ellis Levin, M.D., University of California, Irvine
Elisabeth Murphy, Ph.D., National Heart, Lung, and Blood Institute
Jane Reckelhoff, Ph.D., University of Mississippi Medical Center
Kathryn Sandberg, Ph.D., Georgetown University Medical Center
Robert Simari, M.D., Kansas University Medical Center
Nanette Wenger, M.D., Emory University School of Medicine

Federal Staff:

Claudette Brooks, M.D., NIH ORWH
Robin Boineau, M.D., NHLBI
Liza Bundesen, Ph.D., NIH OER
Denis Buxton, Ph.D., NHLBI
Lawrence Boerboom, Ph.D., CSR
Yuanna Cheng, M.D., Ph.D., CSR
Janine Clayton, M.D., NIH ORWH
Nakela Cook, M.D., M.P.H., NHLBI
Patrice Desvigne-Nickens, M.D., NHLBI
Gayathri Dowling, Ph.D., NHLBI
Beverly Lyn-Cook, Ph.D., FDA NCTR
Li Pang, Ph.D., FDA NCTR
Casey Sullivan, Ph.D., NIH ORWH

Acknowledgements:

Special thanks to Kelin Fuentes, Keisha Palmer, and William Trout for the logistical planning of the meeting and to Drs. Boineau and Sullivan for their note taking.