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Strategies and methods to study sex differences in cardiovascular structure and function: a guide for basic scientists

Virginia M Miller1*, Jay R Kaplan2, Nicholas J Schork3, Pamela Ouyang4, Sarah L Berga5, Nanette K Wenger6, Leslee J Shaw7, R Clinton Webb8, Monica Mallampalli9, Meir Steiner10, Doris A Taylor11, C Noel Bairey Merz12 and Jane F Reckelhoff13

Author Affiliations

1 Departments of Surgery, Physiology and Biomedical Engineering, Mayo Clinic, 200 First Street SW, Rochester, MN, 55905, USA

2 Department of Pathology (Comparative Medicine), Wake Forest School of Medicine, Winston-Salem, NC, USA

3 The Scripps Research Institute and The Scripps Translational Science Institute, La Jolla, CA, USA

4 Department of Medicine, Johns Hopkins University, Baltimore, MD, USA

5 Department of Obstetrics and Gynecology, Wake Forest University, Winston-Salem, NC, USA

6 Department of Medicine, Division of Cardiology, Emory University School of Medicine, Atlanta, GA, USA

7 Emory Clinical Cardiovascular Research Institute, Emory University School of Medicine, Atlanta, GA, USA

8 Department of Physiology, Georgia Health Sciences University, Augusta, GA, USA

9 Science Department, Society for Women's Health Research, Washington, DC, USA

10 St Joseph's Healthcare, Hamilton, Ontario, Canada

11 Department of Integrative Biology and Physiology, Center for Cardiovascular Repair, University of Minnesota, Minneapolis, MN, USA

12 Women's Heart Center, Cedars-Sinai Heart Institute, Los Angeles, CA, USA

13 Women's Health Research Center and Department of Physiology and Biophysics University of Mississippi Medical Center, Jackson, MS, USA

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Biology of Sex Differences 2011, 2:14  doi:10.1186/2042-6410-2-14

Published: 12 December 2011



Cardiovascular disease remains the primary cause of death worldwide. In the US, deaths due to cardiovascular disease for women exceed those of men. While cultural and psychosocial factors such as education, economic status, marital status and access to healthcare contribute to sex differences in adverse outcomes, physiological and molecular bases of differences between women and men that contribute to development of cardiovascular disease and response to therapy remain underexplored.


This article describes concepts, methods and procedures to assist in the design of animal and tissue/cell based studies of sex differences in cardiovascular structure, function and models of disease.


To address knowledge gaps, study designs must incorporate appropriate experimental material including species/strain characteristics, sex and hormonal status. Determining whether a sex difference exists in a trait must take into account the reproductive status and history of the animal including those used for tissue (cell) harvest, such as the presence of gonadal steroids at the time of testing, during development or number of pregnancies. When selecting the type of experimental animal, additional consideration should be given to diet requirements (soy or plant based influencing consumption of phytoestrogen), lifespan, frequency of estrous cycle in females, and ability to investigate developmental or environmental components of disease modulation. Stress imposed by disruption of sleep/wake cycles, patterns of social interaction (or degree of social isolation), or handling may influence adrenal hormones that interact with pathways activated by the sex steroid hormones. Care must be given to selection of hormonal treatment and route of administration.


Accounting for sex in the design and interpretation of studies including pharmacological effects of drugs is essential to increase the foundation of basic knowledge upon which to build translational approaches to prevent, diagnose and treat cardiovascular diseases in humans.

animal models; estrogen; gender; genomics; sex chromosomes; sex steroid hormones; study design; testosterone