Author + information
- Nanette K. Wenger, MDa,
- Pamela Ouyang, MBBSb,
- Virginia M. Miller, PhDc and
- C. Noel Bairey Merz, MDd,∗ ()
- aDepartment of Cardiology, Emory University School of Medicine, Atlanta, Georgia
- bDepartment of Cardiology, Johns Hopkins University, Baltimore, Maryland
- cDepartment of Surgery Research, Mayo Clinic, Rochester, Minnesota
- dDepartment of Cardiology, Barbra Streisand Women’s Heart Center, Cedars-Sinai Heart Institute, Los Angeles, California
- ↵∗Reprint requests and correspondence:
Dr. Noel Bairey Merz, Cedars-Sinai Heart Institute, Barbra Streisand Women's Heart Center, 127 South San Vicente Boulevard, Suite A3206, Suite 600, Los Angeles, California 90048.
Substantial disparities exist in the prevention, diagnostic methodology, recognition, management, and clinical outcomes of cardiovascular disease (CVD) in women. Under-representation of women in cardiovascular clinical trials and data registries, coupled with lack of sex-specific data analysis, has constrained the evidence base for clinical decision-making. Addition of sex-specific strategies and methods for the study of women and cardiovascular health and disease across the lifespan can enhance the information available from clinical trials and a variety of databases and registries.
Sex-specific strategies for the study of women and cardiovascular health and disease across the lifespan exist and should be considered when conducting clinical investigation in health areas that affect women and men, such as CVD. These include data collection on reproductive history, psychosocial variables, and other factors that disproportionately affect CVD in women. Lack of consideration of many of these variables in the design of: 1) population; 2) physiology; and 3) clinical trial research limits the ability to determine sex-specific contributors to cardiovascular health and disease.
Variables relative to reproductive health include hormone levels, oral contraceptive use, pregnancy history and complications, polycystic ovary syndrome, measures of menopause, and menopausal hormone therapy. A detailed pregnancy history, including pregnancy complications, is likely to provide new insight into sex differences in CVD and to identify women who might benefit from the early application of cardiovascular preventive interventions. Women are also adversely affected by diabetes mellitus and autoimmune inflammatory disorders. Vasomotor dysfunction has a disproportionate adverse effect on women’s cardiovascular health.
Differences in psychosocial variables include depression, stress, abuse and domestic violence, post-traumatic stress disorders, and aging, all of which affect the risk of CVD. The lifetime prevalence of depressive disorders in women is double that of men, and there is no explanation as to the causative features of this sex difference in mood-related disorders. Increased exposure to stressful events, increased vulnerability due to genetic predisposition to these events, and modulation of the neuroendocrine system by gonadal hormones have been proposed. A number of validated instruments are available to assess and measure depression, anxiety, post-traumatic stress disorder, and history of childhood trauma.
Population researchers should consider including additional relevant clinical information in addition to the commonly collected demographic variables including hormonal phenotype (1), hormonal level status (2), pregnancy-related disorders (3), polycystic ovary syndrome (4), depression (5), abuse (6), domestic violence (7), and post-traumatic stress disorders (8,9). Including this information in appropriate databases will expand the scientific understanding of sex differences in clinical CVD and provide additional evidence of specific sex-related variables influencing CVD in women.
There are many important physiological and pathophysiological sex differences in CVD with implications for outcomes and therapies, including coronary microvascular dysfunction, heart failure with preserved ejection fraction, Takotsubo cardiomyopathy, adverse digoxin and QT prolonging medications mortality, and post-MI depression, to name a few (10). The mounting published data document important sex differences in pharmacology, including beta-blockers, angiotensin-converting enzyme inhibitors, and chemotherapeutic agents that have cardiovascular toxicity (11). Accordingly, it is useful to examine the spectrum of physiological mechanisms for CVD that may differ between women and men to most appropriately design sex-specific clinical studies and trials.
Clinical Trial Research
In clinical trials, the cohort of women should be sufficiently powered to enable comparative analysis of the primary trial outcome. Discussions include how to analyze in a sex-specific fashion and analyze for interaction by sex. Strategies to improve the quality of healthcare for women with CVD have been identified and recommendations made (12).
Overall, key components to improve cardiovascular quality care for women include:
1. Enhancing the quantity and quality of evidence-based medicine to guide care of women through improving trial design, enrollment, and retention of women subjects; improving results analysis and reporting; and providing better incentives to perform research in women;
2. Providing incentives to develop better data in women through mandating changes in the drug and device development and approval processes;
3. Incorporating specific recommendations for women into guidelines when data are sufficient; and
4. Applying proven sex-based differences in risk stratification, diagnostic testing, and drug usage and dosing in clinical care.
The Cardiovascular Network of the Society for Women’s Health Research has recently compiled a well-referenced inventory of sex-specific strategies for the study of women and cardiovascular health and disease across the lifespan. This resource for clinical investigators, entitled “Strategies and Methods to Study Sex Specific Cardiovascular Health and Disease in Women: A Guide for Clinical Scientists” (13), provides approaches to increase the sex-specific usefulness of their data in clinical research, all vital to improve the understanding of sex differences in clinical cardiovascular research and healthcare variables. Incorporation of sex-specific knowledge is designed to improve clinical CVD outcomes and decrease health disparities in women.
The authors have reported that they have no relationships relevant to the contents of this paper to disclose.
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