JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY
18, 2016
ª 2016 BY THE AMERICAN COLLEGE OF CARDIOLOGY FOUNDATION
PUBLISHED BY ELSEVIER
GUEST EDITORS’ PAGE
Strategies and
Methods for Clinical
Scientists to Study
Sex-Specific
Cardiovascular Health
and Disease in Women
Nanette K. Wenger, MD,a Pamela Ouyang, MBBS,b
Virginia M. Miller, PHD,c C. Noel Bairey Merz, MDd
S ubstantial disparities exist in the prevention,
diagnostic methodology, recognition, manage-
ment, and clinical outcomes of cardiovascular
disease (CVD) in women. Under-representation of
women in cardiovascular clinical trials and data regis-
tries, 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 cardiovas-
cular 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 var-
iables, 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
From the a
Department 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; and the dDepartment of Cardiology, Barbra
Streisand Women’s Heart Center, Cedars-Sinai Heart Institute,
Los Angeles, California. The authors have reported that they have no
relationships relevant to the contents of this paper to disclose.
VOL. 67, NO.
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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 neuro-
endocrine 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 child-
hood trauma.
JACC VOL. 67, NO. 18, 2016 Wenger et al. 2187
MAY 10, 2016:2186–8 Guest Editors’ Page

POPULATION RESEARCH
Population researchers should consider including
additional relevant clinical information in addition to
the commonly collected demographic
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 dis-
orders (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.
PHYSIOLOGICAL RESEARCH
There are many important physiological and patho-
physiological sex differences in CVD with implica-
tions for outcomes and therapies, including coronary
microvascular dysfunction, heart failure with pre-
served 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 impor-
tant sex differences in pharmacology, including beta-
blockers, angiotensin-converting enzyme inhibitors,
and chemotherapeutic agents that have cardiovascu-
lar 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
of healthcare for women with CVD have been identi-
fied and recommendations made (12).
Overall, key components to improve cardiovascu-
lar quality care for women include:
variables
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), pro-
vides approaches to increase the sex-specific useful-
ness of their data in clinical research, all vital to
improve the understanding of sex differences in
clinical cardiovascular research and healthcare vari-
ables. Incorporation of sex-specific knowledge is
designed to improve clinical CVD outcomes and
decrease health disparities in women.

In clinical trials, the cohort of women should be suf-
ficiently 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
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. E-mail: merz@cshs.org.

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