Heart Disease in Women: Formulating Research Questions

The Challenge

Ischemic heart disease (IHD) is the number one killer of U.S. and European women (WHO, 2008). Nonetheless heart disease has been defined as primarily a male disease, and “evidence-based” clinical standards have been created based on male pathophysiology and outcomes. As a result, women are often mis- and under-diagnosed (Regitz-Zagrosek, 2011; Taylor et al., 2011).

Method: Formulating Research Questions

Improving women's healthcare has required scientific and technical breakthroughs; it has also required new social, medical, and political judgments about women's social worth, and a new willingness to support women's health and well-being. Analyzing sex and gender in heart disease has required formulating new research questions about disease definitions, symptoms, diagnosis, prevention strategies, and treatments. Once sex and gender were factored into the equation, knowledge about heart disease increased dramatically. As is often the case, including women subjects—of diverse social and ethnic backgrounds—in research has led to a better understanding of disease in both women and men.

Gendered Innovations:

Research on heart disease offers one of the most developed examples of gendered innovations. From the expanding literature on sex and gender analysis in this area, we highlight several key developments:

1. Redefining the pathophysiology of IHD. Analyzing sex in clinical research has led to an understanding that heart disease in women often has a different pathophysiology than in men—particularly in younger adults.
2. New diagnostic techniques—some still experimental—are more effective than angiography for understanding the causes of IHD in women with chest pain in the absence of obstructive coronary artery disease (CAD).
3. Understanding sex differences in symptoms has led to earlier and better diagnosis of IHD in women.
4. Rethinking the estrogen hypothesis in light of large-scale trials of menopausal hormone therapy has challenged the (oversimplified) concept of a cardioprotective effect of estrogens.
5. Gender analysis in risk factors and prevention reveals that smoking has historically been far more common among men than women; however, in some countries, such as Sweden and Iceland, smoking rates are now higher among women (Shafey et al., 2009). The harmful effects of tobacco smoke on atherosclerosis are greater in women than in men (Tremoli et al., 2010).

The Challenge
Gendered Innovation 1: Redefining the Pathophysiology of Myocardial Ischemia
Method: Analyzing Sex
Gendered Innovation 2: New Diagnostic Techniques
Gendered Innovation 3: Understanding Sex Differences in Symptoms
Gendered Innovation 4: Rethinking the Estrogen Hypothesis
Method: Formulating Research Questions
Gendered Innovation 5: Gender Analysis in Risk Factors and Prevention
Method: Analyzing Gender Assumptions
Conclusions
Next Steps

The Challenge

Heart disease has been considered primarily a male disease. This perception may exist because myocardial infarction (MI) manifests about ten years later in women than in men. Nonetheless, ischemic heart disease (IHD) is a major killer of women (WHO, 2008). Now, after twenty years of research, biomedical study of heart disease offers one of the most developed examples of gendered innovations. Sex and gender analysis prompted policy changes, increased the representation of women subjects in heart disease research, and enhanced knowledge about how biological sex and gender behaviors influence heart disease. Results include improved diagnosis and treatment in women and men alike, as well as prevention campaigns that utilize an understanding of gender to promote heart-healthy behaviors and target risk behaviors.

Gendered Innovation 1: Redefining the Pathophysiology of Myocardial Ischemia

The pathophysiology underlying myocardial ischemia often differs between women and men (Bairey Merz et al., 2010). Coronary angiography, the "gold standard" for diagnosing patients with angina (chest pain), typically results in a diagnosis of obstructive coronary artery disease (CAD) in men (see chart below, right), but frequently fails to identify the cause in a large proportion of women (Shaw et al., 2009; Bugiardini et al., 2005). As a result, many women with chest pain, but “normal” angiograms (see chart below, left), are under- and mis-diagnosed and treated. Many women with angina are told that they have no significant heart disease.

New studies show, however, that the prognosis for these women is not benign: Women with a primary diagnosis of “non-specific chest pain” may suffer heart attack or stroke shortly after being discharged from hospitals (Robinson et al., 2008). This may also be true for men with angina and no obstructive CAD. Large-scale randomized trials are needed to better understand the pathophysiology and optimal therapies for women and men with angina and “normal” angiograms (Shaw et al., 2009).

Large-scale studies have found that coronary angiography is often ineffective in diagnosing heart disease in women. The U.S. National Heart, Lung, and Blood Institute’s Women’s Ischemic Syndrome Evaluation (WISE) used innovative diagnostic tests and techniques (selected to obviate difficulties relevant to women, such as breast imaging artifact) to examine women who experienced chest pain but did not have obstructive CAD (Bairey Merz et al., 1999).

New research also suggests that “ischemic heart disease” (IHD) may better describe women’s underlying disease than obstructive CAD or coronary heart disease (CHD) (Shaw et al., 2009)—see Rethinking Concepts and Theories. Important to reconceptualizing heart disease in women is that women are more likely than men to have normal or nonobstructive coronary angiograms (i.e., open coronary arteries) despite the presence of unstable angina, acute coronary syndrome, or other coronary conditions—see table below:

Method: Analyzing Sex

To interpret sex-specific physiology, disease, and outcomes, data must be collected and analyzed by sex. The WISE study evaluated only women, yet has been cited as evidence of sex differences in pathophysiology. To determine sex differences, sufficient numbers of both women and men are needed, and samples should be matched or data should be adjusted to control for potential confounding factors, such as age, reproductive status, socioeconomic status, body composition, protective and risk behaviors, etc. (see Designing Health and Biomedical Research).

View General Method

Gendered Innovation 2: New Diagnostic Techniques

Coronary angiography is widely considered the “gold standard” for evaluating coronary heart disease. Angiography, however, can cause hematomas and other bleeding complications; these occur more often in women patients than men patients (Berry et al., 2004). Gendered innovations in diagnosis include new angiography procedures—such as entry through the radial artery—which reduce bleeding complications (Cantor et al., 2007). These innovations, especially important to women patients, can also benefit men patients.

Important future gendered innovations will include new diagnostic techniques that provide evidence of pathophysiologic causes of myocardial ischemia in individuals with chest pain but no obstructive CAD—and who are at risk for subsequent MI or unstable angina. These include:

• Coronary reactivity testing (von Mering et al., 2004; Pepine et al., 2010).
• Intravascular ultrasound (IVUS) (Khuddus et al., 2010).
• Cardiac magnetic resonance imaging (MRI) and cardiac spectroscopy (Ishimori et al., 2011; Buchthal et al., 2000).
• Advanced radionuclide imaging including positron emission tomography (PET) (Johnson et al., 2011).
• Perfusion stress echocardiography (Kaul, 2011).

Gendered Innovation 3: Understanding Sex Differences in Symptoms

Understanding symptoms of acute coronary syndrome (ACS) is critical to optimizing treatment and outcomes. An international study of 26,755 patients (29% women) with ACS found that “chest pain was the most common symptom for both men (94%) and women (92%)” (Dey et al., 2009). However, statistically significant sex differences were observed for nausea and jaw pain, both of which are more common in women. These symptoms are often labeled “atypical” (Omran et al., 2006; Chen et al., 2005). Recognizing sex differences in symptomatology is important to improving diagnosis and timely treatment, especially for women (Zbierajewski-Eischeid et al., 2009).

Gendered Innovation 4: Rethinking the Estrogen Hypothesis

The later age of heart disease onset and death in women versus men generated the hypothesis that estrogen is cardioprotective. Hormonal treatment for postmenopausal women was advocated in the past on the grounds that it would reduce the risk of heart disease. The estrogen hypothesis drove considerable basic and clinical research, and “until the appearance of the Heart and Estrogen Replacement Study (HERS) in 1998, it was erroneously believed that [hormone therapy] provided protection against development of cardiovascular disease” (Khan et al., 2009).

Controversy emerged when conflicting reports regarding the relationship between heart disease and menopausal hormone therapy (MHT) use appeared in 1985: The Framingham Study reported about 2-fold higher CHD in users versus nonusers (Wilson et al., 1985), while the Nurses’ Health Study (a younger cohort) reported half the rates in MHT users (Stampfer et al., 1985). Several large clinical trials reported increased heart attacks within the first year of MHT use and no long term benefit (Hulley et al., 1998)—see Method.

Method: Formulating Research Questions

The earlier onset of CHD in men directed women’s heart disease research toward a broadly accepted hypothesis that premenopausal estrogen was protective. This resulted in widespread promotion of postmenopausal hormone therapy as a preventive strategy for older women. Questioning these assumptions and reformulating research questions has shown that MHT increases (rather than decreases) risk and has challenged bias in interpretation of over a decade of research.

View General Method

Reformulating research questions led to new studies that show that MHT is ineffective for reducing risk of heart disease in the general population. The landmark placebo-controlled Women’s Health Initiative (WHI) MHT trials confirmed increased MI, stroke, and serious blood clots for estrogen-progestin therapy. Estrogen-only therapy increased stroke risk and did not modify CHD risk. As a result, the U.S. Food and Administration (FDA) required the addition of “black box” warnings on estrogen and progestin products stating that neither should be used to prevent CHD (Stefanick, 2005). The American College of Cardiology states that “hormone therapy and selective estrogen-receptor modulators (SERMs) should not be used for the primary or secondary prevention of CVD” (Mosca et al., 2011).

Gendered Innovation 5: Gender Analysis in Risk Factors and Prevention

Most risk factors for IHD (e.g. older age, adverse lipoprotein profiles, high blood pressure, high blood glucose, diabetes, smoking, obesity, physical inactivity, and high fat diets) apply to both women and men. However, there are differences in the prevalence and adverse impact of these risk factors (Mosca et al., 2012).

Smoking, for example, has historically been far more common among men than women; about 20% of the world’s tobacco smokers are women (WHO, 2010). However, in some countries, such as Sweden and Iceland, smoking rates are now higher among women than men (Shafey et al., 2009). Overall, cigarette smoking is declining among women in the U.S. and Western Europe and other industrialized nations but is either stable or increasing in Southern, Central, and Eastern Europe, and many parts of the developing world (Shafey et al., 2009).

Smoking is the major preventable cause of death in the U.S. and Europe, and is a major risk factor for heart attack and stroke (Shafey et al., 2009). Researchers examining 3,587 women and men in five European countries for the European Carotid Intima Media Thickness and IMT-PROgression as Predictors of Vascular Events (IMPROVE) study have found that tobacco smoking increases atherosclerosis in both women and men; however, the effect in women is more than twice that in men (Tremoli et al., 2010).

Method: Analyzing Gender

Transnational tobacco companies’ advertisements have long linked smoking to liberation, thinness, sexiness, intelligence, and modernity, a tactic increasingly deployed in developing countries (“Not a Cough in a Carload”). Analyzing gender can help consumers understand how tobacco advertising plays on popular images of femininity and masculinity to sell a product. Banning the manufacture and sale of cigarettes, combined with efforts to de-romanticize smoking in movies, television, and other media, can help prevent this disease (Proctor, 2011).

 

View General Method

Conclusions

Sex analysis in the context of heart disease research has revealed clinically-significant differences in pathophysiology between women and men. Awareness of these sex differences has guided the development of new diagnostics, such as measurement of coronary flow reserve. Formulating research questions allowed researchers to dismiss the assumption that menopausal hormone therapy is protective against heart disease. Combating tobacco smoking has required both gender analysis and sex analysis—gender roles influence women’s and men’s patterns of tobacco usage, while biological sex differences exist in women’s and men’s susceptibility to smoking-related heart disease.

Next Steps

1. WHO has called for research to systematically “incorporate attention to sex and gender in design, analysis, and interpretation of findings.” WHO also recommends increasing the number of older women in clinical trials in order to establish both sex- and age-specific guidelines for treatment (WHO, 2009).
2. In 2008, the U.S. FDA held workshops to prepare a guidance document on “the study and analysis of sex/gender differences in cardiovascular medical device trials.” Further, the U.S. Congress passed the Heart Disease Education, Analysis and Research, and Treatment for Women Act that seeks to promote sex and gender analysis in health and medical research (Dhruva, 2011). Since the 1980s, the U.S. NIH and the FDA have encouraged the inclusion of women and minorities in all federally funded research. Yet, despite federal guidelines, women are still under-enrolled in study populations (see, for example, CVD clinical trials in Designing Health & Biomedical Research) (Maas et al., 2010). More progress is needed in these areas.
3. In 2005, the European Society of Cardiology launched its Women at Heart initiative, with the aim of closing “a disturbing gap in the knowledge, understanding, and general awareness of cardiovascular disease in women, across medical audiences as a whole.” The primary goal of Women at Heart is to improve medical professionals’ handling of women at risk for cardiovascular diseases (European Society of Cardiology, 2011). The European Medicines Agency has articulated the need for clinical trials to enroll proportions of women that are representative of women’s share of actual heart disease patients, and for researchers to collect sex-disaggregated data to assess the safety and efficacy of treatments in women and men (European Medicines Agency, 2006).

Heart disease is a major killer of women in developed countries. Nonetheless, it has been defined as primarily a male disease, and "evidence-based" clinical standards have been created based on male pathophysiology and outcomes. As a result, women are often mis- and under-diagnosed.

Gendered Innovation:

Heart disease research in women offers one of the most developed examples of gendered innovations. To take just one, consider how underlying pathophysiology may differ between women and men. Coronary angiography, the "gold standard" for diagnosing patients with chest pain, typically results in a diagnosis of obstructive coronary artery disease (CAD) in men (see chart below, right), but frequently fails to identify the cause in a large proportion of women. As a result, many women with chest pain, but "normal" angiograms (see chart below, left), may be told that they have no significant disease and sent home.

New studies show, however, that women with a primary diagnosis of "non-specific chest pain" may suffer heart attack or stroke shortly after being discharged from hospitals. This may also be true for men. Large-scale randomized trials are needed to better understand the pathophysiology and optimal therapies for women and men with angina and "normal" angiograms.

Twenty years of sex and gender analysis in heart disease has enhanced knowledge of diagnosis and treatment in women and men alike. In addition, robust prevention campaigns have utilized understandings of gender to promote heart-healthy behaviors, such as exercise and tobacco smoking cessation.