Cardiovascular Disease in Women: Understanding the Journey

Throughout most of the 20th century, cardiovascular disease was considered a problem for men, despite more women than men dying annually from a cardiovascular cause. Based on this misconception, most clinical research related to cardiovascular disease was undertaken in populations exclusively or predominately composed of men. It is probably best illustrated by a cartoon from the 1991 Fort Worth Star Telegram. The cartoon shows a male physician seated across a desk from a female patient with the caption, “We have studies of fruit flies, mice, hamsters, frogs, monkeys and men with this condition – but medical research using women as subjects just never occurred to anybody.” Fortunately, that concept subsequently occurred to many with favorable consequences. Prior to 2000, the decrease in cardiovascular mortality in the USA was virtually exclusively in the male population, with female deaths relatively unchanged. After 2000, derived substantially from clinical research identifying gender differences in prevention, diagnosis, and management, the cardiovascular mortality of women declined abruptly, even more abruptly than that for men. Since 2013–2014, more men than women have died annually from cardiovascular disease, which is an enormous change.

To illustrate the prevalent emphasis on cardiovascular disease as a problem for men, the first women’s conference on coronary heart disease, held by the Oregon Heart Association in 1964, identified safeguards recommended for women to reduce the risk of heart attack in their husbands; the conference was entitled Hearts and Husbands. Similarly, when the American Heart Association’s Prudent Diet was disseminated to the general public, the pamphlet was entitled “The Way to a Man’s Heart.” Indeed, in 1977, when Dr. Harriett Dustan and I began television presentations addressing women’s vulnerability to heart disease, our programs were scheduled at 11:00 PM; indeed, we were the late-night show.

The contemporary era of cardiovascular disease in women began with a 1986 National Heart, Lung, and Blood Institute (NHLBI) Workshop on Coronary Heart Disease, followed by a 1992 NHLBI conference: Cardiovascular Health and Disease in Women. It was my privilege to cochair both the workshop and the conference.

The presentations challenged the flawed assumptions that women did not experience heart disease until they were elderly, nor did they experience it as seriously as their male counterparts. The conference highlighted the new information that was appropriate for clinical application, but equally importantly identified the knowledge gaps that impeded optimal cardiovascular care for women. In the New England Journal of Medicine article reporting on the Conference (1), the concept of coronary heart disease (CHD) in women was introduced both to the professional and public communities.

Fast forward to 2001 and the report from the Institute of Medicine “Exploring the Biological Contributions to Human Health: Does Sex Matter?” (2), which emphasized the need for the evaluation of sex-based differences in human disease and in medical research and translation of these differences into clinical practice.

A major advance for women’s health related to the randomized controlled trials of menopausal hormone therapy. At the time these studies were initiated, women were considered protected from heart disease premenopausally by their intrinsic hormones, and at menopause, hormone therapy was considered to manage all female problems from wrinkles to dementia. The advent of the randomized controlled trials: the Heart and Estrogen/Progestin Replacement Study (HERS) (3) in women with heart disease and the Women’s Health Initiative (WHI) (4) in healthy women dramatically changed clinical practice. Menopausal hormone therapy was not shown to prevent either incident or recurrent cardiovascular disease and, subsequently, the US Preventive Services Task Force published their recommendations (5) that menopausal hormone therapy was not indicated for the primary or secondary prevention of cardiovascular disease in women. The importance of these research studies was that they refocused attention on the established cardiovascular preventive therapies for women.

In 2003, the Agency for Healthcare Research and Quality (AHRQ) reported on the diagnosis and treatment of coronary disease in women (6, 7). This systematic review of relevant research highlighted that most contemporary recommendations for the prevention, diagnostic testing, and medical and surgical treatments of CHD in women were extrapolated from studies conducted predominately in middle-aged men, usually Caucasian men. The AHRQ report identified fundamental knowledge gaps regarding the biology, clinical manifestations, and optimal management strategies for women.

My invited Laennec Lecture to the American Heart Association 2004 Scientific Sessions (8) highlighted that attention to female-specific features of CHD offered the potential to improve women’s health. Angina was emphasized as the predominant initial and subsequent presentation of coronary disease in women, such that assessing and treating chest pain had the potential to avert subsequent myocardial infarction. In the GUSTO IIb trial, women with acute coronary syndromes were more likely than men to have unstable angina rather than myocardial infarction (MI), and women with unstable angina had a better prognosis than men. Women with non-ST elevation MI (NSTEMI) in CRUSADE had greater hospital mortality than men but received both less aggressive hospital management and fewer beneficial discharge medications. I highlighted that although chest pain remains the most common presentation of MI for both sexes, more women additionally describe shortness of breath and extreme fatigue, which may have contributed to their delayed diagnosis at presentation and delay in receiving acute life-saving therapies. Further, women younger than 50 years of age had almost twice the MI hospital mortality than comparably aged men. At that time, we were just beginning to accumulate percutaneous coronary intervention (PCI) registry data; these reports showed that even higher risk women who underwent PCI had improved angiographic and clinical success rates and decreased rates of major complications, although they continued to have more anginal symptoms after PCI. In most reported coronary artery bypass grafting (CABG) series, women were older and more likely to have diabetes and hypertension. They also had more severe chest pain and greater functional limitation preoperatively. Female sex independently predicted greater CABG operative mortality, save for in the highest risk category. There was a suggestion that off-pump CABG might reduce mortality, but more data were deemed to be needed. My lecture highlighted that clinical presentations of CHD and management strategies differed between the sexes and emphasized that underutilization of proven beneficial therapies contributed to less-favorable outcomes in women.

The importance of advocacy in this journey cannot be overemphasized. Beginning in 2004, the NHLBI Heart Truth campaign focused on the concept that heart disease does not care what you wear; following that, the American Heart Association introduced its Go Red for Women program, designed to educate women about heart disease, and establishing the Red Dress as the icon for heart disease in women. Equally supportive was the advocacy from WomenHeart, the National Coalition for Women with Heart Disease, founded in 1999.

Further research studies followed. The Women’s Health Study (WHS) (9) identified that aspirin prevented stroke but not incident MI in women younger than age 65. These findings were diametrically opposed to the results in men, where in the Physician’s Health Study (PHS) (10), aspirin provided protection for MI but not stroke for the male physician. The CRUSADE Quality Improvement Registry added data for women with non-ST-elevation acute coronary syndrome (11). The prognosis for NSTEMI was worse for women who had an excess of hospital death, MI, heart failure, stroke, and requirement for transfusion. Nonetheless, these high-risk women were less likely to receive coronary interventions and guideline-based medical therapy, despite their high-risk status. The question was raised whether their prognosis reflected raised baseline risk, or suboptimal admission and discharge therapies. The question must be asked whether this was biology, bias, or both, and I believe the latter to be true.

A landmark study, the NHLBI Women’s Ischemia Syndrome Evaluation (WISE) Study (12) enrolled women with myocardial ischemia documented on noninvasive testing who subsequently underwent coronary arteriography. A sizable number of these women did not have obstructive disease of their epicardial coronary arteries. At that time, the common clinical reaction would have been “false positive noninvasive test,” but that is far from the truth. These women did indeed have myocardial ischemia, but it was not the consequence of obstructive disease of the epicardial coronary arteries. Because these women were in a study, they were followed, with the demonstration that their myocardial ischemia was associated with adverse clinical outcomes, MI, and cardiac death, in the absence of obstructive coronary disease. WISE established the importance of microvascular disease and of nonobstructive coronary disease in women, both current topics for active clinical research (13). Further, these problems are also evident in men, although not as prominently as in women.

Several other research studies added to the data. The Women’s Antioxidant Cardiovascular Study, and the Women’s Antioxidant and Folic Acid Cardiovascular Study (WAFCAS) (14, 15) identified that vitamins E, C, and beta carotene failed to prevent incident or recurrent cardiovascular disease in women, nor did folic acid and vitamin B supplements prevent incident or recurrent cardiovascular disease in women. These research endeavors removed ineffective therapies from the recommended preventive regimens for women.

In 2008, based on a Get with the Guidelines Coronary Artery Disease database (16), women were shown to have greater mortality from ST elevation MI then men, 10.2% compared with 5.5%. This was predominantly during the initial 24 hours and was associated with their lesser receipt of early aspirin, beta blockers, reperfusion therapy, and timely reperfusion. Certainly, this did not reflect physician decisions to suboptimally treat women—it was simply that ST elevation MI was recognized only in a belated fashion, such that the life-saving initial therapies were provided in a delayed time frame. Obviously, these data identified opportunities to lessen gender disparities in care and improve clinical outcomes for women.

In 2010, the Institute of Medicine (IOM) issued a Report on Women’s Health Research: Progress, Pitfalls, and Promise (17) identifying that medical research historically neglected the health needs of women. I have referred to this as “bikini medicine,” signifying that research in women was relegated to areas covered by the bikini bathing suit, the breast and the reproductive tract, with the remainder of women’s health essentially ignored. The IOM defined women’s health as sex differences, i.e., biological factors; and gender differences, those affected by broader social, environmental, and community factors. The IOM acknowledged major progress in reducing cardiovascular mortality in women, but highlighted the need for greater research attention to quality of life issues—functionality, mobility, and wellness. Further, the IOM emphasized disparities in disease burden among subgroups of women, identifying women as disadvantaged because of race, ethnicity, income level, and educational attainment, and advocating for targeted research on women with the highest risks and burdens of disease. The IOM also noted the lack of analysis and reporting of sex-stratified analyses of clinical research studies, citing that this limited the ability to identify potentially important sex/gender differences, including differences in care. The IOM highlighted that journal editors should require clinical trial outcomes to be presented separately for women and for men; and advocated for translation of women’s health research findings into clinical practice and public policy, with effective communication of research-based health messages to women, to the public, providers, and policy makers.

In my 2011 invited Herrick Lecture to the November 2011 Annual Scientific Sessions of the American Heart Association, “Women and Coronary Heart Disease: A Century after Herrick, Understudied, Underdiagnosed, and Undertreated,” I noted that although once viewed as a man’s disease, CHD is the leading cause of mortality for US women (18). Despite their cardiovascular disease burden, women remain underrepresented in clinical trials and are disadvantaged by absence of sex-specific analyses. Lack of public and professional awareness of women’s coronary risk; knowledge gaps regarding women’s symptom presentation, optimal screening, and diagnostic procedures; and sex disparities in the application of evidence-based therapies contribute to adverse CHD outcomes.

Major advances in the science of gender-based medicine in cardiology were evident just into this decade. The 2011 update to the American Heart Association’s Women’s Cardiovascular Disease Prevention Guidelines (19) importantly presented pregnancy complications—preeclampsia, gestational diabetes, pregnancy-induced hypertension, small for gestational age infants, and preterm births—as early indicators of increased cardiovascular risk. A detailed history of pregnancy complications was advocated as a routine component of risk factor assessment for women. In addition, the Prevention Guidelines emphasized the increased cardiovascular risk for women with systemic autoimmune collagen vascular diseases, such that screening for conventional cardiovascular risk factors was warranted, with intervention as appropriate. Depression screening was also advocated for women with cardiovascular disease who have an excess of this problem. The Prevention Guidelines also addressed stroke prevention in women with atrial fibrillation, citing their 4-fold increase in stroke risk compared with their male counterparts. Undertreatment with anticoagulants doubled the risk of recurrent stroke.

The Peripheral Arterial Disease (PAD) Guidelines (20) noted the limited epidemiologic data for women who have a total burden of PAD greater than men, with suggestion of higher event rates for women. Just like men, most women with PAD do not have classical claudication symptoms, such that physical and laboratory examination of the arterial pulses is important. Women, and especially black women, are more likely to experience graft failure when revascularized, and limb loss when not. The manuscript highlighted the need for gender-specific data for the diagnosis and treatment of PAD in women, and patient and provider education.

Important information derives from the Guidelines for the Prevention of Stroke in Women (21) that cite sex-specific stroke risk factors for women, including pregnancy, preeclampsia, gestational diabetes, oral contraceptive use, postmenopausal hormone use, and changes in hormonal status. In addition, several risk factors are either stronger or have greater prevalence for women than for men; these include migraine with aura, atrial fibrillation, diabetes mellitus, hypertension, depression, and psychosocial stress.

Diagnostic testing has been addressed in more detail. In 2014, a Consensus Statement on the role of noninvasive testing in the clinical evaluation of suspected ischemic heart disease in women (22) posited that low-risk women with ischemic heart disease symptoms are generally not candidates for further diagnostic testing. The exercise electrocardiogram (ECG) was recommended as the initial diagnostic strategy for low- and intermediate-risk women who have an interpretable ECG and are able to exercise. Asymptomatic women with functional disability, and those with indeterminate or abnormal resting ECGs should be referred for echocardiography. Myocardial perfusion imaging (MPI) and magnetic resonance imaging are reasonable alternatives. Coronary computed tomography angiography (CTA) is also reasonable for intermediate-risk women.

The 2015 Statement on Sex Difference in the Cardiovascular Consequences of Diabetes Mellitus (23) indicated that lifestyle interventions may improve cardiovascular mortality more in prediabetic women than in prediabetic men and cited abdominal adiposity and insulin resistance as increased predictors of cardiovascular events in women than men. Women with diabetes mellitus were noted to require an increased frequency and intensity of physical activity compared with men to lessen their cardiovascular event risk. Most important was that the gender advantage of fewer cardiovascular events in women vs comparably aged men was lost in the context of type 2 diabetes mellitus.

Further in the imaging arena was the statement on Noninvasive Imaging to Evaluate Women with Stable Ischemic Heart Disease (24). Symptomatic women with ischemic heart disease were noted to experience worse outcomes than their male counterparts. The statement cited that the emergence of fractional flow reserve computed tomography, and of coronary CTA with vasodilator perfusion imaging likely will aid in directing specific treatment strategies for women. Trials are needed focusing on noninvasive approaches and therapeutic strategies for nonobstructive coronary disease, a major knowledge gap.

Acute Myocardial Infarction in Women was addressed in 2016 (25). Marked reductions in cardiovascular mortality for women have occurred in the past decade. Important contributors include the increased awareness and focus on women and cardiovascular disease risk, as well as the increased application of evidence-based treatments for CHD. Nonetheless, there is a multifactorial excess mortality in women with acute MI. Women remain undertreated with guideline-based recommendations resulting in an increase in readmissions, reinfarction, and death in the first year following MI. Cardiac rehabilitation is underused and underprescribed for women. Public health educational messages are needed to target racial and ethnic minority women regarding their presentation of acute MI and the vulnerability of women.

Again, the imaging community issued a statement on Myocardial Perfusion Imaging in Women for the Evaluation of Stable Ischemic Heart Disease—state-of-the-evidence and clinical recommendations (26). Both single photon emission computed tomography and positron emission tomography (PET) MPI were described to effectively stratify women with stable ischemic heart disease. The addition of coronary flow reserve (CFR) with PET improves risk detection for women, including the detection of nonobstructive coronary disease and coronary microvascular dysfunction. Multiparametric imaging may enable integration of MPI and CFR, with computed tomography visualization of anatomic atherosclerotic plaque, a combination likely to uniquely identify at risk women. With all the imaging studies, there is a continuing need for radiation dose-reduction strategies. And, with the newer and hybrid testing modalities, randomized comparative effectiveness trial data are needed in female patients.

The intersection of Cardiovascular Disease and Breast Cancer was noted in 2018 (27) citing overlapping risk factors for cardiovascular disease and breast cancer, such as obesity and smoking. The emphasis was that current very effective breast cancer treatments may result in left ventricular dysfunction and accelerated cardiovascular disease. Currently an increasing population, breast cancer survivors are at risk of long-term cardiac complications from breast cancer treatments. There is a need for surveillance, prevention, and secondary management of cardiotoxicity during breast cancer treatments.

Finally, the Joint Statement from the American Heart Association and American College of Obstetricians and Gynecology addresses promoting risk identification and reduction of cardiovascular disease in women through collaboration with obstetricians and gynecologists (28).

Ninety percent of women have at least one risk factor for cardiovascular disease, with women less likely to receive guideline-recommended diagnostic testing and therapies. Healthy cardiovascular lifestyles and behaviors should be discussed at each obstetrical and cardiovascular visit. Screening for cardiovascular disease and cardiovascular risk factors should be enhanced. This shared information will promote the assessment of risk, the initiation of interventions, and facilitate significant lifestyle changes for women.

Let us return to the challenge of women in clinical trials (29–33), noting that women have been underrepresented in mixed-gender National Institutes of Health (NIH) clinical trials (27%) from 1997 through 2006.

Even when included, they were disadvantaged by the absence of gender-specific analysis. Although there has been an increase of women in clinical trials of CHD over time, only 20% of the acute coronary syndromes study population between 1966 and 1990 were women. A more recent Cochrane Review of 258 cardiovascular clinical trials showed that only 1/3 examined outcomes by sex. But among the trials with sex-based analysis, 20% reported significant differences in outcomes between women and men. Additionally, exclusion of elderly patients from clinical trials doubly disadvantages women, who have a predominance of coronary events at elderly age.

Major progress has occurred from H.R 2101: A Research for All Act of 2015 (34). Previously, gender issues for clinical research and clinical trials both within the NIH and the US Food and Drug Administration (FDA) were guided by recommendations and guidelines, which varied enormously in their adoption. However, this legislation, introduced in 2015, was a mandate by the Government Accountability Office to update reports on women and minority inclusion in medical research both at the NIH and the FDA. The NIH was required to ensure that both male and female cells, tissues, or animals be included in basic research, with results evaluated according to sex and sex differences examined. Sadly, in prior years, many prestigious basic research scientists did not know the provenance of their cells or tissues, uncertain whether they were derived from male or female animals. The NIH was further mandated to update guidelines on inclusion of women and minorities in clinical research. For the FDA, it was mandated to ensure that clinical drug trials for expedited drug approval were sufficient to determine the safety and effectiveness for both women and men; this was to be supported by results of clinical trials that separately examined the outcomes for women and men.

Summary

Despite the progress cited in this manuscript, I advocate strongly for expanding the landscape of women’s cardiovascular health research. My vision of needed cardiovascular health research in the next decade is that it include beliefs and behaviors, community issues (local, national, and global), economic issues, environmental concerns, ethical issues, legislative/political issues, public policy, and societal/sociocultural variables. Women’s cardiovascular health quite obviously is not solely a medical issue, and a number of the topics above require intensive research examination. It is this approach to examine gender differences in cardiovascular disease that has the potential to improve the cardiovascular health of women.

Author Contributions

All authors confirmed they have contributed to the intellectual content of this paper and have met the following 4 requirements: (a) significant contributions to the conception and design, acquisition of data, or analysis and interpretation of data; (b) drafting or revising the article for intellectual content; (c) final approval of the published article; and (d) agreement to be accountable for all aspects of the article thus ensuring that questions related to the accuracy or integrity of any part of the article are appropriately investigated and resolved.

Authors' Disclosures or Potential Conflicts of Interest: No authors declared any potential conflicts of interest.

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